A new combination therapy for treatment-resistant depression in patients with co-morbid metabolic syndrome

Abstract

The invention provides a composition and method of treating depression by administering to a patient in need of such treatment a combination of pindolol and fenofibrate in a ratio of about 3mg pindolol / 33mg fenofibrate and is useful in augmentation to treatment of depression.

Description

A NEW COMBINATION THERAPY FOR TREATMENT-RESISTANT DEPRESSION IN PATIENTS WITH CO-MORBID METABOLIC SYNDROMEAlexander B. Niculesc, MD, PhDFIELD OF THE INVENTION

[0001] Depression is a growing health care crisis, despite substantial investments in the treatment of depression, in antidepressant medications and therapy. Data do not indicate that depression has decreased in recent decades: on the contrary, it has increased. Although in 50% of cases antidepressants and quality of treatment reduced episode duration, treatment does not always improve long-term outcomes.

[0002] Among common types of depression, bipolar depression (BP) is particularly difficult to manage. . Conventional psychopharmacologic therapy may not address weight cycling and development of obesity leading to early cardiovascular events in BP subgroups. BP is characterized by chronic inflammation, oxidative stress, and disturbed energy metabolism. (Weight Gain During Treatment of Bipolar Disorder (BD) — Facts and Therapeutic Options Front. Nutr., 11 June 2019 Sec. Obesity Volume 6 - 2019 | https: / / doi.Org / 10.3389 / fnut.2019.00076).

[0003] Antidepressants used in treatment of humans fall into a number of classes or mechanisms of action, and some have mechanisms that are not fully understood. Moreover, it is unclear how a particular patient may respond to any specific antidepressant. The result has been that many patients are forced to ‘try and see" over a period of time to determine how, or if, any specific antidepressant works for them. The outcome of this method of treatment is many patients may take several courses of treatment before settling on an antidepressant that is empirically more effective. Moreover, a lot of the antidepressants and other medications used to treat depression lead to weight gain and metabolic syndrome as a side-effect. MindX had developed diagnostics aimed at identifying patient response well before the “try and see” period historically used to define a responder or non-responder to various treatments. Alexander B. Niculescu, Helen Le-Niculescu. Precision medicine in psychiatry: biomarkers to the forefront. Neuropsychopharmacology: 2021 Sept 28; doi: 10.1038 / s41386-021 -01183-3. The blood biomarkers are used by MindX Sciences to assess patient’s disease severity, future risk, match them to medications, and monitor response to treatment. In particular for mood disorders such as depression and bipolar disorders, the underlying methodology is described in Le-Niculescu, Roseberry, et al. Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs1.State of the Art Paradigms of Treatment are Imperfect

[0004] Established methods of treating with various classes of drugs include: SSRIs (selective serotonin reuptake inhibitors) such as fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), citalopram (Gelexa) and escitalopram (Lexapro); SNRIs — (serotonin and norepinephrine reuptake inhibitors, such as duioxetme (Cymbalta, Drizalma Sprinkle), venlafaxine (Effexor XR), desvenlafaxine (Pristiq) and levomilnacipran (Fetzima(; Tricyclic Antidepressants, such as imipramine, nortriptyline (Pamelor), amitriptyline, doxepin and desipramine (Norpramin); Monoamine Oxidase Inhibitors (MAOIs), such as tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan); and a number of atypical antidepressants, such as Bupropion, trazodone, mirtazapine (Remeron), voriioxetine (Trinteliix), vilazodone ( Viibryd) and others — ail modulate levels of neurotransmitters. However, the normalization of neurotransmitters cause other secondary issues.

[0005] White antidepressants may improve symptoms, that often do not address stress or other internal conditions that could allow healing. In fact, even once a patient is stable on an antidepressant; many patients still suffer depressive symptoms. Some patients end up on more than one drug to manage symptoms. Among the commonly used antidepressants many (e.g., the SSRIs) have unwieldy side effects, such as weight gain, and sexual side-effects.

[0006] For exampie, some commonly used drugs in treating bipolar depression cause weight gain and can contribute to metabolic syndrome. This is especially true for SSRIs (serotonin reuptake inhibitors). It is not uncommon to gain several pounds and end up displaying clinical characteristics of metabolic syndrome as a resuit of being treated with antidepressants.

[0007] In fact, metabolic syndrome is often associated with depression. ('Is increased antidepressant exposure a contributory factor to the obesity pandemic?” Transl Psychiatry (2016) 6, e759; doi:10.1038 / tp.2016.25) Without speculating as to cause or effect, an augmentation strategy aimed at metabolic syndrome in treatment- resistant depression (TP.D) may be useful for the following reasons: Improvements in metabolic syndrome / syndrome X may result in improvements in brain energy metabolism and mitochondrial function and mood disorders2. Most individuals with TRD have a lifestyle that increases metabolic syndrome / syndrome X risk or occurrence3. Most individuals with TRD are on medications that increase metabolic syndrome risk or occurrence'1.Metabolic Syndrome may be Associated with Treatment or Depression

[0008] Key features of metabolic syndrome / syndrome X are hypertension, tachycardia and excessive response to stress ), hyperlipidemia, inflammation.

[0009] Generally, metabolic syndrome is characterized by a) a large waist (at least 35 inches (89 centimeters) for women and 40 inches (102 centimeters) for men), b) high triglyceride level 150 milligrams per deciliter (mg / dL), or 1 .7 millimoles per liter (mmoi / L), or higher, c) reduced "good" or HDL(high-density lipoprotein) cholesterol Less than 40 mg / dL (1 .04 mmol / L) in men or less than50 mg / 'dL (1 .3 mmol / L) in women d) increased blood pressure — 130 / 85 millimeters of mercury (mm Hg) or higher and e) elevated fasting blood sugar — 100 mg / dL (5.6 mmol / L) or higher.Diagnostics Shorten the “try and see” Timeframe for Patients

[0010] Emerging diagnostics can shorten this “try and see” timeframe by determining if patients will be responders to a drug early in the “try and see” period. It has long been hoped that this set of diagnostics may one day identify new antidepressants, including those that avoid weight gain and the metabolic syndrome issue. It would be advantageous to find an adjunct therapy to treat depression and the symptomoiogy related to it and its treatment.

[0011] Failed drugs have been tested for other new uses or purposes. It has long been hoped that some of these may be useful in treating depression.Pindolol

[0012] Pindolol (CAS 13523-86-9) is a beta blocker (Adrenergic beta-Antagonist) and is used alone or in combination with other medications to treat high blood pressure. At clinically relevant doses, it works by relaxing blood vessels and slowing heart rate to improve blood flow and decrease blood pressure. Pindolol was granted FDA approval on September 3, 1982. Pindolol is a racemic misture, and exists in the S and R form. Doses are at least 5 mg per day and range upward from there. However, this drug has a short half-iife, which is a disadvantage for cardiovascular applications: Most beta blockers need long half-life to be clinically preferred. In addition, some beta-blockers are associated with causing depression because of their action It would be counterintuitive to attempt to use this class of compounds to treat the malady that they may actually be creditied with causing.

[0013] Fibrates (including Fenofibrate)Fibrates, such as fenofibrates (salts of fenofibric acid CAS Number: 4201 7-89-0), are used together with a proper diet to reduce and treat high cholesterol and triglyceride (fat-like substances) levels in the blood. This may help prevent the development of pancreatitis (inflammation or swelling of the pancreas) caused by high levels of triglycerides in the blood. It works by increasing the breaking down and removal of triglycerides from the blood. Although fibrates in general (including fenofibrate) are effective at lowering levels of triglycerides, VLDL cholesterol, total cholesterol, and apolipoprotein C -III , they do not appear to reduce the risk of cardiovascular events or cardiovascular / non -cardiovascular mortality, even when used in combination with a statin. Treatment with fibrates, a widely used class of iipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations. Recent investigations indicate that the effects of fibrates are mediated, at least in part, through alterations in transcription of genes encoding for proteins that control lipoprotein metabolism. Fibrates activate specific transcription factors belonging to the nuclear hormone receptor superfamily, termed peroxisome proliferator-activated receptors (PPARs). The PPAR-aipha formmediates fibrate action on HDL cholesterol levels via transcriptional induction of synthesis of the major HDL apolipoproteins, apoA-l and apoA-fl. Fibrates lower hepatic apoC-lll production and increase lipoprotein lipase-mediated lipolysis via PPAR. Fibrates stimulate cellular fatty acid uptake, conversion to acyl-CoA derivatives, and catabolism by the beta-oxidation pathways, which, combined with a reduction in fatty acid and triglyceride synthesis, results in a decrease in VLDL production. The long term use of fenofibrate in severely burned patients may improve hyperglycemia and insulin resistance, as well as improve wound healing, and reduce apoptosis, and oxidative stress. (“Role of the PPAR-a agonist fenofibrate in severe pediatric burn” Burns Volume 38, Issue 4, June 2012, Pages 481 -486). Normal doses clinically used for reduction off VLDL range from 40 to 200 mg daily. These drugs include Tricon, Lofibra, Antara, Triglide, Lipofen, and Fenoglide.SUMMARY OF THE INVENTION

[0014] By the use of MindX biomarker screening toois, MindX has serendipitously discovered that Pindolol and FenofibrateveSurprisingly, it has been found that acombinations of Pindoioi and a fibrate do treat depression.: Moreover, patient diagnostics that the inventor has used further correlate with observed symptomology, showing that patients ’ responses are predicted by the diagnostics. Surprisingly, the doses of each component of this combination are lower that the standard clinical doses currently used in therapy. The inventor has found that a preferred combination, MTX-303, a mixture of Pindodoi (a beta blocker) and Fenofibrate (used for hyperlipidemia), when administered as a once daily at bedtime as an oral treatment is useful as an ‘add on” or adjunct therapy for treatment-resistant depression. This combination enhances the effects of antidepressant therapy, and may help address side effects of existing antidepressant therapy (such asmetabolic syndrome). Depression symptoms as defined by the PHQ-9 show that treatment with the invention in the preferred ratio of 3mg pindolol / 33mg fenofibrate is effective as an adjunctive therapy for depression. Surprisingly, the ratio and amount provides effective treatment in amounts lower than the routine doses used in medicine for either of these compounds. Further, it is shown that 6mg pindolol / 66mg fenofibrate is also effective for more serious cases.DETAILED DESCRIPTION OF THE INVENTIONPharmaceutical Compositions

[0015] In one aspect, the present disclosure relates to a pharmaceutical composition comprising a physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof: and a compound disclosed herein. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, flavoring agents, and the like may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, sulfated aliphatic alcohols, and the like may be used as surface active agents: sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasiiicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate- methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.

[0016] The term ‘pharmaceutical composition” refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, ni trie acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0017] The term “carrier” defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism

[0018] The term “diluent” defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0019] The term “physiologically acceptable” defines a carrier or diluent that does not abrogate the biological activity and properties of the compound. The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compound of formula I may be found in “Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa., 18th edition, 1990.

[0020] In some embodiments, the invention may be formulated in any acceptable pharmaceutical form, in some embodiments, it may be preferred to provide a solid dosage form. In some embodiments, thecombination of the invention is provided as rapidly dissolving dosage forms. In some embodiments, the formulations have one or more of: improved friability, compression, dissolution, uniformity, dissolvabiiity , paiatability , and the like. Also, in some embodiments, the formulations may be designed for rapid onset, greater and / or more rapid plasma levels, and the like.

[0021] Some embodiments provide a pharmaceutical composition comprising the combination of the invention or pharmaceutically acceptable salts of either or both of the actives therein, and at least one excipient, wherein the combination of the invention comprises a suitable amount to provide the claimed dosage form with the excipients comprising a suitable amount to provide a dosage form that is convenient for a patient to take. In some embodiments, excipients may be selected from pharmaceutically acceptable excipients, for example in a solid dosage form. Such excipients include microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, poloxamer 188, sodium starch glycolate, and croscarmellose sodium.Excipients

[0022] Acceptable excipients for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Handbook of Pharmaceutical Excipients, 5th edition (Raymond C Rowe, Paul J Sheskey and Sian C Owen, eds. 2005), and Remington: The Science and Practice of Pharmacy, 21 st edition (Lippincott Williams & Wilkins, 2005), each of which is hereby incorporated in its entirety. The term 'carrier” material or "excipient” herein can mean any substance, not itself a therapeutic agent, used as a carrier and / or diluent and / or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule, tablet, film coated tablet, caplet, gel cap, pill, pellet, bead, and the like suitable for oral administration. Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, weting agents, polymers, lubricants, glidants, coatings, sweetens, solubilizing agens substances added to mask or counteract a disagreeable taste or odor, flavors, colorants, fragrances, and substances added to improve appearance of the composition.

[0023] The compositions and formulations can include any other agents that provide improved transfer, delivery, tolerance, and the like.

[0024] The compositions and formulations can include any other agents that provide improved transfer, delivery, tolerance, and the like. These compositions and formulations can include, for example, powders, pastes, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as Lipofectin™), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax.

[0025] Any of the foregoing mixtures can be appropriate in treatments and therapies in accordance with the disclosure herein, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. "Pharmaceutical excipient development: the need for prechriical guidance." Regul. Toxicol. Pharmacol. 32(2):210-8 (2000), Charman W N "Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts.” J. Pharm. Sci. 89(8):967-78 (2000), and the citations therein for additional information reiated to formulations, excipients and carriers weii known to pharmaceutical chemists.Disintegrants

[0026] In some embodiments, disintegrants are used, for example, to facilitate tablet disintegration after administration, and are generally starches, clays, celluloses, algins, gums, or crosslinked polymers. Suitable disintegrants include, but are not limited to, crosslinked polyvinylpyrrolidone (PVP-XL), sodium starch glycoiate, alginic acid, methacrylic acid DYB, microcrystailine cellulose, crospovidone, polacriiine potassium, sodium starch glycolate, starch, pregelatinized starch, croscarmellose sodium, and the like. If desired, the pharmaceutical formulation can also contain minor amounts of nontoxic auxiliary substances such as ’wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium sulfosuccinate, polyoxyethylene sorbitan fatty acid esters, etc. and the like.

[0027] Any ranges used herein are exampies of preferred ranges. One of ordinary skil! in the art would recognize additional disintegrants and / or amounts of disintegrants that can be used in the formulations described herein. As would be recognized by one of ordinary skill in the art, when incorporated Into the formulations disclosed herein, the amounts of the major filler(s) and / or other excipients can be reduced accordingly to accommodate the amount of disintegrant added in order to keep the overall unit weight of the tablet unchanged.Coatings

[0028] In some embodiments, the formulations can include a coating, for example, a film coating. Where film coatings are involved, coating preparations can include, for example, a film-forming polymer, a plasticizer, or the like. Also, the coatings can include pigments and / or opacifiers. Non-limiting examples of film-forming polymers include hydroxypropyl methylcellulose, hydroxypropyi cellulose, methylcellulose, polyvinyl pyrrolidine, and starches. Non-limiting examples of plasticizers include polyethylene glycol, tributyl citrate, dibutyl sebecate, castor oil, and acetylated monoglyceride. Furthermore, non-limiting examples of pigments and opacifiers include iron oxides of various colors, lake dyes of many colors, titanium dioxide, and the like.Diluents

[0029] In some embodiments, diluents are used, and are generally selected from one or more of the compounds sucrose, fructose, glucose, galactose, lactose, maltose, invert sugar, calcium carbonate, lactose, starch, microcrystalline cellulose, lactose monohydrate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, a pharmaceutically acceptable polyol such as xylitol , sorbitol, maltitol, mannitol, isomalt and glycerol, polydextrose, starch, or the like, or any mixture thereof.Surfactants

[0030] In some embodiments, surfactants are used. The use of surfactants as wetting agents in oral drug forms is described in the literature, for example in H. Sucker, P. Fuchs, P. Speiser, Pharmazeutische Technologie, 2nd edition, Thieme 1989, page 260. it is known from other papers, such as published in Advanced Drug Delivery Reviews (1997), 23, pages 163-183, that it is also possible to use surfactants, inter alia, to improve the permeation and bioavaiiabi lity of pharmaceutical active compounds. Examples of surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, zwitterionic surfactants and a mixture thereof. Preferably, the surfactants is selected from the group consisting of poiy(oxyethylene) sorbitan fatty acid ester, poiy(oxyethylene) stearate, poiy(oxyethylene) alkyl ether, poiyglycoiated glyceride, poly(oxyethylene) caster oil, sorbitan fatty acid ester, poioxamer, fatty acid salt, bile salt, alkyl sulfate, lecithin, mixed micelle of bile salt and lecithin, glucose ester vitamin E TPGS (D-a- tocopheryl polyethylene glycol 1000 succinate), sodium lauryl sulfate, and the like, and a mixture thereof.Glidants

[0031] In some embodiments, glidants are used. Examples of glidants which may be used include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and calcium phosphate, or the like, and mixtures thereof.

[0032] Pharmaceutical compositions for use m accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

[0033] Any of the foregoing mixtures can be appropriate in treatments and therapies in accordance with the disclosure herein, provided that the active ingredient in the formulation is not inactivated by the formulation and the formulation is physiologically compatible and tolerable with the route of administration. See also Baldrick P. “Pharmaceutical excipient development: the need for preclinical guidance.” P.egul. Toxicol. Pharmacol. 32(2):210-8 (2000), Charman W N “Lipids, lipophilic drugs, and oral drug delivery-some emerging concepts." J. Pharm. Sci. 89(8):967-78 (2000), and the citations thereinfor additional information related to formulations, excipients and carriers well known to pharmaceutical chemists.

[0034] In some embodiments, one or more, or any combination of the listed excipients can be specifically included or excluded from the formulations and / or methods disclosed herein.

[0035] In some embodiments, the composition further comprises one or more lubricants, which are known in the art to be useful in ease of manufacture and storage of dosage forms. In some embodiments, one or more lubricants comprise up to about 5% w / w of the composition. In some embodiments, the one or more lubricants are selected from pharmaceutically acceptable lubricants, for example, such lubricants may be selected from the group comprising of sodium lauryl sulfate, magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil, glyceryl behenate, and polyethylene glycol or others. In some embodiments, one lubricant is magnesium stearate, used in an amount of about 0.5% to about 1 .5% w / w, or as appropriate to provide proper release in manufacture and storage. In some embodiments, a preferred lubricant is sodium lauryl sulfate, in such cases sodium lauryl sulfate is used in an amount of about 0.1 % to about 5% w / w. In some embodiments, the composition further comprises a glidant. In some embodiments, the glidant is selected from pharmaceutically acceptable giidents, one of these, for example, is colloidal silicon dioxide, though other glidants may be pharmaceutically acceptable. Preferably, a glidant is used to facilitate manufacturing, and preferably comprises about 0.01% to about 1 .5% w / w of the composition. In some embodiments, the composition further comprises one or more surfactants.

[0036] In some embodiments, the composition is in the form of a tablet, a film coated tablet, a capsule, a gel cap, a caplet, a pellet, or a bead. In some embodiments, the composition is in the form of a film coated tablet.

[0037] Some embodiments provide a tablet having a suitable hardness. Such hardness is generally accepted as at least about 4 Kiloponds (Kp), to at least about 16 Kp. One Kilopond is a standard unit of hardness, equal to 9.807 Newtons (N) or 1 .4 Strong Cobb Units (SCU).

[0038] Some embodiments provide a pharmaceutical composition comprising the combination of the invention, or pharmaceutically acceptable salts of either or both of the actives therein, wherein the composition having at least an 85 percent release of the combination of the invention, or the salt of the combination of the invention, withi n 45 minutes using U.S. Pharmacopeia (USP) type II dissolution Apparatus I at 50 rpm or 60 rpm in 0.1 N HCI, which mimics gastric conditions. In some embodiments, the composition has at least an 85 percent release rate at 30 minutes.

[0039] Some embodiments provide a method of treating chronic or persistent depression, comprising identifying an individual in need of such treatment, and administering the pharmaceutical compositions ofthe combination of the invention. In some embodiments, the method of treatment will benefit from objective diagnostics, such as a ciinicaily validated questionnaire (e.g., the American Psychological Association’s Patient Health Questionnaire - 9 (https: / / www.aDa.org / depression-guideline / patient-health- questionnaire.pdf) or body fluid diagnostics (Such as those offered by MindX Sciences (https : / / www. https: / / mindxsciences.com / bioodtests / ), etc.

[0040] Some embodiments provide a method of making a pharmaceutical composition comprising blending together the combination of the invention, and one or more excipients.

[0041] The following are definitions of terms used in this specification. The initial definition provided for a group or term herein applies to that group or term throughout the present specification, individually or as part of another group, unless otherwise indicated.

[0042] The combination of the invention includes salts of the actives, an active being pindolol and / or a fibrate. Reference to a combination of the invention herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)". as employed herein, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. In addition, when the combination of the invention contains both a basic moiety and an acidic moiety, zwitterions (“inner salts”) may be formed and are included within the term “salt(s)” as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, e.g., in isolation or purification steps which may be employed during preparation. Salts of the combination of the invention may be formed, for example, by reacting an active with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.Actives in the composition

[0043] Actives that are a basic moiety may form salts with a variety of organic and inorganic acids. Exemplary acid addition salts include acetates (such as those formed with acetic acid or trihaloacetic acid, for example, trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisuifates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid), methanesulfonates (formed with methanesulfonic acid), 2- naphthaienesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (such as those formed with sulfuric acid), sulfonates (such as those mentioned herein), tartrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates, acidic amino acids, such as aspartate, and the like.

[0044] Actives that are an acidic moiety may form salts with a variety of organic and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as benzathines, dicyclohexylamines, hydrabamines (formed with N,N- bis(dehydroabietyl)ethyienediamine), N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and salts with basic ammo acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyi sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyi sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.

[0045] Prodrugs and solvates of the actives in the combination of the invention are also contemplated. The term “prodrug" denotes a compound which, upon administration to a subject, undergoes chemical conversion by metabolic or chemical processes to yield an active used in the combination of the invention, or a salt and / or solvate thereof. Solvates of the invention are preferably hydrates. Any tautomers are also contemplated.

[0046] All stereoisomers of the actives as used in the combination of the invention, including enantiomeric forms (which may exist even in the absence of asymmetric carbons, e.g., atropisomers) and diastereomeric forms, are contemplated. Individual stereoisomers of the combination of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the combination of the invention can have the S or R configuration.Detailed Description of the Invention

[0047] MTX-3030 is combination treatment or a “polypill" (combination treatment) preferably used as an “add-on" treatment, composed of two existing compounds that are FDA approved for other indications.The preferred dosage is 3mg Pindoiol / 33 mg Fenofibrate. The ratio of these actives appears to provide a clear advantage, both over each individual active, and apparently other ratios. It is possible that multiples of this dose (e.g., 6mg Pindolol / 66 mg Fenofibrate, etc.).

[0048] Solid dosage forms, such as capsules, tablets, powders and solid formulations are the preferred formulations. Such formulations of these actives into the combination of the invention is accomplished via state of the art formulation techniques available to the skilled artisan. It is also possible to formulate in semisolid, liquid, and other formulations.

[0049] Preferably dosing is oral. Preferably, dosage is one dose at bedtime daily. Without being bound by any theory, it appears advantageous to dose at bedtime due to higher inflammation overnight and perhaps enhanced adrenergic effect experienced at night: it may be that blunting this effect enhances itsability to treat treatment-resistant depression and bipolar depression . In addition, the half-life of the actives (especially Pindolol having a half-life of 3-4 hours) allow for a dose at bedtime to clear by morning, and avoid residual side effects including lethargy, fatigue, and hypotension during waking hours.

[0050] The skilled artisan or practicing clinician will be aware that monitoring kidney and liver functions may be advantageous in the administration of any new drug to a patient, in this case, it may be useful to modify dose based on kidney function as the actives in the invention are processed via the kidney.However, it is noted that the invention uses doses at levels well below current dosing, and regimens less frequently than currently common.

[0051] MTX-303 was initially identified as a consequence of empirical drug repositioning analyses using RNA blood biomarkers signatures for mood disorder (Le-Niculescu, H. et al. Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics. and repurposed drugs. Mol Psychiatry 26, 2776-2804, doi:10.1038 / s41380-021 -01061 -w (2021 ).

[0052] It has also been found that the preferred combination of this invention, MTX-303, also is supportive of a metabolic psychiatry approach beneficial as an augmentation strategy in treatment- resistant depression (TRD) for the following reasons: improvements in metabolic syndrome / syndrome X may result in improvements in brain energy metabolism and mitochondrial function and mood disorders (Pan, L. A. et al. Metabolic features of treatment-refractory major depressive disorder with suicidal ideation. Trans! Psychiatry 13, 393, doi:10.1038 / s41398-023-02696-9 (2023)); Most individuals with treatment-resistant depression have a lifestyle that increases metabolic syndrome / syndrome X risk or occurrence (Chan, K. L., Cathomas, F. & Russo, S. J. Central and Peripheral Inflammation Link Metabolic Syndrome and Major Depressive Disorder. Physiology (Bethesda) 34, 123-133, doi:10.1152 / physiol.00047.2018 (2019)); Most individuals with treatment-resistant depression are on medications that increase metabolic syndrome risk or occurrence (Sarnyai, Z. & Palmer, C. M. Ketogenic Therapy in Serious Mental Illness: Emerging Evidence. Int J Neuropsychopharmacol 23, 434-439, doi:10.1093 / ijnp / pyaa036 (2020)).

[0053] It is likely that this invention and this approach may be useful more broadly that TRD, in depression in general, bipolar depression, stress disorders (e.g., PTSD, alcohol and other sedative addictions), and in prevention of psychiatric disease in people with a family history of (or recently exposure to) trauma. Without being bound by any theory, it is possible that the invention essentially “removes the irritant” that maintains the depression or other psychological disorder. Thus this supplementation or augmentation potentiate, modulate or allow remission or recovery by blunting any adrenergic response, enhancing the reduction or effect of stress. Without being bound by any theory, it is possible that the invention blunts the adrenergic response, and associated manifestations thereof.

[0054] The invention is also expected to treat depression and associated metabolic syndrome, which is common in such cases. This may be the case whether the metabolic syndrome is due to lifestyle or to medications being used to treat the condition: As used herein Metabolic Syndrome (also known as “Syndrome X”) typically presents as obesity, high blood pressure, high blood triglycerides (hyperlipidemia), low levels of HDL cholesterol and insulin resistance. While not ail presents requiring treatment for depression exhibit all five symptoms of Metabolic Syndrome, at least the first three of these- ■obesity, high blood pressure, high blood triglycerides (hyperlipidemia) tend to be common, and indicate that these are good candidates for therapy of the invention.

[0055] In addition, for effective treatment it is preferable to identify “fast” vs. “slow” metabolizers of drugs. This is generally done using the cytochrome P450 test: The cytochrome P450 (CYP450) test, also known as a GYP test, analyzes a blood sample to determine how well the body metabolizes certain drugs. The test can help mental health professionals prescribe psychiatric medications and tailor drug therapy for patients that aren't responding to pharmacotherapy. The GYP test is well known in the art. Preferably those identified as fast metabolizers (who may be less responsive to standard doses or regimens) may have their timing of doses closer together, or may have their dose increased.Examples

[0056] Having generally described the invention, the following examples describe the inventions use and experience with it.Example 1

[0057] A middle aged man, undergoing treatment for refractory bipolar depression with complicating stressful situations sought further treatment. Though stable, he still exhibited symptoms. He also presented with metabolic syndrome and hypertension. He was currently taking fenofibrate (45 mg daily fibrofibric acid). The patient was prescribed 5 mg pindolol (an added active), and reported improvement in mood, and also improved his weight. The clinically validated PHQ-9 questionnaire (which relates to depressive symptoms) showed the patient’s progress.Example 2

[0058] A Patient presented with depression, but (though stable as to treatment) still exhibited symptoms. The patient was already prescribed and actively using 5 mg pindolol daily for hypertension. The patient was provided fenofibrate in a ratio according to the invention, and showed improvement per PHQ-9.Example 3

[0059] Patient is a middle aged, overweight, a diagnosis of bipolar depression, and though stable as to treatment is not responding completely to exisitng anti-depressant treatment. The patient sought further treatment for depressive symptoms. The patient was prescribed 3mg pindolol and 33mg Fenofibrate, and showed rapid improvement. PHQ-9 showed the progress of this patient.Example 4

[0060] A small investigator clinical trial is designed: The inclusion criteria require subjects between 18 and 70 years of age with a diagnosis of depression and being treated via a stable dose of an antidepressant, but still experiencing depressive symptoms. Subject exhibits or has a diagnosis of metabolic syndrome. Any potential subject with a diagnosis of paranoia or schizophrenia in addition to depression is excluded. The period of participation tor each subject is approximately 18 weeks. The trial shows that the combination of the invention provides significant improvement.Example 5

[0061] Using the recruitment and inclusion criteria and time period of Example 4, two cohorts are recruited.

[0062] Cohort A: Dose escalation of Pindolol: Take blood at baseline and one-week intervals to measure biomarkers. Escalate dose at weekly intervals until dose reached that alter blood levels. Determine symptomology using PHQ-9 each week.

[0063] Cohort B: Dose escalation of Fenofibrate: Take blood at baseline and one-week intervals to measure biomarkers. Escalate dose at 'weekly intervals until dose reached that alter blood levels. Determine symptomology using PHQ-9 each week.

[0064] Cohort C will receive Combination for 6 weeks, washout for 6 weeks and receive placebo for 6 weeks.[006b] Cohort D will receive placebo for 6 'weeks washout for 6 weeks and receive combination for 6 weeks.

[0066] Biomarkers and depression symptoms as above between placebo and active dosing periods for each subject.Example 6

[0067] Using the methodology of Example 5, at the target dose, treat with both drugs for 6 weeks.Primary endpoints will be improvements in PHQ9 and MADRAS, and secondarily, differences in biomarkers between placebo and active periods for each subject, not as a population, but can compare a) baseline, b) lead-in with single agent and c) dual drug periods.

[0068] Having described how to make and use the invention.

Claims

What is claimed is:1 . A method of treating depression by administering to a patient in need of such treatment a combination of pindolol and fenofibrate.

2. A method of treating depression by administering to a patient in need of such treatment a combination of pindolol and fenofibrate in a ratio of about 3mg pindolol / 33mg fenofibrate or a combination in a similar ratio thereof.

3. A method of treating depression by administering to a patient in need of such treatment a combination of pindolol and fenofibrate in a ratio of about 3mg plndolol / 33mg fenofibrate or a combination in a similar ratio thereof, wherein the patient is undergoing treatment for depression.

4. A method of treating depression by administering to a patient in need of such treatment a combination of pindolol and fenofibrate in a ratio of about 3mg pindolol / 33mg fenofibrate or a combination in a similar ratio thereof, wherein the patient is undergoing treatment for depression, and augmentation of treatment is desired.

5. A method of treating refractory depression by administering to a patient in need of such treatment a combination of about 3mg pindolol / 33mg fenofibrate or about 6mg pindolol / 66mg fenofibrate.

6. The method of any preceding claim wherein the depression is bipolar depression.

7. The method of any preceding ciaim wherein the depression is refractory depression.

8. The method of any preceding claim wherein a dose is administered daily at bedtime.

9. The method of any preceding claim wherein the patient has metabolic syndrome or Syndrome X.

10. The method of any preceding claim wherein the patient also has one or more symptoms of metabolic syndrome.1 1 . The method of any preceding claim wherein the patient currently being treated with an antidepressant.

12. The method of any preceding claim wherein treatment augments treatment with an antidepressant.

13. The method of any preceding claim wherein the antidepressant is an SSRI, SNRI.

14. The method of any preceding claim wherein pindolol is S-pindolol.