Major depression is one of the most impacting disorders worldwide in terms of patient suffering and economic burden [1]. Pharmacologic treatments for major depression have been available for more than 50 years, in this period many new drugs have been discovered and marketed. At present, in most countries over 40 antidepressants are available in the market [2]. This quite large of possible pharmacologic treatments however do not translate into optimal treatment for patients due to limitations in various aspects for all available antidepressants. The main limitation is that the large majority of treatments need quite a long time to be effective, in the range of weeks, moreover also tolerability is far from optimal for many antidepressants, with side effects ranging from mild to severe. Finally, only one third of patients completely respond to the first treatment and further treatment trials are needed in the majority of patients with about one third not responding to two or more antidepressant trials. Therefore, despite the number of currently available antidepressant drugs, further developments are needed from a clinical perspective.

In recent years, some new antidepressants have been approved for routine clinical use, but many more are under various stages of development and will soon be available in the market. This surge of new drugs was mainly unexpected, given that clinicians were used to the traditional monoamine modulators for many decades. It is therefore important to acquire knowledge about the features of the new and upcoming drugs for an effective and targeted use. Overall new drugs promise a range of amelioration compared to previous antidepressants, in terms of speed of action, tolerability and range of treatable disorders.

In the present review the most promising drugs will be briefly discussed. The focus will be on drugs which have been recently approved or that showed promising findings in phase II or phase III studies. Each chapter will focus on the most promising drugs that are already available or in advanced stages of development discussing critically their potential in treating depression.

Neurosteroids are positive allosteric modulators of gamma-aminobutyric acid type A receptors and their involvement in the pathophysiology of depression has been studied for many years [3]. More recently, neurosteroids have been hypothesized to have an antidepressant effect [4,5] and following clinical trials confirmed the antidepressant effect of the neurosteroid brexanolone [6,7]. It was then approved in 2019 by the Food and Drug Admin-istration (FDA) as an intravenous treatment for postpartum depression. The antidepressant effect is fast, within days, and it is usually maintained for weeks. The positive evidence showed by brexanolone prompted further research for drugs with more convenient administration routes. Zuranolone was then developed, with the advantage of an oral administration, and it was also approved by the FDA in 2023. Interestingly, it resulted effective in patients with depression and anxiety features and also in bipolar depression, without increasing the risk of switching to mania, thus extending the range of possible disorders to treat. Response was maintained after 6 weeks, though not in all subjects [8-12], also considering that it is administered for 2 weeks only. It resulted effective in subjects with residual insomnia and showed improvement in objective measures of quality of sleep. It was also well tolerated, with most common side effects being somnolence, dizziness, and sedation. Neurosteroids are therefore very interesting new antidepressant drugs which may result useful not only in postpartum depression but also in major depression, major depression with anxiety features and, even more interesting, in bipolar depression, a condition which is usually more difficult to treat compared to major depression [13]. However each new drug should be used considering the best match between the pharmacodynamic profile and the clinical profile of the patient [2]. Therefore, as an example, neurosteroids are unlikely to be first-line treatment for people with atypical depression, considering their potential sedative effect. Similar, there is not at present an indication for very severe forms of depression, such as psychotic depression or treatment resistant depression.

The combination of dextromethorphan and bupropion is probably one of the most interesting examples of (partial) drug repurposing, as both drugs were already on the market, but their combination surprisingly showed a relevant and very interesting efficacy in the treatment of depression. Dextromethorphan is an uncompetitive antagonist of N-methyl-d-aspartate receptors and a sigma-1 receptor agonist, with some effects on nicotinic acetylcholine receptors and on monoamine transporters [14], however, despite the potentially interesting antidepres-sant pharmacodynamic profile, it is approved and has been used as a cough suppressant. Bupropion is well known as a dopamine transporter inhibitor but is not frequently prescribed for treating depression despite its good tolerability probably due to the risk of increasing anxiety and insomnia [15]. The combination of the two drugs is interesting because preliminary data suggested that bupropion could modulate the cytochrome P450 2D6 activity therefore prolonging dextromethorphan bioavailability [16,17]. But only years later the potential antidepressant benefits of the combination was tested, after the evidence of involvement of N-methyl-d-aspartate receptors in depression treatment [18]. Results were very promising in the treatment of depression also in comorbidity with anxiety disorders [19,20]. Moreover a very rapid onset of action was observed, as early as week 1. Those results led to the FDA approval in August 2022. Ongoing trials are exploring in detail potential benefits of this combination also including other conditions such as suicidal ideation and long term effects. However not all data are clearly in line with early trials, and also a combination of dextromethorphan with quinidine has been suggested [21]. In any case, it remains a valid tool with the potential for rapid efficacy and good tolerability, with the advantage that it can be used as monotherapy, while other new treatments are suggested to be used as potentiation. Another interesting potential target is treatment-resistant depression, usually considered difficult to treat, and preliminary results are encouraging. In addition, studies have reported a potential benefit on cognitive function, again a relevant finding given that many antidepressants have a variable degree of adverse effect on cognitive function, especially those with anticholinergic properties.

The dextro isomer of racemic methadone (dextromethadone or esmethadone) is an interesting drug that differs from methadone, commonly used for opioid dependence, in terms of its pharmacodynamic profile. It has a lower affinity when compared to methadone for opioid receptors and therefore does not cause the side effects of methadone, such as tolerance and dependence or sedation/respiratory depression, but it has a more relevant N-methyl-d-aspartate receptor antagonist profile and a lower affinity for serotonin and norepinephrine transporters [22-24]. It has originally been tested for its potential antitussive effects [25] and as a substitute to methadone [26]. Recently, it has been observed an antidepressant effect in animal models [27,28] and it therefore sparked attention for a repurposing in depressed subjects [29]. The glutamatergic mechanism, similar to ketamine, also suggests an effect on brain plasticity that was indeed observed in animal models [28]. Phase I and II studies followed with interesting results: the antidepressant effect was observed as early as day 4 and persisted after 2 weeks. Interestingly the antidepressant effect extended also to an enhancement in cognitive and social functioning, anxiety, agitation, anger, irritability, and sleep quality. It also showed a favorable safety profile, characterized by dose-related nausea and somnolence only at higher doses [30-33]. It therefore received the FDA fast-track designation as an adjunctive treatment for major depression disorder. The evidence at present suggests that dextromethadone is a very promising and well tolerated possible complementation of antidepressant treatment in cases of partial response. Ongoing studies will further clarify its role. However the mild effect on opioid receptors may raise some concerns regarding tolerability and safety.

Interest in glutamatergic modulators began more than 15 years ago with ketamine [34], suggesting for the first time a new antidepressant mechanism that showed efficacy within hours rather than weeks. In the years that followed, many studies confirmed the initial findings and we now have ketamine in clinical practice plus the more convenient nasal esketamine [35-38]. Research then expanded to include similar psychoactive drugs such as the serotonergic psychedelics, especially psilocybin. It has been studied for many years for its hallucinogenic properties [39], but more recently it raised interest also as an antidepressant [40,41]. Therefore a number of studies have been performed [42-44]. Again, the antidepressant effect is very rapid. The main difference with the above mentioned new drugs is that psilocybin is often combined with psychotherapy because of its synergistic effect on the brain plasticity and because of the risks associated with the psychedelic effects. In fact, it has been suggested that the mechanism of action of psilocybin involves plasticity effects with a rewiring of brain connectivity [45], and this may explain the fact that a single dose produces a long-lasting effect even over several months. However, there are also some aspects that need further research. Psilocybin is still a controlled substance and there is potential for recreational abuse. In any case it showed promising effects also in obsessive compulsive disorders [46-48] and substance dependence [49-51].

Psilocybin was recognized as a breakthrough therapy for treatment resistant depression by the FDA in 2018 and for major depression in 2019.

The interesting feature of psilocybin is that it has not only antidepressant properties, in the various trials also ameliorated anhedonia, which is usually resistant to standard antidepressants [52], pessimism bias, cognitive empathy and emotional face recognition, cognitive flexibility [53] with a possible synergistic effect with common antidepressants [54]. An interesting feature is the influence on personality, in the direction of improvement of extraversion and openness, more than what is observed with traditional antidepressants and that may last for months or more [55-57], even though a recent trial observed a reduced effect in this direction [58]. A number of trials are ongoing to clarify its role and improve its clinical use, as an example an interesting trial will evaluate if it is possible to avoid the psychological support by co-administering risperidone which should prevent the psychedelic effect [59]. We may therefore expect that psilocybin will be soon available in the market, however the peculiar pharmacodynamic and clinical profile of this drug will suggest caution for a large use. Patients should be carefully screened for abuse potential, clinical profile and tolerability for side effects, in any case it still remains at present an experimental treatment [60]. Moreover the long lasting effects, though mainly beneficial, should be further investigated.

Ayahuasca is a traditional drink used in some South American ceremonial contexts, consisting of a mixture of plants. It is a controlled substance in most countries. It has a complex pharmacodynamic profile as a serotonin and sigma-1 receptor agonist and a reversible monoamine oxidase inhibitor.

Early studies evidenced a series of positive psychotropic effects of ayahuasca in religious users [61], an effect that was confirmed by a similar observational study years later [62]. Following studies evidenced a rapid antidepressant effect [63]. Then a randomized placebo-controlled trial confirmed a very rapid effect in treatment resistant depression since day 1, with an impressive effect size of d = 1.49 at day 6 of treatment, with a remission of 36% after 7 days [64]. However tolerability was suboptimal, in particular regarding nausea and vomiting that was observed in more than half of the subjects. Following studies replicated the antidepressant effects [65] also suggesting a complementary anti-inflammatory mechanism [66]. Interestingly, it proved effective also on suicidal ideation, starting from one hour after administration, thus suggesting a potential also in emergency settings [67,68] and in residual suicidal ideation after antidepressant treatment [69]. Clearly there is much debate about the use of psychedelics as antidepressants [70,71], and further studies are needed to understand which patients will have an optimal risk-benefit profile.

Inflammation is a well known mechanism modulating and possibly causing depression [72]. Therefore it was hypothesized that monoclonal antibodies, which proved effective in the treatment of other medical disorders, could be effective in depression as well. A series of studies focused on the potential antidepressant effects of monoclonal antibodies targeting interleukin-6 [73,74] and interleukin-17A [75]. Overall results were positive, however unfortunately this line of research has not been carried on and at present there is not clear evidence of a readily translatable clinical use. However it remains of interest also considering the continuous development in biomarkers discoveries in depression [76]. An alternative approach is the administration of immunomodulatory interleukins, such as interleukin-2. A recent pilot study reported very promising results of interleukin-2 subcutaneous administration in resistant depression [77], however the small sample size requires replication.

Botulinum toxin A is an unexpected potential anti-depressant. It is commonly used for cosmetic purposes given its effects on muscular tissue, but it has been demonstrated that it also acts in the central nervous system [78]. Interestingly, it is administered as a single injection and its effects last for several weeks or months. A number of studies focused on its potential antidepressant effect. Indeed it resulted in effective treatment of depression versus placebo [79]. An early randomized double-blind placebo-controlled trial reported an impressive effect size of d = 1.8 after 6 weeks of a single administration [80], with a relevant improvement of depression scores of 47.1% versus only 9.2% with placebo. A following study with a careful crossover design confirmed the magnitude of the effect [81], with benefits up to 24 weeks after injection despite the fact that cosmetic effects vanished after 12−16 weeks. A more recent randomized placebo controlled clinical trial further replicated the finding though with a smaller effect size [82].

Another study involved an active comparator [83], this study is very interesting given that the comparator was sertraline, a known very effective antidepressant, and with doses up to 200 mg, therefore avoiding any underdosing effect. Results showed that botulinum was as effective as sertraline. Moreover the onset of effect was more rapid, and it resulted better tolerated. Patients treated with botulinum reported half the rate of side effects observed with sertraline.

Another interesting aspect is that botulinum injection persists for a relevant time in the body, functioning as a sort of depot antidepressant [84], a treatment modality that is unique among current antidepressants.

It has also been suggested that botulinum may be useful in other conditions, as other antidepressants, such as for example borderline personality disorder [85]. A recent case series study reported in fact benefit across a range of psychiatric disorders [86]. It is probably too early to identify which patients may benefit more from botulinum. However it may be hypothesized that patients with low compliance could be an ideal target, given the need of a single administration.

The use of microbiota manipulation as an antidepressant is an intriguing prospect. Indeed there is increasing evidence of a bidirectional influence between microbiota composition and depression [87]. Abnormalities in the microbiota affect gut permeability, inflammatory status and, indirectly, brain neurotransmitters. It is therefore reasonable to manipulate them to obtain an antidepressant effect. Manipulation can be based on dietary interventions, such as increasing the intake of fruit, vegetables and, in general, polyphenols and fibers, typical of the Mediterranean diet. But also probiotics, which are live microorganisms, prebiotics, substrates that promote the growth of some beneficial bacteria, postbiotics, inanimate microbial cells and/or their components, and fecal transplants from healthy donors. Probiotics are by far the most extensively studied. A meta-analysis of over 8,000 people showed a significant antidepressant effect [88]. The study also suggested that the antidepressant effect was more relevant when using high doses of probiotics and for at least 8 weeks. Considering that probiotic treatment is usually well tolerated, and beneficial also on metabolic disorders [89-91], it may be useful to use it more in routine clinical practice while awaiting further studies. In fact, it is not yet fully understood which exact composition should be administered, given the high number and complexity of bacterial species present in the gut. In addition, although relatively safe, any external manipulation may lead to some tolerability issues that remain to be clarified.

More details on some new and upcoming drugs mentioned in the present review and others may be found elsewhere [92], however it is clear that we are at a turning point in antidepressant treatment. A large number of new drugs with innovative mechanisms of action are under investigation, and given the wide variability in the clinical manifestations of major depression, the new drugs will be relevant to targeted treatment. However, much information is still missing. It has been recently discussed that many of the new and upcoming antidepressants need further studies to establish their role in routine clinical care [93].

In addition to the drugs mentioned in the present review, there are also a number of other new or repurposed drugs potentially useful with preliminary studies [94-97]. It is therefore important that clinicians are kept up to date with new evidence so that it can be easily translated into clinical practice.

In the more distant future, a number of potentially interesting new antidepressant mechanisms will be available, including new drug targets, drug repurposing and genetic or epigenetic manipulations [98-102]. Rapid scientific advances in bioinformatics and artificial intelligence are already yielding exciting results. As an example, a recent report describes a study that used a combination of artificial intelligence and biomarker patient stratification to produce very promising phase II results for a new antidepressant [103].

In conclusion, after decades of stagnation in antidepressant treatment, at present many new drugs are available or are in development with improved efficacy, latency of the antidepressant effect and tolerability. Table 1 summarizes the most relevant drugs with a critical perspective for each of them. Treating clinicians should monitor new developments and evidence to translate the benefit to routine clinical care.

None.

Prof. Serretti is or has been a consultant to or has received honoraria or grants unrelated to the present work from: Abbott, Abbvie, Angelini, Astra Zeneca, Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, Servier, Taliaz.