Abstract
Major depressive disorder (MDD) is a common and debilitating mental illness, which leads to serious functional impairment in patients, and treatment-wise, there are currently a number of different classes of antidepressants already on the market. However, emerging evidence from numerous clinical trials has confirmed that there is still an unmet need for antidepressant efficacy in terms of response and remission. Approximately only 30% of patients with MDD may remit after adequate treatment with antidepressants in clinical practice. The drawbacks of the currently available antidepressants also include inadequate overall efficacy, safety issues and the lag prior to onset of clinical improvement. The need for new agents with novel mechanisms of action has led to the development of several newer antidepressants including vilazodone, edivoxetine, ketamine, atomoxetine and vortioxetine, which have been approved for the treatment of MDD. However, the efficacy and safety of these next-generation antidepressants, in clinical trials, are still unsatisfactory. This paper provides a brief updated overview of the progress and critical limitations in the development of novel antidepressants.
1. Introduction
Major depressive disorder (MDD) is a common debilitating illness, affecting 15 – 20% of the population at some point in their lives, which can cause severe functional impairment. Although numerous antidepressants are available, more than 30% of patients with MDD do not achieve an adequate response and remission Citation[1]. Other crucial problems with conventional antidepressants include the lag of 2 – 4 weeks between antidepressant administration and onset of clinical improvement, as well as safety and tolerability issues such as significant weight gain that can result in metabolic syndrome, increasing the risk of cardiovascular diseases. Moreover, recent studies suggest that conventional antidepressants, selective serotonin reuptake inhibitors (SSRIs), are also associated with a significant increase in the QTc interval Citation[2]. Serotonin syndrome is another critical toxicity of serotonergic drugs Citation[3].
The monoamine hypothesis of MDD has been controversial for more than a decade, but almost all currently approved antidepressants were developed based on this theory. Furthermore, mounting evidence suggests that a large proportion of patients with treatment-resistant depression (TRD), especially to multiple antidepressants, require agents with mechanisms of action distinct from those of currently available drugs Citation[4].
Therefore, novel antidepressants that are more effective in controlling symptoms and have fewer adverse effects and a more rapid therapeutic effect are urgently needed to allow full functional recovery in a greater proportion of patients. As many potential agents have recently been identified, this review provides an update on the clinical results of these novel drugs and discusses their critical limitations as well as future research directions.
2. Monoamine hypothesis-related issues: the broader, the better?
Since the late 1980s, a number of new antidepressants have been developed and introduced in the market in hopes that they will be more effective, as well as better tolerated, in the treatment of MDD patients. However, inhibiting the serotonin receptors (5-HT; e.g., SSRIs), norepinephrine (NE; e.g., NE reuptake inhibitors [NRIs]) and/or dopamine (DA; e.g., DA reuptake inhibitors) transporters; dual reuptake inhibition (e.g., 5-HT and NRIs [SNRIs]); blocking 5-HT2 receptors; activating 5-HT1A receptors or specifically inhibiting the α2-adrenergic receptor and certain 5-HT receptors noradrenergic and specific serotonergic antidepressants (NaSSA) remain the major mechanisms even of newer antidepressants. In addition, the mechanisms of the recently approved drugs vilazodone and vortioxetine also involve the 5-HT neurotransmitter system. Indeed, vilazodone is a SSRI and 5-HT1A receptor partial agonist Citation[5], whereas vortioxetine is an SSRI and antagonist of 5-HT3, 5-HT1D and 5-HT7, partial agonist of 5-HT1B and agonist of 5-HT1A receptors Citation[6]. Despite these novel actions, neither vilazodone nor vortioxetine appears to be more effective than current drugs. The numbers needed to treat for response and remission with vilazodone were only 8 – 9 and 12 – 17, respectively Citation[7,8], and the odds ratios for response and remission with vortioxetine are 0.719 and 0.672, respectively Citation[9]. Despite these controversies, the number needed to harm (NNH) versus placebo for discontinuation because of an adverse event (AE) was relatively superior in vortioxetine (NNH = 36) than in SNRIs including venlafaxine (NNH = 10) or duloxetine (NNH = 20) Citation[10]. Its potential advantage in improving cognitive functions in patients with depression is also promising. Among four clinical trials Citation[11-14] assessing the effects of short-term treatment with vortioxetine on cognitive function, three studies Citation[12-14] showed superior efficacy of vortioxetine over placebo in improving cognitive performance in patients with depression Citation[15]. Thus, some consider vortioxetine as a new class of antidepressants endowed with multiple molecular mechanisms in addition to inhibition of 5-HT transporter Citation[16].
Edivoxetine (LY2216684) is a selective and potent NRI. In two clinical trials, the efficacy of edivoxetine monotherapy Citation[17,18] was uncertain when compared to that of placebo for treatment of MDD; the drug also presented safety and tolerability issues such as significant increases in pulse rate and systolic and diastolic blood pressure and a significantly higher rate of discontinuation due to AEs or death. In addition, a recent combination trial of edivoxetine with SSRIs Citation[19] also failed to show superiority to placebo combined with SSRIs. These findings suggest that antidepressants targeting monoamine receptors and transporters cannot avoid the problems observed with contemporary antidepressants. presents the actions of contemporary antidepressants on monoamine transporters and receptors.
Table 1. Representative pharmacological profile of contemporary ADs.
Furthermore, given the association of complex alterations in signaling by the neurotransmitters 5-HT, NE and DA with MDD, triple reuptake inhibitors (TRIs) were designed to be more effective and safer antidepressants Citation[20,21]. Likewise, stimulants that induce release and block reuptake of NE and DA have been found to augment and hasten the antidepressant response when combined with various classes of antidepressants Citation[20].
However, development of novel agents characterizing specific receptor profiles with clinically relevant activity at all three monoamine reuptake sites is difficult, that is, the ideal ratio of 5-HT, DA and NE transporter site potencies for a TRI remains unknown; the critical issue with TRIs is to add the appropriate amount of dopamine transporter activity to SNRIs with ideal ratios of 5-HT versus NE transporter inhibition Citation[21].
Researchers in both academia and the pharmaceutical industry have discovered agents that potently inhibit all three monoamine transporters Citation[21]. However, clinical research findings are mixed regarding whether broader-spectrum agents or highly 5-HT-selective agents confer the best efficacy, likely resulting from the involvement of each neurotransmitter in multiple biological functions Citation[20,22]. For instance, the superiority of liafensine (BMS-820836) over duloxetine and escitalopram in patients with TRD has not been shown, leading the manufacturer to cease development. Currently, EB-1010 (amitifadine) remains the most promising candidate among the currently available TRIs. Although the drug failed to meet the primary end point in Phase IIb/IIIa efficacy trials, it was well tolerated compared to paroxetine in terms of weight gain, blood pressure and heart rate changes and sexual dysfunction. In addition, a trend toward positive efficacy in post hoc analyses with high-dose-treated patients suggests that it may be beneficial to some patients with MDD.
Unlike EB-1010, concerns have also arisen that TRIs may produce a broader side effect burden without enhancing efficacy over more selective agents for individual neurotransmitter Citation[22]. If this is replicated in subsequent studies, future TRIs should be designed to minimize blockade at histaminergic, 5-HT, cholinergic and α-adrenergic receptors, as AEs such as sexual dysfunction, sedation and weight gain are common in SSRIs and SNRIs Citation[20].
Similarly, whether combining antidepressants, affecting different neurotransmitters, causes synergistic effects was investigated in a recent, large clinical trial in an outpatient setting (The Combining Medications to Enhance Depression Outcomes [CO-MED]) Citation[23]. Neither the combination of bupropion plus escitalopram nor mirtazapine plus venlafaxine, yielded greater remission or response rates at either 12 weeks or 7 months than escitalopram monotherapy, whereas patients receiving combination therapy experienced more AEs. The CO-MED trial also emphasizes the limited utility of targeting multiple neurotransmitters in MDD treatment. However, prior clinical trials have shown that several antidepressant combinations such as tricyclic antidepressants (TCAs) plus SSRIs, dopamine-norepinephrine reuptake inhibitors (DNRIs) plus SSRIs, 5-HT antagonists plus SSRIs and NaSSAs plus SSRIs led to greater remission rates than antidepressant monotherapy at the end of treatment Citation[24-30] and hastened the onset of treatment effects (weeks 1 or 2) in some trials Citation[25,30].
In fact, the dilemma of choosing between a broader or selective antidepressant is not something new. Before selective antidepressants prevailed, drugs having multiple pharmacological mechanisms, mainly the TCAs, were widely used Citation[31]. These TCAs were termed ‘dirty drugs’ because the drugs’ broad mechanisms caused diverse side effects. The concept then was to make ‘clean’ antidepressants by minimizing unwanted mechanism that led to the development of SSRIs Citation[32].
Therefore, many of the remaining questions concerning monoamine-based development of antidepressants will be answered by well-designed subsequent research. The diversity of molecules in development may shed light on this issue. Future research will undoubtedly involve clinical studies of various TRIs to determine whether any TRI offers an advantage over currently approved antidepressants in efficacy, rapidity of onset or AE profile. presents currently available TRI data.
Table 2. Triple reuptake compounds under development.
3. Methodological issues in clinical trials with antidepressants
There are a number of critical issues that must be addressed in both clinical trials and drug development programs, including clinical heterogeneity of subjects (e.g., gender and symptomatology differences), diagnostic stability, sensitivity and validity of rating scales in detection of depressive symptom changes, antidepressant dosing, efficacy versus placebo, efficacy versus active reference drug, AEs and acute versus continuation versus maintenance antidepressant efficacy. In addition, the future research with newly developed antidepressants must investigate antidepressant efficacy or AEs in subpopulations such as geriatric depression, MDD patients having inadequate response to a single course of SSRI or SNRI and others.
Indeed, inadequate dosing of candidate compounds has often been a problem in clinical trials. For instance, 5-HT reuptake inhibition must retain a sustained threshold of 80% occupancy of transporter to present an antidepressant action Citation[33]. However, duloxetine was initially tested at insufficient doses to obtain even a threshold inhibition of 5-HT reuptake; such dosing issues were also reported in antidepressant combination therapy expecting synergistic effects between two different neurotransmitters in the CO-MED trial Citation[33,34].
The placebo response appears to have increased over time in antidepressant clinical trials. A number of possible contributing factors have been identified, but further studies are needed. The sequential parallel comparison design has been proposed to address this issue and its ability to minimize the placebo effect has been demonstrated Citation[35-37]. Statistical modeling has demonstrated that sequential parallel design reduces sample size by 20 – 25% relative to traditional parallel design, while retaining similar power, leading to financial savings and shortening total study length by reducing the enrollment period Citation[35-37]. Adaptive design (e.g., treatment algorithms) and equipoise-stratified design (e.g., flexibility in randomization by allowing participants and investigators to choose among groups) will also improve design issues Citation[35-37].
Data interpretation may also be adjusted to control for varying placebo effects. For instance, Kirsch et al. proposed that drug–placebo differences in antidepressant efficacy increase with baseline severity, with small effect size even in severely depressed patients, based on a meta-analysis of all clinical trials submitted to the US FDA Citation[38]. However, a recent analysis of the same dataset Citation[39] and another meta-analysis Citation[40] suggests that antidepressant effect is greater than that of placebo and not related to MDD severity, that is, the most probable effect size of antidepressants relative to placebo is 0.34 (0.27 – 0.42) and initial severity of MDD has no significant effect.
Research on antidepressant efficacy shows that demonstrating the superiority of interventions to placebo is becoming more challenging, in part because of increasing placebo response rates. Hence, various design innovations and other tactics will ultimately improve sensitivity toward antidepressant–placebo differences and reduce bias in antidepressant clinical trials.
4. Development of rapid, robust and tolerable putative antidepressants
The pathophysiology of MDD is multifactorial; aberrations in neurotrophic factors, neurotransmitters and receptor signaling pathways, the hypothalamic–pituitary–adrenal (HPA) axis, inflammation, immune dysfunction, imbalance between oxidative stress and antioxidant defenses, neurodegeneration and mitochondrial dysfunction including DNA damage have been consistently reported to contribute to the development of MDD Citation[41,42].
For instance, glutamate alterations are well known as a common and crucial pathophysiology of MDD, as robust and rapid antidepressive effects of glutamatergic NMDA receptor antagonists (e.g., ketamine) have been clearly demonstrated in TRD patients. Another potential action of NMDA antagonists is increasing activation of endoplasmic reticulum sigma-one (σ1) receptors Citation[43]. The first placebo-controlled study with ketamine confirmed prior reports of robust antidepressive effects within 72 h Citation[44]. This effect was replicated and extended by other placebo-controlled studies illustrating ketamine’s rapid antidepressant effects in patients with TRD Citation[45], depressed patients with suicidal ideation Citation[46] and patients with treatment-resistant bipolar depression Citation[47].
Interestingly, NMDA antagonists (e.g., ketamine) may also promote neuroplasticity by modulating neurotrophic pathways (e.g., brain-derived neurotrophic factor [BDNF]) or mammalian target of rapamycin expression, leading to neuronal recovery and enhanced resilience Citation[48]. A recent study Citation[49] has investigated the effect of antidepressants on the response to stress. Stress induced rapid increases in circulating corticosterone, and glutamate release was blocked by administration of a selective glucocorticoid receptor antagonist (e.g., mifepristone [RU486]). According to a recent animal study Citation[50], the BDNF-activated MAPK/ERK pathway was inhibited by glucocorticoids and downregulation of glucocorticoid receptors dampened this effect.
Ketamine’s rapid onset of efficacy, even in treatment-resistant depressed patients, is encouraging as a prototypical antidepressant having novel mechanisms of actions. However, its antagonism at GABA interneurons reduces thalamic inhibition, causing unwanted psychotic symptom Citation[51]. Very few studies have systematically followed patients beyond 72 h after ketamine injections, so long-term adverse and antidepressant effects are obscure.
MDD is also characterized by an increase in central cholinergic activity relative to noradrenergic tone; muscarinic acetylcholine receptor (mAChR) antagonists may also decrease glutamatergic excitotoxicity by off-target effects on NMDA receptors Citation[48]. Scopolamine, a mAChR antagonist, enhances neuropeptide Y (NPY) levels in the hippocampus by upregulating NPY receptor mRNA expression Citation[52]. It is also suggested to enhance DA influx of nucleus accumbens by attenuating tonic cholinergic inhibition resulting in improvement of motivational dysfunction Citation[53]. Unwanted anticholinergic side effects including dry mouth, blurred vision and dizziness were almost two times higher than in the placebo group. Moreover, the fact that reduction of brain mAChR is associated with many severe psychiatric conditions such as Alzheimer’s dementia, Parkinson’s disease and schizophrenia is also a concern Citation[48].
Another novel antidepressant class may be antioxidants, which may improve neuroplasticity by increasing the expression of neurotrophic factors such as BDNF, glial-derived factor artemin, nerve growth factor and others. These agents might also improve membrane molecular and lipid metabolism by increasing myo-inositol levels and/or alter neurotransmitter regulation, especially in serotonergic and possibly in dopaminergic activities Citation[54].
Another emerging area of interest is blockade of proinflammatory cytokines. Elevated levels of proinflammatory cytokines, including IL-1, IL-6 and TNF-, have been consistently reported in MDD patients Citation[41,55]. In addition, inflammatory, cell-mediated immune, oxidative and nitrosative stress, mitochondrial, antioxidant and neuroprogressive pathways have been proposed as new antidepressant targets based on MDD pathophysiology Citation[41]. Drugs that target these pathways include cytokine antagonists, probiotics such as minocycline, COX-2 inhibitors, statins, acetylsalicylic acid, ketamine, ω3 poly-unsaturated fatty acids, antioxidants and neurotrophic factors. In particular, ω3 poly-unsaturated fatty acids are known to compensate for the destabilization of neuron membranes caused by the arachidonic acid cascade Citation[56]. Drugs that target all six pathways simultaneously Citation[41] would also be ideal antidepressant molecules; examples of such drugs include nuclear factor (erythroid-derived 2)-like 2 activators and glycogen synthase kinase-3 inhibitors.
One of most promising drug targets among the monoamine receptors should be the 5-HT7 receptor, the most recently identified member of the 5-HT receptor family. The 5-HT7 receptor is most abundant in the cortex, hippocampus, thalamus and hypothalamus of the human brain Citation[57]. Studies showed that, after long-term treatment of depression, 5-HT7 receptors are downregulated. Moreover, it can improve depression by restoring circadian rhythm through induction of c-For protein activity located in the suprachiasmatic nucleus Citation[58]. Since its identification, 5-HT7 antagonism has received attention as an antidepressant based on numerous preclinical studies. After vortioxetine, an antidepressive agent that inhibits both the 5-HT7 receptor and the 5-HT transporter, received FDA approval for treatment of depression in September 2013, attention on 5-HT7 receptor antagonists has intensified.
Likewise, lisdexamfetamine dimesylate (d-amphetamine prodrug), mifepristone, CP-101,606, MK-0657 (selective GluN2B subunit NMDA receptor antagonist), GLYX-13, bitopertin (RG1678, glycine reuptake inhibitor) and d-cycloserine (glycine site partial agonist) may be robust putative antidepressive compounds targeting specific neuronal receptors and pathways.
5. Expert opinion
As stated before, all current pharmacological treatments for MDD (SSRIs, SNRIs, DNRI and NaSSA) were designed based on the classical monoamine hypothesis. To avoid the side effects of these drugs and enhance the proportion of patients who respond, future drugs should be designed with better understanding of the neuronal networks in MDD, including the intricate interactions among neurotransmitters and other neuronal pathways related to the pathophysiology of MDD.
For instance, neuropeptides can act as neurotransmitters or co-transmitters; many modulate the action of monoamine neurotransmitters and the HPA axis, both of which have been implicated in MDD Citation[59]. Neurotransmitters also interact with one another; in particular, 5-HT systems inhibit the activity of the NE and DA systems through 5-HT2A and 5-HT2C receptors, respectively Citation[60]. On the other hand, complex positive and negative influences of the NE system on 5-HT neurotransmission are mediated through α1- and α2-adrenergic receptors, respectively. Such interactions may provide a biological rationale for the design of novel multimodal therapeutics for MDD that act on both traditional targets such as the 5-HT and/or the NE transporter and other putative targets, which could improve their efficacy and their tolerability Citation[61].
So long as novel agents are under development, combination formulations or psychotropics approved for other indications should also be considered. For instance, a combination agent of low-dose pipamperone (a DA D4 and 5-HT2A receptor antagonist) and citalopram (SSRI) is in Phase III development Citation[43] and ALKS 5461 (buprenorphine [μ-opioid receptor partial agonist] plus samidorphan [antagonist of μ-opioid receptors]) has been under investigation for TRD. Lurasidone (D2, 5HT2A and 5HT7 receptor antagonist and partial 5HT1A agonist), a newer antipsychotic, is also in Phase III trials for MDD and was approved for bipolar depression in 2013. In fact, aripiprazole and quetiapine XR have been approved and are widely used in treating MDD, although they were initially developed for schizophrenia. Aripiprazole’s actions as a 5-HT1A partial agonist, 5-HT2A antagonist and D2 partial agonist are known to play an important role in treatment of depression Citation[62]. For quetiapine, 5-HT1A partial agonism, 5-HT2A and 5-HT2C antagonism and inhibition of norepinephrine reuptake transporter contribute to its antidepressant effects Citation[63].
Indeed, a more deliberate and deeper understanding of the mechanisms underlying the antidepressant effects of novel MDD therapeutic candidates such as ketamine may help uncover novel therapeutic targets. Major advances will likely also be enabled by recently developed techniques, such as optogenetic stimulation of neural circuits and methods for sophisticated tracking of the connectome Citation[55,64]. Another promising direction is the recent discovery that expression of miR-1202, a primate-specific and brain-enriched microRNA, predicts citalopram treatment response, indicating that miR-1202 may be a biomarker of treatment response Citation[65]. Additional new targets are likely to be revealed by further basic and patient-based studies of the neurobiological mechanisms underlying MDD and the treatment response.
Declaration of interest
This work was supported by a grant of the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (HI12C0003). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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