This review (2015) discusses research developments regarding therapeutic compounds that exert their antidepressant efficacy via the glutamatergic, cholinergic, and opioid systems. The authors encourage innovative research strategies for improving the efficacy of treatments such as ketamine, whose effects are rapid but not long-lasting.
Review: Depression is a devastating disorder that places a significant burden on both the individual and society. As such, the discovery of novel therapeutics and innovative treatments-especially for treatment-resistant depression (TRD)-are essential. Research into antidepressant therapies for TRD has evolved from explorations of antidepressants with primary mechanisms of action on the monoaminergic neurotransmitter system to augmentation agents with primary mechanisms both within and outside of the serotonin/norepinephrine system. Now the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are in the forefront of antidepressant exploration. In this review, we will discuss the most recent research surrounding these novel compounds. In addition, we will discuss novel device-based therapeutics, with a particular focus on transcranial magnetic stimulation. In many cases of antidepressant drug discovery, the role of serendipity coupled with meticulous clinical observation in drug development in medicine was crucial. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far to advance the field of antidepressant research.
Depression is described as a highly burdensome, pervasive disorder for which a large proportion of patients do not achieve adequate benefit from standard treatments. The paper focuses on treatment-resistant depression (TRD), operationalised in the text as failure to achieve response to one or more adequate antidepressant trials, and highlights that, after decades of monoaminergic drug development, many patients remain symptomatic and therefore require new therapeutic strategies. Papakostas outlines a shift in research trajectories away from sole reliance on monoaminergic mechanisms towards agents acting on glutamatergic, cholinergic and opioid systems, as well as device-based and procedural therapies. The review updates an earlier overview of TRD from roughly five years prior, organising the discussion by drug class and addressing both pharmacological and device interventions with an emphasis on novel and rapidly acting approaches.
Papers cited by this study that are also in Blossom
Berman, R. M., Cappiello, A., Anand, A. et al. · Biological Psychiatry (2000)
Sos, P., Klirova, M., Novák, T. et al. · Neuropsychiatric Disease And Treatment (2013)
Murrough, J. W., Iosifescu, D. V., Chang, L. C. et al. · American Journal of Psychiatry (2013)
Ionescu, D. F., Luckenbaugh, D. A., Niciu, M. J. et al. · Bipolar Disorders (2014)
Glutamatergic modulators were a major focus. Ketamine, given most commonly as a subanaesthetic intravenous infusion (typically 0.5 mg kg-1 over 40 minutes), is reported to produce a rapid antidepressant effect within about 110 minutes that can persist for around 7 days in patients with TRD. A randomised, double-blind trial using midazolam as an active comparator (n = 73) found a large effect on Montgomery–Åsberg Depression Rating Scale (MADRS) scores for ketamine versus midazolam (Cohen's d = 0.81) at 24 hours, with sustained benefit for several days. Intranasal ketamine (50 mg) produced significant symptom reduction at 24 hours in an 18-completer proof-of-concept trial, although the effect was not significant at 72 hours. Safety data summarised include a pooled report in which 4 of 205 ketamine infusions were stopped due to adverse events and no persistent psychotomimetic effects or increased substance use were observed in a subgroup followed long term. Several other NMDA- and glutamate-targeting agents are reported. Lanicemine (AZD6765), a low-trapping NMDA blocker, produced rapid MADRS decreases within 80–110 minutes in small studies; in a larger adjunctive trial (n = 124) thrice-weekly infusions for 3 weeks produced a mean difference from placebo in MADRS of −5.5 (P < 0.02), and a 100 mg dose showed effects lasting up to 5 weeks after the last infusion, without significant psychotomimetic or dissociative side effects. Memantine trials were largely negative in depression. Riluzole showed antidepressant signals in small open-label and augmentation studies, but a double-blind trial following an open-label ketamine infusion (n = 42) found no difference between riluzole and placebo for prolonging ketamine response. NR2B-selective antagonist MK-0657 (oral) did not produce significant improvement on the MADRS in a small crossover trial (n = 21) though some secondary measures showed rapid benefits; a Phase II programme with CERC-301 (MK-0657) was noted as completed with results pending. Inhaled nitrous oxide produced rapid antidepressant effects within 2 hours in a crossover pilot (n = 20), with effects lasting at least 24 hours; reported response was 20% and remission 15% in that sample. Agents aimed at modulating NMDA glycine or AMPA receptor function are also reviewed. GLYX-13, a functional partial agonist at the NMDA-receptor glycine site, improved depressive symptoms within hours and effects were sustained for 1–2 weeks in a Phase IIa trial of TRD patients (n = 116) without observed psychotomimetic effects. AVP-786 (deuterated dextromethorphan plus low-dose quinidine) was described as entering Phase II testing. Org 26576, an AMPA positive allosteric modulator, was well tolerated in Phase I (n = 36) and Phase Ib (n = 54) studies, improved certain cognitive measures and showed larger symptomatic improvements than placebo; biomarker changes included increased growth hormone and decreased cortisol. Metabotropic glutamate receptor modulators are at earlier stages; antagonists of mGluR2/3 showed promising preclinical data, whereas basimglurant (mGluR5 antagonist) in a 9-week adjunctive, randomised trial (n = 333) produced consistent efficacy across endpoints but narrowly missed statistical significance on the clinician-rated MADRS (P = 0.061), with a sizable placebo response noted. Anticholinergic approaches included scopolamine, a competitive muscarinic antagonist, which produced rapid antidepressant and anxiolytic effects within about 3 days across unipolar and bipolar samples, with apparently larger effects in women and in treatment-naive patients; evidence on maintenance of benefit is limited. Nicotinic antagonists showed mixed results: mecamylamine augmented to citalopram showed superiority over placebo in incomplete responders, but the active enantiomer dexmecamylamine (TC-5214) failed to show benefit in Phase III trials that exhibited high placebo response rates. CP-601,927, an α4β2 partial agonist, was not superior to placebo in a Phase II trial, although a post hoc signal appeared in non-obese participants. Opioid-system modulation is represented by ALKS 5461, a combination of buprenorphine and samidorphan intended to produce functional κ-opioid antagonism while limiting μ-opioid-related abuse. A published study reported positive efficacy and safety data without evidence of abuse or withdrawal concerns; Phase III trials were ongoing at the time of the review. Among monoaminergic and catecholaminergic agents, vortioxetine (approved by the FDA in 2013) demonstrated superior antidepressant efficacy versus placebo in pooled analyses of multiple trials and showed advantages over agomelatine when used as a switch strategy after SSRI/SNRI failure. Lisdexamfetamine (LDX) augmentation trials in partially remitted patients did not find statistically significant benefit over placebo in Phase II and subsequently failed Phase III development. Edivoxetine (LY2216684) showed higher remission in a Phase II adjunctive trial (24.2% vs 11.8%, P = 0.044 by last observation carried forward) but failed to demonstrate efficacy in Phase III studies. Pramipexole produced modest, non-significant augmentation benefit in small trials and combination strategies did not show superiority while sometimes being poorly tolerated. Nutraceuticals and behavioural approaches yielded mixed findings. L-methylfolate augmentation produced divergent results: a 148-patient adjunctive trial showed no difference, whereas a smaller 75-patient trial reported efficacy at 15 mg day-1; post hoc work suggested inflammatory and genetic markers might predict response. SAMe augmentation (800 mg twice daily) showed greater response and remission than placebo in a 73-patient TRD sample. An exercise trial in SSRI non-remitters (n = 126) comparing high- versus low-dose exercise over 12 weeks did not show a statistically significant difference on primary depression outcomes overall, but a trend to higher remission (P ≈ 0.06) and subgroup benefits in men and women without family history of mental illness were reported. Hormonal and anti-inflammatory strategies provided selective signals. Repeated erythropoietin (EPO) administration in a double-blind, placebo-controlled trial (n = 39) did not reduce depression on the primary outcome but improved verbal memory and showed a benefit on one secondary depression measure. Testosterone trials after an initial positive report did not replicate augmentation effects in men. Anti-inflammatory treatment with infliximab (three intravenous infusions) improved depressive symptoms only in patients with elevated baseline inflammatory biomarkers (for example C-reactive protein) in a 60-patient randomised trial. Meta-analyses and pooled trials indicated adjunctive celecoxib (a COX-2 selective NSAID) is associated with improved antidepressant effects without increased NSAID-related adverse events. Device-based therapies are summarised with standard repetitive transcranial magnetic stimulation (rTMS) described as effective in TRD, albeit with smaller effect sizes and slower onset than electroconvulsive therapy (ECT). Deep TMS (dTMS), which uses an H-coil to reach deeper cortical regions, showed promising results: an open study (n = 29) reported a maintained response rate of 81% and remission rate of 71% over extended treatment, and a randomised, double-blind, multi-centre trial in 212 unmedicated TRD patients found significantly higher response (38.4% versus 21.4%) and remission (32.6% versus 14.6%) rates for active dTMS versus sham (P's ≤ 0.01), with effects persisting up to 4 months with maintenance therapy. The authors note the logistical burden of daily administration and challenges in sustaining long-term benefit.
Papakostas and colleagues interpret the body of evidence as indicating incremental progress in treating TRD, with several novel mechanisms showing promise but persistent limitations. They note that atypical antipsychotics have expanded their evidence base as adjunctive treatments and that olanzapine, aripiprazole and quetiapine are the only FDA-approved pharmacological adjuncts; however, tolerability concerns and slow onset of action limit their utility. The repeated failure of some Phase III programmes for catecholaminergic agents (for example LDX, edivoxetine) and for dexmecamylamine highlights an ongoing unmet need, while glutamatergic modulators and scopolamine represent more successful development of rapidly acting agents. Several important caveats are emphasised. Rapid-acting interventions often face exceptionally large placebo responses, limited durability of effect beyond a few days in many studies, and practical limitations related to intravenous administration. Device-based therapies such as rTMS and dTMS have favourable safety profiles compared with ECT but typically exhibit smaller effect sizes and slower clinical onset; daily treatment burden and challenges in maintaining long-term efficacy are additional concerns. The authors recommend better operationalisation of TRD in trials (for example, specifying degrees of resistance such as 1–3 failed trials versus ≥ 4), more head-to-head and blinded comparisons among devices, pharmacotherapies and ECT, and broader enrolment of difficult cases into clinical trials. Finally, Papakostas stresses the value of serendipity and clinical observation in drug discovery and advocates for combining innovation with biomarker-driven, target-engagement and neuroscience-informed approaches to advance antidepressant research. The ongoing NIMH-funded RAPID initiative is cited as an exemplar programme that will test low-field magnetic stimulation, a κ-opioid receptor antagonist (LY2456302), and ketamine dose-finding strategies, reflecting the translational priorities outlined by the authors.
Without a doubt, depression is one of the most devastating medical disorders known to mankind. The emotional, social and financial tolls of depression rank among the highest of all diseases.Depression's pervasiveness leaves hundreds of millions of people in need of treatment throughout their lifetime. For approximately two-thirds of patients with depression, treatments and therapies do not work sufficiently,and many are deemed 'treatment resistant', which is defined as the failure to achieve response to one or more standard antidepressant treatment trials of adequate dosing and duration.For this group of patients with treatment-resistant depression (TRD), novel therapeutics and innovative treatments are especially essential. The evolution of antidepressant therapy for TRD is undergoing a remarkable revolution. Following the serendipitous discovery of monoaminergic antidepressants (which typically modulate the transmission of serotonin and/or norepinephrine in the brain) in the mid-twentieth century, research in both academia and industry focused on targeting this neurotransmitter system for decades, in search of the elusive 'magic bullet' for depression. However, for depressed patients with treatment resistance, such treatments simply did not work well enough. Innovation began to move away from the monoamines early on and into the realm of non-monoaminergic augmentation agents-such as lithium and thyroid hormone. Despite relative advances made with these and similar compounds over the years, as well as traditional monoaminergic ones (such as the atypical antipsychotic agents),many patients still continue to have debilitating disease. As such, the field of antidepressant research has changed trajectories yet again; this time, compounds with primary mechanisms of action on the glutamatergic, cholinergic and opioid systems are now in the forefront of antidepressant exploration. Perhaps as a sign of the technological times, therapeutic development now also focuses on the use of device based and procedural therapies for patients with difficult-to-treat depression. Indeed, we may be standing in the middle of a paradigm shift for the treatment of resistant depression. The purpose of this paper is to provide an update to an earlier review published approximately 5 years agoon TRD, with a specific focus on novel therapeutics and treatments for this patient population. Sections are divided by drug classification.
Ketamine. Ketamine research in psychiatry has quickly expanded over the past decade-and-a-half since the landmark paper by Berman et al.describing ketamine's antidepressant properties. Several randomized, double-blind, placebo-controlled trialshave further demonstrated ketamine's rapid (within 110 min), robust (across a variety of symptoms) and relatively sustained (approximately 7 days) antidepressant efficacy at subanesthetic intravenous doses (typically, 0.5 mg kg -1 over 40 min) in wellcharacterized patients with TRD (for a recent comprehensive review, see). Recently, Murrough et al.further confirmed ketamine's antidepressant effects by using midazolam as an active comparator, thereby attempting to minimize functional unblinding due to the side effects associated with the use of ketamine. In this trial of 73 patients with TRD, ketamine had a high effect in reducing scores on the Montgomery Asberg Depression Rating Scale (MADRS) compared with midazolam (Cohen's d = 0.81). These results were significant 24 h following infusion and were sustained for several days. Of particular interest, ketamine has been shown to decrease depressive symptoms in the typically difficult-to-treat subtype of patients with unipolarand bipolaranxious depression. Further, it has also been shown to rapidly decrease suicidal ideationand anhedonia-two symptoms of depression that are particularly difficult to treat. A recent report confirmed intravenous ketamine's favorable safety and tolerability profile treating patients with depression; only 4 of a total of 205 infusions were stopped due to adverse events.Further, there were no cases of persistent psychotomimetic effects, adverse medical effects or increased substance use in a subgroup of long-term follow-up patients. Recently, a proof-of-concept trial of intranasal ketamine (50 mg) significantly reduced depressive symptoms within 24 h of administration compared with placebo in 18 completers with TRD, though its antidepressant effects were no longer significant at 72 h posttreatment.These results are particularly promising due to the ease of intranasal (versus intravenous) administration. Ketamine is classified as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, though its antidepressant mechanism of action remains largely unknown. Modulation of synaptogenesis likely has a role in its antidepressant properties. As recently reviewed by Zunszain et al.,actions on glutamatergic NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors stimulate translation pathways for proteins involved in neuronal plasticity. Specifically, the stimulation of mammalian target of rapamycin (an essential kinase in regulating proteins involved in synaptic plasticity) may have a role in ketamine's antidepressant effects. Furthermore, ketamine potentiates brain-derived neurotrophic factor (BDNF)-a factor implicated in neurogenesis and synaptic remodeling. Ketamine has also been shown to decrease inflammation via inhibition of inflammatory responses.Needless to say, ketamine's mechanism of antidepressant action is likely complex; several trials are underway to understand its unique mechanism (ClinicalTrials.gov identifiers NCT02122562 and NCT00088699), including a dose-finding study conducted by the National Institute of Mental Health (NIMH)funded Rapidly Acting Treatments for Treatment-Resistant Depression (RAPID) network of sites. These and similar studies may pave the way for the development of more rapidly acting, targeted antidepressant therapies. Lanicemine. The exciting antidepressant effects of ketamine have propelled the field towards exploring other compounds that modulate the glutamate system. One such compound-Lanicemine (AZD6765)-is a moderate-affinity low-trapping NMDAreceptor blocker that has been tested as an antidepressant in both preclinicaland clinicalsettings. Following a single intravenous infusion of lanicemine 150 mg, MADRS scores significantly decreased compared with placebo within 80 min in medicationfree patients (n = 22) with TRD.This rapid antidepressant onset, though similar to ketamine, remained significant only through 110 min. Regarding Hamilton Depression Rating Scale (HDRS) scores, significant improvements compared with placebo were observed at 80 and 110 min, and day 2, postinfusion. Though the antidepressant action of lanicemine was short-lived, its psychotomimetic and dissociative side effects did not differ compared with placebo, underscoring lanicemine's superior safety profile compared with ketamine.Another larger study provides further evidence for lanicemine's rapidly acting antidepressant properties and superior side effect profile.Depressed patients (n = 34) were initially randomized to receive a single infusion of lanicemine 100 mg or placebo. In this sample, lanicemine decreased MADRS scores at both 1 and 72 h postinfusion compared with placebo. Similar to the previous study, no significant psychotomimetic, dissociative or cognitive side effects were observed. However, MADRS scores within 24 hthe primary outcome measure-did not differ significantly from placebo; this was confounded by a large placebo response (more than 14 point average). Next, depressed patients (n = 124) were randomized to lanicemine 100 mg, 150 mg or placebo as adjunctive therapy to their current antidepressant medication regimen.Infusions were given thrice weekly for 3 weeks, followed by 5 weeks of observation. Compared with placebo, lanicemine significantly decreased MADRS scores from baseline to week 3-regardless of dose-with the difference from placebo in mean scores of -5.5 (P o 0.02). Further, this significant antidepressant efficacy lasted for up to 5 weeks following the last infusion in the patients randomized to 100 mg-a first instance where sustained treatment effects were seen following repeated infusions with an antiglutamatergic agent (P o0.05). Lanicemine showed no significant psychotomimetic or dissociative side effects in that trial. Together, these findings highlight the antidepressant effectiveness of an antiglutamatergic agent, without the unwanted side effects. Memantine. Memantine is a low-to-moderate affinity NMDAreceptor antagonist already approved for Alzheimer's dementia. Unfortunately, trials examining the antidepressant effects of memantine have been largely negative. Specifically, one 8-week double blind, placebo-controlled study in 32 patients with major depressive disorder (MDD) did not find a significant treatment effect of memantine monotherapy (5-20 mg day -1 ) on depression scores compared with placebo.A similarly designed trial in depressed outpatients failed to demonstrate significant antidepressant efficacy differences between memantine augmentation (20 mg day -1 ) versus placebo.Riluzole. Riluzole, an Food and Drug Administration (FDA)approved medication for amyotrophic lateral sclerosis, inhibits glutamate release via sodium channel inactivation, while blocking NMDA-receptor activation and enhancing AMPA expression.One small (n = 19) open-labeled study of riluzole monotherapy for TRD showed significant improvements in depression symptoms.Furthermore, riluzole augmentation to antidepressant therapy has resulted in significant improvements in both depression and anxiety symptoms.Given these positive findings, it has been hypothesized that oral riluzole could extend the antidepressant properties of a single ketamine infusion by continuing to influence the glutamatergic system without requiring intravenous medication, while simultaneously avoiding ketamine's unwanted side effects. In one trial, patients (n = 42) were randomized in a doubleblind manner to receive either riluzole or placebo following an open-label infusion of ketamine.After 28 days, no significant differences were seen between placebo versus riluzole with regards to antidepressant symptoms, suggesting that riluzole does not significantly alter the course of antidepressant response to ketamine.Furthermore, in this same sample, riluzole did not have antidepressant efficacy in ketamine non-responders.A larger clinical trial is currently underway to examine the efficacy and tolerability of adjunctive riluzole in the treatment of resistant depression (ClinicalTrials identifier: NCT01204918). MK-0657. MK-0657 is an antagonist at the NR2B (also known as GluN2B) subunit of the NMDA receptor, originally developed by Merck. One small (n = 21), randomized, double-blind, placebocontrolled, crossover pilot study examined the antidepressant efficacy and tolerability of oral MK-0657 monotherapy (4-8mg day -1 ) in medication-free patients with TRD.Unfortunately, no significant mood improvements were seen on the MADRS (the primary outcome measure), though no serious or dissociative adverse events were appreciated. Rapid (within 5 days) antidepressant effects were significant on secondary outcome measures (HDRS and the Beck Depression Inventory). Cerecor recently completed a Phase II clinical trial with CERC-301-the compound formally known as MK-0657-as adjunctive antidepressant therapy; results are pending (ClinicalTrials.gov identifier: NCT01941043). Nitrous oxide. Nitrous oxide, or 'laughing gas', is similar to ketamine in that it is a non-competitive antagonist of the NMDA receptor. One recently published randomized, blind, placebocontrolled crossover pilot study compared the antidepressant effects of inhaled nitrous oxide (administered over 1 h) with placebo in patients with TRD (n = 20).Nitrous oxide rapidly decreased symptoms of depression within 2 h; these effects were sustained for at least 24 h. Response to nitrous oxide was 20%, and remission was 15%. Side effects were mild to moderate in nature, with no dissociation or psychotomimetic side effects appreciated. A Phase II trial is currently underway (ClinicalTrials.gov identifier: NCT02139540).
In order for the NMDA receptor to be activated, glycine must also bind to the NMDA-receptor glycine site. GLYX-13 is a functional partial agonist at the NMDA-receptor glycine site that has been shown to produce antidepressant effects in rats, without the unwanted side effects that accompany ketamine.A Phase I (safety and pharmacokinetics) and a single-dose Phase IIa (safety and efficacy) study have been completed in humans.Specifically, TRD patients in the Phase IIa study (n = 116) received either intravenous GLYX-13 or placebo in a randomized, double-blind manner. Depression scores improved within hours; this improvement was sustained for 1-2 weeks. Furthermore, no serious treatment-associated adverse events were observed, including psychotomimetic effects. It is thought to work by activating the NR2B receptor of the NMDA channel, causing calcium influx and increasing the expression of AMPA receptors. This increases learning and memory and is thought to contribute to its antidepressant effects. AVP-786. AVP-786 is a novel combination of deuterium-modified dextromethorphan hydrobromide (DXM) and low-dose quinidine sulfate. Deuterium (a nonradioactive isotope of hydrogen) incorporation enhances the DXM molecule to decrease hepatic metabolism on first pass, which allows for more active drug to reach the brain; quinidine has been found to also increase its bioavailability.DXM is a low-to-moderate affinity NMDAreceptor antagonist, in addition to having serotonin and norepinephrine reuptake properties and sigma-1 receptor agonism-all thought to contribute to its potential antidepressant properties.Avanir has recently started recruiting patients for Phase II testing of the compound (ClinicalTrials.gov Identifier: NCT02153502). Org 263576. Continuing on the theme of developing new antidepressants targeted toward the glutamatergic system, Org 26576 is an AMPA positive allostergic modulator (AMPA PAM) in development. Because ketamine is thought, in part, to exert its mechanism of action via enhancing AMPA-receptor throughput of glutamate(thereby increasing BDNF, neuronal plasticity, and neurogenesis-all processes thought to be disrupted in depression), AMPA PAMs hold theoretical promise for treating depression. A completed Phase I trial (n = 36)showed that Org 26576 was well tolerated in healthy volunteers. Phase Ib testing (n = 54)confirmed its positive tolerability profile, established 450 mgday -1 as the maximum tolerated dose and improved clinically relevant cognitive measures of executive functioning and speed of processing-domains all relevant to depression. Furthermore, symptomatic improvements on depression scores were greater in the Org 26576 group compared with placebo. With regard to biomarkers, Org 26576 was associated with increases in growth hormone and decreases in cortisol at the end of treatment; prolactin and BDNF levels were not influenced. Metabotropic glutamate receptor modulators. Thus far, all the previously discussed glutamatergic modulators primarily exhibit their mechanisms of action on ionotropic glutamate receptors. However, several compounds are currently in clinical and preclinical testing that work on the metabotropic glutamate receptors (mGluRs). Specifically, mGluR2 and mGluR3 modulators (that is, LY341495, MGS0039) are of particular interest,as antagonism of these autoreceptors may lead to antidepressant responses. Significant preclinical datademonstrating their antidepressant effects is promising, though no large clinical trials in humans have been completed. Interestingly, antagonism of the mGluR5 postsynaptic receptor by basimglurant (1.5 mg day -1 ) as an adjunctive treatment to antidepressant treatments showed consistent antidepressant efficacy across primary and secondary end points in one 9-week double-blind, placebo control study in 333 patients with TRD, with good tolerability and safety.However, the study just missed statistical significance on the primary outcome measure (clinician rated MADRS) (P = 0.061), likely due to a sizeable placebo response rate (approximately 14 point mean score reduction).
Scopolamine. It has been hypothesized that depression may be due to, in some cases, a hypercholinergic state.Scopolamine, often used for motion sickness, is a competitive antimuscarinic (specifically, at the muscarinic M1 receptor) compound. It has been found to rapidly (within 3 days) and robustly decrease symptoms of depression and anxiety in both unipolar and bipolar patients with treatment-naive and resistant depression,though those with treatment-naive depression showed greater improvements.Interestingly, though both men and women experience rapid antidepressant and anxiolytic effects following scopolamine, effects appear to be greater in women.However, similar with ketamine, studies on how to maintain short-term gains seen with intravenous scopolamine are lacking. Mecamylamine and dexmecamylamine (TC-5214). Excessive nicotinic-receptor stimulation may also contribute to the hypercholinergic state that results in depression in some cases;therefore, nicotinic antagonists may have a role to play in the treatment of depression. One such nicotinic-receptor antagonist, mecamylamine, was superior to placebo in improving primary and secondary depression outcomes when augmented to citalopram treatment in incomplete responders with depression.Antidepressant efficacy and tolerability of augmentation dexmecamylamine (TC-5214), the biologically active enantiomer of mecamylamine, was compared with placebo in at least identical Phase III clinical trials in patients with TRD.No significant antidepressant advantage was found for dexmecamylamine compared with placebo, though placebo response rates noted in both published studies were well above the 30% threshold for uninformative studies;this occurred despite an 8-week openlabel 'lead-in', which, generally, reduces placebo response rates.CP-601,927. CP-601,927 is a high-affinity, selective nicotinic acetylcholine receptor (α4β2) partial agonist developed by Pfizer after it showed antidepressant qualities in animal models of depression.Unfortunately, it failed to show superior antidepressant efficacy to placebo as an augmentation agent to selective serotonin reuptake inhibitors (SSRIs) in one Phase II randomized trial.However, post hoc analyses showed a drug-placebo separation in non-obese patients (body mass index o 35 kg m -2 ), suggesting that the overall findings were adversely affected by obesity. Opioid system modulators ALKS 5461. The euphoric (thought to be modulated via μ-opioid receptors) and dysphoric (thought to be mediated via κ-opioid receptors) properties of opioids are well known by clinicians, especially in pain medicine. Indeed, the opioid system may also be important in the pathophysiology and treatment of depression.As the search for novel antidepressants continues, researchers have turned towards the opioid system for potential therapeutic targets, with the goal of finding an effective antidepressant compound, sans addiction potential. One such Alkermes compound-ALKS 5461-combines buprenorphine (a μ-opioid receptor partial agonist and functional kappa-opioid receptor antagonist) with samidorphan (a potent μopioid receptor antagonist) in an attempt to create a functional kappa receptor antagonist. A recently published study has yielded positive efficacy and safety data, with no abuse with withdrawal concerns.Phase III clinical trials are ongoing (ClinicalTrails.gov identifier: NCT02085135; NCT02218008; NCT02158546; NCT02158533).
Vortioxetine. Vortioxetine was approved by the FDA in 2013 for the treatment of MDD.Though its exact antidepressant mechanism of action is unknown, it is thought to combine direct serotonin receptor modulation with serotonin transporter inhibition. Data from both preclinical and clinical studiessuggest that vortioxetine may interrupt negative feedback mechanisms that control neuronal activity in several brain areas (that is, the dorsal and median raphe nuclei, and the prefrontal cortex) implicated in the pathophysiology of MDD. A recent review of the clinical efficacy data from 13 studies has shown that vortioxetine (5, 10 and 20 mg day -1 ) has significantly superior antidepressant efficacy compared with placebo.Of particular interest to this review, switching to vortioxetine demonstrated superior response and remission rates than switching to agomelatine (a melatonergic antidepressant) in depressed patients with an inadequate response to a course of SSRI/selective norepinephrine reuptake inhibitor monotherapy, with a lower rate of discontinuation due to adverse events.Lisdexamfetamine dimesylate. Lisdexamfetamine dimesylate (LDX) is an inactive prodrug; once orally ingested, it is metabolized to dextroamphetamine, thereby gaining approval for the treatment of attention-deficit hyperactivity disorder. Trivedi et al.examined the efficacy and safety of LDX augmentation (20-50 mg day -1 ) in a 6-week randomized, placebo controlled Phase II trial in unremitted (n = 129) and partially remitted (n = 173) depressed patients maintained on escitalopram. Although LDX decreased symptoms of depression, no statistically significant advantage was found over placebo. However, 90% of the study patients had anxious depression, a traditionally difficultto-treat subtype of major depression.Recently completed Phase III trials failed to find an advantage of LDX augmentation over placebo; further development has been halted.Edivoxetine (LY2216684). Edivoxetine (LY2216684) is a highly selective norepinephrine reuptake inhibitor that was studied as adjunctive therapy in depressed patients partially responsive to SSRIs (n = 131). One 10-week randomized, double-blind, placebo controlled Phase II trial showed significantly higher rates of remission in the adjunctive edivoxetine group compared with the placebo group (24.2% versus 11.8%, P = 0.044) when analyzed with the last observation carried forward; however, there were no statistically significant difference in response rates (27.4% versus 16.2%, P = 0.077).Subsequent Phase III trials by Eli Lilly failed to show efficacy for edivoxetine augmentation, halting further development as an antidepressant.Pramipexole. Pramipexole is a dopamine agonist (preferential to D3 receptors)that is FDA approved for the treatment of Parkinson's disease and Restless Leg Syndrome. Because D3 receptors that are widely distributed in the mesolimbic system have been implicated in the motor and anhedonic symptoms of depression (and have been suggested as a possible mechanism for pramipexole's action on mood symptoms in Parkinson's disease), activation of these receptors may be beneficial for treating depression. A small 8-week trial demonstrated a modest antidepressant augmentation benefit with flexible-dose adjunctive pramipexole in TRD that was not statistically significant at end point using the last-observation-carried-forward analysis.Furthermore, pramipexole combined with an SSRI for TRD has proven to be no more effective than either agent alone in a subsequent sample of 39 patients, and may be poorly tolerated, with only 15% of the combination sample able to tolerate dose increases.These studies add to the broader literature suggesting that catecholaminergic-selective agents do not appear to be efficacious as adjunctive therapies in depression.
L-methylfolate and S-adenosyl-methionine (SAMe). Folate (an essential amino acid derived from the human diet) is metabolized to SAMe through the one-carbon cycle (a necessary metabolic pathway that is also important for neurotransmitter synthesis). L-methylfolate (5-methyltetrahydrofolate)-a biologically active intermediary molecule in this pathway-crosses the blood-brain barrier. Because of their role in neurotransmitter synthesis, as well as anti-inflammatory properties, L-methylfolate and SAMe have been studied as augmentation agents to antidepressants. Outpatients with TRD (n = 148) on an SSRI antidepressant regimen were randomized to placebo for 60 days, L-methylfolate (7.5mg day -1 for 30 days followed by 15 mg day -1 for 30 days) or a combination of placebo for 30 days followed by L-methylfolate (7.5 mg day -1 ) for 30 days as adjunctive therapy.No significant differences between the groups were observed. However, a second trial in 75 depressed patientsfound statistically significant antidepressant efficacy for adjunctive L-methylfolate at 15 mg day -1 compared with placebo, with comparable safety profiles. Further post hoc testing showed that certain inflammatory biomarkers and genetic markers associated with the synthesis and metabolism of L-methylfolate may be useful predictors for adjunctive treatment response.Likewise, SAMe (800-1600 mg day -1 ) was safe and effective as an augmentation agent to serotonin reuptake inhibitors.Specifically, patients with TRD (n = 73) had significantly greater response and remission rates with SAMe augmentation (800 mg twice daily) compared with placebo.Along these lines, MSI Methylation Sciences are currently conducting a large Phase II trial, which aims to examine the efficacy and safety of SAMe augmentation compared with placebo in depressed patients with an inadequate response to their current antidepressant therapy (ClinicalTrials.gov Identifier: NCT01912196). Exercise. Anecdotally, it is known that exercise can improve mood and overall wellbeing, such as the phenomenon of 'runners high'. For patients with depression, exercise may help with mood. In one study,depressed SSRI non-remitters (n = 126) were assigned to either high (16 kcal per kg per week) or low (4 kcal per kg per week) exercise expenditure treatment groups over the course of 12 weeks, in addition to their SSRI. Although there was no statistically significant difference in reduction in depression scores between the two groups, there was a trend for higher remission rates in the higher-dose exercise group (Po 0.06). Interestingly, all men (regardless of family history of mental illness) and women without a family history of mental illness in the highexercise group had significantly better remission rates by week 12 compared with their counterparts in the low-exercise group (P o 0.001). If replicated, this may serve as a potentially useful clinical marker for predicting response to higher levels of exercise.Further, if modulation of the endogenous opioidergic system is partially responsible for the antidepressant effects of exercise, it would be interesting to test whether such effects would be further boosted if combined with κ-opioid receptor antagonists.
Erythropoietin (EPO). Though EPO is typically thought for its role in the production of red blood cells, it also has several roles in the central nervous system, including neuroprotection, neurodevelopment, and in cognitive functions-which is especially important as cognitive dysfunction is prevalent in depression and can have an adverse effect on treatment course.As such, one study explored the antidepressant and neurocognitive effects of a repeated EPO administration in patients with treatmentresistant depression (n = 39) in a double-blind, placebo-controlled parallel-group design trial.However, depression severity was not reduced by EPO on the primary outcome measure, although verbal recall and recognition were significantly enhanced and sustained. Furthermore, depression was significantly reduced on one secondary outcome measure. Given these mixed results, further research is necessary before conclusions as to EPO's antidepressant usefulness can be drawn. Testosterone. Following the promising report from a doubleblind, randomized clinical trial in a TRD population,subsequent studieshave failed to show any statistically significant augmentation effects for testosterone in men with depression. A pilot adjunctive study involving the use of the testosterone precursor dehydroepiandrosterone in women with depression is currently underway (NCT01783574).
Infliximab. Inflammation has been suggested to have a role in the pathophysiology of mood disorders, including depression.Three intravenous infusions of infliximab (a monoclonal antibody inhibitor of tumor necrosis factor-α, an inflammatory cytokine) improved symptoms of depression in patients with elevated biomarkers of inflammation (for example, C-reactive protein) in one randomized, double-blind, placebo-controlled study medically stable outpatients with depression (n = 60).However, tumor necrosis factor-α-antagonism did not appear to have generalized efficacy in TRD in that sample, unless patients demonstrated elevated baseline inflammatory markers. Although a mechanistically sound hypothesis, larger confirmatory studies are necessary before any definitive conclusions can be made. Celecoxib. One recent meta-analysis found an association between nonsteroidal anti-inflammatory drugs (NSAIDs) and improvements in depression, without an increased risk for NSAID-related adverse events.When sub-analyzed, this same meta-analysis found that adjunctive celecoxib (an NSAID that selectively inhibits cyclooxygenase-2 (a proinflammatory cytokineproducing enzyme)) particularly improved antidepressant effects, remission and response.Two similar reviews of randomized controlled trials confirmed celecoxib's superiority to placebo in the adjunctive treatment of MDD.Device-based therapies Transcranial magnetic stimulation (TMS). Mood and anxiety are thought to be regulated, in part, by the connections between the evolutionarily younger ventral and medial prefrontal cortices and the deeper, more primitive, brain structures of the limbic system (for example, amygdala, hippocampus and insula).Theoretically, stimulation of the cortex via superficial devices may 'reset' this dysfunctional relationship that characterizes psychiatric disorders.One method of external superficial stimulation is TMS.The therapeutic hypothesis behind TMS uses magnetic pulses to induce electrical currents within the brain; depending on the dose and duration of the stimulation, neuronal activity is modulated, resulting in phenotypic behavioral changes. Standard TMS uses an 8-coil (named for its figure 8 shape) to modulate neuronal activity to a maximum depth of 1.5-2.5 cm from the scalp.Standard repetitive TMS (rTMS) has been found to be an effective antidepressant therapy for depressed patients, especially those with treatment resistance,though it does not appear to have a clear advantage over electroconvulsive therapy (ECT), the 'gold standard' of device-based antidepressant therapies.One recent study found that monotherapy with low-frequency rTMS was as effective as venlafaxine plus low-frequency rTMS and venlafaxine alone for TRD; in addition, rTMS was found to be safe.As opposed to standard TMS, deep TMS (dTMS) utilizes an H-shaped coil, which can modulate neuronal activity in deeper regions of the brain-up to 6 cm below the surface of the scalp.For this reason, dTMS has been hypothesized as useful for treating depression. dTMS appears to be effective and well tolerated in TRD as both monotherapy and as adjunctive therapy.In addition, dTMS can be effective in patients who failed to respond to ECT or who relapsed after previous dTMS.Specifically, one study examined the antidepressant effects of repetitive dTMS treatments.Patients (n = 29) were treated for 18 weeks following 4 weeks of acute treatment, for a total of 22 weeks. Significant decreases in depression symptoms were recorded at the end of the acute treatment phase and were maintained throughout the duration of the research study (Po 0.0001), with an 81% response rate and a 71% remission rate by the study's end. One randomized, double-blind, controlled multi-center trial recently evaluated the efficacy and safety of an acute 4-week course of dTMS with a 12-week maintenance phase in 212 unmedicated TRD patients.Compared with sham treatment, dTMS patients showed significantly higher response (21.4% versus 38.4%) and remission (14.6% versus 32.6%) rates (P's ⩽ 0.01); these effects persisted for up to 4 months with maintenance therapy. Though these results are encouraging, further double-blind, sham-coil controlled studies are needed, and blinded head-to-head comparisons of standard TMS, dTMS, pharmacotherapy (particularly any emerging rapidly acting therapy) and ECT are necessary (although often seen as the 'undisputed' gold standard for the treatment of MDD, double-blind trials comparing ECT to an alternative therapy for MDD have never been conducted).
Over the past 5 years, the atypical antipsychotic agents have continued to expand their evidence base supporting their efficacy as adjunctive treatments in MDD (for a review, see Nelson and Papakostasas well Kamijima et al.for the most recently published clinical trial). Indeed, at this time, olanzapine, aripiprazole and quetiapine represent the only pharmacological agents approved by the FDA as adjunctive therapies for use when standard antidepressants have failed to produce significant symptom improvement. However, the relative safety and tolerability concerns, as well as their slow onset of action (similar to other contemporary antidepressants) pose two main limitations to their use. The recent failure of Phase III programs involving the use of other cathecholaminergic-selective agents (LDX, edivoxetine), as well as dexmecamylamine, highlights a continued unmet need, but one which hopefully can be met by other compounds cited in this review. Thus far, more success has been noted with respect to the development of rapidly acting agents (for example, glutamatergic modulators and scopolamine), though there are several limitations, including a placebo response rate of unprecedented magnitude, 101 an inability to extend antidepressant effects beyond a few days and the relative limitations of intravenous (versus oral/intranasal) administration. Regarding the two magnetic devices approved by the FDA for depression (8-coil and H-coil rTMS) although their side effect is relatively low and anesthesia is not required (as compared with ECT), studies show a relatively smaller effect size and slower onset of action compared with ECT. In addition, the burden of daily administration of rTMS and the current inability to prolong its antidepressant effects longterm remains problematic. Furthermore, very little has been done with respect to studying switch strategies for MDD-the only exception being for vortioxetine and agomelatine. Given that partial responders often outnumber non-responders,and that clinicians often prefer to use adjunctive therapies in partial responders versus switching, an excessive reliance on polypharmacy strategies versus switching may result patients more often achieving remission with more complex treatment regimens than simpler ones. Finally, although treatment resistance in depression appears to be more of a continuous than a dichotomous variable with respect to treatment outcome, 103 it may be worthwhile operationalizing study inclusion and exclusion criteria to address a population with a more conventional degree of treatment resistance (for example, 1-3 failed trials during the current episode) versus a greater degree of resistance (for example, treatment refractoriness-⩾ 4 failed trials) and tailoring these according to the efficacy and tolerability of the intervention to be studied. Needless to say, the human brain is complex. Billions of neuronal connections are constantly working to manage every aspect of human life. For patients with TRD, finding psychopharmacological and therapeutic treatment breakthroughs that manipulate aberrant brain circuitry and neurotransmission must be a top priority-not only for the field of psychiatry but also for the society as a whole.To this aim, the ongoing RAPID study is a large NIMH-funded multi-site initiative that aims to examine and develop rapidly acting novel therapeutics for patients with TRD. Specifically, RAPID will examine the antidepressant efficacy and tolerability of low-field magnetic stimulation augmentation of antidepressants (ClinicalTrials.gov identifier: NCT01654796), as low-field magnetic stimulation was shown to rapidly improve mood in patients with unipolar and bipolar depression. 105 RAPID will also assess the antidepressant efficacy and tolerability of LY2456302, a potent, centrally acting, selective kappa-opioid receptor antagonist (ClinicalTrials.gov identifier: NCT01913535). Animal models have suggested that κ-opioid receptor antagonists decrease depressive and anxiety behaviors in preclinical trials; 106,107 similarly, LY2456302's efficacy in the treatment of both mood and addictive disorders has been suggested.In addition, RAPID will include a dose-finding trial for ketamine, with intravenous doses ranging from 0.1 to 1 mg kg -1 per day for 3 days, compared with the active comparator midazolam (ClinicalTrials.gov identifier: NCT01920555). Taking a nod from our oncology colleagues, psychiatrists must begin to refer their difficult cases of treatment resistance to clinical trials. Without human data, our field is doomed for a standstill in novel therapeutics for our most difficult-to-treat cases. As reviewed, explorations into experimental treatments for resistant depression have broken away from the monoaminergic antidepressant 'dogma' of the late twentieth century and into a wider realm of possibilities. Throughout all this excitement of novel therapeutics, we must keep in mind that the modulation of the monoaminergic system through medications with primary mechanisms of action outside of the monoaminergic system (and vice versa) is very possible. In fact, given the that brain's intricate highway system of neurocircuitry and neurotransmission are intimately connected, the consideration of neurotransmitter systems and circuits in isolation and the excessive reliance on a 'rational' development of 'single-target' designer drugs seems unrealistic. The role of serendipity coupled with meticulous clinical observation in drug development in medicine should be emphasized. Moving forward, we must look toward the combination of innovation plus improvements on the remarkable discoveries thus far. As seen with the ketamine story, patients with difficult-to-treat depression have been observed to respond and remit within hours-an incredible finding from both a clinical and research perspective. The discovery of ketamine's rapidly acting antidepressant properties also reminds us of the importance of serendipity in antidepressant research. Maintaining the ability to uncover breakthroughs by creatively re-examining 'knowns' is a crucial part of drug discovery. Serendipity combined with biomarkers' breakthroughs, target-engagement research and neuroscience-driven discovery are the keys to the future of antidepressant research.
Dr Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca, Avanir Pharmaceuticals, Brainsway, Bristol-Myers Squibb Company, Cephalon, Dey Pharma, Eli Lilly, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB , Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos and Wyeth. Dr Papakostas has received honoraria from Abbott Laboratories, Astra Zeneca, Avanir Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway, Cephalon, Dey Pharma, Eli Lilly, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, H. Lundbeck A/S, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB, Pfizer, Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos, Titan Pharmaceuticals and Wyeth. Dr Papakostas has received research support from AstraZeneca, Bristol-Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental Health, PAMLAB, Pfizer, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals and Theracos. Dr Papakostas has served (not currently) on the speaker's bureau for Bristol-Myers Squibb and Pfizer. Dr Ionescu has no conflict of interest to disclose, financial or otherwise.
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Murrough, J. W., Wan, L., Levitch, C. F. et al. · Journal of Clinical Psychiatry (2015)
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