Mifepristone

The synthetic steroid mifepristone, also known as RU-486, is an antagonist with a high affinity at progesterone and glucocorticoid receptors (GR) ( ). Following oral administration of a single dose, mifepristone is rapidly absorbed, with a peak plasma concentration occurring approximately 90 min after ingestion. Despite rapid degradation and poor brain penetration, mifepristone can reach the brain, leading to a decrease in GR-mediated negative feedback, which increases cortisol and ACTH secretion. However, the mechanism of action induced by mifepristone has not been fully elucidated, and it is speculated that it may act by a rebound increase in GR function. Other effects could be attributed to an indirect effect of higher circulating cortisol levels on mineralocorticoid receptors, which may lead to its downregulation and resetting of the HPA axis ( ; ).

Early work highlighted the potential for mifepristone to normalize endocrine parameters in patients with MDD ( ; ). Murphy and colleagues (1993) conducted the first open-trial study, including four patients with chronic severe depression who were resistant to conventional therapies. Mifepristone (200 mg/day, up to 8 weeks) produced a 16% to 66% improvement in Hamilton Depression Rating Scale scores in three patients ( ). Recently, studies are focusing on mifepristone’s potential to treat psychotic depression, a form of depression with pronounced HPA axis dysfunction and hypercortisolemia ( ). Randomized controlled trials also suggested positive effects of mifepristone for psychotic depression ( ; ). However, data interpretation and the possible application in clinical settings were challenged by . The positive findings have been followed by a larger negative trial that found no statistically significant differences between mifepristone and placebo on reduction in psychotic symptoms ( ). However, a positive linear correlation between plasma concentration of mifepristone and efficacy was observed. The authors argued that mifepristone has good tolerability and might elicit more robust responses at higher doses.

One interesting characteristic of antiglucocorticoid strategies for the treatment of psychotic depression is that their effects appear to initiate a rapid, short-term clinical response. Thus, we can speculate that they might be helpful for TRD, used to increase the efficacy of treatment regimens in medicated patients, or initiate a response that can be maintained with conventional treatments ( ).

Metyrapone

Metyrapone inhibits the enzyme 11-β hydroxylase, which catalyzes the conversion of 11-deoxycortisol to cortisol. This effect reduces cortisol synthesis and attenuates the HPA axis negative feedback, resulting in increased ACTH, desidroepiandrosterona (DHEA), and 11-deoxycortisol levels after repeated administration ( ; ). Metyrapone is well tolerated and rapidly absorbed in humans following oral administration, and blood levels peak 1 h after ingestion.

Since the late 1970s, metyrapone has been suggested for the treatment of psychiatric complications of Cushing’s disease ( ). However, evidence supporting the role of metyrapone in treatment-resistant depression is limited and inconclusive. Most studies have utilized metyrapone as an augmenting agent for antidepressants, and no double-blind, randomized controlled trials of metyrapone monotherapy are available so far.

described a patient with TRD in an early case report responding to metyrapone and aminoglutethimide, another inhibitor of cortisol synthesis, who remained in remission for more than 2 years ( ). Also, the authors conducted an open-label study using one or more steroid suppressive agents (aminoglutethimide, ketoconazole, and/or metyrapone) in eight patients with TRD for 2 months. The study shown that six patients achieved symptoms remission for 5 months after the end of the treatments, and two patients had partial remission ( ). Positive responses for patients with TRD treated with compounds that decrease corticosteroid biosynthesis (aminoglutethimide, ketoconazole) combined with metyrapone were also observed in 13 out of 20 patients ( ). Metyrapone was also combined with hydrocortisone in a single-blind crossover study to assess the therapeutic value of blocking and replacing glucocorticoids. Treatment with metyrapone for 2 weeks produced a significant reduction in symptoms in 8 patients with depression compared to placebo, even in the presence of normal replacement levels of hydrocortisone ( ). Iizuka and colleagues treated six patients with TRD with Metyrapone (doses that varied up to a maximum of 2 g per day) for 4 weeks. Three patients achieved complete remission, and one went into partial remission.

Metyrapone was also used as an augmentation strategy of serotonergic antidepressants. In an open-trial study conducted by Rogoz and colleagues, metyrapone produced augmentation of imipramine’s effects in patients with treatment-resistant depression ( ). Additionally, in a placebo-controlled double-blind study including 63 patients treated with nefazodone or fluvoxamine, metyrapone (250 mg four times daily for 3 weeks) also showed improvement compared to placebo ( ). However, in recent studies, negative results were observed. In a double-blind, randomized, placebo-controlled trial including 83 treated with metyrapone and 82 with placebo, metyrapone, in addition to standard serotonergic antidepressants, did not produce augmentation effects when compared to placebo. Moreover, , in a double-blind, randomized controlled trial including patients with TRD, no benefits were observed with metyrapone augmentation to ongoing serotonergic antidepressants. These negative findings might be related to the relative absence of HPA axis dysfunction in this population ( ).

It is important to highlight that metyrapone might act through different mechanisms that do not seem to involve a simple reduction in plasma cortisol. It is speculated that some of the potential beneficial effects for TRD might be associated with GR upregulation, changes in serotonergic 5-HT1A receptors sensitivity, activation of the MR, or effects induced by other hormones in the steroid pathway, including 11-deoxycortisol, ACTH, and DHEA ( ).

Serum and glucocorticoid-inducible kinase I (SGKI)

SGK1 is a member of the serum/glucocorticoid-regulated kinase (SGK) family, a ubiquitously expressed serine/threonine kinase regulated by a wide variety of factors, including glucocorticoids ( ). In the brain, SGK1 expression is positively regulated by glucocorticoids ( ). Moreover, SGK1 is a downstream target of GR signaling and exerts a positive feedback loop, favoring nuclear translocation and activation of GR ( ). Besides this role in GR regulation, SGK1 has multiple effects relevant for brain function, including the regulation of ion channels, neuronal activity, BDNF, and VEGF signaling, cell proliferation and neurogenesis, and apoptosis ( ; ).

SGK1 has been investigated as a potential target in psychiatric conditions, including depression ( ). Most data associating SGK1 and depression come from preclinical studies. In preclinical models of stress or chronic corticosterone administration, different nutraceutical compounds with antidepressant-like effects counteract the increase in cytosolic GR and SGK1 levels in the hippocampus and prefrontal cortex ( ). Moreover, SGK1 is upregulated in the striatum and hippocampus of mice treated with ketamine, a drug recently approved for treatment-resistant depression ( ). However, human studies are by far more complex. SGK1 polymorphisms were associated with susceptibility to depression in a Chinese cohort of coronary heart disease patients. Additionally, SGK1 mRNA increased in the blood of drug-free depressed patients ( ). On the other hand, found that MDD patients with less peripheral expression of SGK1 had smaller hippocampal volumes, suggesting SGK1 as a marker of reduced activation of the glucocorticoid system. Collectively, the causative role of SGK1 in MDD is made more confusing in the presence of different splicing variants, altered distribution in distinct cell types, and different levels of expression. However, in light of the potential mechanisms associated with SGK1, compounds targeting SGK1 might represent potential treatment strategies that deserve future investigation, especially for their effect in counteracting stress-induced impairments in neuroplasticity and neurogenesis.

Fludrocortisone

Fludrocortisone is a synthetic adrenal steroid that acts as an MR agonist. In the brain, although both GRs and MRs inhibit cortisol secretion through negative feedback, MRs have 10 times the affinity of GRs to glucocorticoids and are vital to controlling the HPA responses ( ).

Clinical studies examining MR function in MDD revealed mixed results. Polymorphisms of the MR gene were associated with MDD ( ). Besides that, increased MR function was found in patients with MDD, and an upregulation in MR was found in postmortem hypothalamic tissue of patients with MDD. On the other hand, other studies found a decreased MR density in postmortem anterior hippocampus and prefrontal cortex samples of MDD subjects ( ) and in suicide victims ( ), suggesting that stimulating MR might be beneficial in MDD. In fact, the previously described results with GR antagonists reinforce this notion by pointing that a possible shift in MR/GR balance toward predominant MR effects after GR antagonism is responsible for the beneficial effects of GR antagonists such as mifepristone ( ; ). MR dysfunction has been demonstrated in TRD ( ). showed that fludrocortisone’s ability to inhibit cortisol secretion was attenuated in patients with psychotic depression, suggesting impaired MR function. No studies assessed the effects of fludrocortisone as monotherapy in MDD ( ). Nevertheless, two studies failed to show beneficial effects of fludrocortisone treatment as monotherapy on depressive symptoms in patients with chronic fatigue syndrome ( ; ). However, the stronger evidence supporting the beneficial effects of fludrocortisone for MDD came from its use as an adjuvant treatment to classical antidepressants. In a randomized controlled clinical trial including 64 patients, fludrocortisone used as add-on therapy to standard antidepressants accelerated the antidepressant response ( ). Thus, more studies are necessary, especially in patients with TRD, but it is possible that fludrocortisone acts as an accelerator at least in a subgroup of patients.

Agomelatine

Agomelatine is an agonist at melatonergic MT1/MT2 receptors and antagonist at serotonergic 5-HT2C receptors. One of the most important pharmacological properties of agomelatine is its pro-chronobiological effect. Melatonin is a hormone involved in the regulation of the sleep–wake cycle, and depressed patients have decreased concentrations of melatonin as well as dysfunctions in the circadian rhythms. Agomelatine was demonstrated to improve disrupted sleep–wake rhythms, enhance dopamine and noradrenaline levels in the frontal cortex, and produce neuroplasticity and neurogenesis effects ( ). The recommended therapeutic dose of agomelatine is 25–50 mg/day ( ).

The antidepressant efficacy of agomelatine and better tolerability, compared to other antidepressants, was evaluated in several controlled clinical trials ( ). One randomized clinical trial, including 164 patients treated with agomelatine and 160 patients treated with escitalopram, showed that agomelatine was better tolerated than escitalopram and displayed long-term benefits on sleep–wake quality and emotional responses in depressive patients ( ). Agomelatine was also studied in combination with other antidepressants, especially selective serotonin reuptake inhibitors. However, only a few studies evaluated agomelatine for TRD, most of them with small samples and uncontrolled designs. Different case reports have looked at combinations of agomelatine with escitalopram, venlafaxine, and clomipramine, which resulted in improved outcomes in depression ( ). Moreover, better remission rates and successful remission for TRD were achieved by combining agomelatine with moclobemide in a case report ( ) and with bupropion in a sample of 15 patients ( ).

A larger 12-week open-label noninterventional study (VIVALDI study) evaluated the effects of agomelatine alone or in combination with other antidepressants in 3317 patients. According to the results, remission was achieved for 66.5% of the patients treated with agomelatine as monotherapy, 44.7% of the patients treated with agomelatine as add-on-therapy, and 50.9% of the patients who switched to agomelatine after another antidepressant. The results suggest that agomelatine improved depressive symptoms, daytime functioning, and sleep-wake rhythm ( ). Agomelatine was also investigated in combination with electroconvulsive therapy (ECT) but without significant results in terms of baseline effect and prevention of relapse ( ). Thus, considering the neurobiological targets of agomelatine, its safety profile, and its ability to improve the effectiveness of other antidepressants, larger studies with TRD might be indicated.

Esketamine

Recently, the researchers found that ketamine’s antidepressant effects appeared to be produced by one of its metabolites—(2 R ,6 R )-hydroxynorketamine (HNK)—through an NMDA receptor-independent mechanism that seems to enhance AMPA receptor activation ( ). Esketamine is the S (+) enantiomer of ketamine and has a three- to fourfold higher affinity for NMDA receptors ( ). Clinical trials are currently underway to study the efficacy of intranasal and intravenous esketamine in TRD. Singh et al. (2016) investigated the efficacy of intravenous esketamine in patients with TRD in a multicenter, randomized, placebo-controlled trial. Esketamine 0.20 mg/kg and 0.40 mg/kg had a robust and rapid (within 2 h) antidepressant effect (as assessed by the Montgomery–Asberg Depression Rating Scale – MADRS) compared to placebo ( ). A phase III, double-blind, active-controlled, multicenter study conducted in 67 individuals with TRD evaluated the efficacy of each individual dose of esketamine nasal spray (28 mg, 56 mg, or 84 mg) compared to placebo. All three esketamine doses improved depressive symptoms in participants with TRD, as assessed by MADRS total score on day 8 ( ). Another multicenter, placebo-controlled, double-blind, randomized, 12-week study investigated the efficacy of intranasal esketamine (84 mg) in 68 adults with MDD and active suicidal ideation. Intranasal esketamine significantly reduced depressive symptoms (MADRS) within 4 h, as well as suicidal thoughts, which were measured by Scale for Suicide Ideation (SSI) ( ). Currently, clinical trials are in course to evaluate the efficacy and safety of switching elderly TRD participants from a prior unsuccessful antidepressant treatment to either intranasal esketamine plus a new oral antidepressant or to a new oral antidepressant plus intranasal placebo.

Rapastinel

Rapastinel (GLYX-13) is a positive allosteric modulator of NMDA receptors with glycine-like partial agonist properties ( ). Preclinical studies demonstrated that rapastinel has a promising behavioral profile, with ketamine-like effects. The results reported that GLYX-13 administration produces rapid antidepressant effects that last for 1 week. The mechanisms included an increase in synaptic number and function in the medial prefrontal cortex (mPFC), an effect mediated by the release of brain-derived neurotrophic factor (BDNF) ( ).

A phase IIb safety and efficacy trial randomized 116 TRD unmedicated inpatients to receive either a single intravenous GLYX-13 or placebo administration over three to 15 min. Adjunctive GLYX-13 significantly improved depressive symptoms 1-week postadministration in patients who had received 5 or 10 mg/kg (IV) ( ). A recent pilot phase II randomized clinical trial (RCT) showed that a weekly intravenous dose of rapastinel (5 or 10 mg/kg, IV) reduced depressive symptoms as assessed by the HAMD 17 within 2 h, and this effect was maintained for around 7 days ( ). Otherwise, a recently terminated phase III RCT failed to demonstrate a reduction in the depressive symptoms after adjunctive or monotherapy with rapastinel in TRD. However, another compound with a similar mechanism of rapastinel is being developed. NRX-1074 has similar effects to those of rapastinel, but with the advantage of being orally active, and might potentially be a novel antidepressant for TRD.

AVP-923 (Nuedexta)

AVP-923 is a dextromethorphan and quinidine fixed combination that is now being studied for TRD ( ; ). Commonly known by its brand name, Nuedexta is the first FDA-approved treatment for pseudobulbar affect. Dextromethorphan is a nonselective and noncompetitive NMDA receptor antagonist and 1-receptor agonist. Additionally, quinidine acts as a cytochrome 2D6 enzyme inhibitor, which is usually used to increase dextromethorphan plasma concentrations and prolong its half-life ( ; ). AVP-923 was tested in a small one-arm phase II study designed to evaluate its efficacy, safety, and tolerability in patients with TRD. The primary outcomes after 10 weeks demonstrated that in 20 patients with TDR who received oral doses of AVP-923 every 12 h, 45% of subjects remitted, and 35% responded (MADRS total score) ( ).

AVP-786

AVP-786 is a new investigational compound consisting of a combination of deuterated (d6)-dextromethorphan and an ultra-low dose of quinidine. This compound differs from Nuedexta because it contains deuterium, a heavier hydrogen isotope that reduces dextromethorphan first-pass liver metabolism and quinidine dosage. A 10-week, phase II randomized controlled trial is currently investigating the efficacy, safety, and tolerability of AVP 786 as adjunctive therapy in patients with MDD and inadequate response to antidepressant treatment. The study was recently completed, but the results have not been presented yet.

AXS-05

AXS-05 is an orally administrated, rapidly acting, investigational combination of dextromethorphan and bupropion. The purpose of adding norepinephrine-dopamine reuptake inhibitor bupropion to the formulation, in addition to its antidepressant effects, is to increase the bioavailability of dextromethorphan through inhibition of CYP2D6. AXS-05 is currently in a late-stage of clinical development for MDD, including TRD. AXS-05 is currently recruiting for an ongoing phase III clinical trial in patients with TRD (N ~ 350), where the active comparator is bupropion. With pharmacological properties similar to ketamine, AXS-05 represents a promising new investigational agent for TRD ( ).

Rislenemdaz (CERC-301/MK-0657)

Rislenemdaz/CERC-301 (MK-0657) is a highly selective, orally bioavailable NMDA receptor antagonist acting at the NMDA receptor 2B (NR2B) subunit. Preclinical studies demonstrated that CERC-301 has acute antidepressant-like effects in the forced swim test (FST), a predictive rodent model of antidepressant efficacy ( ). A small RCT was completed with an oral formulation of the drug, which suggested antidepressant efficacy for Rislenemdaz/CERC-301 in TRD ( ). Another phase II RCT designed to evaluate the antidepressant effects of intermittent doses of CERC-301 in TRD is currently recruiting participants.

AV-101

AV-101 (L-4-chlorokyurenine or 4-CI-KYN) is a pro-drug that is rapidly converted in vivo into the active metabolite 7-chloro-kynurenic acid (7-Cl-KYNA), a potent and highly selective antagonist at the glycine-binding site of the NMDAR NR1 subunit. AV-101 has been designed as an oral formulation to be used once daily ( ). An animal study exploring potential ketamine-like antidepressant agents of AV-101 demonstrated rapid, dose-dependent, and persistent antidepressant effects following a single treatment, with no psychotomimetic effects ( ). However, there are no published results in humans so far. A phase II randomized controlled trial investigating the antidepressant efficacy of AV-101 in individuals with TRD is currently recruiting participants.

AZD6765 (Lanicemine)

AZD6765 (Lanicemine) is a low-affinity, nonselective NMDA receptor channel blocker. A recent phase II RCT designed to evaluate whether a single AZD6765 infusion (150 mg) could produce rapid antidepressant effects in TRD subjects showed some promising results ( ). The primary outcome measured was the MADRS, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on days 1, 2, 3, and 7 postinfusion. AZD6765 infusion was associated with a rapid (within 80 min) response that was not as robust or sustained as the one observed after ketamine administration. Besides that, the effects of AZD6765 were short-lived and the response rate low, but no dissociative side effects were noted.

MK-1942

The structure and mechanism of action of MK-1942 were not yet disclosed. However, a phase II RCT is being conducted to assess the efficacy and safety of daily and intermittent dosing of MK-1942 compared to placebo among participants with TDR on a stable course of antidepressant therapy. The primary outcome of the trail is to see whether of MK-1942 treatment is superior to placebo in reducing depressive symptoms (MADRS). It is currently in clinical development ( ClinicalTrials.gov Identifier: NCT04663321 ) with no results posted yet.

Nitrous oxide

Nitrous oxide (N ₂ O) is a gas used for inhalational general anesthesia and analgesia for short procedures. It possesses several biological properties, including the ability to act as a noncompetitive antagonist at NMDA receptors. N ₂ O has a broad mechanism of action similar to ketamine but is not believed to have strong addiction potential. A phase II, double-blind, placebo-controlled, crossover study has demonstrated that 2 h as well as at 24 h postinhalation, N ₂ O significantly improved antidepressant response rates (as measured by the HAM-D) compared to placebo; however, the size effect was not large. Moreover, no psychotomimetic effects were observed after the administration, but some adverse effects included anxiety, headache, and nausea/vomiting ( ). Further investigation is needed to evaluate the potential of N ₂ O to TRD.

Ziprasidone

Among the available drugs for the TRD treatment, second-generation antipsychotics (SGAs) have been reported as one possible adjunctive therapy for the management of TRD ( ). Ziprasidone is an antipsychotic approved by the FDA to treat schizophrenia and bipolar disorder, but it is used off-label for MDD. Preclinical studies have been shown in vitro inhibition of the neuronal serotonin and norepinephrine uptake, with a potency comparable to imipramine ( ). A pilot trial with an open-label design demonstrated that 10 of 20 patients with TRD had increased antidepressant effects after 6 weeks of ziprasidone augmentation ( ).

Brexpiprazole

Brexpiprazole is an atypical antipsychotic which acts as a partial agonist at dopamine D2 receptors and, possibly, as an antagonist at 5-HT2A receptors ( ). Due to its mechanism of action, brexpiprazole has been discussed as a promising candidate for targeting both depressive and cognitive deficits observed in TRD. A recent phase III/IV trial was designed to investigate the maintenance of efficacy and safety profile during long-term treatment with brexpiprazole in adults with an inadequate response to antidepressant treatment. The study was recently completed, but results were not posted to ClinicalTrials.com .

Cariprazine

Cariprazine is a novel antipsychotic drug that exerts partial agonist properties at dopamine D2/D3 receptors with preferential affinity for dopamine D3 receptors. Besides, cariprazine also interacts with the serotonergic system as an antagonist of 5HT2B receptors and a partial agonist of 5HT1A. Animal studies revealed antianhedonic effects of cariprazine, suggesting a potential to treat TRD ( ). In patients, a phase II RCT aimed to evaluate the efficacy, safety, and tolerability of cariprazine as an adjunctive treatment in MDD patients who have had an inadequate response to standard antidepressant therapy. The results showed that compared with placebo, reduction in MADRS total score at week 8 was significantly greater with adjunctive cariprazine treatment (2–4.5 mg/d) ( ). However, in a phase III RCT which evaluated flexible doses of cariprazine as adjunctive therapy in TRD patients, no significant efficacy was observed compared with placebo.

Pilocybin

Psychedelics were first investigated as therapeutic agents in the 1960s, and although studies carried out then had several methodological shortcomings, they provided preliminary evidence that such compounds could be effective as a mood enhancer and potential antidepressant ( ). Psilocybin is a naturally occurring plant alkaloid, which is rapidly converted by the body to psilocin, a partial agonist for several brain serotonergic receptors, particularly 5-HT2A ( ). An open-label feasibility study assessed the efficacy and safety of adjunctive psilocybin in 12 patients with TRD ( ). The acute psychedelic effects peaked 2–3 h after dosing and declined to negligible levels at least 6 h after dosing. Depressive symptoms were markedly reduced (defined as ≥ 50% reduction in Beck Depression Inventory (BDI) score relative to baseline) 1 week and 3 months after high-dose (25 mg) treatment. A 6-month follow-up study, in which a further eight participants were enrolled, found that the antidepressant and anxiolytic effects of psilocybin were sustained and remained significant at 6 months posttreatment ( ). One RCT observed at pre- and posttreatment data with psilocybin using functional magnetic resonance imaging (fMRI) in 19 patients. All patients decreased depressive symptoms at 1-week posttreatment, and 47% met the criteria for responsiveness after 5 weeks ( ). Psilocybin is a promising paradigm for unresponsive depression that deserves further investigation in larger samples.

Cannabidiol

Cannabidiol (CBD), a nonpsychotomimetic cannabinoid present in the Cannabis sativa plant, seems to be a promising compound for MDD since it shows large-spectrum therapeutic potential in preclinical models and humans ( ). However, its antidepressant properties have not been thoroughly investigated. The mechanisms involved in CBD-induced psychotropic effects involve the activation of serotonergic 5-HT1A receptors and peroxisome proliferator-activated (PPAR) receptors. Indeed, recent preclinical studies have been demonstrated that CBD effects may be related to rapid changes in synaptic plasticity in the mPFC through activation of the BDNF-TrkB signaling pathway ( ). Currently, Epidiolex (CBD) is being evaluated in crossover, placebo-controlled, double-blind RCT including 10 depressed adults with TRD over 16 weeks. The antidepressant effects of CBD will be measured by standard rating scales. The results were not posted on ClinicalTrials.com so far.

Minocycline

Minocycline is a tetracycline antibiotic approved by the FDA for various bacterial infections (Food and Drug Administration, 2021). Preclinical studies have reported pleiotropic effects of minocycline in animal models and humans, including antiinflammatory and neuroprotective actions ( ). Several clinical trials are underway to explore the efficacy of off-label minocycline treatment for augmentation in TRD. A small pilot double-blind placebo-controlled 12-week study demonstrated that minocycline treatment produced a large decrease in HAMD scores compared to the placebo ( ). These findings require replication in larger samples to confirm the efficacy and tolerability of this approach. Another RCT evaluating the antidepressant efficacy of adjunctive minocycline in TRD patients is currently recruiting participants.