Pharmacotherapies for improving treatment adherence after discontinuation of incretin-based therapies

Abstract

Disclosed are methods of improving treatment adherence and compliance after discontinuation of incretin-based therapies, such as GLP-1 and / or GIP agonists, using pharmacotherapies comprising the disclosed therapeutic compounds and combinations. In some aspects, methods include treatment of psychological factors affecting other medical conditions (PFAOMC) following the administration of incretin-based therapies to treat obesity or hyperglycemia, and related disorders. In some aspects, disclosed pharmacotherapies for use in the methods include agents that modulate monoaminergic neurotransmission, administered alone or together, such as in disclosed combinations having advantageous synergistic effects.

Description

PHARMACOTHERAPIES FOR IMPROVING TREATMENT ADHERENCE AFTER DISCONTINUATION OF INCRETIN-BASED THERAPIESINVENTORS: Igor Elman, David Bleakman, and Louis HerlandsCROSS-REFERENCE

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U.S. Provisional Appl. Nos. 63 / 555,074, filed February 18, 2024; 63 / 757,344, filed February 12, 2025; and 63 / 760,107, filed February 18, 2015; each of which is hereby incorporated by reference for all purposes as if fully set forth herein.FIELD OF THE INVENTION

[0002] This disclosure relates to methods for improving treatment adherence after discontinuing incretinbased therapies, such as GLP-1 and / or GIP agonist therapy, through pharmacotherapy, including modulation of monoaminergic neurotransmission. In some aspects, the methods address psychological factors affecting other medical conditions (PFAOMC) following incretin-based therapy for obesity or hyperglycemia.BACKGROUND OF THE INVENTION

[0003] Obesity is a serious public health crisis characterized by excessive and unhealthy fat accumulation. In the United States, 42.4% of adults have obesity, including 9.2% with severe obesity (NIDDK, Overweight & Obesity Statistics, NIH, Sept. 2021). The societal burden of obesity is immense, contributing to rising healthcare expenditures. In 2020 alone, obesity-related medical costs in the U.S. totaled $1.96 trillion and are projected to surpass $4 trillion (Lobstein et al., World Obesity Federation, World Obesity Atlas 2023). As obesity rates continue to rise, policymakers have urged preventive measures to mitigate its impact.

[0004] Obesity significantly affects multiple organ systems and is associated with a range of comorbidities, including cardiovascular, respiratory, endocrine, neurological, musculoskeletal, reproductive, gastrointestinal, and urinary tract disorders. Obese individuals also have higher incidences of psychiatric disorders, including depression, dementia, schizophrenia, and addiction, as well as an increased risk of falls and post-procedural infections (Lim & Boster, StatPearls, 2023; Elman et al., Sci Rep. 2020;10(1):5617; Elman et al., Neuropsychopharmacol. 2006;31 (10):2091 -2120). Approximately 30% of obese patients receive incretin-based therapies, such as glucagon-like peptide-1 (GLP-1) receptor agonists, which signal satiety to the brain, reducing food cravings and intake. Clinical trials show that GLP-1 agonists can induce an average weight loss of 15%, making them effective for initial weight reduction (UT Southwestern Med., Anti-Obesity Drugs, Sept. 2023). Currently available GLP-1 agonists include semaglutide (e.g., OZEMPIC®, WEGOVY®, RYBELSUS®), exenatide (e.g., BYETTA®, BYDUREON BCise®), liraglutide (e.g., VICTOZA®, SAXENDA®), tirzepatide (e.g., MOUNJARO®, ZEPBOUND®), and dulaglutide (e.g., TRULI CITY®), among others.

[0005] However, weight loss achieved with incretin-based therapies is often rapidly regained upon discontinuation, along with other obesity-related symptoms (Wilding et al., Diabetes Obes Metab. 2022;24(8): 1553-1564). Additionally, incretin-based therapies have significant limitations, including adverse effects (e.g., anhedonia, suicidality, pancreatic and renal injury, and digestive disturbances) and high costs, which limitlong-term use and render them economically unviable for maintenance therapy (Yapici-Eser et al., Acta Neuropsychiatr. 2020;32(4):218-225; Filippatos et al., Rev Diabet Stud. 2014;11 (3-4):202-230; Bagepally et al., BMJ Open Diabetes Res Care. 2020;8(1 ):e001020). Insurance coverage is also a growing challenge. For example, North Carolina eliminated all coverage for weight loss medications in January 2024, citing unsustainable costs, and many employer-sponsored plans have imposed similar restrictions or lifetime caps.

[0006] Due to these limitations, there is a critical unmet need for effective strategies to help patients maintain weight loss and adhere to treatment plans after discontinuing incretin-based therapies. Weight loss management is clinically recommended to prevent weight regain and improve metabolic health markers (e.g., blood pressure, cholesterol, and triglycerides), reducing cardiovascular and all-cause mortality risks. Additionally, sustained weight loss is associated with improved self-esteem, higher energy levels, reduced stress, better sleep, enhanced immune function, hormonal balance, and overall mental well-being.

[0007] The present disclosure provides novel methods to address this need, offering advantages and improvements that will become apparent from the following description.INCORPORATION BY REFERENCE

[0008] Each cited patent, publication, and non-patent literature is hereby incorporated by reference in its entirety, as if each was incorporated by reference individually and fully set forth herein. However, no such citation should be construed as an admission that a reference is from an analogous art or is directly applicable to the invention, nor should any citation be construed as an admission that a document or any underlying information, in any jurisdiction, is prior art or is part of the common general knowledge in the art.BRIEF SUMMARY OF THE INVENTION

[0009] The following provides a brief summary of certain aspects and embodiments of the invention to facilitate an understanding of the disclosure. It is not intended to be exhaustive or to define the scope of the invention, but rather to introduce some embodiments as a prelude to the detailed description that follows.

[0010] In some aspects are provided methods of improving adherence to a lifestyle modification recommendation in a subject who has discontinued a primary treatment for obesity or hyperglycemia, comprising: (a) providing a lifestyle modification recommendation to the subject; and (b) administering to the subject a compound that modulates monoaminergic neurotransmission; wherein the primary treatment for obesity or hyperglycemia comprises incretin-based therapy; and wherein the subject exhibits adherence to the lifestyle modification recommendation.

[0011] In some embodiments, the lifestyle modification recommendation is provided by a healthcare professional, a registered dietitian, a fitness coach, a behavioral therapist, a digital health device, or a digital health platform. In some embodiments, the lifestyle modification recommendation comprises a dietary or consumption modification. In some embodiments, the dietary or consumption modification comprises modifying food, drug, or alcohol consumption. In some embodiments, modifying food, drug, or alcohol consumption comprises reducing or eliminating alcohol, tobacco, nicotine, or processed foods; following a specific daily caloric intake; eating a defined number of meals per day; maintaining regularly scheduled meals; eatingwithout distractions; cooking a specified number of meals at home per week; leaving the table after meals; grocery shopping only from a list or only when full; measuring portion sizes; drinking filtered water; consuming living foods; taking food supplements, probiotics, prebiotics, or enzymes; adopting a fruitarian, sproutarian, ovo-vegetarian, lacto-vegetarian, or Mediterranean diet; following a personalized nutrition plan; following time-restricted eating patterns; or consuming fermented foods.

[0012] In some embodiments, the lifestyle modification recommendation comprises a physical exercise modification. In some embodiments, the physical exercise modification comprises following an exercise regimen; increasing daily step count; committing to a structured exercise schedule; attending an exercise class or walking group; attending physical training or physical therapy; or committing to choosing stairs over elevators when possible. In some embodiments, the lifestyle modification recommendation comprises a medication adherence modification. In some embodiments, the medication adherence modification comprises following a prescribed dosage, frequency, and duration of a medication; taking a medication at a directed time; refilling a prescription when needed; purchasing a prescribed medication; or attending necessary follow-up visits with a prescribing healthcare provider. In some embodiments, the lifestyle modification recommendation comprises a microbiome- targeted therapy modification. In some embodiments, the microbiome-targeted therapy modification comprises implementing probiotic supplementation or prebiotic supplementation; undergoing fecal microbiota transplantation (FMT); following a regimen of postbiotic and short-chain fatty acid modulation; or following dietary modifications to support a healthy microbiome.

[0013] In some embodiments, the lifestyle modification recommendation comprises another health-enhancing habit modification. In some embodiments, the other health-enhancing habit modification comprises practicing meditation; prayer; maintaining a positive attitude; mindful breathing; engaging in sun exposure; cold plunge therapy; sauna or hot bath followed by a cold shower; massage; skin brushing; maintaining a regular sleep pattern; using an infrared sauna; consuming green drinks; undergoing a liquid fast; receiving enemas; implementing detoxification; eliminating addictive behaviors; following a structured sleep hygiene routine; engaging in stress management techniques; implementing cognitive-behavioral strategies; participating in social support engagement; practicing self-monitoring; or engaging in mindfulness-based practices.

[0014] In some embodiments, the compound that modulates monoaminergic neurotransmission is a compound that modulates dopaminergic, serotonergic, or norepinephrinergic neurotransmission. In some embodiments, the compound also modulates glutamatergic neurotransmission. In some embodiments, the compound that modulates monoaminergic neurotransmission is a monoamine oxidase inhibitor, an antidepressant, a cognitive enhancer, an anticonvulsant, an atypical antipsychotic, an anti-hyperglycemic agent, an anti-inflammatory agent, an anxiolytic agent, an antihistamine, an antibiotic, an opioid modulator, an anti-craving agent, an antioxidant, a benzodiazepine, a serotonergic agent, a mood stabilizer, an N-methyl-D-aspartate (NMDA) receptor agent, an anticholinergic agent, a psychedelic, an entactogen, an empathogen, a tryptamine, a phenethylamine, a benzofuran, a 2C-x compound, an ergoline, a lysergamide, a beta-carboline, a harmala alkaloid, an iboga alkaloid, a natural plant or fungal alkaloid, a neurotropic agent, anadaptogen, an actoprotector, an anti hypoxant, an anti-hypertensive agent, an anti-ischemic agent, an antimigraine agent, an anticholinergic agent, or a phosphodiesterase inhibitor.

[0015] In some embodiments, the monoamine oxidase inhibitor is a reversible inhibitor of monoamine oxidase-A (RIMA). In some embodiments, the RIMA is moclobemide, brofaromine, caroxazone, CX157, CX2614, eprobemide, metralindole, minaprine, pirlindole, or toloxatone. In some embodiments, the RIMA is moclobemide. In some embodiments, the compound is an antidepressant. In some embodiments, the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (NRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a dual norepinephrine / dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a noradrenaline and specific serotonergic antidepressant (NASSA), a serotonin antagonist and reuptake inhibitor (SARI), or a norepinephrine-dopamine disinhibitor (NDDI). In some embodiments, the SSRI is fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vortioxetine, or vilazodone. In some embodiments, the NRI is atomoxetine or reboxetine. In some embodiments, the SNRI is desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine. In some embodiments, the NDRI is amineptine, bupropion, desoxypipradrol, dexmethylphenidate, difemetorex, diphenylprolinol, ethylphenidate, fencamfamine, fencamine, lefetamine, methylenedioxypyrovalerone, methylphenidate, nomifensine, 0-2172, pipradrol, prolintane, pyrovalerone, solriamfetol, tametraline, or WY-46824. In some embodiments, the NDRI is bupropion. In some embodiments, the NDRI is solriamfetol. In some embodiments, the TCA is amitriptyline, doxepin, clomipramine, nortriptyline, imipramine, desipramine, protriptyline, dosulepin, maprotiline, trimipramine, or amoxapine. In some embodiments, the NASSA is aptazapine, esmirtazapine, mianserin, mirtazapine, or setiptiline. In some embodiments, the SARI is etoperidone, lorpiprazole, mepiprazole, nefazodone, or trazodone. In some embodiments, the NDDI is agomelatine, fluoxetine, flibanserin, or mirtazapine.

[0016] In some embodiments, the antidepressant is amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine, phenelzine, tranylcypromine, isocarboxazid, selegiline, mirtazapine, nefazodone, trazodone, bupropion, a neurotropic agent, an adaptogen, an actoprotector, a nootropic, a eugeroic, a racetam, an antihypoxant, a cognitive enhancer, potassium orotate, asparkam, a psychedelic, an entactogen, an empathogen, a tryptamine, a phenethylamine, a benzofuran, a 2C-x compound, an ergoline, a lysergamide, a beta-carboline, a harmala alkaloid, an iboga alkaloid, a natural plant or fungal alkaloid, solriamfetol, vilazodone, atomoxetine, milnacipran, dosulepin, duloxetine, escitalopram, venlafaxine, citalopram, fluoxetine, fluvoxamine, vortioxetine, reboxetine, sertraline, paroxetine, esketamine, ketamine, dextromethorphan, dextromethorphan / bupropion, and lithium.

[0017] In some embodiments, the cognitive enhancer is a eugeroic or a nootropic. In some embodiments, the eugeroic is modafinil, pitolisant, solriamfetol, or armodafinil. In some embodiments, the eugeroic is modafinil. In some embodiments, the nootropic is meldonium, acetyl L-carnitine, alpha-GPC, alpha-lipoic acid (ALA), aniracetam, ashwagandha, astaxanthin, bacopa monnieri, berberine, black seed oil, cacao, caffeine, cannabidiol (CBD), CDP-choline, centrophenoxine, coconut oil, coluracetam, coenzyme Q10 (CoQ10),creatine, docosahexaenoic acid (DHA), dehydroepiandrosterone (DHEA), dimethylaminoethanol (DMAE), fisetin, ginkgo biloba, ginseng, glutathione, gotu kola, glycine, holy basil (tulsi), huperzine-A, kava kava, kratom, lion’s mane mushroom, L-carnosine, lemon balm, L-glutamine, L-theanine, maca, magnolia bark, N-acetyl L-cysteine, N-acetyl L-tyrosine, nicotinamide adenine dinucleotide + hydrogen (NADH), nefiracetam, oxiracetam, passionflower, picamilon, pine bark extract, piperine, piracetam, rhodiola rosea, phenylalanine, phenylethylamine (PEA), phenylpiracetam, phosphatidylcholine (PC), phosphatidylserine (PS), pyrroloquinoline quinone (PQQ), pramiracetam, pterostilbene, quercetin, resveratrol, St. John’s wort, taurine, tryptophan, turmeric, L-tyrosine, thiamine (vitamin B1), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), inositol (vitamin B8), folate (vitamin B9), cobalamin (vitamin B12), D-serine, vitamin D (vitamin D3), L-serine, panax ginseng, gingko biloba, tanakan, salvia officinalis, lavandulaefolia, centella asiatica, nicotene, noopept, phenotropil, an amphetamine, a dextroamphetamine, a cholinergic, citicholine, choline bitartrate, ethomersol, bemithyl, pyrazidol, actovegin forte, bemethyl, phenibut, or zinc. In some embodiments, the nootropic is meldonium, vitamin D, a racetam, or phenylpiracetam. In some embodiments, the nootropic is meldonium. In some embodiments, the nootropic is phenylpiracetam.

[0018] In some embodiments, the anticonvulsant is carbamazepine, oxacarbazepine, lamotrigine, valproic acid, topiramate, levetiracetam, brivaracetam, or seletracetam. In some embodiments, the atypical antipsychotic is aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, or clozapine.

[0019] In some embodiments, the NMDA receptor agent is D-cycloserine (DCS), NRX-1074, rapastinel (GLYX-13), plazinemdor, LY-2140023, NYX-458, NYX-783, NYX-2925, NRX-1074, SAGE-718, a substituted 1 ,2,3-triazole NMDA modulator, a spiro-lactam NMDA modulator, a NMDA modulator, ketamine, S-ketamine, R-ketamine, a non-racemic mixture of ketamine enantiometers, a ketamine metabolite, a ketamine analog, memantine, amantadine, rimantadine, nitromemantine (YQW-36), acamprosate, pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, ketobemidone, dextromethorphan (DXM), dextrorphan, dextrallorphan (DXA), gacyclidine (GK-11), neramexane, lanicemine (AZD6765), diphenidine, dizocilpine (MK-801), 8a-phenyldecahydroquinoline (8A-PDHQ), remacemide, ifenprodil, traxoprodil (CP-101 ,606), eliprodil (SL-82.0715), etoxadrol (CL-1848C), dexoxadrol, WMS-2539, NEFA, delucemine (NPS-1506), aptiganel (Cerestat; CNS-1102), midafotel (CPPene; SDZ EAA 494), dexanabinol (HU-211 or ETS2101), selfotel (CGS-19755), 7-chlorokynurenic acid (7-CKA), 5,7-dichlorokynurenic acid (5,7-DCKA), L-683344, L-689560, L-701324, GV150526A, GV196771A, CERC-301 (MK-0657), atomoxetine, LY-235959, CGP 61594, CGP 37849, CGP 40116 or CGP 37849, LY-233536, PEAQX (NVP-AAM077), ibogaine or noribogaine, an ibogaine metabolite, an ibogaine analog, an ibogaine derivative, Ro 25-6981 , GW468816, EVT-101, indantadol, perzinfotel (EAA-090), SSR240600, 2-MDP (U-23807A) AP-7, phencyclidine, a phencyclidine analog, methoxetamine, a methoxetamine analog, arylcyclohexylamine, or an arylcyclohexylamine derivative.

[0020] In some embodiments, the anti-hyperglycemic agent is an insulin, a sulfonylurea, a meglitinide, a biguanide, a thiazolidinedione, an a-glucosidase inhibitor, a DPP-4 inhibitor, a SGLT2 inhibitor, or a dopaminereceptor agonist. In some embodiments, the anti-hyperglycemic agent is insulin glulisine, insulin aspart, insulin lispro, regular insulin, NPH insulin, glipizide, glyburide, gliclazide, glimepiride, repaglinide, nateglinide, metformin, rosiglitazone, pioglitazone, acarbose, miglitol, voglibose, sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, dapagliflozin, canagliflozin, or bromocriptine. In some embodiments, the anti-hyperglycemic agent is metformin. In some embodiments, the anti-inflammatory agent is prednisone, hydrocortisone, diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, meclofenamate, mefenamic acid, nabumetone, naproxen, tolmetin, piroxicam, celecoxib, etoricoxib, aspirin, naproxen, meloxicam, an anti-cytokine agent, or a selective COX-2 inhibitor.

[0021] In some embodiments, the anti-cytokine agent is adalimumab, etanercept, infliximab, or tocilizumab. In some embodiments, the selective COX-2 inhibitor is lumiracoxib. In some embodiments, the anti-inflammatory agent is ibuprofen. In some embodiments, the anxiolytic agent is a benzodiazepine, an azapirone, an alpha blocker, a beta blocker, an antidepressant, a barbiturate, a nonbenzodiazepine sedative, a hypnotic, nefazodone, pregabalin, mirtazapine, or gabapentin. In some embodiments, the benzodiazepine is lorazepam, diazepam, alprazolam, clonazepam, chlordiazepoxide, or chlordiazepoxide / clidinium bromide. In some embodiments, the benzodiazepine is lorazepam. In some embodiments, the azapirone is buspirone. In some embodiments, the barbiturate is pentobarbital, phenobarbital, or amobarbital. In some embodiments, the hypnotic is zolpidem, zaleplon, or zopiclone. In some embodiments, the beta blocker is propranolol.

[0022] In some embodiments, the antihistamine is brompheniramine, cyproheptadine, chlorpheniramine, promethazine, claritin, fexofenadine, vistaril, hydroxyzine, alavert, diphenhydramine, levocetirizine, carbinoxamine, meclizine, dimenhydrinate, or azelastine. In some embodiments, the antibiotic is augmentin, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole, trimethoprim, or levofloxacin. In some embodiments, the opioid modulator is naltrexone, kratom, ignavine, salvinorin-A, DPI-289, UFP-505, samidorphan, vivitrol, buprenorphine, or LP1. In some embodiments, the opioid modulator is naltrexone. In some embodiments, the anti-craving agent is ondansetron, disulfiram, buprenorphine, topiramate, rimonabant, bupropion, modafinil, vigabatrin, or varenicline. In some embodiments, the antioxidant is N-acetylcysteine, acetyl-L-carnitine, L-methylfolate, ascorbic acid, glutathione, a flavonoid, alpha lipoic acid, beta-carotene, alpha-tocopherol, ubiquinone, lycopene, coenzyme Q10, ellagic acid, retinol, masoprocol, pramipexole, nitric oxide, allopurinol, pentoxifylline, melatonin, probucol, quercetin, or acetylcysteine. In some embodiments, the antioxidant is N-acetylcysteine. In some embodiments, the antioxidant is acetyl-L-carnitine. In some embodiments, the antioxidant is L-methylfolate. In some embodiments, the antimigraine agent is a triptan. In some embodiments, the phosphodiesterase inhibitor is a phosphodiesterase type-1 (PDE-1) inhibitor, a phosphodiesterase type-2 (PDE-2) inhibitor, a phosphodiesterase type-3 (PDE-3) inhibitor, a phosphodiesterase type-4 (PDE-4) inhibitor, or a phosphodiesterase type-5 (PDE-5) inhibitor. In some embodiments, the PDE-4 inhibitor is apremilast.

[0023] In some embodiments, the anti-hypertensive agent is nimodipine, a diuretic, a beta-blocker, an ACE inhibitor, an Angiotensin II receptor blocker, a calcium channel blocker, an alpha blocker, an alpha-2 receptoragonist, a combined alpha and beta-blocker, a central agonist, a peripheral adrenergic inhibitor, or a vasodilator. In some embodiments, the anti-hypertensive agent is nimodipine.

[0024] In some embodiments, the compound that modulates monoaminergic neurotransmission is administered daily. In some embodiments, the compound that modulates monoaminergic neurotransmission is administered once per day. In some embodiments, the compound that modulates monoaminergic neurotransmission is administered twice per day. In some embodiments, the compound that modulates monoaminergic neurotransmission is administered at least once per day for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 15 weeks, 16 weeks, or 20 weeks.

[0025] In some embodiments, the methods further comprise administering an additional active agent. In some embodiments, the additional active agent is also a compound that modulates monoaminergic neurotransmission. In some embodiments, the additional active agent is a compound that modulates monoaminergic neurotransmission as disclosed herein.

[0026] The method of claim 75, wherein the additional active agent is an amino acid, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-hyperglycemic agent, an antineuropathic or antinociceptive agent, an antimigraine agent, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD agent, a cannabinoid, a dissociative, an immunostimulant, an anti-cancer agent, an antiemetic, an orexigenic, an antiulcer agent, an anticholinergic agent, an anti-ischemic agent, an antihistamine, an anti-craving agent, an antihypertensive, an antimigraine agent, an anticonvulsant, an anticholinergic agent, an antiepileptic, a bronchodilator, a mood stabilizer, a cognitive enhancer, a neuroprotectant, a serotonergic agent, a neuroactive agent, a neurotropic agent, an adaptogen, an actoprotector, an anti hypoxant, an entactogen or empathogen, an entheogen, a psychedelic, a monoamine oxidase inhibitor, a tryptamine, a terpene, a phenethylamine, a sedative, a stimulant, an opioid modulator, a NMDA receptor agent, a vitamin, a SSRI, a SNRI, a NRI, a NDRI, a TCA, a benzodiazepine, or a phosphodiesterase inhibitor.

[0027] In some embodiments, the moclobemide is administered daily. In some embodiments, the moclobemide is administered at a dose of between about 300 and 600 mg per day. In some embodiments, the moclobemide is administered at a dose of about 150 mg twice per day. In some embodiments, the moclobemide is administered daily for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks. In some embodiments, the meldonium is administered daily. In some embodiments, the meldonium is administered at a dose of between about 500 and 1000 mg per day. In some embodiments, the meldonium is administered at a dose of about 500 mg twice per day. In some embodiments, the phenylpiracetam is administered daily. In some embodiments, the phenylpiracetam is administered at a dose of between about 200 and 600 mg per day. In some embodiments, the phenylpiracetam is administered at a dose of between about 100 and 200 mg twice or three times per day. In some embodiments, the naltrexone is administered daily. In some embodiments, the naltrexone is administered at a dose of between about 1 and 5 mg per day. In some embodiments, the naltrexone is administered at a dose of between about 1 and 5 mg once per day. In some embodiments, the apremilast is administered daily. In some embodiments, theapremilast is administered at a dose of between about 10 and 40 mg per day. In some embodiments, the apremilast is administered at a dose of between about 10 and 30 mg once or twice per day.

[0028] In some embodiments, improving adherence to a lifestyle modification recommendation comprises treating a psychological factor affecting another medical condition in the subject. In some embodiments, the psychological factor is any of psychological distress, a pattern of interpersonal interaction, a coping style, a maladaptive health behavior, anhedonia, emotional numbing, and affective flattening. In some embodiments, the maladaptive health behavior is any of denial of symptoms, poor adherence to medical recommendations, and medication nonadherence. In some embodiments, the methods further comprise treating the other medical condition in the subject. In some embodiments, the other medical condition is any of an insulin resistance and related disorder (IRARD), chronic obesity, hyperglycemia, and an additional other medical condition. In some embodiments, the additional other medical condition is hypertension, an inflammatory disorder, a sleep disorder, a musculoskeletal condition, a renal disorder, a hematological disorder, a neurodegenerative disorder, cancer, allergies, an immunological condition, a neurological condition, an infection, a genetic disorder, a pulmonary condition, a urinary or bladder disorder, a digestive disorder, a hepatic disorder, an otolaryngological disorder, a dental or oral health issue, a vascular disorder, a gynecological condition, a skin disorder, a rare disease, endocrinopathy, or congestive heart failure. In some embodiments, IRARD is insulin resistance, a glucoregulatory disorder, a glucoregulatory disorder induced by treatment with a mood stabilizer, a gluco- regulatory disorder induced by treatment with an antipsychotic, a glucoregulatory disorder induced by treatment with an opioid, insulin resistance induced by pharmacotherapy, coronary artery disease, ischemic heart disease, obesity, stroke, being overweight, a genetic disorder, or polycystic ovary disease. The glucoregulatory disorder may be prediabetes, diabetes, metabolic syndrome, obesity, or dyslipidemia.

[0029] In some embodiments, the subject has a co-occurring mental health disorder. In embodiments, the cooccurring mental health disorder is any of a depressive disorder, major depressive disorder (MDD), treatmentresistant depression (TRD), a mood disorder, an anxiety disorder, generalized anxiety disorder (GAD), a trauma- or stressor-related disorder, PTSD, obsessive-compulsive disorder (OCD), a neurocognitive disorder, a feeding or eating disorder, intermittent explosive disorder, an addiction disorder, a substance use disorder, an impulse control disorder, compulsive buying disorder, repetitive self-mutilation syndrome, a nonparaphilic sexual addiction or paraphilia, a personality disorder, and attention deficit hyperactivity disorder (ADHD).

[0030] In some embodiments, the incretin-based therapy comprises glucose-dependent insulinotropic polypeptide (GIP) agonist therapy and / or glucagon-like peptide-1 (GLP-1) agonist therapy. In some embodiments, adherence to the lifestyle modification recommendation is determined by comparing a post-discontinuation measurement and a baseline measurement of body weight; average adipocyte diameter; body mass index (BMI); body fat index (BFI); body fat mass (FM) and fat-free mass; liver enzyme levels; insulin resistance; systolic blood pressure; diastolic blood pressure; HbA1c values; lipid levels; glucose levels; satiety-related hormone levels; total cholesterol; high-density lipoprotein (HDL) cholesterol; low-density lipoprotein (LDL) cholesterol; or a self-report measure. In some embodiments, the post-discontinuationmeasurement is at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or greater than 12 months after the baseline measurement. In some embodiments, the post-discontinuation measurement is within 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the baseline measurement.

[0031] In some embodiments, the compound that modulates monoaminergic neurotransmission is formulated for oral, buccal, sublingual, injectable, subcutaneous, intravenous, intramuscular, or transdermal administration. In some embodiments, the compound that modulates monoaminergic neurotransmission is formulated for oral administration. In some embodiments, the compound that modulates monoaminergic neurotransmission is in unit dosage form.

[0032] In some embodiments, the methods further comprise administering to the subject a second compound. In embodiments, the methods comprise administering to the subject any of: moclobemide and metformin; moclobemide and nimodipine; moclobemide and propranolol; moclobemide and solriamfetol; moclobemide and modafinil; moclobemide and lumiracoxib; moclobemide and ibuprofen; moclobemide and lorazepam; moclobemide and phenylpiracetam; moclobemide and bupropion; moclobemide and meldonium; moclobemide and vitamin D; moclobemide and N-acetylcysteine; moclobemide and acetyl-L-carnitine; moclobemide and L-methylfolate; moclobemide and apremilast; moclobemide and naltrexone; phenylpiracetam and naltrexone; phenylpiracetam and apremilast; meldonium and naltrexone; and meldonium and apremilast.

[0033] In some embodiments, the methods further comprise administering to the subject a third compound. In some embodiments, the methods comprise administering to the subject any of: moclobemide, naltrexone, and apremilast; phenylpiracetam, naltrexone, and apremilast; and meldonium, naltrexone, and apremilast.

[0034] In some further aspects are provided pharmaceutical combinations, pharmaceutical compositions, and pharmaceutical kits for improving adherence to a lifestyle modification recommendation, comprising the compounds that modulate monoaminergic neurotransmission, and / or a second compound, and / or a third compound. In some further aspects are provided the use of the disclosed pharmaceutical combinations, pharmaceutical compositions, and pharmaceutical kits for improving adherence to a lifestyle modification recommendation in a subject who has discontinued a primary treatment for obesity or hyperglycemia.

[0035] The foregoing provides a general summary of certain aspects and embodiments of the disclosure to facilitate an understanding of the detailed description that follows and to contextualize the present contribution to the art. This summary is not intended to limit the scope of the invention or the range of equivalents to which the claims are entitled. Additional features and embodiments are described in further detail below.

[0036] It will be understood that all disclosed compositions and methods are exemplary and may serve as a basis for modifications or alternative embodiments achieving the same objectives. Such variations, including equivalent compositions and methods, are within the scope and spirit of the invention as set forth in the claims.

[0037] Headings are provided for ease of reference only and do not limit the disclosure in any way.BRIEF DESCRIPTION OF THE FIGURES

[0038] Further details of the invention are provided through exemplary embodiments of certain aspects illustrated in the figures. These figures depict only some embodiments and are not limiting in any way. Rather,they serve as illustrative examples of select concepts. These embodiments are described with additional specificity and detail below, solely by way of example, with reference to the accompanying figures, in which:

[0039] FIG. 1 illustrates an interplay between physiological and psychological conditions present in PFAOMC as it relates to brain function in a subject and pharmacotherapy, according to embodiments.

[0040] FIG. 2 illustrates an interplay between a stressor, a subject, and the subject’s external environment with a focus on PFAOMC, according to embodiments.

[0041] FIG. 3 illustrates exemplary independent, interactive, and common processes occurring between physiological factors and psychological factors in conjunction with a medical condition, such as diabetes.DETAILED DESCRIPTION OF THE INVENTION

[0042] While certain aspects and embodiments of the invention are summarized above, the following detailed description provides further exemplary embodiments to enable a person skilled in the art to practice the full scope of the invention, but which are still provided for illustration and not to limit the invention or its applications. It will be understood that various modifications, substitutions, and variations may be made by those skilled in the art without departing from the spirit or scope of the invention, as recited by the claims.I. General Definitions and Terms

[0043] The singular forms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Thus, “a compound” includes reference to not only one but also to two or more compounds, and “an excipient” includes reference to not only one but also to two or more excipients. While the term “one or more” also may be used, its absence (or its replacement by the singular “a” or “an”) does not signify the singular only, but simply provides emphasis to the possibility of multiples in some particular embodiments.

[0044] “Or” means, and is interchangeable with, “and / or” unless context clearly indicates otherwise.

[0045] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[0046] A shorthand may be used for some terms and, unless context clearly indicates otherwise, will have the same meaning as the full term. For example, a “pharmaceutical composition” may be referred to simply as a “composition,” and other such shorthand terms will be readily appreciated in view of the disclosure.

[0047] Unless context indicates a distinction relevant to a described or claimed embodiment, a “composition” and a “formulation,” when used as nouns, are used interchangeably and equivalently herein.

[0048] “In embodiments” may be used equivalently with, and only as shorthand for, “in some embodiments.”

[0049] Numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the examples are reported as precisely as practicable. Numerical values in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0050] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, should be understood as being modified in some instances bythe term “about,” even where not so stated explicitly. In alternative embodiments, such numbers should be understood as not being modified by the term “about.” In embodiments, the numerical parameters are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In other embodiments, “about” refers to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, the term “about 1 , 2, or 3” is understood to mean “about 1 , about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.” The term “substantially,” where it is used to modify a feature or limitation, must be read in the context of the disclosure and in light of the knowledge in the art to provide the appropriate certainty, such as by using a standard recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the relevant art.

[0051] Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, such as medicine, biology, pharmacology, chemistry, statistics, and the like, and are those that will be well known and commonly employed in such fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art.

[0052] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs (as shorthand, “one of skill”).

[0053] Further definitions to assist a reader in understanding the embodiments are below and throughout; however, it will be appreciated that such definitions are not intended to limit the scope of the disclosure, which is properly interpreted and understood by reference to the full specification (as well as any plain meaning known to one of skill in the relevant art) in view of the language used in the claims. The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0054] Besides the definitions below, the definitions in the priority documents (see Cross-Reference) are also incorporated by reference, and the meaning of any term may be best understood with reference to all of the definitions used herein and in such documents, together with the plain meaning understood by those in the art.

[0055] Additional definitions and abbreviations are provided below and throughout.II. Additional Definitions and Terms

[0056] “ACE inhibitor” (angiotensin-converting enzyme inhibitor) refers to a compound (and as with such other compounds herein, to a composition comprising such a compound, unless context clearly indicates otherwise) that inhibits angiotensin-converting enzyme (ACE), reducing the production of angiotensin II. ACE inhibitors promote vasodilation by relaxing blood vessels, thereby lowering blood pressure. Examples of ACE inhibitors include benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, and ramipril.

[0057] “Actoprotector” refers to a compound that enhances physical endurance and resistance to stress without increasing oxygen consumption or heat production.

[0058] “Adaptogen” refers to a compound that supports the body’s adaptation to stress, anxiety, or fatigue bystabilizing physiological processes and promoting homeostasis.

[0059] “Addiction” refers to a chronic, relapsing disorder characterized by compulsive seeking, craving, and use of the object of addiction, despite the risk of adverse consequences.

[0060] “Agent” refers to a compound that modulates the activity of a biological target, such as a receptor. In some embodiments, the agent is a ligand that modulates receptor activity. In embodiments, an agent binds to, blocks, activates, inhibits, or otherwise influences (e.g., via allosteric modulation) activity at a given receptor system. “Agent” and “compound” may be used interchangeably herein unless expressly indicated otherwise.

[0061] “Alpha blocker” or “a-blocker” refers to a compound that reduces blood pressure by preventing norepinephrine from increasing arterial resistance. Alpha blockers include a1 blockers and a2 blockers. Exemplary a1 blockers include alfuzosin, doxazosin, terazosin, tamsulosin, and prazosin. Exemplary a2 blockers include atipamezole, efaroxan, idazoxan, yohimbine, rauwolscine, and phentolamine.

[0062] “Alpha-2 receptor agonist” or “a2 agonist” refers to a compound that reduces blood pressure and modulates affective states by decreasing sympathetic nervous system activity, such as brimonidine, clonidine, dexmedetomidine, guanfacine, guanabenz, lofexidine, methyldopa, naphazoline, tizanidine, and xylazine.

[0063] “Angiotensin II receptor blocker” refers to a compound that blocks the effects of angiotensin II, a peptide hormone that induces vasoconstriction and increases blood pressure. Examples include candesartan, eprosartan, irbesartan, losartan, telmisartan, and valsartan.

[0064] “Antagonist” refers to a compound that binds to a receptor and partially or fully blocks, inhibits, attenuates, prevents, or delays the receptor’s biological response. An antagonist may prevent an agonist from binding to and activating the receptor. Without being bound by theory, an antagonist may act by binding to: (i) an active site that directly regulates receptor activation; (ii) an allosteric site or other regulatory site; or (iii) a site not typically involved in biological regulation of receptor activity (Hopkins AL, Groom CR. Nat. Rev. Drug Discov. 2002; 1 (9):727— 730). In some embodiments, an antagonist is an “indirect antagonist” or “physiological antagonist” (used interchangeably), and modulates the biological response of a receptor without directly binding thereto. The antagonistic activity of a disclosed agent may be reversible or irreversible, and competitive or noncompetitive, depending on its mechanism of action.

[0065] “Anti-hyperglycemic agent” refers to a compound that reduces blood glucose levels. For example, biguanides such as metformin lower glucose by inhibiting hepatic glucose production, decreasing gastrointestinal glucose absorption, and increasing insulin sensitivity at target cells.

[0066] “Anti hypoxant” refers to a compound that prevents or mitigates the effects of hypoxia, a condition characterized by insufficient oxygen supply to tissues.

[0067] “Baseline body weight” refers to the body weight of a subject at the initiation of treatment.

[0068] “Beta blocker” or “P-blocker” refers to a compound that reduces blood pressure by blocking the effects of epinephrine (adrenaline), resulting in decreased heart rate and cardiac output. Exemplary beta blockers include acebutolol, atenolol, betaxolol, bisoprolol, metoprolol, nadolol, penbutolol, propranolol, pindolol, labetalol, timolol, carteolol, carvedilol, oxprenolol, nebivolol, sotalol, pronethalol, alprenolol, esmolol,butoxamine, and ritodrine.

[0069] “Body fat mass” or “FM” refers to the total weight of fat in a human body. The term “fat-free mass” refers to the total weight of all body components excluding fat deposits, including bone, muscle, connective tissue, water, and vital organs.

[0070] “Body mass index” or “BMI” refers to a weight-to-height ratio measurement used to estimate whether an individual’s weight is appropriate for their height. BMI is calculated as a person’s weight in kilograms (or pounds) divided by the square of their height in meters (or feet). Although BMI does not directly measure body fat, it serves as a widely used and cost-effective screening tool for clinical assessment. For adults, BMI is categorized as follows: Underweight: Less than 18.5 kg / m2; Normal / healthy weight: 18.5-24.9 kg / m2; Overweight: 25.0-29.9 kg / m2; Obese: 30.0 kg / m2or greater; Morbidly obese: exceeding 35 kg / m2. Both low and high BMI values outside the normal range are associated with increased disease risk.

[0071] “Calcium channel blocker” refers to a compound that prevents calcium ions from entering the cells of the heart and arteries. Calcium channel blockers may relax and dilate blood vessels, reduce heart rate, and lower blood pressure. Exemplary calcium channel blockers include amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, and verapamil.

[0072] “Central agonist” refers to a compound that lowers heart rate and reduces blood pressure by inhibiting central nervous system signals that increase heart rate and cause vasoconstriction. Exemplary central agonists include methyldopa, clonidine, lofexidine, guanabenz, and guanfacine.

[0073] “Combined alpha and beta blocker” refers to a compound that exhibits both alpha-blocking and beta-blocking activity. Combined alpha and beta blockers include propranolol, carvedilol, and labetalol.

[0074] “Diuretic” refers to a compound that enhances the excretion of sodium and water by the kidneys. Diuretics are commonly used to regulate blood pressure and support cardiac function. Exemplary diuretics include chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, metolazone, amiloride hydrochloride, spironolactone, triamterene, furosemide, and bumetanide.

[0075] “Dyslipidemia” refers to a condition characterized by abnormal concentrations of lipids and lipoproteins in the blood.

[0076] “Hyperglycemia” or “hyperglycemic” refers to a fasting plasma glucose concentration above the normal range, typically exceeding 100 mg / dL. Hyperglycemia is commonly associated with prediabetes or diabetes but may also result from non-disease-related factors.

[0077] “Lifestyle modifications” and “lifestyle modification recommendations” refer to a combination of dietary, physical activity, and behavioral interventions prescribed by a healthcare professional for the treatment of obesity or hyperglycemic disorders.

[0078] “Lipid test,” “complete cholesterol test,” or “lipid panel” refers to a test that measures the concentration of cholesterol and triglycerides in a subject’s blood. Lipid test results are reported in milligrams per deciliter (mg / dL). For adults: Normal cholesterol levels: Less than 200 mg / dL; Borderline high cholesterol levels: 200— 239 mg / dL; High cholesterol levels: 240 mg / dL or greater. A lipid test can detect lipid abnormalities, includingcholesterol and triglyceride imbalances, and may help identify genetic conditions or assess disease risk.

[0079] “Maladaptive behaviors” refer to actions that impair a subject’s ability to adapt, adjust, or function in various aspects of life. These behaviors may be disruptive and contribute to increased distress, discomfort, or health-related issues over time.

[0080] “Medication discontinuation-related rebound weight gain” or “medication discontinuation-related weight regain” refers to weight regain following the cessation of a medication used for weight loss, hyperglycemia, or related conditions. For example, rebound weight gain is commonly observed after discontinuing incretin-based therapies, which are typically effective for initial weight loss but often lead to significant weight regain within 12-18 months after cessation (Wilding et al., Diabetes Obes Metab. 2022;24(8):1553-1564 (“Wilding et al., 2022”)). In some embodiments, the disclosed methods prevent or mitigate medication discontinuation-related rebound weight gain, such as following the cessation of GLP-1 and / or GIP agonist therapy. In the context of the disclosed methods, discontinuation refers to the cessation of an incretin-based therapy, such as was previously administered for the treatment of obesity or hyperglycemia. Discontinuation may occur due to various factors, including adverse effects, lack of efficacy, patient preference, clinical guidance, or treatment plan modifications. Treatment following discontinuation, according to the disclosed methods, may begin immediately upon cessation of the incretin-based therapy or after a clinically appropriate interval, depending for example on factors such as metabolic stability, withdrawal effects, or persistence of the underlying condition. In embodiments, pharmacological interventions to improve adherence to a lifestyle modification recommendation are initiated concurrently with discontinuation. In embodiments, treatment may commence after a delay, such as within hours, days, or weeks following the final dose of the incretin-based therapy.

[0081] “Mental health disorder” refers to a condition in a subject that generally involves clinically significant changes in emotion, mood, cognition, and / or behavior. Unless otherwise specified, the term “mental health disorder” refers to a disorder as defined in the DSM-5. In some embodiments, it may refer to a disorder as defined in the DSM-IV or based on other clinically accepted diagnostic criteria, including the ICD-10, ICD-11 , or other classifications recognized by those skilled in the art.

[0082] “Metabolic hormone” refers to a hormone released by the endocrine system to regulate metabolic networks in cells and organs. Metabolic hormones may include peptide-based hormones that influence metabolic processes. Exemplary metabolic hormones include insulin, glucagon, ghrelin, cortisol, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide tyrosine tyrosine (peptide YY, PYY).

[0083] “Modulate” or “modulation” as used herein with respect to cell membrane receptor activity and / or a quantifiable biological event (e.g., monoaminergic neurotransmitter release), refers to the process of altering or interfering with such activity or event. Modulation may involve increasing, decreasing, or maintaining the activity or biological event, such as adjusting the release of monoaminergic neurotransmitters.

[0084] “Monoaminergic neurotransmission” refers to the neuronal process in which a monoaminergic neurotransmitter is released from a presynaptic cell upon excitation, crosses the synapse, and stimulates or inhibits the postsynaptic cell.

[0085] “Monoaminergic neurotransmitter” refers to a neurotransmitter or neuromodulator containing a single amino group linked to an aromatic ring by a two-carbon chain (— CH2— CH2— ). Monoamines are derived from aromatic amino acids such as phenylalanine, tyrosine, and tryptophan through enzymatic action by aromatic amino acid decarboxylases. Illustrative examples of monoaminergic neurotransmitters include: catecholamines (e.g., dopamine, norepinephrine, epinephrine); tryptamines (e.g., serotonin (5-HT), melatonin); trace amines (e.g., p-phenylethylamine (PEA, 0-PEA), tyramine, tryptamine, octopamine); and histamine.

[0086] “Negative affective state,” “negative affectivity,” or “negative affect” refers to a psychological variable encompassing negative emotions and poor self-concept. High negative affectivity is characterized by states such as sadness, anxiety, paranoia, anger, contempt, disgust, guilt, fear, and nervousness. Negative affectivity may be associated with demoralization, maladaptive coping, and increased susceptibility to physical and mental health conditions.

[0087] “Neurotropic agent” or “neurotrophic agent” refers to a compound that acts on the central and / or peripheral nervous system by supporting the growth, survival, or differentiation of developing or mature neurons. Some neuroprotective agents may also exhibit neurotropic activity.

[0088] “Obese” or “obesity” refers to a condition characterized by a body mass index (BMI) of 30 kg / m2or greater, primarily due to excess adipose tissue. Obesity may also be defined by body fat percentage, such as greater than 25% for males and greater than 30% for females. Obesity is sub-classified as: Class 1 obesity: BMI 30-35 kg / m2; Class 2 obesity: BMI 35-40 kg / m2; and Class 3 obesity: BMI 40 kg / m2or greater

[0089] “Opioid modulator” refers to a compound that exhibits both agonistic and (partial) antagonistic effects by binding to different opioid receptors, preventing classification as solely an agonist or antagonist.

[0090] “Oral glucose tolerance” refers to a subject’s physiological response to orally administered glucose, assessed by measuring blood glucose levels over time. “Glucose tolerance” refers to the body’s ability to metabolize and clear a glucose load.

[0091] “Peripheral adrenergic inhibitor” refers to a compound that reduces blood pressure by inhibiting neurotransmitter activity in the peripheral nervous system. Exemplary peripheral adrenergic inhibitors include guanadrel, guanethidine, monosulfate, and reserpine.

[0092] “Psychological functioning” refers to the interplay of emotions, cognition, life circumstances, intellect, thought patterns, and levels of consciousness in shaping mood and cognitive abilities. The term may also encompass a subject’s ability to achieve personal and external goals, as reflected in behavior, emotions, social skills, and overall mental health.

[0093] “Psychotic disorder” refers to a mental health condition characterized by impaired reality perception, including delusions, hallucinations, disorganized thinking, and abnormal behavior. Psychotic disorders may also involve cognitive impairment, emotional dysregulation, and significant functional decline. A psychotic disorder includes the conditions defined in the DSM-5, such as schizophrenia, schizoaffective disorder, delusional disorder, brief psychotic disorder, schizophreniform disorder, substance / medication-induced psychotic disorder, and psychotic disorder due to another medical condition. Other psychotic disorders includepsychosis associated with neurodegenerative diseases (e.g., Parkinson’s disease psychosis, Alzheimer’s disease psychosis), postpartum psychosis, bipolar disorder with psychotic features, major depressive disorder with psychotic features, and psychosis secondary to metabolic or endocrine dysfunctions (e.g., Cushing’s syndrome, thyroid dysfunction). Psychotic symptoms may also occur in autoimmune or paraneoplastic disorders (e.g., anti-NMDA receptor encephalitis), epilepsy-related psychosis, and functional or transient psychoses with unclear etiology. Other psychotic disorders will be known by those in the art.

[0094] “Selective COX-2 inhibitor” refers to a type of non-steroidal anti-inflammatory drug (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2), an enzyme involved in inflammation and pain. Exemplary COX-2 inhibitors include lumiracoxib, celecoxib, rofecoxib, and valdecoxib.

[0095] “Thanatophobia” refers to an intense or irrational fear of death or dying. In some contexts, thanatophobia may include a subjective sensation of impending death, such as angor animi.

[0096] “Vasodilator” refers to a compound that induces the dilation of blood vessels, leading to reduced vascular resistance and lowered blood pressure. Exemplary vasodilators include hydralazine, minoxidil, and sodium nitroprusside.

[0097] Yet further definitions and abbreviations are provided elsewhere herein.III. Methods of Improving Adherence

[0098] Monoaminergic neurotransmitters (e.g., serotonin, dopamine) and metabolic hormones (e.g., insulin) influence emotions and behaviors, including those related to food intake and reward processing (see, e.g., Jiang et al., Pharmaceuticals (Basel). 2022; 15(10): 1203). Modulating monoaminergic neurotransmission in conjunction with improving glucoregulatory function, such as according to the disclosed methods, can affect behavioral patterns, including those associated with adherence to weight management strategies. In some embodiments, the disclosed methods modulate monoaminergic neurotransmission by inhibiting monoamine oxidase (MAO) enzymes (e.g., MAO-A) to enhance neurotransmitter signaling (see, e.g., Chen et al., Pol. J. Pharmacol. 1999;51 (1):25-9). Post-synaptic signal transduction may be further enhanced through improved insulin sensitivity and glucoregulatory function (see, e.g., Shpakov et al., Future Sci OA. 2015; 1 (3):FSO25).

[0099] Insulin plays a role in regulating dopaminergic pathways involved in hedonic and motivational drives for palatable food consumption (see, e.g., Elman et al., Neuropsychopharmacol. 2006;31 (10):2091 -120; Elman et al., Sci. Rep. 2020; 10(1 ):5617). However, insulin resistance impairs this regulatory function, contributing to excessive food intake and metabolic dysregulation. Subjects experiencing insulin resistance following the discontinuation of incretin-based therapies for obesity or hyperglycemia may be particularly susceptible to weight regain and unhealthy eating patterns. Disclosed methods provide approaches to mitigate these effects, improving adherence to weight management strategies following the cessation of a primary treatment. For clarity, the discontinued treatment for obesity or hyperglycemia may be referred to as the "primary treatment."

[0100] Metabolic conditions and psychiatric disorders frequently co-occur, with significant clinical overlap.

[0101] Individuals with obesity or diabetes have an increased prevalence of psychiatric conditions such as depression and anxiety, while those with psychiatric disorders may be at higher risk for metabolic dysfunction.This bidirectional relationship may involve metabolic disturbances affecting neurotransmitter systems and psychiatric symptoms influencing metabolic regulation and health behaviors, posing challenges for long-term treatment adherence.

[0102] Certain medications used to manage psychiatric conditions, particularly antipsychotics, may contribute to metabolic dysfunction, including weight gain, insulin resistance, and lipid abnormalities. These effects may exacerbate existing metabolic conditions or increase metabolic risk in psychiatric patients, potentially further impairing adherence. Subjects managing both metabolic and psychiatric symptoms may experience additional barriers to adherence, including: cognitive impairment or mood disturbances that interfere with following treatment regimens; decreased motivation or energy levels that hinder lifestyle modifications; metabolic side effects of psychiatric medications that discourage continued use; exacerbation of psychiatric symptoms due to metabolic dysfunction; and difficulties managing multiple treatment regimens for comorbid conditions.

[0103] The disclosed methods provide approaches to mitigate these barriers by addressing the interplay between metabolic and psychiatric symptoms to improve adherence to long-term treatment strategies.

[0104] Subjects may experience difficulty adhering to lifestyle modifications recommended by a healthcare professional after discontinuing primary treatment for obesity or hyperglycemia, leading to weight regain. The disclosed methods and pharmacotherapies enhance adherence to lifestyle modification recommendations and reduce the likelihood of weight regain following the cessation of incretin-based therapies or other primary treatments for obesity or hyperglycemia.

[0105] In some aspects, provided are methods for improving adherence to lifestyle modification recommendations in a subject who has discontinued primary treatment for obesity or hyperglycemia (e.g., incretin-based therapy, such as GIP, GLP-1 , or GIP / GLP-1 agonist therapy).

[0106] In some embodiments, the methods involve pharmacotherapies that modulate monoaminergic neurotransmission, including reversible inhibitors of monoamine oxidase-A (e.g., moclobemide).

[0107] In some embodiments, the methods are of use in treating a subject after discontinuation of incretin-based therapies, including but not limited to GIP, GLP-1 , or GIP / GLP-1 agonist therapy. In embodiments, the GIP, GLP-1 , or GIP / GLP-1 agonist comprises any clinically available agent, including but not limited to: semaglutide (e.g., OZEMPIC®, WEGOVY®, RYBELSUS®, Novo Nordisk); exenatide (e.g., BYETTA®, AstraZeneca); exenatide extended release (e.g., BYDUREON BCise®, AstraZeneca); liraglutide (e.g., VICTOZA®, SAXENDA®, Novo Nordisk); tirzepatide (e.g., MOUNJARO®, ZEPBOUND®, Eli Lilly & Co.); insulin degludec / liraglutide (e.g., XULTOPHY®, Novo Nordisk); lixisenatide (e.g., ADLYXIN®, LYXUMIA®, Sanofi); insulin glargine / lixisenatide (e.g., SOLI QUA® 100 / 33, SULIQUA®, Sanofi); retatrutide (LY3437943, Eli Lilly & Co.); dulaglutide (e.g., TRULICITY®, Eli Lilly & Co.)

[0108] The disclosed methods are applicable to any GIP, GLP-1 , or GIP / GLP-1 agonist therapy available for clinical use, as will be recognized by those skilled in the art.

[0109] Therapeutic compounds included herein also encompass dual GIP / GLP-1 receptor agonists, such as tirzepatide and LY3298176, as well as triple GIP, GLP-1, and glucagon receptor agonists, such as LY3437943.

[0110] It will be appreciated that GIP, GLP-1, or GIP / GLP-1 agonists may be prescribed and discontinued for both on-label and off-label uses. In some embodiments, the GIP, GLP-1 , or GIP / GLP-1 agonist is prescribed for an on-label indication; in other embodiments, it is prescribed for an off-label indication. Likewise, in some embodiments, the GIP, GLP-1, or GIP / GLP-1 agonist is discontinued following an on-label use, while in other embodiments, it is discontinued following an off-label use. As used herein: “On-label use” refers to the prescription of a drug for an indication and dosage for which it has received regulatory approval. “Off-label use” refers to the prescription of a drug for an indication and / or dosage not approved by regulatory authorities.

[0111] In some embodiments, the disclosed methods are used to treat a subject who has discontinued incretin-based therapy and has begun to regain weight. In certain embodiments, the methods are applied to a subject who has discontinued GIP, GLP-1 , or GIP / GLP-1 agonist therapy and has experienced weight regain.

[0112] In some embodiments, the disclosed methods are used to treat a subject with a psychotic disorder. In some embodiments, the psychotic disorder is schizophrenia, schizoaffective disorder, delusional disorder, shared psychotic disorder, a specified schizophrenia spectrum disorder, or an unspecified schizophrenia spectrum disorder. In some embodiments, the psychotic disorder is secondary to another medical condition.

[0113] Antipsychotic medications used to treat psychotic disorders may induce metabolic side effects in some patients. In some embodiments, the disclosed methods are used to treat a subject experiencing metabolic side effects of an antipsychotic medication such as weight gain, insulin resistance, and lipid abnormalities.

[0114] As used herein, the terms “subject,” “patient,” “individual,” and the like are used interchangeably and refer to any person for whom a disclosed method may be efficacious or otherwise beneficial. Unless otherwise specified, the disclosed methods are applicable to all individuals, recognizing that individual variation is expected and understood by those in the art in view of the teachings herein.

[0115] As used herein, “treating” or “treatment” refers to the management or intervention of a disease or disorder in a mammal, preferably a human, to induce a desired biological or pharmacological effect, treatment includes, but is not limited to: (a) preventing a disorder in a subject predisposed to the disorder but not yet diagnosed; (b) inhibiting a disorder by arresting its development; (c) relieving a disorder by causing regression; (d) protecting against or alleviating symptoms or pathologies associated with a disorder; (e) reducing, decreasing, inhibiting, ameliorating, or preventing the onset, severity, duration, progression, frequency, or probability of one or more symptoms or pathologies of a disorder; and (f) preventing or inhibiting the worsening or progression of symptoms or pathologies associated with or comorbid with a disorder.

[0116] In some embodiments, treatment includes prevention. In other embodiments, treatment excludes prevention. Other measurable benefits, surrogate markers, and clinical endpoints, alone or in combination, are within the scope of the disclosed methods as understood by those skilled in the art.A. Treatment Adherence

[0117] In some aspects, disclosed are methods for improving treatment adherence in a subject. In some embodiments, the disclosed methods improve treatment adherence following incretin-based therapies, including after discontinuation of GIP, GLP-1 , or GIP / GLP-1 agonist therapy.

[0118] In some embodiments, the disclosed methods improve treatment adherence in a subject with a psychotic disorder following incretin-based therapies.

[0119] In some embodiments, the disclosed methods improve treatment adherence in a subject experiencing metabolic side effects from an antipsychotic medication following incretin-based therapies

[0120] As used herein, “treatment adherence” and “treatment compliance” refer to the extent to which a patient’s behavior aligns with a healthcare professional’s recommendations (see, e.g., Chakrabarti, World J Psychiatry. 2014;4(2):30-36). Non-adherence and non-compliance may arise from similar psychological and physiological factors and lead to comparable health outcomes. The disclosed methods are generally applicable to improving both adherence and compliance, as literature supports substantial overlap between these terms (e.g., Jin et al., Ther Clin Risk Manag. 2008;4(1):269-286; Mir, T„ HCA Healthcare J Med 2023;4(2):219-220).

[0121] Accordingly, unless context dictates otherwise, the terms “adherence” and “compliance” (and likewise, “non-adherence” and “non-compliance”) are used interchangeably herein, and the disclosed methods are understood to address both unless explicitly stated otherwise. However, recognizing that the terms may be used separately in certain contexts, individual definitions are provided for purposes of further clarity below:

[0122] “Treatment adherence” refers to the extent to which a patient’s behavior (e.g., taking medication, following a diet, maintaining lifestyle modifications) aligns with a healthcare professional’s recommendations (WHO, Adherence to Long-Term Therapies: Evidence for Action, 2003). The terms “treatment adherence” and “adherence” are used interchangeably. Adherence is proactive and engaged, such as following a prescribed exercise regimen as part of a lifestyle modification plan.

[0123] “Treatment compliance” refers to a patient’s adherence to directly prescribed medical instructions, without necessarily engaging in broader lifestyle changes (Mir, T., HCA Healthcare J Med. 2023;4(2):219-220). The terms “treatment compliance” and “compliance” are used interchangeably. Non-compliance occurs when a patient intentionally deviates from medical instructions, such as: failing to fill a prescription; taking incorrect doses; altering dosage frequency; prematurely discontinuing treatment; delaying medical care; skipping clinic visits; taking “drug holidays” (pausing and restarting therapy); and engaging in “white-coat compliance” (adhering only around medical appointments).

[0124] Maintaining a healthy weight after weight loss is challenging. Studies indicate that most individuals regain approximately two-thirds of their weight within a year of discontinuing weight loss treatment (Wilding et al., 2022). Due to the high rate of recidivism, weight management is generally considered a chronic issue requiring long-term adherence to a treatment plan.

[0125] Traditional medical models poorly predict adherence, as they often fail to account for a patient’s subjective experience; disease-related factors (e.g., knowledge about the disease or treatment course); treatment-related factors (e.g., medication perceptions, side effects, cost, access); and life circumstances (e.g., available resources, social support) (Bak-Sosnowska et al., Healthcare (Basel). 2022; 10(3):426).

[0126] Adherence to lifestyle modification recommendations involves fundamental cognitive and behavioral processes, including information processing, habit formation, and behavioral regulation within a medicalcontext. Neuroanatomically, adherence may be influenced by activity in the prefrontal cortex (e.g., behavioral monitoring and control); striatum (e.g., reward processing and reinforcement learning); amygdala (e.g., emotional modulation and fear-related responses); and insula (e.g., detecting and integrating bodily sensations related to treatment effects or side effects). These brain regions also may influence compliance by a subject.

[0127] In certain psychotic disorders, such as schizophrenia and related disorders, underlying disruptions in dopaminergic, glutamatergic, and / or opioid neurocircuits can affect reward processing and executive function, leading to poor motivation, limited insight, and inconsistent engagement with recommended care. The hyper- or hypoactivity of these circuits, coupled with metabolic and inflammatory complications, can diminish the capacity to anticipate positive treatment outcomes, worsen behavioral reinforcement (e.g., failing to internalize the benefits of weight management or medication adherence), and exacerbate cognitive deficits that get in the way of routine health behaviors. Consequently, individuals may underestimate the importance of ongoing therapy or avoid medication due to side effects, resulting in low adherence rates. In embodiments, disclosed methods address such disruptions, such reward processing and executive function, and such hyper- or hypoactivity of these circuits, as well as improve adherence to a lifestyle modification recommendation.

[0128] In embodiments, disclosed methods comprise improving adherence to a lifestyle modification recommendation following primary treatment (e.g., incretin-based therapy) by modulating neurotransmission.

[0129] The modulation of monoaminergic neurotransmitters according to disclosed embodiments affects treatment adherence. For example, modulation of dopamine may influence reward, motivation, and reinforcement; modulation of serotonin may regulate mood, emotional well-being, motivation, and impulse control, thereby influencing compliance; and modulation of norepinephrine may affect attention, arousal, and stress response, supporting focus and motivation to adhere to treatment. In embodiments, modulation of monoaminergic neurotransmission also influences glutamatergic signaling, and facilitates synaptic plasticity, learning, and memory, enabling retention of treatment-related information and behavioral adaptation. Monoaminergic systems, including dopaminergic, serotonergic, and noradrenergic pathways, regulate glutamatergic activity in brain regions involved in habit formation, cognitive control, and reinforcement learning, such as the prefrontal cortex, striatum, and hippocampus. In embodiments, modulation of monoaminergic neurotransmission enhances cognitive and motivational processes critical for treatment adherence.

[0130] In some embodiments, administering an effective amount of a compound that modulates monoaminergic neurotransmission affects dopaminergic, serotonergic, and / or norepinephrinergic neurotransmission in a subject, thereby improving adherence to lifestyle modifications. In certain embodiments, the disclosed method promotes behavioral changes by targeting negative affective states, which significantly contribute to food cravings and consumption.

[0131] In some embodiments, the disclosed method improves adherence to lifestyle modifications following primary treatment through metabolic changes. Herein, “metabolism” refers to the biochemical processes through which food is converted into energy to sustain physiological functions. More specifically, metabolism comprises a network of enzyme- and metabolite-driven mechanisms essential for maintaining homeostasis. Ahealthy metabolism depends on multiple factors, including dietary habits, physical activity, sleep, energy intake, and energy expenditure. Balanced lifestyle behaviors (e.g., healthy eating, regular physical activity, adequate sleep) are key regulators of body weight and metabolic function, particularly in sustaining weight loss.

[0132] Maintaining a healthy weight after weight loss requires balancing energy input and output to regulate metabolism. This may include, but is not limited to, modulating enzymatic activities; ATP synthesis; hormonal functions; neurological processes; and muscular activities (see, e.g., Farhana A., Rehman A., Metabolic Consequences of Weight Reduction, StatPearls, 2023). In some embodiments, the disclosed method affects leptin; insulin; triiodothyronine (T3); thyroxine (T4); peptide YY (PYY); gastric inhibitory peptide; GLP-1 ; amylin; pancreatic polypeptide; cholecystokinin (CCK); free fatty acids; triglycerides; HDL; cholesterol; P-hydroxybutyrate; and glucose concentrations.

[0133] In embodiments, a disclosed method improves adherence to a lifestyle modification recommendation after discontinuation of incretin-based therapy. Improving adherence may: maintain the outcomes of incretin-based therapy; enhance the outcomes of primary treatment; sustain weight loss achieved following primary treatment; and / or further reduce weight after primary treatment (e.g., facilitate additional weight loss).

[0134] In some embodiments, a disclosed method comprises improving a subject’s adherence after discontinuation of incretin-based therapy. In some embodiments, improving adherence may comprise any one or more of: maintain the outcomes of incretin-based therapy; enhance the outcomes of the primary treatment; sustain weight loss achieved following primary treatment; further reduce weight after primary treatment (e.g., facilitate additional weight loss).B. Psychological Factors Affecting Other Medical Conditions (PFAOMC)

[0135] The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) (Am. Psych. Assoc., 2022) defines psychological factors affecting other medical conditions (PFAOMC) as a distinct diagnostic category. “PFAOMC” (sometimes “PFAMC”) describes a disorder in which a general medical condition is adversely affected by psychological or behavioral factors. These factors may precipitate or exacerbate the medical condition, interfere with treatment, or contribute to morbidity and mortality. “Exacerbation” refers to an increase in the severity of a disease or any of its symptoms. One or more clinically significant psychological or behavioral factors can adversely impact a medical condition by increasing the risk of suffering, disability, or death. The co-occurrence of medical and psychiatric morbidity is associated with increased mortality, reduced quality of life, and greater healthcare utilization. Several psychosocial and biological mechanisms contribute to this, including promotion of risk factors, amplification of somatic symptoms, nonadherence, and pathophysiologic effects. PFAOMC contributes to approximately 50% of chronic medication nonadherence, 50% of treatment failures, and 25% of hospitalizations, and is estimated to cause 125,000 annual deaths from otherwise treatable conditions (Dimatteo et al., Med Care, 2002;40(9):794-811 ; Kim et al., US Pharmacist, Jan 19, 2019). Despite this, treatable psychiatric symptoms and psychological factors in medically ill patients often remain undiagnosed and undertreated.

[0136] PFAOMC can occur across the lifespan and affects a wide range of medical conditions. Such medicalconditions include diseases with clear pathophysiology (e.g., diabetes, cancer, cerebrovascular disease, coronary artery disease, asthma, psoriasis, systemic lupus erythematosus, inflammatory bowel disease, helicobacter pylori infection, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections); functional syndromes (e.g., migraines, irritable bowel syndrome, fibromyalgia); and idiopathic medical symptoms (e.g., insomnia, pain, fatigue, dizziness). Depending on the underlying (“other”) medical condition, the prognosis varies significantly. Some conditions have immediate medical consequences (e.g., myocardial infarction, takotsubo cardiomyopathy), while others lead to chronic complications over time, such as chronic occupational stress increasing the risk for hypertension or denial of symptoms, refusal of treatment, and nonadherence leading to heightened morbidity and mortality.

[0137] Currently, there are no safe and effective treatments for patients with PFAOMC, particularly those with insulin resistance and related disorders (IRARD), chronic obesity, hyperglycemia, and other medical conditions. Accordingly, there is a need for treatments that address PFAOMC, particularly as it pertains to improving treatment adherence.

[0138] Insulin resistance and related disorders (IRARD) may be influenced by psychological factors. While insulin resistance most commonly occurs in conjunction with diabetes, it may also arise from other underlying causes. Psychological stress can negatively impact glucose control in subjects with IRARD; studies indicate that glycemic control is poorer in diabetic subjects experiencing higher perceived stress (see, e.g., Elman et al., Neuropsychopharmacol. 2006;31 (10):2091 -2120; Sharma et al., Cureus, 2022 Sep;14(9):e29142). In some embodiments, a disclosed method synergistically reduces stress and improves glycemic control.

[0139] Exemplary disorders related to insulin resistance include glucoregulatory disorders (e.g., prediabetes, diabetes, metabolic syndrome, obesity, dyslipidemia) of any etiology, including glucoregulatory disorders induced by treatment with mood stabilizers; antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, aripiprazole, paliperidone, cariprazine, lurasidone, iloperidone, brexpiprazole, asenapine, lumateperone, pimavanserin); opioids; insulin resistance induced by pharmacotherapy; coronary artery disease, ischemic heart disease, stroke; excessive stress; reduced number or function of insulin receptors; pancreatic failure to produce insulin; genetic disorders; polycystic ovary disease (see, e.g., Elman et al., Neuropsychopharmacol. 2006;31 (10):2091 -2120; Kurbanov et al., J Psychopharmacol. 2012;26(9): 1244- 1251 ; Taviera et al., J Psychopharmacol. 2014;28(4):395-400; Guina et al., Human Psychopharmacol: Clinical & Experimental. 2017;32(4); Elman et al., Sci Reports-Nature. 2020;10:5617).

[0140] In some embodiments, IRARD is any of insulin resistance; glucoregulatory disorders (e.g., prediabetes, diabetes, metabolic syndrome, obesity, dyslipidemia); glucoregulatory disorders induced by treatment with mood stabilizers, antipsychotics, or opioids; insulin resistance induced by pharmacotherapy; coronary artery disease; ischemic heart disease; stroke; overweight; obesity; genetic disorders; and polycystic ovary disease. In some embodiments, IRARD is insulin resistance.

[0141] In some embodiments, IRARD is a glucoregulatory disorder. In some embodiments, the glucoregulatory disorder is prediabetes. In some embodiments, the glucoregulatory disorder is diabetes. Insome embodiments, the glucoregulatory disorder is metabolic syndrome. In some embodiments, the glucoregulatory disorder is obesity. In some embodiments, the glucoregulatory disorder is dyslipidemia.

[0142] In some embodiments, IRARD is a glucoregulatory disorder induced by treatment with a mood stabilizer. In some embodiments, IRARD is a glucoregulatory disorder induced by treatment with an antipsychotic. In some embodiments, IRARD is a glucoregulatory disorder induced by treatment with an opioid.

[0143] In some embodiments, IRARD is insulin resistance induced by pharmacotherapy.

[0144] In some embodiments, IRARD is coronary artery disease. In some embodiments, IRARD is ischemic heart disease. In some embodiments, IRARD is obesity. In some embodiments, IRARD is a stroke. In some embodiments, IRARD is being overweight. In some embodiments, IRARD is polycystic ovary disease.

[0145] In some embodiments, IRARD is a genetic disorder. In some embodiments, the genetic disorder is Prader-Willi syndrome. In some embodiments, the genetic disorder is Prader-Willi-Like syndrome.

[0146] As used herein, “psychological factors of PFAOMC” or “psychological factors” refer to elements related to mental function, emotions, and behavior that adversely affect an underlying medical condition or arise in the context of a medical condition in the subject, leading to a diagnosis of PFAOMC. The terms “psychological factors of PFAOMC” and “psychological factors” also include “behavioral factors of PFAOMC” and “behavioral factors,” unless context indicates otherwise.

[0147] Examples of psychological or behavioral factors include psychological distress; patterns of interpersonal interaction; coping styles (e.g., symptom denial); maladaptive health behaviors (e.g., denial of symptoms, poor adherence to medical recommendations, smoking, substance use, sedentary lifestyle) (see, e.g., Levenson & Bledowski, Psychiatry, 2015:2398-2422); symptoms of depression or anxiety; stressful life events; relationship styles; personality traits; stress coping styles; regression to dysfunctional behavioral patterns; anger; denial; bereavement; conflict defense mechanisms.

[0148] As used herein in relation to psychological factors or PFAOMC, the term “other medical condition” refers to the medical condition that is adversely affected by the psychological or behavioral factors underlying a diagnosis of or diagnosable PFAOMC. The psychological or behavioral factors may precipitate or exacerbate the other medical condition; interfere with treatment of the other medical condition; contribute to the morbidity and mortality of the other medical condition; or some combination thereof.

[0149] In some embodiments, the other medical condition is chronic obesity. In some embodiments, the other medical condition is hyperglycemia. In some embodiments, the other medical condition is any of IRARD, chronic obesity, hyperglycemia, and additional other medical conditions.

[0150] In embodiments, the other medical condition is an additional other medical condition. An “additional” other medical condition refers to a medical condition other than IRARD, chronic obesity, or hyperglycemia.

[0151] In some embodiments, the additional other medical condition is hypertension. In embodiments, it (the medical condition) is an inflammatory disorder. In embodiments, it is a sleep disorder. In embodiments, the sleep disorder is insomnia. In embodiments, the sleep disorder is a dyssomnia. In embodiments, the sleep disorder is a parasomnia. In embodiments, it is a musculoskeletal condition. In embodiments, themusculoskeletal condition is arthritis. In embodiments, the musculoskeletal condition is osteoporosis. In embodiments, the musculoskeletal condition is dystonia. In embodiments, it is a renal disorder. In embodiments, the renal disorder is renal failure. In embodiments, it is a hematological disorder. In embodiments, the hematological disorder is anemia. In embodiments, the hematological disorder is a clotting disorder. In embodiments, the hematological disorder is polycythemia vera. In embodiments, it is a neurodegenerative disorder. In embodiments, the neurodegenerative disorder is Alzheimer's disease. In embodiments, the neurodegenerative disorder is Parkinson's disease. In embodiments, it is cancer. In embodiments, it is an allergy. In embodiments, it is an immunological condition. In embodiments, it is a neurological condition. In embodiments, the neurological condition is a seizure disorder. In embodiments, the neurological condition is head trauma. In embodiments, the neurological condition is multiple sclerosis. In embodiments, the neurological condition is a tremor. In embodiments, it is an infection. In embodiments, the infection is helicobacter pylori infection. In embodiments, the infection is pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections. In embodiments, it is a genetic disorder. In embodiments, psychological factors impact the expression or management of the genetic disorder. In embodiments, it is a pulmonary condition. In embodiments, the pulmonary condition is chronic obstructive pulmonary disease (COPD). In embodiments, the pulmonary condition is interstitial lung disease. In embodiments, it is a urinary or bladder disorder. In embodiments, the urinary or bladder disorder is urinary incontinence. In embodiments, the urinary or bladder disorder is interstitial cystitis. In embodiments, the urinary or bladder disorder is benign prostatic hyperplasia. In embodiments, it is a digestive disorder. In embodiments, the digestive disorder is gastroesophageal reflux. In embodiments, the digestive disorder is chronic gastritis. In embodiments, the digestive disorder is a peptic ulcer. In embodiments, it is a hepatic disorder. In embodiments, the hepatic disorder is cirrhosis. In embodiments, the hepatic disorder is cholelithiasis. In embodiments, the hepatic disorder is hepatitis. In embodiments, it is an otolaryngological disorder. In embodiments, the otolaryngological disorder is chronic otitis media. In embodiments, the otolaryngological disorder is Meniere's disease. In embodiments, it is an ophthalmic condition. In embodiments, the ophthalmic condition is glaucoma. In embodiments, the ophthalmic condition is dry eye syndrome. In embodiments, it is a dental or oral health issue. In embodiments, the dental or oral health issue is a temporomandibular joint disorder. In embodiments, it is a vascular disorder. In embodiments, the vascular disorder is peripheral artery disease. In embodiments, the vascular disorder is venous insufficiency. In embodiments, it is a gynecological condition. In embodiments, the gynecological condition affects the tissue lining the uterus. In embodiments, the gynecological condition is endometriosis. In embodiments, it is a skin disorder. In embodiments, it is a rare disease. In embodiments, the rare disease is a condition with psychological components in its management or impact. In embodiments, the rare disease is Prader-Willi syndrome. In embodiments, it is an endocrinopathy. In embodiments, the endocrinopathy is Cushing's disease. In embodiments, it is congestive heart failure. In embodiments, it is postpartum depression. In embodiments, it is seasonal affective disorder.

[0152] Yet further additional other medical conditions will be known to those of skill in view of the disclosure.

[0153] In embodiments, the psychological factor is any of psychological distress; patterns of interpersonal interaction; coping styles; and maladaptive health behaviors (e.g., denial of symptoms, poor adherence to medical recommendations, or medication nonadherence) (see, e.g., DSM-5-TR). In embodiments, the psychological factor is psychological distress. In embodiments, the psychological factor is a pattern of interpersonal interaction. In embodiments, the psychological factor is a coping style. In embodiments, the psychological factor is a maladaptive health behavior.

[0154] Where an item, such as a therapeutic compound, is selected from a disjunctive list of items, is “any of’ a list (i.e., a group) of items, such as a conjunctive list, or is “selected from a group consisting of’ the items, it will be appreciated that the group is closed (i.e., a Markush group); however, in some embodiments, multiple items may be selected together from the group, as each such group is considered to include the implied term “or a combination thereof,” unless the words “only one of’ are used. In embodiments, the disclosure also expressly includes an embodiment wherein “only one of’ the group of items is intended. Accordingly, where “or” is used in a disjunctive list, the “or” should be understood to mean “and / or,” and in some embodiments mean one item is selected, and in other embodiments, mean more than one item is selected.

[0155] In embodiments, the psychological factor is any of impaired quality of life; health anxiety; thanatophobia; disease phobia; illness denial; persistent somatization; conversion symptoms; functional somatic symptoms secondary to a psychiatric disorder; anniversary reaction; demoralization; irritable mood; type A behavior; alexithymia; stressful life events; depression; general anxiety; anger; hostility; maladaptive health behaviors (e.g., non-adherence to a prescribed regimen); and hypochondriasis.

[0156] In embodiments, the psychological factor is any of anhedonia; emotional numbing; and affective flattening. In embodiments, the psychological factor is anhedonia. In embodiments, the psychological factor is emotional numbing. In embodiments, the psychological factor is affective flattening.

[0157] In embodiments, the psychological factor influences treatment adherence. In embodiments, the psychological factor influences treatment compliance.

[0158] In embodiments, the psychological factor influences a cognitive process or cognition of the subject (e.g., contextual processing, perception, attention, memory, problem-solving, decision-making, selective attention, divided attention, pragmatics, sustained attention, heuristics, biases, decisional conflict, goal-setting, or self-regulation) (see, e.g., Elman et al., Addiction Neuroscience, 2023;7:100100).

[0159] In embodiments, the psychological factor influences an emotion of the subject (e.g., happiness, sadness, anger, fear, or disgust). In embodiments, the psychological factor influences a personality trait of the subject (e.g., risk-seeking, risk-averse, novelty-seeking, conscientious, honest, dishonest, extraverted, agreeable, or neurotic). In embodiments, the psychological factor influences sensations and perceptions of the subject (e.g., sensory processing, illusions, or hallucinations).

[0160] In embodiments, the psychological factor influences the motivation of the subject (e.g., intrinsic motivation, extrinsic motivation, achievement motivation, affiliation motivation, urges, or craving). In embodiments, the psychological factor influences individual beliefs and attitudes of the subject (e.g., cognitivedissonance, attitude formation, change in attitude, stereotyping, prejudice, implicit bias, or discrimination).

[0161] In embodiments, the psychological factor influences perceptions of control of the subject (e.g., locus of control, learned helplessness, social influence, peer pressure, conformity, obedience, social norms, social facilitation, stress coping, or resilience). In embodiments, the psychological factor influences a developmental factor of the subject (e.g., attachment style, self-concept, or identity). In embodiments, the developmental factor relates to Erikson’s stages of psychosocial development. In embodiments, the developmental factor relates to Piaget’s stages of cognitive development.

[0162] In embodiments, the psychological factor influences the self-esteem of the subject (e.g., self-efficacy or identity formation). In embodiments, the psychological factor influences language and communication of the subject (e.g., verbal or nonverbal). In embodiments, the psychological factor influences interpersonal relationships of the subject (e.g., familial relationships, relationships with friends, relationships with romantic partners, relationships with work colleagues, or platonic relationships).

[0163] In embodiments, the psychological factor influences the mental health of the subject (e.g., anxiety, depression, compulsions, obsessions, paranoia, narcissistic traits, histrionic traits, antisocial traits, shyness, schizoid traits, or immaturity). In embodiments, the psychological factor influences a health behavior of the subject (e.g., sick role, health beliefs, health-promoting behaviors, or health risk behaviors).

[0164] In embodiments, the psychological factor influences the body image of the subject (e.g., anorexia, bulimia, or dysmorphic perceptions). In embodiments, the psychological factor influences addictive behavior of the subject (e.g., substance abuse, gambling, excessive shopping, or excessive use of pornography). In embodiments, the psychological factor influences cross-cultural factors (e.g., cross-cultural influences on behavior and attitude, influence of (social) media, media literacy, cultural intelligence, adaptability to different cultures, cultural empathy, or cross-cultural communication). In embodiments, the psychological factor influences the learning and conditioning of the subject (e.g., classical conditioning, operant conditioning, fear conditioning, or observational learning).

[0165] In embodiments, the psychological factor influences a therapeutic factor (e.g., therapeutic alliance, transference, countertransference, or therapeutic techniques). In embodiments, the psychological factor influences the subject’s ethical decision-making skills (e.g., informed consent, confidentiality). In embodiments, the psychological factor influences the subject’s ability to experience pleasure (e.g., reward deficiency) (see, e.g., Bowirrat et al., Psychol Res Behav Manag, 2023;16:4839-4857; Borsook et al., Neurosci Biobehav Rev, 2016;68:282-297; Elman & Borsook, Neuron, 2016;89(1):11 -36; Elman et al., Prog Neurobiol, 2013;109:1-27).

[0166] In embodiments, the psychological factor disrupts compliance. A psychological factor that disrupts compliance includes stigma, shame, or humiliation regarding the medical condition; helplessness or depression regarding the medical condition; mistrusting clinicians; or anger with clinicians or the medical condition (see, e.g., Claxton et al. Clin Ther. 2001 ;23(8): 1296-1310).

[0167] Psychological factors, both in general and as specific conditions, will be understood by those of skill in the art in view of the teachings herein and general knowledge in the field (see, e.g., Porcelli et al.,Psychological Factors Affecting Medical Conditions: A New Classification for DSM-V, Karger, 2007).

[0168] PFAOMC is diagnosed when the following three criteria are met: (A) a medical symptom or condition (other than a mental disorder) is present; (B) psychological or behavioral factors adversely affect the medical condition in at least one of the following ways: (1) the factors have influenced the course of the medical condition, as demonstrated by a close temporal association between the psychological factors and the development, exacerbation, or delayed recovery from the medical condition; (2) the factors interfere with treatment of the medical condition (e.g., poor adherence); (3) the factors constitute additional well-established health risks for the subject; or (4) the factors influence the underlying pathophysiology, precipitating or exacerbating symptoms or necessitating medical attention; and (C) the psychological and behavioral factors in criterion (B) are not better explained by another mental disorder (e.g., panic disorder, major depressive disorder, post-traumatic stress disorder) (see, e.g., Am Psych Assoc., DSM-5-TR, 2022).

[0169] In embodiments, a subject experiences PFAOMC in the context of insulin resistance and related disorders (IRARD), wherein PFAOMC adversely affects IRARD. For example, a subject diagnosed with hyperglycemia experiences distress and, consequently, impaired quality of life due to the diagnosis. The subject’s impaired quality of life interferes with the course of treatment for hyperglycemia, as the subject continues to consume high-caloric foods to alleviate distress, contrary to instructions from their healthcare professional. The subject’s impaired quality of life is not better explained by another mental disorder, indicating the presence of PFAOMC.

[0170] In embodiments, a subject has more than one psychological factor that affects a medical condition. For example, in embodiments, a subject has two psychological factors. In embodiments, a subject has three psychological factors. In embodiments, a subject has four psychological factors. In embodiments, a subject has five psychological factors. In embodiments, a subject has more than five psychological factors. In embodiments, multiple psychological factors affect the other medical condition. In embodiments, two psychological factors, three psychological factors, four psychological factors, five psychological factors, or more than five psychological factors affect the other medical condition.

[0171] As used herein, “treating a psychological factor” or “treating PFAOMC” refers to treating a single psychological factor, unless context indicates otherwise, including where a subject has multiple psychological factors. Nonetheless, among the advantages of the disclosure is that in some embodiments, the disclosed methods are useful for treating more than one psychological factor. In embodiments, the methods treat more than one psychological factor of a subject. In embodiments, the methods treat two psychological factors. In embodiments, the methods treat three psychological factors. In embodiments, the methods treat four psychological factors. In embodiments, the methods treat five psychological factors. In embodiments, the disclosed treat more than five psychological factors.

[0172] In embodiments, the psychological factor, or multiple psychological factors, affect more than one medical condition. In embodiments, the psychological factor affects two medical conditions. In embodiments, the psychological factor affects three medical conditions. In embodiments, the psychological factor affectsmore than three medical conditions.

[0173] In embodiments, treating a psychological factor prevents the psychological factor from increasing in severity or worsening, such as to the point of meeting diagnostic criteria for a mental health disorder.

[0174] In embodiments, treating a psychological factor prevents a medical condition from increasing in severity or worsening.

[0175] In embodiments, a subject with PFAOMC has a co-occurring mental health disorder. As used herein, “co-occurring mental health disorder” refers to a mental health disorder present in a subject in addition to both PFAOMC and the other medical condition. In embodiments, the co-occurring mental health disorder is from any of depressive disorders; mood disorders; anxiety disorders; anxiety-related disorders; schizophrenia; other psychotic disorders; stressor-related disorders; obsessive-compulsive disorder (OCD); feeding and eating disorders; breathing-related sleep disorders; parasomnias; sexual dysfunctions; gender dysphoria; neurocognitive disorders; disruptive behavior or dissocial disorders; conduct disorders; intellectual disabilities; addiction and substance use disorders (SUDs); autism spectrum disorder; trauma- and stressor-related disorders; dissociative disorders; somatic symptom and related disorders; impulse control disorders; compulsive buying disorder (alternatively, “compulsive shopping” or “compulsive spending”); repetitive self-mutilation syndrome; nonparaphilic sexual addiction; paraphilic disorders; personality disorders; and attention deficit hyperactivity disorder (ADHD).

[0176] In embodiments, treating a psychological factor prevents a co-occurring mental health disorder from increasing in severity or worsening. In embodiments, a subject has symptoms of a mental health disorder (e.g., symptoms of depression). In some embodiments however, these symptoms do not meet the diagnostic criteria for a mental health disorder and instead constitute psychological factors of PFAOMC. For example, where a diagnosis of depression requires five depressive symptoms occurring every day, nearly all day, for at least two weeks, a subject who exhibits fewer symptoms, or symptoms of lesser frequency or persistence, does not meet the diagnostic threshold for a depressive disorder.

[0177] Where a subject has symptoms of a mental health disorder sufficient to meet diagnostic criteria, or has received a diagnosis of a mental health disorder, the disorder is a co-occurring mental health disorder, and the symptoms are those of the co-occurring disorder, rather than psychological factors of PFAOMC. In some embodiments however, a subject has psychological factors that do not rise to the level of a clinical diagnosis for a mental health disorder, while also having a separately diagnosed co-occurring mental health disorder based on other symptoms (i.e., the psychological factors and the symptoms of the co-occurring mental health disorder are distinct). For example, when diagnosing PFAOMC using DSM-5 criteria, psychological factors should not meet diagnostic criteria for a specific mental disorder. Criterion C of the DSM-5 framework states that the psychological and behavioral factors (as described in Criterion B) must not be better explained by another mental disorder (e.g., panic disorder, major depressive disorder, PTSD). However, when psychological symptoms do not meet the diagnostic threshold for a mental disorder, a subject may remain inadequately treated. For example, pharmacotherapy is generally not indicated for depressive symptoms or mood states(e.g., emptiness, anhedonia, hopelessness, emotional numbing, affective flattening, avolition, or irritability), or for minor (subsyndromal) depression, in the absence of a formal diagnosis such as major depressive disorder (MDD), PTSD, or a psychotic disorder.

[0178] In embodiments, the co-occurring mental health disorder is any of a depressive disorder; a mood disorder; an anxiety disorder; a trauma- or stressor-related disorder; OCD; a neurocognitive disorder; a feeding or eating disorder (e.g., binge eating disorder); intermittent explosive disorder; an addiction disorder; an impulse control disorder; compulsive buying disorder (alternatively, compulsive buying behavior); repetitive self-mutilation syndrome; a nonparaphilic sexual addiction or paraphilia; a personality disorder; and ADHD.

[0179] In embodiments, the co-occurring mental health disorder is a depressive disorder. In embodiments, the co-occurring mental health disorder is a mood disorder. In embodiments, the co-occurring mental health disorder is an anxiety disorder. In embodiments, the co-occurring mental health disorder is a trauma- or stressor-related disorder. In embodiments, the co-occurring mental health disorder is PTSD. In embodiments, the co-occurring mental health disorder is obsessive-compulsive disorder (OCD). In embodiments, the co-occurring mental health disorder is a neurocognitive disorder. In embodiments, the co-occurring mental health disorder is feeding or eating disorder, e.g., binge eating disorder. In embodiments, the co-occurring mental health disorder is intermittent explosive disorder. In embodiments, the co-occurring mental health disorder is an addiction disorder. In embodiments, the co-occurring mental health disorder is a substance use disorder (SUD). In embodiments, the co-occurring mental health disorder is alcohol use disorder (AUD). In embodiments, the co-occurring mental health disorder is opioid use disorder (OLID). In embodiments, the co-occurring mental health disorder is an impulse control disorder. In embodiments, the co-occurring mental health disorder is a behavioral addiction. In embodiments, the co-occurring mental health disorder is compulsive buying disorder. In embodiments, the co-occurring mental health disorder is repetitive self-mutilation syndrome. In embodiments, the co-occurring mental health disorder is a nonparaphilic sexual addiction or paraphilia. In embodiments, the co-occurring mental health disorder is a personality disorder. In embodiments, the co-occurring mental health disorder is ADHD.

[0180] In some embodiments, the co-occurring mental health disorder is a mental health disorder due to the other medical condition. In some other embodiments, the co-occurring mental health disorder is not due to the other medical condition.

[0181] In embodiments, PFAOMC adversely affects a subject’s treatment adherence. In embodiments, PFAOMC adversely affects a subject’s treatment compliance. In embodiments, provided are methods of treating PFAOMC. In embodiments, adherence involves treatment of PFAOMC in a subject in need thereof.

[0182] In embodiments, provided are methods of treating PFAOMC in a subject after discontinuing use of incretin-based therapies for obesity or hyperglycemia. In embodiments, provided are methods of treating PFAOMC in a subject after discontinuing use of incretin-based therapies for obesity. In embodiments, provided are methods of treating PFAOMC in a subject after discontinuing use of incretin-based therapies for hyperglycemia. In embodiments, a disclosed method is useful for treating PFAOMC in a subject afterdiscontinuing use of incretin-based therapies for obesity or hyperglycemia by improving a subject’s adherence to lifestyle modification recommendations given by a healthcare professional.

[0183] In embodiments, PFAOMC contributes to a subject’s non-adherence to a lifestyle modification recommendation given by a healthcare professional following treatment for obesity or hyperglycemia, resulting in weight (re)gain. Symptoms of PFAOMC which remain unaddressed can exacerbate known risks for medical conditions, influence how subjects respond to their symptoms, and reduce treatment adherence.

[0184] Thus, there remains a need for methods of treatment for subjects with PFAOMC, especially for subjects with PFAOMC who have discontinued a primary treatment for obesity or hyperglycemia. This need is among those solved by the present disclosure.C. Metabolic Disturbance in Subjects with Psychotic Disorders

[0185] Subjects with psychotic disorders, particularly schizophrenia, frequently experience metabolic disturbances. The relationship between psychotic disorders and metabolic dysfunction is complex and bidirectional, involving shared neurobiological mechanisms that have been termed "diabetophrenia," reflecting overlapping pathophysiology between metabolic and neuropsychiatric symptoms.

[0186] The inflammation-oxidative stress-insulin resistance axis plays a critical role in both metabolic and neuropsychiatric disorders. Chronic low-grade inflammation, driven by pro-inflammatory cytokines released from adipose tissue, contributes to neuroinflammation, impairing brain function and exacerbating psychiatric symptoms. This inflammatory state, compounded by oxidative stress and insulin resistance, forms a self-sustaining cycle that increases allostatic load, worsening both physical and psychiatric health.

[0187] In embodiments, the psychotic disorder is any of schizophrenia; schizoaffective disorder; delusional disorder; a shared psychotic disorder; a specified schizophrenia spectrum disorder; and an unspecified schizophrenia spectrum disorder. In some embodiments, the psychotic disorder is due to another medical condition. Schizophrenia is characterized by dysregulated dopaminergic signaling, which not only contributes to psychiatric symptoms but also impacts metabolic function. The dopamine hypothesis of schizophrenia postulates that hyperactivity within mesolimbic dopaminergic pathways underlies key symptoms such as delusions and hallucinations. This dysregulation may also affect food-related behaviors, contributing to metabolic disturbances. Without being bound by theory, opioidergic dysregulation is another hallmark of schizophrenia, with elevated endogenous opiate concentrations often paralleling the severity of psychosis. This dysregulation may interfere with neurotrophins such as brain-derived neurotrophic factor (BDNF), leading to vascular dysfunction and neuronal damage. Additionally, excessive opioidergic activity can desensitize insulin receptors and increase cravings for sweet and fatty foods, further exacerbating metabolic dysfunction.

[0188] Antipsychotic medications used to treat psychotic disorders frequently induce metabolic side effects, including weight gain, insulin resistance, and lipid abnormalities. Atypical antipsychotics are associated with particularly pronounced metabolic disturbances. The degree of weight gain varies by medication, with a dose-response relationship observed in meta-analyses. Some antipsychotics (e.g., brexpiprazole, cariprazine, haloperidol, lurasidone, quetiapine extended-release) exhibit an initial increase in weight followed bystabilization. Others (e.g., asenapine, iloperidone, paliperidone LAI, quetiapine immediate-release, oral risperidone) show weight gain that plateaus after an initial rise. Still others (e.g., oral and LAI aripiprazole, oral and LAI olanzapine, oral paliperidone, risperidone LAI) demonstrate continuous weight gain at higher doses.

[0189] Among the advantages of the invention are that the disclosed methods synergistically address the interplay between psychotic disorders, their treatments, and metabolic dysfunction, providing a novel, multidisciplinary approach that includes monitoring metabolic parameters, selecting antipsychotic medications with favorable metabolic profiles, and implementing lifestyle interventions to mitigate metabolic risks.D. Lifestyle Modification Recommendations

[0190] In embodiments, a disclosed method improves adherence to a lifestyle modification recommendation, which is provided to subjects who have completed a primary treatment (e.g., an incretin-based therapy) for a health condition (e.g., obesity, hyperglycemia). Following completion of primary therapy, long-term management of the condition often requires self-directed behavioral changes, referred to as lifestyle modifications. Healthcare professionals recommend lifestyle modifications to promote sustained health management and regular monitoring of a subject's condition.

[0191] Disclosed methods improve adherence to lifestyle modifications aimed at sustaining health outcomes after primary treatment, supporting long-term well-being through dietary changes, increased physical activity, improved medication adherence, and other behavioral adjustments.

[0192] In embodiments, adherence to a lifestyle modification recommendation comprises modifying any of food, drug, and alcohol consumption; physical exercise; medication regimen; and other lifestyle habits.

[0193] Dietary and Consumption Modifications: In embodiments, the lifestyle modification recommendation comprises modifying any of food, drug, and alcohol consumption. Desired outcomes may include adherence to any of: following a specific daily caloric intake; eating a defined number of meals per day; maintaining regularly scheduled meals; eating without distractions; cooking a certain number of meals at home per week; leaving the table after meals; grocery shopping only from a list or only when full; measuring portion sizes; reducing or eliminating alcohol, tobacco, nicotine, or processed foods; drinking filtered water; consuming living foods; taking food supplements, probiotics, prebiotics, or enzymes; or adopting a specific diet (e.g., fruitarian, sproutarian, ovo-vegetarian, lacto-vegetarian). In embodiments, the lifestyle modification recommendation comprises adherence to a personalized nutrition plan. In some embodiments, adherence is to a Mediterranean diet, comprising fruits, vegetables, whole grains, legumes, nuts, and olive oil, with moderate fish and poultry and limited red meat. In some embodiments, the recommendation comprises consuming fermented foods, such as yogurt, kefir, sauerkraut, kimchi, and kombucha. In embodiments, the lifestyle modification recommendation is adherence to time-restricted eating patterns. In embodiments, the desired outcome is adherence to limiting food intake to specific hours of the day to support metabolic health.

[0194] Physical Exercise Modifications: In embodiments, the lifestyle modification recommendation comprises increasing physical activity to support weight maintenance and metabolic health (see, e.g., Farhana & Rehman, Metabolic Consequences of Weight Reduction, StatPearls, 2023). Desired outcomes may includeadherence to any of: increasing daily step count; committing to a structured exercise schedule (daily, weekly, or monthly); attending an exercise class, walking group, physical training, or physical therapy; or choosing stairs over elevators when possible. In embodiments, the lifestyle modification recommendation comprises improving adherence to any of: aerobic exercise (e.g., moderate-intensity continuous training, high-intensity interval training, low-impact); resistance (strength) training (e.g., progressive resistance training, compound movements, eccentric training); flexibility and mobility training (e.g., dynamic stretching routines, yoga, pilates, foam rolling); functional and lifestyle movement strategies (e.g., non-exercise activity thermogenesis, balance and coordination exercises, daily movement goals); and recovery and regeneration (e.g., active recovery days, sleep optimization strategies, cold exposure or contrast therapy). In embodiments, the physical activity regimen(s) provides a balanced approach to physical activity and improves insulin sensitivity, enhances metabolic flexibility, reduces inflammation, and supports weight management.

[0195] Medication Adherence Modifications: In embodiments, the lifestyle modification recommendation comprises improving adherence to a prescribed medication regimen. Desired outcomes may include adherence to any of: following the prescribed dosage, frequency, and duration of a medication; taking medication at the directed time; refilling prescriptions as needed; purchasing prescribed medications; or attending necessary follow-up visits with the prescribing healthcare provider.

[0196] Microbiome-targeted Therapy Modifications: In embodiments, the lifestyle modification recommendation comprises improving adherence to a microbiome-targeted therapy. By reducing systemic inflammation and enhancing nutrient absorption, a balanced gut microbiota can modulate stress response and neurotransmitter signaling, which are linked to motivation, emotional regulation, and executive functioning (e.g., planning and decision-making). For example, certain short-chain fatty acids (SCFAs) have been implicated in dampening inflammatory pathways that contribute to dopamine dysregulation and cognitive deficits, ultimately supporting more consistent and proactive engagement in healthy behaviors (e.g., dietary modifications, medication adherence, or regular physical activity). Improvements in the gut microbiome may lessen treatment-related gastrointestinal side effects, reduce appetite dysregulation, and mitigate weight fluctuations, which are often factors that act as barriers to following a long-term care plan in metabolic- psychiatric populations. Individuals who experience better gut health may be more inclined to sustain changes in diet, exercise, and pharmacotherapy regimens, thereby amplifying overall treatment success and long-term adherence.

[0197] Desired outcomes include adherence to any of probiotic supplementation (e.g., consuming Lactobacillus species, Bifidobacterium species, Akkermansia muciniphila, Faecalibacterium prausnitzii), prebiotic supplementation (e.g., consuming inulin and fructooligosaccharides, galactooligosaccharides, resistant starch), fecal microbiota transplantation (FMT), postbiotic and short-chain fatty acid modulation, and dietary modifications to support a healthy microbiome (e.g., increased fiber intake, increased polyphenol-rich foods, increased fermented foods). In embodiments, microbiome-targeted therapy modulates gut microbiota composition, enhances gut barrier integrity, reduces systemic inflammation, or improves metabolic function.

[0198] In some aspects, the modulation of gut microbiota composition may involve increasing the abundanceof beneficial bacteria such as Bifidobacterium and Lactobacillus species, while reducing the prevalence of potentially harmful bacteria. In some embodiments, the microbiome-targeted therapy may include strategies to increase the production of short-chain fatty acids (SCFAs) such as butyrate, propionate, and acetate. SCFAs may play a role in maintaining gut barrier integrity, reducing inflammation, and improving insulin sensitivity. In some cases, SCFA production may be enhanced through the consumption of fermentable fibers or direct supplementation with SCFA precursors. In some embodiments, the microbiome-targeted therapy may aim to reduce levels of lipopolysaccharides (LPS) in the gut and circulation. Elevated LPS levels may contribute to systemic inflammation and metabolic dysfunction. Strategies to reduce LPS may include improving gut barrier function and modulating the composition of gut bacteria that produce LPS. In some aspects, the microbiome-targeted therapy may include personalized interventions based on an individual's gut microbiome profile. This may involve analyzing the relative abundance of specific bacterial species or functional groups of bacteria, and tailoring interventions to address identified imbalances or deficiencies.

[0199] Other Health-Enhancing Habit Modifications: In embodiments, the lifestyle modification recommendation comprises modifying other behaviors to promote general health and well-being. Desired outcomes may include adherence to any of: meditation; prayer; maintaining a positive attitude; mindful breathing; sun exposure; cold plunge therapy; sauna or hot bath followed by a cold shower; massage; skin brushing; maintaining a regular sleep pattern; using an infrared sauna; consuming green drinks; undergoing a liquid fast; receiving enemas; detoxification; or eliminating addictive behaviors (e.g., excessive consumption of food, alcohol, drugs, compulsive behaviors, or toxic social influences). In embodiments, the desired outcome is increased attention to self-care. In embodiments, the desired outcome is reduced engagement in self-harm.

[0200] In embodiments, the lifestyle modification recommendation is adherence to a structured sleep hygiene routine. In embodiments, the desired outcome is adherence to maintaining consistent sleep and wake times; creating a sleep-conducive environment; and avoiding sleep-disrupting behaviors. In embodiments, the lifestyle modification recommendation is adherence to stress management techniques. In embodiments, the desired outcome is adherence to regularly practicing stress-reduction methods, such as progressive muscle relaxation, guided imagery, or biofeedback. In embodiments, the lifestyle modification recommendation is adherence to cognitive-behavioral strategies. In embodiments, the desired outcome is adherence to implementing cognitive restructuring techniques and behavioral activation to support healthy lifestyle choices.

[0201] In embodiments, the lifestyle modification recommendation is adherence to social support engagement. In embodiments, the desired outcome is adherence to regularly participating in support groups and maintaining connections with a support network to reinforce healthy behaviors. In embodiments, the lifestyle modification recommendation is adherence to self-monitoring practices. In embodiments, the desired outcome is adherence to regularly tracking health metrics, food intake, physical activity, and mood using digital tools or journals. In embodiments, the lifestyle modification recommendation is adherence to mindfulness-based practices. In embodiments, the desired outcome is adherence to regularly engaging in mindfulness meditation and mindful eating practices.1. Multidisciplinary Management

[0202] In embodiments, a disclosed method comprises implementing a multidisciplinary management plan, which integrates lifestyle modifications, pharmacological interventions, and continuous monitoring to optimize treatment outcomes post-incretin therapy discontinuation. A “multidisciplinary management plan” refers to a coordinated set of recommendations provided by healthcare professionals with distinct expertise.

[0203] In embodiments, a multidisciplinary management plan is developed by a healthcare team comprising a psychiatrist, dietitian, diabetologist, exercise specialist, and / or other relevant professionals. In embodiments, the plan addresses both metabolic and psychiatric health, combining lifestyle modifications with pharmacological interventions. In some embodiments, the plan includes psychotherapeutic approaches, such as motivational interviewing or cognitive-behavioral therapy.

[0204] In embodiments, a multidisciplinary management plan comprises continuous monitoring of metabolic and psychiatric health parameters. Continuous monitoring may include regular check-ins with healthcare professionals and / or the use of a digital holistic health service platform. In embodiments, the platform enables real-time tracking of any of body weight, body composition, blood glucose levels, treatment adherence, treatment compliance, physical activity levels, dietary intake, sleep patterns, mood / emotional state, stress levels, treatment side effects, and adverse events. In embodiments, digital health service platforms (including e.g., mobile apps for self-monitoring, virtual coaching, and reminder systems) help track progress, give real-time feedback, and foster supportive peer or professional networks in multidisciplinary management. In embodiments, the platform facilitates communication between the subject and the healthcare team, enabling timely interventions and treatment adjustments. Continuous engagement and accountability can translate to greater compliance because individuals can see measurable outcomes in real time.

[0205] In embodiments, multidisciplinary management may include psychosocial support (such as motivational interviewing, cognitive-behavioral therapy, or group counseling) to address behavioral barriers related to reward deficiency, low mood, or cognitive impairment. In embodiments, by reinforcing the intrinsic rewards of healthy behaviors, improving emotional regulation, and enhancing planning and decision-making skills, these approaches further increase adherence to lifestyle modification recommendations, especially important in populations where metabolic or psychiatric comorbidities often result in sustained challenges.

[0206] In embodiments, the multidisciplinary management plan includes an educational component to empower the subject in self-management. Educational initiatives may include workshops or seminars on the relationship between metabolic health and mental well-being; strategies for maintaining healthy lifestyle habits; recognizing and managing relapse triggers; and / or effective use of self-monitoring tools and technologies.

[0207] Additionally, in embodiments, personalization of lifestyle interventions through multidisciplinary management (e.g., adjustable dietary plans, tailored exercise schedules, customized microbiome-targeted therapies) enhances patient empowerment. In some embodiments, individuals are more likely to adhere to recommendations that feel relevant to their specific experiences and preferences.E. Primary Medical Treatment1. Chronic Obesity Treatment

[0208] In embodiments, disclosed methods are useful for improving adherence to lifestyle modification recommendations and compliance in a subject following primary treatment for obesity. In embodiments, disclosed methods treat PFAOMC in a subject following obesity treatment where poor adherence is a contributing factor. In embodiments, a subject undergoing primary treatment for obesity receives GLP-1 or GLP-1 / GIP therapies, which are among the leading pharmacological treatments for obesity.

[0209] In embodiments, disclosed methods address the challenge of post-treatment weight regain by improving adherence to recommended lifestyle modifications. Obesity is a chronic and complex disease, often associated with hypertension, type 2 diabetes, dyslipidemia, and cardiovascular disease, and imposes a significant socioeconomic burden (see, e.g., Wilding et al., 2022). Given its high relapse rate, obesity management requires long-term intervention strategies.

[0210] In embodiments, disclosed methods improve weight maintenance and cardiometabolic health in subjects after discontinuing GLP-1 or GLP-1 / GIP therapies. These therapies, which are used in approximately 30% of adults with obesity in the U.S., can induce substantial initial weight loss. However, discontinuation often leads to rapid weight regain, with most subjects regaining lost weight within one year. Cardiometabolic benefits similarly trend toward baseline post-treatment. This weight regain is driven by compensatory biological mechanisms that resist sustained weight loss, posing a significant challenge in obesity management (see, e.g., Wilding et al., 2022). In embodiments, disclosed methods mitigate post-treatment weight regain and support sustained metabolic improvements through improved adherence strategies. Disclosed methods address behavioral and psychological factors and provide a novel approach to maintaining the benefits of obesity treatment and preventing relapse.2. Chronic Hyperglycemia Treatment

[0211] In some aspects, disclosed methods improve adherence to lifestyle modifications in a subject following primary treatment for hyperglycemia. In some aspects, disclosed methods improve compliance in a subject following primary treatment. In some aspects, the methods are useful in treating psychological factors affecting other medical conditions (PFAOMC) in a subject following primary treatment, particularly where poor adherence is a contributing factor. In some aspects, the primary treatment is hyperglycemia treatment. Whether a subject has hyperglycemia can be determined according to ordinary skill in the art.

[0212] In embodiments, PFAOMC contributes to non-adherence to lifestyle modifications following discontinuation of primary hyperglycemia treatment. Hyperglycemia, characterized by elevated blood glucose levels, is a significant risk factor for various complications, including damage to the eyes, kidneys, nervous system, heart, and peripheral vascular system. A diagnosis of hyperglycemia (e.g., high blood sugar) may be made when a subject’s blood glucose exceeds 100 mg / dL in a fasted state or 180 mg / dL in a fed state. Prediabetes, a precursor to diabetes, may be diagnosed when fasting blood glucose falls between 100 mg / dL and 125 mg / dL. Left untreated, hyperglycemia can progress to severe metabolic dysfunction (Mouri &Badireddy, Hyperglycemia. Statpearls. 2023;NBK430900).

[0213] In embodiments, disclosed methods address the interplay between obesity and hyperglycemia, as excess body fat is a primary driver of insulin resistance and metabolic dysfunction. Obesity is a key risk factor for prediabetes and type 2 diabetes, with increased body mass index (BMI) directly correlating with higher diabetes risk (Klein et al. Cell Metabolism. 2022; 34(1): 11 -20). Approximately 85% of individuals with type 2 diabetes are overweight or obese (Pi-Sunyer. Postgrad Med. 2009; 121 (5):94-107). The global burden of obesity-induced diabetes is expected to double from 171 million cases in 2000 to 366 million by 2030, underscoring the urgent need for effective interventions (Martyn et al. Anesthesiology. 2008; 109(1): 137-148).

[0214] In embodiments, disclosed methods facilitate weight reduction and long-term weight maintenance in hyperglycemic subjects, directly improving cardiovascular risk factors, glycemic control, blood pressure, and lipid profiles (Pi-Sunyer. Postgrad Med. 2009; 121 (5):94-107; Feldstein et al. Diabetes Care. 2008;31 (10):1960-65). However, weight regain following hyperglycemia treatment is common. For example, in a study of type 2 diabetics, subjects who initially lost an average of 10.7 kg experienced near-complete weight regain within 36 months (Feldstein et al. Diabetes Care. 2008;31 (10): 1960-65). Among the advantages of the disclosed methods is their ability to address weight regain and support sustained metabolic improvements.

[0215] In embodiments, disclosed methods include treatment with GLP-1 and / or GLP-1 / GIP receptor agonists, prescribed for both on-label indications (such as approved treatments for obesity and glycemic control) and off-label applications, as determined by physicians exercising their clinical judgment.

[0216] Terms such as “obesity,” “chronic obesity,” “hyperglycemia,” and “chronic hyperglycemia” are used herein according to their broadest general art-accepted meanings, and encompass all relevant indications for which the disclosed therapies may be prescribed, whether on- or off-label. For example, treatment for “obesity” or “chronic obesity” includes treatment for adults with BMI >30 or overweight adults (BMI >27) with weight-related medical conditions. Similarly, treatment for “hyperglycemia” and “chronic hyperglycemia” includes therapeutic interventions to improve glycemic control in adults with type 2 diabetes mellitus.F. Modulating Neurotransmission1. Neurocircuitry of Treatment Adherence

[0217] Behaviors and mood, including those related to food consumption, are regulated by the brain's homeostatic and reward systems (Kleinridders et al. Curr Nutr Rep. 2019;8:83-91). The homeostatic system, governed by metabolic hormones such as insulin and leptin, monitors the body's energy state and regulates food intake through hypothalamic neurons. Id. The reward system responds to physiological stimuli such as hunger, taste, and palatable food cues, influencing food enjoyment and cravings. Id.

[0218] These systems are further modulated by the inflammation-oxidative stress-insulin resistance loop, a self-sustaining cycle in which chronic low-grade inflammation promotes oxidative stress, leading to insulin resistance, which in turn exacerbates both metabolic and psychiatric symptoms. This loop increases allostatic load, contributing to declining physical and mental health and potentially impairing treatment adherence.

[0219] Evidence suggests significant neurochemical and functional overlap between physical and emotionalpain within the reward system (see, e.g., Elman et al. Prog Neurobiol. 2013;109:1-27). For example, loneliness is associated with systemic changes, including altered immunometabolism, which may contribute to cardiovascular, glucoregulatory, and oncological morbidity (see, e.g., Bowirrat et al. Psychol Res Behav Manag. 2023;16:4839-4857). Additionally, improved treatment adherence, including for PFAOMC, correlates with improved BMI in opioid-dependent subjects (Li et al. Front Psychiatry. 2023; 14: 1247961 ).

[0220] In embodiments, modulating monoaminergic neurotransmission improves treatment adherence. In embodiments, modulating monoaminergic neurotransmission is useful for treating subjects with PFAOMC. Modulating monoaminergic neurotransmission may also indirectly disrupt the inflammation-oxidative stressinsulin resistance loop, potentially by exerting anti-inflammatory effects or improving metabolic regulation.

[0221] Subjects with psychotic disorders, particularly schizophrenia, are at increased risk of poor treatment adherence due to neurocircuitry disruptions affecting the prefrontal cortex, limbic system, and striatum. Schizophrenia is characterized by dopaminergic dysregulation, impaired executive function, and deficits in reward processing, all of which contribute to anosognosia (poor insight), avolition (reduced motivation), and impaired decision-making, key factors in nonadherence.

[0222] The prefrontal cortex, which governs impulse control, planning, and self-awareness, exhibits functional deficits in schizophrenia, impairing a patient's ability to recognize the necessity of ongoing treatment. Hyperactivity in the salience network, particularly within the striatum and amygdala, may reinforce delusional beliefs about medication, fostering mistrust toward healthcare providers and resistance to pharmacotherapy. Negative symptoms, such as amotivation and cognitive inflexibility, may further exacerbate adherence difficulties, making it challenging for patients to follow complex medication regimens or maintain regular clinical appointments. In some embodiments, modulating monoaminergic neurotransmission improves treatment adherence in subjects with psychotic disorders by targeting these neurobiological vulnerabilities. Additionally, social and environmental factors, such as stigma, medication side effects, and lack of supportive care, may compound these neurobiological challenges, further underscoring the need for interventions, such as those of the disclosure, that enhance adherence through both neurochemical and behavioral mechanisms.

[0223] FIG. 1 illustrates exemplary interactions between physiological measures (e.g., glucose control) and psychological measures (e.g., hedonic well-being) as they relate to brain regions involved in PFAOMC, according to some embodiments. In a healthy subject, homeostasis is maintained when physical and emotional states remain stable. These states are assessed using physiological and psychological measures, respectively. In contrast, in subjects with a medical condition, this balance is disrupted, leading to a feed-forward cycle such as allostasis— a process in which the body adapts to stressors at the expense of other critical functions. Increased allostatic load may negatively impact mental or emotional health, and if psychological factors exacerbate the medical condition, a diagnosis of PFAOMC may result. FIG. 1 further illustrates an exemplary mechanism by which the disclosed methods treat PFAOMC. In embodiments, the disclosed methods influence a subject’s physical and / or emotional states. In some embodiments, the methods predominantly affect the physical state; in others, they primarily target the emotional state. In furtherembodiments, the methods improve physical symptoms, emotional symptoms, or both. The disclosed methods may also improve one or more psychological factors, one or more other medical conditions, or both.

[0224] FIG. 2 provides a schematic overview of the interplay among a stressor, the subject, and the external environment, emphasizing PFAOMC. In embodiments, the stressor is the medical condition, which has both physical and psychological (PFAOMC-related) components. The stressor acts upon the subject, while external environmental factors modulate the subject’s response. The subject and their environment are influenced by both the psychological and physical aspects of the condition. Successful adaptation through recovery and habituation is necessary to restore health. Failure to adapt may increase allostatic load, leading to medical and / or psychiatric morbidity.

[0225] FIG. 3 illustrates independent, interactive, and common processes in the progression of a medical condition (e.g., diabetes). Initially, physiological factors and psychological factors act independently. Over time, they interact more closely, ultimately converging into common mechanisms that can intensify the medical condition and lead to a diagnosis of PFAOMC. In embodiments, the disclosed methods modulate neurocircuitry involved in treatment non-adherence or non-compliance. In some embodiments, the methods modulate neurocircuitry associated with PFAOMC. Modulating neurocircuitry may involve modulating neurotransmission (e.g., monoaminergic neurotransmission) in the subject.

[0226] In embodiments, the disclosed methods modulate homeostatic and reward system interactions to improve treatment adherence in subjects with metabolic and psychological conditions. Dysregulation of these systems is associated with obesity, where deficiencies in the brain’s reward system, stress, and overeating contribute to disease progression (see, e.g., Kleinridders, 2019). In some embodiments, the disclosed methods mitigate the impact of stress-induced reward deficiencies that contribute to compulsive eating behaviors and metabolic dysfunction.

[0227] In embodiments, the disclosed methods address the dysregulation of physiological and psychological factors that occur in disease progression. Before the onset of a medical condition, physiological factors act independently from psychological factors. However, after the onset of chronic obesity, chronic hyperglycemia, or other metabolic conditions, physiological and psychological factors increasingly interact until they act together in common, intensifying disease progression. The disclosed methods modulate this interaction to mitigate disease exacerbation and improve treatment outcomes.

[0228] In embodiments, physiological factors refer to processes primarily involving physical functions independent of psychological influences. For example, insulin release in response to elevated blood glucose levels is a fundamental physiological response. In healthy subjects, pancreatic insulin secretion facilitates glucose absorption without direct involvement from psychological factors, such as thoughts, emotions, or perceptions. In contrast, meal anticipation is an example of a psychological factor that influences food intake independently of direct physiological control. Psychological factors can indirectly affect metabolic health by altering insulin sensitivity through modulating variables such as demographics, stress, drug metabolism, and neuropsychopathology.

[0229] In embodiments, the disclosed methods address cross-sensitization, an interactive process in which exposure to one stimulus, such as stress, heightens the response to another stimulus, such as palatable food. In some embodiments, the disclosed methods mitigate the spiraling distress cycle that occurs when metabolic stressors (e.g., insulin resistance) heighten the motivational salience of food-related cues, while food consumption increases stress-related responses.

[0230] In embodiments, aberrant learning processes exacerbate cross-sensitization effects, reinforcing maladaptive food-reward behaviors. For example, learning new food rewards or expecting prior food stimuli can be influenced by diabetes-related stress through interactions between tonic (baseline) and phasic spikes in dopaminergic neurons. In embodiments, methods modulate dopaminergic neurotransmission to reduce stress- induced reinforcement of maladaptive eating behaviors and improve adherence to lifestyle modifications.

[0231] In embodiments, the disclosed methods modulate neurocircuitry to improve treatment adherence in a subject. Consumption of long-chain saturated fatty acids can impair central insulin signaling and inhibit monoaminergic neurotransmitter function, including dopaminergic activity in the brain. Dysregulation of homeostatic and reward systems can promote preferences for high-calorie diets, lead to hyperphagia, and establish a cycle of overeating that contributes to chronic obesity and type 2 diabetes. These systems also regulate emotional behavior, and their dysfunction is linked to mood disorders, motivational deficits, and poor treatment adherence. In embodiments, modulating monoaminergic neurotransmission improves adherence motivation by reinforcing positive treatment outcomes, thereby increasing a subject’s likelihood of maintaining lifestyle modifications after discontinuing incretin-based therapies. Methods enhance adherence to any of food, alcohol, or drug consumption behaviors; physical activity; medication regimens; and other lifestyle habits.

[0232] The prefrontal cortex, striatum, amygdala, and insula are implicated in adherence mechanisms, influencing decision-making, motivation, reward processing, and impulse control. The disclosed methods modulate monoaminergic neurotransmission in these brain regions to improve adherence. In some embodiments, neurotransmission modulation is targeted to, and / or occurs in, any one or more of the following regions: prefrontal cortex, associated with impulse control, planning, and self-regulation; striatum, involved in reward processing and motivation; amygdala, implicated in emotional regulation and associative learning; and insula, responsible for interoceptive awareness and decision-making. By modulating neurotransmitter activity in these regions, the disclosed methods mitigate treatment non-adherence related to behavioral abnormalities, mood disorders, and metabolic dysfunction, supporting long-term adherence to lifestyle modifications.

[0233] In embodiments, the disclosed methods modulate monoaminergic neurotransmission in brain regions involved in treatment adherence, including the prefrontal cortex, striatum, amygdala, and insula. By targeting these regions, the methods influence decision-making, impulse control, reward processing, emotional regulation, and interoceptive awareness, improving adherence to lifestyle modification recommendations.

[0234] Prefrontal Cortex. In embodiments, the disclosed methods modulate monoaminergic neurotransmission in the prefrontal cortex, a critical hub for cognitive control, goal-directed behavior, and flexible decision-making. The prefrontal cortex (PFC) regulates responses to external and internal stimuli,bridging sensory input with behavioral output. Deficits in PFC function impair impulse control, task coordination, and executive functioning, contributing to non-adherence to treatment recommendations. Pharmacological interventions targeting PFC neurotransmission according to disclosed embodiments will enhance cognitive control, and improve adherence to lifestyle modifications.

[0235] Striatum. In embodiments, the disclosed methods modulate monoaminergic neurotransmission in the striatum, a key structure in reinforcement learning and reward-driven behavior. The striatum integrates dopaminergic reward prediction error signals with glutamatergic inputs, shaping habit formation, motivation, and decision-making. Dysfunctional striatal processing can reinforce maladaptive behaviors that counteract lifestyle modification efforts. By modulating dopaminergic signaling in the striatum, disclosed methods enhance reward sensitivity to positive behavioral changes, reinforcing adherence to treatment recommendations.

[0236] Amygdala. In embodiments, the disclosed methods modulate monoaminergic neurotransmission in the amygdala, a region responsible for emotional regulation and associative learning. The amygdala processes emotionally salient stimuli, influencing stress responses, fear learning, and motivation. Dysregulation in this region can impair emotional control, leading to anxiety, avoidance behaviors, and reduced treatment adherence. Modulating amygdala neurotransmission improves emotional regulation, allowing subjects to better manage distress, cravings, and motivational barriers, thereby supporting adherence to lifestyle modifications.

[0237] Insula. In embodiments, the disclosed methods modulate monoaminergic neurotransmission in the insula, a cortical region involved in interoception, self-awareness, and behavioral adaptation. The insula integrates somatosensory, autonomic, and cognitive-affective information, guiding health-related decision-making and adherence behaviors. Dysfunction in the insula can lead to diminished interoceptive awareness, reducing a subject’s ability to recognize physiological cues related to hunger, satiety, or metabolic needs, which may contribute to treatment non-adherence. By modulating insula neurotransmission, disclosed methods enhance interoceptive sensitivity and self-regulation, improving adherence to lifestyle modifications. a. Monoaminergic Neurotransmission

[0238] In embodiments, the disclosed methods modulate monoaminergic neurotransmission to improve treatment adherence by influencing cognitive control, motivation, reward processing, emotional regulation, and attention. The methods target dopaminergic, serotonergic, and / or norepinephrinergic neurotransmission to enhance a subject’s ability to engage in lifestyle modifications and sustain long-term behavioral changes. In some embodiments, modulation of monoaminergic neurotransmission also indirectly affects glutamatergic neurotransmission, further supporting synaptic plasticity and adaptive learning.

[0239] Dopamine. In embodiments, the disclosed methods modulate dopaminergic neurotransmission to enhance reward-driven motivation, cognitive control, and decision-making, thereby promoting adherence to treatment recommendations. Dopamine plays a critical role in reinforcement learning, facilitating behavioral adaptations based on positive feedback and anticipated outcomes. Dysregulated dopaminergic signaling is associated with reduced reward sensitivity, impaired motivation, and maladaptive behaviors, which can hinder adherence to lifestyle modifications. By targeting dopaminergic pathways, the disclosed methods enhancegoal-directed behavior, support habit formation, and reinforce adherence to beneficial lifestyle changes. Modulation of dopaminergic neurotransmission includes, by way of example, modulating the activity of a dopamine receptor, such as any of D1 , D2, D3, D4, and D5 receptors; modulating the activity of dopamine transporters, such as the dopamine transporter (DAT, SLC6A3); modulating dopamine synthesis via tyrosine hydroxylase and aromatic L-amino acid decarboxylase (AADC, DOPA decarboxylase); modulating dopamine degradation via monoamine oxidase A (MAO-A), monoamine oxidase B (MAO-B), and catechol-O- methyltransferase (COMT); and modulating dopamine release or reuptake at the synapse.

[0240] Serotonin. In embodiments, the disclosed methods modulate serotonergic neurotransmission to improve emotional regulation, impulse control, and behavioral flexibility, thereby enhancing adherence to lifestyle modifications. Serotonin regulates mood, stress responses, and appetite, influencing behaviors related to food intake, motivation, and treatment engagement. Reduced serotonergic signaling is associated with emotional dysregulation, compulsive behaviors, and poor impulse control, all of which may contribute to non-adherence. By enhancing serotonin-mediated cognitive and affective processes, the disclosed methods support adherence to dietary, exercise, and medication regimens. Modulation of serotonergic neurotransmission includes, by way of example, modulating the activity of a serotonin receptor, such as any of a 5-HT1 receptor, e.g., 5-HT1A, 5-HT1 B, 5-HT1 D, and 5-HT1 E; a 5-HT2 receptor, e.g., 5-HT2A, 5-HT2B, and 5-HT2C; a 5-HT3 receptor, e.g., 5-HT3A; a 5-HT4 receptor; a 5-HT5 receptor, e.g., 5-HT5A; a 5-HT6 receptor; and a 5-HT7 receptor; modulating the activity of serotonin transporters, such as the serotonin transporter (SERT, SLC6A4); modulating serotonin synthesis via tryptophan hydroxylase (TPH1 , TPH2); modulating serotonin degradation via monoamine oxidase A (MAO-A) and aldehyde dehydrogenase; and modulating serotonin release or reuptake at the synapse.

[0241] Norepinephrine. In embodiments, the disclosed methods modulate norepinephrinergic neurotransmission to improve focus, arousal, and executive functioning, thereby enhancing a subject’s ability to follow structured treatment plans. Norepinephrine plays a key role in processing relevant vs. irrelevant information, regulating attention allocation, and facilitating cognitive control over reward-seeking behaviors. Dysfunction in the locus coeruleus-norepinephrine system is implicated in conditions that disrupt motivation, impulse control, and adherence behaviors. By enhancing attentional control and stress resilience, the disclosed methods support engagement in treatment adherence strategies. Modulation of norepinephrinergic neurotransmission includes, by way of example, modulating the activity of a norepinephrine receptor, such as any of a1A, a1 B, a1 D (formerly a1C), a2A, a2B, and a2C receptors; modulating the activity of norepinephrine transporters, such as the norepinephrine transporter (NET, SLC6A2); modulating the synthesis of norepinephrine via enzymes such as tyrosine hydroxylase and dopamine p-hydroxylase; modulating norepinephrine degradation via enzymes such as monoamine oxidase A (MAO-A) and catechol-O- methyltransferase (COMT); and modulating the release or reuptake of norepinephrine at the synapse.

[0242] Glutamate. In embodiments, the disclosed methods modulate glutamatergic neurotransmission, either directly or indirectly, to enhance learning, memory, and adaptive decision-making. Glutamate facilitatessynaptic plasticity, allowing subjects to encode and retain treatment-related information and adjust behaviors based on feedback. Impaired glutamatergic function is associated with rigid thinking, difficulty adapting to new habits, and maladaptive responses to stress, which can interfere with adherence to treatment recommendations. By supporting neuroplasticity and behavioral flexibility, the disclosed methods improve adherence to lifestyle modifications. Modulation of glutamatergic neurotransmission includes, by way of example, modulating the activity of a glutamate receptor, such as any of an AMPA receptor, NMDA receptor, kainate receptor, mGlul receptor, mGlu2 receptor, mGlu3 receptor, mGlu4 receptor, mGlu5 receptor, mGlu6 receptor, mGlu7 receptor, and mGlu8 receptor; modulating the activity of glutamate transporters, such as EAAT1 (SLC1A3), EAAT2 (SLC1A2), EAAT3 (SLC1A1), EAAT4, and EAAT5; modulating the activity of enzymes involved in glutamate metabolism, such as glutamine synthetase, glutaminase, and glutamate dehydrogenase; and modulating the release or reuptake of glutamate at the synapse.

[0243] In embodiments, the disclosed methods modulate one or more of dopaminergic, serotonergic, norepinephrinergic, and glutamatergic neurotransmission to optimize multiple cognitive and behavioral mechanisms underlying treatment adherence. By addressing reward processing, impulse control, attentional regulation, and behavioral learning, these methods help subjects sustain long-term adherence to treatment regimens, reducing relapse and enhancing clinical outcomes.

[0244] Although certain scientific hypotheses and theories are discussed herein, in part to demonstrate support for and show the plausibility of certain embodiments of the disclosure, including to those of ordinary skill, it will be appreciated that the disclosed embodiments are not limited by any such hypotheses or theories.G. Modulating the Inflammation-Oxidative Stress-Insulin Resistance Pathway

[0245] In embodiments, the disclosed methods modulate the inflammation-oxidative stress-insulin resistance pathway, either directly or indirectly, to reduce proinflammatory cytokines, reduce oxidative damage, and improve insulin sensitivity. The inflammation-oxidative stress-insulin resistance pathway is a core pathophysiological mechanism linking metabolic disturbances (e.g., insulin resistance, weight gain) and neuropsychiatric manifestations (e.g., psychotic symptoms, cognitive impairments) through a self-reinforcing cycle of chronic inflammation, excessive reactive oxygen species production, and insulin signaling disruptions.

[0246] In embodiments, the disclosed methods treat metabolic disturbances in individuals with schizophrenia and related psychotic disorders by targeting the inflammation-oxidative stress-insulin resistance pathway. In embodiments, the disclosed methods are useful for treating metabolic disturbances in individuals with schizophrenia and related psychotic disorders following the discontinuation of incretin-based therapies.

[0247] Peripheral and Central Nervous System Inflammation. In embodiments, the disclosed methods improve peripheral and central nervous system inflammation, reducing the negative effects of proinflammatory cytokines to mitigate oxidative stress and stabilize neuropsychiatric symptoms. Chronic, low-grade inflammation— characterized by elevated proinflammatory cytokines (e.g., interleukin-6, tumor necrosis factor-a, interleukin-1 P)— can impair insulin signaling and exacerbate psychotic symptoms. In embodiments, disclosed methods mitigate this negative cycle by reducing proinflammatory mediators while supportingneuroprotective mechanisms. In embodiments, by reducing neuroinflammation in key brain regions (e.g., the mesolimbic pathway), the disclosed methods help stabilize dopaminergic and opioidergic systems that may become dysregulated in schizophrenia. Improvements in psychotic symptom control, in turn, increase motivation to remain compliant with post-discontinuation recommendations.

[0248] Oxidative Stress Reduction. In embodiments, the disclosed methods reduce oxidative stress to preserve the functional integrity of insulin-sensitive tissues and protect neuronal pathways. Reactive oxygen species (ROS) and related byproducts (e.g., malondialdehyde, F2-isoprostanes) can promote insulin resistance and neuronal dysfunction. In embodiments, the disclosed methods reduce ROS levels and restore redox balance by enhancing endogenous antioxidant defenses, including glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT). In embodiments, a more favorable oxidative state correlates with improved metabolic control and neurocognitive control. Enhancing metabolic outcomes and improving psychiatric functioning are both important for long-term treatment adherence.

[0249] Insulin Resistance and Metabolic Regulation. In embodiments, the disclosed methods improve insulin resistance and metabolic regulation to mitigate weight regain, stabilize glycemic control, and support overall wellbeing. Dopaminergic and opioidergic imbalances in schizophrenia and related disorders can perpetuate overeating and reinforce insulin resistance. In embodiments, by improving insulin sensitivity, the disclosed methods help prevent the resurgence of metabolic complications that often follow the discontinuation of incretin-based treatments. As insulin resistance declines, individuals typically experience fewer metabolic side effects (e.g., hyperglycemia, weight gain), which can be major contributors to noncompliance with antipsychotic and other post-discontinuation regimens. Metabolic improvements, such as weight loss, better glycemic control, and decreased inflammation can help individuals feel physically healthier and more energized, making them more likely to continue following their recommended treatment protocols.

[0250] Reward Deficiency. Chronic inflammation, oxidative stress, and insulin resistance disrupt dopaminergic and opioidergic signaling in the central nervous system, contributing not only to metabolic disturbances but also to reward deficiency. Reward deficiency generally refers to an altered or diminished response in the brain’s reward circuitry, often involving dopaminergic and opioid signaling, where pleasurable stimuli (e.g., food, social interaction) do not yield the anticipated level of reward. As a result, individuals may seek intensified or maladaptive behaviors (e.g., overeating) to compensate, which may worsen metabolic disturbances. When reward circuits are compromised, individuals may lack motivation for healthy behaviors or adherence to pharmacotherapy and lifestyle modifications. By reducing systemic inflammation, normalizing insulin sensitivity, and restoring neurotransmitter balance, the disclosed methods can improve reward deficiencies to enhance metabolic outcomes and treatment adherence.

[0251] Mood Instability. Chronic inflammation, excessive oxidative stress, and insulin resistance can synergistically worsen mood instability. In embodiments, mood instability refers to depressive, anxious, or dysphoric states that can disrupt a person’s daily functioning and overall well-being. Emotional volatility can make it difficult to sustain effort over time, leading to problems adhering to medication, therapy, or lifestylemodifications. Rapid changes in mood can also strain relationships with family, friends, and care providers. Additionally, emotional dysregulation can contribute to poor self-care, including unhealthy eating or disrupted sleep, ultimately undermining metabolic and cardiovascular health. By stabilizing mood, the disclosed methods can help with maintaining healthy behaviors and committing to treatment plans, thereby improving both psychiatric and physical health outcomes.

[0252] Cognitive Impairment. Individuals experiencing chronic inflammation, heightened oxidative stress, and insulin resistance are at greater risk for cognitive impairment, including deficits in attention, memory, executive functioning, and processing speed. In embodiments, by modulating the inflammation-oxidative stress-insulin resistance pathway, the disclosed methods preserve or improve cognitive function. Improving cognitive function may help individuals find it easier to engage in and adhere to recommended therapy protocols, lifestyle modifications, and everyday responsibilities.H. Outcome Measures and Clinical Endpoints

[0253] In embodiments, the disclosed methods assess therapeutic effects using clinical outcome measures, including physiological, behavioral, and patient-centered outcomes (PCOMs). These measures evaluate adherence to lifestyle modifications, treatment effectiveness, and psychological and physiological responses to the intervention. In embodiments, an outcome measure may be a physiological measure, a behavioral factor measure, or a PCOM. Physiological measures monitor biological responses, including BMI, blood pressure, blood glucose levels, or biomarker concentrations. Behavioral factor measures assess treatment adherence through medication compliance, exercise frequency, dietary habits, alcohol or substance use, and self-reported behaviors. Patient-centered outcomes (PCOMs) capture a subject’s subjective experiences, beliefs, and attitudes regarding adherence, including self-reported adherence, patient surveys, and digital diaries.

[0254] In embodiments, an outcome measure may be a primary or secondary measure. A primary outcome measure is a key endpoint that determines treatment success (e.g., sustained adherence to lifestyle modifications), while secondary outcome measures assess exploratory or supplemental effects (e.g., psychological well-being, stress reduction). The classification of primary vs. secondary depends on the clinical context and research objectives; both types of outcome measures are encompassed within the methods.

[0255] In embodiments, treatment outcomes are monitored through self-reporting, clinician evaluation, digital tracking tools, and physiological assessments. Self-monitoring and clinician monitoring includes tracking adherence through paper diaries, digital surveys, and electronic medical records. Wearable and mobile health technology includes measuring real-time data from fitness trackers, biosensors, heart rate monitors, and accelerometers to assess physical activity, sleep, stress responses, and treatment adherence. Computer-assisted assessments include utilizing electronic tools, mobile health applications, telemedicine platforms, and Al-driven analysis to monitor psychological and behavioral factors affecting adherence.

[0256] In embodiments, computer-assisted assessments may involve digital phenotyping, where a subject’s interactions with smartphones, wearables, or online tools provide continuous insights into treatment adherence, behavioral patterns, and mental health status. In some embodiments, an Al-based assessmentsystem analyzes adherence trends and treatment responses to support personalized interventions.

[0257] In embodiments, the disclosed methods integrate with digital health systems to track adherence, optimize treatment plans, and enable real-time intervention. For example, automated monitoring platforms that collect longitudinal adherence data and alert healthcare providers to non-compliance risks; telehealth and electronic medical records (EMRs) that provide a centralized system for tracking psychological and physiological changes related to treatment adherence; and Al-driven decision support tools that analyze wearable device metrics, behavioral patterns, and patient-reported outcomes to identify adherence challenges and optimize interventions.

[0258] In embodiments, the disclosed methods enable a robust evaluation of treatment adherence and clinical outcomes by combining any of objective physiological data (e.g., biomarkers, blood tests, wearable sensor metrics); behavioral tracking (e.g., diet, exercise, medication adherence, lifestyle modifications); and psychological assessment (e.g., patient-reported surveys, digital phenotyping, Al-based adherence analytics).

[0259] By leveraging multiple outcome measures and clinical endpoints, the disclosed methods enable comprehensive assessment, real-time intervention, and long-term adherence optimization, ultimately improving treatment efficacy and patient outcomes.

[0260] In embodiments, the disclosed methods address adherence challenges following discontinuation of incretin-based therapies, such as GLP-1 , GIP, and GLP-1 / GIP receptor agonists, which are among the most efficacious weight-loss pharmacotherapies available. Incretin-based therapies, including semaglutide (e.g., OZEMPIC®, WEGOVY®), induce an average body weight reduction of up to 15% in obese patients (Jensen et al. Obes Surg. 2023;33(4):1017-1025). These therapies function by enhancing satiety, reducing appetite, and slowing gastric emptying, leading to sustained caloric reduction. Evidence also suggests that semaglutide may lower diabetes risk, particularly in prediabetic individuals. However, treatment discontinuation is associated with substantial weight regain, limiting the long-term efficacy of these therapies. For example, in a clinical study of 1 ,961 obese adults undergoing semaglutide therapy combined with lifestyle interventions, participants achieved a mean weight loss of 17.3% after 68 weeks. However, within one year of discontinuation (week 120), participants regained an average of 11.6% of the lost weight. Cardiometabolic improvements (e.g., blood pressure, HbA1c, lipid levels) also trended back toward baseline post-treatment (Wilding et al., 2022). On average, two-thirds (66%) of lost weight was regained within a year after stopping semaglutide, underscoring the need for interventions that sustain long-term weight management post-therapy.

[0261] “Baseline” herein includes measures or values at the time of incretin-based therapy discontinuation.

[0262] In embodiments, the disclosed methods improve adherence to lifestyle modifications after discontinuing incretin-based therapies, thereby helping subjects maintain weight loss and metabolic benefits. By targeting neurocircuitry involved in adherence behaviors, these methods address barriers to sustained treatment success, such as dysregulated appetite control, motivational deficits, and behavioral relapse.

[0263] In embodiments, the effectiveness of the disclosed methods is assessed by measuring changes in a subject’s body weight following discontinuation of incretin-based therapy. In some embodiments, the subject’sbody weight is compared to their baseline weight. In embodiments, body weight is measured over a specified period post-treatment, such as 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or beyond 12 months, such as 15 months, 18 months, 24 months, 36 months, or longer. In embodiments, a subject maintains their baseline weight, where maintaining weight is defined as remaining within 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% of baseline weight. In some embodiments, the subject experiences less weight regain following therapy discontinuation, with weight regain limited to less than 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, or 65% of the total weight lost during incretin-based therapy (i.e., relative to pre-treatment weight). In embodiments, the disclosed methods support sustained weight management post-therapy by improving adherence to lifestyle modifications, thereby reducing the extent of post-treatment weight regain.

[0264] In embodiments, the effectiveness of the disclosed methods is assessed by measuring changes in a subject’s waist circumference, hip circumference, or waist-to-hip ratio following discontinuation of incretin-based therapy. Waist circumference refers to the measurement around the narrowest part of the waist, typically just above the iliac crest. Hip circumference refers to the measurement around the widest portion of the buttocks. Waist circumference and waist-to-hip ratio are established predictors of cardiometabolic risk (Janssen et al. Am J Clin Nutr. 2002;75(4):683-8). In some embodiments, the subject’s waist circumference, hip circumference, or waist-to-hip ratio is compared to baseline. In embodiments, these measurements are tracked over a specified period post-treatment (such as the periods defined above). In embodiments, the subject maintains a stable waist circumference, hip circumference, or waist-to-hip ratio, where stability is defined as remaining within a percentage (such as the percentages defined above) of their baseline values. In embodiments, the disclosed methods support sustained metabolic health and reduce the extent of post-treatment increases in waist circumference, hip circumference, or waist-to-hip ratio, contributing to improved long-term cardiometabolic outcomes.

[0265] In embodiments, the effectiveness of the disclosed methods is assessed by measuring changes in the subject’s average adipocyte diameter. Studies indicate that adipocyte diameter correlates with insulin resistance, type 2 diabetes, and dietary interventions (Stenkula & Erlanson-Albertsson. Am J Physiol Regul Integr Comp Physiol. 2018;315(2):284-295). Adipocyte diameter can be measured using standard techniques known to those skilled in the art. In some embodiments, the subject’s average adipocyte diameter is compared to baseline. These measurements are tracked over a specified period post-treatment (such as the periods defined above). In embodiments, the subject’s average adipocyte diameter remains within a percentage (such as the percentages defined above) of their baseline value. In embodiments, the subject’s average adipocyte diameter remains within 1 pm, 2 pm, 3 pm, 4 pm, 5 pm, 6 pm, 7 pm, 8 pm, 9 pm, or 10 pm of baseline. In embodiments, the disclosed methods support sustained metabolic health by limiting post-treatment increases in adipocyte diameter, contributing to improved insulin sensitivity and reduced risk of metabolic dysfunction.

[0266] In embodiments, the effectiveness of the disclosed methods is assessed by measuring changes in the subject’s body mass index (BMI). BMI is commonly used as a gauge of disease risk associated with excessbody fat, including high blood pressure, type 2 diabetes, gallstones, breathing problems, and certain cancers. However, BMI has limitations, as it does not differentiate between weight from water, fat, or muscle, nor does it account for medical conditions that cause fluid retention (Pathak, Baylor College of Medicine, April 20, 2021). In some embodiments, the subject’s BMI is compared to their baseline measurement, defined as the BMI at the time of therapy discontinuation. These measurements are tracked over a specified period post-treatment (such as the periods defined above). In embodiments, the subject’s BMI remains within a percentage (such as the percentages defined above) of their baseline BMI. Preferably, the subject’s BMI remains within 1 %, 5%, or 10% of their baseline BMI. In embodiments, the disclosed methods support long-term weight maintenance by mitigating BMI fluctuations following incretin-based therapy discontinuation, thereby contributing to sustained metabolic health and reduced obesity-related risks.

[0267] In embodiments, the results are assessed by measuring a change in the subject’s sagittal abdominal diameter (SAD). SAD is measured with the subject in a supine position by recording the distance from the exam table to the abdomen at the midpoint between the iliac crests (see, e.g., Kahn et al. Int J Obes (Lond). 2021 ;45(4):765-775). SAD has been shown to outperform BMI in predicting metabolic syndrome. In embodiments, the subject’s SAD is compared to baseline. These measurements are tracked over a specified period post-treatment (such as the periods defined above). In embodiments, the subject’s SAD remains within a percentage (such as the percentages defined above) of their baseline SAD.

[0268] In embodiments, the results are assessed by measuring a change in the subject’s body fat index (BFI). Unlike BMI, BFI provides a more precise measure of body fat distribution by incorporating body composition scans, including subcutaneous and visceral adipose tissue measurements (Benchahong et al. Cureus. 2023; 15(5):e39615). In embodiments, the subject’s BFI is compared to baseline. These measurements are tracked over a specified period post-treatment (such as the periods defined above). In embodiments, the subject’s BFI remains within a percentage (such as the percentages defined above) of their baseline BFI.

[0269] In embodiments, the results are assessed by measuring a change in the subject’s body fat mass (FM) and fat-free mass. FM and fat-free mass may be determined using bioelectrical impedance analysis (BIA) or dual-energy X-ray absorptiometry (DEXA) scans, both of which are standard techniques known to those of skill (see, e.g., Taveira et al. J. Psychopharmacol. 2014;28(4):395-400; Elman et al. Sci Rep. 2020;10(1):5617). BIA estimates body composition based on the rate of electrical current travel, with adipose tissue creating greater resistance than lean mass. DEXA scans use imaging technology to measure whole-body composition, with precise quantification of fat and lean mass. In embodiments, the subject’s FM and fat-free mass are compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, FM and fat-free mass remain within a percentage (such as the percentages defined above) of baseline values.

[0270] In embodiments, the results are assessed by measuring a change in the subject’s liver enzyme levels via a liver function test. A “liver function test” refers to a blood test measuring key liver enzymes, including alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT). These tests also assess serum bilirubin, prothrombin time (PT), international normalizedratio (INR), total protein, and albumin levels. Liver function tests can indicate hepatic injury patterns; for example, disproportionate elevations in ALT and AST suggest hepatocellular damage, whereas elevations in ALP and bilirubin suggest cholestasis. In embodiments, the subject’s liver enzyme levels are compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, liver enzyme levels remain within a percentage (such as the percentages defined above) of baseline values.

[0271] In embodiments, the results are assessed by measuring a change in the subject’s insulin resistance (Taveira et al. J Psychopharmacol. 2014; 28(4): 395-400; Guina et al. J Clin Psychiatry. 2016;77(12):e1650- e1651 ; Guina et al. Hum Psychopharmacol. 2017;32(4):10.1002 / hup.2604). Insulin resistance is a key factor in the development of type 2 diabetes, atherosclerosis, and hypertension (Lebovitz. Exp Clin Endocrinol Diabetes. 2001 ; 109(2): 135-148). In embodiments, insulin resistance is assessed using the triglyceride-glucose (TyG) index, a validated surrogate marker of insulin resistance. The subject’s insulin resistance is compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, insulin resistance remains within a percentage (such as the percentages defined above) of baseline values.

[0272] In embodiments, the results are assessed by measuring a change in the subject’s blood pressure, including systolic and / or diastolic blood pressure. A stabilized blood pressure is characterized by systolic and diastolic values below 140 / 90 mm Hg. In embodiments, weight loss is associated with a decline in systolic blood pressure in overweight and obese individuals (e.g., an average weight loss of 2-4 kg correlates with a 3-8 mm Hg systolic decline), whereas weight gain is linked to an increase in systolic blood pressure (Harsha & Bray. Hypertension. 2008;51 :1420-1425). Similarly, diastolic blood pressure declines with weight loss and increases with weight gain in overweight and obese individuals (Fogari et al. Hypertens Res. 2010;33:236-242). In embodiments, the subject’s systolic and / or diastolic blood pressure is compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, blood pressure remains within a percentage (such as the percentages defined above) of baseline values.

[0273] In embodiments, the results are assessed by measuring a change in the subject’s hemoglobin A1c (HbA1c) levels using an HbA1c test, which measures average blood glucose levels over the preceding 8-12 weeks. HbA1c is a key indicator of glycemic control (Sherwani et al. Biomark Insights. 2016;11 :95-104). No fasting or glucose consumption is required for testing. HbA1c levels are classified as follows: Normal: <5.7%; Prediabetes: 5.7%-6.4%; Diabetes: >6.5%. In embodiments, the subject’s HbA1c levels are compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, HbA1c levels remain within a percentage (such as the percentages defined above) of baseline values.

[0274] In embodiments, the results are assessed by measuring a change in the subject’s lipid levels using a lipid test. Lipid levels include total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. Weight loss is associated with a decrease in LDL and an increase in HDL cholesterol. In embodiments, the subject’s lipid levels are compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, lipid levels remain within a percentage (such as the percentages defined above) of baseline values.

[0275] In embodiments, the results are assessed by measuring a change in the subject’s fasting plasma glucose (FPG) concentrations. FPG refers to the amount of glucose in a subject’s blood after fasting. Normal FPG levels are defined as <100 mg / dL, with weight loss and weight maintenance generally correlated with improved FPG regulation. Elevated FPG levels trigger insulin release, which can lead to increased fat storage and weight gain (Means et al. Levels Metabolic Insights. Understanding blood sugar and weight loss. Updated October 12, 2023). In embodiments, the subject’s FPG levels are compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, FPG levels remain within a percentage (such as the percentages defined above) of baseline values.

[0276] In embodiments, the results are assessed using the Matsuda Index, a measure of overall insulin sensitivity derived from plasma insulin and glucose levels sampled at multiple time points during an oral glucose tolerance test (oGTT) (e.g., 0, 30, 60, 90, and 120 minutes after glucose ingestion) (Guina et al. Hum. Psychopharmacol. 2017; Guina et al. J Clin Psych. 2016), which evaluates how a subject processes glucose after consumption of a glucose-enriched beverage (Elman et al. Sci Rep. 2020; 10(1):5617). Blood glucose concentrations following oGTT are categorized as: Normal: <140 mg / dL; Prediabetes: 140-199 mg / dL; Diabetes: >200 mg / dL. In embodiments, Matsuda Index data is used to compare post-treatment insulin sensitivity to baseline over a specified period post-treatment (such as the periods defined above).

[0277] In embodiments, the results are assessed by measuring blood glucose levels, which can be obtained via glucometers or continuous glucose monitors (CGMs) and analyzed using tracking applications. In embodiments, blood glucose metrics include: Time in range, time above range, and time below range; mean, median, standard deviation, and coefficient of variation; glycemic variability indices (e.g., MAGE, GMI, MODD, CONGA, ADRR, AUG); and fasting glucose, postprandial glucose excursion, and nocturnal glucose variability. In embodiments, these metrics are compared to baseline over a specified period post-treatment (such as the periods defined above).

[0278] In embodiments, the results are assessed using HOMA-IR, a method for estimating p-cell function and insulin resistance (IR) from fasting glucose and insulin levels (Taveira et al. J Psychopharmacol. 2014;28(4):395-400). Si can be determined from a nomogram, and from the equation Si= 22.5 / I x G, where I and G represent fasting insulin and glucose levels, and may be averaged over three time points to adjust for pulsatile secretion (Raziuk, Diabetes. 2014;63(6): 1850-1854). In embodiments, the subject’s HOMA-IR score is compared to baseline over a specified period post-treatment (such as the periods defined above).

[0279] In embodiments, the results are assessed by measuring changes in satiety-related hormone levels, including leptin and ghrelin (Kurbanov et al. J Psychopharmacol. 2012;26(9): 1244-1251 ; Elman et al. Neuropsychopharmacol. 2006;31 :2328). Leptin suppresses food intake and regulates energy balance; ghrelin stimulates hunger and initiates food consumption (Klok et al. Obes Rev. 2007;8(1 ):21 -34). In embodiments, satiety-related hormone levels are compared to baseline over a specified period post-treatment (such as the periods defined above). In embodiments, hormone levels remain within a percentage (such as the percentages defined above) of baseline values.

[0280] In embodiments, the results of a disclosed method are assessed by measuring changes in metabolic biomarkers using a metabolic biomarker panel, which includes laboratory tests evaluating metabolic health and related physiological processes. In embodiments, the metabolic biomarker panel measures: Serum triglycerides; Inflammatory markers (e.g., high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-a), interleukin-1 beta (IL-10), interleukin-8 (IL-8), myeloperoxidase (MPO), ferritin, adiponectin, resistin, and fibrinogen); Insulin resistance indicators, including fasting triglycerides (TG) and fasting glucose (Glu), which together form the triglyceride-glucose (TyG) index; Oxidative stress biomarkers, such as malondialdehyde (MDA), 8-hydroxy-2'-deoxyguanosine (8-OHdG), or total antioxidant capacity (TAG). In embodiments, metabolic biomarkers are compared to baseline levels over a specified period post-treatment (such as the periods defined above). In embodiments, the disclosed methods produce one or more results including: Inflammatory markers show a reduction compared to baseline; TyG index improves, indicating enhanced insulin sensitivity; Oxidative stress biomarkers decrease, reflecting reduced oxidative stress; Metabolic biomarkers remain within a percentage (such as the percentages defined above) of baseline.

[0281] In embodiments, the results are assessed by measuring changes in sleep patterns, including: Total sleep time (TST); Sleep efficiency (SE); Wake after sleep onset (WASO); and Sleep stages (REM, light, deep). Sleep data may be collected using wearable devices, actigraphy, polysomnography, or self-reported sleep logs. In embodiments, sleep parameters are compared to baseline over a specified period post-treatment (such as the periods defined above).

[0282] In embodiments, the results are assessed by measuring changes in psychological factors experienced by the subject. Improvements are monitored using outcome measures, which may include any one or more of: Physiological measures (e.g., biomarker changes, autonomic nervous system markers); Patient-centered outcome measures (PCOMs) (e.g., self-reported well-being, mood assessments, perceived stress levels); and Behavioral factor measures (e.g., adherence to lifestyle modifications, participation in therapeutic interventions). In embodiments, psychological outcome measures are compared to baseline over a specified period post-treatment (such as the periods defined above).

[0283] In embodiments, improvements in psychological factors are assessed using psychodiagnostic and psychometric tools commonly employed by those skilled in the art. Such tools include: Structured Clinical Interview for DSM-5 (SCID-5) (see, e.g., Am Psych Assoc. The Structured Clinical Interview for DSM-5®, 2017; Elman et al. Sci Rep. 2020; 10(1):5617); Depression and Anxiety Scales: Beck Depression Inventory, Hamilton Rating Scale for Depression, Hamilton Rating Scale for Anxiety, State-Trait Anxiety Inventory; Stress and Quality of Life Measures: Daily Stress Inventory, Perceived Stress Scale, Health-Related Quality of Life, Profile of Mood States questionnaire; Eating and Food-Related Assessments: Yale Food Addiction Scale, Eating Disorder Examination Questionnaire, Eating Disorder Inventory, Food Craving Inventory, Yale-Brown Obsessive-Compulsive Scale, Food Craving Questionnaire, Three-Factor Eating Questionnaire; Psychiatric and Addiction Measures: Relationship Patterns Questionnaire, Treatment Adherence Perception Questionnaire, Reward Deficiency Syndrome Questionnaire, Genetic Addiction Risk Severity (GARS) test(Blum et al. Psychol Res Behav Manag. 2023;16:4287-4291); PTSD and Trauma Scales: Clinician-Administered PTSD Scale, Civilian Mississippi PTSD Scale; and Addiction and Psychiatric Symptom Measures: Addiction Severity Index, Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS). These tools are well-established in the field and may be referenced in the scientific and clinical literature. In embodiments, a disclosed method utilizes one or more of these assessments to evaluate psychological factors relevant to treatment adherence, metabolic health, and associated conditions. Other such tools and assessments will be appreciated in view of the disclosure and the general knowledge in the art.

[0284] In embodiments, improvements in psychological factors are assessed using psychodiagnostic and psychometric tools commonly employed in the field, that measure various psychological constructs, including depression, anxiety, stress, mood states, food-related behaviors, adherence, and psychiatric symptoms, such as the tools above and now described in further detail, and as will also be understood in the art.

[0285] Depression and Anxiety Assessment Tools

[0286] Beck Depression Inventory (BDI): A 21 -item self-report inventory measuring depressive symptoms and severity, with higher scores indicating greater depression severity (Beck et al., Arch Gen Psychiatry, 1961). In embodiments, the BDI is used to assess changes in depressive symptoms following treatment. Hamilton Rating Scale for Depression (HAM-D): A clinician-administered tool for assessing depression severity, originally developed with 17 core items (J Neurol Neurosurg Psychiatry, 1960). In embodiments, the HAM-D is used to evaluate treatment-related changes in depressive symptoms. Hamilton Rating Scale for Anxiety (HAM-A): A 14-item clinician-administered scale evaluating anxiety severity, covering psychological and somatic symptoms (Occup Med, 2015). In embodiments, the HAM-A is used to assess changes in anxiety-related symptoms post-treatment. State-Trait Anxiety Inventory (STAI): A 40-item self-report tool distinguishing between transient state anxiety and stable trait anxiety (Spielberger, Manual for the STAI). In embodiments, the STAI is used to monitor reductions in anxiety levels over time.

[0287] Stress and Mood-Related Tools. Daily Stress Inventory (DSI): A self-report tool measuring daily stressors and their impact (Am J Addict, 2010). In embodiments, the DSI is used to assess how stress influences adherence to treatment. Perceived Stress Scale (PSS-10): A 10-item self-report measure evaluating perceived stress over the past month (J Health Soc Behav, 1983). In embodiments, the PSS-10 is used to track stress reduction post-treatment. Health-Related Quality of Life (HRQoL): A multidimensional assessment of an individual’s physical, mental, and social well-being, often measured using SF-36 or EQ-5D. In embodiments, HRQoL is used to evaluate improvements in overall well-being. Profile of Mood States (POMS): A 65-item questionnaire assessing transient mood states, including tension, depression, anger, vigor, fatigue, and confusion (J Addict Dis, 2011). In embodiments, the POMS is used to assess mood stability.

[0288] Eating Behavior and Food-Related Measures. Yale Food Addiction Scale (YFAS): A 25-item tool assessing addictive-like eating behaviors based on DSM-IV substance dependence criteria (Appetite, 2009). In embodiments, the YFAS is used to measure changes in compulsive eating behaviors. Eating Disorder Examination Questionnaire (EDE-Q): A 28-item self-report tool assessing eating disorder severity across foursubscales: Restraint, Eating Concern, Shape Concern, and Weight Concern (Eating Disorder Exam, 17th ed.). In embodiments, the EDE-Q is used to assess disordered eating behaviors. Eating Disorder Inventory (EDI): A multi-subscale self-report questionnaire measuring psychological traits associated with eating disorders (Psychol Assess, 1983). In embodiments, the EDI is used to evaluate cognitive and behavioral patterns linked to disordered eating. Food Craving Inventory (FCI): A self-report tool measuring subjective food cravings and actual consumption patterns (Obes Res, 2002). In embodiments, the FCI is used to assess reductions in food cravings. Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating (Y-BOCS-BE): A modified version of the Y-BOCS designed to assess the severity of binge eating-related obsessions and compulsions (Arch Gen Psychiatry, 1989). In embodiments, the Y-BOCS-BE is used to track compulsive eating behaviors. Food Craving Questionnaire (FCQ): A self-report tool measuring food cravings across emotional, physiological, and cognitive domains (Front Psychol, 2014). In embodiments, the FCQ is used to evaluate changes in food-related urges. Three-Factor Eating Questionnaire (TFEQ-R18): A self-report tool assessing cognitive restraint, uncontrolled eating, and emotional eating (J Nutr, 2004). In embodiments, the TFEQ-R18 is used to measure changes in eating behaviors.

[0289] Behavioral and Adherence-Related Tools. Relationship Patterns Questionnaire (RPQ): A self-report measure assessing relational behavior patterns (Psychother Psychosom Med Psychol, 2005). In embodiments, the RPQ is used to examine interpersonal influences on adherence. Treatment Adherence Perception Questionnaire (TAPQ): A self-report tool assessing perceptions of adherence, including perceived benefit and burden (Psychol Assess, 2020). In embodiments, the TAPQ is used to monitor patient-reported adherence factors. Reward Deficiency Syndrome Questionnaire (RDSQ-29): A self-report measure evaluating impulsive, compulsive, and addictive tendencies related to dopamine dysfunction (Med Res Arch, 2023). In embodiments, the RDSQ-29 is used to assess motivational factors in adherence. Genetic Addiction Risk Severity (GARS) Test: A genetic screening tool predicting susceptibility to addiction and compulsive behaviors (Psychol Res Behav Manag, 2023). In embodiments, the GARS test is used to assess genetic factors influencing adherence.

[0290] PTSD and Psychiatric Symptom Assessment Tools. Clinician-Administered PTSD Scale (CAPS): A structured interview assessing PTSD symptoms and severity (Biol Psychiatry, 2009). In embodiments, the CAPS is used to monitor PTSD symptom changes post-treatment. Civilian Mississippi PTSD Scale: A 35-item self-report measure of PTSD symptom severity (J Behav Addict, 2017). In embodiments, the Civilian M-PTSD Scale is used to assess PTSD symptomatology. Addiction Severity Index (ASI): A semi-structured interview assessing addiction severity across multiple domains, including medical, psychological, and social aspects (Nord J Psychiatry, 2020). In embodiments, the ASI is used to evaluate the impact of treatment on substance use behaviors. Positive and Negative Syndrome Scale (PANSS): A 30-item clinician-administered tool measuring schizophrenia symptoms, including positive, negative, and general psychopathology (Schizophr Bull, 1987). In embodiments, the PANSS is used to assess psychiatric symptoms. Brief Psychiatric Rating Scale (BPRS): An 18-item clinician-administered scale assessing the severity of psychiatric symptoms,including psychosis and mood disorders (Psychol Rep, 1962). In embodiments, the BPRS is used to evaluate broad psychiatric symptomatology.

[0291] Other methods for assessing outcome measures, as useful in the practice of the disclosed methods, will be recognized by those of skill in view of the present disclosure and general knowledge in the art.

[0292] In embodiments, treating PFAOMC in a subject results in improvement in a psychological factor, as assessed using a described outcome measure. In embodiments, treating PFAOMC in a subject results in improvement in another medical condition, as assessed using a described outcome measure.IV. Therapeutic Compounds

[0293] In some aspects, disclosed are methods of treating a subject with one or more therapeutic compounds, pharmaceutical compositions comprising such compounds, and kits comprising such compounds.

[0294] Unless expressly stated otherwise, the terms “therapeutic compound” and “compound” are used interchangeably herein. Where a method, composition, or kit includes more than one therapeutic compound, the compounds may be collectively referred to as a “therapeutic combination.”

[0295] A therapeutic combination refers to the administration of multiple therapeutic compounds as part of a disclosed method but does not require simultaneous or co-administration, identical preparation or formulation, or the same route of administration, dosing regimen, or other treatment parameters.

[0296] While therapeutic compounds are categorized herein by class and generally attributed to a single class, such classifications are not exclusive, and a compound may belong to multiple classes. Classifications are provided for reference, and other categorizations will be recognized by those of skill in the art.

[0297] Unless otherwise specified, disclosure of any compound herein encompasses its pharmaceutically acceptable salts, solvates, hydrates, solid forms, polymorphs, isotopologs, stereoisomers, non-racemic and racemic mixtures, prodrugs, derivatives, metabolites, and any combinations of any of the foregoing thereof.

[0298] “Pharmaceutically acceptable salt” refers to a salt form of a compound prepared using non-toxic acids or bases suitable for pharmaceutical use. Such salts can be synthesized by conventional chemical methods, typically by reacting the free acid or base form of a compound with a stoichiometric amount of a suitable acid or base in aqueous or organic solvent systems. The selection of a specific salt form may influence the compound’s solubility, stability, or bioavailability, as is well known in the art. Exemplary pharmaceutically acceptable salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, acetate, citrate, fumarate, lactate, maleate, succinate, tartrate, tosylate, benzoate, gluconate, pamoate, mesylate, and their equivalents (see, e.g., Berge et al., J. Pharm. Sci. 1997;66:1-19).

[0299] A disclosed compound may exist in solid or liquid form. In solid form, it may be crystalline or noncrystalline and may form solvates, including hydrates when water is incorporated into the crystalline lattice. Certain crystalline forms may exhibit polymorphism. Polymorphs may differ in physical properties such as stability, solubility, and melting point, and be influenced by factors like temperature, pressure, solvent choice, and crystallization conditions. The disclosed subject matter includes solvates, hydrates, and polymorphs.

[0300] Disclosed therapeutic compounds may exist as enantiomers, diastereomers, racemates, or opticallypure forms, with chiral centers defined as (R)- or (S)-. Such isomers can be prepared using chiral synthons, asymmetric synthesis, enzymatic resolution, or chiral chromatography. When applicable, both E and Z geometric isomers and tautomeric forms are included. Non-racemic and enantiomerically enriched mixtures, in any proportion, as well as single enantiomers of varying degrees of purity, are also within the disclosure.

[0301] Disclosed compounds may be isotopically enriched, where at least one atom is substituted with an isotope above its natural abundance (“isotopologs”). Substituting heavier isotopes, such as deuterium (2H), may enhance metabolic stability, prolong in vivo half-life, or reduce dosage requirements. These generally can be made with standard procedures by replacing a non-isotopically labeled reagent with its labeled counterpart.

[0302] The disclosure includes prodrugs, which may undergo enzymatic, oxidative, reductive, hydrolytic, or other transformations to the active compound. They typically feature cleavable groups, such as esters, carbonates, carbamates, amides, phosphates, or sulfonamides, designed for controlled activation under physiological conditions. The selection of prodrug moieties depends on stability, synthesis feasibility, enzymatic activity, and desired conversion rate, all of which will be appreciated in view of the disclosure by those of skill.

[0303] Disclosed therapeutic compounds are generally administered as pharmaceutical compositions containing isolated or purified compounds. “Isolated,” “purified,” or “substantially pure” refers to material free from accompanying impurities, with chromatographic purity exceeding 90%, preferably 95%, and more preferably 99% or higher, as determined by HPLC or similar methods. Preferably, the compound is free of unintended active agents, with any contaminants below detection thresholds.A. Monoamine Oxidase Inhibitors

[0304] Monoamine oxidase (MAO) is a mitochondrial enzyme expressed in gastrointestinal, hepatic, and neuronal tissues, where it regulates monoamine levels by catalyzing oxidative deamination. This enzymatic process detoxifies dietary monoamines and prevents neurotransmitter accumulation in nervous and peripheral tissues (Finberg et al. Front Pharmacol. 2016;7:340).

[0305] There are two isoforms of MAO: MAO-A and MAO-B. While both isoforms metabolize dopamine (DA) and tyramine, MAO-A preferentially deaminates hydroxylated amines such as serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (NA), whereas MAO-B exhibits greater affinity for non-hydroxylated amines such as benzylamine and beta-phenylethylamine (PEA). Given their role in neurotransmitter regulation, alterations in MAO activity have been implicated in various neurological and psychiatric disorders, making MAO inhibitors (MAOIs) a therapeutic target for several decades. In embodiments, monoaminergic neurotransmission is enhanced by inhibiting MAO-A (see, e.g., Chen et al. Pol J Pharmacol. 1999;51 (1 ):25-9).

[0306] As used herein, “MAO inhibitor” or “MAOI” refers to any natural or synthetic compound that inhibits monoamine oxidase (MAO) activity, including both MAO-A and MAO-B. This term encompasses all chemical structures capable of interfering with MAO enzymatic function, including organic molecules, peptides, proteins, nucleic acids, derivatives, analogs, and combinations thereof. MAOIs prevent or reduce the metabolism of monoamine neurotransmitters by inhibiting MAO activity. The term further includes reversible, irreversible, competitive, non-competitive, selective, and non-selective inhibitors, as well as compounds that modulateMAO activity through allosteric or indirect regulatory mechanisms.

[0307] As used herein, “MAO-A-selective inhibitor” refers to an MAOI with preferential inhibition of MAO-A over MAO-B. Selectivity is determined by comparing the inhibitory constant (Ki) for MAO-A and MAO-B. For example, an inhibitor with a Ki of 0.2 pM for MAO-A and 1.0 pM for MAO-B exhibits 5-fold selectivity for MAO-A. Ki values can be measured using standard methods known in the art..

[0308] In some embodiments, the therapeutic compound, or one of one or more therapeutic compounds is a MAOI. In other embodiments, the therapeutic compound is not, or no therapeutic compounds are, a MAOI.

[0309] In embodiments, the MAOI is a MAO-A-selective inhibitor.

[0310] In embodiments, the MAOI has a selectivity for MAO-A inhibition over MAO-B inhibition of at least 5-fold, 10-fold, 50-fold, 100-fold, 150-fold, 200-fold, 300-fold, 500-fold, or 1 ,000-fold.

[0311] In embodiments, the MAOI does not result in a detectable level of MAO-B inhibition.

[0312] In embodiments, the MAOI is isocarboxazid, pargyline, selegiline, furazolidone, phenelzine, amiflamine, iproniazid, nialamide, tranylcypromine, octamoxin, phenoxypropazine, pivalylbenzhydrazine, iproclozide, bifemelane, prodipine, benmoxin, etryptamine, fenoxypropazine, mebanazine, pheniprazine, safrazine, hypericine, iproniazid, tranylcypromine, methylene blue, moclobemide, brofaromine, befloxatone, toloxatone, clorgyline, cimoxatone, bazinaprine, harmine, harmaline, sercloremine, esuprone, pirlindole, metralindole, or tetrindole.

[0313] In embodiments, the MAOI is irreversible and selective. In some embodiments, the MAOI is selegiline. In some embodiments, the MAOI is a reversible MAO-B inhibitor. In some embodiments, the MAOI is irreversible and non-selective. In embodiments, the MAOI is phenelzine, tranylcypromine, or isocarboxazid.

[0314] In embodiments, the selective MAO-A inhibitors has advantages over non-selective MAO inhibitors, such as in reducing cardiovascular risks and dietary restrictions commonly associated with traditional MAOIs.

[0315] In some embodiments, the MAOI is a reversible MAO-A inhibitor (RIMA). In embodiments, the RIMA is moclobemide, brofaromine, caroxazone, 0X157 (3-fluoro-7(2,2,2-trifluorethoxy)phenoxathiine-10,10- dioxide), 0X2614 (3-(2,2,2-trifluoro-1-methylethoxy)phenoxathiin-10,10-dioxide), eprobemide, metralindole, minaprine, pirlindole, or toloxatone. In embodiments, the RIMA is moclobemide, brofaromine, caroxazone, eprobemide, metralindole, minaprine, or pirlindole. In embodiments, the RIMA is brofaromine. In embodiments, the RIMA is caroxazone. In embodiments, the RIMA is 0X157. In embodiments, the RIMA is 0X2614. In embodiments, the RIMA is eprobemide. In embodiments, the RIMA is metralindole. In embodiments, the RIMA is minaprine. In embodiments, the RIMA is pirlindole. In embodiments, the RIMA is toloxatone.

[0316] In embodiments, the RIMA is moclobemide. As with all other disclosed compounds, unless context clearly indicates otherwise, “moclobemide” refers not only to the drug substance (4-chloro-N-[2-(morpholin-4-yl)ethyl]benzamide; CAS 71320-77-9) and its salts, but also to the drug products comprising moclobemide, e.g., AMIRA®, AURORIX®, CLOBEMIX®, DEPNIL®, and MANERIX®. Thus, in embodiments, moclobemide is AMIRA®, AURORIX®, CLOBEMIX®, DEPNIL®, or MANERIX®, or another drug product comprising moclobemide or a pharmaceutically acceptable salt thereof.

[0317] For any disclosed therapeutic compound, the compound may be formulated as a pharmaceutical composition, e.g., may be prepared for administration or as a dosage form, including a unit dosage form, and may further comprise one or more carriers, diluents, or excipients, in accordance with the disclosure herein and the general knowledge in the art. Where a disclosed therapeutic compound is already known as a component of one or more drug products, while those drug product(s) will not be exclusive of the disclosed pharmaceutical compositions that comprise the therapeutic compound, those drug product(s) will be understood to be expressly part of this disclosure, and their product labels, package inserts, medication guides, and associated prescribing information shall be incorporated by reference as if fully set forth herein.

[0318] In embodiments, the MAOI is an antidepressant. In embodiments, the MAOI is not an antidepressant.B. Antidepressants

[0319] “Antidepressant” refers to a compound used to treat depressive disorders, anxiety disorders, chronic pain conditions, and certain addictions. An antidepressant may act by modulating monoaminergic neurotransmitters including dopamine, serotonin, and norepinephrine. In embodiments, a subject has dysregulation of one or more of these neurotransmitters, and such dysregulation affects treatment non-adherence, such as for conditions including chronic obesity and hyperglycemia. In embodiments, antidepressants enhance adherence in subjects following the discontinuation of incretin-based therapies.

[0320] In embodiments, the therapeutic compound is an antidepressant. In embodiments, the antidepressant is any of a selective serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (NRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a dual norepinephrine / dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a noradrenaline and specific serotonergic antidepressant (NASSA), a serotonin antagonist and reuptake inhibitor (SARI), or a norepinephrine-dopamine disinhibitor (NDDI).

[0321] In embodiments, the antidepressant is a selective serotonin reuptake inhibitor (SSRI). In embodiments, the SSRI is any of fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vortioxetine, or vilazodone. In embodiments, the SSRI is fluoxetine. In embodiments, the SSRI is sertraline. In embodiments, the SSRI is fluvoxamine. In embodiments, the SSRI is paroxetine. In embodiments, the SSRI is citalopram. In embodiments, the SSRI is escitalopram. In embodiments, the SSRI is vortioxetine. In embodiments, the SSRI is vilazodone.

[0322] In embodiments, the antidepressant is not a selective serotonin reuptake inhibitor (SSRI). In embodiments, the SSRI is not any of fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vortioxetine, and vilazodone. In embodiments, the SSRI is not fluoxetine. In embodiments, the SSRI is not sertraline. In embodiments, the SSRI is not fluvoxamine. In embodiments, the SSRI is not paroxetine. In embodiments, the SSRI is not citalopram. In embodiments, the SSRI is not escitalopram. In embodiments, the SSRI is not vortioxetine. In embodiments, the SSRI is not vilazodone.

[0323] In embodiments, the antidepressant is a selective norepinephrine reuptake inhibitor (NRI). In embodiments, the NRI is atomoxetine or reboxetine. In embodiments, the NRI is atomoxetine. In embodiments, the NRI is reboxetine.

[0324] In embodiments, the antidepressant is a serotonin and norepinephrine reuptake inhibitor (SNRI). In embodiments, the SNRI is any of desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine. In embodiments, the SNRI is desvenlafaxine. In embodiments, the SNRI is duloxetine. In embodiments, the SNRI is levomilnacipran. In embodiments, the SNRI is milnacipran. In embodiments, the SNRI is venlafaxine.

[0325] In embodiments, the antidepressant is a dual norepinephrine / dopamine reuptake inhibitor (NDRI). In embodiments, the NDRI is any of amineptine, bupropion, desoxypipradrol, dexmethylphenidate, difemetorex, diphenylprolinol, ethylphenidate, fencamfamine, fencamine, lefetamine, methylenedioxypyrovalerone, methylphenidate, nomifensine, 0-2172, pipradrol, prolintane, pyrovalerone, solriamfetol, tametraline, or WY-46824. In embodiments, the NDRI is amineptine. In embodiments, the NDRI is bupropion. In embodiments, the NDRI is desoxypipradrol. In embodiments, the NDRI is dexmethylphenidate. In embodiments, the NDRI is difemetorex. In embodiments, the NDRI is diphenylprolinol. In embodiments, the NDRI is ethylphenidate. In embodiments, the NDRI is fencamfamine. In embodiments, the NDRI is fencamine. In embodiments, the NDRI is lefetamine. In embodiments, the NDRI is methylenedioxypyrovalerone. In embodiments, the NDRI is methylphenidate. In embodiments, the NDRI is nomifensine. In embodiments, the NDRI is 0-2172. In embodiments, the NDRI is pipradrol. In embodiments, the NDRI is prolintane. In embodiments, the NDRI is pyrovalerone. In embodiments, the NDRI is solriamfetol. In embodiments, the NDRI is tametraline. In embodiments, the NDRI is WY-46824.

[0326] In embodiments, the antidepressant is a tricyclic antidepressant (TCA). In embodiments, the TCA is any of amitriptyline, doxepin, clomipramine, nortriptyline, imipramine, desipramine, protriptyline, dosulepin, maprotiline, trimipramine, or amoxapine. In embodiments, the TCA is amitriptyline. In embodiments, the TCA is doxepin. In embodiments, the TCA is clomipramine. In embodiments, the TCA is nortriptyline. In embodiments, the TCA is imipramine. In embodiments, the TCA is desipramine. In embodiments, the TCA is protriptyline. In embodiments, the TCA is dosulepin. In embodiments, the TCA is maprotiline. In embodiments, the TCA is trimipramine. In embodiments, the TCA is amoxapine.

[0327] In embodiments, the antidepressant (also for shorthand herein, “AD”) is not a tricyclic antidepressant (TCA). In embodiments, the AD is a TCA, but is not a specific TCA. In embodiments, the AD is not any of amitriptyline, doxepin, clomipramine, nortriptyline, imipramine, desipramine, protriptyline, dosulepin, maprotiline, trimipramine or amoxapine. In embodiments, the AD is not amitriptyline. In embodiments, the AD is not doxepin. In embodiments, the AD is not clomipramine. In embodiments, the AD is not nortriptyline. In embodiments, the AD is not imipramine. In embodiments, the AD is not desipramine. In embodiments, the AD is not protriptyline. In embodiments, the AD is not dosulepin. In embodiments, the AD is not maprotiline. In embodiments, the AD is not trimipramine. In embodiments, the AD is not amoxapine.

[0328] In embodiments, the antidepressant is a noradrenaline and specific serotonergic antidepressant (NASSA). In embodiments, the NASSA is any of aptazapine, esmirtazapine, mianserin, mirtazapine, or setiptiline (teciptiline). In embodiments, the NASSA is aptazapine. In embodiments, the NASSA is esmirtazapine. In embodiments, the NASSA is mianserin. In embodiments, the NASSA is mirtazapine. Inembodiments, the NASSA is setiptiline (teciptiline).

[0329] In embodiments, the antidepressant is a serotonin antagonist and reuptake inhibitor (SARI). In embodiments, the SARI is any of etoperidone, lorpiprazole, mepiprazole, nefazodone, or trazodone. In embodiments, the SARI is etoperidone. In embodiments, the SARI is lorpiprazole. In embodiments, the SARI is mepiprazole. In embodiments, the SARI is nefazodone. In embodiments, the SARI is trazodone.

[0330] In embodiments, the antidepressant is a norepinephrine-dopamine disinhibitor (NDDI). In embodiments, the NDDI is any of agomelatine, fluoxetine, flibanserin, or mirtazapine. In embodiments, the NDDI is agomelatine. In embodiments, the NDDI is fluoxetine. In embodiments, the NDDI is flibanserin. In embodiments, the NDDI is mirtazapine.

[0331] In embodiments, the antidepressant (“AD”) is a compound having antidepressant effects, or administered to provide antidepressant effects, and is any of, or is from any of the classes of, amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine, phenelzine, tranylcypromine, isocarboxazid, selegiline, mirtazapine, nefazodone, trazodone, bupropion, neurotropic agents, adaptogens, actoprotectors, nootropics, eugeroics, racetams, anti hypoxants, cognitive enhancers, potassium orotate, asparkam, psychedelics, mescaline and scalines, entactogens and empathogens (e.g., MDMA), 4-bromo-2,5-dimethoxyphenethylamine (2C-B) and other 2C compounds, trimethoxyamphetamines, tryptamines, benzofuran, ibogaine, ibogamine, ibogoids and iboga alkaloids, LSD, ergolines and lysergamides, phenethylamines, benzocyclobutene derivatives, NBOMe derivatives, NBOH derivatives, NBMD derivatives, NBF derivatives, 3C compounds (3,5-dimethoxy, 4-substituted phenethylamines) (see, e.g., Elman et al. Neurosci. Biobehav. Rev. 2022; 134: 104482)), DOM, DOB, DOC, and other DOx compounds (2,5-dimethoxy, 4-substituted amphetamines), phenylcyclopropylamine derivatives, DMMDA, DMMDA-2, benzoxazines, cannabinoids, harmaline, harmala alkaloids, other beta-carbolines, ayahuasca, salvinorin A, salvinorin B, methoxymethyl, piperazines, myristicin, elemicin, cryogenine, the active constituents of a Hernia species, atropine, scopolamine, hyoscyamine, psilocybin, psilocin, DMT, 5-MeO-DMT, ketamine, esketamine, arketamine, the active constituents of a Solanaceae species, ibotenic acid, muscimol, other active constituents of A. muscaria, solriamfetol, vilazodone, atomoxetine, milnacipran, dosulepin, duloxetine, escitalopram, venlafaxine, citalopram, fluoxetine, fluvoxamine, vortioxetine, reboxetine, sertraline, paroxetine, dextromethorphan, dextromethorphan / bupropion, and lithium.

[0332] In embodiments, the AD is not atropine. In embodiments, the AD is not hyoscyamine. In embodiments, the AD is not scopolamine. In embodiments, the AD is not bupropion. In embodiments, the AD is not mirtazapine. In embodiments, the AD is not an amphetamine.

[0333] In embodiments, the AD is amitriptyline. In embodiments, the AD is amoxapine. In embodiments, the AD is clomipramine. In embodiments, the AD is desipramine. In embodiments, the AD is doxepin. In embodiments, the AD is imipramine. In embodiments, the AD is maprotiline. In embodiments, the AD is nortriptyline. In embodiments, the AD is protriptyline. In embodiments, the AD is trimipramine. In embodiments, the AD is phenelzine. In embodiments, the AD is tranylcypromine. In embodiments, the AD is isocarboxazid. Inembodiments, the AD is selegiline. In embodiments, the AD is mirtazapine. In embodiments, the AD is nefazodone. In embodiments, the AD is trazodone. In embodiments, the AD is bupropion.

[0334] In embodiments, the AD is a neurotropic agent. In embodiments, the AD is an adaptogen. In embodiments, the AD is an actoprotector. In embodiments, the AD is a nootropic. In embodiments, the AD is a eugeroic. In embodiments, the AD is a racetam. In embodiments, the AD is an antihypoxant. In embodiments, the AD is a cognitive enhancer. In embodiments, the AD is potassium orotate. In embodiments, the AD is asparkam. In embodiments, the AD is a psychedelic. In embodiments, the AD is an entactogen or an empathogen. In embodiments, the AD is not a psychedelic. In embodiments, the AD is not an empathogen or an entactogen.

[0335] In embodiments, the AD is solriamfetol. In embodiments, the AD is vilazodone. In embodiments, the AD is atomoxetine. In embodiments, the AD is milnacipran. In embodiments, the AD is dosulepin. In embodiments, the AD is duloxetine. In embodiments, the AD is escitalopram. In embodiments, the AD is venlafaxine. In embodiments, the AD is citalopram. In embodiments, the AD is fluoxetine. In embodiments, the AD is fluvoxamine. In embodiments, the AD is vortioxetine. In embodiments, the AD is reboxetine. In embodiments, the AD is sertraline. In embodiments, the AD is paroxetine. In embodiments, the AD is esketamine. In embodiments, the AD is ketamine. In embodiments, the AD is dextromethorphan / bupropion. In embodiments, the AD is lithium.

[0336] In some embodiments, the antidepressant is also an MAOI, such as any of the MAOIs described herein. In some embodiments, the antidepressant is not also an MAOI. In some embodiments, the antidepressant is not any of the MAOIs described or expressly listed herein.

[0337] In some embodiments, the antidepressant is also an anxiolytic agent. In some embodiments, the antidepressant is not also an anxiolytic agent.

[0338] In some embodiments, the antidepressant is also a cognitive enhancer. In some embodiments, the antidepressant is not also a cognitive enhancer.C. Cognitive Enhancers

[0339] Cognitive enhancers are compounds which act on the central nervous system to improve cognitive functions. In embodiments, the cognitive enhancer improves cognitive functions such as memory, motivation, reward, and / or overall mental performance.

[0340] In embodiments, the cognitive enhancer is an amphetamine. In embodiments, the cognitive enhancer is a racetam. In embodiments, the cognitive enhancer is phenylpiracetam. In embodiments, the cognitive enhancer is meldonium. In embodiments, the cognitive enhancer is not an amphetamine. In embodiments, the cognitive enhancer is not a racetam. In embodiments, the cognitive enhancer is not phenylpiracetam. In embodiments, the cognitive enhancer is not meldonium.

[0341] Herein, for each embodiment where a therapeutic compound is a specific disclosed compound, in another embodiment, the therapeutic compound is not the specific disclosed compound.

[0342] In embodiments, the cognitive enhancer is a eugeroic. In embodiments, the eugeroic promoteswakefulness and alertness. In embodiments, the eugeroic is modafinil, pitolisant, solriamfetol, or armodafinil.

[0343] In embodiments, the cognitive enhancer is a nootropic. In embodiments, the nootropic improves human thinking, learning, and memory, including or especially in cases where these functions are impaired.

[0344] In embodiments, the nootropic is any of acetyl L-carnitine, alpha-GPC, alpha-lipoic acid (ALA), aniracetam, ashwagandha, astaxanthin, bacopa monnieri, berberine, black seed oil, cacao, caffeine, cannabidiol (CBD), CDP-choline, centrophenoxine, coconut oil, coluracetam, coenzyme Q10 (CoQ10), creatine, docosahexaenoic acid (DHA), dehydroepiandrosterone (DHEA), dimethylaminoethanol (DMAE), fisetin, ginkgo biloba, ginseng, glutathione, gotu kola, glycine, holy basil (tulsi), huperzine-A, kava kava, kratom, lion’s mane mushroom (Hericium erinaceus) or any hericenones or erinacines therefrom, L-carnosine, lemon balm, L-glutamine, L-theanine, maca, magnolia bark, N-acetyl L-cysteine, N-acetyl L-tyrosine, nicotinamide adenine dinucleotide + hydrogen (NADH), nefiracetam, oxiracetam, passionflower, picamilon, pine bark extract, piperine, piracetam, rhodiola rosea, phenylalanine, phenylethylamine (PEA), phenylpiracetam, phosphatidylcholine (PC), phosphatidylserine (PS), pyrroloquinoline quinone (PQQ), pramiracetam, pterostilbene, quercetin, resveratrol, St John’s wort, taurine, tryptophan, turmeric, L-tyrosine, thiamine (vitamin B1), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), inositol (vitamin B8), folate (vitamin B9), cobalamin (vitamin B12), D-serine, vitamin D (e.g., vitamin D3), L-serine, panax ginseng, gingko biloba, tanakan, salvia officinalis, lavandulaefolia, centella asiatica, nicotene, noopept, phenotropil, cholinergics, citicholine, choline bitartrate, ethomersol, bemithyl, pyrazidol, actovegin forte, bemethyl, phenibut, meldonium (e.g., mildronate), amphetamines, dextroamphetamines, or zinc.

[0345] In some embodiments, the cognitive enhancer is also an antidepressant. In some embodiments, the cognitive enhancer is not also an antidepressant.D. Other Agents to Improve Adherence

[0346] Anti-Inflammatory Agents. In embodiments, the therapeutic compound is an anti-inflammatory agent. “Anti-inflammatory agent” refers to a compound that can reduce inflammation or swelling, including common non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, diclofenac, and aspirin. In embodiments, the anti-inflammatory agent exerts neuroprotective and pro-cognitive effects, such as aspirin, for example, due to its ability to modulate neuroinflammation and central nervous system processes (see, e.g., Ng et al. Brain Sei. 2019;9(11):296). In embodiments, the anti-inflammatory agent reduces chronic, low-grade inflammation and reduces fatigue, pain, or mood disturbances, all of which can diminish motivation to adhere to diet, exercise, or medication instructions (see, e.g., Hotamisligil. Nature. 2006;444(7121 ):860— 867). In embodiments, the anti-inflammatory agent is any of prednisone, hydrocortisone, diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, meclofenamate, mefenamic acid, nabumetone, naproxen, tolmetin, piroxicam, celecoxib, etoricoxib, aspirin, meloxicam, an anti-cytokine agent (e.g., adalimumab, etanercept, infliximab, tocilizumab), or a selective COX-2 inhibitor (e.g., lumiracoxib). In embodiments, the anti-inflammatory agent is prednisone. In embodiments, the anti-inflammatory agent is hydrocortisone. In embodiments, the anti-inflammatory agent is diclofenac. In embodiments, the anti-inflammatory agent isetodolac. In embodiments, the anti-inflammatory agent is fenoprofen. In embodiments, the anti-inflammatory agent is flurbiprofen. In embodiments, the anti-inflammatory agent is ibuprofen. In embodiments, the antiinflammatory agent is indomethacin. In embodiments, the anti-inflammatory agent is meclofenamate. In embodiments, the anti-inflammatory agent is mefenamic acid. In embodiments, the anti-inflammatory agent is nabumetone. In embodiments, the anti-inflammatory agent is naproxen. In embodiments, the anti-inflammatory agent is tolmetin. In embodiments, the anti-inflammatory agent is piroxicam. In embodiments, the antiinflammatory agent is celecoxib. In embodiments, the anti-inflammatory agent is etoricoxib. In embodiments, the anti-inflammatory agent is aspirin. In embodiments, the anti-inflammatory agent is meloxicam. In embodiments, the anti-inflammatory agent is an anti-cytokine agent. In embodiments, the anti-cytokine agent is any of adalimumab, etanercept, infliximab, or tocilizumab. In embodiments, the anti-inflammatory agent is a selective COX-2 inhibitor. In embodiments, the selective COX-2 inhibitor is lumiracoxib.

[0347] Anxiolytic Agents. In embodiments, the therapeutic compound is an anxiolytic agent. “Anxiolytic agent” refers to a compound used for treatment of anxiety disorders and their related psychological and physical symptoms. In embodiments, the anxiolytic agent may work in different ways to reduce anxiety, such as by increasing or decreasing cell activity, by slowing down activity in the sympathetic nervous system, or by modulating monoaminergic neurotransmission. In embodiments, the anxiolytic agent is non-addictive (e.g., is not known to be habit-forming). In embodiments, the anxiolytic agent is any of a benzodiazepine, an azapirone (e.g., buspirone), an alpha blocker, a beta blocker, an antidepressant, a barbiturate (e.g., pentobarbital), a nonbenzodiazepine sedative, a hypnotic (e.g., zolpidem, zaleplon, or zopiclone), nefazodone, pregabalin, mirtazapine, baclofen, cyclobenzaprine, and gabapentin. In embodiments, the anxiolytic agent is a benzodiazepine. In embodiments, the benzodiazepine is any of alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, etizolam, flunitrazepam, flurazepam, flutoprazepam, halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, midazolam, nimetazepam, nitrazepam, oxazepam, prazepam, quazepam, temazepam, tetrazepam, or triazolam; or a pharmaceutically acceptable salt thereof. In some embodiments, the benzodiazepine is lorazepam, diazepam, alprazolam, or clonazepam. In embodiments, the therapeutic compound is not a benzodiazepine. In embodiments, the anxiolytic agent is not a benzodiazepine. In embodiments, the anxiolytic agent is a benzodiazepine, but is not a specific benzodiazepine. In embodiments, the anxiolytic agent is not lorazepam. In embodiments, the anxiolytic agent is not diazepam. In embodiments, the anxiolytic agent is not alprazolam. In embodiments, the anxiolytic agent is not clonazepam. In embodiments, the anxiolytic agent is not chlordiazepoxide. In embodiments, the anxiolytic agent is not chlordiazepoxide / clidinium bromide. In embodiments, the anxiolytic agent is a barbiturate. In embodiments, the barbiturate is pentobarbital. In embodiments, the pentobarbital is phenobarbital. In embodiments, the pentobarbital is amobarbital. In embodiments, the anxiolytic agent is an azapirone. In embodiments, the anxiolytic agent is an alpha blocker. In embodiments, the anxiolytic agent is a beta blocker. In embodiments, the beta blocker is propranolol. In embodiments, the anxiolytic agent is a nonbenzodiazepine sedative. In embodiments, the anxiolytic agent is a hypnotic. In embodiments, theanxiolytic agent is nefazodone. In embodiments, the anxiolytic agent is a pregabalin. In embodiments, the anxiolytic agent is mirtazapine. In embodiments, the anxiolytic agent is baclofen, a GABABreceptor agonist at pre- and post-synaptic neurons. In some embodiments, the anxiolytic agent is cyclobenzaprine, a muscle relaxant similar to TCAs. In embodiments, the anxiolytic agent is gabapentin. In embodiments, the anxiolytic agent is also an antidepressant. In other embodiments, the anxiolytic agent is not also an antidepressant.

[0348] Anti-Hyperglycemic Agents. In embodiments, the therapeutic compound is an anti-hyperglycemic agent. ‘Anti-hyperglycemic agent” refers to a compound that lowers glucose levels in the blood. For example, biguanides such as metformin decrease glucose production, decrease gastrointestinal glucose absorption, and increase target cell insulin sensitivity. “Insulin sensitivity” may refer to the ability of cells to respond to insulin and take up glucose from the bloodstream. Improved insulin sensitivity enhances monoaminergic neurotransmission, such as by stabilizing dopaminergic function, for example, which can improve a subject’s affective state(s) (see, e.g., Wiernsperger et al., Drugs. 1999; 58(1 Supp.): 31-39). In some embodiments, the anti-hyperglycemic agent is any of an insulin, a sulfonylurea (e.g., glipizide, glyburide, gliclazide, glimepiride), a meglitinide (e.g., repaglinide and nateglinide), a biguanide (e.g., metformin), a thiazolidinedione (e.g., rosiglitazone, pioglitazone), an a-glucosidase inhibitor (e.g., acarbose, miglitol, voglibose), a DPP-4 inhibitor (e.g., sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin), a SGLT2 inhibitor (e.g., dapagliflozin and canagliflozin), or a dopamine receptor agonist (e.g., bromocriptine). In embodiments, the anti-hyperglycemic agent is an insulin. Exemplary insulins include insulin glulisine (e.g., APIDRA®), insulin aspart (e.g., NOVOLOG®), insulin lispro U-100 / U-200 (e.g., HUMALOG®), regular insulin (e.g., Novolin R, Humulin R), and Neutral Protamine Hagedorn (NPH) insulin (e.g., Novolin N, Humulin N). In embodiments, the anti-hyperglycemic agent is insulin glulisine. In embodiments, the anti-hyperglycemic agent is insulin aspart. In embodiments, the anti-hyperglycemic agent is insulin lispro U-100 / U-200. In embodiments, the anti-hyperglycemic agent is regular insulin. In embodiments, the anti-hyperglycemic agent is NPH insulin. In embodiments, the anti-hyperglycemic agent is a sulfonylurea. In embodiments, the anti-hyperglycemic agent is a meglitinide. In embodiments, the anti-hyperglycemic agent is a biguanide. In embodiments, the anti-hyperglycemic agent is a thiazolidinedione. In embodiments, the anti-hyperglycemic agent is an a-glucosidase inhibitor. In embodiments, the anti-hyperglycemic agent is a DPP-4 inhibitor. In embodiments, the anti-hyperglycemic agent is a SGLT2 inhibitor. In embodiments, the anti-hyperglycemic agent is a dopamine receptor agonist. In embodiments, the anti-hyperglycemic agent is any of insulin glulisine, insulin aspart, insulin lispro, regular insulin, NPH insulin, glipizide, glyburide, gliclazide, glimepiride, repaglinide, nateglinide, metformin, rosiglitazone, pioglitazone, acarbose, miglitol, voglibose, sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, dapagliflozin, canagliflozin, or bromocriptine. In some embodiments, the anti-hyperglycemic agent is metformin.

[0349] Anticonvulsants. In embodiments, the therapeutic compound is an anticonvulsant. In embodiments, the anticonvulsant is any of carbamazepine, oxcarbazepine, lamotrigine, valproic acid, topiramate, levetiracetam, brivaracetam, or seletracetam. In some embodiments, the anticonvulsant is carbamazepine. Insome embodiments, the anticonvulsant is oxcarbazepine. In some embodiments, the anticonvulsant is lamotrigine. In some embodiments, the anticonvulsant is valproic acid. In some embodiments, the anticonvulsant is topiramate. In some embodiments, the anticonvulsant is levetiracetam. In some embodiments, the anticonvulsant is brivaracetam. In some embodiments, the anticonvulsant is seletracetam.

[0350] Atypical Antipsychotics. In embodiments, the therapeutic compound is an atypical antipsychotic. In embodiments, the atypical antipsychotic is aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, or clozapine. In embodiments, the atypical antipsychotic is aripiprazole. In embodiments, the atypical antipsychotic is lurasidone. In embodiments, the atypical antipsychotic is quetiapine. In embodiments, the atypical antipsychotic is cariprazine. In embodiments, the atypical antipsychotic is brexpiprazole. In embodiments, the atypical antipsychotic is olanzapine. In embodiments, the atypical antipsychotic is ziprasidone. In embodiments, the atypical antipsychotic is asenapine. In embodiments, the atypical antipsychotic is risperidone. In embodiments, the atypical antipsychotic is paliperidone. In embodiments, the atypical antipsychotic is lumateperone. In embodiments, the atypical antipsychotic is iloperidone. In embodiments, the atypical antipsychotic is pimavanserin. In embodiments, the atypical antipsychotic is clozapine.

[0351] NMDA Agents. In embodiments, the therapeutic compound is an N-methyl-D-aspartate (NMDA) receptor agent (“NMDA agent”). In embodiments, the NMDA agent is a partial NMDA receptor agonist, such as D-cycloserine (DCS). In embodiments, the NMDA agent is a partial agonist and is NRX-1074 or rapastinel (GLYX-13). In embodiments, the NMDA agent is any of plazinemdor, rapastinel, LY-2140023, NYX-458, NYX-783, NYX-2925, NRX-1074, SAGE-718, a substituted 1 ,2,3-triazole NMDA modulator such as disclosed in WO2017 / 139428A1 , a spiro-lactam NMDA modulator such as disclosed in WO2018 / 026798A1 , or an NMDA modulator disclosed in W02017 / 066590A1 (see, e.g., id. at

[0006] ). In embodiments, the NMDA agent is an NMDA antagonist. In embodiments the NMDA antagonist is memantine, amantadine, rimantadine, nitromemantine (YQW-36), or acamprosate. In embodiments, the NMDA agent is an NMDA antagonist, and the NMDA antagonist is acamprosate. In embodiments, the NMDA antagonist is pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, or ketobemidone. In embodiments the NMDA antagonist is dextromethorphan (DXM), dextrorphan, or dextrallorphan (DXA). In embodiments, the NMDA antagonist is gacyclidine (GK-11), neramexane, lanicemine (AZD6765), diphenidine, dizocilpine (MK-801), 8a-phenyldecahydroquinoline (8A-PDHQ), remacemide, ifenprodil, traxoprodil (CP-101 ,606), eliprodil (SL-82.0715), etoxadrol (CL-1848C), dexoxadrol, WMS-2539, NEFA, delucemine (NPS-1506), aptiganel (Cerestat; CNS-1102), midafotel (CPPene; SDZ EAA 494), dexanabinol (HU-211 or ETS2101), selfotel (CGS-19755), 7-chlorokynurenic acid (7-CKA), 5,7-dichlorokynurenic acid (5,7-DCKA), L-683344, L-689560, L-701324, GV150526A, GV196771A, CERC-301 (MK-0657), atomoxetine, LY-235959, CGP 61594, CGP 37849, CGP 40116 or CGP 37849, LY-233536, PEAQX (NVP-AAM077), ibogaine or noribogaine (or an ibogaine metabolite, ibogaine analog, or ibogaine derivative), Ro 25-6981 , GW468816, EVT-101, indantadol, perzinfotel (EAA-090), SSR240600, 2-MDP (U-23807A) or AP-7. In embodiments, the NMDA antagonist isketamine (and its analogs, e.g., tiletamine), phencyclidine (and its analogs, e.g., tenocyclidine, eticyclidine, rolicyclidine), or methoxetamine (and its analogs). In embodiments, the NMDA antagonist is ketamine, or a pharmaceutically acceptable salt thereof. In embodiments, the ketamine is racemic (±)-ketamine, or a pharmaceutically acceptable salt thereof. In embodiments, the ketamine is S(+)-ketamine (esketamine) or R(-)-ketamine (arketamine), or a pharmaceutically acceptable salt thereof. In embodiments, the ketamine is a non-racemic mixture of esketamine and arketamine, in any enantiomeric excess between 0% and 100% of either enantiomer. In embodiments, the NMDA antagonist is a ketamine metabolite. In embodiments, the ketamine metabolite is any of the 12 HNK metabolites formed from the metabolism of ketamine in vivo, including any of the stereoselective metabolites of esketamine or arketamine, including (R,S)-norketamine (NK), (R,S)-dehydronorketamine, hydroxyketamines, and hydroxynorketamines (HNKs), including by example (2S,6S;2R,6R)-HNK, (2R,4R;2S,4S-2S,6R;2R,6S)-HNK, and (2R,4S;2S,4R-2S,5S;2R,5R)-HNK (see, e.g., Farmer, 2020), and 2R,6R-hydroxynorketamine as well as its prodrugs (see, e.g., U.S. Pub. No. 2019 / 0380978A1), 2S,6S-hydroxynorketamine (see, e.g., U.S. Pub. No. 2020 / 0157040A1), as well as conformationally stabilized analogs of ketamine metabolites, e.g., 6-hydroxyketamine and 6-hydroxynorketamine (see, e.g., PCT Pub. No. WO2018 / 104729A1), and dehydronorketamines (DHNKs) such as R-5,6-dehydronorketamine and S-5,6-dehydronorketamine (see, e.g., PCT Pub. No. WO2019 / 058145A1); each of the above applications are incorporated by reference as if fully set forth herein.

[0352] In embodiments, the NMDA antagonist is ephenidine (NEDPA, EPE), p-keto-ephenidine, diphenidine (1,2-DEP, DPD, DND), isopropylphenidine (NPDPA), methoxphenidine (MXP), fluorolintane (2-FPPP, 2-F-DPPy), remacemide, or another diarylethylamine. In embodiments, the NMDA antagonist is a ketamine analog such as methoxetamine (2-MeO-2-deschloroketamine, MXE), 3-MeO-PCE, KEA-1010, N-ethyl-deschloroketamine (2'-Oxo-PCE, O-PCE), 2-fluoro-deschloroketamine [2-(2-fluorophenyl)-2-methyl- amino-cyclohexanone] (2-FDCK), deschloroketamine (2-phenyl-2-methylamino-cyclohexanone), DXE (2'-Oxo-PCM, aka DCK), alkyne-norketamine (A-NK), and the like. In embodiments, the NMDA antagonist is an arylcyclohexylamine or an arylcyclohexylamine derivative, such as disclosed in, e.g., WO2022 / 047256A1 , US2022 / 0041540A1 , and WO2021 / 255737A1 , incorporated by reference as if fully set forth. In embodiments, the NMDA antagonist is not an arylcyclohexylamine or an arylcyclohexylamine derivative. In embodiments, the NMDA receptor agent is rapastinel. In embodiments, the NMDA receptor agent is not rapastinel.

[0353] Phosphodiesterase Inhibitors. In embodiments, the therapeutic compound is a phosphodiesterase inhibitor. In embodiments, the phosphodiesterase inhibitor is a PDE-1 inhibitor. In embodiments, the phosphodiesterase inhibitor is a PDE-2 inhibitor. In embodiments, the phosphodiesterase inhibitor is a PDE-3 inhibitor. In embodiments, the phosphodiesterase inhibitor is a PDE-4 inhibitor. In embodiments, the PDE-4 inhibitor is apremilast. In embodiments, the phosphodiesterase inhibitor is a PDE-5 inhibitor.

[0354] Anti-Ischemic Agents. In embodiments, the therapeutic compound is an anti-ischemic agent. In embodiments, the anti-ischemic agent is meldonium.

[0355] Antimiqraine Agents. In embodiments, the therapeutic compound is an antimigraine agent. Inembodiments, the antimigraine agent is a triptan.

[0356] Antihistamines. In embodiments, the therapeutic compound is an antihistamine. In embodiments, the antihistamine is any of brompheniramine, cyproheptadine, chlorpheniramine, promethazine, claritin, fexofenadine, vistaril, hydroxyzine, alavert, diphenhydramine, levocetirizine, carbinoxamine, meclizine, dimenhydrinate or azelastine. In embodiments, the antihistamine is brompheniramine. In embodiments, the antihistamine is cyproheptadine. In embodiments, the antihistamine is chlorpheniramine. In embodiments, the antihistamine is promethazine. In embodiments, the antihistamine is claritin. In embodiments, the antihistamine is fexofenadine. In embodiments, the antihistamine is vistaril. In embodiments, the antihistamine is hydroxyzine. In embodiments, the antihistamine is alavert. In embodiments, the antihistamine is diphenhydramine. In embodiments, the antihistamine is levocetirizine. In embodiments, the antihistamine is carbinoxamine. In embodiments, the antihistamine is meclizine. In embodiments, the antihistamine is dimenhydrinate. In embodiments, the antihistamine is azelastine. In embodiments, the therapeutic compound is not an antihistamine. In embodiments, the antihistamine is not diphenhydramine. In embodiments, the antihistamine is not brompheniramine. In embodiments, the antihistamine is not dimenhydrinate. In embodiments, the antihistamine is not vistaril.

[0357] Anti-Craving Agents. In embodiments, the therapeutic compound is an anti-craving agent. In embodiments, the anti-craving agent is any of ondansetron, disulfiram, buprenorphine, topiramate, rimonabant, bupropion, modafinil, vigabatrin, or varenicline.

[0358] Antibiotics. In embodiments, the therapeutic compound is an antibiotic. In embodiments, the antibiotic agent is any of augmentin, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole, trimethoprim, or levofloxacin. In embodiments, the antibiotic is augmentin. In embodiments, the antibiotic is amoxicillin. In embodiments, the antibiotic is doxycycline. In embodiments, the antibiotic is cephalexin. In embodiments, the antibiotic is ciprofloxacin. In embodiments, the antibiotic is clindamycin. In embodiments, the antibiotic is metronidazole. In embodiments, the antibiotic is azithromycin. In embodiments, the antibiotic is sulfamethoxazole. In embodiments, the antibiotic is trimethoprim. In embodiments, the antibiotic is levofloxacin.

[0359] Opioid Modulators. In embodiments, the therapeutic compound is an opioid modulator. In embodiments, the opioid modulator is any of kratom, ignavine, salvinorin-A, DPI-289, UFP-505, naltrexone, samidorphan, vivitrol, buprenorphine, or LP1. In embodiments, the opioid modulator is kratom. In embodiments, the opioid modulator is ignavine. In embodiments, the opioid modulator is salvinorin-A. In embodiments, the opioid modulator is DPI-289. In embodiments, the opioid modulator is UFP-505. In embodiments, the opioid modulator is naltrexone. In embodiments, the opioid modulator is samidorphan. In embodiments, the opioid modulator is vivitrol. In embodiments, the opioid modulator is buprenorphrine. In embodiments, the opioid modulator is LP1. In embodiments, the therapeutic compound is not an opioid modulator. In embodiments, the opioid modulator is not any of kratom, ignavine, salvinorin-A, DPI-289, UFP-505, naltrexone, samidorphan, vivitrol, buprenorphine, or LP1. In embodiments, the opioid modulator isnot kratom. In embodiments, the opioid modulator is not ignavine. In embodiments, the opioid modulator is not salvinorin-A. In embodiments, the opioid modulator is not DPI-289. In embodiments, the opioid modulator is not UFP-505. In embodiments, the opioid modulator is not naltrexone. In embodiments, the opioid modulator is not samidorphan. In embodiments, the opioid modulator is not vivitrol. In embodiments, the opioid modulator is not buprenorphrine. In embodiments, the opioid modulator is not LP1.

[0360] Muscarinic Modulators. In embodiments, the therapeutic compound is a muscarinic modulator. A "muscarinic modulator" refers to a compound that binds to and influences the activity muscarinic acetylcholine receptors. In embodiments, the muscarinic receptor agonist is any of xanomeline, cevimeline, pilocarpine, bethanechol, carbachol, methacholine, arecoline, oxotremorine, or milameline. In embodiments, the muscarinic receptor agonist is xanomeline. In embodiments, the muscarinic receptor agonist is cevimeline. In embodiments, the muscarinic receptor agonist is pilocarpine. In embodiments, the muscarinic receptor agonist is bethanechol. In embodiments, the muscarinic receptor agonist is carbachol. In embodiments, the muscarinic receptor agonist is methacholine. In embodiments, the muscarinic receptor agonist is arecoline. In embodiments, the muscarinic receptor agonist is oxotremorine. In embodiments, the muscarinic receptor agonist is milameline. In embodiments, the therapeutic compound is not a muscarinic receptor agonist. In embodiments, the muscarinic receptor agonist is not any of xanomeline, cevimeline, pilocarpine, bethanechol, carbachol, methacholine, arecoline, oxotremorine, or milameline. In embodiments, the muscarinic receptor agonist is not xanomeline. In embodiments, the muscarinic receptor agonist is not cevimeline. In embodiments, the muscarinic receptor agonist is not pilocarpine. In embodiments, the muscarinic receptor agonist is not bethanechol. In embodiments, the muscarinic receptor agonist is not carbachol. In embodiments, the muscarinic receptor agonist is not methacholine. In embodiments, the muscarinic receptor agonist is not arecoline. In embodiments, the muscarinic receptor agonist is not oxotremorine. In embodiments, the muscarinic receptor agonist is not milameline.

[0361] Tryptamines. In embodiments, the therapeutic compound is a tryptamine psychedelic or entactogen. Exemplary tryptamine psychedelics and entactogens include those described in Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997), which is incorporated by reference as if fully set forth herein.

[0362] Phenethylamines. In embodiments, the therapeutic compound is a phenethylamine psychedelic or entactogen. Exemplary phenethylamine psychedelics and entactogens include those described in Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991)), and Oeri. Psychopharmacol., 2021 ;35(5):512- 536, both of which are incorporated by reference as if fully set forth herein.

[0363] Antioxidants. In embodiments, the therapeutic compound is an antioxidant. “Antioxidant” refers to a class of compounds that may prevent or delay cell damage. An antioxidant may work by inhibiting oxidation, or by removing potentially damaging oxidizing agents in a living organism. For example, antioxidants can fight damaging free radicals in an organism which can cause harm if levels become too high. Antioxidants are found in many foods, including fruits and vegetables. Antioxidants are also available as dietary supplements. In embodiments, the antioxidant is any of vitamin C (e.g., abcorbic acid), glutathione, flavonoids, alpha lipoic acid(ALA), B-carotene, vitamin E (e.g., alpha-tocopherol), ubiquinone, lycopene, coenzyme Q10 (CoQ10), ellagic acid, vitamin A (e.g., retinol), masoprocol, pramipexole, nitric oxide, allopurinol, pentoxifylline, melatonin, probucol, quercetin, acetylcysteine, N-acetylcysteine (NAC), acetyl-L-carnitine, or L-methylfolate. In embodiments, the antioxidant is vitamin C. In embodiments, the antioxidant is ascorbic acid. In embodiments, the antioxidant is glutathione. In embodiments, the antioxidant is flavonoids. In embodiments, the antioxidant is alpha lipoic acid. In embodiments, the antioxidant is B-carotene. In embodiments, the antioxidant is vitamin E. In embodiments, the antioxidant is alpha-tocopherol. In embodiments, the antioxidant is ubiquinone. In embodiments, the antioxidant is lycopene. In embodiments, the antioxidant is coenzyme Q10. In embodiments, the antioxidant is ellagic acid. In embodiments, the antioxidant is vitamin A. In embodiments, the antioxidant is masoprocol. In embodiments, the antioxidant is pramipexole. In embodiments, the antioxidant is nitric oxide. In embodiments, the antioxidant is allopurinol. In embodiments, the antioxidant is pentoxifylline. In embodiments, the antioxidant is melatonin. In embodiments, the antioxidant is probucol. In embodiments, the antioxidant is quercetin. In embodiments, the antioxidant is acetylcysteine. In embodiments, the antioxidant is N-acetylcysteine. In embodiments, the antioxidant is acetyl-L-carnitine. In embodiments, the antioxidant is L-methylfolate.

[0364] Serotonergic Agents. In embodiments, the therapeutic compound is a serotonergic agent. “Serotonergic agent” refers to a compound which modifies the effects of serotonin in a subject by acting on neurotransmission pathways involving serotonin. In embodiments, a “serotonergic agent” will be an agent that binds to, blocks, or otherwise influences (e.g., via an allosteric reaction) activity at one or more serotonin receptors, including any one or more serotonin receptor subtypes. In embodiments, a serotonergic agent is not a psychedelic. In embodiments, a serotonergic agent binds to a serotonin receptor. In embodiments, a serotonergic agent indirectly affects a serotonin receptor, e.g., via interactions affecting the reactivity of other molecules at the serotonin receptor. In embodiments, a serotonergic agent is an agonist, e.g., an agent activating a serotonin receptor. In embodiments, a serotonergic agent is an antagonist, e.g., an agent binding to, but not activating a serotonin receptor, e.g., blocking a receptor. In embodiments, a serotonergic agent is an effector molecule, e.g., an agent binding to an enzyme for allosteric regulation. In embodiments, a serotonergic agent acts (either directly or indirectly) at more than one type of receptor, including receptors other than serotonergic or other monoaminergic receptors. In embodiments, a serotonergic agent blocks the serotonin transporter (SERT) and results in an elevation of the synaptic concentration of serotonin, and an increase of neurotransmission. In embodiments, a serotonergic agent acts as a reuptake modulator and inhibits the plasmalemmal transporter-mediated reuptake of serotonin from the synapse into the presynaptic neuron, leading to an increase in extracellular concentrations of serotonin and an increase in neurotransmission. In embodiments, a serotonergic agent inhibits the activity of one or both monoamine oxidase enzymes, resulting in an increase in concentrations of serotonin and an increase in neurotransmission. In embodiments, a serotonergic agent is an antidepressant or anxiolytic, such as an SSRI, a serotonin-norepinephrine reuptake inhibitor (SNRI), a tricyclic antidepressant (TCA), a monoamine oxidase inhibitor (MAOI), or an atypical antidepressant. In other embodiments, a serotonergic agent is any of: (1) serotonin transport inhibitors; (2)serotonin receptor modulators; (3) serotonin reuptake inhibitors; (4) serotonin and norepinephrine reuptake inhibitors; (5) serotonin dopamine antagonists; (6) monoamine reuptake inhibitors; (7) pyridazinone aldose reductase inhibitors; (8) stimulants of serotonin receptors; (9) stimulants of serotonin synthesis; (10) serotonin receptor agonists; (11) serotonin receptor antagonists; and (12) serotonin metabolites. Additional serotonergic agents will be known to those in the art, found, for example, on DrugBank (https: / / go.drugbank.com).

[0365] In embodiments, the serotonergic agent is ondansetron. In embodiments, the therapeutic compound is not a serotonergic agent. In embodiments, the serotonergic agent is not ondansetron.

[0366] As appreciated by those in the art, additional agents of any disclosed class can be found, for example, on DrugBank and other known databases available to the ordinary artisan.

[0367] Mood Stabilizers. In embodiments, the therapeutic compound is a mood stabilizer. In embodiments, the mood stabilizer is lithium. In embodiments, the therapeutic compound is not a mood stabilizer. In embodiments, the mood stabilizer is not lithium.

[0368] Anticholinergic Agents. In embodiments, the therapeutic compound is an anticholinergic agent. In embodiments, the therapeutic compound is not an anticholinergic agent.

[0369] Neurotropic Agents. In embodiments, the therapeutic compound is a neurotropic agent. In embodiments, the therapeutic compound is an adaptogen. In embodiments, the therapeutic compound is an actoprotector. In embodiments, the therapeutic compound is an antihypoxant. In embodiments, the therapeutic compound is not a neurotropic agent. In embodiments, the therapeutic compound is not an adaptogen. In embodiments, the therapeutic compound is not an actoprotector. In embodiments, the therapeutic compound is not an anti hypoxant.

[0370] Anti-Hypertensive Agents. In embodiments, the therapeutic compound is an anti-hypertensive agent. “Anti-hypertensive agent” refers to a compound that lowers blood pressure when administered to a subject. Anti-hypertensive agents are commonly used for treatment of hypertension, or high blood pressure.

[0371] In embodiments, the anti-hypertensive agent is any of nimodipine, a diuretic, a beta-blocker, an ACE inhibitor, an Angiotensin II receptor blocker, a calcium channel blocker, an alpha blocker, an alpha-2 receptor agonist, a combined alpha and beta-blocker, a central agonist, a peripheral adrenergic inhibitor, or a vasodilator. In embodiments, the anti-hypertensive agent is nimodipine. In embodiments, the anti-hypertensive agent is a diuretic. In embodiments, the anti-hypertensive agent is a beta-blocker. In embodiments, the anti-hypertensive agent is an ACE inhibitor. In embodiments, the anti-hypertensive agent is an Angiotensin II receptor blocker. In embodiments, the anti-hypertensive agent is a calcium channel blocker. In embodiments, the anti-hypertensive agent is an alpha blocker. In embodiments, the anti-hypertensive agent is an alpha-2 receptor agonist. In embodiments, the anti-hypertensive agent is a combined alpha and beta-blocker. In embodiments, the anti-hypertensive agent is a central agonist. In embodiments, the anti-hypertensive agent is a peripheral adrenergic inhibitor. In embodiments, the anti-hypertensive agent is a vasodilator.

[0372] Neuroendocrine Agents. In embodiments, the therapeutic compound is a neuroendocrine agent. A "neuroendocrine agent" refers to a compound that modulates the interaction between the nervous system andthe endocrine system, such as by influencing the inflammation-oxidative stress-insulin resistance pathway. In embodiments, agents modulating the inflammation-oxidative stress-insulin resistance pathway can improve metabolism, mood, and energy levels, thus aiding adherence. Some neuroendocrine agents may help regulate appetite and body weight, reinforcing maintaining healthy habits. In embodiments, the neuroendocrine agent is any of metformin, omega-3 fatty acids, curcumin, N-acetylcysteine, resveratrol, acetyl-L-carnitine, pioglitazone, vitamin D, meldonium, solriamfetol, aspirin, aripiprazole, brexpiprazole, cariprazine, haloperidol, lurasidone, topiramate, progesterone, bupropion, a GLP-1 receptor agonist, GLP1 / glucose-dependent insulinotropic polypeptide receptor dual agonist, dipeptidyl peptidase-4 inhibitor, sodium / glucose cotransporter 2 inhibitor, sulfonylurea, meglitinide, or thiazolidinedione. In embodiments, the neuroendocrine agent is metformin. In embodiments, the neuroendocrine agent is omega-3 fatty acids. In embodiments, the neuroendocrine agent is curcumin. In embodiments, the neuroendocrine agent is N-acetylcysteine. In embodiments, the neuroendocrine agent is resveratrol. In embodiments, the neuroendocrine agent is acetyl-L-carnitine. In embodiments, the neuroendocrine agent is pioglitazone. In embodiments, the neuroendocrine agent is vitamin D. In embodiments, the neuroendocrine agent is meldonium. In embodiments, the neuroendocrine agent is solriamfetol. In embodiments, the neuroendocrine agent is aspirin. In embodiments, the neuroendocrine agent is aripiprazole. In embodiments, the neuroendocrine agent is brexpiprazole. In embodiments, the neuroendocrine agent is cariprazine. In embodiments, the neuroendocrine agent is haloperidol. In embodiments, the neuroendocrine agent is lurasidone. In embodiments, the neuroendocrine agent is topiramate. In embodiments, the neuroendocrine agent is progesterone. In embodiments, the neuroendocrine agent is bupropion. In embodiments, the neuroendocrine agent is a GLP-1 receptor agonist. In embodiments, the neuroendocrine agent is a GLP1 / glucose-dependent insulinotropic polypeptide receptor dual agonist. In embodiments, the neuroendocrine agent is a dipeptidyl peptidase-4 inhibitor. In embodiments, the neuroendocrine agent is a sodium / glucose cotransporter 2 inhibitor. In embodiments, the neuroendocrine agent is a sulfonylurea. In embodiments, the neuroendocrine agent is a meglitinide. In embodiments, the neuroendocrine agent is a thiazolidinedione. In embodiments, the therapeutic compound is not a neuroendocrine agent. In embodiments, the neuroendocrine agent is not any of metformin, omega-3 fatty acids, curcumin, N-acetylcysteine, resveratrol, acetyl-L-carnitine, pioglitazone, vitamin D, meldonium, solriamfetol, aspirin, aripiprazole, brexpiprazole, cariprazine, haloperidol, lurasidone, topiramate, progesterone, bupropion, a GLP-1 receptor agonist, GLP1 / glucose-dependent insulinotropic polypeptide receptor dual agonist, dipeptidyl peptidase-4 inhibitor, sodium / glucose cotransporter 2 inhibitor, sulfonylurea, meglitinide, or thiazolidinedione. In embodiments, the neuroendocrine agent is not metformin. In embodiments, the neuroendocrine agent is not omega-3 fatty acids. In embodiments, the neuroendocrine agent is not curcumin. In embodiments, the neuroendocrine agent is not N-acetylcysteine. In embodiments, the neuroendocrine agent is not resveratrol. In embodiments, the neuroendocrine agent is not acetyl-L-carnitine. In embodiments, the neuroendocrine agent is not pioglitazone. In embodiments, the neuroendocrine agent is not vitamin D. In embodiments, the neuroendocrine agent is not meldonium. In embodiments, the neuroendocrine agent is notsolriamfetol. In embodiments, the neuroendocrine agent is not aspirin. In embodiments, the neuroendocrine agent is not aripiprazole. In embodiments, the neuroendocrine agent is not brexpiprazole. In embodiments, the neuroendocrine agent is not cariprazine. In embodiments, the neuroendocrine agent is not haloperidol. In embodiments, the neuroendocrine agent is not lurasidone. In embodiments, the neuroendocrine agent is not topiramate. In embodiments, the neuroendocrine agent is not progesterone. In embodiments, the neuroendocrine agent is not bupropion. In embodiments, the neuroendocrine agent is not a GLP-1 receptor agonist. In embodiments, the neuroendocrine agent is not a GLP1 / glucose-dependent insulinotropic polypeptide receptor dual agonist. In embodiments, the neuroendocrine agent is not a dipeptidyl peptidase-4 inhibitor. In embodiments, the neuroendocrine agent is not a sodium / glucose cotransporter 2 inhibitor. In embodiments, the neuroendocrine agent is not a sulfonylurea. In embodiments, the neuroendocrine agent is not a meglitinide. In embodiments, the neuroendocrine agent is not a thiazolidinedione.E. Synergistic Effects

[0373] In some embodiments where a combination or method comprises two or more therapeutic compounds and other active agents (e.g., additional active agents), such compounds and / or agents are selected to provide synergy or a synergistic effect.

[0374] “Synergy” or a “synergistic effect” include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect (including one or more additional therapeutic effects), that are greater than the additive contributions of the components (e.g., compounds or agents) acting alone. A synergistic effect may, for example, enable treatment using lower amounts (doses) of one or more compounds, including of only one compound in a combination (“apparent one-way synergy”), or of two or more compounds in a combination (e.g., “two-way synergy”), than would normally be required when each compound is used alone. Lower doses may result in lower toxicity without reduced efficacy. A synergistic effect also may result in improved efficacy.

[0375] Numerous methods will be known to those of skill to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1 +1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch Exp Pathol Pharmacol. 114: 313-326). A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981 , Clin Pharmacokinet. 6: 429-453) and the median-effect equation (Chou & Talalay, 1984, Adv Enzyme Regul. 22:27-55). The corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing synergistic effects.F. Additional Active Agents

[0376] In embodiments, a combination or method further comprises one or more additional active agents.

[0377] In embodiments, the one or more additional active agents may contribute to or provide an additional therapeutic effect, or a synergistic effect. An additional active agent may decrease an unwanted effect, improvebioavailability, increase efficacy, alter a property in a desirable way, such as pharmacokinetics (PK) or pharmacodynamics (PD), or modulate a desired system or pathway (e.g., a neurotransmitter system).

[0378] In embodiments, the additional active agent is selected to provide an additional therapeutic effect, such as antioxidant, anti-inflammatory, analgesic, anti neuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, anticholinergic, anti-ischemic, antihistamine, anti-craving, antibiotic, antihypertensive, anticonvulsant, anticholinergic, antiepileptic, bronchodilator, mood stabilizing, neuroprotective, serotonergic, neuroactive, entactogenic, empathogenic, entheogenic, euphoric, neurotropic, psychedelic, sedative, stimulant, adaptogenic, actoprotectant, antihypoxant, and opioidergic effects.

[0379] In embodiments, the additional active agent is an amino acid, antioxidant, anti-inflammatory agent, analgesic, anti-hyperglycemic agent, anti neuropathic or antinociceptive agent, antimigraine agent, anxiolytic, antidepressant, antipsychotic, anti-PTSD agent, cannabinoid, dissociative (e.g., dissociative anesthetic), immunostimulant, anti-cancer agent, antiemetic, orexigenic, antiulcer agent, anticholinergic agent, anti-ischemic agent, antihistamine (e.g., diphenhydramine, meclizine, promethazine, dimenhydrinate), anti-craving agent, antibiotic, anti-hypertensive agent, antimigraine agent, anticonvulsant, anticholinergic agent, antiepileptic, bronchodilator, mood stabilizer, cognitive enhancer, neuroprotectant, serotonergic agent, neuroactive agent, neurotropic agent, adaptogen, actoprotector, antihypoxant, entactogen or empathogen, entheogen, psychedelic, monoamine oxidase inhibitor (MAOI), tryptamine, terpene, phenethylamine, sedative, stimulant, opioid modulator, N-methyl-D-aspartate (NMDA) receptor agent, vitamin, SSRI, SNRI, NRI, NDRI, TCA, benzodiazepine, or phosphodiesterase inhibitor (e.g., a PDE-1 inhibitor, a PDE-2 inhibitor, a PDE-3 inhibitor, a PDE-4 inhibitor such as apremilast, or a PDE-5 inhibitor).

[0380] For any disclosed class of compounds, additional compounds in such class will be known to those in the art, or can be found according to skill in the art, for example, on DrugBank (https: / / go.drugbank.com / ).

[0381] In embodiments, the additional active agent is zolpidem tartrate, e.g., up to a maximum dose of 10 mg / day, or zaleplon, e.g., up to a maximum dose of 20 mg / day for insomnia as clinically indicated.

[0382] In embodiments, the additional active agent is lorazepam, e.g., for agitation. Administration of lorazepam within six hours of the administration of rating scales is preferably avoided.

[0383] In embodiments, a disclosed method comprises administering one or more disclosed therapeutic compounds in combination with a nicotinamide adenine dinucleotide (NAD+) and enkephalinase inhibitor infusion (IV1114589NAD) (see, e.g., Blum et al. Curr Psychiatry Res Rev. 2022; 18(2): 125-143).

[0384] In other embodiments, concomitant administration of other active agents is not employed. For example, in some embodiments, agents with prominent orexigenic / anorexigenic effects, e.g., anticholinergics, amphetamines, mood stabilizers, opioid analgesics, antidepressants including tricyclics, SSRIs, MAO inhibitors, bupropion, and mirtazapine, are excluded from the disclosed combinations and methods.

[0385] In some embodiments, the additional active agent is another “therapeutic compound” disclosed herein (e.g., a MAOI, antidepressant, cognitive enhancer, anti-inflammatory agent, anxiolytic agent, anti-hyper-glycemic agent, anticonvulsant, atypical antipsychotic, NMDA agent, antihistamine, anti-craving agent, antibiotic, opioid modulator, tryptamine, phenethylamine, antioxidant, benzodiazepine, serotonergic agent, mood stabilizer, anticholinergic agent, neurotropic agent, adaptogen, actoprotector, antihypoxant, or anti-hypertensive agent). For example, in embodiments, a disclosed method comprises administering a RIMA in combination with an additional therapeutic compound (e.g., antidepressant, cognitive enhancer, anti-inflammatory agent, anxiolytic agent, anti-hyperglycemic agent, anticonvulsant, atypical antipsychotic, NMDA agent, antihistamine, anti-craving agent, antibiotic, opioid modulator, tryptamine, phenethylamine, antioxidant, benzodiazepine, serotonergic agent, mood stabilizer, anticholinergic agent, neurotropic agent, adaptogen, actoprotector, antihypoxant, or anti-hypertensive agent). In other words, certain combinations and methods comprise two or more therapeutic compounds, and in some such embodiments, one or more of the therapeutic compounds may be referred to or considered an “additional active agent.”G. Combinations

[0386] In embodiments, administering a first therapeutic compound in combination with a second therapeutic compound, as disclosed herein, produces beneficial effects for improving adherence to a lifestyle modification recommendation in a subject following discontinued primary treatment, such as for obesity or hyperglycemia. In embodiments, administering a first therapeutic compound in combination with a second therapeutic compound, as disclosed herein, produces synergistic effects for improving adherence to a lifestyle modification recommendation in a subject following discontinued primary treatment, such as for obesity or hyperglycemia. In embodiments, administering a first therapeutic compound in combination with a second therapeutic compound, as disclosed herein, improves adherence to a lifestyle modification recommendation in a subject following discontinued primary treatment, such as for obesity or hyperglycemia.

[0387] In embodiments, administering a first therapeutic compound in combination with a second therapeutic compound produces synergistic effects for treatment of PFAOMC in a subject, such as where the PFAOMC pertains to improving adherence following primary treatment for chronic obesity or chronic hyperglycemia.

[0388] In some embodiments, the first therapeutic compound is moclobemide. In embodiments, administering moclobemide to a subject affects motivation, emotion, and insulin sensitivity via release of monoaminergic neurotransmitters (e.g., norepinephrine, serotonin, and dopamine), administering moclobemide to a subject does not have significant negative effects on psychomotor performance, cognitive function or cardiovascular system (see, e.g., Hindmarch et al. Dementia. 1992;3(5-6): 355-359). In embodiments, administering moclobemide to a subject provides antioxidant or anti-inflammatory effects.

[0389] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with one or more other therapeutic compounds produces beneficial effects, such as synergistic effects, for improving adherence to a lifestyle modification recommendation in a subject following discontinued primary treatment for obesity or hyperglycemia. In embodiments, moclobemide causes a decrease in the metabolism and destruction of monoamines in neurotransmitters (see, e.g., Moclobemide. go.drugbank.com).

[0390] In embodiments, administering a therapeutic compound, such as moclobemide, in combination withmetformin improves adherence to a lifestyle modification recommendation in a subject following discontinued primary treatment for obesity or hyperglycemia. In embodiments, metformin improves the metabolic profile, cognitive function, and emotional function in a subject, as metformin acts on the limbic system of the brain. In embodiments, metformin improves glucoregulatory function in a subject by increasing insulin sensitivity in conjunction with decreased gluconeogenesis in the liver. In embodiments, metformin does not put a subject at risk for hypoglycemia, as it does not alter insulin secretion (see, e.g., Can Fam Physician. 2006; 52(4):449— 452). In embodiments, metformin exerts robust antioxidant and anti-inflammatory effects, such as decreased growth / differentiation factor 15 (see, e.g., Obi et al. J Diabetes Res. 2016;2016:1635361 ; Bai et al. Front Pharmacol. 2021 ; 12:622262; Dehkordi et al. J Renal Injury Prevention. 2018;8(1):54-61 ; and Bootcov et al. Proc. Natl. Acad. Sci. U.S.A. 1997;94(21):11514-11519). In embodiments, metformin improves affective states including because of its anti-inflammatory, antioxidant, neuro-restorative, and / or neuro-protective effects (see, e.g., Khedr et al., Naunyn Schmiedebergs Arch Pharmacol. 2018;391 (4):407-422; Poggini et al. Neural Plast. 2019;2019:4651031 ; Hosseini et al. World J Biol Psychiatry. 202217:1-14; Abrahamian et al. Neuropsychiatr Dis Treat. 2009;5:261-6; Guo et al. Clin Exp Pharmacol Physiol. 2014;41 (9):650-6; Abrahamian et al. Neuropsychiatr Dis Treat. 2012;8:355-60; Isoda et al. Arterioscler Thromb Vase Biol. 2006;26(3):611-7; and Afshari et al. Spinal Cord. 2018;56(11): 1032-1041).

[0391] In embodiments, co-administration of moclobemide and metformin treats both mood and metabolic derangements in a subject, such as synergistically. In embodiments, co-administration of moclobemide and metformin increases monoamine neurotransmitters and improves insulin sensitivity is correlated with motivation, emotions, and mood (Jiang et al., 2022; and Gruber, et al., Neurosci Biobehav Rev. 2023; 149). In embodiments, co-administration of moclobemide and metformin provides advantages because of their half-lives of 6.3 hours and 6.4 hours, respectively (Isbister et al. BrJ CIin Pharmacol. 2003; 56(4):441 -450).

[0392] In embodiments, a RIMA and an anti-hyperglycemic agent are co-administered. In embodiments, moclobemide and an anti-hyperglycemic agent are co-administered. In embodiments, a RIMA and metformin are co-administered. In embodiments, moclobemide and metformin are co-administered.

[0393] In embodiments, administering a RIMA in combination with an anti-hyperglycemic agent improves treatment adherence in a subject following discontinued treatment for obesity or hyperglycemia, such as synergistically. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with an anti-hyperglycemic agent improves treatment adherence in a subject. In embodiments, administering a RIMA in combination with metformin synergistically improves treatment adherence in a subject. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with metformin improves treatment adherence in a subject.

[0394] Herein, where a combination is administered, such as where two or more therapeutic compounds are co-administered, it will be understood that in some embodiments, the combination and the methods of administering the combination, provide synergy or have synergistic effects, even where not stated explicitly. In other embodiments, the effects may not be synergistic, such as may be additive, or need not be to be useful.

[0395] Non-limiting exemplary combinations, which may be synergistic combinations, include moclobemide and nimodipine; moclobemide and propranolol; moclobemide and solriamfetol; moclobemide and modafinil; moclobemide and lumiracoxib; moclobemide and N-acetylcysteine; moclobemide and vitamin D; moclobemide and meldonium; moclobemide and phenylpiracetam; moclobemide and L-methylfolate; moclobemide and acetyl-L-carnitine; moclobemide and apremilast; moclobemide and lorazepam; moclobemide and bupropion; moclobemide and naltrexone; moclobemide, naltrexone, and apremilast; moclobemide and ibuprofen; meldonium and naltrexone; meldonium and apremilast; meldonium, naltrexone, and apremilast; phenylpiracetam and naltrexone; phenylpiracetam and apremilast; and phenylpiracetam, naltrexone, and apremilast.

[0396] In some embodiments, naltrexone is administered at a low dose, e.g., lower than a standard dose, as would be understood in the art, e.g., in view of the product labeling and routine clinical practice.

[0397] In embodiments, a RIMA and an anti-hypertensive agent are co-administered. In embodiments, moclobemide and an anti-hypertensive agent are co-administered. In embodiments, a RIMA and nimodipine are co-administered. In embodiments, moclobemide and nimodipine are co-administered. In embodiments, a RIMA and an anxiolytic agent are co-administered. In embodiments, moclobemide and an anxiolytic agent are co-administered. In embodiments, a RIMA and propranolol are co-administered. In embodiments, a RIMA and lorazepam are co-administered. In embodiments, moclobemide and propranolol are co-administered. In embodiments, moclobemide and lorazepam are co-administered. In embodiments, a RIMA and an antidepressant are co-administered. In embodiments, a RIMA and an NRDI are co-administered. In embodiments, moclobemide and an antidepressant are co-administered. In embodiments, moclobemide and an NRDI are co-administered. In embodiments, a RIMA and solriamfetol are co-administered. In embodiments, moclobemide and solriamfetol are co-administered. In embodiments, a RIMA and bupropion are co-administered. In embodiments, moclobemide and bupropion are co-administered.

[0398] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with phenylpiracetam improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia, such as synergistically. In embodiments, administering phenylpiracetam (e.g., Phenotropil) enhances cognition and improves physical performance in a subject (Napoletano et al. Front Psychiatry. 2020; 11 :546796). In embodiments, administering phenylpiracetam improves glucose metabolism and enhances mood, focus, and motivation (Zvejniece et al. Pharmacol Biochem Behav. 2017;160:21-29).

[0399] In embodiments, a therapeutic compound administered is meldonium (e.g., Mildronate). In embodiments, administering a therapeutic compound, such as moclobemide, in combination with meldonium improves adherence to a lifestyle modification in a subject following primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administering meldonium or another anti-ischemic agent improves blood flow to the heart and reduces its workload. In embodiments, administering meldonium or another anti-ischemic agent acts as an anti-ischemic cell protector in subjects with angina pectoris, chronic heart failure, or brain circulation disorders, and improves physical capacity and mental function.

[0400] In embodiments, administering meldonium or another anti-ischemic agent induces beneficial effects in cardiovascular, neurological and metabolic diseases. In embodiments, meldonium or another anti-ischemic agent is administered to provide cardioprotective properties, such as because of inhibition of p-oxidation and activation of glycolysis. In embodiments, meldonium or another anti-ischemic agent is administered to interfere with L-carnitine metabolism, especially in relation to metabolism for the mitochondrial oxidation of fatty acids.

[0401] In embodiments, meldonium or another anti-ischemic agent is administered to decrease blood glucose concentrations in subjects with chronic obesity or chronic hyperglycemia (Liepinsh et al. Eur J Pharmacol. 2011 ;658(2-3):277-283). In embodiments, meldonium or another anti-ischemic agent is administered to improve mood and enhance cognition (Sjakste et al. CNS Drug Rev. 2005; 11 (2): 151 -168; Schobersberger, 2017). In embodiments, meldonium or another anti-ischemic agent is administered for improvement of reduced work capacity, as well as for physical and psycho-emotional overexertion. In embodiments, meldonium or another anti-ischemic agent is administered to improve mood, motivation, and glucoregulation in a subject.

[0402] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with vitamin D improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administration of vitamin D (e.g., vitamin D3) induces beneficial effects on cognition, behavior, mood, and glucoregulation (Huiberts & Smolders. Sleep Med Rev. 2021 ;55: 101379).

[0403] In embodiments, a RIMA and a cognitive enhancer are co-administered. In embodiments, a RIMA and a eugeroic are co-administered. In embodiments, a RIMA and a nootropic are co-administered. In embodiments, moclobemide and a cognitive enhancer are co-administered. In embodiments, moclobemide and a eugeroic are co-administered. In embodiments, moclobemide and a nootropic are co-administered. In embodiments, a RIMA and modafinil are co-administered. In embodiments, moclobemide and modafinil are co-administered. In embodiments, a RIMA and meldonium are co-administered. In embodiments, moclobemide and meldonium are co-administered. In embodiments, a RIMA and phenylpiracetam are co-administered. In embodiments, moclobemide and phenylpiracetam are co-administered. In embodiments, a RIMA and vitamin D are co-administered. In embodiments, moclobemide and vitamin D are co-administered.

[0404] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with naltrexone improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administering a therapeutic compound in combination with low-dose naltrexone, or administering low-dose naltrexone alone, such as in a daily dose of between about 1 to 5 mg, provides paradoxical effects, such as analgesia and anti-inflammatory actions (Choubey et al. J Biol Chem. 2020 Nov 27;295(48): 16359-16369). In embodiments, administering a therapeutic compound in combination with low-dose naltrexone, or administering low-dose naltrexone alone, simultaneously has an antagonistic effect on nonopioid receptors that is not provided at higher doses. In embodiments, such as where insulin resistance is associated with a chronic low-grade inflammatory state, administration of low-dose naltrexone improves insulin sensitivity and treats insulin resistance, inflammation,and associated metabolic disease.

[0405] In embodiments, a RIMA and an opioid modulator are co-administered. In embodiments, moclobemide and an opioid modulator are co-administered. In embodiments, a RIMA and naltrexone are co-administered. In embodiments, moclobemide and naltrexone are co-administered.

[0406] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with apremilast improves adherence to a lifestyle modification recommendation in a subject following (i.e., after discontinuing) primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with apremilast reduces the production of inflammatory mediators and decreases the inflammatory response in subjects. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with apremilast improves insulin sensitivity and improves treatment adherence to a lifestyle modification recommendation. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with apremilast improves motivation and reduce alcohol consumption in subjects with alcohol use disorder (AUD) by increasing neural activity in the nucleus accumbens (see, e.g., Grigsby et al. J Clin Invest. 2023; 133(6):e159103).

[0407] In embodiments, a RIMA and a phosphodiesterase inhibitor are co-administered. In embodiments, a RIMA and a PDE-4 inhibitor are co-administered. In embodiments, moclobemide and a phosphodiesterase inhibitor are co-administered. In embodiments, moclobemide and a PDE-4 inhibitor are co-administered. In embodiments, moclobemide and apremilast are co-administered.

[0408] In embodiments, a RIMA and an anti-inflammatory agent are co-administered. In embodiments, moclobemide and an anti-inflammatory agent are co-administered. In embodiments, a RIMA and ibuprofen are co-administered. In embodiments, moclobemide and ibuprofen are co-administered. In embodiments, a RIMA and a selective COX-2 inhibitor are co-administered. In embodiments, moclobemide and a selective COX-2 inhibitor are co-administered. In embodiments, a RIMA and lumiracoxib are co-administered. In embodiments, moclobemide and lumiracoxib are co-administered.

[0409] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with an anti-inflammatory agent, improves insulin resistance and glucoregulatory function, and results in suppression of inflammatory responses and improved monoaminergic neurotransmission (Katsiki et al. J. Diabetes Complications. 2020;34(12):107723; Ostadkarampour et al. Front Pharmacol. 2021 ;12:676239; Yaribeygi et al. J. Cell Physiol. 2019;234(6):8286-8294; and Gonzalez-Hunt et al. Current Opinion on Toxicology. 2018;7:87-94). In embodiments, administering a therapeutic compound, such as moclobemide, in combination with an anti-inflammatory agent decreases the amount of inflammatory cytokines in the blood. In some embodiments, moclobemide provides synergistic anti-inflammatory effects (Lin et al. J. Affect Disord. 2000;58(1):69-74; and Bielecka et al. Naunyn Schmiedebergs Arch Pharmacol. 2010;382(5-6):409-17).

[0410] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with an antioxidant improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administering a therapeuticcompound, such as moclobemide, in combination with an antioxidant targets different free radicals and various junctures of oxidative stress, and increases concentrations of glutathione, nitric oxide, and superoxide dismutase (see, e.g., Herraiz et al. Biomed. Res. Int. 2018:4810394; Krauss et al. Med. Sci. Monit. 2003;9(11 ): BR389-393; and Albayrak et al. Eurasian J. Med. 2015;47(1 ):32-40).

[0411] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with N-acetylcysteine (NAC) improves adherence to a lifestyle modification recommendation in a subject following treatment for obesity or hyperglycemia. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with NAC decreases glutamatergic dysfunction, improves cognitive performance, enhances mood, and boosts energy and motivation (see, e.g., NACET: Review of Nootropic Benefits, Dosage, & Side Effects. Wholisticresearch.com; Wright et al. Hum Mol Genet. 2016;25(14):2923-2933). In embodiments, administration of NAC improves symptoms of anxiety or depression.

[0412] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with acetyl-L-carnitine improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with acetyl-L-carnitine improves mood, energy levels, general functioning, and glucose homeostasis (see, e.g., Di Emidio et al., Antioxidants 2020;9:867; and Malaguarnera et al. Scand J Gastroenterol. 2011 ;46(6):750-759). In embodiments, administration of acetyl-L-carnitine improves mood and glucoregulatory function.

[0413] In embodiments, administering a therapeutic compound, such as moclobemide, in combination with L-methylfolate improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia. In embodiments, administering a therapeutic compound, such as moclobemide, in combination with L-methylfolate regulates the synthesis of monoaminergic neurotransmitters, and improves mood, behavior, and emotion (Stahl SM. J Clin Psych. 2008; 69(9):1352-1353). In embodiments, administration of L-methylfolate improves insulin resistance. In embodiments, administration of L-methylfolate has beneficial effects on mood and glucoregulation. In embodiments, L-methylfolate is administered to subjects with a methylenetetrahydrofolate reductase (MTHFR) deficiency.

[0414] In embodiments, a RIMA and an antioxidant are co-administered. In embodiments, a therapeutic compound, such as moclobemide, and an antioxidant are co-administered. In embodiments, a RIMA and N-acetylcysteine are co-administered. In embodiments, a therapeutic compound, such as moclobemide, and N-acetylcysteine are co-administered. In embodiments, a RIMA and acetyl-L-carnitine are co-administered. In embodiments, a therapeutic compound, such as moclobemide, and acetyl-L-carnitine are co-administered. In embodiments, a RIMA and L-methylfolate are co-administered. In embodiments, a therapeutic compound, such as moclobemide, and L-methylfolate are co-administered.

[0415] In embodiments, a RIMA, an opioid modulator, and a phosphodiesterase inhibitor (including a PDE-4 inhibitor) are co-administered. In embodiments, a therapeutic compound, such as moclobemide, an opioid modulator, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, aRIMA, naltrexone, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, a RIMA, an opioid modulator, and apremilast are co-administered. In embodiments, a therapeutic compound, such as moclobemide, naltrexone, and apremilast are co-administered. Such co-administration of any of the foregoing improves adherence to a lifestyle modification recommendation in a subject following primary treatment, such as for chronic obesity or chronic hyperglycemia. For example, in embodiments, administering a therapeutic compound, such as moclobemide, in combination with an opioid modulator and a phosphodiesterase inhibitor improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia.

[0416] In embodiments, a cognitive enhancer, an opioid modulator, and a phosphodiesterase inhibitor are co-administered. In embodiments, a cognitive enhancer, an opioid modulator, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, phenylpiracetam, an opioid modulator, and a phosphodiesterase inhibitor are co-administered. In embodiments, phenylpiracetam, an opioid modulator, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, a cognitive enhancer, naltrexone, and a phosphodiesterase inhibitor are co-administered. In embodiments, a cognitive enhancer, naltrexone, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, a cognitive enhancer, an opioid modulator, and apremilast are co-administered. In embodiments, phenylpiracetam, naltrexone, and apremilast are co-administered. In embodiments, meldonium, an opioid modulator, and a phosphodiesterase inhibitor are co-administered. In embodiments, meldonium, an opioid modulator, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, a cognitive enhancer, naltrexone, and a phosphodiesterase inhibitor are co-administered. In embodiments, a cognitive enhancer, naltrexone, and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, a cognitive enhancer, an opioid modulator, and apremilast are co-administered. In embodiments, meldonium, naltrexone, and apremilast are co-administered. Such co-administration of any of the foregoing improves adherence to a lifestyle modification recommendation in a subject following primary treatment, such as for chronic obesity or chronic hyperglycemia. For example, in embodiments, administering phenylpiracetam in combination with an opioid modulator and a phosphodiesterase inhibitor improves adherence to a lifestyle modification recommendation in a subject following primary treatment. For example, in embodiments, administering meldonium in combination with an opioid modulator and a phosphodiesterase inhibitor improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia.

[0417] In embodiments, a cognitive enhancer and an opioid modulator are co-administered. In embodiments, meldonium and an opioid modulator are co-administered. In embodiments, phenylpiracetam and an opioid modulator are co-administered. In embodiments, a cognitive enhancer and naltrexone are co-administered. In embodiments, meldonium and naltrexone are co-administered. In embodiments, phenylpiracetam and naltrexone are co-administered. In embodiments, a cognitive enhancer and a phosphodiesterase inhibitor are co-administered. In embodiments, a cognitive enhancer and a phosphodiesterase inhibitor (e.g., a PDE-4inhibitor) are co-administered. In embodiments, meldonium and a phosphodiesterase inhibitor are co-administered. In embodiments, meldonium and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, phenylpiracetam and a phosphodiesterase inhibitor are co-administered. In embodiments, phenylpiracetam and a phosphodiesterase inhibitor (e.g., a PDE-4 inhibitor) are co-administered. In embodiments, a cognitive enhancer and apremilast are co-administered. In embodiments, meldonium and apremilast are co-administered. In embodiments, phenylpiracetam and apremilast are co-administered. Such co-administration of any of the foregoing improves adherence to a lifestyle modification recommendation in a subject following primary treatment, such as for chronic obesity or hyperglycemia. For example, in embodiments, administering a cognitive enhancer in combination with an opioid modulator improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia. For example, in embodiments, administering a cognitive enhancer in combination with an phosphodiesterase inhibitor improves adherence to a lifestyle modification recommendation in a subject following primary treatment for chronic obesity or chronic hyperglycemia.

[0418] In embodiments, a muscarinic receptor agonist and an atypical antipsychotic are co-administered. In embodiments, xanomeline and an atypical antipsychotic are co-administered. In embodiments, a muscarinic receptor agonist and any of aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, and clozapine are co-administered. In embodiments, xanomeline and any of aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, and clozapine are co-administered. In embodiments, an opioid receptor antagonist and an atypical antipsychotic are co-administered. In embodiments, samidorphan and an atypical antipsychotic are co-administered. In embodiments, an opioid receptor antagonist and any of aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, and clozapine are co-administered. In embodiments, samidorphan and any of aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, and clozapine are co-administered.

[0419] In embodiments, co-administration of any of the foregoing combinations, including of one or more pharmaceutical compositions comprising the compounds, and including according to the disclosed methods, improves adherence to a lifestyle modification recommendation in a subject following primary treatment, such as a primary treatment for chronic obesity or chronic hyperglycemia, as will be appreciated in view hereof. In some embodiments, co-administration of any of the foregoing combinations, including of one or more pharmaceutical compositions comprising the compounds, and including according to the disclosed methods, improves adherence to a lifestyle modification recommendation by providing one or more synergistic effects.

[0420] Other embodiments of the combinations, methods and pharmaceutical kits include each of the above exemplary embodiments, but where the first and second therapeutic compounds are substituted by another disclosed therapeutic compound, which may be from the same class, or which may be from another disclosedclass of therapeutic compounds, or any other broader, narrower, or other class of compounds disclosed herein.

[0421] For example, further embodiments of the combinations, methods and pharmaceutical kits include each of the above exemplary embodiments, but where moclobemide is substituted by another RIMA, such brofaromine, caroxazone, CX157, CX2614, eprobemide, metralindole, minaprine, pirlindole, or toloxatone.

[0422] Yet other embodiments of the disclosed methods, compositions, and pharmaceutical kits include each of the above exemplary embodiments, further comprising an additional active agent disclosed herein.

[0423] In some embodiments, the therapeutic compounds in a disclosed combination are formulated as separate pharmaceutical compositions and co-administered. That is, in embodiments, rather than formulated together as a single composition, the compounds in a combination are individually formulated as separate compositions, e.g., as separate dosage forms, which are administered to a subject separately, sequentially, or simultaneously. In some embodiments, “sequential” means a second composition is administered soon after administering a first composition (e.g., within about five minutes, 10 minutes, or 15 minutes); “simultaneous” means each composition is administered at substantially the same time (e.g., within one minute, or within no more than five minutes); and “separate” means a greater amount of time elapses between two administrations. Further embodiments of co-administration and administration together are described elsewhere herein.

[0424] In other aspects are provided pharmaceutical compositions comprising two or more compounds in an embodiment, e.g., where the compounds are co-formulated as a fixed-dose combination drug (FDC).V. Pharmaceutical Compositions

[0425] In some aspects are provided compositions, such as pharmaceutical compositions, comprising the disclosed therapeutic compounds, such as a composition providing a therapeutic compound, or a composition comprising a combination of therapeutic compounds, and optionally comprising an additional active agent

[0426] A “pharmaceutical composition” (or simply, a “composition”) comprises a disclosed compound and one or more (preferably, pharmaceutically acceptable) carriers, diluents, and / or excipients.

[0427] A “pharmaceutically acceptable” carrier, diluent, excipient, or other ingredient means the ingredient is generally safe and, within the scope of medical judgment, suitable for use in humans or animals without undue toxicity, irritation, allergic response, or complication, commensurate with a reasonable risk / benefit ratio.

[0428] A composition can be prepared by standard formulation techniques such as disclosed in, e.g., Remington: Science & Practice of Pharmacy. 23rd ed. Cambridge, MA: Acad Press (2020); Budavari et al. Merck Index. 12th ed. Whitehouse, NJ: Merck Pub Group (1996); Carstensen. Pharm Principles of Solid Dosage Forms. Lancaster, PA: Technomic Pub Co. (1993); Ansel & Stoklosa. Pharm Calculations. 11th ed. Baltimore, MD: LWW (2001); Poznansky & Cleland. Drug Delivery Systems. NY: Oxford Univ Press (1980).

[0429] A composition may be formulated in a unit dosage form, each containing a therapeutically effective amount of the disclosed compound (also, “API” or “active agent”), for example, in disclosed dosage amounts, or a portion (preferably, a defined fraction) of a therapeutically effective amount, e.g., 14, 1 , or1 / 4.

[0430] Reference to “a” compound or “an” active agent, in embodiments, includes or refers to more than one compound or active agent, and should be understood as “one or more” unless context demands otherwise.

[0431] Compositions comprising disclosed compounds can be formulated for any route of administration suitable for delivery thereof, such as for as mucosal (e.g., buccal, sublingual), rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, or intranasal compositions. Compositions prepared or formulated, such as for a specific route of administration, may be prepared in a manner well known in the art.

[0432] In some embodiments, a disclosed composition is suitable for administration by one or more of a variety of routes. Exemplary routes of administration include enteral administration, such as oral, sublingual, rectal, and buccal administration; and parenteral administration, such as bolus injection, continuous infusion, intravenous (IV), intra-arterial, intraperitoneal, intraosseous, intramuscular (IM), intrathecal, intracerebro- ventricular, vaginal, ocular, nasal, cutaneous, topical, otic, ocular, transdermal, and subcutaneous administration. A disclosed composition can be administered by one or more such routes of administration. In embodiments, administration of a composition accordingly may be sublingually, buccally, topically, rectally, vaginally, ocularly, oticly, nasally, cutaneously, topically, or transdermally; or by intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, or subcutaneous injection.

[0433] In embodiments, pharmaceutical compositions are prepared for oral administration. In embodiments, pharmaceutical compositions are prepared for oral transmucosal (e.g., buccal, sublingual) administration.

[0434] In embodiments, pharmaceutical compositions are prepared for intravenous, intramuscular, subcutaneous, implantable / insertable, or transdermal administration (see, e.g., Kilts C.D., J. Clin. Psychiatry. 2003;64 Suppl. 18:31-33; and Tijani et al. J. Control Release. 2022;348:970-1003). In embodiments, compositions are administered intravenously. In embodiments, compositions are administered intramuscularly. In embodiments, compositions are administered subcutaneously. In embodiments, compositions are administered using an implant or insert. In embodiments, compositions are administered transdermally. In embodiments, compositions are administered orally. Other routes of administration will be appreciated.

[0435] In embodiments, pharmaceutical compositions are prepared in a unit dosage form, each dosage containing an effective amount of the active ingredients, for example in the dosage amounts disclosed below or known in the art, such as based on standard medical practice. Unit dosage forms include capsules, troches, cachets, lozenges, tablets, ampules, and vials (including a composition in a freeze-dried or lyophilized state together with a sterile liquid carrier to be added prior to administration). Unit dosage forms include liquid compositions in ampules and vials. Unit dosage forms include preparations for transdermal administration.

[0436] In embodiments, a composition is formulated as an oral or oral transmucosal dosage form. An oral or oral transmucosal dosage form comprises one or more disclosed compounds, or a disclosed combination, and one or more carriers, diluents, or excipients. Oral or oral transmucosal dosage forms include solid dosage forms and liquid dosage forms. In some embodiments, the dosage form is an oral or oral transmucosal solid dosage form. In some embodiments, the dosage form is an oral or oral transmucosal liquid dosage form. In some embodiments, a composition is formulated as an oral or oral transmucosal solid dosage form. Solid dosage forms include lozenges, troches, films, tablets, capsules, caplets, powders, pellets, multiparticulates, beads, spheres, and / or any combinations thereof. Oral transmucosal solid dosage forms include oral strips andfilms, such as orally dissolvable or dispersible sublingual strips and buccal strips. In some embodiments, the strip or film is a mouth dissolvable film. In some embodiments, the oral strip or film is a quick-melt strip. In some embodiments, the strip or film is a thi n-film strip for rapid drug delivery.

[0437] In embodiments, an oral or oral transmucosal solid dosage form is in the form of a tablet. Exemplary tablet forms include a suspension tablet, chewable tablet, orally disintegrating tablet (ODT), bite-disintegration tablet, rapid-disintegration tablet, fast-melt tablet, effervescent tablet, sublingual tablet, buccal tablet, enteric-coated tablet, film-coated tablet, extended-release tablet, multi-layer tablet, matrix tablet, and mini-tablet. Tablet forms also include immediate-release (IR) tablets, uncoated tablets, and conventional tablets. In some embodiments, a solid dosage form is in the form of a caplet, a pill, a powder (e.g., a sterile packaged powder, dispensable powder, or effervescent powder), or a soft or hard capsule.

[0438] Oral and oral transmucosal solid dosage forms may comprise additives such as one or more carriers, complexing agents, ionic dispersion modulators, disintegrating agents, surfactants, lubricants, colorants, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, preservatives, antioxidants, and antimicrobial agents. Preservatives include EDTA, EGTA, benzalkonium chloride, benzoic acid, and benzoates. Antioxidants include provitamins, vitamins A, C, and E, and ALA.

[0439] Solid dosage forms may be prepared by conventional pharmaceutical techniques, e.g., dry mixing, direct compression, milling, dry or non-aqueous granulation, wet granulation, fusion, spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., Wurster coating), tangential coating, top spraying, tableting, and extruding, and combinations thereof (see, e.g., Lachman et al. 1986).

[0440] In embodiments, an oral or oral transmucosal solid dosage form is formulated to achieve a specific release profile. Solid dosage forms may be formulated as an immediate release formulation or as a modified release formulation. Modified release formulations include controlled release, sustained release, extended release, delayed release, and pulsatile release formulations. In some embodiments, an oral or oral transmucosal solid dosage form is an immediate release formulation. In some embodiments, an oral or oral transmucosal solid dosage form is a modified release formulation. In some embodiments, the modified release formulation is a controlled release, sustained release, extended release, delayed release, or pulsatile release formulation. In some embodiments, the formulation is a mixed release formulation, for example where one compound is formulated for immediate release, and the other compound is formulated for modified release.

[0441] In embodiments, a composition is formulated as an oral liquid dosage form. Oral liquid dosage forms include tinctures, drops, emulsions, syrups, elixirs, suspensions, solutions, and the like. Oral liquid dosage forms may be formulated with solvents, carriers, diluents, excipients, and the like, chosen as appropriate to the solubility and other properties of the compounds and other ingredients. Non-limiting examples of solvents include water, glycerin, alcohol, medium chain triglycerides (MOT), and combinations thereof. Oral liquid dosage forms may be in monophasic forms (e.g., syrups, linctuses, spirits / essences, elixirs, and fluid extracts) or biphasic forms (e.g., oral suspensions, oral emulsions, and mixtures), and also may be in the form of emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.Liquid dosage forms for oral administration may be prepared as liquid suspensions or solutions using a sterile liquid, including an oil, water, an alcohol, as well as surfactants, suspending agents, and emulsifying agents. Oral liquid dosage forms include aqueous suspensions such as aqueous oral dispersions, emulsions, solutions, and syrups (e.g., Singh et al. 2002; Warbrick J, Boylan JC. Encyc Pharm Tech. 2nd ed. CRC Press; 2002:754-757), and may comprise one or more additives, e.g., disintegrating agents, dispersing agents, wetting agents, preservatives, viscosity enhancing agents, sweetening agents, and / or flavoring agents. Liquid formulations also may comprise inert diluents, e.g., water, solvents, solubilizing agents, emulsifiers, flavorants, and sweeteners. Liquid dosage forms also may comprise co-solvents and adjuvants. Oral liquid dosage forms include capsules. In some embodiments, the capsule is a softgel capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the capsule is a sustained-release capsule. In some embodiments, the capsule is an extended-release capsule. In some embodiments, the capsule is a pellet-filled capsule. In some embodiments, the capsule is a liquid-filled hard capsule. In some embodiments, the capsule is a gastro-resistant capsule, enteric-coated capsule, or delayed-release capsule. A composition also may be formulated as an effervescent powder, for example as effervescent salts added to water for oral administration.

[0442] In embodiments, a composition is formulated into a topical dosage form. Topical dosage forms include transmucosal and transdermal formulations, such as aerosols, emulsions, sprays, ointments, salves, gels, pastes, lotions, liniments, oils, and creams. Topical dosage forms may comprise a penetrant or carrier. Penetrants include, for transmucosal administration, detergents, bile salts, fusidic acid derivatives, and combinations thereof. Carriers include Vaseline®, lanolin, PEG, alcohols, transdermal enhancers, and combinations thereof. In embodiments, a composition is formulated for transdermal administration. Transdermal formulations include ointments, creams, suspensions, lotions, pastes, gels, sprays, foams, oils, and combinations thereof. Transdermal delivery forms include transdermal patches, which may be constructed for continuous, gradual, pulsatile, or on demand delivery of the agents. A patch may be a medicated adhesive patch, a single-layer or multi-layer drug-in-adhesive patch, a matrix patch, a monolithic patch, or a r...

Claims

CLAIMSThe invention claimed is:1 . A method of improving adherence to a lifestyle modification recommendation in a subject who has discontinued a primary treatment for obesity or hyperglycemia, comprising: a. providing a lifestyle modification recommendation to the subject; and b. administering to the subject a compound that modulates monoaminergic neurotransmission; wherein the primary treatment for obesity or hyperglycemia comprises incretin-based therapy; and wherein the subject exhibits adherence to the lifestyle modification recommendation.

2. The method of claim 1 , wherein the lifestyle modification recommendation is provided by a healthcare professional, a registered dietitian, a fitness coach, a behavioral therapist, a digital health device, or a digital health platform.

3. The method of claim 1 , wherein the lifestyle modification recommendation comprises a dietary or consumption modification.

4. The method of claim 3, wherein the dietary or consumption modification comprises modifying food, drug, or alcohol consumption.

5. The method of claim 4, wherein modifying food, drug, or alcohol consumption comprises reducing or eliminating alcohol, tobacco, nicotine, or processed foods; following a specific daily caloric intake; eating a defined number of meals per day; maintaining regularly scheduled meals; eating without distractions; cooking a specified number of meals at home per week; leaving the table after meals; grocery shopping only from a list or only when full; measuring portion sizes; drinking filtered water; consuming living foods; taking food supplements, probiotics, prebiotics, or enzymes; adopting a fruitarian, sproutarian, ovo-vegetarian, lacto-vegetarian, or Mediterranean diet; following a personalized nutrition plan; following time-restricted eating patterns; or consuming fermented foods.

6. The method of claim 1 , wherein the lifestyle modification recommendation comprises a physical exercise modification.

7. The method of claim 6, wherein the physical exercise modification comprises following an exercise regimen; increasing daily step count; committing to a structured exercise schedule; attending an exercise class or walking group; attending physical training or physical therapy; or committing to choosing stairs over elevators when possible.

8. The method of claim 1 , wherein the lifestyle modification recommendation comprises a medication adherence modification.

9. The method of claim 8, wherein the medication adherence modification comprises following a prescribed dosage, frequency, and duration of a medication; taking a medication at a directed time; refilling a prescription when needed; purchasing a prescribed medication; or attending necessary follow-up visits with a prescribing healthcare provider.

10. The method of claim 1 , wherein the lifestyle modification recommendation comprises a microbiome- targeted therapy modification.

11. The method of claim 10, wherein the microbiome-targeted therapy modification comprises implementing probiotic supplementation or prebiotic supplementation; undergoing fecal microbiota transplantation (FMT); following a regimen of postbiotic and short-chain fatty acid modulation; or following dietary modifications to support a healthy microbiome.

12. The method of claim 1 , wherein the lifestyle modification recommendation comprises another health-enhancing habit modification.

13. The method of claim 12, wherein the other health-enhancing habit modification comprises practicing meditation; prayer; maintaining a positive attitude; mindful breathing; engaging in sun exposure; cold plunge therapy; sauna or hot bath followed by a cold shower; massage; skin brushing; maintaining a regular sleep pattern; using an infrared sauna; consuming green drinks; undergoing a liquid fast; receiving enemas; implementing detoxification; eliminating addictive behaviors; following a structured sleep hygiene routine; engaging in stress management techniques; implementing cognitive-behavioral strategies; participating in social support engagement; practicing self-monitoring; or engaging in mindfulness-based practices.

14. The method of claim 1 , wherein the compound that modulates monoaminergic neurotransmission is a compound that modulates dopaminergic, serotonergic, or norepinephrinergic neurotransmission.

15. The method of claim 14, wherein the compound also modulates glutamatergic neurotransmission.

16. The method of claim 1 , wherein the compound that modulates monoaminergic neurotransmission is a monoamine oxidase inhibitor, an antidepressant, a cognitive enhancer, an anticonvulsant, an atypical antipsychotic, an anti-hyperglycemic agent, an anti-inflammatory agent, an anxiolytic agent, an antihistamine, an antibiotic, an opioid modulator, an anti-craving agent, an antioxidant, a benzodiazepine, a serotonergic agent, a mood stabilizer, an N-methyl-D-aspartate (NMDA) receptor agent, an anticholinergic agent, a psychedelic, an entactogen, an empathogen, a tryptamine, a phenethylamine, a benzofuran, a 2C-x compound, an ergoline, a lysergamide, a beta-carboline, a harmala alkaloid, an iboga alkaloid, a natural plant or fungal alkaloid, a neurotropic agent, an adaptogen, an actoprotector, an antihypoxant, an anti-hypertensive agent, an anti-ischemic agent, an antimigraine agent, an anticholinergic agent, or a phosphodiesterase inhibitor.

17. The method of claim 16, wherein the monoamine oxidase inhibitor is a reversible inhibitor of monoamine oxidase-A (RIMA).

18. The method of claim 17, wherein the RIMA is moclobemide, brofaromine, caroxazone, CX157, CX2614, eprobemide, metralindole, minaprine, pirlindole, or toloxatone.

19. The method of claim 18, wherein the RIMA is moclobemide.

20. The method of claim 16, wherein the compound is an antidepressant.21 . The method of claim 20, wherein the antidepressant is a selective serotonin reuptake inhibitor (SSRI), a selective norepinephrine reuptake inhibitor (NRI), a serotonin and norepinephrine reuptake inhibitor (SNRI), a dual norepinephrine / dopamine reuptake inhibitor (NDRI), a tricyclic antidepressant (TCA), a noradrenaline and specific serotonergic antidepressant (NASSA), a serotonin antagonist and reuptake inhibitor (SARI), or a norepinephrine-dopamine disinhibitor (NDDI).

22. The method of claim 21 , wherein the SSRI is fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, escitalopram, vortioxetine, or vilazodone.

23. The method of claim 21 , wherein the NRI is atomoxetine or reboxetine.

24. The method of claim 21 , wherein the SNRI is desvenlafaxine, duloxetine, levomilnacipran, milnacipran, or venlafaxine.

25. The method of claim 21 , wherein the NDRI is amineptine, bupropion, desoxypipradrol, dexmethylphenidate, difemetorex, diphenylprolinol, ethylphenidate, fencamfamine, fencamine, lefetamine, methylenedioxypyrovalerone, methylphenidate, nomifensine, 0-2172, pipradrol, prolintane, pyrovalerone, solriamfetol, tametraline, or WY-46824.

26. The method of claim 21 , wherein the NDRI is bupropion.

27. The method of claim 21 , wherein the NDRI is solriamfetol.

28. The method of claim 21 , wherein the TCA is amitriptyline, doxepin, clomipramine, nortriptyline, imipramine, desipramine, protriptyline, dosulepin, maprotiline, trimipramine, or amoxapine.

29. The method of claim 21 , wherein the NASSA is aptazapine, esmirtazapine, mianserin, mirtazapine, or setiptiline.

30. The method of claim 21 , wherein the SARI is etoperidone, lorpiprazole, mepiprazole, nefazodone, or trazodone.31 . The method of claim 21 , wherein the NDDI is agomelatine, fluoxetine, flibanserin, or mirtazapine.

32. The method of claim 20, wherein the antidepressant is amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, trimipramine, phenelzine, tranylcypromine, isocarboxazid, selegiline, mirtazapine, nefazodone, trazodone, bupropion, a neurotropic agent, an adaptogen, an actoprotector, a nootropic, a eugeroic, a racetam, an antihypoxant, a cognitive enhancer, potassium orotate, asparkam, a psychedelic, an entactogen, an empathogen, a tryptamine, a phenethylamine, a benzofuran, a 2C-x compound, an ergoline, a lysergamide, a beta-carboline, a harmala alkaloid, an iboga alkaloid, a natural plant or fungal alkaloid, solriamfetol, vilazodone, atomoxetine, milnacipran, dosulepin, duloxetine, escitalopram, venlafaxine, citalopram, fluoxetine, fluvoxamine, vortioxetine, reboxetine, sertraline, paroxetine, esketamine, ketamine, dextromethorphan, dextromethorphan / bupropion, or lithium.

33. The method of claim 16, wherein the cognitive enhancer is a eugeroic or a nootropic.

34. The method of claim 33, wherein the eugeroic is modafinil, pitolisant, solriamfetol, or armodafi nil .

35. The method of claim 34, wherein the eugeroic is modafinil.

36. The method of claim 33, wherein the nootropic is meldonium, acetyl L-carnitine, alpha-GPC, alpha-lipoic acid (ALA), aniracetam, ashwagandha, astaxanthin, bacopa monnieri, berberine, black seed oil, cacao, caffeine, cannabidiol (CBD), CDP-choline, centrophenoxine, coconut oil, coluracetam, coenzyme Q10 (CoQ10), creatine, docosahexaenoic acid (DHA), dehydroepiandrosterone (DHEA), dimethylaminoethanol (DMAE), fisetin, ginkgo biloba, ginseng, glutathione, gotu kola, glycine, holy basil (tulsi), huperzine-A, kava kava, kratom, lion’s mane mushroom, L-carnosine, lemon balm, L-glutamine, L-theanine, maca, magnolia bark, N-acetyl L-cysteine, N-acetyl L-tyrosine, nicotinamide adenine dinucleotide + hydrogen (NADH), nefiracetam, oxiracetam, passionflower, picamilon, pine bark extract, piperine, piracetam, rhodiola rosea, phenylalanine, phenylethylamine (PEA), phenylpiracetam, phosphatidylcholine (PC), phosphatidylserine (PS), pyrroloquinoline quinone (PQQ), pramiracetam, pterostilbene, quercetin, resveratrol, St. John’s wort, taurine, tryptophan, turmeric, L-tyrosine, thiamine (vitamin B1), niacin (vitamin B3), pantothenic acid (vitamin B5), pyridoxine (vitamin B6), inositol (vitamin B8), folate (vitamin B9), cobalamin (vitamin B12), D-serine, vitamin D (vitamin D3), L-serine, panax ginseng, gingko biloba, tanakan, salvia officinalis, lavandulaefolia, centella asiatica, nicotene, noopept, phenotropil, an amphetamine, a dextroamphetamine, a cholinergic, citicholine, choline bitartrate, ethomersol, bemithyl, pyrazidol, actovegin forte, bemethyl, phenibut, or zinc.

37. The method of claim 33, wherein the nootropic is meldonium, vitamin D, a racetam, or phenylpiracetam.

38. The method of claim 37, wherein the nootropic is meldonium.

39. The method of claim 37, wherein the nootropic is phenylpiracetam.

40. The method of claim 16, wherein the anticonvulsant is carbamazepine, oxacarbazepine, lamotrigine, valproic acid, topiramate, levetiracetam, brivaracetam, or seletracetam.41 . The method of claim 16, wherein the atypical antipsychotic is aripiprazole, lurasidone, quetiapine, cariprazine, brexpiprazole, olanzapine, ziprasidone, asenapine, risperidone, paliperidone, lumateperone, iloperidone, pimavanserin, or clozapine.

42. The method of claim 16, wherein the NMDA receptor agent is D-cycloserine (DCS), NRX-1074, rapastinel (GLYX-13), plazinemdor, LY-2140023, NYX-458, NYX-783, NYX-2925, NRX-1074, SAGE-718, a substituted 1 ,2,3-triazole NMDA modulator, a spiro-lactam NMDA modulator, a NMDA modulator, ketamine, S-ketamine, R-ketamine, a non-racemic mixture of ketamine enantiometers, a ketamine metabolite, a ketamine analog, memantine, amantadine, rimantadine, nitromemantine (YQW-36), acamprosate, pethidine, levorphanol, methadone, dextropropoxyphene, tramadol, ketobemidone, dextromethorphan (DXM), dextrorphan, dextrallorphan (DXA), gacyclidine (GK-11), neramexane, lanicemine (AZD6765), diphenidine, dizocilpine (MK-801), 8a-phenyldecahydroquinoline (8A-PDHQ), remacemide, ifenprodil, traxoprodil (CP-101 ,606), eliprodil (SL-82.0715), etoxadrol (CL-1848C), dexoxadrol, WMS-2539, NEFA, delucemine (NPS-1506), aptiganel (Cerestat; CNS-1102), midafotel(CPPene; SDZ EAA 494), dexanabinol (HU-211 or ETS2101), selfotel (CGS-19755), 7-chlorokynurenic acid (7-CKA), 5,7-dichlorokynurenic acid (5,7-DCKA), L-683344, L-689560, L-701324, GV150526A, GV196771A, CERC-301 (MK-0657), atomoxetine, LY-235959, CGP 61594, CGP 37849, CGP 40116 or CGP 37849, LY-233536, PEAQX (NVP-AAM077), ibogaine or noribogaine, an ibogaine metabolite, an ibogaine analog, an ibogaine derivative, Ro 25-6981 , GW468816, EVT-101, indantadol, perzinfotel (EAA-090), SSR240600, 2-MDP (U-23807A) AP-7, phencyclidine, a phencyclidine analog, methoxetamine, a methoxetamine analog, arylcyclohexylamine, or an arylcyclohexylamine derivative.

43. The method of claim 16, wherein the anti-hyperglycemic agent is an insulin, a sulfonylurea, a meglitinide, a biguanide, a thiazolidinedione, an a-glucosidase inhibitor, a DPP-4 inhibitor, a SGLT2 inhibitor, or a dopamine receptor agonist.

44. The method of claim 16, wherein the anti-hyperglycemic agent is insulin glulisine, insulin aspart, insulin lispro, regular insulin, NPH insulin, glipizide, glyburide, gliclazide, glimepiride, repaglinide, nateglinide, metformin, rosiglitazone, pioglitazone, acarbose, miglitol, voglibose, sitagliptin, saxagliptin, vildagliptin, linagliptin, alogliptin, dapagliflozin, canagliflozin, or bromocriptine.

45. The method of claim 16, wherein the anti-hyperglycemic agent is metformin.

46. The method of claim 16, wherein the anti-inflammatory agent is prednisone, hydrocortisone, diclofenac, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, meclofenamate, mefenamic acid, nabumetone, naproxen, tolmetin, piroxicam, celecoxib, etoricoxib, aspirin, naproxen, meloxicam, an anti-cytokine agent, or a selective COX-2 inhibitor.

47. The method of claim 46, wherein the anti-cytokine agent is adalimumab, etanercept, infliximab, or tocilizumab.

48. The method of claim 46, wherein the selective COX-2 inhibitor is lumiracoxib.

49. The method of claim 46, wherein the anti-inflammatory agent is ibuprofen.

50. The method of claim 16, wherein the anxiolytic agent is a benzodiazepine, an azapirone, an alpha blocker, a beta blocker, an antidepressant, a barbiturate, a nonbenzodiazepine sedative, a hypnotic, nefazodone, pregabalin, mirtazapine, or gabapentin.51 . The method of claim 50, wherein the benzodiazepine is lorazepam, diazepam, alprazolam, clonazepam, chlordiazepoxide, or chlordiazepoxide / clidinium bromide.

52. The method of claim 51 , wherein the benzodiazepine is lorazepam.

53. The method of claim 50, wherein the azapirone is buspirone.

54. The method of claim 50, wherein the barbiturate is pentobarbital, phenobarbital, or amobarbital.

55. The method of claim 50, wherein the hypnotic is zolpidem, zaleplon, or zopiclone.

56. The method of claim 50, wherein the beta blocker is propranolol.

57. The method of claim 16, wherein the antihistamine is brompheniramine, cyproheptadine, chlorpheniramine, promethazine, claritin, fexofenadine, vistaril, hydroxyzine, alavert, diphenhydramine,levocetirizine, carbinoxamine, meclizine, dimenhydrinate, or azelastine.

58. The method of claim 16, wherein the antibiotic is augmentin, amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, azithromycin, sulfamethoxazole, trimethoprim, or levofloxacin.

59. The method of claim 16, wherein the opioid modulator is naltrexone, kratom, ignavine, salvinorin-A, DPI-289, UFP-505, samidorphan, vivitrol, buprenorphine, or LP1.

60. The method of claim 59, wherein the opioid modulator is naltrexone.61 . The method of claim 16, wherein the anti-craving agent is ondansetron, disulfiram, buprenorphine, topiramate, rimonabant, bupropion, modafinil, vigabatrin, or varenicline.

62. The method of claim 16, wherein the antioxidant is N-acetylcysteine, acetyl-L-carnitine, L-methylfolate, ascorbic acid, glutathione, a flavonoid, alpha lipoic acid, beta-carotene, alpha-tocopherol, ubiquinone, lycopene, coenzyme Q10, ellagic acid, retinol, masoprocol, pramipexole, nitric oxide, allopurinol, pentoxifylline, melatonin, probucol, quercetin, or acetylcysteine.

63. The method of claim 62, wherein the antioxidant is N-acetylcysteine.

64. The method of claim 62, wherein the antioxidant is acetyl-L-carnitine.

65. The method of claim 62, wherein the antioxidant is L-methylfolate.

66. The method of claim 16, wherein the antimigraine agent is a triptan.

67. The method of claim 16, wherein the phosphodiesterase inhibitor is a phosphodiesterase type-1 (PDE-1) inhibitor, a phosphodiesterase type-2 (PDE-2) inhibitor, a phosphodiesterase type-3 (PDE-3) inhibitor, a phosphodiesterase type-4 (PDE-4) inhibitor, or a phosphodiesterase type-5 (PDE-5) inhibitor.

68. The method of claim 67, wherein the PDE-4 inhibitor is apremilast.

69. The method of claim 16, wherein the anti-hypertensive agent is nimodipine, a diuretic, a beta-blocker, an ACE inhibitor, an Angiotensin II receptor blocker, a calcium channel blocker, an alpha blocker, an alpha-2 receptor agonist, a combined alpha and beta-blocker, a central agonist, a peripheral adrenergic inhibitor, or a vasodilator.

70. The method of claim 69, wherein the anti-hypertensive agent is nimodipine.

71. The method of claim 1 , wherein the compound that modulates monoaminergic neurotransmission is administered daily.

72. The method of claim 71 , wherein the compound that modulates monoaminergic neurotransmission is administered once per day.

73. The method of claim 71 , wherein the compound that modulates monoaminergic neurotransmission is administered twice per day.

74. The method of claim 1 , wherein the compound that modulates monoaminergic neurotransmission is administered at least once per day for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 10 weeks, 15 weeks, 16 weeks, or 20 weeks.

75. The method of claim 1 , further comprising administering an additional active agent.

76. The method of claim 75, wherein the additional active agent is also a compound that modulates monoaminergic neurotransmission.

77. The method of claim 75, wherein the additional active agent is a monoamine oxidase inhibitor, an antidepressant, a cognitive enhancer, an anticonvulsant, an atypical antipsychotic, an anti-hyperglycemic agent, an anti-inflammatory agent, an anxiolytic agent, an antihistamine, an antibiotic, an opioid modulator, an anti-craving agent, an antioxidant, a benzodiazepine, a serotonergic agent, a mood stabilizer, an N-methyl-D-aspartate (NMDA) receptor agent, an anticholinergic agent, a psychedelic, an entactogen, an empathogen, a tryptamine, a phenethylamine, a benzofuran, a 2C-x compound, an ergoline, a lysergamide, a beta-carboline, a harmala alkaloid, an iboga alkaloid, a natural plant or fungal alkaloid, a neurotropic agent, an adaptogen, an actoprotector, an antihypoxant, an anti-hypertensive agent, an anti-ischemic agent, an antimigraine agent, an anticholinergic agent, or a phosphodiesterase inhibitor.

78. The method of claim 75, wherein the additional active agent is an amino acid, an antioxidant, an anti-inflammatory agent, an analgesic, an anti-hyperglycemic agent, an anti neuropathic or antinociceptive agent, an antimigraine agent, an anxiolytic, an antidepressant, an antipsychotic, an anti-PTSD agent, a cannabinoid, a dissociative, an immunostimulant, an anti-cancer agent, an antiemetic, an orexigenic, an antiulcer agent, an anticholinergic agent, an anti-ischemic agent, an antihistamine, an anti-craving agent, an antihypertensive, an antimigraine agent, an anticonvulsant, an anticholinergic agent, an antiepileptic, a bronchodilator, a mood stabilizer, a cognitive enhancer, a neuroprotectant, a serotonergic agent, a neuroactive agent, a neurotropic agent, an adaptogen, an actoprotector, an antihypoxant, an entactogen or empathogen, an entheogen, a psychedelic, a monoamine oxidase inhibitor, a tryptamine, a terpene, a phenethylamine, a sedative, a stimulant, an opioid modulator, a NMDA receptor agent, a vitamin, a SSRI, a SNRI , a NRI, a NDRI, a TCA, a benzodiazepine, or a phosphodiesterase inhibitor.

79. The method of claim 19, wherein the moclobemide is administered daily.

80. The method of claim 19, wherein the moclobemide is administered at a dose of between about 300 and 600 mg per day.81 . The method of claim 19, wherein the moclobemide is administered at a dose of about 150 mg twice per day.

82. The method of claim 19, wherein the moclobemide is administered daily for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, or at least 20 weeks.

83. The method of claim 38, wherein the meldonium is administered daily.

84. The method of claim 38, wherein the meldonium is administered at a dose of between about 500 and 1000 mg per day.

85. The method of claim 38, wherein the meldonium is administered at a dose of about 500 mg twice per day.

86. The method of claim 39, wherein the phenylpiracetam is administered daily.

87. The method of claim 39, wherein the phenylpiracetam is administered at a dose of between about 200 and 600 mg per day.

88. The method of claim 39, wherein the phenylpiracetam is administered at a dose of between about 100 and 200 mg twice or three times per day.

89. The method of claim 60, wherein the naltrexone is administered daily.

90. The method of claim 60, wherein the naltrexone is administered at a dose of between about 1 and 5 mg per day.91 . The method of claim 60, wherein the naltrexone is administered at a dose of between about 1 and 5 mg once per day.

92. The method of claim 68, wherein the apremilast is administered daily.

93. The method of claim 68, wherein the apremilast is administered at a dose of between about 10 and 40 mg per day.

94. The method of claim 68, wherein the apremilast is administered at a dose of between about 10 and 30 mg once or twice per day.

95. The method of claim 1 , wherein improving adherence to a lifestyle modification recommendation comprises treating a psychological factor affecting another medical condition in the subject.

96. The method of claim 95, wherein the psychological factor is any of psychological distress, a pattern of interpersonal interaction, a coping style, a maladaptive health behavior, anhedonia, emotional numbing, and affective flattening.

97. The method of claim 96, wherein the maladaptive health behavior is any of denial of symptoms, poor adherence to medical recommendations, and medication nonadherence.

98. The method of claim 95, further comprising treating the other medical condition in the subject.

99. The method of claim 98, wherein the other medical condition is any of an insulin resistance and related disorder (IRARD), chronic obesity, hyperglycemia, and an additional other medical condition.

100. The method of claim 99, wherein the additional other medical condition is hypertension, an inflammatory disorder, a sleep disorder, a musculoskeletal condition, a renal disorder, a hematological disorder, a neurodegenerative disorder, cancer, allergies, an immunological condition, a neurological condition, an infection, a genetic disorder, a pulmonary condition, a urinary or bladder disorder, a digestive disorder, a hepatic disorder, an otolaryngological disorder, a dental or oral health issue, a vascular disorder, a gynecological condition, a skin disorder, a rare disease, endocrinopathy, or congestive heart failure.

101. The method of claim 99, wherein IRARD is insulin resistance, a glucoregulatory disorder, a glucoregulatory disorder induced by treatment with a mood stabilizer, a glucoregulatory disorder induced by treatment with an antipsychotic, a glucoregulatory disorder induced by treatment with an opioid, insulin resistance induced by pharmacotherapy, coronary artery disease, ischemic heart disease, obesity,stroke, being overweight, a genetic disorder, or polycystic ovary disease.

102. The method of claim 101 , wherein the gl ucoreg ulatory disorder is prediabetes, diabetes, metabolic syndrome, obesity, or dyslipidemia.

103. The method of claim 1 , wherein the subject has a co-occurring mental health disorder.

104. The method of claim 103, wherein the co-occurring mental health disorder is any of a depressive disorder, major depressive disorder (MDD), treatment-resistant depression (TRD), a mood disorder, an anxiety disorder, generalized anxiety disorder (GAD), a trauma- or stressor-related disorder, PTSD, obsessive-compulsive disorder (OCD), a neurocognitive disorder, a feeding or eating disorder, intermittent explosive disorder, an addiction disorder, a substance use disorder, an impulse control disorder, compulsive buying disorder, repetitive self-mutilation syndrome, a nonparaphilic sexual addiction or paraphilia, a personality disorder, and attention deficit hyperactivity disorder (ADHD).

105. The method of claim 1 , wherein the incretin-based therapy comprises glucose-dependent insulinotropic polypeptide (GIP) agonist therapy and / or glucagon-like peptide- 1 (GLP-1) agonist therapy.

106. The method of claim 1 , wherein adherence to the lifestyle modification recommendation is determined by comparing a post-discontinuation measurement and a baseline measurement of body weight; average adipocyte diameter; body mass index (BMI); body fat index (BFI); body fat mass (FM) and fat-free mass; liver enzyme levels; insulin resistance; systolic blood pressure; diastolic blood pressure; HbA1c values; lipid levels; glucose levels; satiety-related hormone levels; total cholesterol; high-density lipoprotein (HDL) cholesterol; low-density lipoprotein (LDL) cholesterol; or a self-report measure.

107. The method of claim 106, wherein the post-discontinuation measurement is at least 1 month, 2 months, 3 months, 6 months, 9 months, 12 months, or greater than 12 months after the baseline measurement.

108. The method of claim 106, wherein the post-discontinuation measurement is within 1 %, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of the baseline measurement.

109. The method of claim 1 , wherein the compound that modulates monoaminergic neurotransmission is formulated for oral, buccal, sublingual, injectable, subcutaneous, intravenous, intramuscular, or transdermal administration.

110. The method of claim 109, wherein the compound that modulates monoaminergic neurotransmission is formulated for oral administration.

111. The method of claim 1 , wherein the compound that modulates monoaminergic neurotransmission is in unit dosage form.

112. The method of claim 1 , further comprising administering to the subject a second compound.

113. The method of claim 112, comprising administering to the subject any of: a. moclobemide and metformin; b. moclobemide and nimodipine; c. moclobemide and propranolol;d. moclobemide and solriamfetol; e. moclobemide and modafinil; f. moclobemide and lumiracoxib; g. moclobemide and ibuprofen; h. moclobemide and lorazepam; i. moclobemide and phenylpiracetam; j. moclobemide and bupropion; k. moclobemide and meldonium; l. moclobemide and vitamin D; m. moclobemide and N-acetylcysteine; n. moclobemide and acetyl-L-carnitine; o. moclobemide and L-methylfolate; p. moclobemide and apremilast; q. moclobemide and naltrexone; r. phenylpiracetam and naltrexone; s. phenylpiracetam and apremilast; t. meldonium and naltrexone; and u. meldonium and apremilast.

114. The method of claim 112, further comprising administering to the subject a third compound.

115. The method of claim 114, comprising administering to the subject any of: a. moclobemide, naltrexone, and apremilast; b. phenylpiracetam, naltrexone, and apremilast; and c. meldonium, naltrexone, and apremilast.

116. A pharmaceutical combination, pharmaceutical composition, or pharmaceutical kit for improving adherence to a lifestyle modification recommendation, comprising the compound that modulates monoaminergic neurotransmission of claim 1.

117. A pharmaceutical combination, pharmaceutical composition, or pharmaceutical kit for improving adherence to a lifestyle modification recommendation, comprising the compound that modulates monoaminergic neurotransmission and the second compound of claim 112.

118. A pharmaceutical combination, pharmaceutical composition, or pharmaceutical kit for improving adherence to a lifestyle modification recommendation, comprising the compound that modulates monoaminergic neurotransmission, the second compound, and the third compound of claim 114.

119. Use of the pharmaceutical combination, pharmaceutical composition, or pharmaceutical kit of any of claims 116-118 for improving adherence to a lifestyle modification recommendation in a subject who has discontinued a primary treatment for obesity or hyperglycemia.

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