Towards New Mechanisms: an Update on Therapeutics for Treatment-Resistant Major Depressive Disorder

Home , Edivoxetine, Lanicemine, Opioidergic, Samidorphan

EXPERT REVIEW Towards new mechanisms: an update on therapeutics for treatment-resistant major depressive disorder

GI Papakostas and DF Ionescu

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.

Molecular Psychiatry (2015) 20, 1142–1150; doi:10.1038/mp.2015.92; published online 7 July 2015

INTRODUCTION on the glutamatergic, cholinergic and opioid systems are now in Without a doubt, depression is one of the most devastating the forefront of antidepressant exploration. Perhaps as a sign of medical disorders known to mankind. The emotional, social and the technological times, therapeutic development now also financial tolls of depression rank among the highest of all focuses on the use of device based and procedural therapies for 1,2 fi diseases. Depression’s pervasiveness leaves hundreds of millions patients with dif cult-to-treat depression. Indeed, we may be of people in need of treatment throughout their lifetime. For standing in the middle of a paradigm shift for the treatment of approximately two-thirds of patients with depression, treatments resistant depression. fi 3 The purpose of this paper is to provide an update to an earlier and therapies do not work suf ciently, and many are deemed 7 ‘treatment resistant', which is defined as the failure to achieve review published approximately 5 years ago on TRD, with a specific focus on novel therapeutics and treatments for this response to one or more standard antidepressant treatment trials fi of adequate dosing and duration.4,5 For this group of patients with patient population. Sections are divided by drug classi cation. treatment-resistant depression (TRD), novel therapeutics and innovative treatments are especially essential. NOVEL THERAPEUTICS: REVIEW The evolution of antidepressant therapy for TRD is undergoing a remarkable revolution. Following the serendipitous discovery of Glutamatergic modulators monoaminergic antidepressants (which typically modulate the Ketamine. Ketamine research in psychiatry has quickly expanded transmission of serotonin and/or norepinephrine in the brain) in over the past decade-and-a-half since the landmark paper by 8 ’ the mid-twentieth century, research in both academia and Berman et al. describing ketamine s antidepressant properties. 9,10 industry focused on targeting this neurotransmitter system for Several randomized, double-blind, placebo-controlled trials decades, in search of the elusive ‘magic bullet' for depression. have further demonstrated ketamine’s rapid (within 110 min), However, for depressed patients with treatment resistance, such robust (across a variety of symptoms) and relatively sustained treatments simply did not work well enough. Innovation began (approximately 7 days) antidepressant efficacy at subanesthetic − 1 to move away from the monoamines early on and into the realm intravenous doses (typically, 0.5 mg kg over 40 min) in well- of non-monoaminergic augmentation agents—such as lithium characterized patients with TRD (for a recent comprehensive and thyroid hormone. Despite relative advances made with these review, see McGirr et al.11). Recently, Murrough et al.12 further and similar compounds over the years, as well as traditional confirmed ketamine’s antidepressant effects by using midazolam monoaminergic ones (such as the atypical antipsychotic agents),6 as an active comparator, thereby attempting to minimize many patients still continue to have debilitating disease. As such, functional unblinding due to the side effects associated with the the field of antidepressant research has changed trajectories yet use of ketamine. In this trial of 73 patients with TRD, ketamine had again; this time, compounds with primary mechanisms of action a high effect in reducing scores on the Montgomery Asberg

Clinical Trials Network and Institute, Massachusetts General Hospital, Boston, MA, USA. Correspondence: Dr GI Papakostas, Clinical Trials Network and Institute, Massachusetts General Hospital, 1 Bowdoin Square, 6th Floor, Boston, MA 02114, USA. E-mail: [email protected] Re-submitted as an invited review to Molecular Psychiatry in March 2015. Received 22 January 2015; revised 24 March 2015; accepted 1 June 2015; published online 7 July 2015 Novel treatments for TRD GI Papakostas and DF Ionescu 1143 Depression Rating Scale (MADRS) compared with midazolam side effects were observed. However, MADRS scores within 24 h— (Cohen’s d = 0.81). These results were significant 24 h following the primary outcome measure—did not differ significantly from infusion and were sustained for several days. placebo; this was confounded by a large placebo response (more Of particular interest, ketamine has been shown to decrease than 14 point average). Next, depressed patients (n = 124) were depressive symptoms in the typically difficult-to-treat subtype of randomized to lanicemine 100 mg, 150 mg or placebo as patients with unipolar13 and bipolar14 anxious depression. Further, adjunctive therapy to their current antidepressant medication it has also been shown to rapidly decrease suicidal ideation15,16 regimen.21 Infusions were given thrice weekly for 3 weeks, and anhedonia17—two symptoms of depression that are particu- followed by 5 weeks of observation. Compared with placebo, larly difficult to treat. A recent report confirmed intravenous lanicemine significantly decreased MADRS scores from baseline to ketamine’s favorable safety and tolerability profile treating week 3—regardless of dose—with the difference from placebo in patients with depression; only 4 of a total of 205 infusions were mean scores of − 5.5 (Po0.02). Further, this significant antide- stopped due to adverse events.18 Further, there were no cases of pressant efficacy lasted for up to 5 weeks following the last persistent psychotomimetic effects, adverse medical effects or infusion in the patients randomized to 100 mg—a first instance increased substance use in a subgroup of long-term follow-up where sustained treatment effects were seen following repeated patients. Recently, a proof-of-concept trial of intranasal ketamine infusions with an antiglutamatergic agent (Po0.05). Lanicemine (50 mg) significantly reduced depressive symptoms within 24 h of showed no significant psychotomimetic or dissociative side administration compared with placebo in 18 completers with TRD, effects in that trial. Together, these findings highlight the though its antidepressant effects were no longer significant at antidepressant effectiveness of an antiglutamatergic agent, with- 72 h posttreatment.19 These results are particularly promising due out the unwanted side effects. to the ease of intranasal (versus intravenous) administration. Ketamine is classified as a non-competitive N-methyl-D-aspar- Memantine. Memantine is a low-to-moderate affinity NMDA- tate (NMDA) receptor antagonist, though its antidepressant receptor antagonist already approved for Alzheimer’s dementia. mechanism of action remains largely unknown. Modulation of Unfortunately, trials examining the antidepressant effects of synaptogenesis likely has a role in its antidepressant properties. As memantine have been largely negative. Specifically, one 8-week recently reviewed by Zunszain et al.,20 actions on glutamatergic double blind, placebo-controlled study in 32 patients with major NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic depressive disorder (MDD) did not find a significant treatment acid (AMPA) receptors stimulate translation pathways for proteins effect of memantine monotherapy (5–20 mg day − 1) on depres- involved in neuronal plasticity. Specifically, the stimulation of sion scores compared with placebo.23 A similarly designed trial in mammalian target of rapamycin (an essential kinase in regulating depressed outpatients failed to demonstrate significant antide- proteins involved in synaptic plasticity) may have a role in pressant efficacy differences between memantine augmentation ketamine’s antidepressant effects. Furthermore, ketamine potenti- (20 mg day − 1) versus placebo.24 ates brain-derived neurotrophic factor (BDNF)—a factor implicated in neurogenesis and synaptic remodeling. Ketamine has also Riluzole. Riluzole, an Food and Drug Administration (FDA)- been shown to decrease inflammation via inhibition of inflam- approved medication for amyotrophic lateral sclerosis, inhibits matory responses.20 Needless to say, ketamine’s mechanism of glutamate release via sodium channel inactivation, while blocking antidepressant action is likely complex; several trials are underway NMDA-receptor activation and enhancing AMPA expression.25 to understand its unique mechanism (ClinicalTrials.gov identifiers One small (n = 19) open-labeled study of riluzole monotherapy for NCT02122562 and NCT00088699), including a dose-finding study TRD showed significant improvements in depression symptoms.26 conducted by the National Institute of Mental Health (NIMH)- Furthermore, riluzole augmentation to antidepressant therapy has funded Rapidly Acting Treatments for Treatment-Resistant resulted in significant improvements in both depression and Depression (RAPID) network of sites. These and similar studies anxiety symptoms.27 Given these positive findings, it has been may pave the way for the development of more rapidly acting, hypothesized that oral riluzole could extend the antidepressant targeted antidepressant therapies. properties of a single ketamine infusion by continuing to influence the glutamatergic system without requiring intravenous medica- Lanicemine. The exciting antidepressant effects of ketamine have tion, while simultaneously avoiding ketamine’s unwanted side propelled the field towards exploring other compounds that effects. In one trial, patients (n = 42) were randomized in a double- modulate the glutamate system. One such compound—Lanice- blind manner to receive either riluzole or placebo following an mine (AZD6765)—is a moderate-affinity low-trapping NMDA- open-label infusion of ketamine.28 After 28 days, no significant receptor blocker that has been tested as an antidepressant in both differences were seen between placebo versus riluzole with preclinical21 and clinical21,22 settings. Following a single intrave- regards to antidepressant symptoms, suggesting that riluzole does nous infusion of lanicemine 150 mg, MADRS scores significantly not significantly alter the course of antidepressant response to decreased compared with placebo within 80 min in medication- ketamine.28 Furthermore, in this same sample, riluzole did not free patients (n = 22) with TRD.22 This rapid antidepressant onset, have antidepressant efficacy in ketamine non-responders.29 A though similar to ketamine, remained significant only through larger clinical trial is currently underway to examine the efficacy 110 min. Regarding Hamilton Depression Rating Scale (HDRS) and tolerability of adjunctive riluzole in the treatment of resistant scores, significant improvements compared with placebo were depression (ClinicalTrials identifier: NCT01204918). observed at 80 and 110 min, and day 2, postinfusion. Though the antidepressant action of lanicemine was short-lived, its psychoto- MK-0657. MK-0657 is an antagonist at the NR2B (also known as mimetic and dissociative side effects did not differ compared with GluN2B) subunit of the NMDA receptor, originally developed by placebo, underscoring lanicemine’s superior safety profile com- Merck. One small (n = 21), randomized, double-blind, placebo- pared with ketamine.22 controlled, crossover pilot study examined the antidepressant Another larger study provides further evidence for lanicemine’s efficacy and tolerability of oral MK-0657 monotherapy (4–8- rapidly acting antidepressant properties and superior side effect mg day − 1) in medication-free patients with TRD.30 Unfortunately, profile.21 Depressed patients (n = 34) were initially randomized to no significant mood improvements were seen on the MADRS (the receive a single infusion of lanicemine 100 mg or placebo. In this primary outcome measure), though no serious or dissociative sample, lanicemine decreased MADRS scores at both 1 and 72 h adverse events were appreciated. Rapid (within 5 days) anti- postinfusion compared with placebo. Similar to the previous depressant effects were significant on secondary outcome study, no significant psychotomimetic, dissociative or cognitive measures (HDRS and the Beck Depression Inventory). Cerecor

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 1142 – 1150 Novel treatments for TRD GI Papakostas and DF Ionescu 1144 recently completed a Phase II clinical trial with CERC-301—the hormone and decreases in cortisol at the end of treatment; compound formally known as MK-0657—as adjunctive anti- prolactin and BDNF levels were not influenced. depressant therapy; results are pending (ClinicalTrials.gov identifier: NCT01941043). Metabotropic glutamate receptor modulators. Thus far, all the previously discussed glutamatergic modulators primarily exhibit Nitrous oxide. Nitrous oxide, or ‘laughing gas', is similar to their mechanisms of action on ionotropic glutamate receptors. ketamine in that it is a non-competitive antagonist of the NMDA However, several compounds are currently in clinical and receptor. One recently published randomized, blind, placebo- preclinical testing that work on the metabotropic glutamate controlled crossover pilot study compared the antidepressant receptors (mGluRs). Specifically, mGluR2 and mGluR3 modulators effects of inhaled nitrous oxide (administered over 1 h) with (that is, LY341495, MGS0039) are of particular interest,39 as placebo in patients with TRD (n = 20).31 Nitrous oxide rapidly antagonism of these autoreceptors may lead to antidepressant decreased symptoms of depression within 2 h; these effects were responses. Significant preclinical data39 demonstrating their sustained for at least 24 h. Response to nitrous oxide was 20%, and antidepressant effects is promising, though no large clinical trials remission was 15%. Side effects were mild to moderate in nature, in humans have been completed. with no dissociation or psychotomimetic side effects appreciated. Interestingly, antagonism of the mGluR5 postsynaptic receptor A Phase II trial is currently underway (ClinicalTrials.gov identifier: by basimglurant (1.5 mg day − 1) as an adjunctive treatment to NCT02139540). antidepressant treatments showed consistent antidepressant efficacy across primary and secondary end points in one 9-week GLYX-13. In order for the NMDA receptor to be activated, glycine double-blind, placebo control study in 333 patients with TRD, must also bind to the NMDA-receptor glycine site. GLYX-13 is a with good tolerability and safety.40 However, the study just functional partial agonist at the NMDA-receptor glycine site that missed statistical significance on the primary outcome measure has been shown to produce antidepressant effects in rats, without (clinician rated MADRS) (P = 0.061), likely due to a sizeable 32 the unwanted side effects that accompany ketamine. A Phase I placebo response rate (approximately 14 point mean score (safety and pharmacokinetics) and a single-dose Phase IIa (safety reduction). and efficacy) study have been completed in humans.33 Specifi- cally, TRD patients in the Phase IIa study (n = 116) received either Anticholinergic modulators intravenous GLYX-13 or placebo in a randomized, double-blind Scopolamine. It has been hypothesized that depression may be manner. Depression scores improved within hours; this improve- 41 ment was sustained for 1–2 weeks. Furthermore, no serious due to, in some cases, a hypercholinergic state. Scopolamine, treatment-associated adverse events were observed, including often used for motion sickness, is a competitive antimuscarinic fi psychotomimetic effects. It is thought to work by activating the (speci cally, at the muscarinic M1 receptor) compound. It has NR2B receptor of the NMDA channel, causing calcium influx and been found to rapidly (within 3 days) and robustly decrease symptoms of depression and anxiety in both unipolar and bipolar increasing the expression of AMPA receptors. This increases 42–44 learning and memory and is thought to contribute to its patients with treatment-naive and resistant depression, antidepressant effects. though those with treatment-naive depression showed greater improvements.45 Interestingly, though both men and women AVP-786. AVP-786 is a novel combination of deuterium-modified experience rapid antidepressant and anxiolytic effects following 46 dextromethorphan hydrobromide (DXM) and low-dose quinidine scopolamine, effects appear to be greater in women. However, sulfate. Deuterium (a nonradioactive isotope of hydrogen) similar with ketamine, studies on how to maintain short-term incorporation enhances the DXM molecule to decrease hepatic gains seen with intravenous scopolamine are lacking. metabolism on first pass, which allows for more active drug to reach the brain; quinidine has been found to also increase its Mecamylamine and dexmecamylamine (TC-5214). Excessive bioavailability.34 DXM is a low-to-moderate affinity NMDA- nicotinic-receptor stimulation may also contribute to the hyperch- 47 receptor antagonist, in addition to having serotonin and olinergic state that results in depression in some cases; norepinephrine reuptake properties and sigma-1 receptor agon- therefore, nicotinic antagonists may have a role to play in the ism—all thought to contribute to its potential antidepressant treatment of depression. One such nicotinic-receptor antagonist, properties.35 Avanir has recently started recruiting patients for mecamylamine, was superior to placebo in improving primary and Phase II testing of the compound (ClinicalTrials.gov Identifier: secondary depression outcomes when augmented to citalopram 48,49 NCT02153502). treatment in incomplete responders with depression. Anti- depressant efficacy and tolerability of augmentation dexmecamy- Org 263576. Continuing on the theme of developing new lamine (TC-5214), the biologically active enantiomer of antidepressants targeted toward the glutamatergic system, Org mecamylamine, was compared with placebo in at least identical 26576 is an AMPA positive allostergic modulator (AMPA PAM) in Phase III clinical trials in patients with TRD.50 No significant development. Because ketamine is thought, in part, to exert its antidepressant advantage was found for dexmecamylamine mechanism of action via enhancing AMPA-receptor throughput of compared with placebo, though placebo response rates noted glutamate36 (thereby increasing BDNF, neuronal plasticity, and in both published studies were well above the 30% threshold for neurogenesis—all processes thought to be disrupted in depres- uninformative studies;51 this occurred despite an 8-week open- sion), AMPA PAMs hold theoretical promise for treating depres- label ‘lead-in', which, generally, reduces placebo response rates.52 sion. A completed Phase I trial (n = 36)37 showed that Org 26576 was well tolerated in healthy volunteers. Phase Ib testing (n = 54)38 CP-601,927. CP-601,927 is a high-affinity, selective nicotinic confirmed its positive tolerability profile, established 450 mg - acetylcholine receptor (α4β2) partial agonist developed by Pfizer day − 1 as the maximum tolerated dose and improved clinically after it showed antidepressant qualities in animal models of relevant cognitive measures of executive functioning and speed of depression.53 Unfortunately, it failed to show superior antidepres- processing—domains all relevant to depression. Furthermore, sant efficacy to placebo as an augmentation agent to selective symptomatic improvements on depression scores were greater in serotonin reuptake inhibitors (SSRIs) in one Phase II randomized the Org 26576 group compared with placebo. With regard to trial.54 However, post hoc analyses showed a drug–placebo biomarkers, Org 26576 was associated with increases in growth separation in non-obese patients (body mass index o35 kg m − 2),

Molecular Psychiatry (2015), 1142 – 1150 © 2015 Macmillan Publishers Limited Novel treatments for TRD GI Papakostas and DF Ionescu 1145 suggesting that the overall findings were adversely affected by 16.2%, P = 0.077).65 Subsequent Phase III trials by Eli Lilly failed to obesity. show efficacy for edivoxetine augmentation, halting further development as an antidepressant.66 Opioid system modulators Pramipexole. Pramipexole is a dopamine agonist (preferential to ALKS 5461. The euphoric (thought to be modulated via μ-opioid D3 receptors)67 that is FDA approved for the treatment of receptors) and dysphoric (thought to be mediated via κ-opioid Parkinson’s disease and Restless Leg Syndrome. Because D3 receptors) properties of opioids are well known by clinicians, receptors that are widely distributed in the mesolimbic system especially in pain medicine. Indeed, the opioid system may also be have been implicated in the motor and anhedonic symptoms of important in the pathophysiology and treatment of depression.55,56 As the search for novel antidepressants continues, depression (and have been suggested as a possible mechanism for pramipexole’s action on mood symptoms in Parkinson’s researchers have turned towards the opioid system for potential 67 fi therapeutic targets, with the goal of finding an effective disease ), activation of these receptors may be bene cial for treating depression. A small 8-week trial demonstrated a modest antidepressant compound, sans addiction potential. One such fi fl Alkermes compound—ALKS 5461—combines buprenorphine (a antidepressant augmentation bene t with exible-dose adjunc- μ tive pramipexole in TRD that was not statistically significant at end -opioid receptor partial agonist and functional kappa-opioid 68 receptor antagonist) with samidorphan (a potent μ- opioid point using the last-observation-carried-forward analysis. receptor antagonist) in an attempt to create a functional kappa Furthermore, pramipexole combined with an SSRI for TRD has receptor antagonist. A recently published study has yielded proven to be no more effective than either agent alone in a positive efficacy and safety data, with no abuse with withdrawal subsequent sample of 39 patients, and may be poorly tolerated, 57 with only 15% of the combination sample able to tolerate dose concerns. Phase III clinical trials are ongoing (ClinicalTrails.gov 69 identifier: NCT02085135; NCT02218008; NCT02158546; increases. These studies add to the broader literature suggesting NCT02158533). that catecholaminergic-selective agents do not appear to be efficacious as adjunctive therapies in depression. Monoaminergics Neutraceuticals and exercise Vortioxetine. Vortioxetine was approved by the FDA in 2013 for the treatment of MDD.58 Though its exact antidepressant L-methylfolate and S-adenosyl-methionine (SAMe). Folate (an mechanism of action is unknown, it is thought to combine direct essential amino acid derived from the human diet) is metabolized serotonin receptor modulation with serotonin transporter inhibi- to SAMe through the one-carbon cycle (a necessary metabolic tion. Data from both preclinical and clinical studies59 suggest that pathway that is also important for neurotransmitter synthesis). — vortioxetine may interrupt negative feedback mechanisms that L-methylfolate (5-methyltetrahydrofolate) a biologically active — – control neuronal activity in several brain areas (that is, the dorsal intermediary molecule in this pathway crosses the blood brain and median raphe nuclei, and the prefrontal cortex) implicated in barrier. Because of their role in neurotransmitter synthesis, as well fl the pathophysiology of MDD. A recent review of the clinical as anti-in ammatory properties, L-methylfolate and SAMe have efficacy data from 13 studies has shown that vortioxetine (5, 10 been studied as augmentation agents to antidepressants. Out- and 20 mg day − 1) has significantly superior antidepressant patients with TRD (n = 148) on an SSRI antidepressant regimen efficacy compared with placebo.60 Of particular interest to this were randomized to placebo for 60 days, L-methylfolate (7.5 - − 1 − 1 review, switching to vortioxetine demonstrated superior response mg day for 30 days followed by 15 mg day for 30 days) or a and remission rates than switching to agomelatine (a melatoner- combination of placebo for 30 days followed by L-methylfolate − 1 70 gic antidepressant) in depressed patients with an inadequate (7.5 mg day ) for 30 days as adjunctive therapy. No significant response to a course of SSRI/selective norepinephrine reuptake differences between the groups were observed. However, a 70 inhibitor monotherapy, with a lower rate of discontinuation due to second trial in 75 depressed patients found statistically adverse events.61 significant antidepressant efficacy for adjunctive L-methylfolate at 15 mg day − 1 compared with placebo, with comparable safety Lisdexamfetamine dimesylate. Lisdexamfetamine dimesylate profiles. Further post hoc testing showed that certain inflammatory (LDX) is an inactive prodrug; once orally ingested, it is meta- biomarkers and genetic markers associated with the synthesis and bolized to dextroamphetamine, thereby gaining approval for the metabolism of L-methylfolate may be useful predictors for treatment of attention-deficit hyperactivity disorder. Trivedi adjunctive treatment response.71 − 1 et al.62 examined the efficacy and safety of LDX augmentation Likewise, SAMe (800–1600 mg day ) was safe and effective as 72 (20–50 mg day − 1) in a 6-week randomized, placebo controlled an augmentation agent to serotonin reuptake inhibitors. Phase II trial in unremitted (n = 129) and partially remitted Specifically, patients with TRD (n = 73) had significantly greater (n = 173) depressed patients maintained on escitalopram. response and remission rates with SAMe augmentation (800 mg Although LDX decreased symptoms of depression, no statistically twice daily) compared with placebo.73 Along these lines, MSI significant advantage was found over placebo. However, 90% of Methylation Sciences are currently conducting a large Phase II the study patients had anxious depression, a traditionally difficult- trial, which aims to examine the efficacy and safety of SAMe to-treat subtype of major depression.63 Recently completed Phase augmentation compared with placebo in depressed patients with III trials failed to find an advantage of LDX augmentation over an inadequate response to their current antidepressant therapy placebo; further development has been halted.64 (ClinicalTrials.gov Identifier: NCT01912196).

Edivoxetine (LY2216684). Edivoxetine (LY2216684) is a highly Exercise. Anecdotally, it is known that exercise can improve selective norepinephrine reuptake inhibitor that was studied as mood and overall wellbeing, such as the phenomenon of ‘runners adjunctive therapy in depressed patients partially responsive to high'. For patients with depression, exercise may help with mood. SSRIs (n = 131). One 10-week randomized, double-blind, placebo In one study,74 depressed SSRI non-remitters (n = 126) were controlled Phase II trial showed significantly higher rates of assigned to either high (16 kcal per kg per week) or low (4 kcal remission in the adjunctive edivoxetine group compared with the per kg per week) exercise expenditure treatment groups over the placebo group (24.2% versus 11.8%, P = 0.044) when analyzed course of 12 weeks, in addition to their SSRI. Although there was with the last observation carried forward; however, there were no no statistically significant difference in reduction in depression statistically significant difference in response rates (27.4% versus scores between the two groups, there was a trend for higher

© 2015 Macmillan Publishers Limited Molecular Psychiatry (2015), 1142 – 1150 Novel treatments for TRD GI Papakostas and DF Ionescu 1146 remission rates in the higher-dose exercise group (Po0.06). Device-based therapies Interestingly, all men (regardless of family history of mental illness) Transcranial magnetic stimulation (TMS). Mood and anxiety are and women without a family history of mental illness in the high- thought to be regulated, in part, by the connections between the exercise group had significantly better remission rates by week 12 evolutionarily younger ventral and medial prefrontal cortices and compared with their counterparts in the low-exercise group the deeper, more primitive, brain structures of the limbic system – (Po0.001). If replicated, this may serve as a potentially useful (for example, amygdala, hippocampus and insula).87 89 Theoreti- clinical marker for predicting response to higher levels of cally, stimulation of the cortex via superficial devices may ‘reset' exercise.74 Further, if modulation of the endogenous opioidergic this dysfunctional relationship that characterizes psychiatric 88 system is partially responsible for the antidepressant effects of disorders. One method of external superficial stimulation is 90 exercise, it would be interesting to test whether such effects TMS. The therapeutic hypothesis behind TMS uses magnetic would be further boosted if combined with κ-opioid receptor pulses to induce electrical currents within the brain; depending on antagonists. 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 Hormones neuronal activity to a maximum depth of 1.5–2.5 cm from the Erythropoietin (EPO). Though EPO is typically thought for its role scalp.91 Standard repetitive TMS (rTMS) has been found to be an in the production of red blood cells, it also has several roles in the effective antidepressant therapy for depressed patients, especially central nervous system, including neuroprotection, neurodevelop- those with treatment resistance,92–94 though it does not appear ment, and in cognitive functions75,76—which is especially to have a clear advantage over electroconvulsive therapy (ECT), important as cognitive dysfunction is prevalent in depression the ‘gold standard' of device-based antidepressant therapies.95 and can have an adverse effect on treatment course.77 As such, One recent study found that monotherapy with low-frequency one study explored the antidepressant and neurocognitive effects rTMS was as effective as venlafaxine plus low-frequency rTMS of a repeated EPO administration in patients with treatment- and venlafaxine alone for TRD; in addition, rTMS was found to be resistant depression (n = 39) in a double-blind, placebo-controlled safe.96 parallel-group design trial.78 However, depression severity was not As opposed to standard TMS, deep TMS (dTMS) utilizes an reduced by EPO on the primary outcome measure, although H-shaped coil, which can modulate neuronal activity in deeper — 91 verbal recall and recognition were significantly enhanced and regions of the brain up to 6 cm below the surface of the scalp. sustained. Furthermore, depression was significantly reduced on For this reason, dTMS has been hypothesized as useful for treating depression. dTMS appears to be effective and well tolerated in one secondary outcome measure. Given these mixed results, 97 further research is necessary before conclusions as to EPO's TRD as both monotherapy and as adjunctive therapy. In addition, dTMS can be effective in patients who failed to respond antidepressant usefulness can be drawn. to ECT or who relapsed after previous dTMS.97 Specifically, one study examined the antidepressant effects of repetitive dTMS Testosterone. Following the promising report from a double- 98 blind, randomized clinical trial in a TRD population,79 subsequent treatments. Patients (n = 29) were treated for 18 weeks following 4 weeks of acute treatment, for a total of 22 weeks. Significant studies80,81 have failed to show any statistically significant decreases in depression symptoms were recorded at the end augmentation effects for testosterone in men with depression. A of the acute treatment phase and were maintained throughout pilot adjunctive study involving the use of the testosterone the duration of the research study (Po0.0001), with an 81% precursor dehydroepiandrosterone in women with depression is response rate and a 71% remission rate by the study’s end. One currently underway (NCT01783574). randomized, double-blind, controlled multi-center trial recently evaluated the efficacy and safety of an acute 4-week course of Anti-inflammatories dTMS with a 12-week maintenance phase in 212 unmedicated Infliximab.Inflammation has been suggested to have a role in TRD patients.99 Compared with sham treatment, dTMS patients the pathophysiology of mood disorders, including depression.82 showed significantly higher response (21.4% versus 38.4%) and Three intravenous infusions of infliximab (a monoclonal antibody remission (14.6% versus 32.6%) rates (P’s ⩽ 0.01); these effects inhibitor of tumor necrosis factor-α,aninflammatory cytokine) persisted for up to 4 months with maintenance therapy. Though improved symptoms of depression in patients with elevated these results are encouraging, further double-blind, sham-coil biomarkers of inflammation (for example, C-reactive protein) in controlled studies are needed, and blinded head-to-head compar- one randomized, double-blind, placebo-controlled study medi- isons of standard TMS, dTMS, pharmacotherapy (particularly any 83 emerging rapidly acting therapy) and ECT are necessary (although cally stable outpatients with depression (n = 60). However, tumor ‘ necrosis factor-α-antagonism did not appear to have generalized often seen as the undisputed' gold standard for the treatment of MDD, double-blind trials comparing ECT to an alternative therapy efficacy in TRD in that sample, unless patients demonstrated for MDD have never been conducted).97 elevated baseline inflammatory markers. Although a mechan- istically sound hypothesis, larger confirmatory studies are necessary before any definitive conclusions can be made. DISCUSSION Over the past 5 years, the atypical antipsychotic agents have Celecoxib. One recent meta-analysis found an association bet- continued to expand their evidence base supporting their efficacy fl ween nonsteroidal anti-in ammatory drugs (NSAIDs) and as adjunctive treatments in MDD (for a review, see Nelson and improvements in depression, without an increased risk for 6 100 84 Papakostas as well Kamijima et al. for the most recently NSAID-related adverse events. When sub-analyzed, this same published clinical trial). Indeed, at this time, olanzapine, aripipra- meta-analysis found that adjunctive celecoxib (an NSAID that zole and quetiapine represent the only pharmacological agents selectively inhibits cyclooxygenase-2 (a proinflammatory cytokine- approved by the FDA as adjunctive therapies for use when producing enzyme)) particularly improved antidepressant effects, standard antidepressants have failed to produce significant remission and response.84 Two similar reviews of randomized symptom improvement. However, the relative safety and toler- controlled trials confirmed celecoxib’s superiority to placebo in the ability concerns, as well as their slow onset of action (similar to adjunctive treatment of MDD.85,86 other contemporary antidepressants) pose two main limitations to

Molecular Psychiatry (2015), 1142 – 1150 © 2015 Macmillan Publishers Limited Novel treatments for TRD GI Papakostas and DF Ionescu 1147 their use. The recent failure of Phase III programs involving the use novel therapeutics, we must keep in mind that the modulation of of other cathecholaminergic-selective agents (LDX, edivoxetine), the monoaminergic system through medications with primary as well as dexmecamylamine, highlights a continued unmet need, mechanisms of action outside of the monoaminergic system (and but one which hopefully can be met by other compounds cited in vice versa) is very possible. In fact, given the that brain’s intricate this review. Thus far, more success has been noted with respect to highway system of neurocircuitry and neurotransmission are the development of rapidly acting agents (for example, glutama- intimately connected, the consideration of neurotransmitter tergic modulators and scopolamine), though there are several systems and circuits in isolation and the excessive reliance on a limitations, including a placebo response rate of unprece- ‘rational' development of ‘single-target' designer drugs seems dented magnitude,101 an inability to extend antidepressant effects unrealistic. The role of serendipity coupled with meticulous clinical beyond a few days and the relative limitations of intravenous observation in drug development in medicine should be (versus oral/intranasal) administration. Regarding the two mag- emphasized. netic devices approved by the FDA for depression (8-coil and Moving forward, we must look toward the combination of H-coil rTMS) although their side effect is relatively low and innovation plus improvements on the remarkable discoveries thus anesthesia is not required (as compared with ECT), studies show a far. As seen with the ketamine story, patients with difficult-to-treat relatively smaller effect size and slower onset of action compared depression have been observed to respond and remit within with ECT. In addition, the burden of daily administration of rTMS hours—an incredible finding from both a clinical and research and the current inability to prolong its antidepressant effects long- perspective. The discovery of ketamine’s rapidly acting antide- term remains problematic. Furthermore, very little has been done pressant properties also reminds us of the importance of with respect to studying switch strategies for MDD—the only serendipity in antidepressant research. Maintaining the ability to exception being for vortioxetine and agomelatine. Given that uncover breakthroughs by creatively re-examining ‘knowns' is a partial responders often outnumber non-responders,102 and that crucial part of drug discovery. Serendipity combined with clinicians often prefer to use adjunctive therapies in partial biomarkers' breakthroughs, target-engagement research and responders versus switching, an excessive reliance on polyphar- neuroscience-driven discovery are the keys to the future of macy strategies versus switching may result in patients more often antidepressant research. 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 CONFLICT OF INTEREST 103 with respect to treatment outcome, it may be worthwhile Dr Papakostas has served as a consultant for Abbott Laboratories, AstraZeneca, operationalizing study inclusion and exclusion criteria to address Avanir Pharmaceuticals, Brainsway, Bristol-Myers Squibb Company, Cephalon, Dey a population with a more conventional degree of treatment Pharma, Eli Lilly, GlaxoSmithKline, Evotec AG, H. Lundbeck A/S, Inflabloc resistance (for example, 1–3 failed trials during the current Pharmaceuticals, Jazz Pharmaceuticals, Novartis Pharma AG, Otsuka fi episode) versus a greater degree of resistance (for example, Pharmaceuticals, PAMLAB , P zer, Pierre Fabre Laboratories, Ridge Diagnostics treatment refractoriness— ⩾ 4 failed trials) and tailoring these (formerly known as Precision Human Biolaboratories), Shire Pharmaceuticals, fi Sunovion Pharmaceuticals, Takeda Pharmaceutical Company, Theracos and Wyeth. according to the ef cacy and tolerability of the intervention to be Dr Papakostas has received honoraria from Abbott Laboratories, Astra Zeneca, Avanir studied. Pharmaceuticals, Bristol-Myers Squibb Company, Brainsway, Cephalon, Dey Pharma, Needless to say, the human brain is complex. Billions of Eli Lilly, Evotec AG, GlaxoSmithKline, Inflabloc Pharmaceuticals, Jazz Pharmaceuticals, neuronal connections are constantly working to manage every H. Lundbeck A/S, Novartis Pharma AG, Otsuka Pharmaceuticals, PAMLAB, Pfizer, aspect of human life. For patients with TRD, finding psychophar- Pierre Fabre Laboratories, Ridge Diagnostics, Shire Pharmaceuticals, Sunovion macological and therapeutic treatment breakthroughs that Pharmaceuticals, Takeda Pharmaceutical Company, Theracos, Titan Pharmaceuticals manipulate aberrant brain circuitry and neurotransmission must and Wyeth. Dr Papakostas has received research support from AstraZeneca, Bristol- — fi Myers Squibb Company, Forest Pharmaceuticals, the National Institute of Mental be a top priority not only for the eld of psychiatry but also for fi the society as a whole.104 To this aim, the ongoing RAPID study is Health, PAMLAB, P zer, Ridge Diagnostics (formerly known as Precision Human Biolaboratories), Sunovion Pharmaceuticals and Theracos. Dr Papakostas has served a large NIMH-funded multi-site initiative that aims to examine and (not currently) on the speaker’s bureau for Bristol-Myers Squibb and Pfizer. Dr Ionescu develop rapidly acting novel therapeutics for patients with TRD. has no conflict of interest to disclose, financial or otherwise. Specifically, RAPID will examine the antidepressant efficacy and tolerability of low-field magnetic stimulation augmentation of antidepressants (ClinicalTrials.gov identifier: NCT01654796), as REFERENCES low-field magnetic stimulation was shown to rapidly improve 1 Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE et al. 105 mood in patients with unipolar and bipolar depression. RAPID Global burden of disease attributable to mental and substance use disorders: will also assess the antidepressant efficacy and tolerability of findings from the Global Burden of Disease Study 2010. 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