by Waguih William IsHak, MD; Ashley Meyer, BS; Luiza Freire, MD; Jayant Totlani, DO; Nathalie Murphy, MD; Sabrina Renteria, MD; Mohamed Salem, BS; Tiffany Chang, MS; Rasha Abdelsalam MD; Rida Khan, MD; Thomas Chandy, MS, DO; Thomas Parrish, BS; Drew Hirsch, BA candidate; Bhumika Patel, DO candidate;
Alexander J. Steiner, PsyD; Sarah Kim, MD; Rebecca Hedrick, MD;
Robert N. Pechnick, PhD; and Itai Danovitch, MD

Drs. IsHak, Murphy, Renteria, Abdelsalam, Khan, Kim, Hedrick, and Danovitch; Mr. Salem; Ms. Chang; Mr. Parrish; and Mr. Hirsch are with Cedars-Sinai Health System in Los Angeles, California. Dr. IsHak is also with David Geffen School of Medicine at UCLA in Los Angeles, California. Ms. Meyer is with University of California Irvine, School of Medicine in Irvine, California. Dr. Freire is with Faculdade Pernambucana de Saude in Recife, PE, Brazil. Drs. Totlani and Pechnick and Ms. Patel are with Western University of Health Sciences in Pomona, California. Dr. Chandy is with Loma Linda University in Loma Lina, California. Dr. Steiner is with Executive Mental Health, Inc. in Los Angeles, California.

Funding: No funding was provided for this article.

Disclosures: The authors have no conflicts of interest relevant to the content of this article.

Innov Clin Neurosci. 2024;21(7–9):27–47.

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Abstract

Objective: This systematic review provides an overview of psychiatric medications in the late stages of development (Phase III clinical trials) as of June 1, 2024. It details the mechanisms of action, efficacy, dosing, and adverse effects of these medications.

Methods: We searched the PubMed database for Phase III studies of psychiatric medications published until June 1, 2024, using the keywords “psychiatric” OR “psychopharm*” AND “medic*” OR “pharm*”. Our review encompassed medications currently undergoing Phase III clinical trials and those that have completed Phase III but are awaiting approval from the United States Food and Drug Administration (FDA). We independently analyzed the identified studies and reached a consensus on the medications to be included in this systematic review.

Results: As of June 1, 2024, a total of 89 pipeline drug trials were identified, including nine for schizophrenia, five for bipolar disorders, 25 for depressive disorders, 11 for anxiety disorders, five for post-traumatic stress disorder (PTSD), one for obsessive compulsive disorder (OCD), two for eating disorders, two for sleep-wake disorders, three for sexual dysfunctions, one for substance-related and addictive disorders, 22 for neurocognitive disorders, and three for neurodevelopmental disorders, specifically attention deficit hyperactivity disorder (ADHD).

Conclusion: The psychiatric medications in the pipeline as of June 1, 2024, demonstrate significant promise in treating psychiatric disorders.

Keywords: Psychiatric medications, Phase III clinical trials, schizophrenia, bipolar disorder, depression, anxiety, psychiatric disorders, FDA

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Psychiatric medications undergoing United States Food and Drug Administration (FDA) evaluation progress through three distinct clinical trial phases. Phase I aims to establish safety profiles and determine appropriate dosages and typically involves 20 to 100 healthy volunteers or individuals with the target disease/condition over a study duration of several months. Phase II assesses efficacy and side effects and typically extends to several hundred participants with the target condition over several months to years. Phase III determines efficacy and safety in a larger population, typically 300 to 3,000 participants diagnosed with the condition, over 1 to 4 years.¹ The purpose of this systematic review is to examine the psychiatric medications in Phase III clinical trials up to June 1, 2024, delineating their mechanisms of action, evidence of efficacy, dosing protocols, and adverse effects. Our goal is to offer clinicians a comprehensive and user-friendly review of these emerging psychiatric medications, equipping them with valuable insights to prepare for potential new treatment options upon regulatory approval.

Methods

Studies of Phase III psychiatric medications published until June 1, 2024, were identified from the PubMed database using the keywords: “psychiatric” OR “psychopharm*” AND “medic*” OR “pharm*”. The authors independently conducted a focused analysis and reached a consensus on the medications to include in this systematic review. Key findings were extracted and summarized from the full text and tables of the selected studies.

Results

Overview. Psychiatric medications undergoing development in Phase III trials were fully described. Medications currently in Phase III studies and those that have completed Phase III and are awaiting FDA approval were included (Table 1). We organized the list of psychiatric medications by psychiatric disorder according to the nomenclature of the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5). An overview of medications for each psychiatric disorder grouped by characteristics and indications is accompanied by an alphabetically organized summary table containing the medication’s generic, as well as other, names, mechanism of action, indication(s) being tested in Phase III, route and dosage, and notes for clinicians, including effects on sedation, weight/lipids, extrapyramidal tract, prolactin, sexual dysfunction, and QTc.

Schizophrenia. Recent Phase III trials have showcased promising investigational medications targeting cognitive and psychotic symptoms in schizophrenia, each with distinct mechanisms of action and pharmacological profiles.

Brilaroxazine (oxaripiprazole, RP-5063), administered at dosages ranging from 5 to 100mg daily, acts as a partial agonist at dopamine D2, D3, D4, and serotonin receptors (5-HT1A, 5-HT2A, 5-HT2B), also blocking 5-HT6 and 5-HT7 receptors. It is being studied for its potential to treat both cognitive and psychotic symptoms, showing minimal impact on weight, lipids, prolactin levels, blood pressure, or electrocardiogram (EKG). The most commonly reported side effects include somnolence and akathisia.^2,3

Iclepertin (BI-425809), a potent glycine transporter 1 (GlyT1) inhibitor, has demonstrated safety and good tolerance in both healthy volunteers and patients with schizophrenia. By inhibiting GlyT1, iclepertin raises glycine levels in the cerebrospinal fluid, thereby enhancing N-methyl-D-aspartate (NMDA) receptor activity and improving glutamatergic signaling. This is crucial for neural synchrony and synaptic plasticity, which are often impaired in schizophrenia due to NMDA receptor hypofunction.^4,5 Early studies indicate that it improves memory performance and electroencephalogram (EEG) parameters, with clinical trials showing significant cognitive improvements at daily doses of 10mg and 25mg, and it was well tolerated at doses up to 75mg. Phase III trials are now assessing its long-term effects on daily functioning.^3,6

Xanomeline plus trospium (KarXT) is a promising treatment for schizophrenia, combining the effects of xanomeline and trospium to target psychotic symptoms effectively while minimizing common side effects. Xanomeline, an M1/M4 muscarinic agonist, can readily cross the blood-brain barrier (BBB) and stimulate muscarinic receptors in the brain, addressing both negative and potentially positive symptoms of schizophrenia. Trospium, a peripheral and nonselective muscarinic antagonist, cannot cross the BBB and thus acts primarily outside the brain. By blocking peripheral muscarinic receptors, trospium reduces side effects that xanomeline might cause in other organs. Clinical trials have demonstrated that KarXT significantly improves outcomes in patients with schizophrenia, including marked improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function, compared to placebo. Additionally, KarXT enhances working memory and linguistic cognition without causing sedation, weight gain, or extrapyramidal side effects often associated with other antipsychotic medications.^7,8

Ulotaront (SEP-363856), a trace amine-associated receptor 1 (TAAR1) and serotonin 5-HT1A receptor agonist administered in 25 to 75mg daily doses, has been noted for its lack of extrapyramidal side effects and minimal impact on weight and metabolism, maintaining stable prolactin levels.^9–12 Over 92 percent of the drug is excreted in urine, with no clinically meaningful drug interactions involving ulotaront or its metabolites and cytochrome P450 (CYP) enzymes or transporters.¹³

Lumateperone is already FDA-approved for treating adult schizophrenia and bipolar disorder, either as monotherapy or adjunctive therapy with lithium or valproate. Currently, it is under investigation for pediatric use. This antipsychotic targets dopaminergic, serotonergic, and glutamatergic pathways. It acts as a presynaptic partial agonist and postsynaptic antagonist at dopamine D2 receptors, reducing dopamine in the synaptic cleft while blocking postsynaptic D2 receptors. It requires only 40-percent D2 receptor occupancy, which results in a lower risk of extrapyramidal side effects. Lumateperone also antagonizes 5-HT2A receptors and augments NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor activity in the prefrontal cortex, contributing to its antipsychotic and antidepressant effects. Clinical trials have shown its efficacy in treating acute schizophrenia with minimal metabolic side effects and potential benefits for negative symptoms. For pediatric use, it is usually taken at 42mg daily, with the most common side effects being dizziness, nausea, and dry mouth.^14–16

The extended-release subcutaneous formulation of olanzapine (TEV-749) is currently being studied as a potential treatment for schizophrenia. This medication acts as an antagonist for dopamine D2 and serotonin 5-HT2A and is administered via subcutaneous injection once a month. The study is comparing three different doses, but the specific milligram amounts have not been disclosed yet. Safety and side effect data for this treatment are still awaiting publication.¹⁷

Raloxifene, an estrogen receptor modulator, is under investigation for its potential to alleviate negative symptoms in postmenopausal women with schizophrenia. Studies have indicated cognitive benefits, particularly in working memory, with a daily oral dose of 120mg. However, weight gain has been noted as a potential side effect of this treatment.^18,19

Roluperidone (MIN-101) acts on serotonin 5-HT2A and alpha-1A adrenergic receptors and is known for its lack of extrapyramidal side effects and its negligible impact on weight, metabolic function, and prolactin levels. Administered at doses of 32 to 64mg per day, this medication has exhibited significant efficacy in addressing negative symptoms in schizophrenia.^20,21

Vortioxetine, a 5-HT multimodal agent, has been approved for major depressive disorder (MDD) since 2013. It is being investigated for cognitive enhancement and action on negative symptoms in patients with schizophrenia at doses of 5 to 20mg daily. Animal studies have shown it improves cognitive and social behaviors, and clinical studies indicate it improves social and physical anhedonia, particularly when combined with olanzapine. Adverse effects include nausea, constipation, potential mania activation, and serotonin syndrome.^22–27

This condensed overview provides a grouped perspective on investigational medications, offering insight into their shared characteristics and potential applications in schizophrenia. For further details, Table 2 presents comprehensive information on each medication.

Bipolar disorders. Pipeline medications for the treatment of bipolar disorders were found to have both traditional and novel mechanisms.

Amisulpride plus esamisulpride (SEP-4199) combines a dopamine D2 and serotonin 5-HT7 antagonism to target bipolar I depression. Administered orally in dosages ranging from 200 to 400mg daily, clinical trials report somnolence and extrapyramidal effects, such as akathisia, minimal changes in weight and lipids, elevated prolactin levels, and QTc prolongation.²⁸

Armodafinil (Nuvigil), a sympathomimetic and dopamine reuptake inhibitor, is also being studied as an adjunctive therapy for depressive symptoms in bipolar disorder with a daily dose of 150mg.  The medication is generally well tolerated, with common side effects being headache and nausea.^29,30

Brexpiprazole (Rexulti) is being investigated for bipolar I depression at dosages of 2 to 4mg daily. It is a partial agonist at D2 and 5-HT1A receptors and an antagonist at 5-HT2A receptors. This medication offers potential benefits with reduced risks of extrapyramidal symptoms and hyperprolactinemia, compared to other antipsychotics. Clinical trials have shown its effectiveness in reducing depressive symptoms in bipolar I disorder, with potential side effects including weight gain, somnolence, and akathisia. Brexpiprazole has a long half-life and stable pharmacokinetics, making it easier for patients to adhere to the treatment regimen. The drug is metabolized by CYP2D6 and CYP3A4, necessitating monitoring for potential interactions.^14,31

The combination of cycloserine plus lurasidone (NRX-101, Cyclurad), acting as an antagonist at the glycine coreceptor of the NMDA receptor plus antagonist at D2, 5-HT2A, and 5-HT7 receptors, is being explored for the maintenance of remission in bipolar depression with suicidal ideation. Administered at a daily combined dose of 950mg (D-cycloserine) and 66mg (lurasidone), it has shown low-to-moderate sedation, elevated prolactin levels, and extrapyramidal effects, with minimal impact on weight and lipids and no clinically relevant QTc prolongation.³²

Lastly, lumateperone is being investigated for its effectiveness in treating major depressive episodes associated with bipolar I or II disorder in pediatric patients aged 10 to 17 years. It is taken orally at a dosage of 42mg daily and generally causes side effects such as dizziness, nausea, sleepiness, and dry mouth.^14,33

For further details on each medication, refer to Table 3.

Depressive disorders. As of June 1, 2024, 25 medications were in the pipeline for approval for the treatment of depressive disorders and their associated symptoms. Many of the medications reviewed showed similar mechanisms of action, notably 5-HT serotonin agonism and antagonism and kappa-opioid receptor antagonism. However, several medications introduce novel or distinct mechanisms of action.

Adjunctive therapy involving a combination of citalopram, chlordiazepoxide, and pioglitazone (used for Type 2 diabetes) has been evaluated for significant depression treatment at a daily dose of 15mg. However, the tolerability and safety of this combination remains a concern. This medication combines a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist (pioglitazone) with a selective serotonin reuptake inhibitor (citalopram) and a benzodiazepine (chlordiazepoxide). Pioglitazone might cause weight gain in patients with diabetes and increase the risk of heart failure and edema, while chlordiazepoxide has shown similar effects in animal models.^34–37

Medications such as rapastinel, seltorexant, toludesvenlafaxine, psilocybin, racemic ketamine, and zuranolone introduce distinct mechanisms of action.

Rapastinel (GLYX-13) is an NMDA receptor modulator with partial agonist properties at the glycine site. It is administered intravenously at doses of 225mg, 450mg, or 900mg on a weekly or biweekly basis. Early trials demonstrated rapid and sustained antidepressant effects in individuals with treatment-resistant depression (TRD) without causing psychotomimetic effects. However, it failed to meet primary or secondary endpoints in subsequent Phase III trials. Ongoing studies are evaluating its long-term antidepressant effects in individuals with MDD, both as an additional treatment and as a standalone therapy. The drug has been shown to have no sedative effects or significant impact on QTc interval, and in animal studies, it has exhibited the potential to alleviate memory deficits.^38–41

Seltorexant (MIN-202, JNJ-42847922) antagonizes orexin-2 receptors, which regulate wakefulness and arousal. It is being investigated for the treatment of MDD and insomnia with daily doses of 10 to 40mg. Common adverse events included somnolence, headache, and nausea, with some participants experiencing elevated liver enzymes and sleep issues, leading to discontinuation.^42,43

Toludesvenlafaxine (ansofaxine), a serotonin-norepinephrine-dopamine reuptake inhibitor (SNDRI), is being evaluated for MDD at oral doses ranging from 40 to 160mg daily. Past studies have shown potential impacts on liver function with elevated bilirubin and alanine transferase levels.^44,45 

Psilocybin, a 5-HT1A/5-HT2A receptor agonist, is presently under investigation for MDD. The compound is typically administered orally in doses ranging from 20 to 30mg. Notably, studies have demonstrated the efficacy of psilocybin in reducing weight gain and altering the trajectory of obesity in animal models.^46–48

Two formulations of racemic ketamine, an NMDA receptor antagonist, are currently under study for the treatment of MDD and TRD: Wafermine, a sublingual racemic ketamine, and subcutaneous racemic ketamine. Wafermine is administered sublingually at doses of 300 to 450mg/kg at various frequencies. It shows promise in treating MDD but is associated with elevated blood pressure and the potential to induce hypertension.⁴⁹ Subcutaneous racemic ketamine is administered at doses of 0.5 to 1mg/kg for TRD. Possible side effects might include hallucinations, dissociation, sedation, disorientation, and insomnia.⁵⁰

Pramipexole, a full dopamine agonist FDA-approved for Parkinson’s disease and restless legs syndrome, demonstrates marked selectivity for D3 receptors. It is implicated in mood regulation and has shown neuroprotective and anti-inflammatory properties, suggesting utility in depression treatment, specifically for anhedonia.^51,52 It is taken orally at 0.125mg twice daily and might cause side effects, such as nausea, dizziness, headache, fatigue, insomnia, constipation, hallucinations, orthostatic hypotension, impulse control disorders, and daytime sleepiness.^51–54

Kappa opioid receptors are targeted by aticaprant and navacaprant, acting as antagonists. Aticaprant (JNJ-67953964) is being studied as an adjunctive therapy for MDD with moderate-to-severe anhedonia. It is taken orally at a 10mg daily dose and has no significant effects on sedation, sexual dysfunction, weight gain, or QTc interval activity.^55,56 Navacaprant (BTRX-335140, NMRA-140) is under investigation as a monotherapy for MDD, administered orally at 80mg daily. In Phase II trials for mild-to-moderate MDD, significant improvements were noted at four weeks, but not sustained at eight weeks, compared to placebo. This compound also improved working memory and executive functioning in animal models.⁵⁷

Buprenorphine plus samidorphan (ALKS 5461) combines a kappa opioid receptor agonist with a mu opioid receptor partial agonist. It is being explored for TRD, taken sublingually in doses ranging from 4mg plus 4mg to 8mg plus 8mg daily. Previous studies on opioid dependence treatment suggest possible adverse effects, including sexual dysfunction and premature ejaculation in more than 80 percent of participants.^58,59

Cariprazine and lurasidone offer promising results in monotherapy for MDD through antagonism at D2 and 5-HT receptors. Cariprazine (Vraylar) is being studied at daily doses of 1 to 4.5mg. It is a partial agonist at central D2 and 5-HT1A receptors, with antagonist activity at the 5-HT2A receptor. It is already FDA-approved for schizophrenia and bipolar disorder, and it was also approved in December 2022 as adjunctive therapy for MDD.^14,60 Lurasidone (Latuda), which antagonizes 5-HT2A/D2 receptors with additional 5-HT7 antagonism, is being tested at doses ranging from 20 to 60mg daily, with infrequent mild sedation reported.^14,32

Solriamfetol and ulotaront both target MDD by acting as agonists at TAAR1. Solriamfetol (Sunosi), a dopamine and norepinephrine reuptake inhibitor and TAAR1 agonist, is being tested at an oral dose of 300mg for MDD. It is approved for managing excessive daytime sleepiness due to obstructive sleep apnea (OSA) or narcolepsy, with common side effects including headache, nausea, and decreased appetite.^61,62 Ulotaront (SEP-363856), a TAAR1 agonist with additional agonism at 5-HT1A, has been studied for treating psychotic symptoms in schizophrenia and as an adjunctive therapy in MDD, with a daily dose of 25 to 75mg and no significant side effects.^10–12

Several novel therapies are under investigation, primarily focusing on modulating the serotonin system. Pimavanserin (Nuplazid), an inverse agonist at serotonin 5-HT2A and 5-HT2C receptors, is being studied for MDD, dementia-related psychotic symptoms, and residual psychotic symptoms in schizophrenia. The recommended daily dose is 20mg. It is already FDA-approved for Parkinson’s disease-related psychosis and might affect QTc interval.^63–67 Lumateperone tosylate (Caplyta) is a 5-HT2A antagonist being investigated for use in MDD. Administered at 42mg daily, it has a low risk of sedation, extrapyramidal side effects, weight gain, prolactin changes, and QTc prolongation.^14,33,68 Mitizodone is a 5-HT receptor antagonist and a 5-HT1A receptor partial agonist being investigated as a monotherapy for MDD and is administered orally at doses ranging from 10 to 40mg daily. Additional research is needed to fully assess the adverse effects of this medication.⁶⁹

Esmethadone, estradiol plus progesterone, ezogabine, and zuranolone represent innovative approaches targeting complex symptoms of depression, including treatment resistance and anhedonia, through unique mechanisms of action.

Esmethadone, an NMDA receptor antagonist, is being studied for TRD with a recommended daily oral dose of 25 to 50mg. Its predecessor, methadone, was known to contribute to weight gain, so further observation of esmethadone for similar effects is warranted.^70,71

Estradiol plus progesterone, acting as an estrogen receptor agonist and progesterone receptor agonist, is being investigated for the prevention of depressive symptoms in peri-and postmenopausal female patients. It is administered orally with a dosage of 0.45mg of estrogen and 200mg of progesterone daily. Reported side effects include nausea, changes in bleeding levels, musculoskeletal pain, weight gain, and headaches.^72,73

Ezogabine (retigabine), a positive allosteric modulator of KCNQ2 and KCNQ3 potassium channels, is being assessed for anhedonia and other depressive symptoms, with an oral dosing regimen titrated up to 900mg/day. Previously approved for focal onset seizures, ezogabine use has been associated with dizziness, confusion, and headaches.⁷⁴ Zuranolone, a GABA_A receptor agonist, is being tested as an adjunctive therapy for MDD at a daily oral dose of 30 to 50mg. It was recently FDA-approved for postpartum depression. Sedation was a frequent side effect in over five percent of participants in clinical trials.⁷⁵

Extensive studies confirm the proinflammatory status in depression, with causal links to neurotransmitter dysregulation.⁷⁶ Some clinical studies have demonstrated the positive benefits of celecoxib and minocycline in improving depressive symptoms. Celecoxib inhibits cyclooxygenase-2 (COX-2) and is currently being investigated as a potential monotherapy or adjunctive therapy for MDD. It is typically prescribed at a daily oral dose of 200 to 400mg and increases the risk of cardiovascular events and gastrointestinal bleeding, with potential renal and hepatic toxicity.^77–81 Minocycline, a tetracycline antibiotic with antineuroinflammatory properties, is being studied as an adjunctive treatment for MDD at 200mg daily. It can penetrate the BBB, contributing to its neuroprotective potential. However, its use is associated with gastrointestinal effects, photosensitivity, and potentially severe autoimmune reactions.^82,83

For more detailed information on each medication, refer to Table 4.

Anxiety disorders. As of June 1, 2024, there were 11 medications in the pipeline for approval in the treatment of anxiety disorders. While the majority are being investigated for generalized anxiety disorder (GAD), some also target symptoms associated with social anxiety disorder.

Several medications under investigation focus on modulating the serotonin system and GABA receptors. Pregabalin and fasedienol work on or modulate GABA receptors, while vortioxetine, quetiapine, and agomelatine act on serotonin (5-HT) family receptors, among others.

Agomelatine, a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist, is being studied for the treatment and relapse prevention of GAD. Administered orally at doses of 25 to 50mg daily, it has shown no effects on weight gain, sexual dysfunction, or sedation, although a single case study observed prolonged QTc intervals.^84,85

Pregabalin (Lyrica), a GABA analogue and voltage-gated calcium channel modulator, is being explored both as an adjunctive therapy and monotherapy for GAD at doses of 300 to 600mg daily. Side effects include sedation, weight gain, and potential sexual dysfunction, such as loss of libido, erectile dysfunction, and anorgasmia.^86,87

Quetiapine extended release (Seroquel XR), a multimodal agent affecting histamine, dopamine, 5-HT, and norepinephrine receptors, is being evaluated for GAD. The typical dose ranges from 50 to 300mg daily. Significant sedation is noted, but it has less of an impact on weight, lipids, extrapyramidal symptoms, prolactin, and QTc intervals.^88,89

Fasedienol (Aloradine, PH94B), which potentially acts on GABA receptors, is being assessed for acute anxiety in patients with social anxiety disorder. It is administered intranasally as needed, up to four doses daily, with side effects similar to placebo.^90,91

Other medications, including ABIO-08/01, buagafuran, SR58611A (Amibegron), toludesvenlafaxine (ansofaxine), ulotaront (SEP-363856), and vortioxetine (Trintellix), focus on specific neurotransmitter pathways.

ABIO-08/01, which inhibits GABA and glutamate-gated chloride channels, is being tested for GAD symptoms. Administered orally at doses of 10 to 40mg daily, it has shown improvements in cognitive functioning and psychomotor activity without significant adverse effects.⁹²

Buagafuran, which modulates central monoamine neurotransmitters and inhibits neuronal delayed rectifier potassium channels, is being studied for GAD treatment at doses of 30 to 120mg daily. Extensive CYP3A and CYP2E metabolism is noted, with dizziness being the most common side effect in early trials.⁹³

SR58611A (Amibegron) introduces a distinct mechanism of action through selective beta-3 adrenoceptor agonism and is administered orally at doses of 0.3 to 10mg/kg daily for the treatment of GAD. Previous studies have reported no adverse effects on cognitive functioning, dependence, or alcohol interaction.⁹⁴

Toludesvenlafaxine (ansofaxine), a first-in-class triple monoaminergic reuptake inhibitor (TRI) blocking the reuptake of serotonin, dopamine, and norepinephrine, is being evaluated for GAD at doses of 80 to 160mg daily. Common adverse events include nausea, vomiting, headache, and drowsiness. Sexual functioning should be monitored due to changes in prolactin and testosterone levels observed in preclinical studies.^44,45

Ulotaront (SEP-363856), a TAAR1 and serotonin 5-HT1A receptor agonist, is being studied for GAD at doses of 25 to 75mg daily. Initial trials have reported somnolence and gastrointestinal symptoms, but no extrapyramidal side effects, changes in weight, metabolic effects, prolactin changes, or QTc interval prolongation were reported.^10,95

Vortioxetine (Trintellix), a 5-HT multimodal agent, is being investigated for relapse prevention in GAD. It is administered orally at 10 to 20mg daily. Dose-dependent sexual dysfunction has been reported, ranging from 16 to 34 percent, compared to 14 to 20 percent with placebo.^22,23,27,96

For more detailed information on each medication, refer to Table 5.

Post-traumatic stress disorder (PTSD). Five medications for PTSD were in the approval pipeline as of June 1, 2024, targeting various mechanisms to address symptoms of PTSD, including sleep disturbances and comorbid conditions, such as hepatitis C infection.

Cyclobenzaprine (TNX-102 SL) is an alpha-1 adrenergic, H1-histaminergic, M1-muscarinic, and 5-HT2A receptor antagonist being studied for its potential to address sleep disturbances related to PTSD, especially those affecting sleep-dependent memory consolidation. This substance is administered sublingually at doses of 5 to 6mg daily and is primarily recognized as a muscle relaxant for sudden-onset and acute muscle spasms. Clinical trials have reported sedative effects associated with its use.⁹⁷

Prazosin, an alpha-1 adrenergic receptor antagonist, is under investigation for its efficacy in treating PTSD, especially nightmares and sleep disturbances, and PTSD associated with alcohol use disorder. It is administered orally at 1 to 20mg daily, and common side effects include dizziness, headache, drowsiness, lack of energy, weakness, palpitations, and nausea.^98,99

Propranolol, a beta-adrenergic receptor blocker, is under investigation for the treatment of PTSD in children. It is taken orally at doses ranging from 20 to 120mg daily. Commonly reported adverse effects include bradycardia, sedation, thrombocytopenic purpura, and bronchospasm. Notably, a trial has observed sex differences in the reduction of PTSD symptoms, with male patients showing more reduction in symptoms compared to female patients.¹⁰¹

Glecaprevir/pibrentasvir is a combination of a NS3/4A protease inhibitor (glecaprevir) and a NS5A protein inhibitor (pibrentasvir), being tested for PTSD in patients infected with hepatitis C. Administered orally as three tablets once daily (glecaprevir 100mg + pibrentasvir 40mg), headache and fatigue are the primary noted side effects.^102,103

3,4-methylenedioxy-methamphetamine (MDMA), known for its action as a releaser of serotonin, dopamine, and noradrenaline, is being evaluated for PTSD treatment. Administered orally at doses of 75 to 125mg daily, it was granted breakthrough therapy designation as assisted therapy for PTSD in 2017. Although risks of dependence, neurotoxicity, and cardiovascular toxicity have been described, recent PTSD trials have not reported these issues.^104,105

For more details on these medications, refer to Table 6.

Obsessive compulsive disorder. As of June 1, 2024, only one medication has advanced to Phase III clinical trials for treating obsessive compulsive disorder (OCD). Troriluzole functions as a glutamate release inhibitor and a glutamate glial uptake stimulator taken orally at 200 to 280mg daily doses. Clinical trials have not reported significant concerns about sedation, weight gain, sexual dysfunction, or QTc interval changes, making it a promising treatment for OCD without notable adverse effects.^106,107 See Table 7 for more details.

Feeding and eating disorders. Two medications currently in Phase III trials target binge eating disorder by utilizing different mechanisms of action.

Naltrexone plus bupropion is an FDA-approved medication for obesity. Early results show potential therapeutic use in treating binge eating disorder. It combines naltrexone, an opioid receptor blocker, and bupropion, a drug that affects norepinephrine and dopamine levels. The medication is taken orally in doses of naltrexone 16mg and bupropion 180mg daily. Common side effects include nausea, vomiting, constipation, dizziness, and headache. Serious side effects might include seizures, high blood pressure, and increased heart rate.¹⁰⁸

Solriamfetol (Sunosi) is FDA-approved for excessive daytime sleepiness due to OSA or narcolepsy and is under Phase III investigation for binge eating disorder in adults. It is a dopamine and norepinephrine reuptake inhibitor and TAAR1 agonist, taken orally once per day at 150mg or 300mg doses. Common side effects include headache, nausea, and decreased appetite.^109,110

For a comprehensive overview, please refer to Table 8.

Sleep-wake disorders. As of June 1, 2024, only two medications were identified in the pipeline for approval in the treatment of sleep-wake disorders.

Sodium oxybate (FT218, Lumryz), which acts as a GABA_B receptor agonist, is under investigation for treating cataplexy and narcolepsy symptoms. It is taken orally at 6 to 9g nightly doses. However, it is under FDA review due to concerns about adverse effects, including the risk of dependence, leading to its classification as a Schedule III controlled substance with a restricted safety program for prescription.^111,112

Quilience (Mazindol ER), a triple-reuptake inhibitor (SNDRI) and partial agonist for orexin (hypocretin)-II receptors, is also being studied for narcolepsy and comorbid cataplexy. Mazindol has shown improvements in narcolepsy symptoms when taken orally at a dose of 3mg nightly. However, it did not demonstrate improvements in cataplexy or sleep paralysis at this dose. At a higher dose of 6mg, it exhibited similar efficacy to dextroamphetamine 50mg for treating narcolepsy, with fewer adverse effects.¹¹³

For further details, refer to Table 9.

Sexual dysfunctions. Three medications are currently in Phase 3 trials for the treatment of sexual dysfunction, specifically erectile disorder. These medications utilize different mechanisms of action to address this condition.

Dutasteride-tamsulosin combines two active components: dutasteride, which blocks the conversion of testosterone to dihydrotestosterone (DHT), a key androgen involved in prostate gland development and growth, and tamsulosin, an alpha-blocker that relaxes the muscles in the bladder and prostate. This combination is administered orally at 0.5mg dutasteride and 0.4mg tamsulosin once daily. Common side effects include dizziness, abnormal ejaculation, decreased libido, and impotence.^114,115

OnabotulinumtoxinA works by blocking the presynaptic release of the neurotransmitter acetylcholine at the neuromuscular junction. It is being tested for erectile disorder through intracavernous injections of 100 units once daily. Reported side effects include mild penile pain on injection and mild penile pain for three days following injection, with no systemic effects noted.^116,117

Sildenafil oral film, a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase 5 (PDE5), is also under investigation for erectile disorder. This medication is taken orally at daily doses of 25 to 100mg. In trials involving healthy volunteers, a small number of patients experienced mild-to-moderate headaches and vomiting.^118,119

For more detailed information about these medications, refer to Table 10.

Substance use disorder. As of June 1, 2024, only one medication was in the approval pipeline for the treatment of substance use disorder. Baclofen (Lioresal), a GABA_B receptor agonist, is being investigated for the treatment of alcohol use disorder. Administered orally at a dose of 30mg daily, baclofen is notable for its limited liver metabolism, which makes it a promising option for patients with liver damage. Clinical trials have reported somnolence as a common side effect. Previous studies have shown that in patients with kidney disease, adverse effects, such as delirium and symptoms of mania, might occur.¹²⁰ Refer to Table 11 for additional details on baclofen.

Neurocognitive disorders. Twenty-two new medications have been investigated for the treatment of neurocognitive disorders in Phase III trials. These medications are generally indicated for the treatment of Alzheimer’s disease and associated agitation and the clinical syndrome of dementia, which is typically operationally defined as a decline in cognition and functional abilities relative to an individual’s baseline level of function. However, such medications are diverse in their unique mechanisms of action.

A significant focus of current research involves targeting amyloid beta, a protein that accumulates abnormally in the brains of individuals with Alzheimer’s disease, contributing to neurodegeneration. These medications aim to reduce or neutralize amyloid beta to slow disease progression and alleviate symptoms.¹²¹

The monoclonal antibody sabirnetug (ACU193) targets soluble amyloid beta oligomers implicated in Alzheimer’s disease progression and neurodegeneration. This medication is delivered through intravenous infusion, with an initial dosage of 35mg/kg for the first two administrations, followed by a maintenance dose of 50mg/kg every four weeks.^122,123

Donanemab is an antibody designed to target the buildup of amyloid beta peptides (N3pG). It is given intravenously at doses of 700 to 1,400mg every four weeks. Clinical trials have not revealed significant concerns regarding fall risk, change in QTc interval, weight fluctuation, sedation, or vital signs. However, there have been observations of potential amyloid-related cerebral edema.^124,125

Gantenerumab, a monoclonal antibody, specifically targets amyloid plaques by promoting their breakdown through microglial recruitment and phagocytosis. It is administered subcutaneously at different doses (120–1,200mg at minimum 1-week intervals). The FDA has recognized its potential by granting it a breakthrough designation.¹²⁶

Simufilam (PTI-125) modulates the conformation and activity of filamin A, a structural protein that undergoes abnormal changes in Alzheimer’s disease, leading to the development and persistence of amyloid beta plaques. It acts as a filamin alpha-7 nicotinic acetylcholine receptor antagonist and is currently under investigation for the treatment of Alzheimer’s disease, with and without accompanying dementia. The recommended dosage is 100mg orally twice daily. While the drug has advanced to Phase III trials, concerns have been raised about the integrity of results. No serious adverse effects on health have been reported.^127,128

Valiltramiprosate (ALZ-801) inhibits the aggregation of amyloid beta-42 through a mechanism involving 3-sulfopropanoic acid (3-SPA) metabolism. In early trials, oral administration of 265mg twice daily resulted in adverse effects, including nausea, dizziness, and vomiting.¹²⁹

Other medications focus on modulating neurotransmitter systems, such as serotonin, GABA, and dopamine, which play crucial roles in cognitive function and psychiatric symptoms.¹²⁹

ACP-204, an inverse agonist at 5-HT2A receptors, is being studied for Alzheimer’s disease-associated psychosis. Administered orally at 30 to 60mg daily, it does not cause QTc prolongation, unlike similar treatments.^130,131

Pimavanserin (Nuplazid), a 5-HT2A and 5-HT2C inverse agonist, is being investigated for preventing relapse in dementia-related psychotic symptoms, residual psychotic symptoms in schizophrenia, and MDD. It is administered orally at 20mg daily and might prolong QTc intervals by 5 to 8ms. Currently, it is approved for Parkinson’s disease psychosis.^132–134

Masupirdine, a 5-HT6 receptor selective antagonist, is being tested for Alzheimer’s disease. Commonly reported adverse effects include agitation, falls, and atrial fibrillation when administered orally at doses of 50 to 100mg daily.¹³⁵

Suvorexant, an orexin-1 and orexin-2 receptor antagonist, was FDA-approved in 2014 for the treatment of insomnia and is being tested for the treatment of dementia. It is taken orally at night at a dose of 10mg, and somnolence is a commonly reported adverse effect.^136,137

Latrepirdine (DMB-1, Dimebon), an H1 histamine receptor antagonist and NMDA receptor antagonist, is being studied for Alzheimer’s disease. Administered orally at doses of 10 to 60mg daily, it shows no significant risk of QTc prolongation, sedation, or falls.¹³⁸

Levetiracetam (AGB101, Keppra), a synaptic vesicle glycoprotein 2A (SV2A) inhibitor, is being studied for mild cognitive impairment due to Alzheimer’s disease at low doses. Administered orally at 220mg daily, it showed no significant risk of QTc interval change or weight gain in Phase II trials, but falls were a common adverse effect.^139,140

AR1001, a PDE5 inhibitor, is being investigated for mild cognitive impairment and early Alzheimer’s disease. The daily dosage is 30mg, taken orally. There are no significant risks related to QTc prolongation or weight gain, but fainting might increase the risk of falls.¹⁴¹

Dextromethorphan-bupropion (Auvelity, AXS-05) is being researched for treating agitation in Alzheimer’s disease and has been approved by the FDA for MDD. The medication combines dextromethorphan, which acts as an NMDA receptor antagonist and sigma-1 receptor agonist, with bupropion, a norepinephrine-dopamine reuptake inhibitor (NDRI) that competitively inhibits CYP2D6, resulting in a prolonged half-life of dextromethorphan to 22 hours. The recommended initial dosage is 45mg of dextromethorphan and 105mg of bupropion taken orally once daily, with a subsequent increase to twice daily after three days. Common side effects can include dizziness, headache, diarrhea, drowsiness, dry mouth, sexual dysfunction, and excessive sweating.^142,143

Nabilone, a partial agonist at CB-1 and CB-2 cannabinoid receptors, is being studied for potential use in treating dementia. It is taken orally in doses ranging from 0.5 to 1.5mg daily and might cause sedation and drowsiness, increasing the risk of falls.^144,145

Certain medications target mild cognitive impairment, early-stage Alzheimer’s disease, and related symptoms by affecting metabolic pathways and providing energy supplementation.

Tricaprilin, a medium-chain triglyceride metabolized to act as a ketogenic energy source, is being studied for Alzheimer’s disease. It is administered orally at 20g twice daily, and typical side effects include gastrointestinal discomfort and nausea.¹⁴⁶

GV1001, a gonadotropin-releasing hormone receptor (GnRHR) activator, is being investigated for Alzheimer’s disease. When administered subcutaneously at doses ranging from 0.56 to 1.12mg weekly or biweekly, no notable adverse effects associated with QTc intervals, weight change, or fall risk were observed.^147,148

Masitinib, a tyrosine kinase inhibitor, is currently under investigation for its potential to treat Alzheimer’s disease. In clinical studies, oral daily doses of 3 to 4.5mg/kg did not show significant risk in terms of changes to QTc interval and vital signs. However, notable adverse effects included neutropenia, hypoalbuminemia, and rash.¹⁴⁹

Metformin extended release is being studied for its potential influence on cognitive function through the gut-brain axis. It regulates insulin levels, thus helping to prevent hyperinsulinemia, which has been associated with neuroinflammation and the accumulation of amyloid beta plaques. It is administered orally at doses ranging from 500 to 2,000mg daily. Some studies suggest a potential risk of cognitive decline in patients with Type 2 diabetes.^150,151

Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, decreases glucose reabsorption in blood and is being studied for cognitive impairment and dementia symptoms in patients with Type 2 diabetes. It is FDA-approved for Type 2 diabetes, heart failure, and chronic kidney disease and is administered at 10mg daily. Serious adverse effects include diabetic ketoacidosis and urinary tract infections.¹⁵²

Nilotinib, a c-Abl tyrosine kinase receptor inhibitor, is being investigated for Alzheimer’s disease. When taken orally at 84 to 112mg daily, common side effects include mood swings, pain, and gastrointestinal discomfort. There are no reports of QTc prolongation, weight change, or fall risk.^153,154

Xanomeline (Lumeron), a muscarinic receptor agonist selectively targeting M1 and M4 receptors, is being studied for Alzheimer’s disease and related cognitive deterioration. The daily oral dose ranges from 75 to 225mg, and it has been associated with weight gain and increased QTc interval at lower doses.^155,156

Additional research is investigating the use of nanoparticles for the diagnosis and treatment of Alzheimer’s disease.¹⁵⁷ Other potential treatments in earlier stages of clinical development remain focused on investigating disease-modifying therapies for various conditions (i.e., multiple sclerosis).¹⁵⁸ See Table 12 for more details on each medication in the approval pipeline for neurocognitive disorders.

Neurodevelopmental disorders (attention deficit hyperactivity disorder [ADHD]). As of June 1, 2024, three pharmaceuticals had advanced to Phase III clinical trials for the treatment of neurodevelopmental disorders, specifically ADHD.

Centanafadine (EB-1020) is a SNDRI being studied for ADHD. It is administered orally at doses of 200 to 400mg daily and is well tolerated, with no significant risk of dependence, liver function issues, or sedation.¹⁵⁹

NRCT-101SR exerts its effects on glutamatergic synapses to augment synaptic plasticity and neurotransmission. It is orally administered at doses ranging from 1,500 to 2,000mg per day, and it is well tolerated, with no significant adverse effects in clinical trials.¹⁶⁰

Solriamfetol (Sunosi) is a dopamine and norepinephrine reuptake inhibitor and TAAR1 agonist approved for excessive daytime sleepiness due to OSA or narcolepsy. It is administered orally at doses of 150mg or 300mg daily. Common side effects include headache, nausea, and decreased appetite.¹⁶¹

Table 13 provides more detailed information on the medications in the pipeline for ADHD.

Discussion

This systematic review identified numerous psychiatric medications of potential interest that were in the late stages of development on the path to FDA approval as of June 1, 2024. A total of 90 pipeline drug trials were identified, including nine for schizophrenia, five for bipolar disorders, 25 for depressive disorders, 11 for anxiety disorders, five for PTSD, one for OCD, two for eating disorders, two for sleep-wake disorders, five for sexual dysfunctions, one for substance-related and addictive disorders, 22 for neurocognitive disorders, and three for neurodevelopmental disorders, specifically ADHD.

Significant activity is observed in the development of new medications for neurocognitive disorders. However, several agents were not reviewed in this manuscript, and some innovative mechanisms of action did not translate into significant clinical effects. For example, solanezumab, which is an intravenous monoclonal immunoglobulin G1 (IgG1) antibody targeting the mid-domain of the amyloid beta peptide for Alzheimer’s disease, did not meet its expected endpoint, leading to the discontinuation of its Phase III trials.¹⁶² Additionally, clinical trials on pimavanserin for schizophrenia were discontinued after they failed to demonstrate significant improvement in negative symptoms.¹⁶³ Similarly, deudextromethorphan plus quinidine (AVP-786), which is an NMDA antagonist and sigma 1 receptor agonist and is FDA-approved for pseudobulbar affect, was studied in Phase III for agitation in dementia due to Alzheimer’s disease; it did not show significant difference from placebo and was thus terminated.¹⁶⁴

Research on medications classified as psychedelic agents expanded to new indications, with several studies now in Phase III, and many others completing Phase II and approaching Phase III, such as ketamine for PTSD; psilocybin for alcohol use disorder, TRD, PTSD, GAD, OCD, fibromyalgia, and anorexia nervosa; and 5‐methoxy‐N, N‐dimethyltryptamine (5‐MeO‐DMT) for TRD, bipolar II disorder, postpartum depression, and alcohol use disorder.¹⁶⁵ Most recently, lysergic acid diethylamide (LSD) was granted an FDA breakthrough designation for GAD; the Phase IIb trials of MM120 (lysergide d-tartrate) showed 65 percent response and 48 percent remission of GAD after 12 weeks of a single dose.¹⁶⁶

Nutriband has partnered with Kindeva Drug Delivery to scale up the production of a new substance use medication that incorporates Nutriband’s AVERSA™ abuse-deterrent transdermal technology into Kindeva’s FDA-approved transdermal fentanyl patch system. The medication, AVERSA™ Fentanyl, aims to be the first abuse-deterrent patch of its kind and is currently in the process of obtaining FDA approval. Notably, the development has already completed a Phase I study, bypassing the need for Phase II and III trials.¹⁶⁷ More progress is still being made with long-acting injectable antipsychotics, with subcutaneous monthly forms, such as olanzapine, being tested for efficacy.¹⁶⁸

The field of psychiatry is in urgent need of innovation to effectively address the alarming rise of mental health disorders worldwide.¹⁶⁹ The lack of effective psychiatric treatments and alternatives is reflected in the relatively high prevalence of treatment-resistant conditions. More research is needed to better understand the biopsychosocial mechanisms underlying mental disorders and the effects of medications.^170,171 Historically, psychiatric disorders have been classified based on symptoms and diagnostic criteria. This poses a challenge, as patients diagnosed with the same disorder might present with a broad spectrum of phenotypes and clinical presentations. To address this challenge, biomarkers in psychiatry are a promising tool to help guide treatment for heterogeneous and complex mental disorders, as patients with the same diagnosis might respond differently to medications based on several mediating and moderating factors that continue to be identified at increasing rates. Several potential biomarkers have been identified and linked to certain neuropsychiatric conditions and neurodegenerative diseases.¹⁷¹ However, few have demonstrated to be useful in clinical practice to date.

Further exploration of the neurochemical pathways and associated biomarkers, in conjunction with comprehensive pharmaceutical reviews such as the present one, might consequently improve and optimize the clinical practice of pharmacotherapy. Many medications under development utilize well-established mechanisms of action. While innovative combinations, formulations, and applications could add significant value, there is also a pressing need for novel medications that achieve breakthroughs on our intolerably long list of refractory psychiatric conditions. However, without rigorous clinical trials, it is challenging to determine the efficacy of medications, their associated risks, and the most suitable treatments for each individual, which is crucial for achieving personalized medicine.

Strengths and limitations. This review’s strengths include a broad search strategy and the inclusion of multiple medication classes, which were systematically organized by psychiatric disorder. It identified medications for a wide range of psychiatric indications. This review also provides concise information for each medication, resulting in a practical resource. In addition, by highlighting mechanisms of action and dosing, this review reflects new trends and developments within the field.

Regarding limitations, this systematic review is limited by the available information and data made public by the agents behind these therapies. It is acknowledged that new medications are continuously being developed, and this review might not have captured all the upcoming developments.

Conclusion

We are entering a new era of psychiatry, which is reflected in the new and innovative treatments included in this review. To continue to advance the field and make a significant impact on the current worldwide burden of mental health conditions, it is critical to continue efforts in promoting innovation, development, and acceptance of new treatments. In this time of need, without efforts promoting research of new medications, there might be a significant delay in the development of new treatments and their impact on the general population.

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