Clinical specificity profile for novel rapid acting antidepressant drugs

Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.


Introduction
Globally, mood disorders are a severe and chronic cause of disability, morbidity, and mortality (James et al., 2018). They impact social functioning, as well as work productivity, resulting in a significant socioeconomic burden (Egede et al., 2016). Moreover, these disorders have a strong impact on physical health and significantly increase the risk of developing other medical conditions, such as heart disease, diabetes, and obesity (Fanelli and Serretti, 2022;Wimberley et al., 2022). We cannot forget to mention one of the most urgent clinical concerns associated with depression, that is, suicide, as the pooled lifetime prevalence of suicide attempts is between 27 and 34% in people with depressive disorders (WHO depressive disorder, 2023). Antidepressant drugs, such as selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and tricyclic antidepressants, are widely prescribed in the general population (Dörks et al., 2022) and used to treat depressive symptoms, as well as anxiety and obsessive symptoms, among others (Castle et al., 2021); however, they are associated with variable treatment outcomes that are difficult to predict . Consequently, finding an effective treatment for all patients with major depressive disorder (MDD), bipolar depression, postpartum depression (PPD), perimenopausal depression (PMD), and depression associated with general medical conditions remains a major unmet need.
Treatment-resistant depression (TRD) is usually defined as an ineffective response to at least two antidepressant drugs of adequate dose and duration (Gaynes et al., 2020), but also in patients who do achieve remission, residual symptoms are common . TRD is particularly common in patients suffering from bipolar depression. The high burden of depressive phases in bipolar disorder is partly linked to the fact that there is only a limited number of approved treatment options for bipolar depression, and in most cases the evidence is controversial (McIntyre and Calabrese, 2019). Poor response to treatment (residual symptoms, slow improvement, or TRD) may be highly burdensome and associated with additional risks in some groups of patients, such as women in the peripartum. If not successfully treated, serious consequences can negatively affect the well being and health of both mother and child (Beck, 2006). More specifically, it increases the risk of preeclampsia, preterm delivery, maternal substance abuse, and suicidality (Vliegen et al., 2014), as well as causing significant impairment in both maternal functioning and mother-infant attachment (Gagliardi et al., 2012). This can have a negative impact on child cognitive, behavioural, and emotional development, with long-lasting repercussions (Frieder et al., 2019).
Poor treatment response is not the only issue of drugs currently approved for depressive disorders. Adverse events are indeed quite common, and not infrequently they compromise treatment adherence (Hu et al., 2004). Standard antidepressant treatments also show delayed action, as they require 4-6 weeks before reaching the complete therapeutic effects, and in the meantime, patients remain vulnerable to the risk of suicide (Machado-Vieira et al., 2009). The discussed points emphasize the urgent need for more broadly effective and rapid interventions in depression, especially with a rapid antisuicidal and antianhedonic effect. Recent preclinical and clinical studies are testing new glutamate drugs, for example, acting as n-methyl-d-aspartate receptor (NMDAR) antagonists (Salituro et al., 1994). Other new compounds target gamma-aminobutyric acid (GABA) neurotransmission, such as GABA A positive allosteric modulators (PAMs) (Althaus et al., 2020), and the orexin system, such as seltorexant (Recourt et al., 2019). Psychedelic drugs such as psilocybin have also attracted renewed interest in treating resistant cases (Griffiths et al., 2016), based on their effects on cognitive flexibility (Boulougouris et al., 2008) and associative learning (Harvey, 2003). Despite new drugs having general mechanisms alternative to the 'classic' monoaminergic hypothesis, pimavanserin is a new compound studied for depression that principally acts on the well studied serotonergic system.
The purpose of this review is to summarize and discuss the available literature on novel rapid acting antidepressants, in various stages of development, with respect to their antidepressant efficacy, safety, and tolerability, in patients with different mood disorders, also considering each drug-specific pharmacodynamic profile.

Search strategy and inclusion criteria
The search was conducted using the National Institutes of Health US National Library of Medicine Clinical Trials Database and PubMed, retrieving relevant data up to September 2022. The used keywords were: 'av-101', 'dextromethorphan-bupropion', 'AXS-05', ' REL-1017', 'esmethadone', 'zuranolone', 'SAGE-17', 'PRAX-114', 'pimavanserin', 'psilocybin', 'seltorexant', 'MIN-202', 'PH-10'; each of these was combined with each of the following: 'major depressive disorder', 'depression', 'antidepressant', 'depressive symptoms', 'bipolar depression', 'post-partum depression'. The drugs of interest were selected based on the availability of at least one clinical trial (any phase), completed or in progress, studying their possible efficacy in the treatment of depressive disorders. We did not include drugs already approved for the treatment of depressive disorders, except for dextromethorphan-bupropion (AXS-05) which was recently approved by the Food and Drug Administration (FDA) and can be still considered a novel rapid acting antidepressant. We did not consider drugs with insufficient evidence of efficacy on specific depressive symptoms, or without an innovative mechanism that would suggest a potential effectiveness.
The eligibility criteria were: published (including congress abstracts) or unpublished clinical trials (relevant information was also extracted from reviews, meta-analysis, and websites of biopharmaceutical companies); focused on the clinical effects on the mentioned new compounds in patients with depressive disorders as main diagnosis or comorbidity, or in healthy volunteers; written in English. This is a narrative review, therefore a quantitative synthesis and systematic evaluation of the quality of the included studies are not among the scope of this work.

Results
The main characteristics and studied indications of the nine compounds included in our review are presented in Table 1. They have been studied mostly for the treatment of MDD, as adjunctive treatment or monotherapy, often for TRD cases. Despite this leaving a gap regarding their potential benefits in other depressive disorders, the focus of this review is on the efficacy profile in terms of specific symptoms with cross-diagnostic relevance, rather than for specific categorical diagnoses. As one of the key parameters for the evaluation of new compounds is the time of antidepressant effect onset, we represented this in Fig. 1, together with the longest observed period in which the antidepressant effect was sustained. Completed and published clinical studies are summarized in Table 2. Completed clinical studies but not published in peer-reviewed journals are shown in Table 3 and incomplete studies until September 2022 are presented in Table 4.

4-Chlorokynurenine
Av-101 (4-chlorokyneurine, 4-Cl-KYN) is a prodrug, rapidly converted to 7-chloro-kynurenic acid (7-Cl-KYNA) by kynurenine aminotransferase (Salituro et al., 1994). 7-Cl-KYNA exerts a neuroprotective action by a full antagonism activity on the glycine B co-agonist site of the NMDAR (Zanos et al., 2015). The effects of this drug are also linked to the metabolite 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), which inhibits the quinolinic acid, a neurotoxic NMDAR agonist (Walsh et al., 1994). Considering the evidence implicating the kynurenine pathway in the aetiology of mood disorders (Brown et al., 2021), and the rapid, dose-dependent, and sustained antidepressant effect following a single administration in an animal study (Zanos et al., 2015), AV-101 was tested in humans; however, it failed to demonstrate benefits on depressive symptoms at week 2, according to two randomized clinical trials (RCTs) in patients with MDD (ClinicalTrials.gov Identifier NCT03078322 and NCT02484456). The drug failed both as adjunctive treatment to standard antidepressants (1440 mg/day for 2 weeks) (VistaGen  and in TRD as monotherapy (1080 mg/day for the first week, then 1440 mg/day for the second week) (Park et al., 2020). These negative results raised the question of whether AV-101 could penetrate the blood-brain barrier. To address this question, dose-related effects of AV-101 (720 and 1440 mg) on NMDARs engagement were examined in a small sample of healthy individuals (ClinicalTrials. gov Identifier NCT03583554) . The dose of 1440 mg, but not 720 mg, showed consistent NMDAR blockade measured by an increase in electroencephalogram γ-band activity. Therefore, the dose of 1440 mg shows antagonist activity on the NMDARs, but no antidepressant effect was demonstrated in the available RCTs, which were both short-term studies.

Esmethadone
Rel-1017 is a dextro-isomer of racemic methadone (esmethadone or dextromethadone), with a low affinity and noncompetitive NMDARs antagonism profile (Bernstein et al., 2019); it also shows a micromolar affinity for the serotonin transporter (SERT) and norepinephrine transporter (NET) (Nemeroff, 2022). Compared to its stereoisomer (levomethadone), it shows a lower affinity for opioid receptors and therefore a lack of opioid-like effects such as analgesic, tolerance and dependence properties, or sedation/respiratory depression (Gorman et al., 1997). After demonstrating antidepressant activity in animal models, with modulation of synaptic connections and plasticity in the medial prefrontal cortex (Fogaça et al., 2019), REL-1017 was tested in phase I clinical trials. In two multiple doses ascending studies, single doses of up to 150 mg and repeated dosing of up to 75 mg daily for 10 days exhibited linear pharmacokinetics and a good safety profile, characterized by dose-related nausea and somnolence at higher doses (Bernstein et al., 2019). Rel-1017 received the FDA fast-track designation as an adjunctive treatment for MDD. There are two ongoing RCTs assessing the efficacy of this drug in MDD as an adjunctive treatment to the ongoing antidepressant in the short term (28 days) (ClinicalTrials. gov Identifier NCT04688164 and NCT04855747), and one well powered open-label study in the long term (1 year) (ClinicalTrials.gov Identifier NCT04855760). Other RCTs will consider REL-1017 as monotherapy (ClinicalTrials.gov Identifier NCT05081167) (Hecking et al., 2021). While these studies are still ongoing and do not have results, a 1-week small pilot study reported promising findings (ClinicalTrials.gov Identifier NCT03051256). In this study, REL-1017 showed a rapid antidepressant effect (by day 4), sustained up to 7 days after the last dose, in patients with MDD maintained on their previous antidepressant regimen (to which they have had an inadequate response). Both 25 and 50 mg showed mood improvement associated with an enhancement in cognitive and social functioning, anxiety, agitation, anger, irritability, and sleep quality .

Dextromethorphan-bupropion
AXS-05 is an oral combination of dextromethorphan and bupropion (Stahl, 2019). Dextromethorphan integrates the uncompetitive antagonism towards NMDARs with the sigma-1 receptor (S1R) agonism, the nicotinic acetylcholine receptors antagonism, and with activities on the SERT and NET (Taylor et al., 2016). Bupropion primarily acts selectively blocking neuronal reuptake of noradrenaline and dopamine (Stahl, 2019). Additionally, bupropion prevents dextromethorphan from being rapidly metabolized by cytochrome P450 2D6 (CYP2D6), leading to an increase in its bioavailability (Hecking et al., 2021). This innovative combination suggests a powerful pharmacological synergy and wide clinical use of AXS-05 across various psychiatric conditions (Stahl, 2019). The effectiveness of AXS-05 was proved with positive results in well powered studies of moderate or severe MDD, also in comorbidity with anxiety disorders. When compared with bupropion (Tabuteau et al., 2022) or placebo , it had a more rapid onset of action (by week 1) and durable effect in the short-medium term (by week 6) in two phases II large RCTs (ClinicalTrials.gov Identifier NCT03595579 and NCT04019704), leading to FDA approval for MDD in August 2022. One open-label study (ClinicalTrials.gov Identifier NCT04039022) confirmed these promising findings in the long term (up to 12 months), showing an improvement in work/study, social and family functioning as well (Mardi, 2022), also in a sample unresponsive to other antidepressants (Axsome Therapeutics, 2020a). A very small study in a group of patients with suicidal ideation found a rapid remission of suicidal ideation by week 1, as well as an improvement in overall functioning by week 6 (Axsome Therapeutics, 2020b). AXS-05 demonstrated encouraging results also in TRD by week 1, with effects on depression, anxiety, and psychosocial functioning lasting up to 12 months (ClinicalTrials.gov Identifier NCT04634669) (Axsome . The drug consistently reduced the risk of depressive symptoms relapse (ClinicalTrials. gov Identifier NCT04608396) (Axsome Therapeutics, 2021). The primary antidepressant action of this drug was associated with an enhancement in cognitive function (Axsome Therapeutics, 2020c), a durable improvement in psychosocial functioning (Axsome , as well as a rapid and progressive relief of anxiety symptoms associated with TRD (Axsome Therapeutics, 2020c; however, one RCT in a well powered sample did not confirm AXS-05 benefits in TRD in a 12-week study (ClinicalTrials.gov Identifier NCT02741791) (Axsome Therapeutics, 2020c). An additional RCT is currently ongoing and aims to evaluate AXS-05 for MDD not responding to standard antidepressants and MDD with suicidal ideation (ClinicalTrials.gov Identifier NCT04971291) (Clinicaltrials.gov, 2021c). To summarize, AXS-05 has good evidence of efficacy on overall depressive and anxiety symptoms but targets well also suicidal ideation and cognitive dysfunction, two symptoms that often do not respond well to standard antidepressants, Earliest time of onset (indicated as the week of initial antidepressant effect) and longest duration of antidepressant efficacy (indicated as the longest period, that is, weeks, months, or years, of sustained antidepressant effect) reported for the included drugs in at least study. For psilocybin, zuranolone, and esmethadone, data are available on the onset of therapeutic effect before the first week of treatment. For AXS-05, PH-10, pimavanserin, seltorexant (MIN-202), and PRAX-114 there are no data about a possible early onset of the therapeutic effect (i.e. during the first hours or first days of treatment). BUP, bupropion; d, day; DXM, dextromethorphan; hr, hour; mth, month; wk, week; yr, year.     For some studies, some data is not available (i.e. phase study, depressive symptoms severity scale at baseline, P value, effect size). BDI, Beck Depression Inventory total score; DS-II, Demoralization Scale-II total score; GRID-HDRS, Grid-Hamilton Depression Rating Scale total score; HADS, Hospital Anxiety and Depression Scale total score; HAM-A, Hamilton Anxiety Rating Scale total score; HDRS, Hamilton Depression Rating Scale total score; IDS-C, Inventory of Depressive Symptomatology Clinician Rating total score; LoM, loss of meaning; MADRS, Montgomery-Asberg Depression Rating Scale total score; MDD, major depressive disorder; NA, not available; PAP, psilocybin assisted psychotherapy; PPD, postpartum depression; QIDS, Quick Inventory of Depressive Symptomatology total score; QIDS-SR, Quick Inventory of Depressive Symptomatology-Self Reported total score; STAI, State-Trait Anxiety Inventory total score; TRD, treatment-resistant depression.
a Refers to the length over time of the pharmacological intervention. b Refers to the length of monitoring over time of participant's health after the end of the pharmacological intervention. Table 2 (Continued )   Refers to the length of monitoring over time of participant's health after the end of the pharmacological intervention. Table 3 (Continued )  with resulting benefits on functioning in relevant areas of life.

Psilocybin
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is a tryptamine alkaloid hallucinogen naturally present in the psilocybe genus of mushrooms (Passie et al., 2002). Its antidepressant effect is putatively mediated by the serotonergic system, specifically by serotonin 2 A receptors (5HT 2A Rs) agonism that leads to a major glutamate release by pyramidal neurons that express these receptors in the PFC. This activation results in a modulation of brain circuit connections (Carhart-Harris et al., 2014); however, the mechanisms behind the persistence over time of these neuroplasticity phenomena remain unknown. Imbalances of serotonin in the brain underpin and modulate depression, as well as emotional and physical symptoms of anxiety, cognition, learning, memory, reward processing, and sleep (Pourhamzeh et al., 2022).
Psilocybin has been studied for the treatment of MDD, but also for depression associated with general medical comorbidities. In addition to its potential therapeutic role in mood disorders, psilocybin showed preliminary benefits in obsessive-compulsive disorder (Moreno et al., 2006) and substance dependence (Veen et al., 2017).
All studies evaluated the effects of psilocybin administered in supportive and controlled environments, in combination with behavioural psychological support provided by trained therapists (psilocybin-assisted psychotherapy, PAP).

Major depressive disorder
PAP may represent a successful option for reducing depressive symptoms, with or without anxiety, with rapid effects lasting for about 6 months. This efficacy was confirmed in a recent meta-analysis of four small trials (Goldberg et al., 2020). Psilocybin was recognized as a breakthrough therapy for TRD by the FDA in 2018 and for MDD in 2019.  administration of psilocybin, as reported in a posthoc study with a small sample size of patients with TRD (Lyons and Carhart-Harris, 2018). Consistent with these cognitive changes, in a recent study psilocybin showed benefits on cognitive empathy in TRD patients with a subsequent improvement in emotional face recognition; this effect correlated also with reduced anhedonia (Stroud et al., 2018). These findings suggest that psilocybin may enhance cognitive flexibility (the capacity to adapt thoughts and behaviours to multiple environmental demands), as confirmed in another study, with an improvement found to persist for at least 4 weeks posttreatment (ClinicalTrials.gov Identifier NCT03181529) (Doss et al., 2021). Therefore, psilocybin seems to act positively on symptoms poorly targeted by standard antidepressants, but another important question is if it is overall superior to standard antidepressants in terms of depressive symptoms improvement. According to two RCTs, psilocybin is not more beneficial than escitalopram on overall depressive symptoms over a short period of time, but a different profile of action on depressive symptoms was confirmed. In a 6-week study (ClinicalTrials.gov Identifier NCT03429075) (Carhart-Harris et al., 2021), two administrations of psilocybin improved the perceived ability to cry and to feel compassion and intensified emotion and pleasure compared to escitalopram, as well as reduced suicidal ideation more than then escitalopram. In a crossover study (ClinicalTrials.gov Identifier NCT03912974) (Becker et al., 2022), a single dose of psilocybin was administered after a 2-week pretreatment with escitalopram or placebo. Escitalopram reduced psilocybin-induced adverse events [increased blood pressure and heart rate (HR), pupil dilatation, and other acute autonomic events], and negative psychic effects such as anxiety ('anxious ego-dissolution'); however, escitalopram did not show additional efficacy on positive mood effects of psilocybin versus placebo. Finally, various phase I (ClinicalTrials.gov Identifier: NCT03554174) and phase II RCTs (ClinicalTrials. gov Identifier: NCT03866174, NCT03715127, NCT04620759, NCT04630964, NCT03380442) are currently ongoing. These trials aim to confirm the efficacy of psilocybin on depressive symptoms and some of them will also investigate neuroplasticity changes and brain mechanisms underpinning these changes (Clinicaltrials.gov, 2018(Clinicaltrials.gov, , 2019a(Clinicaltrials.gov, , 2019b(Clinicaltrials.gov, , 2021d.

Major depressive disorder associated with general medical comorbidities or life-threatening illnesses
There is strong evidence supporting the efficacy of psilocybin on depressive and anxiety symptoms associated with life-threatening illnesses, such as neoplastic diseases or AIDS.
Clinical trials focused on psilocybin use in patients with advanced-stage cancers, located in the breast, colon, ovary, peritoneum, or salivary gland. Lymphoma, leukemia, and myeloma were also included (Doblin et al., 2019). Robust efficacy was confirmed in two systematic reviews as well (Reiche et al., 2018;Ross, 2018). The antidepressant and anxiolytic effects of psilocybin were immediate and persisted in a large percentage of patients for at least 6 months after a single active treatment [ClinicalTrials.gov Identifier: NCT00465595 (Griffiths et al., 2016) and ClinicalTrials.gov Identifier: NCT00957359 (Ross et al., 2016)] or even up to 4.5 years following a single dose, as demonstrated by a long-term follow-up study . Such enduring improvements in anxiety and depression led to a consequent reduction in demoralization, hopelessness, and death anxiety (Ross et al., 2016;Agin-Liebes et al., 2020) and an improvement in optimism, death acceptance, and quality of life (Griffiths et al., 2016); however, these positive findings followed the administration of a high dose of psilocybin (22 or 30 mg/70 kg) and did not occur with a low dose (1 or 3 mg/70 kg) (Griffiths et al., 2016), in line with the results of a pilot study (ClinicalTrials.gov Identifier: NCT00302744). Only trait anxiety decreased at months 1 and 3, whereas a significant decrease in measures of depression was demonstrated only at month 6 (Grob et al., 2011). Of note, there are reports of a major reduction in negative emotionality and increased creativity when assuming psilocybin micro-dosing rather than a single active treatment (Anderson et al., 2019). For micro-dosing, the FDA refers to a dose of the drug that is 1% of the pharmacologically active dose, up to a maximum of 100 µg (EMA 2003); however, no advantage of micro-dosing over placebo was found in patients with depressive/anxious disorders not related to neoplastic diseases (Marschall et al., 2022), while one RCT reported benefits in patients with life-threatening cancer.
In this study, a single dose of psilocybin was associated with acute and sustained reductions in suicidal ideation as early as 8 h and sustained for 6.5 months posttreatment. Loss of meaning (LoM), a component of demoralization, had similar reduction as early as 2 weeks after treatment and was sustained at 4.5 years of follow-up. A positive relationship was found between reductions in LoM and suicidal ideation, and between suicidal ideation and hopelessness and demoralization (Ross et al., 2021). These encouraging results prompted another recent pilot study (ClinicalTrials.gov Identifier: NCT02950467), that showed robust reductions in self-reported demoralization, grief, and psychological trauma in AIDS survivors. Over 7 weeks, patients were treated with both individual and group psilocybin sessions (8 and 12-15 h respectively). The self-reported demoralization, the primary clinical outcome, linearly decreased from baseline to the last follow-up assessment point at month 3 (Anderson et al., 2020).

Pimavanserin
Pimavanserin is an atypical antipsychotic that does not directly target dopamine receptors (Rissardo et al., 2022). Indeed, it predominantly acts on the serotonergic neurotransmission, through an inverse agonism and antagonism on the 5-HT 2A Rs, and the 5-HT 2C Rs at higher doses (Vanover et al., 2006). It is approved by the FDA to treat hallucinations and delusions associated with psychosis in Parkinson's disease with a recommended dose range between 34 and 40 mg once daily.

Major depressive disorder
In light of the serotonergic profile, pimavanserin effectiveness was also tested in mood disorders, particularly in MDD. Short-to medium-term benefits (weeks 1-5) on depressive symptoms were demonstrated by the first stage of one RCT performed in a well powered sample (Clinical trial identification number NCT03018340); however, the second stage did not confirm these positive results, probably due to the smaller sample size (Fava et al., 2019). In this study, pimavanserin was administered as adjunctive treatment to standard antidepressants (SSRI or SNRI) and produced benefits on depressive symptoms that did not respond to previous antidepressant treatments. Moreover, significant improvement was observed for several secondary endpoints including impulsivity, irritability, anxiety, insomnia and daytime sleepiness, sexual and psychosocial functioning, and quality of life. In this regard, results from a secondary analysis have shown a reduction of anxiety and somatic symptoms in a sub-group of patients with severe and anxious MDD at baseline . Of note, in another secondary analysis, pimavanserin reduced both night sleep impairments and excessive day sleepiness and improved global functioning. Therefore, the efficacy of pimavanserin on psychosocial functioning may at least partly be mediated by the reduction of excessive daytime sleepiness . Interestingly, according to another post-hoc analysis, sexual function improved after treatment with pimavanserin. Women reported increased sexual desire, sexual arousal, orgasmic propensity, and general sexual satisfaction; similar results were not observed in male participants, probably due to the small number of men in the sample . Noteworthy, the results of a secondary analysis demonstrated that pimavanserin determined a greater reduction in suicidal ideation by week 3 compared to placebo, despite the exclusion of patients with a history of previous suicide attempts and the small number of participants who reported suicidal ideation during the study . Despite these promising results, three subsequent trials (Clinical trial identification number NCT03968159, NCT03999918, and NCT04000009) did not find any antidepressant effect, in the short or in the long term, and the sponsor decided not to pursue the development of pimavanserin for MDD; however, among secondary outcomes, an improvement in subjective quality of sleep was reported (Acadia, 2020).

Major depressive disorder associated with general medical comorbidities
Notwithstanding pimavanserin was withdrawn from development for MDD, there is currently one trial supporting potential benefits in reducing depressive occurrences in Parkinson's disease, in the short-medium term (week 8), both in monotherapy and as adjunctive therapy to standard antidepressants (SSRI or SNRI) (ClinicalTrials.gov Identifier NCT03482882). This study also reported amelioration in secondary clinical outcomes such as global disease severity, sleep quality, overall quality of life, and motor function, though the sample size was small, and the psychometric instrument used in the study (Hamilton Depression Rating Scale or HDRS) was not developed for use in Parkinson's disease (DeKarske et al., 2020).

Zuranolone
Zuranolone, an allopregnanolone analogous, is a neurosteroid that displays most of its therapeutic effects acting as a PAM of the synaptic and extra-synaptic GABA A Rs. It increases tonic and phasic GABA A currents (Botella et al., 2017). The facilitation of GABA circuits in the central nervous system (CNS) is a common mechanism of action shared also by endogenous neurosteroids (Abramian et al., 2014). Zuranolone is under investigation as a monotherapy for MDD (including PPD) and bipolar depression, using a treatment paradigm of 2 weeks. Its long half-life allows once-daily oral dosing, facilitating its administration and enhancing the therapeutic adherence (Althaus et al., 2020).

Major depressive disorder
Zuranolone shows antidepressant effects, especially in patients with depression and anxiety features, as demonstrated by three RCTs in well powered samples (ClinicalTrials.gov Identifier NCT03000530, NCT04442490, NCT04476030). Both 30 and 50 mg showed a rapid onset of action at day 3 and major benefits at day 15 in monotherapy (Gunduz-Bruce et al., 2019; Sage Therapeutics and Biogen, 2021b). When it was co-initiated with an SSRI or SNRI, benefits were reported during a 2-week treatment period, but not after, suggesting a nonsustained efficacy over time . Although in one study the stabilization of symptoms persisted until day 42-45 (Sage Therapeutics and Biogen, 2021b), in another RCT in a larger sample (ClinicalTrials.gov Identifier NCT03672175), zuranolone 30 mg demonstrated benefits only in the very short term, from day 3 to day 12, and the dose of 20 mg was totally ineffective. Post-hoc analysis indicated that approximately 9% of the patients treated with 30 mg were nonadherent to the treatment. When the data were reanalyzed after excluding these patients, the dose of 30 mg improved depressive symptoms at day 15 (Sage Therapeutics, 2019). Zuranolone demonstrated a dose-dependently effect also in an open-label study, where the dose of 50 mg exhibited a stronger and more prolonged effect than the 30 mg dose in reducing depressive core symptoms, regardless of the co-therapy with an SSRI or SNRI (ClinicalTrials.gov Identifier NCT03864614). The majority of patients did not require more than two 2-week treatment cycles to reach remission (Sage Therapeutics and Biogen, 2021a). Zuranolone 30 mg gave initial evidence of effectiveness in cases with residual insomnia, with improvement in objective measures of quality of sleep, for example, total sleep time, latency to persistent sleep, the median number of awakenings, and mean duration of awakenings (ClinicalTrials. gov Identifier NCT03771664 and NCT04007367); however, both studies were terminated to advance the program with the 50 mg dose (Sage Therapeutics, 2022).

Postpartum depression
Zuranolone, both 30 and 50 mg doses, showed encouraging results as a treatment for PPD in two RCTs with well powered samples of outpatient women with sever mood impairment (ClinicalTrials.gov Identifier NCT02978326 and NCT04442503). The first trial included a sample of women who were up to the sixth month postpartum and had depression with onset between the last trimester and 4 weeks after delivery. Rapid (as soon as day 3) and persistent antidepressant effects (day 45) were demonstrated after 2 weeks of treatment with zuranolone 30 mg, as well as rapid improvement in anxiety, global functioning, and self-reported maternal function, despite a high placebo response (Deligiannidis et al., 2021). In the second trial, zuranolone 50 mg confirmed benefits on depression and anxiety, assessed at the same time points (Clinicaltrials. gov, 2020d); however, the possible persistence of the effect beyond 45 days and the long-term safety and efficacy are currently unknown.

Bipolar depression
Zuranolone 30 mg may provide rapid (by day 3) and prolonged (as far as day 42) relief of depressive symptoms in patients with bipolar depression type I or II, with a current major depressive episode, as suggested by an exploratory open-label study (ClinicalTrials.gov Identifier NCT03692910). In this study, the 2 weeks treatment paradigm was used, and two patients reported mild hypomania in the follow-up period, but no cases of mania, increased suicidal ideation, or suicidal behaviour were observed (Gunduz-Bruce et al., 2020). There is still no evidence of potential benefits for anxiety or insomnia associated with bipolar depression.

Prax-114
Prax-114 is a novel extra-synaptic GABA A Rs PAM, currently in phase II of development for the treatment of MDD (Hecking et al., 2021). In-vitro models it was demonstrated that PRAX-114 potentiates GABA-induced currents at both extra-synaptic and synaptic GABA A Rs, but with 10.5-fold greater potentiation of the former compared to the latter Rs. This pharmacodynamic property was suggested to potentially reduce the risk of sedative side effects, providing a wider therapeutic window versus other GABA A Rs PAMs, while keeping the antidepressant and anxiolytic benefits (Hughes et al., 2021).
Despite this promising pharmacodynamic mechanism, to our best knowledge PRAX-114 did not show any antidepressant effect in MDD when tested as monotherapy in a well powered RCT (ClinicalTrials.gov Identifier NCT04832425) (Praxis, 2022). Another well powered RCT (ClinicalTrials.gov Identifier NCT04969510) will evaluate the efficacy of PRAX-114 10-20-40-60 mg compared to placebo as adjunctive therapy to the current antidepressant treatment but no results are available (Clinicaltrials.gov, 2021a). Efficacy of PRAX-114, apart from mood disorders, is investigated also in posttraumatic stress disorder and essential tremor.

Menopausal and mood symptoms
There is preliminary evidence of efficacy of PRAX-114 in menopausal and mood symptoms. An open-label study used a single daily 60 mg dose in a small sample of outpatient women with menopausal distress and PMD. Prax-114 gradually improved mood symptoms and decreased moderate-to-severe vasomotor symptoms (e.g. hot flashes), in a 2-week treatment paradigm. Participants reported enhancement in energy and volition, sexual interest, sleep, anxiety, and irritability; however, symptoms worsened when treatment was discontinued, suggesting the need for a longer therapy (Praxis, 2021); however, these results were not published in a peer-reviewed journal, and apparently, the study was not preregistered.

Ph-10
Ph-10 (pregn-4-en-20-yn-3-one) is a neuroactive steroid that belongs to the group of 'pherines'. Its intranasal administration engages local nasal chemosensory receptors that connect the olfactory system with limbic circuits through oligosynaptic neural connections (Monti et al., 2019). Extensive evidence demonstrated the fundamental role of the human olfactory system in social interactions, vegetative functions, emotions, and mood (Pause et al., 2001;Krusemark et al., 2013). Ph-10 demonstrated a good safety and tolerability profile versus placebo in a dose escalation study (from 0.8 to 6.4 µg), in a small sample of healthy volunteers (Monti et al., 2019). To the best of our knowledge, only one RCT testing this drug in MDD was published. The study included patients with moderate MDD and showed that self-administrated intranasal PH-10 at high dose (6.4 µg) had antidepressant effects by week 1, which were sustained in the short-to-medium-term (up to the study endpoint at week 8). A small dose-dependent effect favoured the high dose over the low dose (3.2 µg). Amelioration of depressive symptoms was not strongly supported by a significant improvement in quality and life satisfaction. These results cannot be generalized to patients with suicidal ideation, TRD, and bipolar depression, as these groups were excluded from the trial (Monti et al., 2019). Possible benefits of anhedonia, anxious or irritability features, sleep disturbances, or other specific depressive domains were not investigated.

Seltorexant (JNJ-42847922/MIN-202)
Seltorexant is a highly selective antagonist of the human orexin-2 receptor (OX-2R). There are two different orexin types: orexin A (OX-A) and orexin B (OX-B). Both are excitatory neuropeptide hormones, also known as hypocretins, that derive from a common pre-pro-orexin precursor produced in the posterior lateral hypothalamus. Their target is represented by orexin-1 receptor (OX-1R) and OX-2R, which are differently expressed through the CNS. OX-A displays a similar affinity for both receptors, and OX-B shows a greater affinity for OX-2R (Nollet and Leman, 2013).
The orexin system is increasingly being recognized as a key factor involved in hyperarousal and wake/sleeping transition and disturbances, with important implications in stressful or threatening situations. Orexins are involved in multiple functions often compromised during depressive episodes, such as the regulation of circadian rhythms, cognitive (including attention, learning, and memory) and sexual functioning, positive emotions and social interactions, hedonic capabilities and reward process, visceral functions, sensory systems, and pain (Nollet and Leman, 2013), as well as in anxiety and panic states (Johnson et al., 2012). Seltorexant is in phase III of development for MDD and has shown efficacy in normalizing sleep (Bonaventure et al., 2015). In an exploratory clinical study (Clinical trial identification number NCT02067299), the drug demonstrated a dose-dependent normalization of sleep after a single dose of 10-20 or 40 mg in MDD patients treated with SSRI or SNRI with residual insomnia (Brooks et al., 2019); the dose-dependent effect is in line with previous studies of OX2R antagonists in heathy subjects (Ark et al., 2018). The aforementioned study was not designed to test the possible antidepressant effect of seltorexant; however, it was reported that the 40 mg dose as monotherapy improved mood compared with other dosages. In a relatively small sample of patients with mild to moderate depression (Clinical trial identification number NCT02476058), seltorexant showed antidepressant effects as early as day 11 of treatment with 20 mg, with an improvement in self-reported sleep quality. The antidepressant efficacy was sustained with continued treatment for up to 28 days (Recourt et al., 2019). Higher benefits on core symptoms of depression and anxiety were demonstrated by seltorexant as adjunctive therapy to ongoing antidepressants in patients with MDD (Clinical trial identification number and NCT03227224). During these 6-week-period studies, the 20 mg dose showed higher antidepressant efficacy than the 10 and 40 mg doses, and it was even more effective in patients having sleep disturbances. The 40 mg dose improved sleep impairments, but it showed lower efficacy on depressive symptoms (Savitz et al., 2021). This result is in contrast with the findings previously mentioned, therefore it remains unclear which dose is more effective in case of residual insomnia in MDD.
Despite the positive results presented, one long follow-up RCT in a well powered sample did not find any benefit of seltorexant on depression and anxiety, with or without insomnia, when 20 and 40 mg were tested as adjunctive treatment to the ongoing antidepressant versus quetiapine extended-release 150-300 mg (ClinicalTrials.gov Identifier NCT03321526) (Clinicaltrials.gov, 2017).

Adverse events, safety, and tolerability
Considering the impact of the safety profile on treatment adherence, in this paragraph we provide an overview of the most frequent adverse events associated with the drugs of interest, to guide the personalization of treatment choice also based on the tolerability profile, and to properly inform patients.
Overall, the discussed medications were safe and well tolerated, with a few serious adverse events. Details on the adverse events profile of each drug of interest are reported in Fig. 2; however, there is still limited evidence, particularly in the long term, and longitudinal studies are needed.
The neurological safety profile appears to be the most affected by new rapid agents. Headache was one of the most frequently reported adverse events for all compounds (apart from AV-101), with a frequency exceeding 10%; the risk seems to be more elevated in subjects exposed to psilocybin (67%) (Carhart-Harris et al., 2021) and seltorexant (40%) (Brooks et al., 2019). Dizziness was reported by 25% of patients treated with seltorexant (Brooks et al., 2019), despite being a common adverse event of other medications, with a frequency higher than 5%. Extrapyramidal symptoms (EPS), that is, akathisia, bradykinesia, and rigidity, were observed for pimavanserin, and ranged from 1.3% to 3.4%, without compromising motor function even in patients with Parkinson's disease (DeKarske et al., 2020). Tremor is another adverse event that might represent an EPS or be associated with psychomotor agitation. In patients receiving psilocybin, it was mainly coupled with fear, sadness, and a physical experience of feeling the body shake (Doss et al., 2021). In patients treated with zuranolone, it was often associated with insomnia in 7% of patients and, similarly to the other adverse events of zuranolone, occurred predominantly during the 2-week treatment paradigm and then was no longer reported (Sage Therapeutics and Biogen, 2021a).
Pimavanserin and AV-101 appeared to be the safest with respect to psychomotor agitation, arousal and sleeping disturbances. On the other hand, 17-23.2% of patients with MDD and life-threatening illnesses treated with psilocybin, especially at higher doses, developed a mild activation syndrome at the beginning of treatment, mainly characterized by anxiety (Griffiths et al., 2016;Ross et al., 2016); however, in one trial anxiety affected 100% of patients (Carhart-Harris et al., 2016). Anxiety was generally acute and transient, but it also appeared several days after treatment (Anderson et al., 2020). It was mainly attributable to the psychological discomfort during psilocybin sessions, and it improved with reassurance from the clinical team.
Rates of insomnia were found to be over 10% for psilocybin and were sometimes accompanied by posttraumatic stress flashbacks (Anderson et al., 2020). In patients treated with seltorexant, few cases of unexpected insomnia (2.1%), sleep paralysis (1.4%), abnormal dreams (13%), and nightmares (1.4%) led to treatment discontinuation (Recourt et al., 2019;Savitz et al., 2021). In another trial of seltorexant, up to 13% of patients experienced abnormal dreams (Clinicaltrials.gov, 2017). No hypnagogic nor hypnopompic hallucinations were observed and there was no clear evidence of dose-related effect on these adverse events. Seltorexant safety profile seems similar to the first-in-class orexin receptor antagonist, namely suvorexant, already approved by FDA for the treatment of insomnia (Kuriyama and Tabata, 2017); however, unlike seltorexant, suvorexant has a longer half-life (about 12 h), with more severe adverse events, higher rates of sleeping disturbances (Sutton, 2015), as well as a functioning impairment, caused by symptoms similar to cataplexy that may occur the day after treatment (Recourt et al., 2019).
Although somnolence was common for different compounds, there are substantial differences. For seltorexant, Description of adverse events of novel antidepressant drugs. Common adverse events were defined as those having a frequency ≥5%, while rare adverse events as those with a frequency <5%. Serious adverse events are defined as any adverse event causing clinically significant disability and incapacity or immediately life-threatening. BUP, bupropion; DXM, dextromethorphan; NMDAR, n-methyl-d-aspartate receptor; OX-2R, orexin type 2 receptor; R, receptor.
somnolence appeared to be dose-related within the dose range of 10-40 mg/day, and was reported by 25% of patients (Brooks et al., 2019); however, somnolence was most frequent in patients treated with the GABA A Rs modulators PRAX-114 and zuranolone, with maximum rates of 37.5% and 26.5%, respectively (Clinicaltrials. gov, 2020d;Praxis, 2021). Despite resolving within a few hours, sedation may represent a serious adverse event for both compounds, especially when associated with confusion (Deligiannidis et al., 2021;Praxis, 2021). Transient confusion induced by psilocybin, albeit frequent (75%), can probably be considered a psychological effect that subsided after a few hours (60-180 min) (Carhart-Harris et al., 2016). These sleeping and arousal adverse events must be differentiated from fatigue, intended as the lack of energy and motivation to perform daily activities.
Although it often associates with the daytime somnolence and sedation induced by GABAergic and orexinergic compounds, fatigue achieves higher rates during psilocybin trials (7-10%), suggesting more complicated mechanisms that extend beyond the alteration of the hypnic pattern (Carhart-Harris et al., 2021;Compass Pathways, 2021).
Regarding cardiovascular adverse events, psilocybin, and AV-101 caused minimal reductions in SBP/DBP and basal HR that can be related to a mild sympathomimetic effect (Grob et al., 2011;Griffiths et al., 2016;Ross et al., 2016;Doss et al., 2021). For AV-101 these events were not generalizable , whereas patients receiving psilocybin reported cardiovascular adverse events in 76% of cases according to one RCT (Ross et al., 2016). No effects on QT interval prolongation emerged for any of the considered drugs.
Gastrointestinal adverse events were common for all the discussed agents. Psilocybin was associated with the highest rates of nausea (33%) (Carhart-Harris et al., 2016) and REL-1017 with the highest rates of constipation (14%), showing a dose-response relationship probably linked to the weak stimulation of opioid receptors . Dry mouth was a frequent adverse event experienced by 10.3% of patients treated with AXS-05 (Tabuteau et al., 2022) and by 9.6% of subjects with pimavanserin (Fava et al., 2019). Conversely, PH-10 and AV-101 were less likely to cause gastrointestinal adverse events: PH-10 showed a low trend to increase appetite that did not result in weight gain (Monti et al., 2019) and only one participant experienced transient diarrhoea with AV-101 1440 mg . In general, more than 5% of patients treated with the other compounds experienced gastrointestinal adverse events, without resulting in hospitalization or treatment discontinuation. No gastrointestinal bleeding was reported.
Despite the limited data concerning PH-10, local nose irritation due to the intranasal administration, and bitter taste were reported during the treatment period (Monti et al., 2019). No other adverse events related to sensory organs were reported for the other compounds.
Considering all the discussed medications, there was no evidence of abuse or dependency potential, increased suicidal ideation, and/or suicidal behaviour compared with baseline. Only in one trial of psilocybin, 12 patients reported suicidal ideation or suicidal behaviour and intentional self-injury, which are however quite common in patients with TRD (Compass Pathways, 2021). During treatment with zuranolone, one case of suicide attempt and one of bile duct stones were reported; however, these patients had a previous history of suicide attempt and of bile duct repair, respectively (Sage Therapeutics, 2019).
Participants exposed to the discussed NMDAR antagonists experienced no worsening in depression, dissociative or psychotomimetic effects. In reference to this, it has been hypothesized that the unusually rapid rate of NMDAR unblocking may explain the low association of these drugs with psychotomimetic adverse events (Parsons et al., 1995). Only after psilocybin administration, a few cases of paranoid ideation and transient thought disorders were described, but they were generally mild and transient (Ross et al., 2016;Anderson et al., 2020); only in one trial 75% of participants underwent through a transient thought disorder (Carhart-Harris et al., 2016).
No hallucinogen-persisting perception disorder or visual perceptual changes were observed, probably because of the safe environment wherein psilocybin sessions were tested. Accurately informing patients about possible adverse events contributed to avoiding psychotic reactions (Studerus et al., 2012).
Another noteworthy safety consideration is the low tendency of the drugs of interest to produce clinically significant changes in vital signs or consciousness, sexual dysfunction, cognitive impairment, euphoria, or manic episodes (only two cases of hypomania occurred during the follow-up period in the trial testing zuranolone in bipolar depression) (Gunduz-Bruce et al., 2020), withdrawal symptoms and weight gain or metabolic changes. Despite the time of observation being fairly limited to make firm conclusions, novel antidepressant drugs may represent metabolically and sexually friendly antidepressants. The relevance of the latter issue, among the general safety profile, acquires even more importance considering the limitations in the use of conventional antidepressants because of weight gain (Serretti and Mandelli, 2010), sexual impairments (Serretti and Chiesa, 2009) and (hypo) manic switches when used in bipolar depression (Bauer, 2022).

Discussion
Rapid acting antidepressants represent promising alternatives to standard medications for mood disorders, with various levels of evidence and in different phases of development, with overall encouraging findings about their efficacy and tolerability. This review provides an overview of the clinical trials that investigated new rapid acting antidepressants, with the aim to provide clinically useful information to tailor the prescription of these new compounds, based on the individual clinical profile. The specific clinical features targeted by each novel antidepressant drug were identified according to the current evidence and are reported in Fig. 3. There is not sufficient evidence to demonstrate if AV-101 and PH-10 positively target any specific depressive symptoms. Among new drugs acting on the glutamatergic system, we discussed AV-101, AXS-05, and REL-1017. Despite these three compounds primarily targeting the glutamatergic signal, AV-101 and AXS-05 appear to exhibit a major involvement in inflammatory pathways underpinning mood disorders, while the antidepressant action of REL-1017 seems to be primarily related to neuroplasticity phenomena, since the persistence of the therapeutic effect after treatment discontinuation.
Av-101 principally acts through the kynurenine pathway, which plays an important role in various biological functions behind depression. Additionally, it also modulates brain-derived neurotrophic factor (BDNF) levels (Réus et al., 2015). Response to this drug appears to be compromised by comorbid anxiety disorders (Park et al., 2020) unless used as adjunctive treatment to standard antidepressants or with an appropriate dose increment. Higher doses (1440 mg/day) are indeed potentially more effective than lower doses (720 mg/day) in a preclinical study . To further increase bioavailability, despite not overcoming the limitations reported in animal studies, the combination of AV-101 with probenecid (a uricosuric agent) has recently been investigated in rodents, with safe results . Despite the drug was not associated with an improvement in suicidal ideation and/or suicidal behaviour, it was hypothesized to be a promising option for suicidality treatment in emergency settings, because of its ketamine-like glutamatergic mechanism of action, and the lack of dissociative adverse events (Zanos et al., 2015). Additionally, its antisuicidality effect may be not limited to the acute phase. Research in cases of suicide attempts shows that pro-inflammatory cytokines, frequently increased in these patients, lead to a persistent increase in quinolinic acid, which binds to NMDAR, and to a decrease in kynurenic acid (Bay-Richter et al., 2015). Consequently, AV-101 may rebalance quinolinic and kynurenic acids equilibrium, displaying a protective action on suicide risk also in the medium-long term.
Rel-1017, another NMDAR antagonist, demonstrated rapid efficacy in MDD, with the persistence of antidepressant activity up to 1 week after treatment discontinuation . Additionally, changes in anhedonia, motivation, and reward have accompanied antidepressant-like activity in rodent models, after a single dose (Fogaça et al., 2019). Rel-1017 may represent therefore a valid therapeutic option not only in MDD but also in TRD. Importantly, the potential of abuse should be better explored since the low affinity to the opioid receptors does not automatically exclude this issue (Nemeroff, 2022).
AXS-05, presumably due to the multimodal pharmacological activity, was beneficial in rapidly reducing depressive symptoms, even when associated with anxiety features and when unresponsive to other antidepressants, both in the short (by week 1) and long term (up to 12 months). Noteworthy AXS-05, albeit in a limited way, reduced cognitive dysfunctions and produced a tangible improvement in work/family functioning, ameliorating life quality (Axsome Therapeutics, 2020c. Among the pharmacodynamic mechanisms beyond AXS-05 efficacy in MDD, there is also a potential action towards α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (Nguyen and Matsumoto, 2015), shared also by ketamine (Maeng et al., 2008) and esketamine, approved by the FDA in 2019 for adults with TRD (Stachowicz and Sowa-Kućma, 2022). These two compounds demonstrated clear evidence of efficacy in reducing the severity of suicidal ideation with active intent (Siegel et al., 2021), as well as AXS-05 was reported to contrast suicidal ideation since the first week of therapy (Axsome Therapeutics, 2020b). Dextromethorphan itself has also evidence of preliminary efficacy in bipolar depression, both as monotherapy (Majeed et al., 2021) and as add-on therapy with memantine (Lee et al., 2020). Consequently, although AXS-05 clinical profile appears to be useful only in MDD and has not yet been investigated in bipolar depression, it owns the potential of being pursued for the treatment of bipolar depression, especially considering the efficacy in the management of cognitive dysfunction and suicidal ideation; however, it remains to be clarified whether AXS-05 efficacy may be extended to other domains typical of depressive experiences, such as anhedonia, demotivation, and alterations in reward processing. According to several studies reporting a correlation between the reduction of anhedonia and suicidal ideation (Ballard et al., 2017), we can hypothesize that AXS-05 may improve anhedonia.
Other drugs discussed in this review, namely psilocybin and pimavanserin, act mostly by modulating the serotoninergic system. Psilocybin in conjunction with psychotherapy demonstrated efficacy within 8 h of taking a single dose in the alleviation of demoralization and hopelessness (Ross et al., 2021). Initial self-perceived effects occur in approximately 30-60 min upon oral administration (Griffiths et al., 2006), and according to most trials, positive effects on anxiety and depressive experiences persist for up to 6 months after a few psilocybin sessions. Such long-lasting positive changes may be related to psilocybin-induced synaptic remodelling. Consistent with psilocybin-induced neuroplasticity, in some trials patients found relief in reconnecting to their emotionality (Anderson et al., 2019;Carhart-Harris et al., 2021;Ross et al., 2021) and improved cognitive flexibility (Griffiths et al., 2016;Doss et al., 2021) that may facilitate, potentially after a single dose, the recognition of feelings (Stroud et al., 2018), thus improving cognitive empathy. Additionally, one RCT in healthy individuals outlined the enhancement in emotional empathy (Pokorny et al., 2017). As multiple deficits in empathic abilities are extremely common in mood disorders and lead to social impairments (Cusi et al., 2011), these pro-empathic properties may be particularly relevant to enhance social skills in patients with MDD, TRD, and depression associated with neoplastic illnesses. In the latter group of patients, anxious and depressive symptoms are often accompanied by cognitive inflexibility with hopelessness, negative cognitive bias, and suicidal ideation. In these cases, as well as in TRD, the rapid and sustained reduction in suicidal ideation of psilocybin is particularly relevant (Carhart-Harris et al., 2021;Doss et al., 2021;Ross et al., 2021). The long-term antisuicidality potential may be linked to the increase of synaptic plasticity and BDNF levels, through modulation of glutamatergic prefrontal-limbic neural circuits. Another pharmacodynamic mechanism potentially behind this antisuicidal effect is the increase of dopamine levels in mesoaccumbens circuits, which may ameliorate reward process impairments (Sakashita et al., 2015). Of note, subjective and mystical experiences are considered to reduce suicidal ideation in the short term (Ross et al., 2021) and to be potentially implied in the risk of abuse (Griffiths et al., 2018); however, the potential of abuse and risk of dependence is fairly reduced by the lack of psilocybin-induced withdrawal and rebound symptoms.
In contrast to psilocybin, pimavanserin exerts an antagonism action mostly towards 5HT 2A Rs. It showed major efficacy in treating depressive episodes associated with Parkinson's disease and inducing mood improvement associated with amelioration in sleeping and in overall quality of life (DeKarske et al., 2020). Despite the efficacy of pimavanserin in treating psychic symptoms associated with Parkinson's disease, its benefits in MDD remain uncertain, due to the negative results of phase III trials (Acadia, 2020). It is however worth mentioning its positive effect on sexual dysfunction. Although it shares monoaminergic activity with other antidepressants, in contrast to them pimavanserin does not exhibit adrenergic, histaminergic, muscarinic, or dopaminergic activity (Vanover et al., 2006), to which sexual dysfunctions are attributed (Serretti and Chiesa, 2009), and the specific 5-HT 2 antagonism may even improve sexual functioning. Another point to consider is that pimavanserin reduced suicidal ideation more than placebo . This antisuicidality potential may be correlated to its efficacy in targeting irritation and insomnia, which in turn are associated with agitation and with depression with mixed features and an increased risk of suicide (McIntyre et al., 2016). To summarize, despite the development of pimavanserin for MDD was discontinued, future studies may clarify if this compound could be a useful option as adjunctive treatment to another antidepressant for MDD with compromised sexual functioning or sexual side effects, anxiety, irritability, agitation, insomnia, or excessive day sleepiness.
Finally, we discussed new compounds acting as neuroactive steroids, which were developed based on the evidence that dysregulation in neurosteroidogenis and GABAergic transmission are involved in anxiety and depressive disorders, including PPD (Luscher et al., 2011).
Zuranolone is a synthetic neurosteroid and targets GABA A Rs, similarly to other neurosteroids and benzodiazepines (Goetz et al., 2007); however, zuranolone shows a major affinity to extra-synaptic GABA A Rs, responsible for tonic inhibition, rather than synaptic GABA A Rs, mediators of phasic inhibition. Consequently, despite sharing with benzodiazepines phasic channel inhibition (clinically resulting in an anxiolytic and sedative action), it differs since it also exerts a tonic inhibition (responsible for the antidepressant action) (Reddy, 2018). This pharmacodynamic profile may hypothetically provide also anxiolytic, hypnotic, and sedative properties. In line with this, the major benefits of zuranolone 50 mg in a 2-week treatment regimen were reported in patients with anxious depression and those with residual insomnia. Efficacy in alleviating sleeping impairments was reported also in a crossover study of healthy adults with sleep disturbances (Bullock et al., 2022); however, improvements in anxiety and insomnia were not confirmed by all trials (Gunduz-Bruce et al., 2019). Despite in a few cases benefits persisted until days 42-45, generally the rapid improvement in MDD symptoms slightly decreased after the end of the 2-week treatment paradigm, thus requiring additional courses of treatment. Zuranolone was also tested in the treatment of PPD, with rapid reduction of depressive symptoms and anxiety, a common feature in PPD (Radoš, 2018), with sustained effects until day 45. The improvement of global and maternal functioning makes zuranolone a valid option for PPD, especially considering that none of the standard antidepressants have a specific indication for this condition. The oral route of administration facilitates the intake compared to its intravenous analogous brexanolone, already approved by FDA in 2019 for PPD. Positive results of zuranolone in bipolar depression open new horizons about the involvement of neurosteroids in this condition. The current evidence suggests that neurosteroids may act as endogenous mood stabilizers and low levels of neuroactive steroids characterize depressive and mixed episodes in bipolar depression. Consistently, preclinical evidence showed that lithium and olanzapine/fluoxetine modify the levels of neurosteroids, and these are all approved therapeutic compounds in bipolar depression (Carta et al., 2012). In summary, zuranolone was effective in reducing depressive symptoms within 15 days of treatment and may represent a viable therapeutic option with a rapid onset of action, especially in agitated depression, depression with anxious features, and sleep impairment. Benefits of zuranolone in TRD and suicidal ideation are still unknown. Of note, co-therapy with benzodiazepines should be avoided, for a consistent risk of increasing sedative effects.
Ph-10 is another neuroactive steroid, that demonstrated a rapid antidepressant potential in unipolar depression; however, only one trial is available, and it is characterized by several limitations that compromised the generalizability of results (Monti et al., 2019). Unlike zuranolone, PH-10 is not a direct GABARs modulator and consequently has a less sedative profile. Early findings demonstrated that ph-94b, another neuroactive compound, had therapeutic potential in patients with social anxiety disorder, because of a rapid decrease in sympathetic tone (Liebowitz et al., 2016). According to the common neurosteroid structure between PH-10 and ph-94b, and to the administration in µg dosages of both agents, similar efficacy of PH-10 in reducing social anxiety could be hypothesized, but it should be tested in future trials. Notably, PH-10 could represent a rapid onset and easy-to-administer (intranasal) option in this group of patients.
Prax-114 is another neurosteroid modulating the GABAergic system, but it currently shows poor evidence of efficacy in treating mood disorders, as it failed in a phase II/III RCT of MDD (Praxis, 2022). This failure underlines the complexity of developing compounds with effective clinical benefits. Despite the failure to demonstrate efficacy in MDD, the drug was tested for treating mood and perimenopausal symptoms in a small preliminary study, suggesting possible improvement in mood, energy, irritability, anxiety, insomnia, and sexual interest, with an overall safety profile (Praxis, 2021).
Probably increasing the dosage up to 60 mg, compared with the 40 mg dose used in the MDD trial, contributed to reducing the high rates of insomnia that affect affective changes during menopausal transition, with consequent benefits on mood (Caruso et al., 2019).
Finally, we discussed seltorexant, a novel antidepressant acting on the orexinergic system. This drug demonstrated efficacy as an adjunctive treatment to the ongoing antidepressant in MDD, especially when associated with insomnia. In these cases, apart from showing a major effect on mood, it immediately ameliorated both self-reported and objective parameters of sleep experience within a few hours after administration (Brooks et al., 2019). Improvements in other depressive and anxiety symptoms were not as rapid, but generally started within the first week of treatment, or as early as day 11 according to another study, with the greatest amelioration at weeks 3 and 6 (Savitz et al., 2021). Whether seltorexant displays a dose-dependent effect across doses of 10-20-40 mg remains unclear. In this regard, a curvilinear dose-response relationship was hypothesized as previously noted also for esketamine and nortryptiline, with the maximum antidepressant response at 20 mg and a reduction of the therapeutic effects of seltorexant at the doses of 10 and 40 mg (Savitz et al., 2021). Consistently with the role of orexin pathways in the aetiology of mood, anxiety, and panic symptoms, we suggest that seltorexant might be particularly useful for improving depressive and anxiety symptoms associated with panic distress, as well as for inducing an immediate hypnotic effect. The ideal time of administration should consequently be 1 h before bedtime. These positive effects on sleep may also have benefits in preventing depressive relapses/recurrences, as there is a bidirectional connection between depression and insomnia (Oh et al., 2019). The principal mechanism of alleviating sleeping disturbances consists in reducing sleep latency and increasing sleep duration with very low evidence of altering sleep architecture, thus differing from the currently available hypnotic drugs that significantly alter the rapid eye movement phase (Brooks et al., 2019). Additionally, the involvement of orexin neurons in the modulation of irritability/aggressive behaviours supports the idea of possible effectiveness in these clinical features (Flanigan et al., 2020).
To summarize the clinical specificity profiles targeted by the discussed medications, we considered seven clinical domains: negative emotionality, behavioural dysregulation (impulsive or excessive behaviours that may even put life at risk), cognition, psychomotor agitation, circadian rhythm, sexual dysfunction, and interpersonal activities and relationships (Fig. 3). All compounds, except AV-101 and PH-10, may constitute an appropriate option to reduce psychomotor agitation, and REL-1017 shows the widest profile in terms of the number of targeted symptoms. Psilocybin and zuranolone show the strongest potential to target anxiety. No medication with effectiveness in reducing psychomotor retardation was identified, despite this being one of the main features of severe depressive episodes (Buyukdura et al., 2011). Several drugs (pimavanserin, zuranolone, PRAX-114, and seltorexant) showed efficacy for the regularization of the circadian rhythm, with pimavanserin not only favouring sleeping at night but also reducing excessive daytime sleepiness. Pimavanserin also showed effects on behavioural dysregulation, sexual and global functioning. Psilocybin was found to be the only drug with a strong specificity in reducing negative emotionality and in counteracting pessimism and cognitive inflexibility of depression. It also was effective in reducing behavioural dysregulation. AXS-05 displays a wide profile of efficacy among the domains of behavioural dysregulation, cognition, psychomotor agitation, and interpersonal functioning.
Regarding psilocybin, it has been tested as part of structured psychotherapy. A therapeutic approach including psychotherapy requires a significant effort in terms of time and costs, with consequent possible limitations in the applicability to public health services (Doss et al., 2021). Furthermore, it remains unclear whether psilocybin could have an antidepressant effect alone since there were no experimental conditions omitting supportive psychotherapy. The effects of micro-dosing should also be clarified, in relation to positive emotionality/beliefs and in reducing anxiety and depression compared to a single macro-dose.
Concerning some psilocybin trials, strategies to improve the recruitment of more diverse study populations are needed (Carhart-Harris et al., 2021;Doss et al., 2021;Ross et al., 2021). The available evidence supports the efficacy of psilocybin in patients with cancer, but these results may not be generalizable to other end-of-life medical diseases (e.g. neurodegenerative diseases) or in severe pain conditions. Additionally, psilocybin, like other psychedelics, is known to promote suggestibility, which might have enhanced positive outcomes (Carhart-Harris et al., 2015). Future studies should address the role of expectancy and suggestibility by measuring and controlling for these variables. Nonetheless, the approval of psilocybin remains extremely challenging due to the lack of appropriate ethical guidelines that can prevent its misuse and the consequent restrictions imposed by the Drug Enforcement Administration, despite no potential to cause addiction was found in the discussed trials. In this regard, there are no conflicts of interest for the authors of this manuscript.
Regarding seltorexant, although it showed benefits on residual insomnia in MDD, some trials were not primarily powered to demonstrate an antidepressant effect or efficacy on sleep disturbances (Brooks et al., 2019;Recourt et al., 2019).
The discussed drugs were all developed for nonparenteral administration. Considering the more robust and rapid effect of standard antidepressants when administered intravenously versus orally (Buoli et al., 2019), future development of parental formulations (other than oral) should be considered. Although most trials assessed objective symptoms, the evaluation of subjective well being, functional endpoints, and quality of life would be important in future studies. Additionally, most clinical trials used the HDRS (Hamilton, 1960), Mongtomery-Asberg Rating Scale (Montgomery and Åsberg, 1979), or the Quick Inventory of Depressive Symptomatology-Self Report (Rush et al., 2003); however, these instruments were designed to evaluate symptoms over a period of weeks; the use/development of different psychometric instruments to assess changes in symptoms severity within hours to days should be considered.

Conclusion
Novel rapid acting antidepressants represent a promising option, particularly for patients unresponsive to standard medications or those who discontinue treatment due to side effects.
The lack of psychotomimetic, dissociative, metabolic, and rebound side effects greatly increases the safety and tolerability profile of new antidepressants, favouring a good therapeutic adherence; however, some side effects need longer follow-ups to be reliably assessed, such as weight gain and withdrawal symptoms.
The benefits of each compound on specific symptom domains/profiles were discussed, as this should be a key objective of clinical trials, to facilitate the implementation of precision psychiatry.