Method for treating psychiatric disorders and dementia or mild cognitive impairment via intermittent memantine- and amantadine-based dosing regimen and drug combinations

Abstract

Methods and compositions are disclosed for rapidly relieving symptoms in subjects with depressive, stressor and substance abuse conditions, e.g., major depression, treatment-resistant depression, post-partum depression, bipolar depression, post-traumatic stress disorder, substance use disorders, negative and cognitive symptoms of schizophrenia, as well as for slowing progression of mild cognitive impairment and dementia, using an intermittent dosing regimen of memantine or amantadine or a structural analogue or pharmaceutically acceptable salt of memantine or amantadine (optionally no more frequently than every 2 days) at a dose sufficient to activate Set A brain structures, in combination with a second drug at a dose which activates Set B brain structures but which does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions. In some instances the second drug is either 1) a low dose psilocybin or low dose of other psychedelic and stimulant molecules capable of activating Set B of brain structures which is administered at a dose low enough such that it does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions, or is 2) mianserin (S isomer, R isomer, or a racemate comprising both isomers or structural analog or pharmaceutically acceptable salt thereof) or another standard of care antidepressant capable of activating Set B brain structures, or 3) lumateperone or another antipsychotic capable of activating Set B brain structures.

Description

PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013METHOD FOR TREATING PSYCHIATRIC DISORDERS AND DEMENTIA OR MILD COGNITIVE IMPAIRMENT VIA INTERMITTENT MEMANTINE- and AMANTADINE-BASED DOSING REGIMEN AND DRUG COMBINATIONSRELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.: 63 / 720,494, filed on November 14, 2024, the contents of which are incorporated by reference in their entirety herein.FIELD OF THE INVENTION

[0002] This invention relates to methods and compositions for treating psychiatric disorders, such as depressive, stressor-related, and substance abuse disorders, e.g., major depressive disorder (MDD), treatment-resistant depression (TRD) (defined herein as an inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment), bipolar depression, postpartum depression (PPD), post-traumatic stress disorder (PTSD), substance use disorders including addiction and negative and cognitive symptoms of schizophrenia; and methods and compositions for treating dementia or mild cognitive impairment in a subject in need thereof by intermittent administration (every 2 days or longer) of a synergistic drug combination comprising (i) memantine or amantadine, or their structural analogues or pharmaceutically acceptable salts thereof, and (ii) a second drug which is capable of activating Set B brain areas in a mouse brain, optionally psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers or structural analog or pharmaceutically acceptable salt thereof) or lumateperone (or structural analog or pharmaceutically acceptable salt thereof), wherein (i) and (ii) are administered at dosages which in combination activate both Set A and Set B brain areas in a mouse brain using c-fos as a reporter of activity and cellular plasticity and wherein (in instances where compound (ii) at a higher dose is capable of eliciting psychomimetic side effects such as hallucinations (ii) is administered at a low dosage which does not elicit psychomimetic side effects such as hallucinations). The inventive methods and medicaments provide for rapid and prolonged alleviation of the clinical symptoms ofPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013depressive, stressor-related, and substance abuse disorders and when used to treat dementia or mild cognitive impairment achieve improved efficacy in relation to conventional treatment methods for treating dementia or mild cognitive impairment wherein memantine is administered as a monotherapy at least once daily.BACKGROUND OF THE INVENTION

[0003] Major depression stands as the primary cause of disability globally, impacting over 300 million individuals, according to the World Health Organization (WHO). In the United States, a 2023 Gallup poll reported that 17.8% of Americans experienced symptoms of depression. Post-traumatic stress disorder (PTSD), another prevalent psychiatric condition, affects about 3.5% of U.S. adults annually, with a higher estimated prevalence of 8% among adolescents aged 13 to 18, according to the American Psychiatric Association's 2023 data. Bipolar depression is estimated to occur in 4.4% of U.S. adults at some time in their lives according to the National Institute of Mental Health (NIMH). Substance use disorders, including addiction, affect 16.7% Americans according to the 2022 United States National Survey on Drug Use and Health (NSDUH).

[0004] Treatments available for major brain disorders, such as MDD, TRD, bipolar depression, PPD, PTSD, and substance use disorders, have long been recognized as insufficient. In depression, despite the variety of approved treatments spanning different classes like SSRIs, SNRIs, TCAs, TeCAs, MAOIs, NASSAs, and atypical antidepressants, about 30% of patients do not respond to these therapies [1], Consequently, these individuals receive a diagnosis of TRD, defined as a lack of therapeutic response to a minimum of two antidepressants despite adequacy of the treatment. Additionally, antidepressants from these drug classes typically require two to four weeks to manifest efficacy [2], posing a risky period of treatment inefficiency when patients might be at a heightened risk of suicide. Current treatments for PTSD are even less effective than those for depression. Notably, only two SSRIs, sertraline and paroxetine, have FDA approval for PTSD treatment. Although other medications, such as atypical antipsychotics and anxiolytics, are prescribed off-label for PTSD, the overall efficacy of pharmacotherapy in PTSD is even poorer than in depression [3], Bipolar depression treatment typically involves both psychotherapy and a drug treatment,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013often including combination of drugs including lithium, atypical antipsychotics such as aripiprazole and quetiapine, anti-epilepsy drug lamotrigine, as well as standard-of-care (SOC) antidepressants and ketamine [4], The drug combinations used often exert significant side effects, such as weight gain from atypical antipsychotics and short-term and long-term toxicity risk linked to lithium treatment, leading to 30-50% nonadherence to treatment regimen among bipolar patients.

[0005] Negative and cognitive symptoms of schizophrenia represent clinical domains of the disorder that have fewer treatment options than positive symptoms of schizophrenia and hence significantly affect the quality of life of schizophrenic patients [5], Negative symptoms include blunted affect, alogia (reduction in the quantity of words spoken), avolition (reduced goal-directed activity due to decreased motivation), asociality, and anhedonia (reduced experience of pleasure) [6], while cognitive symptoms include deficits in attention, memory and working memory, cognitive abilities such as problem-solving, problem-solving planning and abstract thinking and social cognition [7], While there are currently no proven options for efficacious relief of negative and cognitive symptoms of schizophrenia, some relief can be provided by third-generation antipsychotics that also exert efficacy in bipolar depression, including aripiprazole, brexpiprazole, lumateperone, and cariprazine. Additionally, adjunct treatments with SOC antidepressant may also have a modest efficacy.

[0006] Dementia affects 55 million people worldwide and Alzheimer's disease (AD) accounts for 60 to 70% of all dementia cases (World Health Organization, 2023, Dementia Fact Sheet). AD is a neurodegenerative disorder that typically starts late in life and is characterized by progressive cognitive decline, ranging from MCI to dementia. Other forms of dementia include disorders such as vascular dementia, dementia with Lewy bodies, frontotemporal dementia (FTD), dementia in Huntington's disease, dementia in Parkinson's disease, posterior cortical atrophy (also called Benson's syndrome), Creutzfeldt-Jakob disease dementia and Wernicke-Korsakoff syndrome. Mild MCI is a condition that causes memory and / or cognitive deficits more pronounced than would be typical for a given age group, which can be an early sign of a disease that will eventually cause dementia. It is estimated that 10 to 20% of 65 year old or older people with MCI will develop dementia over a one-year period.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0007] The treatment options for MCI and dementia are even more limited than those for mood disorders and provide only modest slowing of disease progression. For MCI and dementia in AD, acetylcholinesterase (AChE) inhibitors, such as donepezil (Aricept), galantamine (Reminyl), and rivastigmine (Exelon), increase acetylcholine levels in the brain and can help improve memory and daily activities in some AD patients. However, they do not prevent the progression of the disease. Memantine (brand names: Ebixa™, Namenda™, Axura®, Akatinol®, Memary®; D-145) can slow the progression of symptoms in moderate to severe Alzheimer's disease and is sometimes used in combination with AChE inhibitors, but this effect is also only transient and modest in effect size. Memantine is a "low-trapping" (fast unbinding) uncompetitive antagonist of the NMDA receptors [8, 9]. Lecanemab (Leqembi) is the most recent treatment option aimed at slowing cognitive decline in people with early Alzheimer's disease. Lecanemab is a recombinant anti-amyloid monoclonal antibody that binds to amyloid protein and reduces amyloid levels in the brain. However, this treatment is associated with a risk (about 1 in 5 patients) of developing serious side effects, including brain swelling and bleeding, described as amyloid-related imaging abnormalities (ARIA). Given the recent approval of Lecanemab, its long-term efficacy in slowing disease progression remains to be determined.

[0008] Memantine has also been tested in various psychiatric indications, either alone or in combination with other medications. These clinical trials yielded either negative or mixed results, and memantine has not been approved or gained broad off-label use in other indications outside its original approval for the treatment of moderate to severe Alzheimer's dementia (Reference ID: 3394954 - accessdata.fda.gov). For example, in double-blind clinical trials, memantine was found to be ineffective in patients with MDD and late-life MDD [10, 11], Additionally, results from metanalyses of all clinical data were inconsistent, with one study suggesting the possibility of modest efficacy of memantine in depression

[0012] and two other studies reporting inconsistent findings or a lack of efficacy [13, 14],

[0009] Memantine has also been tested as an add-on treatment with SOC antidepressants in patients with MDD and the results were similarly mixed. In double-blind clinical trials, memantine was found to be ineffective as an add to SOC antidepressant treatment in patients with MDD, or in a combination with SSRI escitalopram in elderly patients with MDD and patients with MDD and comorbid alcohol dependance [15-17], OnPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013the other hand, one clinical study reported significantly greater improvements in MDD patients treated with SSRI sertraline and memantine than sertraline and placebo

[0018] , Additionally, two studies in elderly patients with MDD reported that the combination of memantine with escitalopram was more effective than escitalopram and placebo in improving cognitive outcomes, though not depression, than escitalopram and placebo [16, 19],

[0010] Memantine was also found to lack efficacy as an add on to a mood stabilizer lamotrigine in bipolar depression in two randomized, double-blind clinical trials [20, 21], although one single case study reported a positive antidepressant effect of memantine and lamotrigine combination

[0022] , while a second single case study reported a positive effect of adding memantine to the treatment with lithium, olanzapine and mianserin

[0023] , Finally, memantine was also tested with mixed results as an-odd treatment in schizophrenia.Memantine was found to lack efficacy as an adjunctive therapy in schizophrenia patients in two randomized, placebo-controlled studies [24, 25], while two other placebo-controlled studies and a case study reported positive effect on negative symptoms [26-28], and a meta-analysis of memantine found insufficient evidence for conclusive interpretation of the clinical data

[0029] ,

[0011] Amantadine (brand names: Gocovri, Symadine, Symmetrel, PK-Merz) is a second clinically approved low-trapping uncompetitive antagonist of the NMDA receptors, with both antiparkinsonian efficacy and anti-dyskinetic action in Parkinson's disease

[0030] , Additionally, amantadine was described to possess antidepressant-like effects in rodent models

[0031] and there appears to be a modest support for this efficacy from a handful of small and mostly open-label clinical trials: amantadine was found effective as an add-on therapy in MDD

[0032] and TRD

[0033] , though this effect was not seen in another add-on TRD study

[0034] . Finally, several studies described a positive effect of amantadine on secondary depression in patients with hepatitis C, cocaine addiction and depression in patients with Borna disease virus infection

[0031] ,

[0012] Other NMDA receptor antagonists / inhibitors that may act similarly to that of here described memantine and amantadine include AP5 (APV, R-2-amino-5-phosphonopentanoate), AP7 (2-amino-7-phosphonoheptanoic acid), CGP-37849, CPPene (3-[(R)-2-carboxypiperazin-4-yl]-prop-2-enyl-l-phosphonic acid), Selfotel (CGS-19755), 3-MeO-PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013PCP, 8A-PDHQ, atomoxetine, AZD6765, Agmatine, Argiotoxin, Chloroform, Cyclopropane, Delucemine, Desflurane, Dextrallorphan, Dextromethorphan, Dextrorphan, Dextromethadone, Diphenidine, Dizocilpine (MK-801), Ethanol, Eticyclidine, Gacyclidine, Halothane, Isoflurane, Magnesium, Methoxetamine, Methoxydine (4-MeO-PCP), Minocycline, Neramexane, Nitromemantine, Nitrous oxide, PD-137889, Phencyclidine (PCP), Remacemide, Rolicyclidine, Sevoflurane, Tenocyclidine, Tiletamine, Eliprodil, Etoxadrol, Dexoxadrol, WMS-2539, NEFA, Aptiganel (Cerestat, CNS-1102), HU-211, Huperzine A, Dipeptide D-Phe-L-Tyr, Ibogaine, Remacemide, Rhynchophylline, Rubiaceae, Rapastinel (GLYX-13), NRX-1074, 7-Chlorokynurenic acid, 4-Chlorokynurenine (AV-101), 5,7-Dichlorokynurenic acid, Kynurenic acid (a naturally occurring antagonist), TK-40, 1-Aminocyclopropanecarboxylic acid (ACPC), L-Phenylalanine and Xenon.

[0013] In summary, the inconclusive results from various memantine as well as the few amantadine clinical studies demonstrate the complexity of psychiatric drug development. Despite preclinical behavioral and other assays indicating a drug's or drug combination's efficacy for different indications, clinical results often fail to confirm these findings.Therefore, it is crucial to understand the effects of both preclinical drug candidates and approved medications at the level of brain circuits, providing mechanistic and clinically predictive data to support the drug candidate's clinical indication, efficacy, and optimal dosing regimen. The current work presents such data for a range of antidepressant drugs and drug candidates, leading to the identification of a new dosing regimen for memantine-and amantadine-based drug combinations for the treatment of MDD, TRD, PTSD, bipolar depression, substance use disorders, negative and cognitive symptoms of schizophrenia, mild cognitive impairment, and dementia.

[0014] Most recent advancements in psychiatric drug development, particularly for MDD and TRD, promise to deliver new treatments characterized by higher efficacy and rapid therapeutic relief. Ketamine, in the form of esketamine (Spravato) delivered intra nasa I ly, is the first of these treatments to be approved for TRD by the Food and Drug Administration (FDA). Additionally, intravenous racemic ketamine is used as an off-label treatment for MDD and TRD [35, 36], Ketamine is a "high-trapping" (slow unbinding) uncompetitive antagonist of the NMDA receptors [8, 9], Esketamine and ketamine therapy not only demonstrate efficacy in TRD but also provide remarkably rapid relief of depression symptoms, typicallyPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013occurring within twenty-four hours post-dosing and reaching maximum efficacy within seventy-two hours [35, 37], However, esketamine and ketamine treatments are frequently associated with dissociative, psychosis-like side effects, including delusions and delirium, as well as a risk of drug abuse. Consequently, these treatments can only be administered in a doctor's office or other specialized healthcare sites where patients are monitored by a health professional for several hours after the treatment. These side effects and requirements significantly limit the number of patients willing to undergo these procedures, hence limiting the impact of this otherwise remarkable therapeutic option.

[0015] Human brain imaging studies in patients with major depression have implicated abnormal activity in the medial prefrontal perigenual and subgenual anterior cingulate cortex (pgACC and sgACC) in mediating depressive symptoms [38, 39] and subanesthetic ketamine has been shown to acutely modulate pgACC and sgACC activity [38, 40, 41], This suggests that these areas play key roles in both depression and ketamine's rapid antidepressant efficacy. Additionally, a recent imaging study suggested a connection between the ACC and the subcortical nucleus accumbens (NAC) in depression, revealing an expansion of the salience network comprising these structures in depressed patients

[0042] , These findings underscore the importance of the pgACC and sgACC in depression and highlight their involvement in the mechanisms of rapid antidepressant efficacy.

[0016] In addition to ketamine, several psychedelic and stimulant molecules are currently being tested in clinical trials for psychiatric conditions, including MDD, TRD, PTSD, and various types of substance use disorders. These molecules include psilocybin, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), ibogain and N,N-Dimethyltryptamine (DMT). While these compounds are not yet approved as treatments for psychiatric disorders, psilocybin appears particularly promising in delivering a rapid and efficacious treatment for MDD and TRD, with a single dose reported to induce depression relief lasting several weeks [43, 44], However, psychedelic molecules also induce strong psychomimetic side effects, including hallucinations. Therefore, if these treatments receive FDA approval for clinical use, their administration will require regulation similar to that of ketamine, necessitating specialized sites and healthcare professionals to oversee the treatments. This requirement will limit the number of patients willing to undergo such therapy, thereby restricting the broader impact of these promising therapeutic options.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013Ketamine, psilocybin and other psychedelic and stimulant molecules also show promise in early tests for other mental disorders, including PTSD, and substance use disorders, though there is a need for more definitive studies to confirm the early results [45-49], Taken together, these new treatments represent a significant progress and promise compared to previous options. Notwithstanding, there remains a critical need for rapid therapeutic options in TRD, MDD, and PTSD that are not burdened by psychotomimetic side effects. Ideally, these treatments should be suitable for at-home use to reach the largest number of patients.

[0017] The present invention addresses these unmet needs.SUMMARY OF THE INVENTION

[0018] In particular, this invention provides improved methods and compositions for treating depressive, stressor-related, and substance abuse disorders; and improved methods and compositions for treating dementia or mild cognitive impairment in a subject in need thereof by the intermittent administration of a synergistic drug combination comprising (i) memantine or amantadine, or their structural analogues or pharmaceutically acceptable salts thereof, and (ii) a second drug which is capable of activating Set B brain areas in a mouse brain, optionally psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers or structural analog or pharmaceutically acceptable salt thereof) or lumateperone (or structural analog or pharmaceutically acceptable salt thereof), wherein (i) and (ii) are administered at dosages which in combination activate both Set A and Set B brain areas in a mouse brain using c-fos as a reporter of activity but which do not elicit psychomimetic side effects such as hallucinations. These methods and compositions are in particular suitable for treating psychiatric disorders such as major depressive disorder (MDD), treatment-resistant depression (TRD), (representing an inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment), bipolar depression, postpartum depression (PPD), post-traumatic stress disorder (PTSD), substance use disorders including addiction, negative and cognitive symptoms of schizophrenia, mild cognitive impairment (MCI), and dementia.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0019] The treatment involves an intermittent dosing regimen administering a novel pharmaceutical drug combination comprising memantine or amantadine, antagonists of N-methyl-D-aspartate (NMDA) receptors, or their structural analogues and pharmaceutically acceptable salts thereof, and a second pharmaceutical compound selected for its ability to specifically complement memantine's and amantadine's brain activity, as measured by statistically significant increases in the expression of the immediate early gene ( I EG ) c-fos, a marker of cellular plasticity

[0050] , in the mouse brain. This new memantine- or amantadine-based drug combinations evoke a combined Set A and Set B brain activity pattern, encompassing ten brain areas that, based on the data disclosed herein, represent ten key structures which are instrumental in mediating the rapid therapeutic efficacy of ketamine and psilocybin and analogously are instrumental in the rapid therapeutic efficacy of memantine or amantadine and a second drug which activates Set B brain areas in a mouse brain, optionally psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers or structural analog or pharmaceutically acceptable salt thereof) or lumateperone (or structural analog or pharmaceutically acceptable salt thereof). Crucially, this memantine-or amantadine-based synergistic drug combination does not evoke brain activity associated with the dissociative or hallucinogenic perceptions seen with ketamine and psilocybin treatments, respectively. Therefore, the inventive memantine- or amantadine-based drug combinations will achieve efficacy similar to that of ketamine, but without psychomimetic side effects, and higher efficacy than memantine or amantadine used alone.

[0020] The key Set A brain areas activated by memantine and amantadine include the prelimbic (PL) and infralimbic (ILA) cortex in the mouse brain, which correspond to the human perigenual and subgenual anterior cingulate cortex (pgACC and sgACC), respectively, which have been strongly implicated in mediating depression symptoms [38, 39], Additionally, Set A includes the subcortical mediodorsal (MD), centromedial (CM), reuniens (RE), and rhomboid (RH) thalamic nuclei, which are interconnected with the frontocortical PL and ILA regions. The key Set B brain areas activated by the second complementary compound include the subcortical paraventricular thalamus (PVT), the anterior portion of the bed nuclei of the stria terminalis (BSTa), the central amygdala (CEA), and the medial portion of the shell of the nucleus accumbens (ACBsh). A crucial inventor's discovery supporting the rationale for the specific drug combinations proposed here is that thePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013activity of Set A brain areas and the activity of Set B brain areas, while both necessary, are not sufficient alone to induce the therapeutic relief seen with ketamine and potentially psilocybin treatments. Only the combined brain activity of Set A and Set B brain areas is sufficient to induce ketamine-like rapid therapeutic relief in depression and other psychiatric disorders.

[0021] The complementary second pharmaceutical compound of the intermittently administered memantine- or amantadine-based drug combination may include low doses of psilocybin or other psychedelic and stimulant molecules, including but not limited to N,N-Dimethyltryptamine (DMT), ibogain, 3,4-Methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD) and their structural analogues and pharmaceutically acceptable salts thereof. While these drugs may achieve rapid therapeutic relief from a single drug administration, their therapeutic effects are associated with hallucinogenic and other psychotomimetic side effects, limiting their use to specialized healthcare provider sites. A critical distinguishing feature of combining these agents with memantine or amantadine is the use of low doses of psychedelic and stimulant molecules, which neither have standalone therapeutic efficacy similar to that of ketamine nor evoke hallucinogenic or other psychotomimetic perceptions, yet are sufficient to evoke full activity across all of the Set B brain areas. In this application the inventors provide evidence for a specific dose of psilocybin capable of evoking this effect.

[0022] Alternatively, the complementary second pharmaceutical compound of the intermittently administered memantine- or amantadine-based drug combination may also be selected from standard of care (SOC) antidepressant agents, including but not limited to selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), monoamine oxidase inhibitors (MAOIs), noradrenaline and specific serotoninergic antidepressants (NASSAs), and atypical antidepressants.

[0023] Examples of the foregoing include SOC antidepressants and SSRIs such as Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), Sertraline (Zoloft), Dapoxetine (Priligy), Indalpine (Upstene), Zimelidine (Zelmid), Alaproclate (GEA-654), Centpropazine, Cericlamine (JO-1017), Femoxetine (Malexil; FG-4963), Ifoxetine (CGP-15210), Omiloxetine, Panuramine (WY-26002),PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013Pirandamine (AY-23713), Seproxetine ((S)-norfluoxetine), SNRIs such as Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Sibutramine (Meridia), Tramadol (Ultram), Venlafaxine (Effexor), TCAs such as Butripty line (Evadyne), Clomipramine (Anafranil), Imipramine (Tofranil, Janimine, Praminil), Trimipramine, (Surmontil), Desipramine (Norpramin, Pertofrane), Dibenzepinf (Noveril, Victoril), Lofepramine§ (Lomont, Gamanil), Maprotiline (Ludiomil), Nortriptyline (Pamelor, Aventyl, Norpress), Protriptyline (Vivactil), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Amoxapine (Asendin), Demexiptiline (Deparon, Tinoran), Dimetacrine (Istonil, Istonyl, Miroistonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Fluacizine (Phtorazisin), Imipraminoxide (Imiprex, Elepsin), Melitracen (Deanxit, Dixeran, Melixeran, Trausabun), Metapramine (Timaxel), Nitroxazepine (Sintamil), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen / Azaphen), Propizepine (Depressin, Vagran), Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine), Amineptine (Survector, Maneon, Directim) - norepinephrine-dopamine reuptake inhibitor, Iprindole (Prondol, Galatur, Tetran) - 5-HT2 receptor antagonist, Opipramol (Insidon, Pramolan, Ensidon, Oprimol) - o receptor agonist, Tianeptine (Stabion, Coaxil, Tatinol), TeCAs such as Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Amoxapine (Asendin), Quetiapine (Seroquel), Benzoctamine (Tacitin), Loxapine (Adasuve, Loxitane), Mazindol, Aptazapine (CGS-7525A), Esmirtazapine (ORG-50,081), Oxaprotiline (C 49-802 BDA), Ciclazindol, MAOIs such as Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), Tranylcypromine (Parnate), Benmoxin (Nerusil, Neuralex), Iproclozide (Sursum), Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), Mebanazine (Actomol), Nialamide (Niamid), Octamoxin (Ximaol, Nimaol), Pheniprazine (Catron), Phenoxypropazine (Drazine), Pivalylbenzhydrazine (Tersavid), Safrazine (Safra), Minaprine (Cantor), Toloxatone (Humoryl), Moclobemide (Aurorix, Manerix, Moclamine), Brofaromine (Consonar), Caroxazone (Surodil, Timostenil), Eprobemide (Befol), Metralindole (Inkazan), Minaprine (Cantor), Pirlindole (Pirazidol), Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) such as Toludesvenlafaxine (Ruoxinlin), Nefazodone (Serzone), Serotonin modulators and stimulators (SMSs) such as Vilazodone (Viibryd), Vortioxetine (Trintellix, Brintellix), Serotonin antagonist and reuptake inhibitors (SARIs) such as Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Etoperidone (Axiomin, Etonin), Norepinephrine reuptake inhibitors (NRIs) such as Reboxetine (Edronax), TeniloxazinePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013(Lucelan, Metatone), Viloxazine (Qelbree, formerly Vivalan), Atomoxetine (Strattera), PDC-1421 (BLI-1005), Norepinephrine-dopamine reuptake inhibitors (NDRIs) such as Bupropion (Well butrin, Elontril), Amineptine (Survector, Maneon), Nomifensine ( Merita I, Alival), OPC-64005, Atypical antipsychotics used to treat depression such as Amisulpride (Solian), Lumateperone (Caplyta), Lurasidone (Latuda), Quetiapine (Seroquel), and Other atypicals such as Agomelatine (Valdoxan), Brexanolone (allopregnanolone; Zulresso), Gepirone (Exxua), Opipramol (Insidon), Tianeptine (Stabion, Coaxil, Tianeurax), a-Methyltryptamine [aMT] (Indopan), Etryptamine (Monase), Indeloxazine (Elen, Noin), Medifoxamine (Cledial, Gerdaxyl), Oxaflozane (Conflictan), a drugs in investigation such as BTRX-246040 (LY-2940094), Aticaprant (JNJ-67953964, CERC-501, LY-2456302), Navacaprant (BTRX-335140; BTRX-140), Buprenorphine / samidorphan (ALKS-5461), CVL-354, JNJ-61393215 (JNJ-3215; Orexin-1) and Seltorexant (MIN-202, JNJ-42847922, JNJ-922). In some instances the second pharmaceutical compound of the intermittently administered memantine- or amantadine-based drug combination may comprise any of agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazodone, vilazodone, opipramol, tianeptine, vortioxetine, tandosporine and trazodone and their pharmaceutically acceptable salts thereof.

[0024] In the case of SOC antidepressants as well as atypical antipsychotics used to treat depression, while they generally require several weeks to achieve therapeutic efficacy in depression, a critical distinguishing feature of combining these agents with memantine or amantadine is the ability of the drug combination to evoke rapid therapeutic relief within twenty-four to seventy-two hours. A key criterion for selecting a SOC antidepressant or atypical antipsychotic as the second pharmaceutical compound of the intermittently administered memantine- or amantadine-based drug combination is its ability to evoke full activity across all of the Set B structures, which may be determined empirically. Additionally, the strength of the evoked activation may be factored into the selection, as compounds with stronger Set B activity are more likely to support rapid therapeutic efficacy when combined with memantine or amantadine. For example, the present data revealed that the TeCA mianserin, but not the TeCA mirtazapine nor TCAs desipramine and amitriptyline nor the SSRIs fluoxetine or fluvoxamine, is capable of evoking robust activity across all Set B structures from a single treatment.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0025] As proof of concept the inventors demonstrate e.g., that single treatment with memantine and an exemplary second pharmaceutical compound (mianserin (S isomer, R isomer, or a racemate comprising both isomers or structural analog or pharmaceutically acceptable salt thereof) or lumateperone(or pharmaceutically acceptable salt thereof)) induces a lasting antidepressant-like behavioral effect in mice, which is not seen with either mianserin or lumateperone or memantine administered alone.

[0026] Also, the inventors demonstrate that the inventive intermittent therapeutic regimen that involves single or intermittent drug administration, and which provides for drug-free wash-out periods of at least 48 hours between doses is necessary to maintain memantine's activity at the set A of brain structures. This discovery contradicts conventional memantine treatments which rely on daily dosing, typically two times a day, conventionally used in the treatment of moderate-to-severe Alzheimer's disease

[0051] ,

[0027] To the best of the inventors' knowledge the treatment of depressive, stress-related, substance abuse, or dementia-associated disorders, e.g., TRD, PTSD, bipolar depression, opioid or alcohol use disorders, negative and cognitive symptoms of schizophrenia, MCI or Alzheimer's disease, et seq. using an intermittent dosing regimen (every 2 days or longer) which uses intermittent dosing with a pharmaceutical drug combination of 1) memantine or amantadine or their structural analogues and pharmaceutically acceptable salts activating at a dosage which activates Set A of brain structures, and 2) a second compound with complementary brain activity, i.e., a dosage which activates Set B of brain structures, e.g., low dose psilocybin or other psychedelic or stimulant molecule, including DMT, ibogain, MDMA, LSD and their structural analogues, or lumateperone or other atypical antipsychotic, or mianserin or other SOC antidepressant from the classes of SSRIs, SNRIs, TCAs, TeCAs, MAOIs, NASSAs, or atypical antidepressants including but not limited to agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazodone, vilazodone, opipramol, tianeptine, vortioxetine and trazodone has not been previously reported.

[0028] As is shown herein, this novel treatment regimen addresses deficiencies of previous treatment methods used to treat depressive, stress-related, substance abuse and dementia-associated disorders, e.g., TRD, PTSD, bipolar depression, opioid or alcohol usePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013disorders, negative and cognitive symptoms of schizophrenia, MCI or Alzheimer's disease, among others.SUMMARY OF EXEMPLARY EMBODIMENTS

[0029] The intermittent treatment methods described herein should achieve rapid and prolonged therapeutic relief of clinical symptoms associated with depressive, stress-related, substance abuse-related and dementia-associated disorders, e.g., MDD, TRD, bipolar depression, PPD, PTSD, negative and cognitive symptoms of schizophrenia, and Alzheimer's disease among others. Advantageously, in the context of dementia treatment the methods described herein should slow the progression of MCI and dementia in AD and other dementia-related disorders significantly more than a daily treatment with memantine alone.

[0030] In some exemplary embodiments the inventive treatment methods include the intermittent administration (every 2 days or less frequently) to a patient in need thereof of a memantine- or amantadine-based drug combination comprising 1) an amount of memantine or amantadine or their structural analogues and pharmaceutically acceptable salts, along with either: 2a) a low dose psilocybin or a low dose of other psychedelic or stimulant molecule, including but not limited to DMT, ibogaine, MDMA, LSD, or their structural analogues, or 2b) mianserin or other antidepressant, including but not limited to SSRIs, SNRIs, TCAs, TeCAs, MAOIs, NASSAs, or atypical antidepressants, or 2c) lumateperone or other atypical antipsychotic, which is sufficient to achieve rapid therapeutic relief of symptoms in MDD, TRD, bipolar depression, PTSD or substance use disorders, negative and cognitive symptoms of schizophrenia, or significantly delay the progression of MCI and dementia.

[0031] In some exemplary embodiments the treatment methods include treating a depressive, substance abuse or stress related disorder in a subject in need thereof, which treatment method comprises one or more treatments wherein the first treatment comprises or consists of:(a) administering a first dose of memantine or amantadine, their structural analogues or pharmaceutically acceptable salts thereof, which is sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; andPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013(b) administering a first dose of a second pharmaceutical compound which is capable of activating Set B brain areas in a mouse brain, optionally psilocybin or mianserin or lumateperone, wherein the administered dose of said second pharmaceutical compound is sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity (with the caveat in instances where the drug is capable of eliciting hallucinogenic and other psychotomimetic perceptions this drug is administered at a dose ("low dose") which activates Set B brain areas in mouse brain using c-fos as a reporter of activity, but which does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions; and wherein said method alleviates one or more clinical symptoms of said depressive, substance abuse or stress related disorder.

[0032] In some exemplary embodiments the second pharmaceutical compound includes one of the following: selective serotonin reuptake inhibitors (SSRIs), serotoninnorepinephrine reuptake inhibitors (SNRIs), tricyclic (TCAs), tetracyclic (TeCAs) antidepressants, monoamine oxidase inhibitors (MAOIs), noradrenergic and specific serotonergic antidepressants (NASSAs), and atypical antidepressants and their pharmaceutically acceptable salts thereof.

[0033] In some exemplary embodiments the second pharmaceutical compound includes one of the following: SSRIs such as Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), Sertraline (Zoloft), Dapoxetine ( Priligy), Indal pine (Upstene), Zimelidine (Zelmid), Alaproclate (GEA-654), Centpropazine, Cericlamine (JO-1017), Femoxetine (Malexil; FG-4953), Ifoxetine (CGP-15210), Omiloxetine, Panuramine (WY-26002), Pirandamine (AY-23713), Seproxetine ((S)-norfluoxetine), SNRIs such as Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixe I, Savella), Sibutramine (Meridia), Tramadol (Ultram), Venlafaxine (Effexor), TCAs such as Butriptyline (Evadyne), Clomipramine (Anafranil), Imipramine (Tofranil, Janimine, Praminil), Trimipramine, (Surmontil), Desipramine (Norpramin, Pertofrane), Dibenzepini (Noveril, Victoril), Lofepramine (Lomont, Gamanil), Maprotiline (Ludiomil), Nortriptyline (Pamelor, Aventyl, Norpress), Protriptyline (Vivactil), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Amoxapine (Asendin), Demexiptiline (Deparon, Tinoran), Dimetacrine (Istonil, Istonyl, Miroistonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Fluacizine (Phtorazisin), Imipraminoxide (Imiprex, Elepsin), Melitracen (Deanxit,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013Dixeran, Melixeran, Trausabun), Metapramine (Timaxel), Nitroxazepine (Sintamil), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen / Azaphen), Propizepine (Depressin, Vagran), Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine), Amineptine (Survector, Maneon, Directim) - norepinephrine-dopamine reuptake inhibitor, Iprindole (Prondol, Galatur, Tetran) - 5-HT2 receptor antagonist, Opipramol (Insidon, Pramolan, Ensidon, Oprimol) - o receptor agonist, Tianeptine (Stabion, Coaxil, Tatinol), TeCAs such as Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Amoxapine (Asendin), Quetiapine (Seroquel), Benzoctamine (Tacitin), Loxapine (Adasuve, Loxitane), Mazindol, Aptazapine (CGS-7525A), Esmirtazapine (ORG-50,081), Oxaprotiline (C 49-802 BDA), Ciclazindol, MAOIs such as Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), Tranylcypromine (Parnate), Benmoxin (Nerusil, Neuralex), Iproclozide (Sursum), Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), Mebanazine (Actomol), Nialamide (Niamid), Octamoxin (Ximaol, Nimaol), Pheniprazine (Catron), Phenoxypropazine (Drazine), Pivalylbenzhydrazine (Tersavid), Safrazine (Safra), Minaprine (Cantor), Toloxatone (Humoryl), Moclobemide (Aurorix, Manerix, Moclamine), Brofaromine (Consonar), Caroxazone (Surodil, Timostenil), Eprobemide (Befol), Metralindole (Inkazan), Minaprine (Cantor), Pirlindole (Pirazidol), Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) such as Toludesvenlafaxine (Ruoxinlin), Nefazodone (Serzone), Serotonin modulators and stimulators (SMSs) such as Vilazodone (Viibryd), Vortioxetine (Trintellix, Brintellix), Serotonin antagonist and reuptake inhibitors (SARIs) such as Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Etoperidone (Axiomin, Etonin), Norepinephrine reuptake inhibitors (NRIs) such as Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Qelbree, formerly Vivalan), Atomoxetine (Strattera), PDC-1421 (BLI-1005), Norepinephrine-dopamine reuptake inhibitors (NDRIs) such as Bupropion (Wellbutrin, Elontril), Amineptine (Survector, Maneon), Nomifensine (Merital, Alival), OPC-64005, atypical antipsychotics used to treat depression such as Lumateperone (Caplyta), Amisulpride (Solian), Lurasidone (Latuda), Quetiapine (Seroquel), and Other atypicals such as Agomelatine (Valdoxan), Brexanolone (allopregnanolone; Zulresso), Gepirone (Exxua), Opipramol (Insidon), Tianeptine (Stabion, Coaxil, Tianeurax), a-Methyltryptamine [aMT] (Indopan), Etryptamine (Monase), Indeloxazine (Elen, Noin), Medifoxamine (Cledial, Gerdaxyl), Oxaflozane (Conflictan), a drugs in investigation such as BTRX-246040 (LY-2940094), Aticaprant (J NJ-67953964, CERC-501, LY-2456302), Navacaprant (BTRX-335140;PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013BTRX-140), Buprenorphine / samidorphan (ALKS-5461), CVL-354, JNJ-61393215 (JNJ-3215; Orexin-1) and Seltorexant (MIN-202, JNJ-42847922, JNJ-922).

[0034] In some embodiments the second pharmaceutical compound of the intermittently administered memantine- or amantadine-based drug combination may comprise any of agomelatine, bupropion, iprindole, mianserin, mirtazapine, nefazodone, vilazodone, opipramol, tianeptine, vortioxetine, tandosporine and trazodone and their pharmaceutically acceptable salts thereof.

[0035] In some exemplary embodiments the (a) memantine or amantadine, structural analogue thereof or a pharmaceutically acceptable salt thereof, and (b) the second pharmaceutical compound are administered at the same time or within 0.1-8 hours, 0.1-4 hours, 0.1-2 hours, 0.1-1 hours, or 0.1-.5 hours of each other.

[0036] In some exemplary embodiments the memantine or amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof, and the second pharmaceutical compound are administered in the same medicament.

[0037] In some exemplary embodiments the memantine or amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof, and the second pharmaceutical compound are administered in different medicaments.

[0038] In some exemplary embodiments the method comprises an additional treatment also comprising the administration of (a) memantine or amantadine, a structural analogue thereof or a pharmaceutically acceptable salt thereof, and (b) the second pharmaceutical compound capable of activating Set B brain areas in mouse brain using c-fos as a reporter of activity, wherein said second pharmaceutical compound optionally comprises or consists of psilocybin or mianserin or lumateperone, and wherein the memantine or amantadine, structural analogue thereof or pharmaceutically acceptable salt thereof is administered at a dose sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity, and the psilocybin or mianserin or lumateperone is administered at a dose sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity but which does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions and / or does not elicit hallucinogenic and otherPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013psychotomimetic perceptions, and further wherein said additional treatment is not effected until at least 48 hours after the first treatment.

[0039] In some exemplary embodiments the additional treatment is effected at least 3, 4, 5, 6 or 7 days or longer after the first treatment.

[0040] In some exemplary embodiments the method comprises two or more additional treatments, wherein each additional treatment is effected at least 3, 4, 5, 6 or 7 days or longer after the previous additional treatment.

[0041] In some exemplary embodiments the subject treatment results in rapid and prolonged relief of clinical symptoms of depressive, stress-related or substance abuse-related disorders.

[0042] In some exemplary embodiments the patient has not been previously treated with an antidepressant compound and / or has not been previously treated with memantine.

[0043] In some exemplary embodiments the treated patient has a depressive or stress related disorder which includes e.g., any of major depressive disorder (MDD) and / or treatment-resistant disorder (TRD) and / or post -traumatic stress disorder (PTSD).

[0044] In some exemplary embodiments the patient has not been previously treated with, or is not currently being treated with, or is not responding to, an anti-depressive treatment.

[0045] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 5 mg to about 50 mg.

[0046] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 10 mg to about 40 mg.

[0047] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 20 mg to about 30 mg.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0048] In some exemplary embodiments the dosage of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 20 mg to about 1000 mg.

[0049] In some exemplary embodiments the dosage of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 50 mg to about 500 mg.

[0050] In some exemplary embodiments the dosage of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 50 mg to about 250 mg.

[0051] In some exemplary embodiments the second compound in the first treatment comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof ranges from about 1 mg to about 20 mg.

[0052] In some exemplary embodiments the second compound in the first treatment comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof ranges from about 2.5 mg to about 17.5 mg.

[0053] In some exemplary embodiments the second compound in the first treatment comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof ranges from about 5 mg to about 15 mg.

[0054] In some exemplary embodiments the second compound which is administered in the first treatment comprises or consists of a low dose of a psychedelic or stimulant compound, including but not limited to lysergic acid diethylamide (LSD), 3,4-Methylenedioxy methamphetamine (MDMA), ibogain and N,N-Dimethyltryptamine (DMT) and their structural analogues and pharmaceutically acceptable salts thereof, wherein said second compound is preferably administered at a dose which is sufficient to activate the Set B brain structures but which does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions and / or said dose does not appreciably evoke hallucinogenic and other psychotomimetic perceptions.

[0055] In some exemplary embodiments the second compound administered in the first treatment comprises or consists of mianserin (S isomer, R isomer or racemate comprisingPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013both isomers) or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 20 mg to about 200 mg.

[0056] In some exemplary embodiments the second compound administered in the first treatment comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 40 mg to about 150 mg.

[0057] In some exemplary embodiments the second compound administered in the first treatment comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 50 mg to about 100 mg.

[0058] In some exemplary embodiments the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 10 mg to about 100 mg.

[0059] In some exemplary embodiments the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 20 mg to about 50 mg, or 30-45 mg.

[0060] In some exemplary embodiments the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 42 mg.

[0061] In some exemplary embodiments the memantine or amantadine and / or the second compound administered in the first treatment comprise oral dosage forms, optionally orally disintegrating forms.

[0062] In some exemplary embodiments the memantine or amantadine and / or the second compound administered in the one or more additional treatments comprise oral dosage forms, optionally orally disintegrating forms.

[0063] In some exemplary embodiments the memantine or amantadine and / or the second compound administered in the first treatment are administered intranasally or via inhalation.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0064] In some exemplary embodiments the memantine or amantadine and / or the second compound administered in the one or more additional treatments are administered intranasally or via inhalation.

[0065] In some exemplary embodiments the memantine or amantadine and / or the second compound administered in the first treatment are administered topically, e.g., using a patch.

[0066] In some exemplary embodiments the memantine or amantadine and / or the second compound administered in the one or more additional treatments are administered topically, e.g., using a patch.

[0067] In some exemplary embodiments the invention provides a medicament comprising a drug combination suitable for treating a depressive, stress-related, substance abuse related or dementia disorder or mild cognitive impairment (MCI) in a subject in need thereof, which medicament comprises:(a) a dose of memantine or amantadine, a structural analogue or a pharmaceutically acceptable salt thereof, sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; and(b) a dose of a second pharmaceutical compound, optionally psilocybin or mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof or lumateperone, or another compound which is capable of activating Set B brain areas in a mouse brain, wherein the dose of said second pharmaceutical compound is preferably sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity but low enough such that it does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions and / or does not elicit hallucinogenic and other psychotomimetic perceptions.

[0068] In some exemplary embodiments the second pharmaceutical compound in the medicament comprises one of the following: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic (TCAs), tetracyclic (TeCAs) antidepressants, monoamine oxidase inhibitors (MAOIs), noradrenergic and specific serotonergic antidepressants (NASSAs), and atypical antidepressants and their pharmaceutically acceptable salts thereof.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0069] In some exemplary embodiments the second pharmaceutical compound in the medicament comprises psilocybin or a pharmaceutically acceptable salt thereof.

[0070] In some exemplary embodiments the second pharmaceutical compound in the medicament comprises mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof.

[0071] In some exemplary embodiments the one second pharmaceutical compound in the medicament comprises lumateperone or a pharmaceutically acceptable salt thereof.

[0072] In some exemplary embodiments the one second pharmaceutical compound in the medicament a psychedelic or stimulant compound, including but not limited to lysergic acid diethylamide (LSD), 3,4-Methylenedioxymethamphetamine (MDMA), ibogain and N,N-Dimethyltryptamine (DMT) and their structural analogues and pharmaceutically acceptable salts thereof, and the dosage thereof in the medicament is sufficient to activate the Set B brain structures but low enough such that it does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions.

[0073] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the medicament is about 5 mg to about 50 mg.

[0074] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the medicament is about 10 mg to about 40 mg.

[0075] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the medicament is about 20 mg to about 30 mg.

[0076] In some exemplary embodiments the dosage of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the medicament is about 20 mg to about 1000 mg.

[0077] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the medicament is about 50 mg to about 500 mg.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0078] In some exemplary embodiments the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the medicament is about 50 mg to about 250 mg.

[0079] In some exemplary embodiments the second compound in the medicament comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof in the medicament is about 1 mg to about 20 mg.

[0080] In some exemplary embodiments the second compound in the medicament comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof in the medicament is about 2.5 mg to about 17.5 mg.

[0081] In some exemplary embodiments the second compound in the medicament comprises or consists of psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof in the medicament is about 5 mg to about 15 mg.

[0082] In some exemplary embodiments the second compound in the medicament comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 20 mg to about 200 mg.

[0083] In some exemplary embodiments the second compound in the medicament comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 40 mg to about 150 mg.

[0084] In some exemplary embodiments the second compound in the medicament comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 50 mg to about 100 mg.

[0085] In some exemplary embodiments the second compound in the medicament comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 10 mg to about 100 mg.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0086] In some exemplary embodiments the second compound in the medicament comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 20 mg to about 50 mg.

[0087] In some exemplary embodiments the second compound in the medicament comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 35 mg to about 45 mg.

[0088] In some exemplary embodiments the second compound in the medicament comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 42 mg.

[0089] In some exemplary embodiments the medicament comprises an oral dosage form, optionally an orally disintegrating form.

[0090] In some exemplary embodiments the medicament comprises an intranasally or inhalatory administrable dosage form.

[0091] In some exemplary embodiments the medicament comprises a topically administrable dosage form, optionally a patch.

[0092] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, which treatment method comprises repeated treatments which each treatment comprises:(a) administering a dose of memantine or amantadine, a structural analogue or a pharmaceutically acceptable salt thereof, which is sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; and(b) administering psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers) or lumateperone, wherein the administered dose of psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers) or lumateperone is sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity;wherein each treatment (administration of memantine, a structural analogue or a pharmaceutically acceptable salt thereof; and psilocybin or mianserin) is effected no more frequently than every 2, 3, 4, 5, 6 or 7 days rather than conventional daily memantine administration.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0093] In some exemplary embodiments the invention provides a method for treating dementia in a subject in need thereof, wherein the subject has Alzheimer's disease.

[0094] In some exemplary embodiments the invention provides a method for treating dementia in a subject in need thereof, wherein the subject has Lewy body dementia.

[0095] In some exemplary embodiments the invention provides a method for treating dementia in a subject in need thereof, wherein the subject has vascular dementia.

[0096] In some exemplary embodiments the invention provides a method for treating dementia in a subject in need thereof, wherein the subject has frontotemporal dementia.

[0097] In some exemplary embodiments the invention provides a method for treating dementia in a subject in need thereof, wherein the subject has mixed dementia (different forms of dementia).

[0098] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, wherein, wherein the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in each treatment is about 5 mg to about 50 mg, about 10 mg to about 40 mg, about 20 mg to about 30 mg.

[0099] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, wherein, wherein the dosage of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof in each treatment is about 20 mg to about 1000 mg, about 50 mg to about 500 mg, about 50 mg to about 250 mg.

[0100] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, wherein the dosage of psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof ranges from about 1 mg to about 20 mg, about 2.5 mg to about 17.5 mg, or from about 5 mg to about 15 mg.

[0101] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, wherein the dosage of mianserin (S isomer, R isomer, or a racemate comprising both isomers) or aPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013pharmaceutically acceptable salt thereof is about 20 mg to about 200 mg, about 40 mg to about 150 mg, or about 50 mg to about 100 mg.

[0102] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, wherein the dosage of lumateperone or a pharmaceutically acceptable salt thereof is about 10 mg to about 100 mg, about 20 mg to about 50 mg, or about 42 mg.

[0103] In some exemplary embodiments the invention provides a method for treating dementia or mild cognitive impairment (MCI) in a subject in need thereof, wherein the treatment slows and / or reverses the progression of dementia or cognitive impairment more than daily treatment with memantine alone.BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIGURE 1A-D show an exemplary whole-brain mapping drug-screening platform, which enables an unbiased and comprehensive evaluation of a drug's effect across the entire mouse brain at a single cell resolution. In (A) mice receive either a drug or a control vehicle solution via different delivery methods, such as intraperitoneal (i.p.), per oral (p.o.), subcutaneous (s.c. ), intramuscular (i.m.), or intravenous (i.v.) administration. The drug's effect on brain cells, regions, and neuronal circuits induces or inhibits the expression of the immediate early gene c-fos in cells directly affected by the drug action. This typically peaks within 2.5 to 3 hours after drug delivery, depending on the drug's brain concentration (Cmax) and other pharmacokinetic properties. In (B) after the 2.5 to 3 hr period, the mice are killed, their brains are chemically fixed and extracted from the skull and subjected to anti-c-fos immunofluorescence staining. This process visualizes c-fos expression, fluorescently labeling hundreds of thousands to millions of c-fos+ cell nuclei in one hemisphere. In (C) Subsequently, the brains undergo chemical clearing and are imaged via light-sheet fluorescent microscopy (LSFM). This generates three-dimensional (3D) datasets featuring one or both hemispheres, which can be visualized as serial section image stacks. In (D) Subsequently, custom algorithms are employed to computationally detect c-fos+ cells within the 3D whole-brain datasets. Next, the distribution of the detected c-fos+ cells across the brain is registered to a 3D reference mouse brain. The initial statistical analysis involves comparing the counts and distributions of c-fos+ cells between mice treated with thePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013control vehicle and those administered the experimental drug. The differences observed between control- and drug-treated mice are represented in two complementary statistical analyses: (1) spatial brain maps identified by voxel-based statistics, visualizing the spatial areas with statistically significant differences (displayed in red in the 3D reference mouse brain in the left panel), and (2) anatomical regions of interest (ROIs) identified by ROI statistics, quantifying the differences as mean ± SEM per anatomical region of the mouse brain atlas (presented in an Excel spreadsheet in the right panel). Both voxel and ROI statistics employ negative binomial regression, corrected for multiple comparisons by false discovery rate (FDR).

[0105] FIGURE 2A-C show the identification of brain activity by a single treatment with 30 mg / kg (i.p.) ketamine. In (A) ketamine-evoked changes in c-fos+ cell distribution evoked by 30 mg / kg (i.p.) were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) 30 mg / kg (i.p.) ketamine-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity in the ILA2 / 3, ILA5 / 6, PL2 / 3, PL5 / 6, PVT, MD, CM, RE and RH thalamus, CEAm, BSTa I, and ACBsh. In (C) Left panel, phencyclidine (PCP), another dissociative drug acting as an NMDA receptor antagonist, evokes similarly robust activation of the retrosplenial cortex dorsal part (RSPd) as ketamine shown in the last (A) panel. Right panel, quantification of the RSPd activity evoked by ketamine 30 mg / kg (i.p.) and PCP 5 mg / kg (i.p.).

[0106] FIGURE 3A-C show the identification of brain activity by single treatments with 5 and 10 mg / kg (i.p.) psilocybin. In (A) Psilocybin-evoked changes in c-fos+ cell distribution evoked by 5 mg / kg (i.p.) (top panel) and 10 mg / kg (i.p.) (bottom panel) were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) 5 and 10 mg / kg (i.p.) psilocybin-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity in the ILA2 / 3, ILA5 / 6, PL2 / 3, PL5 / 6, PVT, MD, CM, RE and RH thalamus, CEAm, BSTa I, and ACBsh. In addition, psilocybin did not evoke significant activation of the RSPd at either 5 or 10 mg / kg. In (C) Psilocybin-evoked was compared to that of another hallucinogen 2C-T, revealing a similar layer 5-focused cortical activation.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0107] FIGURE 4A-B shows the identification of brain activity by single treatments with 4 and 10 mg / kg (i.p.) memantine. In (A) Memantine-evoked changes in c-fos+ cell distribution evoked by 4 and 10 mg / kg (i.p.) were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) 4 and 10 mg / kg (i.p.) memantine-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity for 4 mg / kg (i.p.) memantine in the ILA2 / 3, 1 LA5 / 6, PL2 / 3, PL5 / 6, MD, CM, RE and RH thalamus, and for 10 mg / kg (i.p.) memantine in the ILA2 / 3, ILA5 / 6, PL2 / 3, PL5 / 6, MD, CM, RE and RH thalamus, CEAm, BSTal, and ACBsh. In addition, memantine at 10 mg / kg, but not at 4 mg / kg, evoke significant activation of the RSPd.

[0108] FIGURE 5A-B show the identification of brain activity by a single treatment with 50 and 100 mg / kg (i.p.) amantadine. In (A) Amantadine-evoked changes in c-fos+ cell distribution evoked by 50 and 100 mg / kg (i.p.) were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) 50 and 100 mg / kg (i.p.) amantadine-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity for 50 mg / kg (i.p.) amantadine in the Set A ILA2 / 3, ILA5 / 6, PL2 / 3, PL5 / 6, MD, CM, RE and RH thalamus, and for 100 mg / kg (i.p.) amantadine in all Set A and B structures. In addition, memantine at 100 mg / kg, but not at 50 mg / kg, evoke significant activation of the RSPd linked to dissociative side effects.

[0109] FIGURE 6A-B show the identification of brain activity by a single treatment with low dose 2.5 mg / kg (i.p.) psilocybin. In (A) Psilocybin-evoked changes in c-fos+ cell distribution evoked by 2.5 mg / kg (i.p.) were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) 2.5 mg / kg (i.p.) psilocybin-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity in the PVT, MD, CM, RE and RH thalamus, CEAm, BSTal, and ACBsh. In addition, psilocybin at 2.5 mg / kg (i.p.) did not evoke significant activation of the RSPd.

[0110] FIGURE 7A-B shows the identification of brain activity evoked by a single treatment with SSRI antidepressants, based on exemplary 15 mg / kg (i.p.) fluoxetine and 60 mg / kg (i.p.) fluvoxamine brain activation patterns. In (A) Fluoxetine- and fluvoxamine-PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013evoked changes in c-fos+ cell distribution were determined by voxel-based statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each 150 urn voxel. The discreet spatial areas with statistically significant increases are visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) Fluoxetine- and fluvoxamine-evoked changes in c-fos+ cell distribution were further quantified by region of interest (ROI) statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each ROI, representing anatomical brain regions. Statistically significant activity evoked by 15 mg / kg (i.p.) fluoxetine and 60 mg / kg (i.p.) fluvoxamine was detected in some Set B structures, including the PVT, CEAm and BSTal, but not ACBsh. In addition, both drugs activated the MD of the Set A structures and fluoxetine activated CM of the Set A structures.

[0111] FIGURE 8A-B shows the identification of brain activity evoked by a single treatment with TCA antidepressants, based on exemplary 40 mg / kg (i.p.) desipramine and 15 mg / kg (i.p.) amitriptyline brain activation patterns. In (A) Desipramine- and amitriptyline-evoked changes in c-fos+ cell distribution were determined by voxel-based statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each 150 urn voxel. The discreet spatial areas with statistically significant increases are visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) Desipramine- and amitriptyline-evoked changes in c-fos+ cell distribution were further quantified by region of interest (ROI) statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each ROI, representing anatomical brain regions. Statistically significant activity evoked by 40 mg / kg (i.p.) desipramine was detected in all Set B structures, the PVT, CEAm, BSTal, and ACBsh. Statistically significant activity evoked by 15 mg / kg (i.p.) amitriptyline was detected in some Set B structures, including the PVT, MD, CEAm and BSTal, but not ACBsh. In addition, the MD of set A structures was activated by both 40 mg / kg (i.p.) desipramine and 15 mg / kg (i.p.) amitriptyline.

[0112] FIGURE 9A-B shows the identification of brain activity evoked by a single treatment with TeCA antidepressants, based on exemplary 10 mg / kg (i.p.) mirtazapine and 10 mg / kg (i.p.) mianserin brain activation pattern. In (A) Mirtazapine- and mianserin-evoked changes (top and bottom panel, respectively) in c-fos+ cell distribution were determined by voxel-based statistics, applying negative binomial regression corrected by FDR for multiplePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013comparisons to each 150 urn voxel. The discreet spatial areas with statistically significant increases are visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) Mirtazapine- and mianserin-evoked changes in c-fos+ cell distribution (left and right panels, respectively) were further quantified by region of interest (ROI) statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each ROI, representing anatomical brain regions. Statistically significant activity evoked by 10 mg / kg (i.p.) mirtazapine and 10 mg / kg (i.p.) mianserin was detected in all Set B structures, the PVT, CEAm, BSTal, and ACBsh, though at higher levels seen with mianserin.

[0113] FIGURE 10A-B shows the identification of brain activity evoked by a single treatment with antipsychotics used in the treatment of depression and bipolar depression, based on exemplary 1.2 mg / kg (i.p.) cariprazine and 8 mg / kg (i.p.) lumateperone brain activation pattern. In (A) Cariprazine- and lumateperone-evoked changes (top and bottom panel, respectively) in c-fos+ cell distribution were determined by voxel-based statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each 150 urn voxel. The discreet spatial areas with statistically significant increases are visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. In (B) Cariprazine- and lumateperone-evoked changes in c-fos-i- cell distribution (left and right panels, respectively) were further quantified by region of interest (ROI) statistics, applying negative binomial regression corrected by FDR for multiple comparisons to each ROI, representing anatomical brain regions. Statistically significant activity evoked by 1.2 mg / kg (i.p.) cariprazine was detected only in a subset of the Set B structures, including BSTa and ACBsh. In contrast 8 mg / kg (i.p.) lumateperone evoked significant activity across all Set B structures.

[0114] FIGURE 11A-B shows the identification of brain activity representing a chronic 2 week treatment with 15 mg / kg (i.p.) fluoxetine. In (A) Fluoxetine-evoked changes in c-fos+ cell distribution after a 2 week treatment were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. Note the overall increased spatial pattern of the 2 week fluoxetine treatment compared to the single fluoxetine treatment shown in FIGURE 1A. In (B) 2 week fluoxetine-evoked changes in c-fos+ cell distribution were further quantified by ROIPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013statistics, revealing statistically significant activity in the infralimbic cortex layers 2 / 3 (ILA2 / 3) and 5 / 6 (ILA5 / 6), prelimbic cortex layers 2 / 3 (PL2 / 3) and 5 / 6 (PL5 / 6), PVT, MD, CM, reunions (RE) and rhomboid (RH ) thalamus, CEAm, BSTal, and ACBsh.

[0115] FIGURE 12A-B shows the identification of brain activity representing a daily 2 week treatment with 4 mg / kg (i.p.) memantine. (A) Memantine-evoked changes in c-fos+ cell distribution after a 2 week treatment were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. Note the overall increased spatial pattern of the 2 week fluoxetine treatment compared to the single fluoxetine treatment shown in FIGURE 1A. In (B) 2 week memantine-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity in the infralimbic cortex layers 2 / 3 (ILA2 / 3) and 5 / 6 (ILA5 / 6), prelimbic cortex layers 2 / 3 (PL2 / 3) and 5 / 6 (PL5 / 6), claustrum (CLA), PVT, MD, CM, reunions (RE) and rhomboid (RH) thalamus, CEAm, BSTal, and ACBsh.

[0116] FIGURE 13A-C shows the identification of brain activity representing an intermittent, twice-a-week treatment with 4 mg / kg (i.p.) memantine for four weeks. In (A) Memantine-evoked changes in c-fos+ cell distribution after the intermittent 4-week treatment were determined by voxel-based statistics as in Fig 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. Note the overall increased cortical activity compared to chronic daily dosing shown in FIGURE 10. In (B) Intermittent 4-week memantine-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity in the infralimbic cortex layers 2 / 3 (ILA2 / 3) and 5 / 6 (ILA5 / 6), prelimbic cortex layers 2 / 3 (PL2 / 3) and 5 / 6 (PL5 / 6), claustrum (CLA), MD, CM, RE and RH thalamus, as well as CEAm. In (C) Intermittent 6 week memantine treatment failed to evoked a significant activation at the RSPd cortex linked to dissociative effects.

[0117] FIGURE 14A-C shows the identification of brain activity representing a single treatment with a drug combination of 4 mg / kg (i.p.) memantine and 10 mg / kg (i.p.) mianserin. In (A) Memantine and mianserin combination-evoked changes in c-fos+ cell distribution after a single treatment were determined by voxel-based statistics as in FIGURE 2 and visualized in red color overlayed on selected coronal planes of the 3D reference mouse brain. Note that all set A and set B structures are activated by the drug combination,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013contrasting with the partial patterns evoked by either memantine or mianserin alone shown in FIGURE 4 and FIGURE 8, respectively. In (B) Memantine and mianserin combination-evoked changes in c-fos+ cell distribution were further quantified by ROI statistics, revealing statistically significant activity in all set A and set B structures. In (C) Memantine and mianserin combination failed to evoked a significant activation at the RSPd cortex linked to dissociative effects.

[0118] FIGURE 15 shows the quantification of an antidepressant-like response in the behavioral forced swim test after single treatment administrations of memantine (4 mg / kg), fluoxetine (15 mg / kg), mianserin (10 mg / kg), ketamine (30 mg / kg), mem+fluox (memantine 4 mg / kg (i.p.) plus fluoxetine 15 mg / kg), and mem+mians (memantine 4 mg / kg (i.p.) plus mianserin 10 mg / kg). Treatments with mianserin and memantine plus fluoxetine induced a statistically significant reduction in the time spent immobile (floating) at 1 hour but not at 24 hours post-dosing. In contrast, treatments with ketamine and memantine plus mianserin induced a statistically significant reduction in the time spent immobile at both 1 hour and 24 hours post-dosing.

[0119] FIGURE 16A-B shows the identification of brain activity in aged mice (18, 22, and 26 months old) versus young adult mice (2 months old). In (A) Aging in mice is associated with a progressive loss of activity in the frontocortical PL and ILA areas in 18, 22, and 26 months old mice. This loss is contrasted with activity evoked in the same regions by memantine at 4 mg / kg, as also shown in FIGURE 4. The c-fos distribution was determined by voxel-based statistics as in FIGURE 2 and visualized in green color for a significant loss of expression and red color for a significant increase in expression overlayed on selected coronal planes of the 3D reference mouse brain. In (B) Changes in c-fos-i- cell distribution in aging and evoked by memantine were further quantified by ROI statistics, revealing statistically significant decreases in the ILA2 / 3, ILA5 / 6, PL2 / 3, PL5 / 6 for aging and increases for 4 mg / kg (i.p.) memantine.DETAILED DESCRIPTION OF THE INVENTIONPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0120] The preferred embodiments of the present disclosure will now be described with reference to the drawings. Identical elements in the various Figures are identified with the same reference numerals.

[0121] Reference will now be made in detail to each embodiment of the present disclosure. Such embodiments are provided by way of explanation of the present disclosure, which is not intended to be limited thereto. In fact, those of ordinary skill in the art may appreciate upon reading the present specification and viewing the present drawings that various modifications and variations can be made thereto.DEFINITIONS

[0122] Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosure herein belongs.

[0123] As used herein, the singular forms "a," "an," and "the," are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0124] The phrase "and / or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Thus, as a non-limiting example, a reference to "A and / or B", when used in conjunction with open-ended language such as "comprising" can refer, in one embodiment, to A only (optionally including elements otherthan B); in another embodiment, to B only (optionally including elements otherthan A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0125] As used herein in the specification and in the claims, the phrase "at least one," in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified. Thus, as a non-PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013limiting example, "at least one of A and B" (or, equivalently, "at least one of A or B," or, equivalently "at least one of A and / or B") can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0126] In certain embodiments, the term "about" or "approximately" as used herein means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system.

[0127] In certain embodiments, "about" can mean within 3 or more than 3 standard deviations, per the practice in the art.

[0128] In certain embodiments, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

[0129] In certain embodiments, when the term "about" or "approximately" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below those numerical values. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 20%, 10%, 5%, or 1%. In certain embodiments, the term "about" is used to modify a numerical value above and below the stated value by a variance of 10%. In certain embodiments, the term "about" is used to modify a numerical value above and below the stated value by a variance of 5%. In certain embodiments, the term "about" is used to modify a numerical value above and below the stated value by a variance of 1%.

[0130] When a range of values is listed herein, it is intended to encompass each value and sub-range within that range. For example, "1-5 mg" or "from about 1 mg to about 5 mg" is intended to encompass 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 1-2 mg, 1-3 mg, 1-4 mg, 1-5 mg, 2-3 mg, 2-4 mg, 2-5 mg, 3-4 mg, 3-5 mg, and 4-5 mg.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0131] It will be further understood that the terms "comprises ' "comprising," "includes," and / or "including," when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0132] "Effective amount" or "therapeutically effective amount" means a dosage sufficient to alleviate one or more symptoms of the condition being treated, or to otherwise provide a desired pharmacological and / or physiologic effect, as may be determined by an objective measure or a patient derived subjective measure.

[0133] "Improvement in next day functioning" or "wherein there is improvement in next day functioning" refers to improvement wherein the beneficial effect of at least one symptom lasts over a period of time, e.g., 6 hours, 12 hours, 24 hours etc.

[0134] "Rapid efficacy" or "rapid clinical efficacy" or "rapid therapeutic efficacy" or "rapid therapeutic relief" or "rapid relief" refers to improvement wherein the beneficial effect of at least one symptom is achieved within twenty-four to seventy-two hours postdosing.

[0135] "Suitable for oral administration" refers to a dosage form which may be conveniently administered orally to a human subject.

[0136] "Suitable for intranasal administration" refers to a dosage form which may be conveniently administered intra nasal ly to a human subject.

[0137] "Pharmaceutically acceptable" refers to molecular entities and compositions that are "generally regarded as safe" - e.g., that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction when administered to a human. In certain embodiments, this term refers to molecular entities and compositions approved by a regulatory agency of the federal or a State government, e.g., the GRAS list under section 204(s) and 409 of the Federal Food, Drug and Cosmetic Act, that is subject to premarket review and approval by the FDA or similar lists, the U.S. Pharmacopeia or another generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0138] "Pharmacokinetic" (PK) parameters are used to describe the rate of absorption of a substance into a biological system. Graphing a substance's serum concentration versusPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013time reveals of the drug's basic PK properties: the maximum concentration the drug attains (Cmax), the time at which this maximum concentration occurs (Tmax), and the area under the concentration-versus-time curve (AUC) which estimates total systemic exposure. AUC0-00is the total area under the plasma drug concentration-time curve, from drug administration until the drug is eliminated ( ng* hr / m I). The area under the curve is governed by clearance. Clearance is defined as the volume of blood or plasma that is totally cleared of its content of drug per unit time (ml / min). "Treating" or "treatment" refers to alleviating the clinical symptoms of a disease or condition in a subject that may be afflicted with the disease or condition. In certain embodiments, "treating" or "treatment" may refer to preventing the appearance of clinical symptoms of a disease or condition in a subject that may be afflicted with or predisposed to the disease or condition. The "treating" or "treatment" can also refer to arresting or reducing development of, or at least one clinical or subclinical symptom of, the disease or condition. "Treating" or "treatment" can refer to a statistically significant, mathematically significant reduction in a symptom of depression. In certain embodiments, "treating" or "treatment" can refer to the improvement of a symptom perceptible to the subject and / or the physician. Permanently curative treatment is not required to achieve "treatment" herein.

[0139] "Unit dosage form" or "UDF" means a physically fixed unit dose of a formulation which is conveniently administered in unit form (e.g. requires no measuring or adjusting of dosage before consumption). A patient may consume one or more UDFs at a time.

[0140] The term "intermittent administration" refers to a dosing regimen in which there drug-free wash-out periods of at least 48 hours between doses. This could include examples of dosing every other day, dosing twice a week, dosing once a week, or even less frequently.

[0141] The term "structural analogs" or "chemical analogs" refers to compounds that have a structure similar to a lead or parental compound but differ from it in certain components, such as functional groups or substructures. They includes but is not limited to structural analogs, functional analogs, prodrug analogs, stereoisomeric analogs, homologous analogs, and bioisosteres. In the present invention such "structural analogues" or "chemical analog" will in general appreciably retain the activity of the corresponding lead or parental compound, e.g., the ability to activate set A or set B brain structures of a mouse brain wherein activation is detectable using a c-fos mapping assay.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0142] The term "including but not limited to" means that the list of items that follows is not exhaustive and may include other items beyond what is explicitly stated.

[0143] The term "depressive disorder" also known as "depression" refers to a common mental disorder which involves a depressed mood or loss of pleasure or interest in activities for long periods of time. Depression is different from regular mood changes and feelings about everyday life. Examples of depressive disorders include major depression, psychotic depression, premenstrual dysphoric disorder, postpartum depression, atypical depression, bipolar depression, seasonal affective disorder, recurrent depressive disorder and bipolar disorder.

[0144] The term "stress related disorder" or "stressor related disorder" refers to disorders that often develop in the aftermath of a traumatic event or stress. They share many features, including dysphoria (general unease or dissatisfaction), irritability, dissociation (disconnection of some aspects of mental functioning from one’s sense of self without conscious awareness), substance use, or insomnia. They differ in the severity and duration of symptoms. Examples thereof include acute stress disorder, Post-traumatic stress disorder (PTSD), depression, adjustment disorder, Disinhibited Social Engagement Disorder, or Disinhibited Attachment Disorder, Reactive attachment disorder, Generalized anxiety disorder, Obsessive-compulsive disorder or "trauma-associated disorder refers to Unclassified and unspecified trauma disorders, and chronic stress.

[0145] The term "substance use disorder" refers to a mental disorder that affects a person's brain and behavior, leading to their inability to control their use of substances like legal or illegal drugs, alcohol, or medications. Symptoms can be moderate to severe, with addiction being the most severe form of SUD. Examples thereof include opioid abuse, alcohol abuse, gambling abuse, internet gambling abuse, tobacco addiction, caffeine addiction, cigarette addiction, vaping addiction, among others.

[0146] The term "negative symptoms of schizophrenia" represents a distinct set of symptoms in patients with schizophrenia which includes blunted affect, alogia (reduction in quantity of words spoken), avolition (reduced goal-directed activity due to decreased motivation), asociality, and anhedonia (reduced experience of pleasure).PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0147] The term "cognitive symptoms of schizophrenia" represents a distinct set of symptoms in patients with schizophrenia which includes deficits in cognitive functions, including processing speed, attention, working memory, verbal learning and memory, visual learning and memory, reasoning and social cognition.

[0148] The term "dementia associated disorder" is a disorder associated with dementia. Dementia refers to a collection of symptoms that can be caused by a number of disorders that affect the brain. People with dementia often have significantly impaired intellectual functioning that interferes with normal activities and relationships, and their ability to solve problems and maintain emotional control, and they may experience personality changes and behavioral problems, such as agitation, delusions, and hallucinations. While memory loss is a common symptom of dementia, memory loss by itself does not mean that a person has dementia. Some of the diseases associated with dementia include Alzheimer's disease (AD), vascular dementia, Lewy body dementia, frontotemporal dementia, Huntington's disease, Normal pressure hydrocephalus (NPH), Wernicke-Korsakoff (WK) syndrome and Creutzfeldt-Jakob disease.

[0149] The term "low dose" in the context of the subject memantine / second compound dosing regimen refers to a dose of the second pharmaceutical compound, optionally psilocybin, which is sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity, but which dose does not elicit hallucinogenic or other psychotomimetic perceptions. Exemplary "low doses" of psilocybin are recited in the exemplary embodiments and the claims.

[0150] The term "memantine" refers to a primary aliphatic amine that is the 3,5-dimethyl derivative of 1-aminoadamantane. Memantine is a low-affinity, high-trapping voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. Memantine is used as a drug, commonly sold under the brand name Axura, Ebixa, Namenda, among others, for slowing the progression of moderate-to-severe Alzheimer's disease. Typically memantine is administered orally.

[0151] The term "memantine analogs" or "memantine derivatives" refers to compounds closely structurally related to memantine which retain the biologic properties of memantine in particular its function as an NMDA antagonist. Examples thereof include amantadine, rimantadine,

[0052] memantine extended-release, Fluoroethylnormemantine, Compounds 1PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013through 19 described in

[0053] , Memit (isothiocyanate prodrug of memantine), memantine nitrate MN-08

[0054] , compound He and other analogues described in

[0055] , MN-05 and other memantine nitrate derivatives described in

[0056] , Memantine derivatives 1 through 6 described in

[0057] , MN-2 (YQW) memantine nitrate derivative

[0058] , memantine analogues described in

[0059] , Vai-Mem, Ala-Mem and Gly-Mem

[0060] , H-4-F-Phe-memantine and H-Tyr-memantine and other memantine analogues

[0061] , Memantine derivatives MP1-10 described in

[0062] , Memantine-sulfur containing conjugates

[0063] , polyamine-memantine hybrids

[0064] , compounds 1 through 21 described in

[0065] , galantamine-memantine hybrids

[0066] , memantine sulfonamide derivatives

[0067] , Cinnamoyl-memantine hybrids

[0068] , memantine analogues containing a chiral cyclopropane skeleton

[0069] , aminotriamantanes

[0070] ,

[0152] The term "amantadine" refers to a 1-aminoadamantane, which is structurally related to other adamantanes including memantine (l-amino-3,5-dimethyladamantane). Amantadine is a very low-affinity, low-trapping voltage-dependent uncompetitive antagonist at glutamatergic NMDA receptors. Amantadine is used as a drug, commonly sold under the brand name Gocovri, Symadine, Symmetrel, PK-Merz and among others, for treatment of Parkinson's disease. Typically amantadine is administered orally.

[0153] The term "amantadine analogs" or "amantadine derivatives" refers to compounds closely structurally related to amantadine which retain the biologic properties of memantine in particular its function as an NMDA antagonist. These compounds as listed above as memantine analogs and derivatives.

[0154] The term "psilocybin" refers to a naturally occurring psychedelic prodrug compound produced by more than 200 species of fungi. The most potent are members of genus Psilocybe, such as P. azurescens, P. semilanceata, and P. cyanescens, but psilocybin has also been isolated from approximately a dozen other genera. Psilocybin is itself biologically inactive but is quickly converted by the body to psilocin, which has mind-altering effects similar, in some aspects, to those of lysergic acid diethylamide (LSD), mescaline, and dimethyltryptamine (DMT). In general, the effects include euphoria, visual and mental hallucinations, changes in perception, distorted sense of time, and perceived spiritual experiences. It can also cause adverse reactions such as nausea and panic attacks.

[0155] The term "psilocybin analogs" or "psilocybin derivatives" or "psilocin analogs" or psilocin derivatives" refers to compounds closely structurally related to psilocybin or psilocinPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013which retain the biologic properties of psilocybin in particular its ability to activate the Set B structures. Examples thereof include 4-hydroxy-N,N-diethyltryptamine (CZ74, 4-HO-DET) and 4-phosphoryloxy-N,N-diethyltryptamine (CEY-19)

[0071] , Norbaeocystin

[0072] , NN-dimethyl-2-(4-hydroxy-3-benzo[b]thienyl)ethylamine and 4-benzyloxy- and 4-methoxy-benzo[b]thiophen derivatives

[0073] , 3-[2-(dialkylamino) ethyl]-and 3-[2-(cycloalkylamino) ethyl] indol-4-ols and 3-[2-(d ialkylamino) ethyl]-, 3-[2-(N-methyl-N-alkylamino) ethyl]-, and 3-[2-(cycloalkylamino) ethyl] indol-4-ols, including 4-hydroxy-N-methyl-N-ethyltryptamine (4-HO-MET), 4-hydroxy-N-methyl-N-isopropyltryptamine (4-HO-MIPT), 4-hydroxy-N, N-dipropyltryptamine (4-HO-DPT), and 4-hydroxy-N, N-diisopropyltryptamine (4-HO-DIPT) [74, 75], 5-methoxy- and 5-hydroxy-l,2,3,4-tetrahydro-9H-pyrido[3,4-b]indoles

[0076] , 4Acetoxy-N,N-dimethyltryptamine (O-acety Ipsilocin, psilacetin, 4-AcO-DMT)

[0077] , 4-AcO-DMT and its N,N-d iethyl, (4-AcO-DET) and N-methyl-N-isopropyl (4-AcO-MIPT)

[0078] , 4-acetoxy-N-methyl-N-ethyltryptamine (4-AcO-MET), 4-hydroxy-N-methyl-N-propyltryptamine (4-HO-MPT) fumarate, 4-acetoxy-N-methyl-N-propyltryptamine (4-AcO-MPT), 4-hydroxy-N-ethyl-N-propyltryptamine (4-HO-EPT), 4-acetoxy-N-ethyl-N-propyltryptamine (4-AcO-EPT), 4-acetoxy-N,N-dipropyltryptamine (4-AcO-DPT), 4-hydroxy-N-methyl-N-allyltryptamine (4-HO-MALT), 4-Acetoxy-N,N-diisopropyltryptamine (4-AcO-DIPT)

[0079] , 4-phosphoryloxy-N-methyltryptamine (baeocystin) and the quaternary ammonium 4-phosphoryloxy-N,N,N-trimethyltryptamine (aeruginascin) [80, 81], deuterated derivatives of psilocybin

[0082] , 5HT2A agonist PSIL-006, Compounds 1 through 17, including l-M ethy Ipsilocin and 4-Fluoro-N,N-dimethyltryptamine, described in

[0083] , psilocin analogs having either a formyl group (9—12) or a bromine atom (13—18) at the 5- or 7-position

[0084] , derivative chosen from [3-(2-Dimethylaminoethyl)-l H-indol-4-y I] di hydrogen phosphate, 4-hydroxy-N, Ndimethyltryptamine, [3-(2-methylaminoethyl)-l H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-Nmethyltryptamine, [3-(aminoethyl)-l H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, [3-(2-trimethylaminoethyl)-l H-indol-4-yl] di hydrogen phosphate, and 4-hydroxy-N, N, Ntrimethyltryptamine, and second derivative chosen from [3-(2-Dimethylaminoethyl)-1 H-indol-4-yl] di hydrogen phosphate, 4-hydroxy-N, Ndimethyltryptamine, [3-(2-methylaminoethyl)-l H-indol-4-yl] dihydrogen phosphate, 4-hydroxy-Nmethyltryptamine, [3-(aminoethyl)-l H-indol-4-yl] dihydrogen phosphate, 4-hydroxytryptamine, [3-(2-trimethylaminoethyl)-l H-indol-4-yl] di hydrogen phosphate, and 4-hydroxy-N, N, Ntrimethyltryptamine

[0085] , bufotenin (5-hydroxy-N,N-dimethyltryptamine,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.0010135-HO-DMT) and bufotenidine [81, 86], compounds 6 through 12 described in

[0087] , aminated psilocybin derivatives

[0088] , Norpsilocin (NPT), 3-(2-(Ethylamino)ethyl)-lH-indol-4-ol Hemisuccinate (4-HONET), 3-(2-(Allylamino)ethyl)-lH-indol-4-ol Hemifumarate (4-HONALT), 3-(2-(lsopropylamino)ethyl)-lH-indol-4-ol Fumarate (4-HONiPT), 3-(2-(tert-Butylamino)ethyl)-lH-indol-4-ol Hemifumarate (4-HO-NtBT), 3-(2-(Cyclohexylamino)ethyl)-lH-indol-4-ol Fumarate (4-HONcHT), 3-(2-(Butylamino)ethyl)-lH-indol-4-ol Fumarate (4-HO-NnBT), 3-(2 (Benzylamino)ethyl)-lH-indol-4-ol Fumarate (4-HO-NBnT)

[0089] , psilocybin analogues containing a stable carbon-phosphorus bond

[0087] , and twenty-eight psilocin prodrugs (PCB, ESDI. ES02, ES03, ES04, ES05, ES06, ES07, ESOO, ES10, C01, C02, C03, C04, C05, T01,T02, ET01, EE01, EE02, EE03, EC01, SE01, SE02, SE03, P02, P03, PA01) described in

[0090] ,

[0156] The term "lysergic acid diethylamide" or "LSD" refers to a psychedelic drug known for its ability to intensify thoughts, emotions, and sensory perceptions, as well as to induce mental, visual, and auditory hallucinations. LSD is structurally related to substituted tryptamines, a class of compounds that includes psilocybin. Its effects are primarily mediated through binding to various serotonergic receptors, including 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, and 5-HT6 receptors, with its psychedelic effects largely attributed to its agonist activity at the 5-HT2A receptor.

[0157] The term "LSD analogs" or "LSD derivatives"" refers to compounds closely structurally related to LSD which retain the biologic properties of LSD in particular its ability to activate the Set B structures. Examples thereof include The analogues ALD-52, 1P-LSD, 1B-LSD, lcP-LSD, ETH-LAD, AL-LAD, MiPLA, LAMPA, LSM-775, LSZ, lcP-AL-LAD and 1V-LSD, 1P-ETH-LAD, lcP-AL-LAD, 1A-LSD (ALD-52) and the stereoisomers iso-LSD, iso-MiPLA, iso-LAMPA, iso-LSZ and iso-ETH-LAD

[0091] , [92-96], N-ethyl-N-isopropyllysergamide (EIPLA) and N6- ethylnorlysergic acid N,N-diethylamide (ETH-LAD)

[0097] , 1-dodecanoyl-LSD (1DD-LSD)

[0098] , l-(2-thienoyl)-6-allyl-nor-d-lysergic acid diethylamide (1T-AL-LAD)

[0099] , l-(thiophene-2-carbonyl)-N,N-diethyllysergamide (1T-LSD)

[0100] , N6-al lyl-6-norlysergic acid diethylamide (AL-LAD) and (2'S,4'S)-lysergic acid 2,4-dimethylazetidide (LSZ)

[0101] , PRO-LAD, ECPLA, BOL, LDM, isoLDM, isoLSD, LAA, isoLAA, Methysergide, isoMethergine, Methergine

[0102] , BetterLife Pharma's lead candidate, BETR-001 (2-bromo-LSD, 2-Br-LSD), compounds I through XLVII

[0103] , metabolites of D-lysergic acid diethylamide (LSD) such as D-lysergic acidPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013ethyl, 2'-hydroxyethylamide (LEO), D-lysergic acid ethyl, vinylamide (LEV), D-lysergic acid ethylamide (LAE) and D-norlysergic acid diethylamide (norLSD) and synthetic N6-a Iky I substituted derivatives such as N6-ethy I-, N6-propyl, N6-al ly I and N6-hexyl-D-norLDS (ethyl-, propyl-, allyl- and hexyl-norLSD, respectively)

[0104] , N(6)-al kyl norlysergic acid N,N-diethylamide derivatives

[0105] , BU-LAD, LSA, PARGY-LAD, and compounds I through XX described in

[0106] ,

[0158] The term "3,4-methylenedioxymethamphetamine" or "MDMA" refers to a potent empathogen-entactogen with stimulant and low psychedelic effects. MDMA is a substituted amphetamine structurally and acts as a monoamine-releasing agent, resulting in increased levels of serotonin, dopamine and noradrenaline.

[0159] The term "MDMA analogs" or "MDMA derivatives" refers to compounds closely structurally related to MDMA which retain the biologic properties of MDMA in particular its ability to activate the Set B structures. Examples thereof include enantiomers S(+)-MDMA or R(-)-MDMA

[0107] , N-ethyl-3, 4-methylenedioxyamphetamine (MDEA)

[0108] , Phenethylamine and BDB: l-(l,3-benzodioxol-5-yl)-2-butanamine and other analogs described in

[0109] , UWA-101

[0110] , 4-hydroxy-3-methoxyamphetamine (HMA), 4-hydroxy-3-methoxymethamphetamine (HMMA), 2,5-dimethoxy-4-bromophenylethylamine (2CB), 3,4-dimethoxymethamphetamine (DMMA), 3,4-methylenedioxyphenyl-2-butanamine (BDB), and 2,3-methylenedioxymethamphetamine (2,3-MDMA)

[0111] , MDMA bioisosteres 1-(2,l,3-benzoxadiazol-5-yl)-N-methylpropan-2-amine (ODMA), 1- (2,l,3-benzothiadiazol-5-yl)-N-methylpropan-2-amine (TDMA), and 1- (2,l,3-benzoselenadiazol-5-yl)-N-methylpropan-2-amine (SeDMA)

[0112] , N-methyl-l-(4-methoxyphenyl)-2-aminopropane (PMMA) and other MDMA analogs described in

[0113] , 5-MAPB [114, 115], 5-(2-aminopropyl)benzofuran (5-APB) and 6-(2-aminopropyl)benzofuran (5-APB)

[0116] , methylone, butylone and pentylone

[0117] , MDMA's enantiomers

[0107] , phenethylamine, cathinone, Ethcathinone, Mephedrone, 4-methylethcathinone (4-MEC), 4-fluoromethcathinone, Buphedrone, Pentedrone, Ethylone, 4-Methylenedioxy-a-pyrrolidinopropiophenone (MDPPP), 3,4-Methylenedioxy-a-pyrrolidinobutiophenone (MDPBP), a-Pyrrolidinovalerophenone (Alpha-PVP), a-Pyrrolidinobutiophenone (Alpha-PBP), a-Pyrrolidinopropiophenone (Alpha-PPP), l-(4-methylphenyl)-2-(pyrrolidinyl)-l-propanone (MPPP)

[0118] , brominated 2-Br-4,5-MDMA

[0119] , 2-Al 2-Aminoindane, 3-MMC 3-Methyl-N-PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013methylcathinone, 4-APB 4-(2-Aminopropyl)benzofuran, 5-APB 5-(2-Aminopropyl)benzofuran, 6-APB 6-(2-Aminopropyl)benzofuran, 7-APB 7-(2-Aminopropyl)benzofuran, 5-APDB 5-(2-Aminopropyl)-2,3-dihydrobenzofuran, 6-APDB 6-(2-Aminopropyl)-2,3-dihydrobenzofuran, 4-FA 4-Fluoroamphetamine, 5-1 Al 5-lodoaminoindan, 5-IT, 5-API 5-(2-Aminopropyl)indole, 4-MA 4-Methylamphetamine, 5-MAPDB l-( 2,3-Dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, MBDB 3,4-Methylenedioxyphenyl-N-methyl-2-butanamine, MDA 3,4-Methylenedioxyamphetamine, MDEA 3,4-Methylenedioxy-N-ethylamphetamine, MMAI 5-Methoxy-6-methyl-2-aminoindan, 4-MTA 4-Methylthioamphetamine,

[0120] , 3,4 MDMA derivatives N-methyl-l-(3,4-methylenedioxyphenyl)-l-ethanamine (MDM1EA) and N-methyl-l-(3,4-methylenedioxyphenyl)-3-butanamine (HMDMA)

[0121] , 2,3-MDA and 3,4-MDA, 2-methyl-MDA and 5-methyl-MDA, MBDB (N-methyl-l,3-benzodioxolbutanamine) and MDE (3,4-methylenedio-xyethylamphetamine), (S)(+)-N-ethylamphetarnine and (±)-N-hydroxyamphetamine, 4-MTA (l-(4-methylthiophenyl)-2-aminopropane), paramethoxyamphetamine (PMA) [122, 123], 2,5-dimetoxy-4-bromo-amphetamine hydrobromide (DOB)

[0124] , 5,6-Methylenedioxy-2-aminoindane (MDAI)

[0125] , chemically masked derivatives of MDMA described in

[0126] , MDMA analogs and derivatives described in

[0127] , 2,3-methylenedioxyamphetamines (2,3-MDA, N-methyl-2,3-MDA, N-ethyl-2,3-MDA and N,N-dimethyl-2,3-MDA

[0128] , 3,4-methylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA)

[0129] , 5-EAPB, l-(benzofuran-5-yl)-N-ethylpropan-2-amine; 6-EAPB, l-(benzofuran-6-yl)-N-ethylpropan-2-amine

[0130] , 2,5-dimethoxyamphetamine (2,5-DMA), 2,5-dimethoxy-4-chloroamphetamine (DOC), 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), 2,5-dimethoxy-4-nitroamphetamine (DON), 2,5-dimethoxy4 propylamphetamine (DOPR), 4-bromo-2,5-dimethoxyphenethylamine (2C-B), 2,5-dimethoxy-4-chlorophenethylamine (2C-C), 2,5-dimethoxy-4-iodophenethylamine (2C-I), 2,5-dimethoxy-4-nitrophenethylamine (2C-N), 2,5-dimethoxy-4-methylphenethylamine (2C-M), 2,5-dimethoxy-4methylthiophenethylamine (2C-T), 2,5-dimethoxy-4-ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-isopropylthiophenethylamine (2C-T-4), 2,5-dimethoxy-4-cyclohexylthiophenethylamine (2C-T-5), 2,5-dimethoxy-4-n-propylthiophenethylamine (2C-T-7), 2,5-dimethoxy-4-cyclopropyl methylthiophenethylamine (2C-T-8), 2,5-dimethoxy-4-(2methoxyethyl)thiophenethylaminePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013(2C-T-13), 2,5-dimethoxy4-l butylthiophenethylamine (2C-T-17), 2,5-dimethoxy-4methylthioamphetarriine (ALEPH), 2,5-dimethoxy-4-ethylthioamphetarriine (ALEPH-2), 2,5-dimethoxy-4-isopropyl thioamphetamine (ALEPH-4), 2,5-dimethoxy-4-cyclohexylthioamphetamine (ALEPH-5), 2,5-dimethoxy-4-n-propylthioamphetamine (ALEPH-7), 2,5-dimethoxy-4-cyclopropylmethylthioamphetamine (ALEPH-8), 2,5-dimethoxy4-(2-methoxyethyl)thioamphetamine (ALEPH-13), 2,5dimethoxy-4-isobutylthioamphetamine (ALEPH-17), 3,4,5trimethoxyamphetamine (TMA), 2,4,5-trimethoxyamphetamine (TMA-2), 2,3,4-trimethoxyamphetamine (TMA-3), 2,4,6-trimethoxyamphetamine (TMA-6), 3,4-methylenedioxy-N-isopropylamphetamine (MDIP), 3,4-methylenedioxy-N-benzylamphetamine (MDBZ), 3,4-methylenedioxy-N-cyclopropylmethylamphetamine (MDCPM), 2-(3,4-methylenedioxyphenyl)-2-methoxyethylamine (BOH), 2-(4-bromo2,5-dimethylenedioxyphenyl)-2-methoxyethylamine (BOB), and 2-(2,5-dimethoxy-4-methylphenyl)-2-methoxyethylamine (BOD)

[0131] , MDMA-benzofuran analogues (1-(benzofuran-5-yl)-propan-2-amine, 5-APB; l-(benzofuran-6-yl)-N-methylpropan-2-amine, 6-MAPB; l-(benzofuran-5-yl)-N-methylpropan-2-amine, 5-MAPB) and one MDMA-indole analogue (l-(lH-indol-5-yl)-2-methylamino-propan-l-ol, 5-IT

[0132] , a-aryl analogues of MDMA described in

[0133] , two amphetamine-based compounds: N,a-DEPEA and DPIA

[0134] , MDOH [N-hydroxy-MDA] and MMDA-2 [2-methoxy-4,5-methylenedioxyamphetamine]

[0135] , methylamphetamine (MMA)

[0136] , b-ketone analogues including bk-DMBDB (b-ketone-N,N-dimethyl-l-(l,3-benzodioxol-5-yl)-2-butanamine)

[0137] , as well as amphetamine and methamphetamine.

[0160] The term "ibogain" and active metabolite "noribogaine" are psychoactive indole alkaloids obtained from plants in the family Apocynaceae, causing psychedelic effects via noribogaine's action as a potent serotonin reuptake inhibitor, as well as moderate K-opioid receptor agonist and weak p-opioid receptor agonist or weak partial agonist.

[0161] The term "ibogain analogs" or "ibogain derivatives"" refers to compounds closely structurally related to MDMA which retain the biologic properties of MDMA in particular its ability to activate the Set B structures. Examples thereof include tabernanthalog and ibogainalog [138, 139], compounds (i)-lbogamine, (i)-coronaridine, (-)-Tabernanthine, (+)-190, (±)-191, (-)-192, 18-methoxycoronaridine (18-MC), (±)-18-MAC, (+)-catharanthine, (±)-195, (±)-196, (±)-XL -008, (±)-198, (±)-199, (±)-200, (±)-201, (±)-202, (±)-203, (±)-204, (±)-205,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013(±)-206, (±)-207, (±)-208 and (±)-209 described in

[0140] , O-desmethylibogain, (±)4-methyl-4-desethylcoronaridine, O-t-butyl-O-desmethylibogaine, and (±)4-desethylcoronaridine

[0141] , albifloranine, (±)-2-methoxyethyl-18-methoxycoronaridine, (±)-18-methylaminocoronaridine, (-)-(19R)-ibogamin-19-ol and (-)-epibatidine

[0142] , a series of tropane-based analogs described in

[0143] .

[0162] The term "N,N-Dimethyltryptamine" or "DMT" refers to a substituted tryptamine causing psychedelic effects primarily via its action at the 5HT2-A and possibly other serotonergic receptors.

[0163] The term "DMT analogs" or "DMT derivatives"" refers to compounds closely structurally related to DMT which retain the biologic properties of DMT in particular its ability to activate the Set B structures. Examples thereof include 5-MeO-DMT and related tryptamines [144-147], 4-OMe and 5-OMe DMT

[0148] , N,N-diethyltryptamine (DET), 6-FDET, N,N-dipropyltryptamine (DPT), dipropyl-T, diallyl-T, alpha-methyl-T, alpha-ethyl-T

[0149] , 4-methoxy-DMT and 6-hydroxy-DMT [150, 151], a series of compounds H-Dmt-NH-X, including H-Dmt-NH-CH3

[0152] , the fumarate salts of the N-isopropyl-N-methyl derivatives of DMT and psilocin

[0153] , Dmt-Tic-containing compounds [154-156], convolutindole A

[0157] , conformationally constrained opioid ligands of the Dmt-Aba, Dmt-Aia and Dmt-Tic scaffold

[0158] , N, N-Dimethyl-Dmt-Tic-NH-CH (R)-R' analogues

[0159] , deuterium labeled tryptamine derivatives

[0160] , analogs described in

[0161] , and DMT analogs described in

[0162] ,

[0164] The term "mianserin" refers to a drug sold under the brand name Tolvon among others, which is an atypical antidepressant used primarily in the treatment of depression in Europe and elsewhere in the world. It is a tetracyclic antidepressant (TeCA). Mianserin is structurally closely related to mirtazapine, although there are significant functional differences between the two drugs.The term "mianserin analogs" or "mianserin derivatives" refers to compounds closely structurally related to mianserin which retain the biologic properties of mianserin in particular its ability to activate the Set B structures. Examples thereof include BRL-34849 and BRL-34969

[0163] , Org 3770, teciptiline, and aptazapine

[0164] , 32 mianserin analogues described in

[0165] , mianserin and 6-azamianserin derivatives described in

[0166] , and mianserin derivatives described in [166-168],PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0165] The term "lumateperone" refers to a drug sold under the brand name Caplyta, which is an atypical antipsychotic of the of the butyrophenone class approved for the treatment of schizophrenia and bipolar depression.

[0166] The term "lumateperone analogs" or "lumateperone derivatives" refers to compounds closely structurally related to lumateperone which retain the biologic properties of mianserin in particular its ability to activate the Set B structures, including 3- tetracyclic quinoxaline derivatives of lumateperone

[0169] ,

[0167] The term "psychedelic or stimulant compound" also referred to as "psychedelics" or "hallucinogens" refers to a class of psychoactive substances that produce changes in perception, mood and cognitive processes. Psychedelics affect all the senses, altering a person's thinking, sense of time and emotions. Classic psychedelics generally cause specific psychological, visual, and auditory changes, and oftentimes a substantially altered state of consciousness. Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides (LSD is considered both a tryptamine and lysergamide). They act via serotonin 2A receptor agonism. When compounds bind to serotonin 5-HT2A receptors, they modulate the activity of key circuits in the brain involved with sensory perception and cognition. However, the exact nature of how psychedelics induce changes in perception and cognition via the 5-HT2A receptor is still unknown. Examples thereof include lysergic acid diethylamide (LSD), 3,4-Methylenedioxy methamphetamine (MDMA), ibogaine, N,N-Dimethyltryptamine (DMT), 2C-B (2,5-dimethoxy-4-bromophenethylamine); Mescaline (3,4,5-trimethoxyphenethylamine) and Psilocin (4-HO-DMT) the dephosphorylated active metabolite of the indole alkaloid psilocybin and a substituted tryptamine; and their structural analogues and pharmaceutically acceptable salts thereof.

[0168] Having provided the definitions for specific terms used herein the present invention is now described in detail.

[0169] The present invention is based on the inventors' discoveries using a whole mouse brain imaging technique applied to the detection of drug-evoked changes in expression of the IEG c-fos combined with computational and statistical analyses. This approach identified two sets of brain structures— cortical-subcortical set A and subcortical set B— that provide a mouse brain representation of human clinical efficacy in rapidly relieving symptoms of MDDPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013and TRD, as well as potentially other mental disorders, and in slowing the progression of MCI and dementia. The inventors' discoveries revealed that while both sets of brain structures are necessary, neither is sufficient alone to achieve rapid antidepressant efficacy. Furthermore, the findings showed that certain drugs can selectively activate either set A or set B structures, and that chronic administration of such drugs changes the evoked pattern in unexpected ways: 1) Two-week daily administration of drugs that activate set B but not set A structures leads to a strengthening of the evoked response, resulting in the activation of both set A and set B structures by the end of the treatment, and 2) In contrast, two-week daily administration of drugs that activate set A but not set B structures lead to tachyphylactic weakening of the evoked response at the set A structures, resulting in a loss of activation of Set A structures by the end of the treatment. These results indicate that drugs and drug combinations acutely activating the set A structures should not be administered daily, as this induces tachyphylaxis of the set A activity. Therefore, the preferred administration of such drugs is intermittent, with a drug-free wash-out period of at least 48 hours Additionally, the inventors' discoveries revealed brain biomarkers of drug-evoked dissociative and hallucinogenic side effects, represented by activation in the dorsal retrosplenial cortex (RSPd) for dissociative effects and in layer 5 across multiple cortical areas, but excluding the RSPd, for hallucinogenic effects. Finally, the inventors discovered that combining a drug that selectively activates set A structures with a drug that selectively activates set B structures, while neither evokes RSPd nor broad layer 5 activity, results in the creation of a complete set A and B brain activity pattern without biomarker activity for dissociative or hallucinogenic side effects. This combination is then capable of evoking a rapid and lasting antidepressant-like behavioral response in mice.

[0170] As examples of such drug combination opportunities, the inventors discovered six examples that fulfill the concept of selectively activating the set A or set B structures without brain activity linked to dissociative or hallucinogenic effects. The first is a combination of memantine (at human doses greater than 10 mg but less than 50 mg) and low-dose psilocybin (at human doses greater than 5 mg but less than 20 mg) which should evoke a combined set A and set B c-fos-based activation pattern, representing sufficient brain activity to induce rapid therapeutic relief in patients with MDD and TRD. This combination is also expected to avoid the psychotomimetic side effects, such as dissociationPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013and hallucinations, associated with individual treatments of ketamine and higher doses of psilocybin. Similar concept drug combinations may include memantine (at human doses greater than 10 mg but less than 50 mg) and low doses of other psychedelic and stimulant molecules, including but not limited to LSD, ibogain, DMT, and MDMA, sufficient to evoke full activity of the Set B structures without inducing psychotomimetic side effects. The second is a combination of memantine (at human doses greater than 10 mg but less than 50 mg) and TeCA mianserin (at human doses greater than 20 mg but less than 200 mg) which evokes an efficacious set A and set B c-fos-based activation pattern without activity linked to psychotomimetic side effects. Similar concept drug combinations may include memantine (at human doses greater than 10 mg but less than 50 mg) and other traditional antidepressants, including but not limited to SSRIs, SNRIs, TCAs, TeCAs, MAOIs, NASSAs, and atypical antidepressants, at doses sufficient to evoke full activity of the Set B structures. The third is a combination of memantine (at human doses greater than 5 mg but less than 50 mg) and lumateperone (at human doses greater than 10 mg but less than 100 mg) which evokes an efficacious set A and set B c-fos-based activation pattern without activity linked to psychotomimetic side effects. The fourth is a combination of amantadine (at human doses greater than 20 mg but less than 1000 mg) and low-dose psilocybin (at human doses greater than 5 mg but less than 20 mg) which should evoke a combined set A and set B c-fos-based activation pattern without activity linked to psychotomimetic side effects. The fifth is a combination of amantadine (at human doses greater than 20 mg but less than 1000 mg) and mianserin (at human doses greater than 20 mg but less than 200 mg) which should evoke an efficacious set A and set B c-fos-based activation pattern without activity linked to psychotomimetic side effects. And the sixth is a combination of amantadine (at human doses greater than 20 mg but less than 1000 mg) and lumateperone (at human doses greater than 10 mg but less than 50 mg) which should evoke an efficacious set A and set B c-fos-based activation pattern without activity linked to psychotomimetic side effects.

[0171] The efficacy of the synergistic drug combination and dosing regimen of the present invention is established e.g., by the demonstration that a combination of memantine 4 mg / kg (i.p.) and mianserin 10 mg / kg (i.p.) evokes both Set A and B brain activity pattern and that such combination evokes a rapid and lasting antidepressant-like behavioral response in mice, which is not seen with either memantine 4 mg / kg (i.p.) or andPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013mianserin 10 mg / kg (i.p.) alone. The findings that led to these discoveries are further summarized below.

[0172] The initial discovery highlighting the roles of the ten brain structures comprising together the Set A and Set B areas came from comparisons of brain activity of two drugs with documented rapid clinical efficacy in MDD and TRD. Subanesthetic S-ketamine (Spravato) has been approved for the treatment of TRD and suicidal ideation, and intravenous subanesthetic ketamine is used off-label in the treatment of MDD and TRD, demonstrating rapid clinical efficacy within twenty-four to seventy-two hours [35, 36], Additionally, clinical trials with psilocybin, a naturally occurring prodrug of the hallucinogen psilocin, suggest that a single treatment, combined with psychological support, can induce similarly rapid depression relief [43, 44], Thus, two drugs with distinct protein targets— ketamine acting as an antagonist at glutamatergic NMDA receptors and psilocybin as an agonist primarily at serotonergic 5HT2A receptors— appear to share a novel and uniquely rapid relief of depression symptoms. This rapid efficacy contrasts with traditional antidepressants, which require several weeks to reach therapeutic efficacy. However, both treatments are also associated with serious psychotomimetic side effects: ketamine can cause dissociation, and psilocybin can induce hallucinations. These side effects restrict the administration of these agents to licensed healthcare sites, significantly limiting their broad acceptance and use among patients.

[0173] Whole mouse brain imaging of c-fos expression (FIGURE 1) evoked by single treatments with subanesthetic ketamine at 30 mg / kg, approximating the subanesthetic therapeutic subanesthetic dose used in clinics, and psilocybin at 5 and 10 mg / kg, approximating the therapeutic doses used in clinical trials, revealed that both drugs activated a shared set of ten brain structures (FIGURE 2 and 3). These structures include the PL and ILA cortex, MD, PVT, CM, RE, and RH thalamic nuclei, as well as the limbic BSTa, CEA, and ACBsh (FIGURE 2 and 3). This finding thus identified a putative mouse brain representation of the rapid antidepressant efficacy shared by the two agents acting at different targets, NMDA receptors for ketamine and 5HT2A, 5HT2C, and 5HT1A receptors for psilocybin. Additionally, ketamine, but not psilocybin, robustly activated the dorsal retrosplenial cortex (RSPd), which has been previously linked to ketamine-evoked dissociative perceptions (FIGURE 2) [170, 171], In contrast, psilocybin, but not ketamine,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013evoked broad cortical activity focused on deep layer 5 neurons, corresponding to the enriched distribution of 5HT2A receptors proposed to mediate psilocybin-evoked hallucinations (FIGURE 3) [172, 173], These two activity patterns— ketamine's focused RSPd and psilocybin's broad cortical layer 5 activity— thus serve as mouse brain biomarkers for the distinct psychotomimetic effects— dissociations and hallucinations, respectively— of each agent.

[0174] Next, in order to determine which of the ten structures are necessary versus sufficient for the efficacy in TRD and MDD, the following sets of whole mouse brain imaging experiments were carried out with additional compounds and a low dose of psilocybin.

[0175] Memantine is an antagonist with a similar NMDA receptor affinity as ketamine, although there are described distinctions in its channel blocking mechanism, with memantine being described as a low-trapping antagonist due to its fast unbinding kinetics and ketamine as a high-trapping antagonist due to its slow unbinding kinetics [8, 9], Additionally, memantine may act more preferentially on extrasynaptic NMDA receptors

[0174] . Importantly, memantine at human daily dose 10 to 20 mg (approximate HED of 2 to 4 mg / kg (i.p.) dose used in mice here) failed to demonstrate antidepressant activity in clinical trials [10, 11], Next, whole mouse brain imaging of c-fos expression after a single treatment with memantine at 4 mg / kg (i.p.) revealed robust activation of the PL and ILA cortex and the interconnected MD, CM, RE, and RH thalamic nuclei, which were classified as cortico-subcortical Set A structures (FIGURE 4). In contrast, memantine did not activate the PVT and the limbic BSTa, CEA, and ACBsh, which were classified as subcortical Set B structures (FIGURE 4). Therefore, since memantine robustly activated the Set A structures but failed in depression trials, this suggests that these brain areas are not sufficient to induce the rapid relief of depression seen with ketamine and psilocybin treatments. Conversely, since memantine failed to activate the Set B structures, this suggests that these brain areas are necessary for the rapid efficacy of ketamine and psilocybin (See Table 1 infra).

[0176] Additionally, memantine at 4 mg / kg (i.p.) did not activate the RSPd or the broad cortical layer 5 pattern (FIGURE 4), consistent with its lack of dissociative or hallucinogenic effects.

[0177] Next, whole mouse brain imaging of c-fos expression after a single treatment with a higher, 10 mg / kg, dose of memantine revealed approximately two to three-timesPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013higher activation of the Set A brain areas— PL, ILA, MD, CM, RE, and RH— compared to the 4 mg / kg (i.p.) dose. It also showed robust activation of most of the Set B brain areas, including BSTa, CEA, and ACBsh, but not the PVT (FIGURE4). Additionally, memantine at 10 mg / kg (i.p.) strongly activated the RSPd cortex (FIGURE 4), which is linked to ketamine's dissociative side effects. This suggests that simply increasing the dose of memantine is unlikely to result in a better treatment option compared to the current standard of ketamine therapy for MDD and TRD. Firstly, the higher 10 mg / kg (i.p.) dose (approximately an HED of 50 mg) failed to evoke activity in the PVT, which has been described as a critical hub in the emotional processing network

[0175] , The incomplete Set B activation pattern with 10 mg / kg (i.p.) of memantine may thus affect its therapeutic efficacy compared to ketamine or psilocybin, both of which evoke robust activity in all Set A and Set B structures. Secondly, since 10 mg / kg (i.p.) memantine evoked robust activation of the RSPd cortex, comparable to that of ketamine at 10 mg / kg, this strongly suggests that this higher dose of memantine will induce ketamine-like dissociative effects. This prediction is also directly supported by reports of memantine's use as a recreational drug, with users describing dissociative effects similar to those of ketamine at doses higher than 40 mg

[0176] (Reports at www.erowid.org). In summary, higher doses of memantine capable of evoking activity in both Set A and Set B structures may achieve rapid antidepressant efficacy, though this treatment would likely be accompanied by similar dissociative side effects as frequently observed with ketamine.

[0178] Taken together, these data demonstrate that memantine can activate the Set A structures without inducing dissociative or hallucinogenic effects. However, at sub-dissociative doses, it lacks activity in the subcortical Set B structures. Therefore, memantine functions as a Set A-acting drug within the drug combinations described here.

[0179] Amantadine is an NMDA receptor antagonist with lower affinity than ketamine or memantine, sharing with memantine the characteristic of low-trapping antagonist activity [8, 9], Next, whole mouse brain imaging of c-fos expression after a single treatment with amantadine at 50 mg / kg (i.p.) revealed robust activation of the Set A structures, including the PL and ILA cortex and the interconnected MD, CM, RE, and RH thalamic nuclei (FIGURE 5). In contrast, the same dose of amantadine (50 mg / kg) did not activate the Set BPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013structures, including the PVT and the limbic BSTa, CEA, and ACBsh (FIGURE 5) (See Table 1 infra).

[0180] Additionally, amantadine at 50 mg / kg (i.p.) did not activate the RSPd cortex linked to dissociative perceptions (FIGURE 5). This aligns with clinical observations showing a lack of dissociative side effects in patients treated with amantadine at doses up to 300 mg, equivalent to approximately 60 mg / kg (i.p.) in mice

[0030] ,

[0181] Next, whole mouse brain imaging of c-fos expression after a single treatment with a higher, 100 mg / kg, dose of amantadine revealed approximately two-times higher activation of the Set A brain areas— PL, ILA, MD, CM, RE, and RH— compared to the 50 mg / kg (i.p.) dose (FIGURE 5). It also showed robust activation of all Set B brain areas, including BSTa, CEA, and ACBsh and PVT (FIGURE 5). Additionally, amantadine at 100 mg / kg (i.p.) strongly activated the RSPd cortex (FIGURE 5), which is linked to ketamine's dissociative side effects. This suggests that similar to the data for memantine, simply increasing the dose of amantadine is unlikely to result in a better treatment option compared to the current standard of ketamine therapy for MDD and TRD, since the robust activation of the RSPd cortex strongly suggests that the 100 mg / kg (i.p.) (HED 500 mg) dose of memantine will induce ketamine-like dissociative effects.

[0182] Taken together, these data identify amantadine as another drug capable of activating the Set A structures without inducing dissociative or hallucinogenic effects.However, since amantadine also lacks activity in the subcortical Set B structures, it serves as a second Set A-acting drug within the drug combinations described here.

[0183] A low, 10 mg human dose of psilocybin lacks the efficacy to induce rapid relief of depression and does not evoke hallucinations

[0043] , Next, whole mouse brain imaging of c-fos expression after a single treatment with 2.5 mg / kg (i.p.) (approximately the HED dose of 10 mg) revealed robust activation of all Set B structures— PVT, BSTa, CEA, and ACBsh— but not the Set A cortical PL and ILA areas (FIGURE 6). Since 10 mg psilocybin lacks efficacy depression, this suggests that the subcortical Set B areas are not sufficient to induce the rapid relief of depression seen with ketamine and psilocybin treatments. Conversely, the activity of the Set A cortical PL and ILA areas, which was absent in the low-dose psilocybin activation pattern, appears necessary for the rapid efficacy of ketamine and psilocybin (See TABLE 1 infra). Additionally, psilocybin at 2.5 mg / kg (i.p.) did not activate the RSPd and onlyPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013sparsely activated the cortical layer 5 pattern (FIGURE 6), consistent with the lack of dissociative or hallucinogenic effects of the low dose 10 mg psilocybin in humans.

[0184] Low-dose psilocybin thus serves as an example of a drug capable of activating the complete Set B structures at a single dose. This establishes low-dose psilocybin as the first Set B-acting drug within the drug combinations described here.

[0185] Traditional monoaminergic antidepressants require several weeks of a chronic treatment to reach therapeutic efficacy. For example, the earliest time point of expected efficacy for SSRI treatment is after two weeks [2], Next, whole mouse brain imaging of single antidepressant treatments, which lack clinical efficacy, was carried out with SSRIs fluoxetine (15 mg / kg) and fluvoxamine (60 mg / kg) (FIGURE 7), TCAs desipramine (40 mg / kg) and amitriptyline (15 mg / kg) (FIGURE 8), and TeCA's mirtazapine (10 mg / kg) and mianserin (10 mg / kg) (FIGURE 9). This revealed a general trend toward activation of the Set B structures— PVT, BSTa, CEA, and ACBsh— but not the Set A structures— PL, ILA, CM, RE, and RH.However, there were notable distinctions between the different treatments. For example, SSRIs fluoxetine and fluvoxamine failed to activate the ACBsh within the Set B structures, and their activity in PVT, BSTa, and CEA was less robust compared to low-dose psilocybin. The activity of TCA amitriptyline also lacked activation of the ACBsh, while desipramine activated all Set B structures, albeit at a lower level compared to low-dose psilocybin.Finally, TeCA mirtazapine activity was comparable to that of desipramine across all set B structures, but mianserin activated the Set B structures at a level comparable to that of low-dose psilocybin. Importantly, since none of these drugs evoke rapid antidepressant efficacy from a single treatment in patients, their acute activity in the Set B structures further suggests that these brain areas are not sufficient to induce rapid relief of depression.Conversely, their lack of activity in the Set A structures further suggests that these areas are necessary for the rapid efficacy seen with ketamine and psilocybin (See TABLE 1 infra).

[0186] Taken together, mianserin serves as a second example of a drug capable of robustly activating the complete Set B structures at a single dose. This establishes mianserin as the second Set B-acting drug within the drug combinations described here.

[0187] Several atypical antipsychotics are used as adjunct therapeutic options to enhance the efficacy of traditional antidepressants in MDD, TRD and in bipolar I or II depression, including adjunct treatments with aripiprazole (Ability) and quetiapinePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013(Seroquel, Atrolak, Sondate and Zaluron) in MDD, a combination of the antipsychotic olanzapine and SSRI fluoxetine (Symbyax) in TRD, cariprazine (Vraylar), lurasidone (Latuda), olanzapine-fluoxetine combination (Symbyax), and quetiapine (Seroquel) and lumateperone (Caplyta) in depressive episodes associated with bipolar disorder [177-179], The mechanism behind these adjunct treatments may involve enhancing the activity of traditional antidepressants within Set A and / or Set B brain structures or introducing activity outside of these circuits. To investigate these mechanisms, whole-brain imaging of c-fos expression was used to map the brain activity patterns evoked by cariprazine and lumateperone. These patterns were compared to the brain responses elicited by standard-of-care (SOC) antidepressants, as described earlier.

[0188] Cariprazine at 1.2 mg / kg (i.p.) induced brain activity associated with antipsychotic effects, including strong activation in the dopaminergic substantia nigra pars compacta (SNc), ventral tegmental area (VTA), and both the ventral and dorsal striatum. However, it produced only partial activation across the Set B structures associated with traditional antidepressant activity (FIGURE 10). In contrast, lumateperone at 8 mg / kg (i.p.) also elicited antipsychotic-associated brain activity, primarily activating the VTA and ventral striatum. Additionally, lumateperone produced full activation across all Set B structures, consistent with traditional antidepressant activity (FIGURE 10). These data suggest that lumateperone exhibits stronger antidepressant activity than cariprazine and may provide therapeutic efficacy as a monotherapy for depression, in addition to its established efficacy as an adjunct treatment.

[0189] Lumateperone thus serves as a third example of a drug capable of robustly activating the complete Set B structures at a single dose. This establishes lumateperone as the third Set B-acting drug within the drug combinations described here.

[0190] While, the acute administration of traditional antidepressants evokes activation of only the Set B structures (FIGURES 7-9), chronic administration of traditional monoaminergic antidepressants can be expected to alter the evoked brain activity pattern compared to single treatments, potentially distinguishing between efficacious and non-efficacious brain activity. Whole mouse brain imaging of c-fos expression after a two-week treatment with the SSRI fluoxetine (15 mg / kg) revealed robust activation of both Set A structures PL, ILA, MD, CM, RE, and RH and Set B structures PVT, BSTa, CEA and ACBsh (SeePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013FIGURE 11). Since, the chronic administration of fluoxetine led to more robust activity in all Set B structures, along with prominent induction of activity in all Set A structures, this suggests that the initial activity in the subcortical Set B structures evoked by a single fluoxetine treatment leads over time to cumulatively increased activity in both Set A and Set B structures. This effect may result, for example, from the initial, single-treatment activation of the subcortical PVT and MD thalamic nuclei, which have reciprocal connectivity to the PL and ILA cortex. Importantly, this result demonstrates that therapeutic efficacy after chronic treatment with traditional antidepressants is represented by the same Set A and Set B brain structures activated by single efficacious treatments with ketamine and psilocybin. This provides a plausible explanation for the delayed efficacy of traditional antidepressants and further supports the notion that the full combination of Set A and Set B structures is both necessary and sufficient to evoke therapeutic relief in depression (See TABLE 1 infra).

[0191] Given the change in the evoked pattern after chronic treatment with fluoxetine, it is possible that chronic treatment with memantine may also induce a different pattern than the single doses of 4 and 10 mg / kg (i.p.) shown in FIGURE 4. However, in contrast to the strengthening of the response seen with after chronic fluoxetine (FIGURE 11), whole mouse brain imaging of c-fos expression after a two-week daily treatment with memantine at 4 mg / kg (i.p.) revealed a selective loss of activation of cortical PL and ILA areas of the Set A structures (FIGURE 12). This loss of activity agrees with a lack of efficacy with memantine in depression after chronic dosing [10, 11], contrasting with the gain of efficacy of traditional antidepressants after chronic dosing. This also suggest that in order to maintain the memantine-evoked activity at the set A frontocortical PL and ILA areas, the drug or its combination needs to be given intermittently, with drug-free wash-out periods, instead of daily. To test this hypothesis, whole mouse brain imaging of c-fos expression was used to measure drug evoked activity after 4 weeks of 4 mg / kg (i.p.) memantine treatment given twice a week, with 3 to 4 day wash-out periods between each doses. This intermittent treatment resulted in maintaining the robust frontocortical activity seen with a single 4 mg / kg (i.p.) memantine treatment, confirming that the daily dosing is the cause for the tachyphylaxis of this response. Additionally, the memantine-evoked response after the 4-week intermittent treatment still comprised deficits in the activation of the set B subcortical structures, including the PVT, CEA and BSTa (FIGURE 13). These data suggest that using thePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013intermittent dosing paradigm alone may not increase the efficacy of memantine in MDD or TRD.

[0192] As demonstrated by the data presented so far, 4 mg / kg (i.p.) memantine or 50 mg / kg (i.p.) amantadine robustly activates the set A brain structures, while a low dose 2.5 mg / kg (i.p.) psilocybin, 10 mg / kg (i.p.) mianserin, or 8 mg / kg (i.p.) lumateperone strongly activate the set B brain structures. Importantly, none of these drugs at the given doses activates the RSPd cortex linked to dissociative effects, nor do they evoke broad layer 5 activity linked with hallucinations. Based on this, combining a Set A-activating with a Set B-activating drug is predicted to evoke the full pattern of set A and set B activity, indicative of rapid antidepressant efficacy in MDD and TRD, without triggering dissociative and hallucinogenic side effects. To test this hypothesis, whole mouse brain imaging of c-fos expression was used to measure the evoked brain activity after a single treatment with a combination of memantine at 4 mg / kg (i.p.) and mianserin at 10 mg / kg. This combination indeed produced a robust activation of both set A and set B structures, without activating RSPd or inducing increased layer 5 activity (FIGURE 14). Therefore, the memantinemianserin combination is expected to have rapid-acting therapeutic efficacy in depression, similar to ketamine. Moreover, 50 mg / kg (i.p.) amantadine may serve as an alternative to 4 mg / kg (i.p.) memantine in these drug combinations, given their analogous effects on Set A structures. Similarly, 2.5 mg / kg (i.p.) psilocybin or 8 mg / kg (i.p.) lumateperone may replace 10 mg / kg (i.p.) mianserin, based on their comparable activation of Set B structures

[0193] To test the hypothesis that the 4 mg / kg (i.p.) memantine and 10 mg / kg (i.p.) mianserin combination have antidepressant efficacy similar to that of ketamine, the following treatments were compared in the behavioral tests "forced swim" and "tail suspension test" used frequently to assess antidepressant activity of preclinical compounds [180, 181]: memantine (4 mg / kg), fluoxetine (15 mg / kg), mianserin (10 mg / kg), ketamine (30 mg / kg), mem+fluox (memantine 4 mg / kg (i.p.) plus fluoxetine 15 mg / kg), and mem+mians (memantine 4 mg / kg (i.p.) plus mianserin 10 mg / kg) (FIGURE 15).

[0194] Chronic treatment with traditional monoaminergic antidepressants— whether through multiple daily doses or two to three doses within a single day— can evoke antidepressant-like effects measurable within 30 minutes to 1 hour after the final dose. Antidepressant-like effects are defined by the reduction in the time animals spendPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013immobile, which reflects decreased "floating" in the forced swim test and reduced "hanging" in the tail suspension test, respectively

[0182] , In contrast, ketamine can induce the antidepressant-like behavioral effect acutely from a single dose and the effect lasts for at least 24 hours

[0183] , The acute and prolonged efficacy of ketamine therefore distinguishes it from traditional antidepressants and is considered a representations of ketamine's rapid and lasting antidepressant efficacy in patients with MDD and TRD.

[0195] The current experiments revealed the following findings in the forced swim test: Memantine and fluoxetine, when administered alone as single treatments, failed to induce a behavioral effect distinct from that of vehicle-treated mice at both the 1-hour and 24-hour post-dosing marks (FIGURE 15A). This aligns with previous research indicating that fluoxetine requires 24 days of dosing to achieve efficacy in the forced swim test (Dulawa, 2004). Additionally, the lack of efficacy observed with memantine supports our conclusion that memantine-induced activation of set A structures is insufficient to evoke a rapid antidepressant effect similar to that of ketamine.

[0196] Interestingly, mianserin administered alone and the combination of memantine and fluoxetine induced a statistically significant reduction in immobility time at 1 hour but not at 24 hours after treatment compared to vehicle-treated mice (FIGURE 15A). These data thus appear to reflect higher activity in set A and B structures compared to treatments with fluoxetine or memantine alone. However, the lack of efficacy at 24 hours post-dosing suggests that mianserin and the combination of memantine and fluoxetine do not exhibit the rapid and lasting behavioral efficacy seen with ketamine.

[0197] In contrast, ketamine and the combination of memantine and mianserin induced significant reductions in immobility time at both 1 hour and 24 hours after treatment compared to vehicle-treated mice (FIGURE 15A). The ketamine data are consistent with previous reports (Autry, 2011), while the memantine and mianserin data suggest that their combination may achieve the rapid efficacy in MDD and TRD observed with ketamine. These findings are also supported by the comparable c-fos-based activation induced by ketamine and the combination of memantine and mianserin across set A and set B structures, as shown in FIGURE 14.

[0198] Additionally, the current experiments revealed the following findings in the tail suspension test: 4 mg / kg (i.p.) memantine and 10 mg / kg (i.p.) mianserin given alone did notPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013evoke any significant reduction in the time spent immobile (hanging) either at 1 hour or 24 hours after the drug treatment (FIGURE 15B). In contrast, the drug combination of 4 mg / kg (i.p.) memantine and 10 mg / kg (i.p.) mianserin induced a statistically reduction in the time spent immobile at both 1 hour or 24 hours afterthe drug treatment (FIGURE 15B). This confirms the acute and lasting effects of the drug combinations seen in the forced swim test.

[0199] Memantine is approved for dementia in Alzheimer's disease and its mechanism is proposed to include liming neurotoxicity by blocking calcium influx. However, our data show that memantine causes strong activation of frontal cortical circuits, suggesting that it may strengthen activity in cognitively brain circuit. To test whether memantine-evoked brain activity patterns may potentially correspond to any activity deficits seen with aging, whole mouse brain imaging of c-fos expression was used to compare baseline activity in aged mice (18, 22, and 26 months old) versus young adult mice (2 months old). These experiments revealed an age-associated progressive loss of c-fos expression in the frontocortical PL and ILA areas (FIGURE 16), suggesting that aging is associated with a chronic loss of activity in the same frontocortical areas where memantine and amantadine exert their effects. This suggests that memantine's efficacy in slowing the progression of dementia may, at least in part, come from counteracting and increasing the activity and cellular plasticity in the frontocortical brain regions. Therefore, the inventors propose that memantine's and also amantadine's efficacy in treating Alzheimer's disease and other forms of dementia can be significantly enhanced by administering memantine or amantadine in combination with a low dose of psilocybin or with mianserin or lumateperone, and / or by employing an intermittent dosing regimen rather than the current approved treatment of daily dosing. Memantine and amantadine intermittent treatment

[0200] Described herein are methods and compositions for the treatment of MDD, TRD, PTSD, bipolar depression, substance use disorders, negative and cognitive symptoms of schizophrenia, mild cognitive impairment, and dementia. These treatments involve the administration of memantine or amantadine, their derivatives, or pharmaceutically acceptable salts thereof, in combination with a second compound that complementsPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013memantine- or amantadine-evoked activity at set A brain areas by providing sufficient activity at set B brain areas.

[0201] The invention employs a first treatment of memantine or amantadine combination with no further administration of memantine or a pharmaceutically acceptable salt thereof in the 2 or more days following the first treatment.

[0202] In certain embodiments, memantine or amantadine combination is administered once with no additional treatment for 2, 3, 4, 5, 6, 7 , 8, 9 or 10 days.

[0203] This invention provides a striking contrast with previous proposed treatment modalities using memantine or amantadine in AD, depression, bipolar depression or schizophrenia. Previous suggested uses in these indications, including approved treatment of memantine for AD, all relied on daily dosing, typically given as 10 mg twice-a-day for memantine. By contrast the invention provides a previously unrecognized "first treatment" approach to dosing of memantine leading to rapid onset effect of treatment at least for MDD and TRD.

[0204] In certain embodiments, the first treatment dose of memantine or amantadine combination leads to a rapid onset and durable effect of treatment for at least 2, 3, 4, 5, 6, or 7 days after administration.

[0205] Embodiments described herein provide that a patient in need thereof is administered a pharmaceutical composition including memantine or amantadine or a pharmaceutically acceptable salt thereof. Memantine or amantadine or pharmaceutically acceptable salt thereof may be provided as an acid addition salt, a zwitter ion hydrate, zwitter ion anhydrate, hydrochloride or hydrobromide salt, or in the form of the zwitterion monohydrate. Acid addition salts, include but are not limited to, maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethane-disulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-amino-benzoic, glutamic, benzene sulfonic or theophylline acetic acid addition salts, as well as the 8-ha lot heophy 11 ines, for example 8-bromo-theophylline. In other suitable embodiments, inorganic acid addition salts, including but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric or nitric acid addition salts may be used.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0206] Deuteration and / or fluorination of pharmaceuticals to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles, has been demonstrated previously with some classes of drugs. Accordingly, the use of deuterium or fluorine enriched memantine, amantadine, psilocybin, other psychedelic and stimulant molecules including but not limited to MDMA, DMT, LSD and ibogain, mianserin and other SSRIs, SNRIs, TCAs, TeCAs, MAOIs, NASSAs, and atypical antidepressants is contemplated and within the scope of the methods and compositions described herein. Deuterium or fluorine can be incorporated in any position in replacement of hydrogen synthetically, according to the synthetic procedures known in the art. For example, deuterium or fluorine may be incorporated to various positions having an exchangeable proton, such as the amine N--H, via proton- deuterium equilibrium exchange. Thus, deuterium or fluorine may be incorporated selectively or non-selectively through methods known in the art to provide, for example, deuterium enriched psilocybin (Palfreyman et al. 2022, Neuropsychopharm. vol. 47. no. suppl 1) or DMT (Layzell et al. 2023, ACS Med Chem Lett 14.9: 1216-1223).

[0207] Deuterium or fluorine enriched memantine, amantadine, psilocybin, mianserin or lumateperone may be described by the percentage of incorporation of deuterium or fluorine at a given position in the molecule in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at that specified position. The deuterium enrichment can be determined using conventional analytical methods, such as mass spectrometry and nuclear magnetic resonance spectroscopy. In certain embodiments deuterium enriched molecule means that the specified position is enriched with deuterium above the naturally occurring distribution {i.e., above about.0156%). In certain embodiments deuterium enrichment is no less than about 1%, no less than about 5%, no less than about 10%, no less than about 20%, no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, or no less than about 98% of deuterium at a specified position.

[0208] Pharmaceutical compositions herein may be provided with immediate release or standard release profiles. Compositions may be prepared using a pharmaceutically acceptable "carrier" composed of materials that are considered safe and effective. The "carrier" includes all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term "carrier" includes, but is not limited to, diluents,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013binders, lubricants, disintegrants, fillers, and coating compositions. Those skilled in the art are familiar with identifying preferred formulation techniques for a unit dosage form (UDF). In a preferred embodiment, the UDF is a pill, tablet, capsule, film, or wafer, any of which may optionally be orally disintegrating, or a lollipop, lozenge, oil, tincture, or syrup. The formulation process will be adjusted accordingly. Pills and tablets are prepared from solid formulations. Syrups, oils and tincture are liquid formulations. An orally disintegrating film, wafer, tablet or a lollipop or lozenge provides the UDF in an oral form wherein the active ingredients are at least partly absorbed directly in the buccal cavity. Capsules may be either solid formulations (e.g. powders or particles in a hard-gel) or liquid formulations (e.g. oilbased formulations used in soft-gels). Oil based formulations with little or no water are typically easily encapsulated. Oil-in-water formulations may comprise microemulsions, liposomes, nanoemulsions and other forms known in the art.

[0209] A wide variety of technologies are available for a buccal or sublingual formulation such as an orally disintegrating thin film, wafer or tablet, or a lollipop, and / or lozenge.Sublingual tablets, wafers, films and strips can be designed to rapidly disintegrate (5-15 seconds) providing rapid access to buccal cavity capillaries and avoid the hostile environment of the gastrointestinal track. Lollipops and lozenges provide a combination of buccal and gastric administration. The technologies are widely used with therapeutic agents where rapid onset is desired {Morales, 2021 #6170}.Dose Form

[0210] The invention contemplates administration of memantine-based drug combinations designed for the treatment of MDD, TRD, PTSD, bipolar depression, substance use disorders, negative and cognitive symptoms of schizophrenia, mild cognitive impairment, and dementia. A wide variety of dose forms may be employed including those described previously in the literature. Preferred dose forms are suitable for oral or intranasal administration, but also intramuscular or subcutaneous administration.

[0211] Oral administration can employ any orally acceptable form including pills, tablets, capsules, syrup etc. Such forms can be manufactured according to techniques well known to those skilled in the art.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0212] A form for rapid onset is an orally disintegrating dosage form (ODDF) which provides immediate release in the patient's buccal cavity enhancing buccal absorption of the drug. An ODDF is a solid dosage form containing a medicinal substance or active ingredient which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue. The disintegration time for ODDFs generally range from one or two seconds to about a minute. ODDFs are designed to disintegrate or dissolve rapidly on contact with saliva. This mode of administration can be beneficial to people who may have problems swallowing tablets as is common with conditions which are psychiatric in nature.

[0213] In preferred embodiments, the ODDF results in pharmacokinetic properties which include a Tmax of 20 minutes or less. In certain embodiments, pharmaceutical compositions herein provide of 20 minutes or less, a Tmax of 19 minutes or less, a Tmax of 18 minutes or less, a Tmax of 17 minutes or less, a Tmax of 16 minutes or less, a Tmax of 15 minutes or less, a Tmax of 14 minutes or less, a Tmax of 13 minutes or less, a Tmax of 12 minutes or less, a Tmax of 11 minutes or less, a Tmax of 10 minutes or less, a Tmax of 9 minutes or less, a Tmax of 8 minutes or less, a Tmax of 7 minutes or less, a Tmax of 6 minutes or less, or a Tmax of 5 minutes or less. Such pharmaceutical compositions include ODDFs such as orally disintegrating tablets (ODTs).

[0214] An ODT is a solid dosage form containing a medicinal substance or active ingredient which disintegrates rapidly, usually within a matter of seconds when placed upon the tongue. The disintegration time for ODTs generally ranges from several seconds to about a minute. ODTs are designed to disintegrate or dissolve rapidly on contact with saliva, thus eliminating the need to chew the tablet, swallow the intact tablet, or take the tablet with liquids. As with ODDFs in general, this mode of administration can be beneficial to people who require rapid onset of treatment.

[0215] In certain embodiments, the fast dissolving property of the ODTs requires quick ingress of water into the tablet matrix. This may be accomplished by maximizing the porous structure of the tablet, incorporation of suitable disintegrating agents and use of highly water-soluble excipients in the formulation. Excipients used in ODTs typically contain at least one superdisintegrant (which can have a mechanism of wicking, swelling or both), a diluent, a lubricant and optionally a swelling agent, sweeteners and flavorings

[0184] , Superdisintegrants can be classified as synthetic, natural and co-processed. In this contextPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013synthetic superdisintegrants can be exemplified by sodium starch glycolate, croscarmellose sodium, cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, microcrystal line cellulose, partially pregelatinized starch, cross-linked alginic acid and modified resin. Natural superdisintegrants can be processed mucilages and gums are obtained from plants and can be exemplified by Lepidium sativum seed mucilage, banana powder, gellan gum, locust bean gum, xanthan gum, guar gum, gum karaya, cassia fistula seed gum, mangifera indica gum, carrageenan, agar from Gelidium amansii and other red algaes, soy polysaccharide and chitosan. Diluents can include, e.g., mannitol, sorbitol, xylitol, calcium carbonate, magnesium carbonate, calcium sulfate, magnesium trisilicate and the like. Lubricants can include, e.g., magnesium stearate and the like. Those skilled in the art are familiar with ODT manufacturing techniques.

[0216] Other ODDFs which may be used herein include rapidly dissolving films which are thin oral strips that release medication such as gaboxadol or a pharmaceutically acceptable salt thereof quickly after administration to the oral cavity. The film is placed on a patient's tongue or any other mucosal surface and is instantly wet by saliva whereupon the film rapidly hydrates and dissolves to release the medication

[0185] , Fastcaps are a rapidly disintegrating drug delivery system based on gelatin capsules. In contrast to conventional hard gelatin capsules, fastcaps consist of a gelation of low bloom strength and various additives to improve the mechanical and dissolution properties of the capsule shell

[0186] , Freeze dried (lyophilized) wafers are rapidly disintegrating, thin matrixes that contain a medicinal agent. The wafer or film disintegrates rapidly in the oral cavity and releases drug which dissolves or disperses in the saliva

[0187] , Those skilled in the art are familiar with various techniques utilized to manufacture ODDFs such as freeze drying, spray drying, phase transition processing, melt granulation, sublimation, mass extrusion, cotton candy processing, direct compression, etc.

[0217] Intranasal forms enhance rapid uptake via the nasal and pulmonary system. Intranasal formulations of therapeutic agents are well known and those skilled in the art may adapt memantine-based drug combinations to such a format. Design choices depend on whetherthe product will be a solution or suspension. Critical parameters include pH and buffer selection, osmolality, viscosity, excipient selection and choice of penetrationPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013enhancers or other components to enhance residence time in the nasal cavity. (See for example DPT Laboratories Ltd publications at www.dptlabs.com).

[0218] Also desirably, plasma Tmax is achieved within 90 minutes the first treatment. More preferably Tmax is achieved at 75, 60, 45 or 30 minutes after first treatment. In certain embodiments, the Tmax of the first treatment is less than 2 hours. In certain embodiments, the Tmax of the first treatment is less than 1.5 hours. In certain embodiments, the Tmax of the first treatment is less than 1 hour. In certain embodiments, the Tmax of the first treatment is about half an hour.

[0219] Having described the invention and its inherent advantages in detail, the invention is further described in the examples which follow. The examples are provided for the purpose of illustration and to describe certain specific embodiments of the invention. However, the scope of the claims is not to be in any way limited by the examples set forth herein. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those relating to the methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.EXAMPLESExample 1: Whole-brain drug screening platform

[0220] Many preclinical assays are currently used to try to elucidate or predict the clinical effects of new drugs on the brain. These include in vitro high-content screening (HCS) assays, in vivo imaging assays such as PET / CT, PET / MRI, fMRI, in vivo and in vitro electrophysiology or two-photon imaging assays, and various behavioral assays [188-190]). Nevertheless, the results from preclinical studies remain poor predictors for outcomes in human clinical trials.

[0221] The preclinical testing of psychiatric drugs described here is based on a direct readout of drug-evoked brain activity, represented by the induction of the immediate early gene (IEG) c-fos, which underscores some forms of cellular plasticity, such as synaptic and structural plasticity

[0050] (FIGURE 1). Importantly, the current method provides an unbiasedPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013analysis of changes in c-fos expression at single-cell resolution across the entire mouse brain. This is achieved using whole-brain immunolabeling, imaging, and computational data analyses developed previously by the inventors and collaborators (FIGURE 1) [191, 192], This approach contrasts with previous methods used for detecting c-fos as a marker of brain activation, which relied on laborious in situ hybridization or immunohistochemistry in selected brain tissue sections rather than across the entire brain. Despite this, numerous studies over the last two decades have used these methods to test drug-evoked activity in the mouse or rat brain for various psychoactive medications. These studies have demonstrated that c-fos expression can detect brain-evoked changes induced by antipsychotics, antidepressants, stimulants, and other psychiatric medications [193, 194]. Thus, these studies, even though typically assaying only a few brain regions at a time, validate the concept of using c-fos expression in the rodent brain for psychoactive drug screening.

[0222] The first generation of the current platform used serial two-photon tomography (STPT) for imaging of brain of c-fos-GFP mice expressing green fluorescent protein (GFP) under the control of the c-fos promoter (US 20140297199A1). The second generation of the platform applied here employs a whole-brain immunostaining and clearing procedure named 1DISCO+ and whole-brain imaging by light-sheet fluorescence microscopy to visualize c-fos-positive neurons in wild-type mouse brains [191, 192], Briefly, the mice are treated with a vehicle (a control group) or a drug (an experimental group), typically via intraperitoneal (i.p.), per oral, (p.o.), subcutaneous (s.c.) or intravenous (i.v.) injection. After a period of 1 % hours to up to 5 hrs, depending on the Cmax of the drug, the mice are killed and the brains are fixed by perfusion and / or immersion in 4% paraformaldehyde in saline. The brains are extracted from the skull and chemically treated to remove lipids before incubation with primary antibodies against c-fos followed by fluorophore-conjugated secondary antibodies in the following sequence: 5 days delipidation in SBiP buffer (17% 2methyl2butenol, 8.3% 2propanol, 2% 4% SDS (pH7.4), 0.2 mM Na2HPO4), followed by permeabilization for 24 hours at room temperature with Bln buffer (0.1% triton-X, 0.01% 10N NaOH, 2% w / v glycine). The brains were then moved to 37C for 3 hours. Following the incubations, brains were washed in 10 ml of PTwH buffer (0.2% tween-20, 0.1% 10 mg / ml heparin, in IX PBS) 3 times at room temperature (1 hour per wash). Whole brainPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013immunostaining was then performed with 5 days of incubation for primary and 5 days for secondary antibody with on day of washing in between. Primary antibodies were diluted in a solution of 5% DMSO and 3% donkey serum in PTwH buffer. Secondary antibodies were diluted in a solution of 3% donkey serum in PTwH buffer. Brain were washed 5 times in PTwH after each antibody incubation which took place at 37C in 4 ml of antibody solution. The brains were then dehydrated in a methanol / H2O series (20%, 40%, 60%, 80%, and 100%) for one hour per step at room temperature. Then, the samples were placed in fresh 100% methanol overnight. The following day the samples were placed in 33% methanol / 66% dichloromethane for 3 hours, then 100% dichloromethane for 15 minutes two times followed by 100% dibenzyl ether to clear overnight with no shaking. The immunolabeled and clear brain samples were then imaged by light-sheet microscopy (LSFM) at voxel resolution of 3x3x5 micron. The imaged brains will be aligned as 3D volumes and the activated c-fos+ cells will be computationally detected. The statistical comparisons between vehicle- and test compound-treated groups will be done by negative binomial regression corrected for multiple comparisons by false discovery rate [191, 195, 196].

[0223] In summary, these procedures leverage the well-established concept of c-fos expression as a cellular marker of drug-evoked activity and cellular plasticity. By applying this concept in a standardized and highly quantitative whole-brain assay, the platform is capable of generating detailed and reproducible drug-evoked whole-brain activation patterns.Example 2: Mapping the brain activation underlying the action of ketamine as a rapid antidepressant.

[0224] Using the whole-brain drug-screening platform, the inventors screened the effect of a single subanesthetic dose of 30 mg / kg (i.p.) of ketamine [170, 197], which is comparable to the clinical subanesthetic doses used in the treatment of depression. This experiment revealed a robust pattern of brain activity (FIGURE 2). Based on comparisons with the activity patterns of other drugs screened here, the ketamine-induced brain activity can be divided into two sets of structures:Set A: Comprising the prelimbic (PL) and infralimbic (ILA) cortex, and the interconnected mediodorsal (MD), centromedian (CM), reuniens (RE), and rhomboid (RH) thalamic nuclei.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013Set B: Comprising the paraventricular nucleus of the thalamus (PVT) and the limbic bed nucleus of the stria terminalis (BSTa), central amygdala (CEA), and nucleus accumbens shell (ACBsh).

[0225] This definition of ketamine's brain activation pattern establishes a set of preclinical mouse brain activity biomarkers to assess the capacity of small molecules to induce rapid ketamine-like antidepressant activity. This set of structures refines a previously reported and broader ketamine-evoked c-fos-based activity pattern described in US Patent No.: 11,123,332: "Gaboxadol for reducing the risk of suicide and rapid relief of depression".

[0226] Additionally, a 30 mg / kg (i.p.) dose of ketamine evoked a high activity increase of over 800% in the dorsal retrosplenial cortex (RSPd), a brain area linked to ketamine's dissociative side effects (FIGURE 2) [170, 171], Similar activity was also detected with PCP, a dissociative anesthetic and recreational drug with the same mechanism of action as ketamine, acting as an antagonist at NMDA receptors (FIGURE 2).Example 3: Discovery of high-dose psilocybin-evoked brain activity and its overlap with ketamine-evoked brain activity

[0227] Psilocybin appears to achieve rapid treatment for MDD and TRD similar to ketamine's rapid efficacy, with a single dose reported to induce rapid depression relief lasting several weeks [43, 44], However, psilocybin also induces psychomimetic side effects, including hallucinations, which are most likely mediated by its action at the 5HT2A receptor

[0173] ,

[0228] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by two doses of psilocybin, 5 and 10 mg / kg, corresponding to HED of 25 and 50 mg used in depression clinical trials (FIGURE 3). Strikingly, this pattern showed a complete overlap of brain activity in both set A and set B brain structures identified for ketamine-evoked response. This suggests that psilocybin and ketamine may achieve their shared rapid therapeutic efficacy by acting on the same sets of cortical and subcortical brain structures.

[0229] Additionally, psilocybin did not activate the RSPd, which is linked to ketamine-evoked dissociations, aligning with psilocybin's lack of dissociative side effects (FIGURE 3).PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013On the other hand, psilocybin evoked broad layer 5-focused activity across many frontal, motor, and sensory cortical areas, which was not detected in the ketamine-evoked activity pattern (FIGURE 3). Given that the primary target of psilocybin's activity, the 5HT2A receptor, is linked to its hallucinogenic effects and shows enriched expression in layer 5 neurons [172, 173], this layer 5 activity pattern may represent a mouse brain biomarker of drug-evoked hallucinogenic activity. To further test this hypothesis, the inventors also tested a pattern evoked by another 5HT2A hallucinogen named 2C-T. This drug evoked similar layer 5-centric cortical activity, confirming that this pattern is inherent to the 5HT2A activation (FIGURE 3) and can be used as a biomarker of hallucinogenic activity in the mouse brain.

[0230] In summary, while ketamine and psilocybin are structurally unrelated and act on distinct targets, the two drugs evoke a clearly overlapping pattern in the set A and set B brain structures. The activity in these brain areas represents a shared brain circuit-based intersection downstream of ketamine's antagonistic action at the glutamatergic NMDA receptor and psilocybin's agonistic action at the serotonergic 5HT2A, 5HT2C, and 5HT1A receptors.Example 4: Discovery of memantine-evoked brain activity and its unique distinctions from ketamine-evoked brain activity

[0231] Memantine is an NMDA receptor antagonist with a similar affinity to ketamine but exhibits differences in cellular activity, including variations in channel blocking mechanisms and a potential preference for extracellular versus synaptic locations [8, 174], Memantine is approved for the treatment of Alzheimer's disease due to its presumed effects in reducing tau- and amyloid-linked neurotoxicity

[0198] , However, unlike ketamine, memantine does not possess antidepressant efficacy [10, 11], and the reasons for this lack of efficacy are not yet understood.

[0232] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by two doses of memantine, 4 mg / kg (i.p.) and 10 mg / kg (i.p.) (FIGURE 4).The lower 4 mg / kg (i.p.) dose, which approximates the clinical dose of 20 mg used in the treatment of AD and in various clinical trials for depression, evoked robust activity in all set A structures. These include the frontocortical PL and ILA areas (analogous to the humanPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013pgACC and sgACC implicated in depression) and the interconnected midline MD, CM, RE, and RH thalamic nuclei. However, 4 mg / kg (i.p.) memantine failed to evoke significant activity in any of the subcortical set B structures, including the PVT and the limbic BSTa, CEA, and ACBsh (FIGURE 4). Additionally, 4 mg / kg (i.p.) memantine did not significantly activate the RSPd cortex, which is linked to ketamine's dissociative effects. This aligns with memantine's lack of such side effects at clinical doses up to 20 mg.

[0233] These data reveal a striking and surprising bias of memantine towards activation of the frontocortical areas and connected midline thalamic nuclei of the set A structures compared to ketamine, which robustly activates both set A and set B structures. Specifically, 4 mg / kg (i.p.) memantine evoked approximately 300% increases in frontocortical PL and ILA activity, which is comparable to ketamine's PL and ILA activity induced by a much higher 30 mg / kg (i.p.) dose. However, memantine at 4 mg / kg (i.p.) failed to activate the set B structures, which were strongly activated by 30 mg / kg (i.p.) ketamine. This provides a plausible explanation for memantine's lack of efficacy in depression at a 20 mg dose, suggesting that the activation of the set B structures is necessary for the therapeutic effect, while the activation of set A structures, including the frontocortical areas implicated in depression [38, 39], is not sufficient.

[0234] To further compare the brain activation induced by memantine and ketamine, the inventors mapped brain activity evoked by 10 mg / kg (i.p.) memantine (FIGURE 4). These experiments confirmed memantine's striking bias towards frontocortical areas, revealing increases higher than 1,000% in set A brain areas. In contrast, memantine evoked lower activity, over 400%, in set B structures such as the CEA, BSTa, and ACBsh, and it failed to significantly activate the set B PVT nucleus even at this higher dose. The activity in the frontocortical areas is particularly striking compared to ketamine, as 10 mg / kg (i.p.) memantine-evoked PL and ILA activity was approximately 2.5 times higher than that of ketamine at a 30 mg / kg (i.p.) dose. Finally, 10 mg / kg (i.p.) memantine evoked robust activity in the RSPd cortex (FIGURE 4), which is linked to dissociations, aligning with recreational drug user reports of dissociative perceptions at corresponding human doses of 50 mg or higher

[0176] ,

[0235] In summary, these data reveal unexpected brain circuit-based differences between memantine and ketamine, despite their similar affinity for NMDA receptors. GivenPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013memantine's lack of efficacy in depression, these findings suggest that activity in the set A structures, despite the proposed key role of the set A frontocortical areas in depression [38, 39], is not sufficient to evoke antidepressant effects without concurrent activity in the subcortical set B limbic structures.Example 5: Discovery of amantadine-evoked brain activity and its similarity to memantine-evoked activity.

[0236] Amantadine is also an NMDA receptor antagonist with lower affinity than ketamine or memantine, but with similar low-trapping activity at channel blocking as memantine [8, 174], Amantadine (brand names: Gocovri, Symadine, Symmetrel, PK-Merz) is approved for treatment of Parkinson's disease

[0030] , Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by two doses of amantadine 50 mg / kg (i.p.) and 100 mg / kg (i.p.) (FIGURE 5). The lower 50 mg / kg (i.p.) dose evoked robust activity in all set A structures. These include the frontocortical PL and ILA areas and the interconnected midline MD, CM, RE, and RH thalamic nuclei. However, 50 mg / kg (i.p.) amantadine failed to evoke significant activity in any of the subcortical set B structures, including the PVT and the limbic BSTa, CEA, and ACBsh (FIGURE 5). Additionally, 50 mg / kg (i.p.) amantadine did not significantly activate the RSPd cortex, which is linked to ketamine's dissociative effects.

[0237] These data reveal a similar surprising bias of amantadine towards activation of the frontocortical areas and connected midline thalamic nuclei of the set A structures as seen with memantine 4 mg / kg, including approximately 300% increases in frontocortical PL and ILA activity. Additionally, amantadine at 50 mg / kg (i.p.) also failed to activate the set B structures, which were not activated by memantine at 4 mg / kg. This suggests that amantadine is also unlikely to exert significant antidepressant activity on its own.

[0238] To further analyze the brain activation induced by amantadine, the inventors mapped brain activity evoked by 100 mg / kg (i.p.) amantadine (FIGURE 5). These experiments confirmed amantadine's similarity to memantine in evoking high activity in set A brain areas. Additionally, while 100 mg / kg (i.p.) amantadine evoked significant activity in the set B structures as well, the high dose also activated the RSPd cortex linked to dissociative perceptions. Thus simply increasing the dose of memantine may be expected toPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013result in increased antidepressant activity but with similar dissociative side effect as seen with ketamine.Example 6: Discovery of low-dose psilocybin-evoked brain activity and its comparison to high dose psilocybin and subanesthetic ketamine

[0239] In contrast to the hallucinogenic doses of 25 and 50 mg of psilocybin, which have shown efficacy in clinical trials for depression, a lower dose of 10 mg was found to be both non-hallucinogenic and lacking in antidepressant efficacy [43, 44],

[0240] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by a low dose of 2.5 mg / kg (i.p.) psilocybin, which approximates the non-hallucinogenic and non-efficacious dose of 10 mg (FIGURE 5). These experiments revealed robust activation of all set B structures as well as the set A midline MD, CM, RH, and RE thalamic nuclei, but not in the Set A frontocortical PL and ILA areas. This suggests that activity in the set B structures alone is insufficient to induce an antidepressant response without concurrent activity in the set A frontocortical PL and ILA areas. Therefore, both set A and set B structures appear necessary, but neither is sufficient on their own for rapid antidepressant efficacy similar to that of subanesthetic ketamine or hallucinogenic doses of psilocybin. Additionally, the 2.5 mg / kg (i.p.) psilocybin evoked only sparse layer 5 cortical activity and failed to significantly activate the RSPd cortex (FIGURE 5), aligning with the lack of hallucinogenic or dissociative effects at the low dose.

[0241] In summary, the data presented so far revealed two complementary patterns of activity in the Set A and Set B structures. One pattern is evoked by memantine at 4 mg / kg (i.p.) or amantadine at 100 mg / kg, which activates set A but not set B structures (FIGURE 4 and 5). The other pattern is evoked by psilocybin at 2.5 mg / kg, which activates set B but not frontocortical PL and ILA set A structures (FIGURE 6). This suggests that combining the two drugs at the given doses may result in a complete set A and set B activation pattern. This combination may induce rapid antidepressant activity similar to that of ketamine and high-dose psilocybin. Furthermore, given that human doses of 20 mg memantine and 10 mg psilocybin lack dissociative and hallucinogenic effects, respectively, the proposed combination may not only be efficacious in rapidly treating depression but also free of thePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013psychotomimetic side effects that limit the broad use of ketamine and psilocybin therapeutic options.Exa m p le 7 : Discovery of a single-treatment antidepressant SSRI-evoked brain activity.

[0242] Standard of care (SOC) treatments for MDD rely on several classes of antidepressant medications that act on monoaminergic neurotransmitter systems, including SSRIs, SNRIs, TCAs, TeCAs, MAOIs, NASSAs, and various atypical antidepressants. However, these medications are effective in only about two-thirds of patients and require several weeks of administration to reach therapeutic efficacy. This delay unnecessarily prolongs the disease progression and increases the risk of suicide before the therapeutic effect is fully achieved. Given the lower efficacy and delayed onset, it can be expected that the brain activity of SOC antidepressants may significantly differ from the brain activity evoked by ketamine and psilocybin, which have shown rapid efficacy in TRD patients who failed to respond to at least two treatments with SOC antidepressants.

[0243] Using the whole-brain drug-screening platform, the inventors first mapped brain activity evoked by single treatments with SSRIs fluoxetine (15 mg / kg) and fluvoxamine (60 mg / kg) (FIGURE 7) which are among the most broadly prescribed and safest antidepressants available. These experiments revealed that single treatments with fluoxetine and fluvoxamine evoked partial activation of the set B structures and partial activation of the set A midline thalamic nuclei, but failed to evoke significant activity in the set A frontocortical ILA and PL areas. Specifically, fluoxetine activated the PVT, CEA, and BSTa but not the ACBsh of the set B structures and the MD and CM thalamic nuclei of the set A structures, while fluvoxamine activated the PVT, CEA, and BSTa but not the ACBsh of the set B structures and the MD thalamus of the set A structures (FIGURE 7). The level of significant activity at these structures evoked by the two SSRI was overall lower compared to the activity of low dose psilocybin described above (FIGURE 6).Exa m p le 8 : Discovery of a single-treatment antidepressant TCA-evoked brain activity[02.44] TCA antidepressants are in general considered more efficacious than SSRI antidepressants, though also more frequently associated with serious side effects, including cardiac arrhythmias, irregular heart rate, disorientation or confusion and others. Two TCA'sPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013tested here, desipramine and amitriptyline, are both potent norepinephrine reuptake inhibitors and weaker serotonin reuptake inhibitors.

[0245] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by single treatments with TCAs desipramine (40 mg / kg) and amitriptyline (15 mg / kg) (FIGURE 8). These experiments revealed that single treatments with desipramine and amitriptyline also evoked activation of the set B structures and partial activation of the set A midline thalamic nuclei, but failed to evoke significant activity in the set A frontocortical ILA and PL areas. Specifically, desipramine activated all four set B structures and the MD thalamus of the set A structures, while amitriptyline activated the PVT, CEA, and BSTa but not the ACBsh of the set B structures and the MD thalamus of the set A structures (FIGURE 8). The level of significant activity at these structures evoked by the two TCAs was lower compared to that of low dose psilocybin described above (FIGURE 6).Example 9: Discovery of a single-treatment antidepressant TeCA's mirtazapine and mianserin-evoked brain activity and its comparison to that of SSRIs, TCAs and psilocybin

[0246] TeCA antidepressants are structurally related to TCA antidepressants, possessing four rings in their chemical structures to TCA's three rings. They are similarly considered more efficacious than SSRI antidepressants. Mirtazapine acts primarily as an antagonist or inverse agonist of the a2 adrenergic receptors, the serotonin 5-HT2A, 5-HT2C, and the histamine Hl receptors. Mianserin is a potent norepinephrine reuptake inhibitor as well as an antagonist / inverse agonist of the histamine Hl receptor, serotonin 5-HT1D, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 receptors, and adrenergic al- and a2-adrenergic receptors.

[0247] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by single treatments with TeCAs mirtazapine (10 mg / kg) and mianserin (10 mg / kg) (FIGURE 9). These experiments revealed that a single treatment with mirtazapine as well as mianserin evoked significant activity across all set B structures but failed to activate the set A frontocortical areas (FIGURE 9). Mianserin's activity at the set B structures was more robust than that of mirtazapine, and was more comparable in strength to that of low-dose psilocybin (FIGURE 6). This suggest that mianserin may offer another opportunity for efficacious drug combination with memantine or amantadine, potentially creating robustPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013activity across both set A and set B structures without activity at the RSPd cortex linked to dissociative side effects or broad layer 5 activity linked to hallucinogenic side effects.Therefore, a drug combination of human doses 20 mg memantine or 250 mg amantadine and 50 mg mianserin may be predicted to induce rapid antidepressant efficacy similar to ketamine's and psilocybin's efficacy, without the dissociative or hallucinogenic side effects.Example 10: Discovery of a single-treatment antipsychotic and antidepressant cariprazine-and lumateperone-evoked brain activity and its comparison to that of psilocybin and mianserin

[0248] Cariprazine and lumateperone are antipsychotic medications with additional antidepressant activity: cariprazine is approved as an adjunct treatment in MDD and bipolar depression, while lumateperone is approved as a monotherapy or as an adjunctive treatment in bipolar depression. Cariprazine acts primarily as a D2 and D3 partial agonist, with higher affinity for the D3 receptors. Lumateperone acts as an antagonist of 5-HT2A receptors and, with a lower affinity, DI, D2, and D4 receptors.

[0249] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by single treatments with cariprazine (1.2 mg / kg) and lumateperone (8 mg / kg) (FIGURE 10). These experiments revealed that a single treatment with 1.2 mg / kg (i.p.) cariprazine evoked only a partial activity at the Set B structures, which included the limbic ACBsh and BSTa but lacked the CEA and PVT. In contrast, a single treatment with 8 mg / kg (i.p.) lumateperone evoked robust activity across all set B structures (FIGURE 10). Lumateperone's activity at the set B structures was comparable in strength to that of low-dose psilocybin and 10 mg / kg (i.p.) mianserin (FIGURE 6 and 9). This suggest that lumateperone may offer another opportunity for efficacious drug combination with memantine or amantadine, potentially creating robust activity across both set A and set B structures without activity at the RSPd cortex linked to dissociative side effects or broad layer 5 activity linked to hallucinogenic side effects. Therefore, a drug combination of human doses 20 mg memantine or 250 mg amantadine and 42 mg lumateperone may be predicted to induce rapid antidepressant efficacy similar to ketamine's and psilocybin's efficacy, without the dissociative or hallucinogenic side effects.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013Example 11: Discovery of a brain activity evoked by a chronic daily treatment with fluoxetine and its comparison to that of ketamine and psilocybin

[0250] The single treatments with SOC antidepressants described in Examples 7, 8, and 9 demonstrate acutely evoked brain activity from single doses of each drug. However, this activity is not sufficient to induce therapeutic relief in patients with depression, as SOC antidepressants typically require a minimum of two weeks of treatment to achieve efficacy [2], Therefore, the above patterns do not represent the efficacy of SOC antidepressants and may be expected to change with chronic dosing.

[0251] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by a chronic two-week treatment with fluoxetine at 15 mg / kg (i.p.) (FIGURE 11). Chronic treatment with fluoxetine resulted in more widespread and higher activation of set B structures compared to the single-dose treatment, as well as full activation of the set A structures, including the frontocortical ILA and PL areas (FIGURE 11). When comparing the chronic fluoxetine-induced brain activity pattern to those evoked by subanesthetic ketamine and hallucinogenic psilocybin, several critical insights emerged:Rapid-acting antidepressants (ketamine and psilocybin): These treatments induced immediate and robust activation of both set A and set B structures, correlating with their rapid onset of antidepressant effects. In contrast, SOC antidepressant fluoxetine required chronic administration to achieve significant brain activity at both set A and set B structures.Delayed efficacy of SOC antidepressants: The conversion of partial activity in the set A and B structures evoked by a single dose of fluoxetine to full activity in these structures after chronic dosing provides a plausible explanation for the delayed efficacy of SOC antidepressants. Initial activity at subcortical structures cumulatively increases over time to achieve activation of the frontocortical PL and ILA areas. This su bcortica l-to-cortica I spread of activity may occur via reciprocal connections between the thalamic PVT and MD nuclei, which were both activated by single doses of each SOC antidepressant tested.Example 12: Discovery of a brain activity evoked by a chronic daily treatment with memantine and its comparison to single dose of memantinePCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0252] Given the increased activity evoked by chronic treatment with fluoxetine, it can be expected that chronic treatment with memantine may also induce a different pattern than the single doses of 4 and 10 mg / kg (i.p.) described in Example 4. However, chronic treatment with memantine at daily doses of up to 20 mg did not result in antidepressant efficacy [10, 11], suggesting that there may remain some deficiencies in the memantine-evoked patterns at the set A and B structures even after chronic administration.

[0253] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by a chronic two-week treatment with memantine at 4 mg / kg (i.p.) given daily (FIGURE 12). Surprisingly, the chronic treatment resulted in a loss of significant activity in the set A frontocortical PL and ILA areas, as well as the connected MD and RE thalamic nuclei, while there was a concurrent increase of activity in the CEA, BSTa, and ACBsh, but not PVT, of the set B structures (FIGURE 12).

[0254] These data suggest that the strong activity in the set A prefrontal PL and ILA areas evoked by single doses of memantine as well as ketamine (subanesthetic dose) and psilocybin (hallucinogenic dose) may undergo a diminishing response (desensitization) to successive doses, a process known as tachyphylaxis. This also suggests that to maintain the memantine-evoked activity in the set A frontocortical PL and ILA areas, the drug or its combination may need to be given intermittently, with drug-free wash-out periods, instead of daily.Example 13: Discovery of a brain activity evoked by a chronic intermittent treatment with memantine and its comparison to memantine's single treatment and chronic daily dosing

[0255] The next set of experiments tested the hypothesis that memantine's tachyphylaxis of evoked activity in the set A frontocortical ILA and PL areas and connected thalamic regions can be avoided using an intermittent rather than daily chronic dosing regimen. Additionally, this dosing paradigm may either maintain memantine's single-dose low activity in the set B structures or induce higher activity, potentially leading to full activation across both set A and set B structures.

[0256] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by a chronic four-week treatment with memantine at 4 mg / kg (i.p.) given intermittently, twice a week (FIGURE 11). This intermittent treatment maintained the robustPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013set A frontocortical PL and ILA activity and the connected MD, CM, RH and RE thalamic activity seen with a single 4 mg / kg (i.p.) memantine treatment (FIGURE 13), confirming that daily dosing is the cause of the tachyphylaxis of this response. However, this regimen did not lead to increased activity in the set B structures, with the exception of modest activation in the CEA (FIGURE 13).

[0257] These results suggest that intermittent dosing with wash-out periods of, for example, three days can maintain memantine's set A activity over chronic periods. It can be expected that the same intermittent dosing paradigm can be used in drug combinations with amantadine where memantine's or amantadine's set A activity is complemented with a drug evoking robust set B activity, such as the non-hallucinogenic dose of psilocybin described in Example 6 (FIGURE 6) or the therapeutic dose of mianserin described in Example 9 (FIGURE 9) or the therapeutic dose of lumateperone described in Example 10 (FIGURE 10).Example 14: Mapping of brain activity evoked by memantine at 4 mg / kg (i.p.) and mianserin at 10 mg / kg

[0258] The experiments described in Examples 4 and 8 revealed complementary patterns of activity for memantine at 4 mg / kg (i.p.) and mianserin at 10 mg / kg. Memantine robustly activates all structures in set A but not those in set B, while mianserin robustly activates set B structures but not those in set A. Additionally, neither compound activates RSPd cortex linked to dissociations, or cortical layer 5 linked to hallucinations. Therefore, it can be expected that a combination of memantine and mianserin would selectively activate both set A and set B structures, without the activity linked to psychotomimetic side effects.

[0259] Using the whole-brain drug-screening platform, the inventors mapped brain activity evoked by memantine at 4 mg / kg (i.p.) and mianserin at 10 mg / kg (i.p.) (FIGURE 14).This experiment revealed the expected combination pattern, with significant activation of both set A and set B structures and without significant activity evoked in either the RSPd cortex or across the layer 5 cortical layer (FIGURE 14). This pattern thus suggests that the drug combination may have a rapid efficacy in treating MDD and TRD, without inducing dissociations or hallucination side effects related to RSPd and layer 5 activity, respectively.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013Example 15: Prolonged antidepressant-like behavioral effect elicited by combined administration of memantine and mianserin

[0260] The forced swim test and tail suspension test are frequently used behavioral assays for assessing the therapeutic efficacy of antidepressants [180, 181, 199], In the forced swim test, a mouse is placed in a beaker filled with water, and the time spent struggling, swimming, and floating is measured. The time spent floating (immobility time), when the mouse ceases struggling to swim, is used as a behavioral correlate of depression. In the tail suspension test, a mouse is hanged by its tail using an adhesive tape, and the time spent moving and struggling is measured. The time spent hanging (immobility time), when the mouse ceases struggling to move, is used as a behavioral correlate of depression.Although some compounds show efficacy in these tests and other behavioral tests for depression but fail in clinical trials, ketamine has been shown to induce a uniquely lasting response compared to traditional antidepressants. Traditional antidepressants typically induce a measurable antidepressant-like behavioral response within an hour after dosing, while ketamine induces a statistically significant response measurable both 1 hour and 24 hours after dosing

[0183] , Other rodent behavior models are commonly used to test neuropsychiatric modulators and may be used to demonstrate the effect of the memantine-or amantadine-based drug combination. Standard tests as described in [200, 201] are incorporated herein by reference in their entireties.

[0261] To test whether the combination of memantine and mianserin exhibits the same lasting behavioral effect as ketamine in the forced swim test, the effects of a single dose of memantine (4 mg / kg), fluoxetine (15 mg / kg), mianserin (10 mg / kg), ketamine (30 mg / kg), memantine (4 mg / kg) plus fluoxetine (15 mg / kg), and memantine (4 mg / kg) plus mianserin (10 mg / kg) were compared at both 1 hour and 24 hours after a single drug treatment (FIGURE 15). These experiments revealed the following:

[0262] Memantine alone and fluoxetine applied alone induced no significant effects on the time spent immobile at either the 1-hour or 24-hour time points compared to mice treated with a vehicle solution (FIGURE 15). These data align with previous literature indicating that memantine and fluoxetine require multiple doses prior to behavioral testing to elicit an antidepressant-like response in the forced swim test. For instance, fluoxetine needed 24 days of dosing to achieve efficacy in the forced swim test

[0202] , Similarly,PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013memantine was found efficacious when administered three times within 24 hours before testing or daily for fifteen days before testing [203, 204], It should be noted, however, that the memantine data represent an example of a false positive result of this test, as memantine alone has not been found to be efficacious in double-blind studies in patients with MDD [10, 11].

[0263] Mianserin alone and the combination of memantine and SSRI fluoxetine induced a statistically significant reduction in immobility time at 1 hour but not at 24 hours after the treatment compared to vehicle-treated mice (FIGURE 15). Previous studies have demonstrated mianserin's efficacy within 1 hour after two doses administered preceding the test [205, 206], Our results suggest that the significant effects of mianserin and the combination of memantine and fluoxetine at 1 hour post-dosing reflect higher activity in set A and B structures compared to treatments with fluoxetine or memantine alone. However, the lack of efficacy at 24 hours post-dosing suggests that mianserin and the combination of memantine and fluoxetine do not exhibit the rapid and lasting behavioral efficacy seen with ketamine.

[0264] Ketamine and the combination of memantine and mianserin both induced significant reductions in immobility time at 1 hour as well as 24 hours after the treatment compared to vehicle-treated mice (FIGURE 15). The ketamine data are consistent with previous reports of immediate and lasting efficacy from a single dose

[0183] , The finding that the combination of memantine and mianserin induced comparable behavioral efficacy to that of ketamine aligns with our c-fos mapping data, which show that this drug combination evokes robust activity in both set A and set B structures, similar to the brain activation pattern evoked by ketamine. Therefore, these data support the prediction that the combination of memantine and mianserin may achieve the rapid efficacy in MDD and TRD observed with ketamine.

[0265] To test whether the combination of memantine and mianserin exhibits the same lasting behavioral effect as ketamine in the tail suspension test, the effects of a single dose of memantine (4 mg / kg), mianserin (10 mg / kg) and memantine (4 mg / kg) plus mianserin (10 mg / kg) were compared at both 1 hour and 24 hours after a single drug treatment (FIGURE 15). These experiments revealed the following:PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0266] Neither memantine nor mianserin administered alone induced antidepressantlike effect in the tail suspension test at either 1 or 24 hours after the treatment (FIGURE 15).In contrast, the combination of memantine and mianserin induced an antidepressant like effect at both 1 hour and 24 hours after the treatment (FIGURE 15). These data further suggest that the combination of memantine and mianserin may provide a fast-acting relief in depression similar to that of ketamine.Example 16: Potentiation of Efficacy of memantine or amantadine for treating Alzheimer's disease and other forms of dementia or mild cognitive impairment (MCI) by combining memantine or amantadine with psilocybin or mianserin or lumateperone, and / or by intermittent instead of daily dosing of memantine(0267) Memantine is approved forthe treatment of Alzheimer's disease, and its therapeutic efficacy is thought to include neuroprotection by reducing glutamatergic transmission through NMDA receptors, thereby decreasing glutamatergic excitotoxicity and reducing tau- and amyloid-linked neurotoxicity [198, 207], However, current data show that memantine evokes robust frontocortical activation at 4 mg / kg (i.p.) in mice, a dose corresponding to the 20 mg daily dose used in treating Alzheimer's disease. Thus, rather than reducing glutamatergic transmission, memantine appears to increase it in a circuitspecific manner. Given the frontocortical focus of memantine's activity, these data suggest an alternative scenario for memantine's efficacy in slowing the progression of dementia in Alzheimer's disease. This scenario posits that memantine enhances and preserves the activity of frontocortical brain circuits, which play critical roles in higher cognitive processes and executive functions affected in Alzheimer's disease and other forms of dementia.Furthermore, amantadine may evoke a similar effect as memantine by analogy of evoking a similar activity at the frontocortical circuits.

[0268] To test whether memantine- and amantadine-evoked brain activity patterns may potentially correspond to any activity deficits seen with aging, the inventors compared baseline c-fos expression in aged mice (18, 22, and 26 months old) versus young adult mice (2 months old). Strikingly, these comparisons revealed an age-associated progressive loss of c-fos expression in the frontocortical PL and ILA areas (FIGURE 16). These data suggest that aging and the progressive loss of cognitive functions are indeed associated with chronic loss of activity in the frontocortical areas. Given that memantine and amantadine evoke activityPCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013and cellular plasticity in the same areas (FIGURE 4, 5 and 16), these findings support the hypothesis that memantine's efficacy in slowing the progression of dementia may, at least in part, come from counteracting and increasing the activity and cellular plasticity in the frontocortical brain regions. Essentially since memantine's frontocortical activity appears to match the activity deficit in an aging brain, this suggests a frontocortical mechanism of protection in dementia and rather than reducing glutamatergic transmission, i.e., memantine appears to increase it in a circuit-specific manner. Given the frontocortical focus of memantine's activity, these data suggest an alternative scenario for memantine's efficacy in slowing the progression of dementia in Alzheimer's disease i.e., that memantine enhances and preserves the activity of frontocortical brain circuits, which play critical roles in higher cognitive processes and executive functions affected in Alzheimer's disease and other forms of dementia.

[0269] Based on our observations, the inventors propose that memantine's efficacy in treating Alzheimer's disease and other forms of dementia can be significantly enhanced by administering memantine in combination with a low dose of psilocybin or a therapeutic dose of mianserin or lumateperone, and / or by employing an intermittent dosing regimen rather than the current approved treatment of daily dosing. Additionally, amantadine-based combinations with a low dose of psilocybin or a therapeutic dose of mianserin or lumateperone, employing an intermittent dosing regimen, may achieve similar efficacy in dementia as the memantine-based combinations.

[0270] In TABLE 1 below we summarize the effects of different drug dosages on Set A and Set B brain structures and on therapeutic efficacy. All drugs were delivered i.p.TABLE 1PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013

[0271] The following references are cited in this application, the contents of each of which are incorporated by reference in their entirety herein.REFERENCES CITED IN THIS APPLICATION1. Zhdanava, M., et al., The prevalence and national burden of treatment-resistant depression and major depressive disorder in the United States. The Journal of Clinical Psychiatry, 2021. 82(2): p. 29169.2. Taylor, M.J., et al., Early onset of selective serotonin reuptake inhibitor antidepressant action: systematic review and meta-analysis. Archives of general psychiatry, 2006.63(11): p. 1217-1223.3. Huang, Z.-D., et al., Comparative efficacy and acceptability of pharmaceutical management for adults with post-traumatic stress disorder: a systematic review and meta-analysis. Frontiers in pharmacology, 2020. 11: p. 559.4. Fel lendorf, F.T., et al., Pharmacological Treatment of Bipolar Depression: A Review of Observational Studies. Pharmaceuticals, 2023. 16(2): p. 182.5. McCutcheon, R.A., T.R. 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Li, T., et al., Potent Dmt-Tic pharmacophoric 8-and p-opioid receptor antagonists.Journal of medicinal chemistry, 2005. 48(25): p. 8035-8044.156. Santagada, V., et al., Assessment of substitution in the second pharmacophore of Dmt-Tic analogues. Bioorganic & medicinal chemistry letters, 2000. 10(24): p. 2745- 2748.157. Ichikawa, K., et al., Synthetic studies toward the marine alkaloid convolutindole A, a structurally remarkable derivative of the hallucinogen N, N-Dimethyltryptamine (DMT). Tetrahedron Letters, 2023. 129: p. 154756.158. Ballet, S., et al., Conformationally constrained opioid ligands: the Dmt-Aba and Dmt- Aia versus Dmt-Tic scaffold. Bioorganic & medicinal chemistry letters, 2009. 19(2): p.433-437.159. Balboni, G., et al., Synthesis and opioid activity ofN, N-Dimethyl-Dmt-Tic-NH-CH (R)- R' analogues: acquisition of potent 8 antagonism. Bioorganic & medicinal chemistry, 2003. 11(24): p. 5435-5441.160. Wang, Y.Y. and C. Chen, Synthesis of deuterium labeled tryptamine derivatives.Journal of the Chinese Chemical Society, 2007. 54(5): p. 1363-1368.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013161. Jacob, P. and A.T. Shulgin, Structure-activity relationships of classic hallucinogens and their analogs. NIDA Research Monograph, 1994. 146: p. 74-91.162. Glennon, R.A. and J.A. Rosecrans, Indolealkylamine and phenalkylamine hallucinogens: a brief overview. Neuroscience & Biobehavioral Reviews, 1982. 6(4): p.489-497.163. Hirst, W.D., et al., Differences in the central nervous system distribution and pharmacology of the mouse 5-hydroxytryptamine-6 receptor compared with rat and human receptors investigated by radioligand binding, site-directed mutagenesis, and molecular modeling. Molecular pharmacology, 2003. 64(6): p. 1295-1308.164. Pinder, R. and J. 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Clinical and experimental pharmacology and physiology, 1992. 19(1): p. 17-23.169. Radan, M., T. Djikic, and K. Nikolic, Discovery of new chemotypes of dual 5-HT2A / D2 receptor antagonists with a strategy of drug design methodologies. Future Medicinal Chemistry, 2022. 14(13): p. 963-989.170. Vesuna, S., et al., Deep posteromedial cortical rhythm in dissociation. Nature, 2020.586(7827): p. 87-94.171. Tian, F., et al., Characterizing brain dynamics during ketamine-induced dissociation and subsequent interactions with propofol using human intracranial neurophysiology. Nature communications, 2023. 14(1): p. 1748.172. Xu, T. and S.C. Pandey, Cellular localization ofserotonin2A (5HT2A) receptors in the rat brain. Brain research bulletin, 2000. 51(6): p. 499-505.173. Kwan, A.C., et al., The neural basis of psychedelic action. Nature Neuroscience, 2022.25(11): p. 1407-1419.174. Tern me, L, et al., Comparative pharmacological study of common NMDA receptor open channel blockers regarding their affinity and functional activity toward GluN2A and GluN2B NMDA receptors. ChemMedChem, 2018. 13(5): p. 446-452.175. Barson, J.R., N.R. Mack, and W.-J. Gao, The paraventricular nucleus of the thalamus is an important node in the emotional processing network. Frontiers in Behavioral Neuroscience, 2020. 14: p. 598469.176. Natter, J. and B. Michel, Memantine misuse and social networks: a content analysis of Internet self-reports. Pharmacoepidemiology and drug safety, 2020.29(9): p. 1189- 1193.177. Jha, M.K. and SJ. Mathew, Pharmacotherapies for treatment-resistant depression: how antipsychotics fit in the rapidly evolving therapeutic landscape. American Journal of Psychiatry, 2023. 180(3): p. 190-199.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013178. Li, S., et al., Efficacy and tolerability of FDA-approved atypical antipsychotics for the treatment of bipolar depression: a systematic review and network meta-analysis. European Psychiatry, 2024: p. 1-26.179. Keramatian, K., et al., New pharmacologic approaches to the treatment of bipolar depression. Drugs, 2023. 83(10): p. 843-863.180. Porsolt, R.D., M. Le Pichon, and M. Ja If re, Depression: a new animal model sensitive to antidepressant treatments. Nature, 1977. 266(5604): p. 730-732.181. Cryan, J.F. and A. Holmes, The ascent of mouse: advances in modelling human depression and anxiety. Nat Rev Drug Discov, 2005. 4(9): p. 775-90.182. Porsolt, R.D., et al., Rodent models of depression: forced swimming and tail suspension behavioral despair tests in rats and mice. Current protocols in neuroscience, 2001. 14(1): p. 8.10 A. 1-8.10 A. 10.183. Autry, A.E., et al., NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature, 2011. 475(7354): p. 91-95.184. Rani, N., D. Dev, and D. Prasad, Recent Trends in developments of Superdisintegrants:An Overview. Journal of Drug Delivery and Therapeutics, 2022. 12(1): p. 163-169. 185. Chaturvedi, K., et al., Fast Dissolving Oral Film: An Innovative Approach for Drug Delivery. Current Research in Pharmaceutical Sciences, 2024: p. 01-09.186. Ciper, M. and R. Bodmeier, Preparation and characterization of novel fast disintegrating capsules (Fastcaps) for administration in the oral cavity. International journal of pharmaceutics, 2005. 303(1-2): p. 62-71.187. Boateng, J.S., et al., Characterisation of freeze-dried wafers and solvent evaporated films as potential drug delivery systems to mucosal surfaces. International journal of pharmaceutics, 2010. 389(1-2): p. 24-31.188. Aldewachi, H., et al., High-throughput screening platforms in the discovery of novel drugs for neurodegenerative diseases. Bioengineering, 2021. 8(2): p. 30.189. den Boer, J. A., et al., Role of Brain Imaging in Drug Development for Psychiatry.Current Reviews in Clinical and Experimental Pharmacology Formerly Current Clinical Pharmacology, 2022. 17(1): p. 46-71.190. Markicevic, M., et al., Emerging imaging methods to study whole-brain function in rodent models. Translational psychiatry, 2021. 11(1): p. 457.191. Renier, N., et al., Mapping of Brain Activity by Automated Volume Analysis of Immediate Early Genes. Cell, 2016. 165(7): p. 1789-802.192. Azevedo, H., et al., The serotonergic and alpha-1 adrenergic receptor modulator ACH- 000029 ameliorates anxiety-like behavior in a post-traumatic stress disorder model. Neuropharmacology, 2020. 164: p. 107912.193. Slattery, D.A., et al., Comparison of alterations in c-fos and Egr-1 (zif268) expression throughout the rat brain following acute administration of different classes of antidepressant compounds. Neuropsychopharmacology, 2005. 30(7): p. 1278.194. Sumner, B.E., et al., Testing the validity of c-fos expression profiling to aid the therapeutic classification of psychoactive drugs. Psychopharmacology (Berl), 2004.171(3): p. 306-21.195. Kim, Y, et al., Mapping social behavior-induced brain activation at cellular resolution in the mouse. Cell Rep, 2015. 10(2): p. 292-305.196. Kim, Y, et al., Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression. Front Neural Circuits, 2016. 10: p. 3.PCT / US25 / 55334 13 November 2025 (13.11.2025)Atorney Docket No. 2969833.001013197. Schmack, K., et al., Striatal dopamine mediates hallucination-like perception in mice.Science, 2021. 372(6537): p. eabf4740.198. Tari, P.K., et al., Memantine: updating a rare success story in pro-cognitive therapeutics. Neuropharmacology, 2024. 244: p. 109737.199. Cryan, J.F. and C. Mombereau, In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. 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Claims

Attorney Docket No. 2969833.001013CLAIMSWhat is claimed is:

1. A method for treating a depressive disorder, stressor-related disorder, substance abuse disorder, dementia or mild cognitive impairment in a subject in need thereof, optionally a subject with major depression, treatment-resistant depression, post-pa rtum depression, bipolar depression, post-traumatic stress disorder, negative and cognitive symptoms of schizophrenia, or Alzheimer's disease, which comprises one or more treatments wherein the first treatment comprises or consists of:(a) administering a first dose of memantine or amantadine, a structural analogue or a pharmaceutically acceptable salt thereof, preferably a dose which is sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; and (b) administering a first dose of a second pharmaceutical compound, preferably psilocybin, mianserin or lumateperone, or another pharmaceutical compound which is capable of activating Set B brain areas in a mouse brain, preferably wherein the administered dose of said second pharmaceutical compound is sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity; and(c) wherein said administration method alleviates one or more clinical symptoms of said depressive disorder, stressor-related disorder, substance abuse disorder, dementia or mild cognitive impairment disorder.

2. The method of claim 1, wherein the first dose of memantine, amantadine, a structural analogue or a pharmaceutically acceptable salt thereof, is sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; and / or the first dose of the second pharmaceutical compound, preferably psilocybin, mianserin or lumateperone, or another pharmaceutical compound which is capable of activating Set B brain areas in a mouse brain, is sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity.

3. The method of claim 1 or 2, wherein the second compound is mianserin, and the administered mianserin comprises the S stereoisomer, the R stereoisomer or a racemate comprising both isomers.Attorney Docket No. 2969833.0010134. The method of claim 1, 2 or 3, wherein each of said treatments (administration of (a) and (b)) are effected no more frequently than every 2 days.

5. The method of any one of claims 1-4, wherein(i) said dementia associated disorder includes any of vascular dementia, dementia with Lewy bodies, frontotemporal dementia (FTD), dementia in Huntington's disease, dementia in Parkinson's disease, posterior cortical atrophy (also called Benson's syndrome), Creutzfeldt-Jakob disease dementia and Wernicke-Korsakoff syndrome; (ii) said depressive disorder includes any of major depression, psychotic depression, premenstrual dysphoric disorder, postpartum depression, atypical depression, bipolar depression, seasonal affective disorder, recurrent depressive disorder and bipolar disorder;(iii) said stress related disorder includes any of acute stress disorder, Post-traumatic stress disorder (PTSD), depression, adjustment disorder, Disinhibited Social Engagement Disorder, or Disinhibited Attachment Disorder, Reactive attachment disorder, Generalized anxiety disorder, Obsessive-compulsive disorder or "trauma- associated disorder", Unclassified and unspecified trauma disorders, and chronic stress:(iv) said substance use disorder includes opioid abuse, alcohol abuse, gambling abuse, internet gambling abuse, tobacco addiction, caffeine addiction, cigarette addiction, and vaping addiction;(v) said second pharmaceutical compound is one of the following: antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic (TCAs), tetracyclic (TeCAs) antidepressants, monoamine oxidase inhibitors (MAOIs), noradrenergic and specific serotonergic antidepressants (NASSAs), and atypical antidepressants and atypical antipsychotics and their pharmaceutically acceptable salts thereof;(vi) said antidepressants / antipsychotics include, but are not limited to, the selective serotonin reuptake inhibitors (SSRIs) include citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; the serotonin norepinephrine reuptake inhibitors (SNRIs) include venlafaxine, duloxetine, atomoxetine, desvenlafaxine,Attorney Docket No. 2969833.001013levomilnacipran, milnacipran, sibutramine, and tramadol; the serotonin modulator and stimulators (SMSs) include vortioxetine and vilazodone; the serotonin antagonist and reuptake inhibitors (SAMs) include trazodone and nefazodone; the norepinephrine reuptake inhibitors (NRIs or NERIs) include atomoxetine, reboxetine, and viloxazine; the norepinephrine-dopamine reuptake inhibitors include bupropion; the tricyclic antidepressants (TCAs) include imipramine, doxepin, amitriptyline, nortriptyline and desipramine; the tetracyclic antidepressants include mirtazapine; the monoamine oxidase inhibitors (MAOIs) include phenelzine, isocarboxazid, tranylcypromine and pyrazidol; the sympatholytics include propranolol, oxprenolol, metoprolol, prazosin, clonidine, and guanfacine; and others such as buspirone, pregabalin, and hydroxyzine;(vii) said second pharmaceutical compound comprises anantidepressant / anti psychotic selected from agomelatine, Allegron, Alventa XL, Amphero XL, amitriptyline, Brintellix, Cipralex, Cipramil, citalopram, clomipramine, Cymbalta, Depefex XL, doxepin, duloxetine, Edronax, Efexor XL, escitalopram, Faverin, fluvoxamine, fluoxetine, fluvoxamine, Foraven XL, imipramine, isocarboxazid, lofepramine, Lomont, Lustral, Majoven XL, Manerix, mianserin, mirtazapine, moclobemide, Molipaxin, Nardil, nortriptyline, Olena, Oxactin, Parnate, phenelzine, Politid XL, Prothiaden, Prozac, Prozep, reboxetine, Seroxat, sertraline, Sinepin, Sunveniz XL, Surmontil, Tonpular XL, tranylcypromine, trazodone, trimipramine, Valdoxan, Venadex XL, Venaxx XL, venlafaxine, Vencarm XL, Venlablue XL, venlafaxine, Venladex XL, Venlasoz XL, Venlalic XL, venlafaxine, Vensir XL, ViePax XL, vortioxetine and Zispin;(viii) said second pharmaceutical compound is selected from the following: SSRIs such as Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), Sertraline (Zoloft), Dapoxetine (Priligy), Indalpine (Upstene), Zimelidine (Zelmid), Alaproclate (GEA-654), Centpropazine, Cericlamine (JO-1017), Femoxetine (Malexil; FG-4963), Ifoxetine (CGP-15210), Omiloxetine, Panuramine (WY-26002), Pirandamine (AY- 23713), Seproxetine ((S)-norfluoxetine), SNRIs such as Desven lafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Save Ila ), Sibutramine (Meridia), Tramadol (Ultram),Attorney Docket No. 2969833.001013Venlafaxine (Effexor), TCAs such as Butriptyline (Evadyne), Clomipramine (Anafranil), Imipramine (Tofranil, Janimine, Praminil), Trimipramine, (Surmontil), Desipramine (Norpramin, Pertofrane), Dibenzepint (Noveril, Victoril), Lofepramine§ (Lomont, Gamanil), Maprotiline (Ludiomil), Nortriptyline (Pamelor, Aventyl, Norpress), Protriptyline (Vivacti I), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Amoxapine (Asendin), Demexiptiline (Deparon, Tinoran), Dimetacrine (Istonil, Istonyl, Miroistonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Fluacizine (Phtorazisin), Imipraminoxide (Imiprex, Elepsin), Melitracen (Deanxit, Dixeran, Melixeran, Trausabun), Metapramine (Timaxel), Nitroxazepine (Sintamil), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen / Azaphen), Propizepine (Depressin, Vagran), Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine), Amineptine (Survector, Maneon, Directim) - norepinephrine-dopamine reuptake inhibitor, I prindole (Prondol, Galatur, Tetran) - 5-HT2 receptor antagonist, Opipramol (Insidon, Pramolan, Ensidon, Oprimol) - o receptor agonist, Tianeptine (Stabion, Coaxil, Tatinol), TeCAs such as Maprotiline (Ludiomil), Mianserin (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Amoxapine (Asendin), Quetiapine (Seroquel), Benzoctamine (Tacitin), Loxapine (Adasuve, Loxitane), Mazindol, Aptazapine (CGS-7525A), Esmirtazapine (ORG-50,081), Oxaprotiline (C 49-802 BDA), Ciclazindol, MAOIs such as Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), Tranylcypromine (Parnate), Benmoxin (Nerusil, Neuralex), Iproclozide (Sursum), Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), Mebanazine (Actomol), Nialamide (Niamid), Octamoxin (Ximaol, Nimaol), Pheniprazine (Catron), Phenoxypropazine (Drazine), Pivalylbenzhydrazine (Tersavid), Safrazine (Safra), Minaprine (Cantor), Toloxatone (Humoryl), Moclobemide (Aurorix, Manerix, Moclamine), Brofaromine (Consonar), Caroxazone (Surodil, Timostenil), Eprobemide (Befol), Metralindole (Inkazan), Minaprine (Cantor), Pirlindole (Pirazidol), Serotonin-norepinephrine-dopamine reuptake inhibitors (SNDRIs) such as Toludesvenlafaxine (Ruoxinlin), Nefazodone (Serzone), Serotonin modulators and stimulators (SMSs) such as Vilazodone (Viibryd), Vortioxetine (Trintellix, Brintellix), Serotonin antagonist and reuptake inhibitors (SARIs) such as Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Etoperidone (Axiomin, Etonin), Norepinephrine reuptake inhibitors (NRIs) such as Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone),Attorney Docket No. 2969833.001013Viloxazine (Qelbree, formerly Vivalan), Atomoxetine (Strattera), PDC-1421 (BLI-1005), Norepinephrine-dopamine reuptake inhibitors (NDRIs) such as Bupropion (Wellbutrin, Elontril), Amineptine (Survector, Maneon), Nomifensine (Merital, Alival), OPC-64005, Atypical antipsychotics used to treat depression such as Amisulpride (Solian), Lurasidone (Latuda), Quetiapine (Seroquel), and Other atypicals such as Agomelatine (Valdoxan), Brexanolone (allopregnanolone; Zulresso), Gepirone (Exxua), Opipramol (Insidon), Tianeptine (Stabion, Coaxil, Tianeurax), a-Methyltryptamine [aMT] (Indopan), Etryptamine (Monase), Indeloxazine (Elen, Noin), Medifoxamine (Cledial, Gerdaxyl), Oxaflozane (Conflictan), a drugs in investigation such as BTRX- 246040 (LY-2940094), Aticaprant (JNJ-67953964, CERC-501, LY-2456302), Navacaprant (BTRX-335140; BTRX- 140), Buprenorphine / samidorphan (ALKS-5461), CVL-354, JNJ-61393215 (JNJ-3215; Orexin-1) and Seltorexant (MIN-202, JNJ-42847922, JNJ-922);(ix) said second pharmaceutical compound is selected from the following antipsychotic medications: aripiprazole (Ability), brexpiprazole (Rexulti), quetiapine (Seroquel), extended-release quetiapine (Seroquel-XR), olanzapine (Zyprexa), asenapine (Saphris), risperidone (Risperdal), a combination of olanzapine and fluoxetine (Symbyax), cariprazine (Vraylar), lurasidone (Latuda), a combination of xanomeline and trospium (Cobenfy), and lumateperone (Caplyta);(x) the (a) memantine or amantadine, structural analogue thereof or a pharmaceutically acceptable salt thereof, and (b) the second pharmaceutical compound are administered at the same time or within 0.1-8 hours, 0.1-4 hours, 0.1-2 hours, 0.1-1 hours, or 0.1-.5 hours of each other;(xi) the memantine or amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof, and the second pharmaceutical compound are in the same medicament;(xii) the memantine or amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof, and the second pharmaceutical compound are in different medicaments;Attorney Docket No. 2969833.001013(xiii) the method comprises an additional treatment comprising the administration of (a) memantine or amantadine, a structural analogue thereof or a pharmaceutically acceptable salt thereof, and (b) the second pharmaceutical compound capable of activating Set B brain areas in mouse brain using c-fos as a reporter of activity, wherein said second pharmaceutical compound comprises or consists of psilocybin or mianserin (S isomer, R isomer or a racemate comprising both isomers) or lumateperone, and wherein the memantine or amantadine, structural analogue thereof or pharmaceutically acceptable salt thereof is preferably administered at a dose sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity, and the psilocybin or mianserin or lumateperone is preferably administered at a dose sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity, and further wherein said additional treatment is not effected until at least 48 hours after the first treatment, preferably wherein the additional treatment is effected at least 3, 4, 5, 6 or 7 days or longer after the first treatment;(xiv) the method comprises one or more additional treatments, wherein each additional treatment is effected at least 3, 4, 5, 6 or 7 days or longer after the previous additional treatment;(xv) the method results in rapid relief of clinical symptoms of said depressive disorder, stressor-related disorder, or substance abuse disorder or which alleviates or improves cognitive function in a subject with dementia or mild cognitive impairment; (xvi) the subject comprises a depressive disorder, stressor-related disorder, or substance abuse disorder and has not been previously treated with an antidepressant compound and / or has not been previously treated with memantine; (xvii) said depressive or stress related disorder includes any of major depressive disorder (MDD) and / or treatment-resistant disorder (TRD) and / or post-traumatic stress disorder (PTSD);(xviii) the patient has not been previously treated with, or is not currently being treated with, or is not responding to, an anti-depressive treatment;Attorney Docket No. 2969833.001013(xix) the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 5 mg to about 150 mg, 5-100 mg, or 5-50 mg.(xx) the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 10 mg to about 40 mg;(xxi) the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in the first and / or additional treatment is about 20 mg to about 30 mg;(xxii) the dosage of amantadine, structural analogue or pharmaceutically acceptable salt thereof, in the first and / or additional treatment is about 20 to 1000 mg, or 50 to 500 mg, or 50 to 250 mg or is 50 mg.(xxiii) the second compound in the first treatment comprises psilocybin, a structural analogue thereof, ora pharmaceutically acceptable salts thereof and the dosage thereof ranges from about 1 mg to about 20 mg;(xxiv) the second compound in the first treatment comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof ranges from about 2.5 mg to about 17.5 mg;(xxv) the second compound in the first treatment comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof ranges from about 5 mg to about 15 mg;(xxvi) the second compound which is administered in the first treatment comprises or consists of a low dose of a psychedelic or stimulant compound, including but not limited to lysergic acid diethylamide (LSD), 3,4-Methylenedioxymethamphetamine (MDMA), ibogain and N,N-Dimethyltryptamine (DMT) and their structural analogues and pharmaceutically acceptable salts thereof, wherein said second compound is preferably administered at a dose which is sufficient to activate the Set B brain structures but which does not appreciably evoke brain activity linked to hallucinogenic or other psychotomimetic perceptions;Attorney Docket No. 2969833.001013(xxvii) the second compound administered in the first treatment comprises or consists of mianserin (S isomer, R isomer, or a racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 20 mg to about 200 mg.(xxviii) the second compound administered in the first treatment comprises or consists of mianserin (S isomer, R isomer, or a racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 40 mg to about 150 mg.(xxix) the second compound administered in the first treatment comprises or consists of mianserin (S isomer, R isomer, or a racemate comprising both isomers) or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 50 mg to about 100 mg;(xxx) the memantine and / or second compound administered in the first treatment comprise oral dosage forms, optionally orally disintegrating forms;(xxxi) the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 10 mg to about 100 mg;(xxxii) the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 20 mg to about 50 mg;(xxxiii) the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 35-45 mg;(xxxiv) the second compound administered in the first treatment comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 42 mg;(xxxvi) the memantine or amantadine and / or the second compound administered in the first treatment is / are administered intranasally or via inhalation;Attorney Docket No. 2969833.001013(xxxvii) the memantine or amantadine and / orthe second compound which is / are administered in the one or more additional treatments is / are administered intranasally or via inhalation;(xxxviii) the memantine or amantadine and / or the second compound administered in the first treatment is / are administered topically, e.g., using a patch.(xxxix) the memantine or amantadine and / or the second compound administered in the one or more additional treatments are administered topically, e.g., using a patch; or(xxxx) any combination of (i) to (xxxix).

6. A medicament comprising a drug combination suitable for treating a depressive, stress related, or substance abuse disorder or dementia or mild cognitive impairment in a subject in need thereof, which medicament comprises:(a) a dose of memantine or amantadine, a structural analogue or a pharmaceutically acceptable salt thereof, sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; and(b) a dose of a second pharmaceutical compound, preferably optionally psilocybin or mianserin (S isomer, R isomer or a racemate comprising both isomers) or lumateperone, or another compound which is capable of activating Set B brain areas in a mouse brain, wherein the dose of said second pharmaceutical compound is preferably a dose sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity but which dose does not appreciably evoke brain activity linked to hallucinogenic or other psychotomimetic perce pho ns.

7. The medicament of claim 6, comprising one or more of the following:(i) said second pharmaceutical compound in the medicament comprises one of the following: selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic (TCAs), tetracyclic (TeCAs) antidepressants, monoamine oxidase inhibitors (MAOIs), noradrenergic and specific serotonergic antidepressants (NASSAs), and atypical antidepressants and their pharmaceutically acceptable salts thereof;Attorney Docket No. 2969833.001013(ii) said second pharmaceutical compound in the medicament comprises one of the following: anxiolytics / antidepressants such as barbiturates; benzodiazepines such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, diazepam, lorazepam, oxazepam, temazepam, and triazolam; selective serotonin reuptake inhibitors (SSRIs) such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; serotonin norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine, duloxetine, atomoxetine, desvenlafaxine, levomilnacipran, milnacipran, sibutramine, and tramadol; serotonin modulator and stimulators (SMSs) such as vortioxetine and vilazodone; serotonin antagonist and reuptake inhibitors (SAMs) such astrazodone and nefazodone; norepinephrine reuptake inhibitors (NRIs or NERIs) such as atomoxetine, reboxetine, and viloxazine; norepinephrine-dopamine reuptake inhibitors such as bupropion; tricyclic antidepressants (TCAs) such as imipramine, doxepin, amitriptyline, nortriptyline and desipramine; tetracyclic antidepressants such as mirtazapine; monoamine oxidase inhibitors (MAOIs) such as phenelzine, isocarboxazid, tranylcypromine and pyrazidol; sympatholytics such as propranolol, oxprenolol, metoprolol, prazosin, clonidine, and guanfacine; and buspirone, pregabalin, or hydroxyzine;(iii) said second pharmaceutical compound in the medicament comprises one of the following: agomelatine, Allegron, Alventa XL, Amphero XL, amitriptyline, Brintellix, Cipralex, Cipramil, citalopram, clomipramine, Cymbalta, Depefex XL, doxepin, duloxetine, Edronax, Efexor XL, escitalopram, Faverin, fluvoxamine, fluoxetine, fluvoxamine, Foraven XL, imipramine, isocarboxazid, lofepramine, Lomont, Lustral, Majoven XL, Manerix, mianserin (S isomer, R isomer, or a racemate comprising both isomers), mirtazapine, moclobemide, Molipaxin, Nardil, nortriptyline, Olena, Oxactin, Parnate, phenelzine, Politid XL, Prothiaden, Prozac, Prozep, reboxetine, Seroxat, sertraline, Sinepin, Sunveniz XL, Surmontil, Tonpular XL, tranylcypromine, trazodone, trimipramine, Valdoxan, Venadex XL, Venaxx XL, venlafaxine, Vencarm XL, Venlablue XL, venlafaxine, Venladex XL, Venlasoz XL, Venlalic XL, venlafaxine, Vensir XL, ViePax XL, vortioxetine and Zispin;(iv) said second pharmaceutical compound in the medicament comprises one of the following: Citalopram (Celexa), Escitalopram (Lexapro), Fluoxetine (Prozac),Attorney Docket No. 2969833.001013Fluvoxamine (Luvox), Paroxetine (Paxil), Sertraline (Zoloft), Dapoxetine (Priligy), Indalpine (Upstene), Zimelidine (Zelmid), Alaproclate (GEA-654), Centpropazine, Cericlamine (JO-1017), Femoxetine (Malexil; FG-4963), Ifoxetine (CGP-15210), Omiloxetine, Panuramine (WY-26002), Pirandamine (AY-23713), Seproxetine ((S)-norfluoxetine), Desvenlafaxine (Pristiq), Duloxetine (Cymbalta), Levomilnacipran (Fetzima), Milnacipran (Ixel, Savella), Sibutramine (Meridia), Tramadol (Ultram), Venlafaxine (Effexor), Butriptyline (Evadyne), Clomipramine (Anafranil), Imipramine (Tofranil, Janimine, Praminil), Trimipramine, (Surmontil), Desipramine (Norpramin, Pertofrane), Dibenzepinf (Noveril, Victoril), Lofepramine§ (Lomont, Gamanil), Maprotiline (Ludiomil), Nortriptyline (Pamelor, Aventyl, Norpress), Protriptyline (Vivactil), Amitriptyline (Elavil, Endep), Amitriptylinoxide (Amioxid, Ambivalon, Equilibrin), Amoxapine (Asendin), Demexiptiline (Deparon, Tinoran), Dimetacrine (Istonil, Istonyl, Miroistonil), Dosulepin (Prothiaden), Doxepin (Adapin, Sinequan), Fluacizine (Phtorazisin), Imipraminoxide (Imiprex, Elepsin), Melitracen (Deanxit, Dixeran, Melixeran, Trausabun), Metapramine (Timaxel), Nitroxazepine (Sintamil), Noxiptiline (Agedal, Elronon, Nogedal), Pipofezine (Azafen / Azaphen), Propizepine (Depressin, Vagran), Quinupramine (Kevopril, Kinupril, Adeprim, Quinuprine), Amineptine (Survector, Maneon, Directim)- norepinephrine-dopamine reuptake inhibitor, Iprindole (Prondol, Galatur, Tetran) - 5-HT2 receptor antagonist, Opipramol (Insidon, Pramolan, Ensidon, Oprimol) - o receptor agonist, Tianeptine (Stabion, Coaxil, Tatinol), Maprotiline (Ludiomil), Mianserin (S isomer, R isomer, ora racemate comprising both isomers), (Tolvon), Mirtazapine (Remeron), Setiptiline (Tecipul), Amoxapine (Asendin), Quetiapine (Seroquel), Benzoctamine (Tacitin), Loxapine (Adasuve, Loxitane), Mazindol, Aptazapine (CGS-7525A), Esmirtazapine (ORG-50,081), Oxaprotiline (C 49-802 BDA), Ciclazindol, MAOIs such as Isocarboxazid (Marplan), Phenelzine (Nardil), Selegiline (Emsam), Tranylcypromine (Parnate), Benmoxin (Nerusil, Neuralex), Iproclozide (Sursum), Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida), Mebanazine (Actomol), Nialamide (Niamid), Octamoxin (Ximaol, Nimaol), Pheniprazine (Catron), Phenoxypropazine (Drazine), Pivalylbenzhydrazine (Tersavid), Safrazine (Safra), Minaprine (Cantor), Toloxatone (Humoryl), Moclobemide (Aurorix, Manerix, Moclamine), Brofaromine (Consonar), Caroxazone (Surodil, Timostenil), Eprobemide (Befol), Metralindole (Inkazan),Attorney Docket No. 2969833.001013Minaprine (Cantor), Pirlindole (Pirazidol), Toludesvenlafaxine (Ruoxinlin), Nefazodone (Serzone), Vilazodone (Viibryd), Vortioxetine (Trintellix, Brintellix), Serotonin antagonist and reuptake inhibitors (SARIs) such as Nefazodone (Dutonin, Nefadar, Serzone), Trazodone (Desyrel), Etoperidone (Axiomin, Etonin), Reboxetine (Edronax), Teniloxazine (Lucelan, Metatone), Viloxazine (Qelbree, formerly Vivalan), Atomoxetine (Strattera), PDC-1421 (BLI-1005), Norepinephrine-dopamine reuptake inhibitors (NDRIs) such as Bupropion (Wellbutrin, Elontril), Amineptine (Survector, Maneon), Nomifensine (Merital, Alival), OPC-64005, Amisulpride (Solian), Lurasidone (Latuda), Quetiapine (Seroquel), Agomelatine (Valdoxan), Brexanolone (allopregnanolone; Zulresso), Gepirone (Exxua), Opipramol (Insidon), Tianeptine (Stabion, Coaxil, Tianeurax), a-Methyltryptamine [aMT] (Indopan), Etryptamine (Monase), Indeloxazine (Elen, Noin), Medifoxamine (Cledial, Gerdaxyl), Oxaflozane (Conflictan), BTRX-246040 (LY-2940094), Aticaprant (JNJ-67953964, CERC-501, LY-2456302), Navacaprant (BTRX-335140; BTRX-140), Buprenorphine / samidorphan (ALKS-5461), CVL-354, JNJ-61393215 (JNJ-3215; Orexin-1) and Seltorexant (MIN-202, JNJ-42847922, JNJ-922);(v) said second pharmaceutical compound in the medicament comprises psilocybin or a pharmaceutically acceptable salt thereof;(vi) said second pharmaceutical compound in the medicament comprises mianserin (S isomer, R isomer, or a racemate comprising both isomers) or a pharmaceutically acceptable salt thereof;(vii) said second pharmaceutical compound in the medicament comprises lumateperone or a pharmaceutically acceptable salt thereof;(viii) said second pharmaceutical compound in the medicament comprises a psychedelic or stimulant compound, including but not limited to lysergic acid diethylamide (LSD), 3,4-Methylenedioxymethamphetamine (MDMA), ibogain and N,N-Dimethyltryptamine (DMT) and their structural analogues and pharmaceutically acceptable salts thereof, and the dosage thereof in the medicament is preferably sufficient to activate the Set B brain structures but low enough such that it does not appreciably evoke brain activity linked to in hallucinogenic and otherAttorney Docket No. 2969833.001013psychotomimetic perceptions, and / or is a dose which does not result in hallucinogenic and other psychotomimetic perceptions;(ix) the medicament comprises memantine, a structural analogue thereof, or pharmaceutically acceptable salt thereof and the dosage thereof is about 5 mg to about 50 mg;(x) the medicament comprises memantine, a structural analogue thereof, or pharmaceutically acceptable salt thereof and the dosage thereof is about 10 mg to about 40 mg;(xi) the medicament comprises memantine, a structural analogue thereof, or pharmaceutically acceptable salt thereof and the dosage thereof is about 20 mg to about 30 mg;(xii) the medicament comprises amantadine, a structural analogue thereof, or pharmaceutically acceptable salt thereof and the dosage thereof is about 20 to 1000 mg, or 50 to 500 mg, or 50 to 250 mg or is 50 mg;(xiii) the second compound comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salt thereof and the dosage thereof in the medicament is about 1 mg to about 20 mg;(xiv) the second compound comprises psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof in the medicament is about 2.5 mg to about 17.5 mg;(xv) the second compound comprises or consists of psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof and the dosage thereof in the medicament is about 5 mg to about 15 mg;(xvi) the second compound comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers), or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 20 mg to about 200 mg;(xvii) the second compound comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers), or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 40 mg to about 150 mg;Attorney Docket No. 2969833.001013(xviii) the second compound comprises or consists of mianserin (S isomer, R isomer or racemate comprising both isomers), or a pharmaceutically acceptable salt thereof and the dose thereof in the medicament is about 50 mg to about 100 mg;(xxix) the second compound comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the administered dose thereof is about 10 mg to about 100 mg;(xx) the second compound comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof is about 20 mg to about 50 mg;(xxi) the second compound comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof is about 35 mg to about 45 mg;(xxii) the second compound comprises or consists of lumateperone or a pharmaceutically acceptable salt thereof and the dose thereof is about 42 mg;(xxiii) the medicament comprises an oral dosage form, optionally an orally disintegrating form;(xxiv) the medicament comprises an intranasally or inhalatory administrable dosage form;(xxv) the medicament comprises a topically administrable dosage form, optionally a patch.

8. A method for treating dementia or mild cognitive impairment in a subject in need thereof, which treatment method comprises repeated treatments which each treatment comprises:(a) administering a dose of memantine or amantadine, a structural analogue or a pharmaceutically acceptable salt thereof, preferably which is sufficient to activate Set A brain areas in mouse brain using c-fos as a reporter of activity; and(b) administering psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers) or lumateperone, wherein the administered dose ofAttorney Docket No. 2969833.001013psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers) or lumateperone is preferably sufficient to activate Set B brain areas in mouse brain using c-fos as a reporter of activity but low enough such that it does not appreciably evoke brain activity linked to hallucinogenic and other psychotomimetic perceptions and / or does not elicit hallucinogenic and other psychotomimetic perceptions; optionally wherein each treatment (administration of memantine or amantadine, a structural analogue or a pharmaceutically acceptable salt thereof; and psilocybin or mianserin (S isomer, R isomer, or a racemate comprising both isomers) or a structural analogue or a pharmaceutically acceptable salt thereof or lumateperone is effected no more frequently than every 2, 3, 4, 5, 6 or 7 days rather than daily or twice daily in the case of memantine conventional daily memantine administration.

9. The method for treating dementia or mild cognitive impairment of claim 8, wherein (i) the subject has Alzheimer's disease;(ii) the subject has Lewy body dementia;(iii) the subject has vascular dementia;(iv) the subject has frontotemporal dementia;(v) the subject has mixed dementia (different forms of dementia);(vi) the method includes the administration of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof and the dosage of memantine, structural analogue thereof, or pharmaceutically acceptable salt thereof in each treatment is about 5 mg to about 50 mg, about 10 mg to about 40 mg, about 20 mg to about 30 mg;(vii) the method includes the administration of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof and the dosage of the dosage of amantadine, structural analogue thereof, or pharmaceutically acceptable salt thereof in each treatment is about 20 to 1000 mg, or 50 to 500 mg, or 50 to 250 mg or is 50 mg;(viii) the method includes the administration of psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salts thereof, and the dosage of psilocybin, a structural analogue thereof, or a pharmaceutically acceptable salt thereof ranges from about 1 mg to about 20 mg, about 2.5 mg to about 17.5 mg, or from about 5 mg to about 15 mg;Attorney Docket No. 2969833.001013(ix) the method includes the administration of mianserin (S isomer, R isomer, or a racemate comprising both isomers), a structural analogue thereof, or a pharmaceutically acceptable salt thereof, and the dosage thereof is about 20 mg to about 200 mg, about 40 mg to about 150 mg, or about 50 mg to about 100 mg;(x) the method includes the administration of lumateperone, a structural analogue thereof, or a pharmaceutically acceptable salts thereof, and the dosage of the dosage of lumateperone or a pharmaceutically acceptable salt thereof is about 10 mg to about 100 mg, about 20 mg to about 50 mg, or about 42 mg;(xi) the treatment slows the progression of dementia more than daily treatment with memantine or amantadine alone; or(xii) the method comprises one or more of the foregoing.

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