Pharmacological Monotherapy for Depressive Disorders: Current and Future-A Narrative Review.

SSRIs are the most prescribed antidepressants for depressive disorders. Although SSRIs share a common mechanism of action by blocking the reuptake of serotonin through occupying pre-synaptic serotonin transporters, some SSRIs at higher doses also block the reuptake of other neurotransmitters (). Some newer antidepressants, such as vilazodone and vortioxetine, also block serotonin reuptake in addition to 5-hydroxyltryptamine (5-HT) receptor agonism or antagonism (). In terms of antidepressant efficacy, there is no significant difference among SSRIs [,]; however, some of them have better acceptability than others, with fluoxetine having the best acceptability . The side effect profiles of SSRIs are also different [,]. SSRIs are the first-line antidepressants for depressive disorders. They were used in the Level 1 and Level 2 treatments in the STAR*D [,], and the dosage of citalopram was 60 mg per day. However, the current FDA-recommended dose limit of citalopram is 40 mg per day due to its potential for QTc prolongation. An electrocardiogram (ECG) may be indicated for patients who need more than 40 mg per day. Table 1 Table 1

SNRIs include venlafaxine, desvenlafaxine, duloxetine, milnacipran, and levomilnacipran. However, their affinities for serotonin and norepinephrine pre-synaptic transporters are different (). To achieve an SNRI antidepressant effect, at least 150 mg or more of venlafaxine should be used per day. SNRIs are also first-line antidepressants for depressive disorders. Venlafaxine was used in the Level 2 treatment in the STAR*D, and its efficacy in patients who failed citalopram was similar to that of sertraline and bupropion . In placebo-controlled trials, venlafaxine and duloxetine showed a larger difference in response rates compared to placebo than SSRIs did [,], which is consistent with the results of Level 2 treatments in the STAR*D. In the Level 2 treatments of the STAR*D, about 25% of patients who received venlafaxine achieved remission compared to about 18% of patients who received sertraline achieving remission . Table 1

Bupropion is a dopamine reuptake inhibitor and blocks norepinephrine reuptake at higher doses (). In the Level 2 treatments of the STAR*D, bupropion monotherapy had a similar remission rate (21%) as venlafaxine (25%) and sertraline (18%) monotherapy in patients who failed citalopram monotherapy . The odds ratio (OR) for response with venlafaxine relative to placebo was 1.78 and the OR for response with bupropion relative to placebo was 1.58 . Due to the overlap of the 95% confidence intervals of the ORs of venlafaxine and bupropion relative to placebo, the difference in response rates between venlafaxine and bupropion was not significant. It is reasonable to consider bupropion monotherapy as the first medication, especially for those who are present with severe anhedonia, lack of energy, poor concentration, and hypersomnia without much anxiety. Since bupropion does not have sexual side effects, for patients who have experienced sexual side effects from SSRIs and SNRIs in previous episodes, bupropion can be initiated as the first medication for a current episode as well. Bupropion is the only antidepressant that has a significantly lower risk of somnolence relative to placebo . Therefore, patients with daytime somnolence/fatigue are likely to have more benefit from bupropion than from other antidepressants. Table 1

Reboxetine is a selective norepinephrine reuptake inhibitor () . Reboxetine is mainly available in Europe, South American countries, and China . However, studies conducted in the US and Canada resulted in a US FDA non-approval decision. In both network meta-analyses [,], reboxetine was the least effective antidepressant among 21 antidepressants. However, it has a linear increase in effect size as its doses increase . Table 1

Toludesvenlafaxine is a prodrug to desvenfafaxine and inhibits serotonin, norepinephrine, and dopamine reuptake through blocking SERT, NET, and DAT, respectively () . Its antidepressant efficacy has been demonstrated with one phase II and one phase III randomized, double-blind, placebo-controlled trial [,]. Currently, it is only available in China. In a recent systematic review and network meta-analysis of 22 antidepressants , toludesvenlafaxine had the largest OR of 4.52 relative to placebo for response. Among the rest of the antidepressants, only amitriptyline had an OR of 2.27 relative to placebo for response, and the rest had ORs of less than 2.0 for response. The larger effect size of toludesvenlafaxine relative to placebo, compared to other antidepressants, might be due to the fact that only a few studies of toludesvenlafaxine were included in the meta-analysis. More studies are needed to validate the efficacy of toludesvenlafaxine in depressive disorders. Table 1

Although there is no standard definition for atypical antidepressants, the mechanisms of action of mirtazapine, trazodone, and nefazodone are quite different from other antidepressants (). Among these medications, trazodone is commonly used for sleep and mirtazapine is used for depression as a second-line medication similar to TCAs. However, patients treated with mirtazapine had the second highest chance for response relative to placebo among all 21 antidepressants, and the acceptability was comparable to that of placebo . Mirtazapine as a second-line medication is mainly due to its side effect profiles, including higher rates of drowsiness/sedation, increased appetite/weight gain, xerostomia, increased serum cholesterol, hypertriglyceridemia, and constipation compared to SSRIs, SNRIs, and dopamine reuptake inhibitors. In addition, mirtazapine also has rare but severe side effects including thrombocytopenia, bone marrow suppression and neutropenia, and acute pancreatitis. Table 1

In the STAR*D, mirtazapine was a Level 3 treatment as nortriptyline monotherapy and augmentation therapy with lithium and T3 (triiodothyronine). There were no significant differences among these treatments, although mirtazapine had the lowest remission rate of 12% . The remission rate of nortriptyline was 20%. It is worth noting that the patients in Level 3 treatments were those who had failed citalopram and sertraline, venlafaxine, bupropion, citalopram plus bupropion, or citalopram plus buspirone.

TCAs include tertiary amines (amitriptyline, clomipramine, doxepin, imipramine, and trimipramine), secondary amines (desipramine, nortriptyline, and protriptyline), and tetracyclics (amoxapine and maprotiline). Their affinities for serotonin transporters, norepinephrine transporters, and 5-THreceptors are different (). Currently, TCAs are considered as the second-line antidepressants and nortriptyline was used as a Level 3 treatment in the STAR*D . In the placebo-controlled studies, amitriptyline had the highest chance of response relative to placebo among all 21 antidepressants . Clomipramine was also significantly more effective than placebo and as effective as most other antidepressants. Amitriptyline and clomipramine had a linear increase in effect size as their doses increased . However, clomipramine had the worst acceptability . 2C Table 1

The effective blood levels of amitriptyline, desipramine, doxepin, imipramine, and nortriptyline are established; however, nortriptyline's level has a bell shape with a narrow window of efficacy. For patients who are indicated for a tricyclic for MDD, monitoring the blood level may be necessary. Due to their atrioventricular (AV) block and quinidine-like antiarrhythmic effects, all patients considering a TCA should be screened for preexisting cardiac conditions, including prolonged QTc intervals, heart disease, and a family history of arrhythmias. A baseline and periodical ECG are essential, especially for those who have cardiac diseases and other cardiac risk factors. More importantly, intentional or accidental overdose of a TCA can be fatal. Careful assessment of suicidal risk and close monitoring of the progress of patients are critical to minimize the risk of intentional or accidental death.

TCAs may be more effective than SSRIs in MDD with melancholic features. A TCA may be considered for this subgroup of patients when an SSRI fails. However, TCAs affect cholinergic and histaminergic systems in addition to serotonin and norepinephrine. Therefore, TCAs have many more side effects than SSRIs, SNRIs, and bupropion. In addition, suddenly stopping TCAs may cause withdrawal symptoms (cholinergic rebound) including excessive salivation, diarrhea, headache, and vivid dreams.

In the STAR*D, only about 7% of patients who failed nortriptyline, mirtazapine, or augmentation with lithium or T3 (Level 3 treatments) achieved remission with tranylcypromine, a non-selective and irreversible MAOI . In the network meta-analysis of 21 antidepressants, no study of MAOIs in MDD was included . The lack of a randomized, placebo-controlled or double-blind head-to-head comparison study of MAOIs in MDD might be due to their potential life-threatening side effect such as hypertensive crisis. In addition to interactions with fermented food and drinks, MAOIs can also interact with other antidepressants, which leads to potential severe consequences. When switching from an MAOI to another antidepressant, patients should wait for at least 14 days before initiating the new treatment to prevent any drug-to-drug interactions. Similarly, when switching from an SSRI, SNRI, or TCA to an MAOI, patients should wait for at least two weeks before initiating the new treatment. However, for those who take fluoxetine, they should wait for five weeks before starting an MAOI.

Gepirone is a 5-HTpartial agonist and 5-HTantagonist and it is in the same family as buspirone but has three times higher affinity for the 5-HTreceptor . Gepirone extended release (ER) was approved by the US FDA for the treatment of NTRMDD in 2023. The approval process took more than 20 years and involved multiple submissions because gepirone in NTRMDD trials had much more negative/failed studies (87%) than positive studies. In contrast, most other US FDA-approved antidepressants have about 49% negative/failed trials . There were two positive studies supporting the efficacy of gepirone-ER for the treatment of NTRMDD, but the US FDA rejected the application three times due to less robust results . After a series of important debates and an internal review, the US FDA finally approved gepirone-ER monotherapy for NTRMDD [,]. 1A 2A 1A

However, even in the two positive studies, the difference between gepirone and placebo in reducing the Hamilton Depression Rating Scale-17 item (HAMD-17) total score was about 2.5 points, which is smaller than the clinically meaningful difference of 3–5 points that was observed for other FDA-approved antidepressants . In contrast, the number needed to treat (NNT) of 6–8 for response and 7 for remission from gepirone relative to placebo was comparable to that of the lower-performing antidepressants approved by the US FDA . It remains unclear if the relative efficacy of gepirone will change if it is included in a network meta-analysis like agometaline [,].

Unlike other antidepressants, gepirone carries a risk of QTc prolongation with an FDA warning and recommendation of ECG monitoring during the treatment. On the other hand, gepirone has minimal sexual side effects and does not cause weight gain, so it may offer relief and improve sexual function in patients with depression like bupropion and vilazodone . While gepirone represents a novel addition to monoamine-based antidepressants, its cardiac risks, limited efficacy, and FDA warnings make it unlikely to become a first-line treatment for depressive disorders.

Agomelatine is an antidepressant that targets the melatonergic system and 5-HTreceptors. Its antidepressant effect is believed to work through the agonism of melatonergic receptors and the antagonism of 5-HTreceptors (). Although agomelatine was approved for the treatment of depression in Europe (2009), Australia (2010), and some other countries, it did not receive approval for NTRMDD from the US FDA. The main issue with agomelatine was its smaller effect size compared to other commonly used antidepressants. Its application for depression was rejected twice by the European Medicines Agency . In an early meta-analysis of nine randomized, double-blinded, placebo-controlled studies of agomelatine versus placebo or other antidepressants (paroxetine, fluoxetine, sertraline, venlafaxine) in 3943 patients with severe NTRMDD , agomelatine was superior to placebo with a standardized mean difference (SMD) of −0.26, which is smaller than the overall antidepressant effect size of −0.3 . The meta-analysis also found a slight superiority of agomelatine over other antidepressants with an SMD of −0.11. In the network analysis of 21 antidepressants, agomelatine was significantly superior to placebo in response rate, as most other antidepressants, and had the best acceptability . Head-to-head comparison studies also suggested that agomelatine along with amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine was more effective than other antidepressants. Moreover, agomelatine has more benign side effects with minimal sexual side effects compared to other antidepressants, and has hypnotic effects. 2C 2C Table 1

St. John's Wort () is an herb that contains many bioactive molecules. It has been used as a homeopathic remedy for different illnesses for decades . Its antidepressant effect is involved with glutamate, acetylcholine, serotonin, norepinephrine, and dopamine . Different studies on St. John's Wort used different doses and formulations, which might have caused the inconsistent results of St. John's Wort versus placebo. Meta-analyses found that St. John's Wort was superior to placebo in mild and moderate depression, and there were no significant differences between second generation antidepressants (SGAs) and St. John's Wort [,]. However, all head-to-head comparison trials of St. John's Wort versus SGAs used low to moderate doses of SGAs. The overall risk of adverse events was higher among patients receiving SGAs than those receiving St. John's Wort, but the risk of serious adverse events did not differ significantly. Hypericum perforatum

S-Adenosyl-L-Methionine (SAMe) and folate are naturally occurring compounds that are present in nearly all tissues in the body. Their role in depressive disorders is based on observations that metabolites from one-carbon metabolism play an important role in the pathogenesis and treatment of depression [,,]. Both SAMe and folate are key components of the one-carbon metabolic cycle (). Currently, L-methyl folate and SAMe monotherapy or adjunctive therapy to an antidepressant have been studied in the treatment of NTRMDD and TRD. L-methyl folate is approved by the US FDA as a medicinal supplement for augmenting antidepressants in the treatment of TRD.

A recent systematic review of eight trials and 1011 subjects (three of the five were SAMe versus placebo) found that SAMe was significantly better than placebo in reducing depressive symptoms . However, a Cochrane Database Systematic Review in 2016 of eight trials of SAMe versus placebo, imipramine, desipramine, or escitalopram (= 934) did not find strong evidence that SAMe was superior to placebo in reducing depressive symptoms . Both reviews did not find significant differences between SAMe and other antidepressants (imipramine or escitalopram). Due to the low quality of published studies so far, large randomized, double-blind, placebo or active controlled studies are necessary to confirm the effectiveness of SAMe in the treatment of NTRMDD as a monotherapy. ^{35 36} n

L-methyl folate is the only form of folate that crosses the blood–brain barrier. Its efficacy and safety in TRD were assessed in two multicenter randomized, double-blind, sequential parallel comparison trials in patients who failed one or two SSRIs. Patients received L-methyl folate 7.5 mg/day, L-methyl folate 15 mg/day, and placebo along with their ongoing antidepressant for 30 days . Patients who received L-methyl folate 15 mg/day had a significant reduction in depression symptoms over those who received the placebo. The response rate in the L-methyl folate 15 mg group was also significantly higher than in the placebo group, 32.5% versus 14.6%, with an NNT for response of 6 favoring L-methyl folate 15 mg/day over the placebo. A recent meta-analysis of six randomized, placebo-controlled trials with a total number of 584 patients found that adjunctive therapy of L-methyl folate/folic acid to SSRIs/SNRIs had significantly higher rates of response and remission compared to placebo . In a real-world patient study (= 554), adding L-methyl folate 7.5 mg or 15 mg to the existing antidepressant treatment, 67.9% of patients achieved response, defined as a 50% reduction in baseline Patient Health Questionnaire-9 (PHQ-9) score and 253 patients (45.7%) achieved remission, defined as a PHQ-9 score < 5 after an average of 95 days of therapy . ^{33 34 37} n

The mechanism of Omega-3 fatty acids (Omega-3) in depression remains unclear. The potential mechanisms are involved with its anti-neuroinflammatory effect, regulation of the hypothalamus–pituitary–adrenal (HPA) axis, anti-oxidative stress, anti-neurodegeneration, neuroplasticity, and modulation of neurotransmitter systems . An early meta-analysis of 2160 patients found that compared with placebo, 100% eicosapentaenoic acid (EPA) and ≥60% EPA-major formulations with an EPA dosage ≤ 1 g/day were significantly superior to placebo in reducing depressive symptoms. However, pure docosahexaenoic acid (DHA) and DHA-major formulations did not significantly differ from placebo . A Cochrane Database Systematic Review of 34 studies with 1924 patients found that Omega-3 supplementation results in a small to modest benefit in improving depressive symptoms with an SMD of −0.40. Overall, the quality of the evidence for all outcomes was rated low to very low .

AXS-05 (Auvelity, Axsome Therapeutics, New York City, NY, USA) was approved by the US FDA for the treatment of NTRMDD in adults in August 2022. Dextromethorphan is an uncompetitive NMDA receptor antagonist like ketamine that increases glutamate release as well as an agonist to sigma-1 receptor that increases serotonin levels (). The approval was based on one phase II and one phase III randomized, double-blind, placebo-controlled trial [,]. The studied population was patients with a DSM-5 diagnosis of MDD for at least four weeks and Montgomery–Asberg Depression Rating Scale (MADRS) scores ≥ 25 points. Eligible patients were randomized to receive AXS-05 monotherapy or placebo for six weeks. In a phase III study , the significant superiority of AXS-05 over placebo occurred as early as week 1 with a difference of 2.23 points on MADRS total scores, week 2 with a difference of 4.22 points, and week 6 with a difference of 3.9 points favoring AXS-05. The remission (MADRS total score of ≤10) rate was significantly higher in the AXS-05 group, with a difference of 9.4% at week 2 and a difference of 22.2% at week 5. For treatment response (≥50% reduction in MADRS total score), patients who received AXS-05 had significantly higher response rates than the placebo group at all time points, with a difference of 20% at week 6. Adverse events occurring in ≥5% of patients in the AXS-05 group were dizziness, nausea, headache, diarrhea, somnolence, and dry mouth. AXS-05 was not associated with psychotomimetic effects, weight gain, or sexual dysfunction. Since dextromethorphan increases serotonin levels, AXS-05 should be used with caution when monoamine-based antidepressant(s) and other serotonin-increasing agents are used. Table 1

Esketamine (S-ketamine) is more potent than the racemic ketamine that is a mixture of R-ketamine and S-ketamine. The bioavailability of intranasal esketamine (SPRAVATPO, Janssen Pharmaceuticals, Titusville, NJ, USA) is approximately 50%. Intranasal esketamine plus an antidepressant was approved by the US FDA on 5 March 2019 for the treatment of TRD, and intranasal esketamine monotherapy for TRD was approved on 21 January 2025. The US FDA also approved intranasal esketamine to treat adult patients with MDD and acute suicidal ideation (SI) or behavior on 3 August 2020.

The approval of intranasal esketamine as an adjunctive therapy for TRD was mainly based on three acute phase III studies [,,], and one long-term phase III study . Among the three acute phase III studies, only one of them demonstrated that intranasal esketamine plus an antidepressant was superior to placebo plus an antidepressant in reducing depressive symptoms . The other two studies did not show the superiority of intranasal esketamine over placebo in the primary outcome, but some secondary outcomes showed significant differences in favor of esketamine. One of the long-term studies also favored esketamine over placebo. The effect size for the change in MADRS score from baseline to day 28 was 0.30 (small), even in the positive study.

The approval of intranasal esketamine as a monotherapy for TRD was mainly based on a phase IV double-blind, placebo-controlled, multiple-center study in patients with MDD who had failed ≥ 2 oral antidepressants (≤25% improvement) based on treatment history for the current episode. Intranasal esketamine, both 56 mg and 84 mg, was superior to placebo in reducing depressive symptoms in 4 weeks and the onset of action occurred as early as 24 h (NCT04599855) . In a post hoc analysis, the remission rates (MADRS score ≤ 12) were 22.5% for intranasal esketamine and 7.6% for placebo. The approval of esketamine as a monotherapy for TRD provides an option for patients who cannot tolerate an antidepressant.

The approval for adults with MDD and acute SI and behavior was mainly based on two phase III studies [,]. Both studies demonstrated that intranasal esketamine plus standard of care antidepressant therapy (SAT) was superior to placebo plus SAT in reducing depressive symptoms' severity. The superiority started as early as four hours after receiving the first dose of esketamine and was sustained until the end of the 25-day study period. However, the change in suicidality severity was not significantly different between the two groups, although the esketamine plus SAT group had more reductions in suicidality than the placebo plus SAT group.

An earlier meta-analysis of four studies with three TRD studies found that a significant difference between esketamine and placebo in response and remission started as early as 2 h after the first dose, peaked at 24 h, and persisted until the end of the study . The NNT of response with three TRD studies was 7 while the NNT of remission (MADRS ≤ 12 or 10) was 9. A more recent meta-analysis of nine studies of esketamine in patients with TRD or MDD with SI and intent found that the difference in remission rate between esketamine and placebo was significantly different, with a risk ratio (RR) of 1.35 with 84 mg and an RR of 1.66 with flexible doses . However, there was no significant difference in remission rates between esketamine 28 or 56 mg and placebo. Common side effects of esketamine included dissociation, vertigo, nausea, dizziness, dysgeusia, headache, somnolence, hypoesthesia, paresthesia, and oral hypoesthesia [,,].

Intranasal esketamine therapy starts twice a week for four weeks, with a first session of 56 mg and seven sessions of 84 mg. Patients who have at least 50% improvement after the first eight sessions continue treatment with the same dose as the last session and at a weekly interval for 4 weeks and biweekly twice. From then on, the treatment interval for future sessions will be determined by the mood stability of patients.

During each session, patients are closely monitored for 2 h after dosing. After each treatment, patients should not engage in potentially hazardous activities such as driving a motor vehicle and operating machinery until the next day after a restful sleep.

Ketamine infusion commonly uses racemic ketamine that is a mixture of R-ketamine and S-ketamine. Ketamine is a noncompetitive NMDA receptor antagonist. Its antidepressant effect is believed to occur through blocking NMDA receptors on pre-synaptic GABAergic interneurons which regulate the release of glutamate from pre-synaptic glutamatergic neurons. Increased glutamate in the synaptic cleft acts on post-synaptic neurons, leading to an increase in the production of brain-derived neurotrophic factor (BDNF), neuroplasticity, and synaptogenesis through activating NMDA receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors . In addition, ketamine and other noncompetitive NMDA receptor antagonists may restore synaptic homeostasis through blocking pathologically hyperactive glutamate N2D subtypes of NMDA receptors in patients with MDD ().

Most studies on ketamine infusion in depression have been conducted in patients with TRD or treatment-resistant bipolar depression using a single infusion. A rapid onset of antidepressant effects (within four hours) with a large effect size was observed in normal saline-controlled or midazolam-controlled studies [,,,]. However, there is no standard protocol for ketamine infusion, although most academic centers have used 0.5 mg/kg to 0.75 mg/kg in 40–60 min two to three times a week for treatment-resistant bipolar or unipolar depression [,]. Some clinicians may use doses up to 1.5 mg/kg or higher in 40–60 min for treatments based on treatment response and side effects. There is also no consensus on the optimal frequency and duration following an acute series of ketamine infusions. It remains unclear whether ketamine infusion for depression can be used as a monotherapy for NTRMDD.

Brexanolone (Zulresso, Sage Therapeutics, Cambridge, MA, USA) is an aqueous formulation of allopregnanolone, which is a major metabolite of progesterone, and it was approved by the US FDA for PPD with a Risk Evaluation and Mitigation Strategy (REMS) in 2019. Its mechanism of action is believed to change neuronal excitability through modulating GABA receptors, especially synaptic and extra synaptic GABAreceptors . The approval was based on two phase III studies which enrolled women aged 18 to 45 years with PPD [,]. Eligible participants were randomized to receive a single 60 h continuous infusion of either brexanolone 90 μg/kg/h, brexanolone 60 μg/kg/h, or placebo . The mean difference in change from baseline in HAMD-17 score between the placebo group and both brexanolone infusion groups was statistically significant. Remission rates at 60 h were significantly higher in the brexanolone 60 μg group compared to the placebo group (51.4% versus 16.3%), but not significant in the brexanolone 90 μg group compared to placebo (30.8% versus 16.3%). The response rates were significantly higher in both groups compared to the placebo group at 60 h, with 86.5% in the brexanolone 60 μg group, 74.4% in the brexanolone 90 μg group, and 55.8% in the placebo group. Brexanolone infusion was generally well tolerated; the most common treatment-emergent adverse events (AEs) in the brexanolone groups were tachycardia, headache, dizziness, and somnolence. The second study compared the efficacy of brexanolone 90 μg/kg/h and placebo and showed similar findings . A

Under the REMS, healthcare facilities and pharmacies are required to be certified, and patients are required to enroll before receiving brexanolone infusion. The goal of these requirements is to mitigate the potential risk of serious harm resulting from excessive sedation and sudden loss of consciousness during the infusion. The concentration of brexanolone varies during a 60 h infusion: 0–4 h at 30 mcg/kg/hour, increases to 60 mcg/kg/hour during 4–24 h, increases to 90 mcg/kg/hour during 24–52 h, decreases to 60 mcg/kg/hour during 52–56 h, and decreases to 30 mcg/kg/hour during 56–60 h. Because of the REMS requirement and 60 h continuous infusion, brexanolone has very limited use in routine clinical practice.

Zuranolone (Zurzuvae, Sage Therapeutics and Biogen, Cambridge, MA, USA) (is a synthetic, oral neuroactive steroid that acts as a positive allosteric modulator on GABAreceptors, similar to brexanolone, and it was approved by the US FDA for PPD on 4 August 2023. The approval was based on the results of two phase III positive studies of zuranolone versus placebo in PDD [,]. In a phase III study , eligible patients were randomized to receive placebo (= 76) or oral zuranolone 30 mg (= 77) each evening for two weeks . Zuranolone had a significant reduction in HAMD-17 total scores from baseline to day 15 compared to placebo, with a 4.2-point mean difference. The significant differences between zuranolone and placebo were observed from day 3 through day 45. A ^{66 67 66 66} n n

Response rates were significantly higher in the zuranolone group than in the placebo, with 72% vs. 48% at day 15 and 75% vs. 57% at day 45, respectively. Remission rates (HAMD-17 ≤ 7) were also significantly higher in the zuranolone group than in the placebo group, with 19% vs. 5% at day 3, and 45% vs. 23% at day 15, respectively. The race, age, stable concomitant antidepressant, body mass index (BMI), onset of PPD, and family history of PPD did not affect the efficacy of zuranolone. The second phase III study using zuranolone 50 mg/day versus placebo showed similar results . Zuranolone was well tolerated. The common side effects with higher rates in the zuranolone group were somnolence, dizziness, upper respiratory tract infection, diarrhea, and sedation.

Currently, the US FDA recommends zuranolone 50 mg at evening with fat-containing food daily for 14 days. A lower dose is an option for those who cannot tolerate 50 mg/day. Due to a higher risk for somnolence from zuranolone 50 mg relative to placebo (36% vs. 6%), patients should not drive a motor vehicle or engage in other potentially hazardous activities requiring complete mental alertness such as operating machinery for at least 12 h after taking zuranolone.

There are four phase III studies of zuranolone for the treatment of MDD [,,,]. In a phase II study , patients were randomized to zuranolone 30 mg (20 mg if necessary) or placebo at evening time for 2 weeks. At day 15, the zuranolone group (= 45) had a significantly greater reduction in HAMD-17 scores from baseline compared to the placebo group (= 44), with −17.4 points versus −10.5 points (< 0.001). From day 2 to day 28, the difference between the groups in HAMD-17 was significant but not at day 35 or day 42. At day 15, the NNT for both response and remission was three. At day 3, the NNT for response and remission was five and ten, respectively. At day 28, the response and remission rates of zuranolone versus placebo were 62% vs. 46%, and 52% vs. 28%, respectively. There were also significant differences in other secondary outcome measures including changes in MADRS, Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impression-Improvement Scale (CGI-I). ^{68 69 70 71 73} n n p

However, the rapid onset and large effect size observed from the zuranolone phase II study were not replicated in the phase III studies . Overall, the efficacy of zuranolone in MDD was less robust compared to the results in PPD. Even in the positive studies, the differences between zuranolone and placebo at the end of study were very small. For this reason, the US FDA declined to approve zuranolone as a monotherapy or as an adjunctive treatment to standard antidepressants in MDD .

Psilocybin is a serotonergic hallucinogen that mainly exerts its effects through the partial agonism of 5-HTreceptors and binding to 5-HT, 5-HT, and 5-HTreceptors in the brain . Psilocybin is the most studied psychedelic in the treatment of depressive disorders . Several small-scale studies have demonstrated the efficacy of psilocybin in the treatment of depression and TRD [,,]. The preliminary evidence of psilocybin in depressive disorders and the limitations of current pharmacological treatments for depressive disorder led the US FDA to grant "breakthrough therapy" status to psilocybin for the treatment of TRD in 2019 . 2A 2C 1A 1B

In a trial of a single, moderate dose of psilocybin (0.215 mg/kg) monotherapy versus placebo with therapeutic support in patients who had mild to severe depressive symptom severity, psilocybin yielded a significantly larger reduction in MADRS score relative to placebo with a large effect size at day 7 and a moderate effect size at day 14 after the treatment. The significant difference between psilocybin and placebo occurred 6 h after the administration. The response and remission rates were also significantly higher in the psilocybin group compared to the placebo group, with 58% versus 15% for response and 54% versus 12% for remission, respectively .

Currently, Compass Pathways of United Kingdom is developing psilocybin for TRD (NCT05711940 and NCT 05624268). Psilocybin is also being studied for NTRMDD (NCT 06308653) and MDD with borderline personality disorder (NCT 05399498). Some researchers are investigating the safety and efficacy of psilocybin in the treatment of patients with back pain and depression (NCT 0635541), Parkinson's disease with depression (NCT 06455293), and mild cognitive impairment/early dementia with depression (NCT 04123314). Psilocybin-assisted cognitive behavioral therapy (CBT) for depression is also under investigation (NCT 05227612). More importantly, psilocybin as a monotherapy has shown efficacy in reducing depressive symptoms in "secondary" depression and NTRMDD [,,,,]. Meanwhile, an open-label study of 12 patients with severe TRD (failure ≥ 5 treatments) showed that a single dose of psilocybin (COMP360) monotherapy with assisted therapy significantly reduced depressive symptom severity from baseline to week 1, week 2, week 3, week 6, week 9, and week 12 . The remission and response rates at week 1 were both 75%, while at week 12, they were 25% and 58.3%, respectively. With the positive results of previous studies, psilocybin is likely to be developed for various depressive disorders as a monotherapy or adjunctive therapy.

Like psilocybin, the hallucinogenic effects of LSD are mainly through the partial agonism of 5-HTreceptors and binding to 5-HT, 5-HT, and 5-HTreceptors in the brain . In addition, LSD also binds to dopamine D2 receptors and increases glutamate release in the frontal cortex. Currently, LSD is being developed by MindBio Therapeutics Corp (Vancouver, BC, Canada) for the treatment of MDD , and by Mind Medicine (MindMed) Inc. for the treatment of generalized anxiety disorder (GAD) and MDD. Previously, LSD was mainly studied in the treatment of alcohol use disorders [,]. 2A 1A 2C 1B

In a MindMed (MindMed Therapeutics Corp., New York City, NY, USA) phase II dose-finding study of LSD (NCT05407064) with MM-120 (LSD D-Tartrate) at doses of 25, 50, 100, 200 μg, or placebo, a 100 µg dose of MM-120 yielded the largest significant difference relative to placebo, with a 7.7-point difference in HAM-A scores. MM-120 was generally well tolerated with most adverse events rated as mild to moderate, transient, and occurring on the dosing day. The findings from this phase II study made the LSD MM-120 receive "breakthrough therapy" designation from the US FDA in March 2024 . Currently, a phase III trial in GAD sponsored by MindMed is ongoing (NCT06741228).

In a phase II study of LSD in MDD sponsored by University Hospital, Basel, Switzerland in collaboration with MindMed (NCT03866252), patients with MDD were randomly and blindly assigned to receive either LSD 25 µg on their first and second dosing days (low dose, placebo), LSD 100 µg at their first and second dosing days (moderate dose, active), or 200 µg on their first and second dosing days (high dose, active). The first and second dose were four weeks apart. Six weeks after the first dose administration, patients in the high dose arm (= 28) had a significant reduction in Inventory of Depressive Symptomatology-Clinician (IDS-C) scores of −12.9 points compared to −3.6 points in the lower dose arm (= 27). The significant benefit was maintained for up to 16 weeks after the first administration compared to placebo. The results were released on 14 April 2023, by MindMed. However, as of December of 2024, no phase III study of LSD in MDD was registered in. Clinicaltials.gov n n

In a phase IIa study by MindBio (ACTRN12623000486628), an open-label microdosing trial of LSD (MB22001), ranging from 5 μg to 15 μg per dosing day, was conducted in 20 patients with MDD and MADRS of 18–35 points at the time of screening . The dose adjustment was based on patients' experience and the severity of side effect(s). The initial dose of LSD was 8 µg for all patients. For patients who tolerated the initial LSD 8 µg, the LSD dose was increased by 1 µg per dosing day to a maximum dose of 15 µg per dosing day. For those who could not tolerate the initial 8 µg, the LSD dose was decreased to 5 µg (new baseline) on the second dosing day and then increased by 1 µg per dosing day from the third dosing day. The decision to adjust the dose was based on the participant's self-report. The frequency of microdosing was twice a week for 8 weeks with at least one day apart in a 7-day period. The dosing was completed at home by patients. Patients with MDD who received MB22001for 8 weeks experienced a 60% reduction in depressive symptoms and 53% of patients achieved complete remission, with a mean reduction of 14.1 points on MADRS total score. The results of the study were posted on the MindBio website (, accessed on 20 December 2024). https://www.mindbiotherapeutics.com↗

Based on these phase IIa results, several phase IIb studies in MDD (ACTRN12624000128594), cancer patients with existential distress/depression (ACTRN12623000478617) , pre-menstrual syndrome, and pre-menstrual syndrome/pre-menstrual dysphoric disorder are underway. The protocol of the ACTRN12624000128594 trials has been published, with a dosing range from 4 to 20 µg per dosing day . MB22001 may become the first psychedelic treatment approved for at-home use for MDD and other depressive disorders if phase III trials prove its efficacy and safety in the studied population.

5-MeO-DMT is a naturally occurring tryptamine that has been synthesized for medical research. It is a nonselective 5-HT receptor agonist with additional binding to serotonin, norepinephrine, and dopamine transporters. 5-MeO-DMT has higher binding affinity for the 5-HTreceptor than for the 5-HTreceptor , which is different from psilocybin and LSD, which both have higher affinity for the 5-HTreceptor than for the 5-HTreceptor . Since oral 5-MeO-DMT is inactive, it is usually administered through smoking, vaporizing, intranasal, sublingual, intramuscular, intravenous, or rectal approaches. Smoking and vaporization are the most used methods. The effects after using 5-MeO-DMT are similar as those of other tryptamine psychedelics such as psilocybin and LSD. However, both 5-MeO-DMT and DMT are ultra-fast and short-acting psychedelics . 1A 2A 2A 1A

A cross-sectional study in a group setting with most patients with a diagnosis of depression or anxiety showed that using 5-MeO-DMT improved depression and anxiety symptoms. The improvement in depression or anxiety symptom severity was associated with the intensity of mystical experiences and the spiritual significance and personal meaning of the 5-MeO-DMT experience, but there were no associations between the symptom improvement and the intensity of physical/psychological effects during the 5-MeO-DMT experience .

Phase I and II studies were conducted by GH Research PLC (Dublin, Ireland), although some other companies were also interested in the development of this compound . In a phase I/IIa study (NCT04698603) , the efficacy and safety of 5-MeO-DMT in a vaporized formulation (GH001) were assessed in eight adult patients with TRD. In phase I, four patients were assigned to a GH001 dose of 12 mg or 18 mg group. On day 7, remission rates (MADRS ≤ 10) were 50% for the 12 mg group and 25% for the 18 mg group, respectively. The mean change in MADRS total score from baseline to day 7 was −21.0 points for the 12 mg group and −12.5 points for the 18 mg group.

During phase II, all eight patients started with 6 mg, but could receive 6 mg, 12 mg, or 18 mg on a single dosing day. The next dose was determined by a peak experience and tolerability at a previous dose and given three hours apart. If a peak experience was not achieved and the patient did not have safety and tolerability concerns, the next dose of the drug would be increased after both the patient and the study clinician agreed. During phase II, 87.5% of patients achieved remission, which occurred from day 1, and the mean change in MADRS from baseline to day 7 was −24.4 points. With this positive study, GH Research moved forward with a phase II study of GH001 in PPD (NCT05804708) , and a phase IIb study in TRD (NCT05800860). The results of the phase IIb study became available in February 2025 . The study found that GH001 had rapid onset of action, and at day 8 yielded a 15.2-point difference on the MADRS total score over placebo. The remission rate was 57.7% in patients receiving GH001 versus 0% in those receiving placebo.

Like psilocybin, LSD, and 5-MeO-DMT, DMT is a classic psychedelic and its hallucinogenic effects are believed to occur mainly through 5-HTagonism, although DMT also binds to 5-HT, 5-HT, and 5-HTreceptors, serotonin and norepinephrine transporters, and other neurotransmitters [,]. DMT is an active ingredient in ayahuasca, with a short hallucinogenic duration ranging from 20 min to an hour. This shorter duration compared to psilocybin and LSD has driven researchers to study the role of DMT in psychiatric disorders as it may shorten the observation period during dosing days. For psilocybin and LSD, patients need to be under close observation and assisted therapy for about 8 h during dosing days. 2A 1A 2C 1B

A phase II open-label, single-ascending, fixed-order study was conducted by Universiade Federal do Rio Grande do Norte. Brazil (NCT06094907) to assess the feasibility and efficacy of inhaled DMT in patients with partial response in depression. Up to two inhaled doses (15 mg, followed by 60 mg) of DMT were administered on a single day one hour apart. The study was completed on 30 March 2024 with an enrollment of 14 patients. In a non-peer-reviewed article , patients with TRD and at least moderate symptoms (MADRS ≥ 20) had significant reductions in MADRS total score from day 1 to the end of one month (M1). The reduction in the mean MADRS score from baseline to day 7 was −22 points and −17 points at M1. At day 7, 83.33% of patients achieved response and 66.67% achieved remission. At M1, 66.67% and 50% of patients maintained response and remission status, respectively.

A phase I study was conducted by Yale University of the United States of America (NCT04711915) to assess the safety, tolerability, and efficacy of intravenous DMT in patients with TRD and healthy controls (HCs) in an open-label, fixed-order, dose-escalation design (0.1 mg/kg followed by 0.3 mg/kg) . Both patients and HCs tolerated the medications well. HAMD-17 scores decreased significantly from baseline in participants with MDD on the next day after receiving 0.3 mg/kg DMT, with a mean difference of −4.5 points. DMT increased blood pressure, heart rate, anxiety, psychedelic effects, and psychotomimetic effects. However, these side effects resolved within 20–30 min after injection.

Small Pharma Ltd (London, United Kingdom). conducted a phase I/IIa study of DMT (SPL026) in patients with MDD and HCs (NCT04673383, ISRCTN63465876). In phase I (Part A), a randomized, double-blind, placebo-controlled, parallel-group, single dose-escalation trial, psychedelic-naive participants were randomized to placebo (= 8) or four different escalating doses [9, 12, 17, and 21.5 mg intravenously (IV)] of SPL026 (= 6 for each dose) in 5 min with psychological support from two therapists. All four SPL026 doses were safe and well tolerated without any serious adverse events. Results of the SPL026 phase I in healthy controls have been published . n n

In Part B, patients with a current major depressive episode (MDE) with moderate to severe symptoms and without taking an antidepressant received up to two single doses of SPL026, two weeks apart. The first dose was randomized, double-blind, and placebo-controlled, in which patients received either SPL026 21.5 mg or placebo. The second dose was open label to receive active SPL026 21.5 mg through I.V. injection in 10 min. During the randomized, double-blind, placebo-controlled phase, there were significant differences between active and placebo in reducing MADRS total scores at week 1 of −10.8 points, and at week 2 of −7.4 points. Of the 34 patients enrolled in the open-label phase, 57% of patients achieved remission at 3 months after a single dose of SPL026. For treatment response, 44% achieved response at week 1 and 35% achieved response at week 2. No apparent difference in antidepressant effect was observed between a one-dose and two-dose regimen of intravenous DMT. The intravenous dose of DMT for MDD was well tolerated by all patients who received an active dose .

Small Pharma Ltd. also conducted a phase Ib study to assess the safety and tolerability of single doses of SPL026 intravenous infusion in patients with mild to severe MDD with (= 15) and without (= 5) an SSRI (NCT05553691). A single dose of DMT 27.5 mg was given intravenously over 10 min. Decreases in depression scores from baseline were observed in both cohorts at Day 8, Day 15, and Day 29 following study drug administration. Overall, the DMT 27.5 mg was safe and well tolerated (ISRCTN10974027) . n n

MDMA is also known as the club drug "ecstasy". Its psychoactive mechanism is believed to be through monoamine release, serotonin and norepinephrine reuptake inhibition, partial agonism of 5-HT, 5-HT, and 5-HTreceptors, and increase in oxytocin in blood levels . It is the most studied psychedelic in psychiatric disorders without considering ketamine . MDMA has been developed by the Multidisciplinary Association for Psychedelic Studies (MAPS) with a new name of Lykos Therapeutics (San Jose, CA, USA), receiving "breakthrough therapy" designation from the US FDA for MDMA-assisted psychotherapy for the treatment of Post-traumatic stress disorder (PTSD) in 2017 . A phase III study demonstrated that MDMA-assisted psychotherapy was superior to placebo-assisted psychotherapy in the treatment of PTSD, with a large effect size . Among patients with depressive symptoms, the MDMA-assisted psychotherapy was significantly superior to placebo-assisted psychotherapy in reducing depressive symptoms, with a moderate effect size. However, the US FDA declined to approve MDMA-assisted psychotherapy for PTSD in August 2024 due to ethical violations and data suppression. A search in Clinicaltrials.gov on 22 December 2024 with keywords of MDMA-assisted psychotherapy or MDMA with or without depression did not find any trial that is registered for MDMA in the treatment of depressive disorders. The majority of the registered trials were related to PTSD or anxiety disorders . However, because of a moderate effect size for depressive symptoms in PTSD, MDMA-assisted psychotherapy or MDMA alone has the potential to be developed for depressive disorders. 2A 1A 2C

Esmethadone (REL-1017, d-methadone, and dextromethadone) is the opioid inactive ()-enantiomer of racemic methadone. It is a noncompetitive NMDA receptor antagonist but has a weaker blockage effect compared to other NMDA receptor blockers such as ketamine, memantine, and MK-801 . Compared to dextromethorphan, the antidepressant component in AXS-05, the affinity of esmethadone for NMDA receptor subtypes is close to that of dextromethorphan in some subtypes, and weaker than that of dextromethorphan in others. In addition to its NMDA receptor antagonism, esmethadone also has binding affinity to calcium and sodium channels, 5-HT receptors, serotonin transporters, and other neurotransmitters (). S

With the success of AXS-05 and esketamine in treating depressive disorders, esmethadone (Relmada Therapeutics, Inc., Coral Gables, FL, USA) has been developed for the treatment of TRD with phase II and III trials [,,]. In a phase IIa study , the onset of a significant antidepressant effect of esmethadone 25 mg/day and 50 mg/day versus placebo adjunctive therapy to a standard antidepressant occurred on day 4 in patients who had a major depressive episode (MDE) lasting from 8 weeks to 36 months and who failed 1–3 antidepressants for both adequate doses and durations. The effect size of esmethadone 25 mg/day or 50 mg versus placebo was large (≥0.8) on day 4 and day 14. However, in the first completed phase III study (NCT04688164) , esmethadone 25 mg/day as an adjunctive to a standard antidepressant was not superior to placebo adjunctive therapy to a standard antidepressant therapy in patients who had the same clinical presentation as those in the Phase III study . In another completed phase III trial of esmethadone monotherapy versus placebo in MDD (NCT05081167), esmethadone 25 mg/day did not appear superior to placebo in reducing depressive symptoms after 4 weeks, with an MADRS score of −14.8 for esmethadone and −13.9 for placebo (). The difference in response and remission rate was also minimal. There are still two ongoing phase III efficacy trials investigating esmethadone as an adjunctive therapy in TRD (NCT06735079, NCT066011577). Clearly, the role of esmethadone as a monotherapy or adjunctive therapy in the treatment of MDD or TRD remains uncertain. clinicaltrials.gov

The involvement of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in the antidepressant effect of ketamine was demonstrated in animal studies [,]. A preclinical study also showed that the activation of AMPA receptors by physiologically released glutamate enhances synaptic and cognitive functions .

: Osavampator (TAK-653 and NBI-1065845) is a selective positive allosteric modulator of the AMPA receptors. In an animal study, TAK-653 showed an antidepressant-like effect . In humans, Osavampator has been developed in the treatment of patients with MDD who have failed at least one antidepressant. A phase II study of Osavampator in TRD (NCT03312894) sponsored by Millennium Pharmaceuticals, Inc. (Takeda) was registered inin 2018, but no patient was enrolled. In 2020, Takeda and Neurocrine Biosciences formed a collaboration to develop Osavampator for the treatment of TRD. Clininicaltrials.gov Osavampator

A phase II study of NBI-1065845 in TRD (NCT05203341) sponsored by Neurocrine Biosciences found that one dose of NBI-1065845 was superior to placebo in reducing depressive symptoms, with a −4.3-point mean difference in MADRS total score at day 28, and a −7.5-point difference in MADRS score at day 56 . The positive results propelled the company to initiate a phase III study to assess the efficacy and safety of NBI-1065845 as an adjunctive treatment in patients with MDD (NCT06786624) .

For the efficacy and safety of aticaprant (JNJ-67953964) (Johnson and Johnson, New Brunswick, NJ, USA), a selective opioid κ receptor antagonist, 10 mg/day in MDD were first explored in patients with anhedonia and a history of depression (bipolar or unipolar depression) or anxiety disorders . The study demonstrated that 8 weeks of aticaprant treatment significantly reduced the severity of anhedonia compared to placebo, with a significant increase in the activation of the ventral striatum during a reward anticipation task. However, there were no significant differences between aticaprant and placebo in reducing depression and anxiety symptom severities. A more recent phase II study of aticaprant in patients who had a diagnosis of MDD with an MDE lasting less than 12 months and who had failed an SSRI or SNRI at an adequate dose for at least 6 weeks found that 6 weeks of aticaprant was superior to placebo in reducing depressive symptoms measured by MADRS, with an effect size of 0.36 . There are four phase III studies (NCT 05455684, NCT 05550532, NCT 065147742, and NCT 0663535) of aticaprant as an adjunctive therapy versus placebo in patients with MDD with moderate-to-severe anhedonia who have had an inadequate response to current antidepressant therapy with an SSRI or SNRI. The trial NCT 05455684 was completed on 18 September 2024, and the rest of the trials are ongoing.

Navacaprant (NRMA-140) (Neumora Therapeutics, Inc., Watertown, MA, USA) is a potent, selective κ opioid receptor antagonist. Its selectivity for the κ receptor is 300-fold over that for the µ receptors. In contrast, the selectivity of aticaprant for the κ receptor is only 30-fold over that for the µ receptors . The antidepressant effect of navacaprant is hypothesized to occur through blocking κ opioid receptors and modulating glutamatergic, GABAergic, serotonergic, and dopaminergic systems .

Navacaprant is developed by Neuroma Therapeutics Inc., Watertown, MA, USA and has been studied in patients with MDD in a phase II study and phase III studies. In the phase II study , patients with MDD and an HAMD-17 score of 14–30 points, and anhedonia with Snaith–Hamilton Pleasure Scale (SHAPS) ≥ 26 points were randomized to receive either navacaprant or placebo. In the total efficacy population, navacaprant significantly reduced HAMD-17 scores compared to placebo at week 4, but not at week 8. In the efficacy population with baseline HAMD-17 ≥ 22 points, navacaprant significantly reduced HAMD-17 scores compared to placebo at week 4 and week 8.

Phase III studies of navacaprant in MDD include KOASTAL-1 (NCT06029426), KOASTAL-2 (NCT06058013), KOASTAL-3 (NCT06058039), and a 52-week open-label extension study KOASTAL-LT (NCT06029439). The results of the KOASTAL-1 study were recently released, but navacaprant did not show superiority over placebo in primary and key secondary outcome measures . Kappa opioid receptor antagonists may become an option for MDD, especially for those with severe anhedonia, if phase III studies confirm their efficacy and safety. However, their onset of action appears similar to monoamine-based antidepressants.

Seltorexant, also known as MIN-202/JNJ-42847922, developed by Janssen Research & Development, LLC and Minerva Neurosciences, is one of the several orexin-2 receptor antagonists approved for insomnia . Its efficacy and safety in the treatment of TRD or NTRMDD have been assessed with randomized, double-blind, placebo-controlled trials. A single dose of seltorexant 10, 20, and 40 mg/day versus placebo was explored with a double-blind, four-way, crossover design in patients with MDD and persistent insomnia . It was found that all doses were superior to placebo in improving sleep in a dose-dependent manner and 40 mg showed a trend toward significance in improving depressive symptoms.

In a phase Ib study conducted in the Netherlands, Belgium, and Germany in patients with MDD with or without ongoing antidepressant treatment , seltorexant, but not diphenhydramine, was significantly superior to placebo in improving core depressive symptoms. Another phase Ib study (NCT03374475) showed that 20 mg seltorexant monotherapy, but not 40 mg monotherapy, was significantly superior to placebo in reducing depressive symptoms . The treatment benefit in the 20 mg arm remained significant even after sleep-related items were removed from HDRS scores. A phase IIb study (NCT03227224) also showed the superiority of seltorexant 20 mg as adjunctive therapy to an antidepressant over placebo in MDD at week 3, but not at week 6 .

A pivotal phase III trial (NCT04533529) was conducted to evaluate the efficacy and safety of seltorexant as an adjunctive treatment in adult and elderly patients who were moderately-to-severely depressed with significant sleep disturbance even with ongoing treatment with SSRI/SNRI treatment. The results indicated that seltorexant 20 mg was both a statistically significant and clinically meaningful improvement in depressive symptoms, based on the MADRS total score, and also improved sleep disturbance outcomes at day 43 . However, the significant difference emerged only at the end of study week 7. Seltorexant was also safe and well tolerated in the study, with similar rates of common adverse events observed in both trial arms, consistent with previous seltorexant clinical trials. However, a similar phase III study in adults (NCT04532749) was terminated after enrolling 212 patients.

A multicenter, double-blind, randomized, placebo-controlled study is ongoing to evaluate efficacy and safety and the maintenance effect of seltorexant 20 mg as an adjunctive therapy to antidepressants in adult and elderly patients with MDD and insomnia symptoms (NCT06559306). Meanwhile, one phase III study (NCT04513912) and one phase II study (NCT03321526) comparing the efficacy and safety of seltorexant to quetiapine XR as an adjunctive therapy in TRD were completed. The results from the phase II study suggested that seltorexant was as effective as quetiapine-XR as an adjunctive therapy in the treatment of patients with TRD.

In contrast to seltorexant, other orexin-2 receptor antagonists in MDD are less studied. A phase II study of filorexant (MK-6096) (Merck Sharp & Dohme LLC, Rahway, NJ, USA) 10 mg as an adjunctive therapy in patients with MDD and partial response to antidepressant monotherapy found that filorexant was not superior to placebo adjunctive therapy in reducing depressive symptoms (NCT01554176). A phase IV study of suvorexant (Institute for Advanced Medical Research, Alpharetta, GA, USA) 10–20 mg treatment for TRD (NCT02669030) was registered as a six-week, randomized, double-blind placebo-controlled trial investigating suvorexant as an augmentation therapy to antidepressant treatment for patients with MDD and residual insomnia. However, the status of the study is unclear.

The role of other orexinergic antagonists in depressive disorders is unclear. The future of this group of medications as a monotherapy for TRD or NTRMDD remains uncertain, although a phase Ib study demonstrated the superiority of seltorexant over placebo . The onset of action of seltorexant in TRD appears like that of most other adjunctive therapies. However, its effect on insomnia may be particularly beneficial for patients with MDD and insomnia, especially for those experiencing early insomnia.

Biomarker-based treatment is the goal of precision psychiatry. ALTO-100 was developed by ALTO Neuroscience (Mountain View, CA, USA) to treat MDD using brain biomarkers to identify patients who are most likely to respond to a specific drug. ALTO-100 is a small molecule and believed to work by increasing BDNF signaling and neuroplasticity in the hippocampus. To identify patients who are likely to respond to ALTO-100, the company used its AI-enabled biomarker platform to evaluate brain function biomarkers by analyzing EEG activity, neurocognitive assessments, wearable data, and other factors.

In a phase IIa open-label clinical trial (NCT05117632) , ALTO-100 showed favorable safety and tolerability in patients who had MDD with or without ongoing antidepressant treatment. Among the patients with a biomarker-defined cognitive profile, 61% of patients achieved a clinical response compared to 33% of patients without the biomarker. After six weeks of treatment, the biomarker-defined patient group achieved a 15.5-point mean reduction in MADRS scores compared to a 10.6-point reduction in the biomarker-negative cohort.

However, a large phase IIb randomized, double-blind, placebo-controlled, multicenter study (NCT05712187) of ALTO-100 in adults with MDD did not find a significant difference between ALTO-100 and placebo in reducing depressive symptoms after 6-week treatment (altoneuroscience.com). The future of ALTO-100 is unclear. ALTO Neuroscience has other compounds including ALTO-203 (NCT06391593) and ALTO-300 in development for treating MDD . ALTO-300 has been evaluated with three phase II studies (NCT05118750, NCT05157945, NCT05922878). Two of them (NCT05118750, NCT05157945) have been completed. The results from these phase II studies will provide insight into whether ALTO-300 can be developed for depressive disorders.