The review, based on a systematic search of Scopus, PubMed, ScienceDirect, Google Scholar, Clarivate, Wiley Online and MDPI covering 2002 to 2025, excluded case reports, studies with overlapping data and trials lacking clear diagnostic criteria or defined randomization methods. Its authors focused on five major areas: schizophrenia, bipolar disorder, major depressive disorder, obsessive-compulsive disorder (OCD) and anxiety disorders. A striking finding is an imbalance in progress. Psychotic and mood disorders have seen a genuine wave of new approvals, while anxiety disorders and OCD have received no new pharmacological treatments at all, leaving clinicians to rely on augmentation strategies built from older drugs.

In schizophrenia, the most consequential shift involves moving beyond the dopamine D2 receptor blockade that has defined antipsychotic pharmacology since chlorpromazine. Lumateperone, a once-daily oral atypical antipsychotic approved at 42 milligrams per day, acts as a high-affinity antagonist at serotonin 5-HT2A receptors, binds moderately to postsynaptic D2 receptors, inhibits serotonin reuptake and partially agonizes D1 receptors, potentially modulating glutamatergic signaling through AMPA and NMDA pathways. Crucially, it shows minimal activity in the nigrostriatal pathway, reducing the risk of movement-related side effects. Two pivotal randomized, double-blind trials involving 334 and 450 adults demonstrated significant improvements in Positive and Negative Syndrome Scale (PANSS) scores over four weeks, with tolerability comparable to placebo and a lower metabolic impact than risperidone.

Delivery innovation is proving as important as molecular novelty. TV46000, a long-acting subcutaneous risperidone formulation approved for administration every four or eight weeks, maintained stabilization in the phase III RISE and SHINE trials involving 543 and 336 patients respectively, with injection-site pain and nodules among the most common adverse events. The EMA separately approved an intramuscular long-acting risperidone extending the dosing interval from 14 to 28 days, supported by trials in 438 and 215 patients showing significant symptom reduction without oral supplementation. A transdermal asenapine patch, FDA-approved in 2019, offers steady release unaffected by food or drink, based on a six-week trial in 607 patients. Long-acting injectables are consistently associated with lower relapse rates, fewer hospitalizations and better adherence, addressing the non-adherence that is a key predictor of relapse.

Two combination products mark a new strategy: pairing established efficacy with side-effect mitigation. Olanzapine/samidorphan (OLZ/SAM), FDA-approved in 2021 for schizophrenia and bipolar I disorder, pairs the atypical antipsychotic olanzapine with samidorphan, a mu-opioid receptor antagonist that dampens the endogenous opioid system implicated in olanzapine-driven hyperphagia. In trials, 33.1 percent of patients on the combination experienced significant weight gain compared with 44.8 percent on olanzapine alone, while waist circumference increases were also lower and antipsychotic efficacy was preserved. KarXT, approved in 2024, goes further by abandoning dopamine blockade entirely: it combines xanomeline, an M1/M4 muscarinic agonist that modulates dopamine neurotransmission indirectly, with trospium, a peripherally acting antagonist that limits cholinergic side effects. Three five-week trials in 179 to 256 patients showed significant PANSS and Clinical Global Impression-Severity improvements, with extrapyramidal symptom rates matching placebo.

Pipeline candidates suggest the muscarinic and trace-amine era is only beginning. Ulotaront, a trace amine-associated receptor 1 (TAAR1) agonist with 5-HT1A activity, outperformed placebo on PANSS total scores in a four-week trial of 245 patients with acute schizophrenia exacerbation, showing no significant changes in lipids, glycated hemoglobin or prolactin, and earned FDA Breakthrough Therapy designation in 2019, though one case of sudden cardiac death in the treatment group warrants longer-term study. Roluperidone, now in phase III trials in the United States, blocks serotonin, delta and alpha-adrenergic receptors and specifically targets the negative symptoms of schizophrenia, such as blunted affect and social withdrawal, which have long resisted dopaminergic drugs.

In bipolar disorder, where approximately one-third of patients fail at least two treatments and suicide remains a devastating complication, lumateperone and OLZ/SAM have both been approved for new indications. Two large studies of lumateperone in bipolar depression, encompassing 377 and 528 adults, showed mean Montgomery-Åsberg Depression Rating Scale reductions of 16.8 and 11.2 points versus 13.5 and 6.6 for placebo, including in patients stabilized on lithium or valproate. Glutamatergic agents are also reshaping treatment-resistant bipolar depression: intravenous ketamine at 0.5 milligrams per kilogram, which antagonizes NMDA receptors and triggers AMPA receptor activation and brain-derived neurotrophic factor release, produced response rates of 24.5 to 73 percent across four open-label studies, with notable anti-suicidal effects. Intranasal esketamine showed a 39 percent combined response rate in a four-week study of 45 patients, though 28.9 percent exhibited hypomanic or manic symptoms during maintenance, underscoring the need for careful mood monitoring. A fixed-dose combination of the NMDA modulator D-cycloserine with lurasidone (NRX-101) outperformed lurasidone alone in maintaining improvement and reducing suicidal ideation in a 22-patient trial.

Major depressive disorder has arguably seen the most dramatic therapeutic expansion. Esketamine nasal spray, the first glutamatergic antidepressant approved for treatment-resistant depression, achieved remission rates of 35.6 percent after induction and 46.1 percent during maintenance in the SUSTAIN-3 extension study of 1,148 patients, with mean treatment duration of 31.5 months. Dextromethorphan/bupropion (AXS-05), approved in 2022, pairs an NMDA antagonist and sigma-1 agonist with a CYP2D6 inhibitor that boosts its bioavailability; in the GEMINI trial of 327 adults, 54 percent responded at week six versus 34 percent on placebo, with improvement beginning within the first week and no psychomimetic effects or sexual dysfunction reported. For postpartum depression, which affects 13 to 19 percent of new mothers, brexanolone, an intravenous formulation of the neurosteroid allopregnanolone acting as a positive allosteric modulator of GABA-A receptors, delivered HAM-D reductions of up to 19.5 points over a 60-hour infusion, while zuranolone, approved in August 2023, offers the same mechanism as a once-daily oral pill taken for just two weeks, with benefits visible by day three. Psilocybin, a 5-HT2A partial agonist, showed rapid antidepressant effects in a phase II trial of 233 patients with treatment-resistant depression, with roughly 20 percent of the 25-milligram group maintaining response from week three to week twelve.

The picture is far less encouraging for OCD and anxiety disorders, where no new FDA-approved drug has emerged in two decades. OCD affects 1 to 2 percent of the global population, and about one-third of patients derive limited benefit from SSRIs and antipsychotic augmentation. The most promising augmentation data come from ondansetron, a 5-HT3 antagonist that reduced Yale-Brown Obsessive-Compulsive Scale scores by 41.5 percent over 14 weeks in 135 treatment-resistant patients, and pregabalin, which cut scores by more than 35 percent when added to sertraline. Memantine trials showed benefit but were small and geographically restricted, while N-acetylcysteine produced inconsistent results across two recent randomized trials. In anxiety disorders, research has turned to psychedelics and glutamatergic agents: LSD significantly reduced anxiety for up to 16 weeks in trials of 42 and 39 patients, ketamine improved social anxiety symptoms, and MDMA-assisted therapy produced marked reductions in PTSD severity, though cannabinoids have yielded mixed and generally low-quality evidence.

The review’s authors argue that the next frontier lies in precision psychiatry. Pharmacogenetic and pharmacogenomic studies could identify the genetic variations that govern treatment response, resistance and adverse effects, while digital phenotyping, using smartphone interaction data to monitor mental status in real time, could assess the long-term impact of medications, particularly in regions with limited access to mental health services. The recent approvals demonstrate that psychiatry can still deliver genuine innovation, from muscarinic antipsychotics to neurosteroid pills that lift postpartum depression within days. But the same analysis makes clear that treatment-resistant patients, and entire diagnostic categories such as anxiety and OCD, still await their breakthrough, making sustained research funding and larger, longer trials the decisive priorities for the decade ahead.

Subject of Research: Current pharmacological treatment of mental disorders and newly approved psychiatric medications

Article Title: Current drug treatment of mental disorders

Article References: Bidan, N., Datkhayev, U., Serikbayeva, E., Zhakipbekov, K., Umurzakhova, G., Omirbayeva, A., & Shimirova, Z. (2026). Current drug treatment of mental disorders. Pharmacia, 73, Article e194894. https://doi.org/10.3897/pharmacia.73.e194894

Image Credits: AI Generated

DOI: 10.3897/pharmacia.73.e194894

Keywords: schizophrenia, bipolar disorder, major depressive disorder, lumateperone, esketamine, zuranolone, KarXT, olanzapine/samidorphan, postpartum depression, treatment resistance, psychopharmacology, FDA approval