Table 3.

Pharmacological and clinical profile of repurposed medications for MDD.

Medication/Bioactive Compound Brand Name/ Ref	US-FDA Approval	Pharmacological Category/Mechanism of Action	Dosage	Significant Adverse Effects	Contraindications
Aripiprazole Abilify® [58]	Bipolar disorder, irritability associated with autistic disorder, MDD, TRD, schizophrenia, Tourette disorder	Partial agonist at the D2 and 5-HT1A receptors, an antagonist at the 5-HT2A/Second-generation (atypical) antipsychotic	MDD and TRD as an adjunctive treatment. Oral: 2 to 5 mg/day	>10%: decreased HDL-C, increased LDL-C, increased serum cholesterol, increased serum TG, weight gain, akathisia, headache, increased serum glucose, constipation, nausea, and vomiting	Hypersensitivity to aripiprazole or any component of the formulation
			Increase dose based on response in 5 mg increments up to a maximum of 15–20 mg/day
Brexanolone Zulresso® [59]	Postpartum depression (PPD) in adults	The mechanism of action is not fully understood, but is thought to be related to its positive allosteric modulation of GABAA receptors/GABAA receptor-positive modulator	Postpartum depression. IV: 0 to 4 h: 30 mcg/kg/h 4 to 24 h: 60 mcg/kg/h 24 to 52 h: 90 (or 60) mcg/kg/h 52 to 56 h: 60 mcg/kg/h 56 to 60 h: 30 mcg/kg/hour	>5%: sedation/somnolence, dry mouth, loss of consciousness, and flushing/hot flush	No contraindications were listed in the US-FDA monograph
Brexpiprazole Rexulti® [60]	MDD, schizophrenia	Partial agonist activity for 5-HT1A and D2 receptors and antagonist activity for 5-HT2A receptors/Second-generation (atypical) antipsychotic	MDD as an adjunct therapy to antidepressants. Oral: 0.5 mg or 1 mg once daily; titrate to 1 mg once daily, followed by 2 mg once daily; maximum daily dose: 3 mg	>10%: increased serum TG, weight gain, akathisia	Hypersensitivity (e.g., anaphylaxis, facial swelling, rash, urticarial) to brexpiprazole or any component of the formulation
Cabergoline Dostinex® [61]	Hyperprolactinemic disorders	Long-acting dopamine receptor agonist with a high affinity for D2 receptors, a potent 5-HT2B-receptor agonist/Ergot derivative	NA	Headache, dizziness, nausea	Known hypersensitivity to cabergoline, ergot derivatives, or any component of the formulation, uncontrolled hypertension; history of cardiac valvular disorders, history of pulmonary, pericardial, or retroperitoneal fibrotic disorders
Cannabidiol Epidiolex® [62]	Treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome in patients with 2 years of age and older	The precise mechanisms of its anticonvulsant effect in humans are unknown; however, it does not appear to exert its effects through interaction with cannabinoid receptors/Anticonvulsant, cannabinoid	NA	>10%: somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise and asthenia, rash, insomnia, sleep disorder and poor quality sleep, infections	Hypersensitivity to cannabidiol or any of the ingredients in Epidiolex®
Celecoxib CeleBREX® [63]	Acute pain, ankylosing spondylitis, juvenile idiopathic arthritis, osteoarthritis, primary dysmenorrhea, rheumatoid arthritis	Inhibits prostaglandin synthesis by decreasing COX-2 enzyme/Analgesic, nonopioid, NSAID, COX-2 selective	NA	Serious cardiovascular thrombotic events, myocardial infarction, and stroke increased the risk of serious gastrointestinal adverse events, including bleeding, ulceration, and perforation of the stomach or intestines	Hypersensitivity to celecoxib, sulfonamides, aspirin, other NSAIDs, or any component of the formulation
Cycloserine Seromycin® [64]	Tuberculosis, UTI	Inhibits bacterial cell wall synthesis by competing with amino acid (D-alanine) for incorporation into the bacterial cell wall/Antibiotic, antitubercular agent	NA	Cardiac arrhythmia, cardiac failure, coma, confusion, dizziness, drowsiness, dysarthria, headache, hyperreflexia, paresis, paresthesia, psychosis, restlessness, seizure, vertigo, skin rash, cyanocobalamin deficiency, folate deficiency, increased liver enzymes, hypersensitivity reaction, tremor	Hypersensitivity to cycloserine or any component of the formulation, epilepsy, depression, severe anxiety, or psychosis, severe renal insufficiency, excessive concurrent use of alcohol
Cyproheptadine Euro-Cyproheptadine®, PMS-Cyproheptadine® [65]	Allergic conditions	Potent antihistamine and serotonin antagonist with anticholinergic effects competes with histamine H1 receptors/First, generation histamine H1 antagonist, a piperidine derivative	NA	Extrasystole, hypotension, palpitations, tachycardia, ataxia, chills, confusion, dizziness, drowsiness, euphoria, excitement, fatigue, hallucination, headache, hysteria, insomnia, irritability, nervousness, neuritis, paresthesia, restlessness, sedation, seizure, vertigo, etc.	MAO inhibitor therapy, close angle glaucoma, stenosing peptic ulcer, symptomatic prostatic hypertrophy, bladder neck obstruction, pyloroduodenal obstruction, elderly, debilitated patients
Dextromethorphan Buckleys cough®, Creomulsion adult®, Cough DM®, Delsym®, etc. [66]	Cough suppressant	Decreases the sensitivity of cough receptors and interrupts cough impulse transmission by depressing the medullary cough center through sigma receptor stimulation/Antitussive, NMDA receptor antagonist	NA	Dizziness, drowsiness, nervousness, restlessness, gastrointestinal distress, nausea, stomach pain, vomiting	Concurrent administration with or within two weeks of discontinuing MAO inhibitor
Esketamine Spravato® [52]	TRD, MDD with suicidality	Nonselective, noncompetitive NMDA receptor antagonist/NMDA receptor antagonist	TRD. Intranasal: induction: 56 mg (may increase to 84 mg) twice weekly for 4 weeks Maintenance: on week 5, the previously established dose (56 or 84 mg) once weekly—on week 9 and onward continue effective dose (56 to 84 mg) once weekly or every 2 weeks MDD with suicidality. Intranasal: 84 mg twice weekly for 4 weeks; may reduce dosage to 56 mg twice weekly	>5%: dissociation, dizziness, nausea and vomiting, sedation, vertigo, hypoesthesia, anxiety, lethargy, increased blood pressure, feeling drunk	Hypersensitivity to esketamine, ketamine, or any of the excipients, Aneurysmal vascular disease or arteriovenous malformation, intracerebral hemorrhage
Etanercept Enbrel®, Erelzi®, Brenzys® [67]	Ankylosing spondylitis, plaque psoriasis, polyarticular juvenile idiopathic arthritis, psoriatic arthritis, rheumatoid arthritis	Binds TNF-α and blocks its interaction with cell surface receptors/Antirheumatic, disease-modifying, TNF-α blocking agent	NA	>10%: skin rash, diarrhea, positive ANA titer, antibody development, infection, injection site reaction, respiratory tract infections	Sepsis, hypersensitivity to etanercept, or any component of the formulation
Gabapentin Fanatrex FusePaq®, Gralise®, Gralise Starter®, Neuraptine®, Neurontin® [68]	Postherpetic neuralgia, seizures	Modulates the release of excitatory neurotransmitters which participate in epileptogenesis and nociception/Anticonvulsant, GABA analog	NA	>10%: dizziness, drowsiness, ataxia, fatigue, viral infections	Hypersensitivity to gabapentin or any component of the formulation
Infliximab Avsola®, Inflectra®, Remicade®, Renflexis® [69]	Ankylosing spondylitis, Crohn disease, plaque psoriasis, psoriatic arthritis, rheumatoid arthritis, ulcerative colitis	Binds to human TNF-α and interfere with endogenous TNF-α activity/Antirheumatic, disease-modifying, gastrointestinal agent, immunosuppressant agent, monoclonal antibody, TNF-α blocking agent	NA	>10%: abdominal pain, nausea, anemia, increased ALT, antibody development, increased ANA titer, abscess, infection, headache, cough, pharyngitis, sinusitis	Hypersensitivity to infliximab, murine proteins, or any component of the formulation
Ketamine Ketalar® [70]	Induction and maintenance of general anesthesia	Noncompetitive NMDA receptor antagonist (blocks glutamate)/General anesthetic	Depressive episodes and MDD. IV: 0.5 mg/kg administered over 40 min; 1 to 3 times weekly; may increase dose to 0.75 to 1 mg/kg. Treatment up to 6 weeks (optimal duration of therapy is unknown)	>10%: prolonged emergence from anesthesia (includes confusion, delirium, dreamlike state, excitement, hallucinations, irrational behavior, vivid imagery)	Hypersensitivity to ketamine or any component of the formulation, conditions in which an increase in blood pressure would be hazardous
Liothyronine Cytomel®, Triostat® [71]	Thyroid disorders, a myxedema coma	Manufactured form of the thyroid hormone triiodothyronine (T3) and exerts its many metabolic effects through control of DNA transcription and protein synthesis/Thyroid product	Antidepressant augmentation. Oral: 25 mcg/day; may be increased to 50 mcg/day after ~1 week. Dose ranges of 20 to 62.5 mcg/day have been studied in clinical trials.	1% to 10%: cardiac arrhythmia, tachycardia, hypotension, myocardial infraction	Hypersensitivity to liothyronine sodium or any component of the formulation, uncorrected adrenal insufficiency, untreated thyrotoxicosis, concurrent use with artificial rewarming of the patient
Lisdexamfetamine Vyvanse® [72]	ADHD, binge eating disorder	Converts to the active component dextroamphetamine, a noncatecholamine, sympathomimetic amines that cause a release of dopamine and NE from their storage sites/Central nervous system stimulant	NA	>10%: insomnia, decreased appetite, xerostomia, upper abdominal pain	Hypersensitivity to amphetamine products or any component of the formulation, concurrent use of MAO inhibitor, or within 14 days of the last MAO inhibitor dose
Lithium Lithobid® [73]	Bipolar disorder	Influence the reuptake of serotonin and/or NE and inhibit 2nd messenger systems involving phosphatidylinositol cycle, increasing glutamate clearance, enhancing the expression of neurotrophic factors (BDNF)/Antimanic agent	MDD and TRD as an adjunctive treatment. Oral: 300 to 600 mg/day in 1 to 2 divided doses; may increase every 1 to 5 days to a target dose of 600 mg to 1.2 g/day in divided doses. Clinical improvement may take up to 6 weeks.	The most significant adverse reaction is lithium toxicity; signs: diarrhea, vomiting, drowsiness, muscular weakness, and lack of coordination	Hypersensitivity to lithium or any component of the formulation
Metformin D-Care DM2®, Fortamet®, Glucophage®, Glumetza®, Riomet® [74]	Type 2 diabetes mellitus	Decreases hepatic glucose production, reduces intestinal absorption of glucose and improve insulin sensitivity, increases peripheral glucose uptake and utilization/Antidiabetic agent, biguanide	NA	>10%: diarrhea, flatulence, nausea and vomiting, dyspepsia, abdominal pain, lactic acidosis, vitamin B12 deficiency	Hypersensitivity to metformin or any component of the formulation, severe renal dysfunction, metabolic acidosis
Mecamylamine Vecamyl® [75]	Hypertension	Inhibits acetylcholine at the autonomic ganglia/Ganglionic blocking agent	NA	Orthostatic hypotension, syncope altered mental status, convulsions, fatigue, paresthesia, sedation decreased libido, anorexia, constipation, glossitis, intestinal obstruction, nausea, vomiting, xerostomia, urinary retention, tremor, weakness, blurred vision, mydriasis, pulmonary edema, pulmonary fibrosis	Hypersensitivity to mecamylamine or any component of the formulation; mild, moderate, labile hypertension, coronary insufficiency or recent myocardial infarction, uremia, glaucoma, organic pyloric stenosis, coadministration with antibiotics or sulfonamides
Minocycline CoreMino®, Minocin®, Minolira®, Solodyn®, Ximino® [76]	Different types of infections, acne, etc.	Inhibits bacterial protein synthesis by binding with the 30S and possibly the 50S ribosomal subunit/Antibiotic, tetracycline derivative	NA	1% to 10%: pruritus, urticaria, dizziness, fatigue, malaise, drowsiness, arthralgia, tinnitus	Hypersensitivity to minocycline, other tetracyclines, or any component of the formulation
Modafinil Provigil®, Alertec® [77,78]	Narcolepsy, obstructive sleep apnea, shift work sleep disorder	Increase dopamine in the brain by blocking dopamine transporters/Central nervous system stimulant	Antidepressant augmentation for MDD. Oral: 100 mg/day for 3 to 7 days, then increase to 200 mg/day; further, adjust dose based on response and tolerability up to 400 mg/day.	Headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, dyspepsia	Contraindicated in patients with known hypersensitivity to modafinil, armodafinil or its inactive ingredients
N-acetyl cysteine Acetadote®, Cetylev®, Parvolex® [79]	Acetaminophen overdose, mucolytic	Restoring hepatic glutathione, serving as a glutathione substitute, exerts mucolytic effects through its free sulfhydryl group, which opens up the disulfide bonds in the mucoproteins/Antidote, mucolytic agent	NA	>10%: autoimmune disease, anaphylactoid reaction	Hypersensitivity to acetylcysteine or any component of the formulation
Nimodipine Nymalize®, Nimotop® [80]	Subarachnoid hemorrhage	Inhibits calcium ion from entering the slow channels/Calcium channel blocker, dihydropyridine	NA	1% to 10%: decrease blood pressure, bradycardia, headache, nausea	Concomitant use with potent CYP3A4 inhibitors
Olanzapine ZyPREXA® [81]	Acute agitation/aggression associated with psychiatric disorders, bipolar disorder, unipolar MDD, TRD, schizophrenia	Combination of dopamine and serotonin type 2 receptor antagonism/Antimanic agent, second-generation (atypical) antipsychotic	MDD and psychotic depression as an adjunctive therapy. Oral: 5 mg once daily; may increase the dose in increments of 5 mg up to 20 mg/day. TRD as an adjunctive therapy. Oral: 5 mg once daily; may increase dose up to 20 mg/day.	Postural hypotension, constipation, weight gain, dizziness, personality disorder, akathisia, sedation, headache, increased appetite, abdominal pain, pain in extremity, fatigue, dry mouth, asthenia, drowsiness, tremor	No contraindication with ZyPREXA® monotherapy, caution in combination therapy with fluoxetine, lithium or valproate
			A fixed-dose of olanzapine/fluoxetine combination may be used instead of separate components.
Pergolide Permax®, Prascend® [82]	Adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson’s disease	Potent dopamine receptor agonist/Ergot derivative	NA	Dyskinesia, hallucinations, somnolence, insomnia, nausea, constipation, diarrhea, dyspepsia, rhinitis	Hypersensitive to pergolide mesylate or other ergot derivatives
Pioglitazone Actos® [83]	Type 2 diabetes mellitus	Improving target cell response to insulin, a potent and selective agonist for PPARγ/Antidiabetic agent, thiazolidinedione	NA	>10%: edema, hypoglycemia, upper respiratory tract infection	Hypersensitivity to pioglitazone or any component of the formulation, NYHA class III/IV heart failure
Phenytoin Dilantin®, Phenytek® [84]	Seizures (non-emergent use), status epilepticus	Stabilizes neuronal membranes and decreases seizure activity by modulating efflux or influx of sodium, shortens action potential in the heart/Anticonvulsant, hydantoin	NA	Nystagmus, ataxia, slurred speech, decreased coordination, somnolence, mental confusion	Hypersensitivity to phenytoin, other hydantoins, or any component of the formulation, concurrent use of delavirdine, history of prior acute hepatotoxicity attributable to phenytoin
Pramipexole Mirapex® [85]	Parkinson disease, restless legs syndrome	Nonergot dopamine agonist with specificity for the D2 subfamily dopamine receptor. Additionally, it binds to D3 and D4 receptors/Anti-parkinson agent, dopamine agonist	NA	>10%: orthostatic hypotension, drowsiness, extrapyramidal reaction, insomnia, dizziness, hallucination, headache, restless leg syndrome, abnormal dreams, nausea, constipation, dyskinesia, asthenia, accidental injury	Parkinson disease, restless legs syndrome
Pregabalin Lyrica®, Lyrica CR® [86]	Fibromyalgia, neuropathic pain associated with diabetic peripheral neuropathy or spinal cord injury, partial-onset seizures, postherpetic neuralgia	modulates calcium influx at the nerve terminals, thereby inhibits excitatory neurotransmitter release, may also affect descending noradrenergic and serotonergic pain transmission pathways from the brainstem to the spinal cord/Anticonvulsant, GABA analog	NA	Peripheral edema, Dizziness, drowsiness, headache, fatigue, weight gain, xerostomia, visual field loss, blurred vision	Hypersensitivity (e.g., angioedema) to pregabalin or any component of the formulation
Quetiapine SEROquel® [87]	Bipolar disorder, unipolar MDD schizophrenia	Antipsychotic activity through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2) antagonism/Second-generation (atypical) antipsychotic	MDD or nonpsychotic depression as an adjunctive therapy. Oral: 50 mg/day on days 1 and 2; increase to 150 mg/day on day 3. Usual dosage range: 150 to 300 mg/day.	>10%: increased blood pressure, orthostatic hypotension, tachycardia, decreased HDL-C, increased serum cholesterol, increased serum TG, weight gain	Hypersensitivity to quetiapine or any component of the formulation
			Doses up to 600 mg/day may be needed in psychotic depression. Nonpsychotic depression, monotherapy. Oral: 20 mg once daily; may be gradually increased up to 300 mg/day.
Risperidone Perseris®, RisperDAL®, RisperiDONE® [88]	Bipolar disorder, schizophrenia, bipolar mania, irritability associated with autistic disorder	High 5-HT2 and dopamine-D2 receptor antagonist activity/Antimanic agent, second-generation (atypical) antipsychotic	MDD and TRD, as an adjunctive therapy. Oral: 0.25 to 0.5 mg/day; may increase dose in increments of 0.25 to 1 mg/day every 3 to 7 days up to 3 mg/day. Usual effective dose: 1 to 1.5 mg/day.	Activating/sedating effects, angioedema, dyslipidemia, extrapyramidal symptoms, hematologic abnormalities, hyperglycemia, weight gain, hyperprolactinemia, neuroleptic malignant syndrome, orthostatic hypotension, QT prolongation, sexual dysfunction, temperature dysregulation	Hypersensitivity to risperidone, paliperidone, or any component of the formulation
Rosiglitazone Avandia® [89]	Type 2 diabetes mellitus	Improving target cell response to insulin, a potent and selective agonist for PPARγ/Antidiabetic agent, thiazolidinedione	NA	>10%: increased HDL-C, increased LDL-C, increased total serum cholesterol, weight gain	Hypersensitivity to rosiglitazone or any component of the formulation; NYHA class III/IV heart failure
Scopolamine (hyoscine) Transderm Scop®, Buscopan® [90]	Prevention of nausea and vomiting associated with motion sickness, recovery from anesthesia, and surgery	Blocks the action of acetylcholine; increases cardiac output, dries secretions, antagonizes histamine and serotonin/anticholinergic agent	NA	>10%: drowsiness, dizziness, xerostomia	Hypersensitivity to scopolamine, other belladonna alkaloids, or any component of the formulation, narrow-angle glaucoma
Statins, for example,Lovastatin Altoprev®, Mevacor® [91]	Adjunctive therapy to diet to reduce elevated total cholesterol, LDL cholesterol, Apo B and TG and to increase HDL-C in patients with primary hypercholesterolemia	competitively blocking the active site of HMG-CoA reductase/Antilipemic agent, HMG-CoA reductase inhibitor	NA	>10%: Increased creatine phosphokinase	Hypersensitivity to lovastatin or any component of the formulation, active liver disease or unexplained persistent elevations of serum transaminases, concomitant use of potent CYP3A4 inhibitors
Telmisartan Micardis® [92]	Cardiovascular risk reduction, hypertension	Nonpeptide AT1 angiotensin II receptor antagonist/Angiotensin II receptor blocker, antihypertensive	NA	1% to 10%: intermittent claudication, chest pain, hypertension, peripheral edema, dizziness, fatigue, headache, pain, dermal ulcer, diarrhea, abdominal pain, dyspepsia, nausea, UTI, back pain, myalgia, upper respiratory tract infection, sinusitis, cough, flu-like symptoms, pharyngitis	Known hypersensitivity (e.g., anaphylaxis, angioedema) to telmisartan or any component of the formulation, concurrent use of aliskiren in patients with diabetes
Valproic acid [93]	Bipolar disorder, focal (partial) onset and generalized onset seizures, migraine prophylaxis	Increased availability and enhance the action of GABA, blocks voltage-dependent Na channels/Anticonvulsant, antimanic agent, histone deacetylase inhibitor	NA	>10: headache, drowsiness, dizziness, insomnia, pain, nervousness, alopecia, nausea and vomiting, abdominal pain, diarrhea, dyspepsia, anorexia, thrombocytopenia, infections, tremor, weakness, diplopia, visual disturbance, flu-like symptoms, accidental injury	Hypersensitivity to valproic acid, divalproex, derivatives, or any component of the formulation, hepatic disease, urea cycle disorders, mitochondrial disorders caused by mutations in mitochondrial DNA
Vorinostat Zolinza® [94,95]	Cutaneous T-cell lymphoma	Inhibits HDAC enzymes, HCAC1, HDAC2, HDAC3, and HDAC6, which catalyze acetyl group removal from protein lysine residues/Antineoplastic agent, histone deacetylase inhibitor	NA	>10%: peripheral edema, fatigue, chills, dizziness, headache, alopecia, pruritus, hyperglycemia, weight loss, dehydration, diarrhea, nausea, dysgeusia, anorexia, xerostomia, constipation, vomiting, decreased appetite, proteinuria, thrombocytopenia, anemia, muscle spasm, increased serum creatinine, cough, fever, upper respiratory tract infection	Severe hepatic impairment
Zinc Galzin®, Wilzin® [96]	Wilson disease	Induces production of the copper-binding protein metallothionein in enterocytes/Chelating agent	NA	Gastric irritation increased serum amylase, increased serum lipase, increased serum ALP	Hypersensitivity to zinc acetate or any component of the formulation

ADHD: Attention-deficit/hyperactivity disorder; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ANA: Antinuclear antibodies; BDNF: Brain-derived neurotrophic factor; COX-2: Cyclooxygenase-2; CYP3A4: Cytochrome P450 3A4; GABA: Gamma-aminobutyric acid; HDAC: Histone deacetylase; HDL-C: High-density lipoprotein-cholesterol; HMG-CoA: 3-Hydroxy-3-Methyl-Glutaryl-CoA; LDL-C: Low-density lipoprotein-Cholesterol; MAO: Monoamine oxidase; MDD: Major depressive disorder; NA: Not available; NE: Norepinephrine; NMDA: N-Methyl-D-aspartate; NSAIDs: Nonsteroidal anti-inflammatory drugs; NYHA: New York Heart Association; PPAR: Peroxisome proliferator-activated receptor; TG: Triglyceride; TNF-α: Tumor necrosis factor-alpha; TRD: Treatment-resistant depression; US-FDA: The United States food and drug administration; UTI: Urinary tract infection.