Mental disorders rank among the top 10 global causes of disease, with treatment resistance prevalent among many patients (Carrier et al. 2017). Major depressive disorder (MDD) and anxiety disorders contribute significantly to the global disease burden, while schizophrenia and bipolar disorder (BD), though less common, incur substantial costs due to associated disabilities. Antidepressants are effective for only approximately half of patients, and one-third of those with schizophrenia remain refractory to treatment (O’Brien et al. 2014; Howes et al. 2022). In 2019, depressive disorders were the 13^th leading cause of disability-adjusted life years (DALYs), with anxiety disorders ranked 24^th. The percentage change in DALYs for both disorders increased significantly from 1990 to 2019. In individuals aged 10–24, depressive disorders are the fourth leading cause of DALYs, following “self-harm.” Despite the rising burden, the development of new pharmacological treatments in psychiatry lags behind that in other medical fields (Giliberto et al. 2024). To address this issue, promoting new drug development and clinical trials, particularly for treatment-resistant patients and varying demographics, is essential. Recent strategies for addressing mental disorders have included drug repurposing of established agents to explore new therapeutic uses (Carrier et al. 2017; Giliberto et al. 2024).

The present narrative review provides an updated overview of advances in pharmacological treatments for psychiatric disorders, focusing on drugs for conditions such as schizophrenia, BD, MDD, anxiety disorders, and obsessive-compulsive disorder (OCD). The review assesses both the efficacy and safety of these new psychiatric drugs, including those with recent approvals involving novel modes of administration, such as long-acting and subcutaneous injections. Notably, no new pharmacological treatments have been approved for anxiety disorders or OCD, leading to less comprehensive sections on these conditions compared with psychotic and mood disorders.

An electronic search was conducted across Scopus, Google Scholar, Clarivate, ScienceDirect, Wiley Online, PubMed, and MDPI from 2002 to 2025 to identify new pharmacological agents explored for the treatment of psychiatric disorders, including schizophrenia, BD, MDD, anxiety disorders, and OCD. Case reports, longitudinal studies, prospective studies, and letters to the editor were excluded from consideration. Additionally, studies with overlapping data were omitted. The eligibility of articles was assessed through the following process: (1) an initial screening based on the title and abstract of all studies and (2) a thorough review of the full manuscript content for those that passed the initial screening. Furthermore, studies lacking a clear diagnosis, those with comorbid severe medical conditions, or those with ambiguous dosages of the newly administered drug were excluded. Studies that did not clearly define inclusion criteria or did not assess outcomes using self- or hetero-administered scales were also omitted. Randomized controlled trials (RCTs) that did not specify the randomization method were excluded. The review considered only articles written in English. The search strategy incorporated the following pertinent terms: “psychiatric disorders,” “mental disorders,” “schizophrenia,” “major depressive disorder,” “bipolar disorders,” “obsessive-compulsive disorder,” “anxiety disorders,” and “antidepressive agents.”

Schizophrenia is a chronic psychiatric disorder that exerts significant physical, social, and economic burdens on affected individuals. Non-adherence to antipsychotic medication is a key predictor of relapse among these patients (Biagi et al. 2017). Antipsychotics are critical in managing acute phases and providing maintenance therapy, with the earliest treatments focusing on dopamine D2 receptor antagonists, reflecting the dopaminergic system’s pivotal role in the disorder (Orzelska-Górka et al. 2022). Recent advancements include the development of second- and third-generation antipsychotics, which possess broader receptor profiles, including antagonism and partial agonism at D2/D3 and 5-HT1A receptors (Table 1). Stimulation of the 5-HT1A receptor may help mitigate negative symptoms by potentially increasing dopamine levels in the prefrontal cortex, an area where reduced dopamine is implicated in these symptoms (Selvaraj et al. 2014). Additionally, 5-HT2C receptor agonism appears to confer antipsychotic benefits without causing extrapyramidal symptoms. Long-acting injectable (LAI) formulations have emerged as beneficial alternatives to daily oral antipsychotics, linked to lower relapse rates, reduced hospitalizations, and enhanced treatment adherence, ultimately improving patients’ quality of life (Subotnik et al. 2015; Greene et al. 2018). Recent developments in schizophrenia treatment include the new antipsychotic lumateperone, various long-acting administration methods such as subcutaneous and intramuscular risperidone, and innovative therapies such as olanzapine/samidorphan and KarXT. Notable candidates under investigation are ulotaront, a trace amine-associated receptor 1 (TAAR1) agonist with promising results without major side effects, and roluperidone, which targets mood, cognition, and negative symptoms through its action as a blocker of serotonin, δ-, and α-adrenergic receptors (Koblan et al. 2020; Davidson et al. 2022).

Lumateperone (ITI-007) is a once-daily oral atypical antipsychotic used to treat depressive episodes in bipolar I or II disorder, as well as schizophrenia, at a dosage of 42 mg/day. It acts primarily as a high-affinity antagonist at serotonin 5-HT2A receptors and has moderate binding to postsynaptic D2 receptors, while also inhibiting serotonin reuptake and acting as a partial agonist at D1 dopamine receptors, which potentially modulates glutamatergic neurotransmission through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) pathways. Importantly, lumateperone shows minimal activity in the nigrostriatal pathway, reducing the risk of extrapyramidal side effects. Two pivotal randomized, placebo-controlled, double-blind trials involved 334 and 450 adult participants diagnosed with schizophrenia or acute psychosis, assessing changes in Positive and Negative Syndrome Scale (PANSS) scores after 4 weeks of treatment. Results indicated significant improvement in total PANSS scores for lumateperone vs. placebo, with optimal efficacy achieved at 42 mg/day; patients experienced notable improvements in global symptom severity and functioning as measured by the Clinical Global Impression-Severity (CGI-S) and Personal and Social Performance (PSP) scales, respectively. Lumateperone was generally well tolerated, with no significant adverse motor effects or notable changes in cardiometabolic or endocrine parameters. An open-label study involving 301 outpatients switching from other antipsychotics to lumateperone also supported its safety profile, showing stable PANSS scores during treatment. Common adverse effects included drowsiness, dizziness, nausea, constipation, and dry mouth, with discontinuation rates due to side effects similar to those with placebo and notably lower than those with risperidone. Moreover, lumateperone displayed a comparable or reduced impact on metabolic parameters compared with placebo and a lower impact than risperidone (Lieberman et al. 2016; Ceskova 2020; Correll et al. 2020a, 2020b; Pahwa et al. 2021).

TV46000 is a long-acting subcutaneous antipsychotic combining risperidone with a novel drug delivery system for administration every 4 weeks (q1m) or 8 weeks (q2m). FDA (Food and Drug Administration, USA) approval was based on two phase III trials, RISE and SHINE, which showed that clinical stabilization from initial oral risperidone therapy was maintained and improved with TV46000. The RISE study involved 543 patients with schizophrenia, showing significant stabilization with both dosing schedules compared with placebo. The SHINE study, with 336 patients over 56 weeks, supported these results. Adverse events included injection-site pain (5% for q1m, 4% for q2m) and nodules (2% for q1m, 6% for q2m). Serious adverse events, such as worsening symptoms and hyperglycemia, occurred in 5% (q1m) and 7% (q2m) of patients, with eight discontinuing treatment due to side effects. Overall, long-term safety data indicate a favorable profile for TV46000, consistent with existing risperidone formulations. In 2022, the European Medicines Agency (EMA) approved an LAI formulation of risperidone, extending the administration interval from 14 to 28 days. Two key studies assessed its efficacy and safety. The first study involved 438 patients with schizophrenia in a 12-week, placebo-controlled trial, in which participants received 75 mg or 100 mg of risperidone monthly. Results showed significant symptom reduction without the need for oral supplementation, with both dosages improving PANSS and CGI-S scores. Common side effects included increased prolactin levels, headaches, hyperprolactinemia, and weight gain, all of which were manageable. The second study included 215 patients over 52 weeks, showing improvements in PANSS scores and CGI-S/CGI-Improvement scores, especially in unstable and stabilized patients. Adverse events reported included headaches, hyperprolactinemia, and weight gain. Overall, these studies confirm the new LAI risperidone formulation as a safe and effective treatment for schizophrenia, with a convenient dosing schedule and manageable side effects (Citrome 2014).

Asenapine is a tertiary amine within the dibenzo-oxepinopyrrole group, metabolized largely in the liver via glucuronidation and oxidation. The transdermal formulation, approved by the FDA in 2019 for schizophrenia, provides a slower, more consistent release unaffected by food or drink (Citrome et al. 2020). Various patch dosages (3.8 mg, 5.7 mg, and 7.6 mg per 24 h) correspond to higher sublingual doses. The FDA’s approval was based on a 6-week phase III RCT involving 607 patients, which demonstrated significant improvements in PANSS and CGI-S scores (Suzuki et al. 2021). Transdermal asenapine was generally well tolerated, with common adverse effects including drowsiness, site erythema, dizziness, headaches, insomnia, and fatigue. This mode of administration may enhance treatment adherence among patients with psychosis.

Olanzapine/samidorphan (OLZ/SAM) is a drug combination approved by the FDA in 2021 for the treatment of schizophrenia and bipolar disorder type I (BD I). Olanzapine is an established atypical antipsychotic, while samidorphan is a novel mu-opioid receptor antagonist that helps downregulate the endogenous opioid system potentially enhanced by olanzapine, thereby potentially reducing hyperphagia and food gratification. Clinical trials evaluated the efficacy of OLZ/SAM as both monotherapy and adjunctive therapy to lithium or valproate, showing stability or improvement in PANSS and CGI-S values compared with monotherapy with olanzapine or placebo. The studies included six RCTs and four open-label studies, with dosages ranging from 5–30 mg/day over durations of 3–52 weeks, involving 36–561 patients with schizophrenia. The combined treatment demonstrated antipsychotic efficacy comparable to olanzapine monotherapy and an improved metabolic profile, particularly in terms of reduced weight gain (Potkin et al. 2020; Kahn et al. 2021). While patients initially experienced weight gain up to week 6, subsequent stabilization was noted, contrasting with continued weight gain in those receiving olanzapine alone. Many studies indicated that OLZ/SAM may reduce weight gain without significantly altering metabolic parameters such as insulin, glucose, or lipids. The combination was well tolerated, exhibiting a safety profile similar to that of olanzapine with placebo, and common side effects included drowsiness, headache, nausea, and dry mouth, without altering QTc values (Correll et al. 2020a, 2020b). Notably, adverse events such as suicidal ideation were reported, underscoring the need for careful monitoring. OLZ/SAM represents a promising therapeutic option with the potential to mitigate the frequent weight gain associated with olanzapine monotherapy.

KarXT, a novel medication approved by the FDA in 2024 for the treatment of schizophrenia, comprises xanomelin, a muscarinic agonist targeting M1/M4 receptors, and trospium, a non-selective muscarinic antagonist that mitigates peripheral cholinergic side effects. The drug’s M1 and M4 receptor activity influences the modulation of dopamine neurotransmission, addressing both positive and negative schizophrenia symptoms, as well as cognitive and psychotic manifestations of Alzheimer’s disease. Three clinical trials involving 179–256 patients with schizophrenia over 5 weeks demonstrated significant efficacy in PANSS total and positive subscale scores and CGI-S scores when treated with KarXT vs. placebo. Adverse events commonly observed included constipation, dyspepsia, headache, nausea, vomiting, hypertension, dizziness, gastroesophageal reflux disease, and diarrhea. However, extrapyramidal symptom rates and discontinuation rates due to adverse effects were comparable between the KarXT and placebo groups. These results suggest that KarXT is a promising, effective, and well-tolerated antipsychotic, leveraging muscarinic receptor activation rather than dopamine D2 receptor antagonism (Brannan et al. 2021; Correll et al. 2022; Kaul et al. 2024).

Ulotaront (SEP-363856) is a promising agent for treating schizophrenia, functioning as a TAAR1 agonist with 5-HT1A agonist activity. In a 4-week, randomized, placebo-controlled trial involving 245 patients with acute schizophrenia exacerbation, 120 patients received SEP-363856 (50 mg or 75 mg), which demonstrated superiority over placebo in reducing the PANSS total score. Reported adverse events primarily included drowsiness and gastrointestinal symptoms, along with one significant incident of sudden cardiac death in the SEP-363856 group. The study observed similar rates of extrapyramidal symptoms and no significant changes in lipid levels, glycated hemoglobin, and prolactin among the groups. Future research involving longer durations and larger samples is necessary to validate the drug’s effects, tolerability, and efficacy relative to current schizophrenia treatments. Notably, the FDA granted ulotaront Breakthrough Therapy designation in 2019 for its potential in the treatment of schizophrenia.

Roluperidone, currently in phase III clinical trials in the USA, functions by blocking serotonin, δ-, and α-adrenergic receptors, which are critical in regulating mood, cognition, sleep, and anxiety. Its primary therapeutic aim is to manage negative symptoms associated with schizophrenia, a set of symptoms that severely hinders patients’ daily functioning and is often resistant to traditional antipsychotic treatments that target dopaminergic pathways.

BD is marked by recurrent mood swings between mania or hypomania and depression, alongside variations in energy and activity levels. Although its precise causes remain unclear, BD is believed to stem from genetic, neurobiological, and environmental interactions. Pharmacological treatment targets the dopaminergic, serotonergic, GABAergic, and glutamatergic systems to manage acute symptoms and stabilize mood, encompassing the management of manic or hypomanic episodes, maintenance therapy to avert relapses, and treatment for bipolar depression. Notably, approximately one-third of patients exhibit treatment resistance, failing to respond to at least two treatment options. A significant complication of BD is suicide, often associated with depressive and mixed episodes. Recently, new treatments such as lumateperone and a novel formulation of olanzapine with samidorphan have been approved by the FDA (Table 2), with further insights into their mechanisms of action being examined in relation to schizophrenia (Pereira et al. 2021; Wilkowska and Cubała 2023).

Two independent clinical studies evaluated lumateperone for the treatment of bipolar depression, both as monotherapy and adjunctive therapy. The primary efficacy outcome was the change in total Montgomery–Åsberg Depression Rating Scale (MADRS) score at week 6. The first study, with 377 adult patients (mean age 45 years), showed that lumateperone as monotherapy led to a mean reduction of 16.8 MADRS points, compared with a 13.5-point reduction in the placebo group.

The second study involved 528 adult patients (mean age 46 years) already on stable doses of lithium or valproate, demonstrating a mean reduction of 11.2 points in the lumateperone group vs. 6.6 points for placebo. Secondary endpoints, including CGI-S and Sheehan Disability Scale (SDS) scores, also showed significant improvements. Adverse events were mostly mild to moderate, consistent with prior schizophrenia studies, although there were increased adverse effects when lumateperone was used with mood stabilizers, notably drowsiness, dizziness, and nausea, and only two cases of mild akathisia were reported. These results underscore lumateperone’s safety and tolerability in diverse psychiatric populations (Calabrese et al. 2021; Suppes et al. 2023).

The OLZ/SAM combination gained approval from the FDA in 2021 for both short-term and maintenance treatment of manic or mixed episodes in bipolar I disorder, also allowing combination with valproate or lithium. This combination aims to reduce weight gain while maintaining olanzapine’s antipsychotic effectiveness, with a study by Kahn et al. indicating that 33.1% of patients receiving OLZ/SAM experienced significant weight gain compared with 44.8% of those receiving olanzapine alone. The increase in waist circumference was also lower in the OLZ/SAM group, and an improvement in clinical condition was noted, with similar safety profiles for both treatments (Kahn et al. 2021).

Ketamine and esketamine are utilized for treating treatment-resistant bipolar depression (TR-BD) by modulating glutamatergic transmission. Ketamine primarily antagonizes NMDA receptors (NMDARs) at subanesthetic doses, enhancing glutamate release in the medial prefrontal cortex (mPFC). This action disinhibits glutamatergic transmission, activating AMPA receptors and increasing brain-derived neurotrophic factor (BDNF), which enhances synaptic plasticity. Additionally, ketamine affects dopaminergic, serotonergic, adrenergic, and cholinergic systems and modulates neuroinflammatory pathways and ionic influx, contributing to its therapeutic effects. Recent research on TR-BD highlights four open-label studies involving 13–53 participants who received intravenous ketamine at a dosage of 0.5 mg/kg, administered between one and eight times. While ketamine is not yet FDA-approved for TR-BD, it shows promise as an adjunctive therapy, demonstrating an overall response rate of 24.5%–73%. Notably, its anti-suicidal effects were significant. Improvements in depressive symptoms were measured using various scales, including the Hamilton Depression Rating Scale (HDRS), MADRS, and Scale for Suicidal Ideation (SSI). The treatment was generally well tolerated, with no serious adverse events reported (Rybakowski et al. 2017; Zheng et al. 2020; Wilkowska et al. 2021). Another open-label study by Zhuo et al. examined the effects of intravenous ketamine infusions over 3 weeks in 38 patients with bipolar depression. After nine infusions, a significant reduction in depressive symptoms was noted following the first three doses. However, patients experienced a subsequent worsening of symptoms and relapse by week 3, potentially due to the small sample size or high treatment resistance. All patients were also receiving antidepressants and mood stabilizers, which may have affected the findings (Zhuo et al. 2020). A retrospective analysis by McIntyre et al. of 201 patients with treatment-resistant MDD or BD found that ketamine quickly alleviated refractory symptoms, particularly anhedonia, anxiety, irritability, and agitation. A significant reduction in overall depressive symptoms and suicidal ideation was noted among patients with anxiety, irritability, and agitation (AIA), measured using the GAD-7 and QIDS-SR16 scales (McIntyre et al. 2019). Additionally, a study by Fancy et al. involving 66 patients with BD indicated that intravenous ketamine infusions led to notable decreases in suicidal thoughts, anxiety, and functional impairment after four infusions. The response rate was 35%, and the remission rate was 20% post-treatment (Fancy et al. 2023).

The use of esketamine nasal spray (ESK-NS) in the treatment of bipolar depression is supported by two primary lines of evidence. Neuroimaging studies indicate that glutamate neurotransmission is altered at various stages of BD, particularly in the dorsolateral prefrontal cortex and anterior cingulate cortex, both vital for mood regulation. Additionally, ketamine, which modulates the glutamatergic system, has shown effective clinical outcomes and tolerability as an antidepressant for bipolar depression (Martinotti et al. 2023). ESK-NS reportedly has a better safety profile than ketamine, making it feasible for outpatient use, as evidenced by the SUSTAIN-2 study, which reported no manic symptoms among adverse events. The EMA does not contraindicate ESK-NS use in patients with BD, advocating for treatment choices based on thorough risk–benefit evaluations. Most existing studies on esketamine do not specifically analyze its effectiveness for bipolar depression but often involve heterogeneous patient samples, including those with MDD, treatment-resistant depression (TRD), and TR-BD. To focus on bipolar depression, only a recent study by Santucci et al. is considered; it examined the efficacy and safety of ketamine and esketamine in a cohort of 45 patients with bipolar depression treated with either intravenous ketamine or intranasal esketamine over a 4-week period. Results indicated a 39% (ketamine 23%; esketamine 16%) clinical response rate and a 13.2% (ketamine 5.4%; esketamine 7.8%) remission rate, with no instances of mania or hypomania during acute treatment. However, during maintenance, 28.9% (ketamine 13.6%; esketamine 15.2%) of participants exhibited symptoms suggesting hypomanic or manic episodes (Wajs et al. 2020; Santucci et al. 2024).

D-cycloserine (DCS) is an antibiotic known for its antidepressant properties, acting as an NMDA receptor agonist at lower doses and an antagonist at higher doses. At doses above 500 mg/day, it has shown antidepressant effects in TRD when combined with selective serotonin reuptake inhibitors (SSRIs) and enhances the effects of ketamine in bipolar depression. A 2023 study by Nierenberg investigated the efficacy of a fixed-dose combination of DCS and lurasidone (NRX-101) in patients with bipolar disorder experiencing severe depression and suicidal ideation. The study involved 22 patients, assessing depressive symptoms using MADRS and suicidal thoughts using the Columbia Suicide Severity Rating Scale (C-SSRS). Results demonstrated that NRX-101 was significantly more effective than lurasidone alone in maintaining improvement in depression and reducing suicidal ideation, alongside a reduction in akathisia among participants, aligning with preclinical findings. DCS is considered a safe oral antidepressant without the neurotoxicity or abuse risks associated with direct NMDA antagonists (Nierenberg et al. 2023).

Celecoxib (CBX), a selective cyclooxygenase-2 (COX-2) inhibitor, has been investigated as a potential adjunct therapy to traditional mood stabilizers such as lithium and valproate for BD. Preliminary studies indicate that anti-inflammatory agents might improve depressive symptoms in BD. A study by Edberg et al. examined inflammatory markers in patients with BD, particularly focusing on the pro-inflammatory biomarker C-reactive protein (CRP). Involving 47 participants, the study randomized them into two groups: one receiving escitalopram alongside CBX and the other receiving escitalopram with placebo. Although initial CRP levels were markedly higher in patients with BD compared with healthy controls, there were no notable differences in CRP levels between the CBX and placebo groups at baseline. However, after 8 weeks, CRP levels significantly decreased in the CBX group, indicating a potential reduction in inflammation and suggesting that CRP might serve as a biomarker for treatment response in patients receiving SSRI and CBX therapy. Furthermore, a randomized controlled trial by Husain et al. evaluated minocycline, an anti-inflammatory antibiotic, alongside CBX vs. either treatment alone or placebo over 12 weeks in a larger cohort of 254 patients undergoing depressive episodes associated with BD. The primary assessment, using the Hamilton Depression Rating Scale (HAMD-17), revealed no significant differences in reductions in depressive symptoms among the treatment groups compared with placebo, and no significant adverse events were noted across the groups. These results raise questions about the therapeutic efficacy of adjunctive anti-inflammatory medications for the treatment of acute BD episodes (Edberg et al. 2018; Husain et al. 2020).

Infliximab, a tumor necrosis factor (TNF) inhibitor, has been investigated in individuals with BD because elevated levels of pro-inflammatory cytokines have been linked to cognitive impairments. An RCT conducted by McIntyre et al. investigated the efficacy of infliximab as an adjunct treatment for patients with BD I or II displaying inflammatory indicators. The study, lasting 12 weeks, involved 60 patients aged 18–65 years who were given either infliximab or placebo over three intravenous infusions. Although no significant differences in depressive symptom severity, measured by MADRS, were found between the groups at week 12, secondary analyses indicated that infliximab might confer benefits to patients with a history of childhood maltreatment. Specifically, those treated with infliximab and with a background of physical maltreatment showed greater improvements in MADRS scores and response rates compared with the placebo group. Despite the overall lack of significant symptom reduction for the entire cohort, these preliminary findings suggest that anti-inflammatory treatments such as infliximab could be advantageous for individuals with BD who have experienced physical or sexual abuse. Additional research is needed to further investigate this connection in patients with inflammation-related depressive symptoms (McIntyre et al. 2019).

MDD is a significant cause of global disability, affecting 5–7% of the population annually and 15–20% over a lifetime, with a higher incidence in women. MDD is linked to various comorbidities and arises from genetic, biological, psychological, and environmental interactions. Key biological factors include neurotransmitter alterations, hypothalamic–pituitary–adrenal (HPA) axis dysfunction, neuroinflammation, and reduced neuroplasticity. Recent studies suggest that the glutamatergic system and neurotrophic pathways, such as BDNF, are critical in depression. Novel antidepressants based on these mechanisms, such as esketamine, dextromethorphan/bupropion, brexanolone, and zuranolone (Table 3), have shown improved efficacy over traditional methods (Zanos et al. 2018; McIntyre and Jain 2024).

A comprehensive review of recent literature on ketamine and esketamine examines their therapeutic potential for MDD, BD, and TRD with suicidal ideation. Four double-blind, placebo-controlled RCTs were analyzed, involving 36–156 patients who received intravenous (IV) infusions of either ketamine or esketamine. The treatment regimens varied, comprising a minimum of one infusion at 0.5 mg/kg and up to four infusions over a 2-week period, with participants aged 13–76 years. The assessment of suicidal ideation utilized several scales, including the SSI, C-SSRS, Suicide Probability Scale (SPS), Positive and Negative Suicide Ideation Inventory (PANSI), and MADRS item 10 score. All studies reported rapid improvements in suicidal ideation, with particularly notable effects in patients with BD and those exhibiting moderate to low refractoriness, defined as having a current depressive episode lasting less than 24 months or having undergone four or fewer failed antidepressant treatments (Abbar et al. 2022; Su et al. 2023; Zhou et al. 2024). A phase III extension study (SUSTAIN-3) evaluated the long-term efficacy of esketamine nasal spray in 1,148 patients aged over 18 years with TRD. Of these, 458 completed a 4-week induction phase of flexible dosing (28 mg, 56 mg, or 84 mg) twice weekly, while 690 discontinued. Patients received oral antidepressants, excluding monoamine oxidase (MAO) inhibitors, throughout the trial. The mean maintenance treatment duration with esketamine was 31.5 months, with a maximum of 4.5 years. Depressive symptoms were measured using MADRS scores, showing remission rates of 35.6% post-induction and 46.1% during maintenance. Common adverse events included headache, dizziness, and nausea. Suicidal ideation occurred in 4.3% of participants without a prior history, while 10 individuals (0.9%) showed new suicidal behaviors, predominantly among those with past ideation. Improvements in C-SSRS severity were noted in 14.0% of participants. Overall, 5.6% experienced adverse events potentially linked to suicidality, with one reported case of suicide (Zaki et al. 2023).

AXS-05 is a novel pharmacological formulation that combines dextromethorphan and bupropion, approved by the FDA in 2022 for treating MDD in adults. The extended-release tablet contains 45 mg of dextromethorphan bromide and 105 mg of bupropion hydrochloride. Dextromethorphan functions by modulating glutamate signaling through NMDA receptor antagonism, sigma-1 receptor agonism, and serotonin reuptake inhibition, while bupropion enhances the bioavailability of dextromethorphan by inhibiting the CYP2D6 enzyme and acts as a norepinephrine and dopamine reuptake inhibitor (McCarthy et al. 2023). Clinical studies have demonstrated that the combination is effective in rapidly alleviating depressive symptoms in patients with MDD, including those with TRD and suicidal ideation. The single-tablet regimen promotes adherence by ensuring a consistent pharmacokinetic profile. A pivotal phase III RCT (GEMINI) assessed 327 adults aged 18–65 years with moderate-to-severe depressive episodes lasting at least 4 weeks. Participants were randomized to receive either AXS-05 or placebo, with significant symptom improvement noted at week 6—54% of the AXS-05 group showed a clinical response compared with 34% in the placebo group. Improvement began within the first week, and the treatment was well tolerated, with adverse effects primarily including dizziness, nausea, headache, drowsiness, and dry mouth, while no psychomimetic effects or sexual dysfunction were reported (Iosifescu et al. 2022). Subsequent studies, including the COMET and EVOLVE trials, involved 876 and 186 patients, respectively, focusing on long-term efficacy. The results showed remission rates of 46% in EVOLVE and 52.5% in COMET at week 6, with sustained improvements in depressive symptoms for up to 1 year. The AXS-05 intervention proved effective across various demographics and treatment histories, as demonstrated by aggregate analyses of multiple trials, underscoring the medication’s broad applicability in managing MDD (McCarthy et al. 2023). Additionally, a separate clinical trial by Tabuteau et al. highlighted the superior efficacy of the dextromethorphan/bupropion combination over bupropion alone, achieving response rates of 60.5% vs. 40.5%, respectively, by week 6.

In March 2019, the FDA approved brexanolone for treating postpartum depression (PPD) in adult women, a condition that affects 13–19% of new mothers. While PPD is classified under MDD with perinatal onset according to DSM-5, its symptoms manifest during pregnancy or within 4 weeks post-delivery, leading to feelings of sadness and worthlessness. Brexanolone, a cyclodextrin-based formulation of the neurosteroid allopregnanolone, acts as a positive allosteric modulator of GABA-A receptors and is administered intravenously. The drug’s efficacy was evaluated in two double-blind, randomized, placebo-controlled phase III trials led by Meltzer-Brody (Kanes et al. 2017; Meltzer-Brody et al. 2018). Study 1 assessed brexanolone at doses of 90 μg/kg/h (BRX90) and 60 μg/kg/h (BRX60) against placebo, while Study 2 compared BRX90 with placebo. Over a 60-h intravenous infusion, Hamilton Depression Rating Scale (HAM-D) scores showed significant reductions, with Study 1 reporting a 19.5-point decrease for BRX60, a 17.7-point decrease for BRX90, and a 14.0-point decrease for placebo. In Study 2, the BRX90 group showed a 14.6-point reduction compared with a 12.1-point reduction in the placebo group. The findings indicated that the treatment groups maintained superior results over the placebo group throughout the 30-day follow-up, with a higher number of patients achieving remission. In Study 1, a participant in the BRX60 group experienced two serious adverse events (suicidal ideation and intentional overdose attempt), while in Study 2, a participant in the BRX90 group experienced two serious adverse events (altered consciousness and syncope), both deemed treatment-related. Generally, side effects among the remaining participants were minimal, mirroring earlier studies, with headache, dizziness, and drowsiness being mild and self-limiting. Brexanolone emerges as a pioneering treatment for moderate-to-severe PPD, offering rapid symptom resolution. However, its application is limited by the necessity for hospitalization, intravenous delivery, high costs, and potential risks of sedation or loss of consciousness. Despite these concerns, the risk–benefit ratio appears favorable, suggesting significant maternal health benefits during the postpartum phase (Cornett et al. 2021). A study by Wald et al. examined the effects of brexanolone on breastfeeding, involving 12 healthy women who had recently given birth. These participants received an intravenous infusion of brexanolone at a maximum dosage of 90 mg/kg/h over 60 h. It was observed that the peak levels of allopregnanolone in breast milk reached 125 mcg/L between 24 and 48 h post-infusion. Most subjects had drug levels in breast milk fall below detectable limits within 3 days following the end of treatment. A pharmacokinetic model indicated that 95% of women would have allopregnanolone levels in breast milk below 10 mcg/L by 36 h after the infusion. The transfer of the drug to infants via breast milk was minimal, with a median transfer of 0.69% of the maternal dose, peaking at a maximum of 1.3% (Wald et al. 2022).

Zuranolone (SAGE-217) received FDA approval in August 2023 as an investigational neuroactive steroid and positive allosteric modulator of GABA-A receptors. Its mechanism is similar to that of brexanolone, but it offers advantages such as once-daily oral administration, eliminating the need for hospitalization and intravenous treatment. Zuranolone is a promising option for treating PPD, requiring a short treatment duration of only 2 weeks and demonstrating rapid action that may surpass traditional SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs) in effectiveness. Two phase III, double-blind, randomized, placebo-controlled trials assessed zuranolone’s efficacy in treating patients with depression. The first study utilized a dosage of 30 mg/day and included 153 patients, while the second study employed a dosage of 50 mg/day with 196 participants. Patients maintained a stable antidepressant regimen for at least 30 days prior to the trial and were followed until day 45 post-treatment. Efficacy was measured using various rating scales, including HAM-D, Hamilton Anxiety Rating Scale (HAM-A), CGI-S, MADRS, and Patient Health Questionnaire-9 (PHQ-9). Results indicated that zuranolone significantly outperformed placebo in achieving a reduction in HAM-D scores, with noticeable improvements beginning on day 3 and persisting throughout the study. Additionally, reductions in anxiety symptoms and positive Clinical Global Impression-Improvement (CGI-I) responses were observed up to day 45. Common adverse events included drowsiness, dizziness, sedation, headache, and diarrhea, while no serious safety concerns, such as loss of consciousness or increased suicidal ideation, were reported (Deligiannidis et al. 2021; Deligiannidis et al. 2023). A recent study by Ahmad analyzed data from four RCTs involving a total of 1,357 patients with MDD treated with various dosages of zuranolone compared with placebo. Assessment of clinical outcomes was conducted using HAM-D, HAM-A, and MADRS scales. Results indicated that patients receiving zuranolone experienced statistically significant improvements across all evaluation metrics as early as day 15 of treatment. Additionally, zuranolone resulted in higher response and remission rates than placebo. It is noted as an effective and safe short-term monotherapy option for MDD, demonstrating benefits within 14 days, unlike SSRIs, which typically take 2–4 weeks. Despite these promising findings, further research is necessary to explore long-term effects in a larger patient population (Ahmad et al. 2024). Postpartum depression is a complex condition influenced by a variety of factors, including cultural context, gender roles, and social expectations that significantly affect maternal mental health. While drug therapies are an important aspect of treatment, a comprehensive approach that considers these multifactorial influences is vital for effective interventions. Future research is necessary to compare zuranolone with other therapies, explore its long-term potential, identify any new indications for use, and determine the safest and most effective administration methods (Hitt 2024).

Several studies have explored the therapeutic potential of psychedelics, particularly focusing on psilocybin’s effects on conditions such as MDD. Psilocybin is a partial agonist of the 5-HT2A receptor, predominantly influencing brain areas such as the neocortex and prefrontal cortex, which are crucial for visual perception and cognitive functions. Its action also involves other serotonergic receptors, including 5-HT1A, and can induce neuroplasticity with antidepressant effects akin to those of ketamine. Research shows that psilocybin affects key neural circuits associated with depression, such as the amygdala (Melani et al. 2025). In a phase II double-blind trial involving 233 patients with TRD, varying doses of psilocybin (25 mg, 10 mg, and a control dose of 1 mg) were tested. The results indicated that the higher psilocybin doses were significantly more effective than the 1 mg dose, as measured using MADRS. The antidepressant effects were rapid, often noticeable by day 2, with approximately 20% of those receiving 25 mg maintaining a response from week 3 to week 12. However, 77% of participants experienced adverse effects, with headache, nausea, and dizziness being the most common, while serious adverse events tended to correlate with higher doses, including increased suicidal ideation. In an additional phase II open-label study, 19 participants received a 25 mg dose of psilocybin with psychological support, intended for patients with TRD concurrently receiving SSRIs—a combination tested for compatibility. This study showed a significant reduction in MADRS scores as early as day 2, with 42.1% meeting both response and remission criteria. Although psilocybin was associated with frequent mild side effects, serious adverse effects were managed effectively by adjusting dosages (Goodwin et al. 2022).

OCD has evolved from being regarded as infrequent to being recognized as a significant psychological and public health issue, affecting 1%–2% of the global population and incurring notable social and economic costs. Established treatments for OCD, which include pharmacological options such as SSRIs and combinations with low-dose antipsychotics, are supported by robust evidence. Cognitive-behavioral psychotherapy (CBT) is also utilized effectively as both a first- and second-line treatment. Despite these options, approximately one-third of patients experience limited or no benefit from existing therapies. This underscores the urgent need for deeper insights into the disorder’s causes and pathophysiology, as well as the development of innovative treatment, prevention, and cure strategies (Stewart et al. 2013). In treatment-refractory cases of OCD, various therapeutic strategies are considered despite limited evidence. While SSRIs are established treatments, their efficacy does not confirm serotonin deficiency as the core issue. The disorder’s heterogeneity complicates pathophysiological studies and the validation of treatments, with genetic factors accounting for 40–50% of risk yet remaining poorly understood (Mattheisen et al. 2015). Recent analyses indicate rare genetic causes of OCD, but their impact is often lost in broader population studies, highlighting treatment challenges. The condition may represent various individual pathways rather than a single disorder, suggesting that group-level studies may yield limited insights. As a result, there has been no new FDA-approved drug for OCD in two decades, emphasizing the ongoing search for effective treatments without confirmatory approvals from agencies such as the EMA (Olatunji et al. 2017).

Pregabalin, a gamma-aminobutyric acid analog, is authorized for conditions such as epilepsy, neuropathic pain, fibromyalgia, and generalized anxiety disorder. Although its exact mechanism is not fully understood, it likely interacts with voltage-dependent calcium channels to decrease neurotransmitter release, including glutamate. Pregabalin has shown anecdotal promise in OCD, supported by a double-blind RCT involving 56 patients with treatment-resistant OCD. In this study, pregabalin (mean dose of 185 mg) added to sertraline significantly reduced Yale–Brown Obsessive-Compulsive Scale (Y-BOCS) scores by over 35% compared with placebo, with good tolerability, suggesting its potential as an augmentation therapy.

Memantine, a low-affinity NMDA receptor antagonist, has been primarily studied for the treatment of refractory OCD, although it is mainly used for Alzheimer’s dementia. Its rapid clearance and distinct pharmacological properties differentiate it from higher-affinity NMDA antagonists such as ketamine. Placebo-controlled studies indicate potential benefits for patients with OCD undergoing memantine treatment alongside existing SSRI therapy or sertraline, with notable improvements in various OCD symptom scales. Two RCTs showed significant positive outcomes among 102 participants over 12 weeks, despite common side effects such as headache and insomnia (Modarresi et al. 2018; Askari et al. 2022). However, these studies are limited by small sample sizes and their geographic restriction to Iran, raising questions about generalizability. A systematic review suggested substantial benefits, yet the small-scale nature of the trials necessitates larger, methodologically robust studies across diverse populations to accurately assess memantine’s efficacy and safety as an OCD treatment (Sahraian et al. 2017).

Existing research provides a strong foundation for utilizing dopamine antagonists as adjunctive treatments for OCD, particularly compared with the limited evidence for enhancing dopaminergic transmission. Notable studies have explored the role of catechol-O-methyltransferase (COMT) in various disorders, including OCD (Jatana et al. 2013). One significant pro-dopaminergic agent, tolcapone, has been investigated in a double-blind, placebo-controlled trial involving 20 patients with OCD. Administration of tolcapone at 200 mg/day demonstrated a significant reduction in obsessive-compulsive symptoms, as measured by the Y-BOCS score, compared with placebo. Participants tolerated tolcapone well, although some reported side effects such as reduced bowel movements, fatigue, and sleep difficulties. Of the participants, 25% were also receiving stable medications (SSRIs or venlafaxine), and 80% had received previous treatments for OCD. Overall, the findings suggest that enhancing dopamine signaling via tolcapone might alleviate OCD symptoms, indicating a potential avenue for treatment (Deleu et al. 2002; Grant et al. 2021).

The serotonin 5-HT3 receptor antagonist ondansetron is primarily utilized as an antiemetic but has also been investigated for its potential in augmenting treatment for OCD. This is due to the role of serotonin 5-HT3 receptors in inhibiting dopamine release in the corticomesolimbic pathway, which, when combined with SSRIs and antipsychotics, may benefit patients with treatment-resistant OCD. Ondansetron appears to reduce activation in cortical networks associated with interoceptive and sensorimotor processing, potentially alleviating symptoms linked to disgust and sensory over-responsiveness. Two RCTs have assessed ondansetron’s efficacy for OCD. The first trial involved 135 patients with treatment-resistant OCD already receiving stable SSRI and antipsychotic therapy. Participants received either ondansetron (4 mg), granisetron (2 mg), or placebo for 14 weeks, resulting in Y-BOCS score reductions of 41.5%, 39.7%, and 15.2%, respectively. Notably, the complete response rate was significantly higher in the ondansetron group compared with the granisetron group, and relapse was absent in patients receiving ondansetron. The second RCT, involving 40 patients, also showed that ondansetron outperformed placebo at 8 and 12 weeks in response rates. The drug was well tolerated, but caution is advised due to its potential to prolong the QTc interval, particularly in patients at risk for arrhythmias or when used with other QT-prolonging medications. The primary side effect reported for ondansetron was diarrhea, while granisetron was linked to constipation and headaches. These findings highlight the promising role of ondansetron as an augmentation therapy in treatment-resistant OCD (Sharafkhah et al. 2019; van Roessel et al. 2023).

N-acetylcysteine (NAC), a prodrug of L-cysteine, enhances glutathione synthesis and modulates glutamatergic neurotransmission through the AMPA and NMDA receptor systems. Its efficacy in treating refractory OCD remains inconsistent. Two recent RCTs highlighted this: Li’s study involved 11 boys aged 8–17 years receiving NAC at increasing doses up to 2,700 mg/day for 12 weeks, resulting in improved scores on the Children’s Yale–Brown Obsessive-Compulsive Scale (CY-BOCS), with the only side effect being a skin rash. In contrast, Sarris’s study involving 89 patients with OCD found no significant difference in Y-BOCS scores between those taking NAC at 500 mg/day and those receiving placebo over 20 weeks. Consequently, the current evidence regarding NAC’s effectiveness for OCD is insufficient and variable, preventing definitive conclusions (Li et al. 2020; Sarris et al. 2022).

The potential for stimulants, particularly methylphenidate, to benefit individuals with OCD is intriguing, despite seeming counterintuitive given OCD’s contrasting neuroactivity compared with attention-deficit/hyperactivity disorder (ADHD), which typically responds well to such treatments. While ADHD is characterized by hypoactivation in the frontostriatal circuits, OCD displays hyperactivation, reflecting differences in compulsive and impulsive behaviors. Nevertheless, both disorders share similar deficits in executive functioning, particularly in response inhibition and attention, suggesting that they may have underlying commonalities in their pathophysiology. Caffeine has been noted to diminish distress and compulsive behaviors in individuals with contamination fears, potentially by enhancing inhibitory control and alleviating compulsion-driven actions (Abramovitch et al. 2012; Naftalovich et al. 2020). Clinical evidence, although limited, supports this concept; an RCT demonstrated the effectiveness of extended-release methylphenidate in adults with OCD who had previously shown an inadequate response to fluvoxamine. In this study involving 44 adults, those receiving a combination of methylphenidate and fluvoxamine exhibited significant reductions in Y-BOCS scores, encompassing improvements in both total scores and the obsession subscale, alongside reductions in anxiety symptoms. Importantly, no significant adverse effects were reported during the trial, indicating that methylphenidate may offer a promising adjunctive treatment strategy for OCD (Zheng et al. 2019).

Anxiety disorders rank among the most common psychiatric conditions and contribute significantly to disability. Research on their etiology has focused on the serotonin system, with first-line treatments involving serotonergic agents such as SSRIs and SNRIs. Common side effects hinder adherence, affecting approximately 50% of patients. Recent investigations have explored new agents targeting different 5-HT receptors, but no new drugs for anxiety disorders have recently been approved by the FDA, and few are in advanced clinical trials. Current research primarily examines psychedelics, glutamatergic drugs, and cannabinoids. Challenges in developing new therapies stem from methodological issues in clinical trials, including inadequate control groups and limited comparison with standard treatments such as SSRIs and benzodiazepines, highlighting a contrast with the extensive research on other psychiatric disorders (Garakani et al. 2020; Caldiroli et al. 2023).

Lysergic acid diethylamide (LSD) is a hallucinogen classified as a Schedule I drug, indicating its high potential for abuse and lack of accepted medical use. It interacts with serotonin receptors and possesses anxiolytic properties. Recent studies, including a phase II trial and a subsequent prospective study, evaluated LSD’s effects on patients with anxiety disorders, specifically panic disorder (PD), generalized anxiety disorder (GAD), and social anxiety disorder. A total of 42 and 39 patients participated in these trials, receiving 200 µg of LSD or a placebo across two sessions. Results showed that LSD significantly reduced anxiety and symptoms of comorbid depression for up to 16 weeks, as measured by various assessment scales, including the State–Trait Anxiety Inventory (STAI-G), Hamilton Depression Rating Scale (HAM-D-21), and Beck Depression Inventory (BDI). Notably, the only severe side effect reported was a transient acute anxiety episode in one participant. The follow-up prospective study, conducted 12 months after the initial trials, confirmed the persistence of the therapeutic effects of LSD-assisted therapy for anxiety (Holze et al. 2023; Holze et al. 2024).

The psychoactive compound 3,4-methylenedioxymethamphetamine (MDMA), classified as a psychedelic amphetamine, was recognized as a Schedule I controlled substance in the 1980s. However, recent studies have provided promising evidence for its efficacy in treating post-traumatic stress disorder (PTSD). Two significant studies, including an RCT and an exploratory data analysis, focused on 90 patients with PTSD receiving MDMA (doses of 80–180 mg) alongside therapy sessions. The 18-week RCT demonstrated that MDMA significantly reduced scores on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and SDS compared with placebo. Additionally, a second trial indicated that MDMA-assisted therapy led to marked improvements on the Toronto Alexithymia Scale (TAS-20) and the Self-Compassion Scale (SCS). These findings suggest that MDMA-assisted therapy is effective for individuals with severe PTSD and is safe and well tolerated, even among those with comorbidities such as dissociation, depression, and histories of substance use disorders. Notably, MDMA did not result in adverse effects related to abuse, suicidal tendencies, or QT prolongation. This research highlights the psychological benefits that psychedelic substances may offer in alleviating PTSD symptoms (Mitchell et al. 2023; van der Kolk et al. 2024).

D-cycloserine (DCS) is an NMDA partial agonist and is the most extensively researched glutamatergic agent in anxiety treatments. A 2015 Cochrane review determined that DCS did not significantly enhance the effectiveness of CBT in treating anxiety disorders among children and adolescents. A subsequent meta-analysis suggested a minor difference between DCS and placebo in treating anxiety disorders, although follow-up improvements were negligible. Since 2018, five studies have evaluated DCS for social anxiety disorder, PD, and agoraphobia. One RCT involving 169 participants with social anxiety found no augmentation of CBT effects with DCS. Another RCT involving 24 adolescents with PD reported similar anxiety reductions in both the DCS and placebo groups. A third RCT involving 33 patients with PD indicated that while DCS (250 mg) showed better clinical recovery at 1 month, gains were equivalent to those with placebo by 6 months. Two trials involving patients with agoraphobia (73 in total) revealed significant symptom reduction for both DCS and placebo during CBT, with exploratory analyses showing potential short-term anxiety reduction in the DCS group during exposure sessions but no enduring benefits. The findings underscore the need for further research to validate these results and explore modifications that could enhance treatment efficacy while managing anxiety during exposure. Confirmatory trials are recommended to further assess the effectiveness of DCS on anxiety levels in patients with agoraphobia (Pyrkosch et al. 2018; Pyrkosch et al. 2025).

Ketamine, originally developed as an anesthetic, has shown rapid antidepressant effects and potential efficacy in treating anxiety disorders in recent studies. Research indicates that daily oral ketamine is beneficial for depressive and anxiety symptoms in hospice care patients. Five studies conducted since 2018 have explored various administration methods—primarily intravenous and subcutaneous routes—along with varying dosages depending on patient weight. For social anxiety disorder, one RCT demonstrated that intravenous ketamine at 0.5 mg/kg significantly improved symptoms based on the Liebowitz Social Anxiety Scale. Another study highlighted the effectiveness of escalating doses of subcutaneous ketamine administered weekly in patients with anxiety disorders. Ketamine has also been evaluated for PTSD treatment; one RCT found significant improvements in PTSD symptoms with 0.5 mg/kg ketamine compared with midazolam, while another study yielded mixed results, indicating no major differences in symptoms. Adverse effects were generally minor, including agitation, nausea, and various dissociative symptoms, but no serious events were recorded. Overall, ketamine exhibits potential as a therapeutic option for treatment-resistant anxiety disorders and chronic PTSD, necessitating further research to fully ascertain its efficacy (Glue et al. 2018; Abdallah et al. 2022; Feder et al. 2023).

Cannabis, cannabidiol (CBD), and other cannabinoids are commonly thought to be safe and effective for anxiety relief; however, current evidence does not support this belief. Clinical trials indicate that cannabinoids might not be safe or effective for individuals with anxiety disorders. Cannabinoids interact with receptors such as CB1, 5-HT1A, and TRPV1, with low doses potentially providing anxiolytic effects, while high doses could induce anxiety. Although some 5-HT1A receptor agonists are effective for anxiety treatment, studies suggest that CBD may have potential benefits for conditions such as PD, GAD, and social anxiety disorder (SAD). Nonetheless, the overall quality of evidence remains low (Blessing et al. 2015). Four RCTs and one open-label study investigated the effects of CBD on anxiety disorders. Sample sizes varied from 31 to 178 patients diagnosed with conditions such as agoraphobia, PTSD, or general anxiety disorders. Trial durations ranged from 8 days to 26 weeks, with CBD dosages ranging from 300 to 800 mg/day. One RCT indicated that a dosage of 300 mg/day for 4 weeks could effectively treat social anxiety in adolescents. An open-label study by Berger et al. suggested that CBD may alleviate anxiety severity and is safe for young people with treatment-resistant anxiety; however, this finding was not corroborated in adult patients with agoraphobia or social anxiety (Kwee et al. 2022). Additionally, a single 300 mg dose of CBD mitigated anxiety and cognitive impairment during a reenactment of non-sexual trauma in patients with PTSD but was ineffective for sexual trauma (Gundugurti et al. 2024). Furthermore, a recent 2024 study showed that nanodispersible CBD was therapeutically safe and well tolerated and was effective for mild-to-moderate anxiety disorders and associated symptoms such as depression and sleep problems. These findings support potential applications of nanodispersible CBD formulations in psychiatric treatments, either alone or alongside other medications. The study reported adverse effects associated with CBD and placebo, including fatigue, dizziness, low mood, drowsiness, and hot flushes or chills, with no serious unexpected adverse events reported (Bolsoni et al. 2022). Notably, the findings regarding CBD are mixed, highlighting the need for controlled, randomized studies with varied dosing regimens to establish the long-term efficacy and safety of the compound. Additionally, while CBD has anxiolytic effects, delta-9-tetrahydrocannabinol (THC), a CB1 receptor partial agonist, exhibits contrasting anxiogenic effects at higher doses, although there are no registered studies examining THC’s impact on anxiety disorders (Freitas-Ferrari et al. 2010; Turna et al. 2017).

Recent advancements in pharmacotherapy for psychiatric disorders have led to new medications such as lumateperone and OLZ/SAM for schizophrenia and bipolar disorder, with the latter mitigating olanzapine-associated weight gain. KarXT combines xanomelin and trospium for schizophrenia, while ketamine and esketamine show effectiveness in treatment-resistant MDD and bipolar disorder, although ketamine is used off-label. Brexanolone and zuranolone target postpartum depression, and new anti-inflammatory agents and combinations, such as DCS with lurasidone, are being explored for bipolar depression. Ulotaront and roluperidone aim to reduce side effects in psychosis treatment. Moreover, hallucinogens are being reconsidered for anxiety disorders, alongside mixed results for cannabis. Ongoing research focuses on personalized treatments integrating genetics and digital phenotyping for improved patient outcomes in psychiatric care. Recent literature on pharmacotherapy advancements for psychiatric disorders highlights a research focus on identifying new molecules or reformulating existing medications to enhance treatment personalization while minimizing adverse effects. There is a pressing need for new research projects and increased funding aimed at gathering comprehensive data on psychiatric treatments, which will be crucial for alleviating the burden of these disorders and enhancing patients’ quality of life. In alignment with the precision medicine paradigm, psychiatric research should leverage pharmacogenetic and pharmacogenomic studies to identify genetic variations affecting treatment responses, resistance, and adverse medication effects. Additionally, the incorporation of digital phenotyping—a strategy utilizing data from smartphone interactions to monitor mental status—should be prioritized to assess the long-term impact of medications, particularly in regions with limited access to mental health services.