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With well over two dozen traditional antidepressants available in the US, and an ever-growing list of other psychotropic compounds with apparent antidepressant properties, pharmacological options for treating clinical depression today are broad and vast. However, recent findings suggest that the magnitude of efficacy for most antidepressants compared with placebo may be more modest than previously thought.1Most depressed patients do not respond fully to a first antidepressant trial, and with each consequent trial, there is less chance of symptom remission.2 About one-third of patients receiving long-term treatment report persistent moderate-to-severe depression.3 Hence, there remains more than a little room for improvement.
Since the late 1950s, the traditional view of treating depression has focused on the role of monoamines (serotonin, norepinephrine, and dopamine) as the main targets for medications. Newer treatments are looking beyond effects on monoamines as potential strategies to leverage depressive symptoms.
A major challenge for progress in novel pharmacotherapies has been our lack of a full understanding about the causes of depression. Advances in functional neuroimaging and genetic markers have begun to shed new light on brain regions and pathways associated with aberrant neural functioning in depression, but not in ways that have led to treatments aimed at remedying its pathogenesis. This makes it hard to think of antidepressant medications as “treating” the pathophysiology of depression (as when antibiotics eliminate the cause of an infection); rather, antidepressant relieve symptoms by counteracting or compensating for depression’s consequences (as when diuretics alleviate peripheral edema regardless of its etiology).
Gone are the days of oversimplified theories that depression is caused by a “chemical imbalance.” More likely, depression involves changes in brain architecture and the interplay of complex circuits in which chemicals, or neurotransmitters, are the messengers of information, rather than the causes of faulty functioning. Table 1 summarizes some of the major conceptual shifts that have occurred in thinking about the probable causes of depression (or at least its neurobiological context), which sets the stage for new ways to consider innovative treatment strategies. Looking beyond the role of monoamines as treatment targets in depression, a number of novel therapeutic strategies have begun to receive growing interest in preclinical and clinical trials. Key points about emerging novel depression pharmacotherapies are summarized in Table 2, and described more fully below.
Subanesthetically dosed intravenous (IV) ketamine currently represents perhaps the most dramatic and innovative antidepressant pharmacotherapy to emerge in decades.4,5 It is pharmacodynamically unique in its rapid onset (hours rather than days to weeks) and its potential ability to reduce suicidal ideation after a single dose, independent of its antidepressant properties.6 (While both lithium and clozapine have been shown to reduce suicidal behaviors, neither has been shown to reduce ideation, much less in the same day after a single dose.) Meta-analyses suggest that 0.5 mg/kg IV ketamine produces nearly a 10-fold greater likelihood of response than placebo at day 1 and a 4- to 5-fold likelihood of sustained response after one week.7
The exact psychotropic mechanism of action of ketamine remains elusive. Initial work focused on blockade of ionotropic N-methyl-D-aspartate (NMDA) receptors as accounting broadly for its antidepressant effects. However, subsequent negative randomized trials with other NMDA receptor antagonists (such as riluzole8) redirected interest toward ketamine’s other, non-NMDA receptor-related mechanisms, such as sigma receptor agonism, mu opioid receptor antagonism, or midbrain monoaminergic inhibition. Other authors have suggested that at low doses, ketamine’s antidepressant effects may derive from an increase in glutamate transmission with increased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression, leading to increased release of brain-derived neurotrophic factor (BDNF).9Murrough and colleagues10 recently observed the necessity of AMPA receptor activation for the antidepressant effects of ketamine. They reported that “directly targeting the NMDA [receptor] may not be required.” As noted by the American Psychiatric Association Council on Research Task Force on Novel Biomarkers and Treatments,11 future advances will depend on a better understanding of the many mechanisms of action relative to the antidepressant properties of ketamine.
Ketamine is currently not approved by the FDA as a treatment for depression. Uncertainty remains as to whether repeated dosing is safe, effective, and necessary to avoid relapse and, if so, when, at what frequency, and for how long. The aforementioned APA Council on Research Consensus Statement on ketamine treatment for depression11 stated that while some clinics already offer 2- to 3-week courses of ketamine delivered 2 to 3 times per week, “there remain no published data that clearly supports this practice, and . . . the relative benefit of each ketamine infusion [should] be considered in light of the potential risks associated with longer term exposure to ketamine and the lack of published evidence for prolonged efficacy with ongoing administration.” 11 Thus far, studies of other pharmacotherapies to sustain an initial ketamine response (such as riluzole or lithium) have proven no better than placebo.
Enantiomeric esketamine remains investigational as a possible easier-to-administer intranasal (IN) antidepressant, although IN bioavailability is only about half that of IV ketamine’s 100%. Two randomized multi-site trials of IN esketamine added to antidepressants showed dose-related better efficacy than placebo: Daly and colleagues12 found that 28 mg to 84 mg of IN ketamine twice weekly over two weeks produced significant improvement in depressive symptoms as compared to placebo beginning after 1 week and continuing through week 9 for the majority of responders. A study by Canuso and colleagues13 demonstrated a significant reduction in depressive symptoms within 4 hours of administration (56 mg to 84 mg insufflated over 15 minutes) and a medium to large effect size, sustained after 25 days; suicidal ideation reduced significantly at 4 hours but not beyond that time. Another recent randomized pilot trial of IN racemic ketamine (the mixture of S- and R-ketamine) was prematurely discontinued due to poor tolerability (including cardiovascular and neurological adverse effects) and highly variable absorption across subjects.14
Modulation of the endogenous opioid system has long been a target of interest in the treatment of mood disorders, but it is limited by safety risks, tolerance, and addiction potential. Recent work has focused on a proprietary combination of the μ-opioid partial agonist/kappa antagonist buprenorphine plus the μ-opioid receptor antagonist samidorphan (ALKS 5461). The potent blockade of μ-opioid receptors in samidorphan, which prevents buprenorphine access to these receptors, effectively renders buprenorphine a selective kappa opiate receptor (KOR) antagonist, which is its putative antidepressant mechanism. After initial favorable Phase II trials, in 2013 the FDA granted ALKS 5461 fast track status for accelerated regulatory review as an antidepressant adjunct. Subsequent randomized trials in treatment-resistant major depression revealed statistically significant differences from placebo on some, but not all, depressive symptom outcome measures and at some, but not all, doses studied.15,16 The FDA initially refused to review the new drug application for ALKS 5461 as an adjunctive therapy for depression because of concerns about bioavailability and lack of evidence, but then reversed its position. ALKS 5461 is currently under regulatory review and a decision regarding its possible approval is expected by early 2019.
Antiinflammatories and immunomodulators
There has been growing recognition of complex interrelationships between depression and inflammation. Some but not all patients with clinically significant depression appear to have elevated serum markers of systemic inflammation, such as high sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines. While causal relationships between depression and inflammation are poorly understood and questions remain whether depression causes inflammation or vice versa, randomized trial data suggest potential antidepressant value of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly the COX-2 inhibitor celecoxib. A pooled meta-analysis of 5447 participants from 10 NSAID trials and 4 cytokine inhibitors (as mono- or add-on therapy for depression) revealed statistically significant advantages over placebo, with small to medium effect sizes, for response (odds ratio = 6.6; 95% confidence interval=2.2-19.4) or remission (odds ratio = 7.9; 95% confidence interval=2.9-21.1)17It has not been established whether adding celecoxib or other NSAIDs to an antidepressant may be more useful only in the setting of elevated serum markers of inflammation. Elsewhere, preliminary studies reveal that inflammatory depressive subtypes (ie, high baseline hs-CRP) may respond better to a tricyclic than SSRI,18 adjunctive L-methylfolate,19 or the tumor necrosis factor (TNF) antagonist infliximab (admnistered IV at 5 mg/kg over 3 doses).20
The antimicrobial minocycline exerts anti-inflammatory and anti-oxidative properties and has been preliminarily studied mostly in small or open/nonrandomized trials. A meta-analysis of 3 randomized controlled trials found an overall significantly greater effect than placebo with a medium to large effect size and good tolerability, although the small number of well-designed studies and samples sizes (total N = 158) limits their generalizability.21
Anticholinergic muscarinic agents
Harkening back to the 1970s hypothesis that depression could reflect cholinergic-adrenergic dysregulation, interest has turned to the possible antidepressant effects of the muscarinic cholinergic antagonist scopolamine. Preliminary studies of intravenous scopolamine dosed at 4 µg/kg in both unipolar and bipolar depression have produced remission rates from 45% to 56% (Cohen’s d ranged from 1.2-3.4) typically within several days of administration, with persistence for 10 to 14 days.22Antimuscarinic adverse effects such as sedation, dry mouth, and blurry vision are common but transient. Neurocognitive measures reaction time during selective attention tasks reveal no significant delays following IV scopolamine infusion.23 Analogous to IV ketamine, questions remain about the optimal number of infusions to minimize relapse as well as the use of nonparenteral formulations.
Brexanolone (SAGE-547), also known as allopregnanolone, is a positive allosteric modulator of GABA-A receptors. It is a progesterone metabolite that exerts neuroprotective, pro-cognitive, and possible antidepressant/anxiolytic properties. Precipitous drops in progesterone and allopregnanolone after childbirth prompted interest in the use of allopregnanolone specifically in postpartum depression. A small (N = 21) initial trial of brexanolone (administered intravenously because of its short half-life and poor oral bioavailability) or placebo for severe postpartum depression yielded a substantial reduction in depressive symptom severity within 60 hours (effect size = 1.2).24 Further data remain pending. SAGE-217 is reformulated brexanolone that has good oral bioavailability, allowing for oral administration, as well as a longer half-life allowing once-a-day dosing. It is currently being studied as an adjunctive agent for treatment resistant depression.
PPAR-γ agonists and incretins
Thiazolidinediones are insulin sensitizers that also demonstrate antidepressant properties in animal studies and appear to possess anti-inflammatory, neuroprotective, antioxidant and anti-excitatory properties. Pioglitazone, a PPAR-γ agonist thiazolidinedione, has been studied versus placebo or metformin in major depression, both as monotherapy and in combination with antidepressants or lithium. A meta-analysis of 4 trials revealed significantly higher remission rates than controls (27% versus 10%, respectively; odds ratio of remission in major depression = 5.9 (95% confidence interval=1.6-22.4), p = .009), with an NNT = 6.25 Even though PPAR-γ agonists can decrease insulin resistance, weight gain can be an undesired adverse effect that is possibly a result of a combination of fat cell proliferation, fluid retention, and increased appetite. Pioglitazone also carries serious adverse risks for congestive heart failure and bladder cancer.
Glucagon-like peptide 1
Another class of antidiabetic drugs known as glucagon-like peptide 1 (GLP-1) agonists mimic the action of insulin (so-called incretins) and are of interest as a potential target for depression. GLP-1 agonists such as liraglutide possess neuroprotective and antiapoptotic properties, and animal studies suggest it has antidepressant and pro-cognitive effects, particularly involving reward and motivation. Human studies have thus far focused more on weight-reducing and possible cognitive benefits of liraglutide more than its potential antidepressant efficacy, but its mechanism represents a promising direction for further study.
This brief overview has focused on emerging novel pharmacotherapies for depression. While the provisional nature of proof-of-concept studies may be encouraging, they are far from definitive. The aforementioned findings are largely preliminary and meant more to prompt larger randomized trials to establish efficacy, safety, and generalizability rather than inspire premature immediate uptake into clinical practice.
Given the focus on neuroprotection and enhanced neuroplasticity as proposed targets of treatment, it would seem remiss not to at least mention the neurobiological impact of depression-specific psychotherapies, mindfulness meditation, and related psychosocial interventions. Psychotherapy is, among other things, a behavioral learning paradigm, presumably rendering alterations in cognitive functions (memory, attention, and decision-making), fear extinction, and emotional processing. Evidence-based psychotherapies for depression have been shown to produce changes in brain network connectivity26 (recapitulating the idea of Hebbian synapses, where “neurons that fire together wire together”) and upregulation of intracellular transcription factors involved in neuronal plasticity.27Enhanced neuroplasticity may represent a common denominator target for effective biological or psychosocial treatments for depression.
Increasingly, drugs we call antidepressants are diversifying to include broader classes of molecules. A more neuroscience-based nomenclature for psychotropic drugs has already been proposed28 and will no doubt invoke more novel drug mechanisms, supplanting older concepts about depression as a chemical imbalance as perspectives continue to evolve about how antidepressants impact neuronal viability and brain microarchitecture.
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4. Zarate CA Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856-864.
5. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134-1142.
6. Wilkinson ST, Ballard ED, Bloch MH, et al. The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis. Am J Psychiatry. 2018;175:150-158.
7. Newport DJ, Carpenter LL, McDonald WM, et al. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015;172:950-966.
8. Mathew SJ, Gueorguieva R, Brandt C, et al. A randomized, double-blind, placebo-controlled, sequential parallel comparison design trial of adjunctive riluzole for treatment-resistant major depressive disorder. Neuropsychopharmacol 2017;42: 2567-2574.
9. Duman RS, Li N, Liu RJ, et al. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacol. 2012;62:35-41.
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11. Sanacora G, Frye MA, McDonald W, et al. A consensus statement on the use of ketamine in the treatment of mood disorders. JAMA Psychiatry. 2017;74:399-405.
12. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine adjunctive to oral antidepressant therapy in treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2018;75:139-148.
13. Canuso CM, Singh JB, Fedgchin M, et al. Efficacy and safety of intranasal esketamine for the rapid reduction of symptoms of depression and suicidality in patients at imminent risk for suicide: results of a double-blind, randomized, placebo-controlled study. Am J Psychiatry. April 2018; Epub ahead of print.
14. Gálvez V, Li A, Huggins C, et al. Repeated intranasal ketamine for treatment-resistant depression – the way to go? Results from a pilot randomised controlled trial. J Clin Psychopharmacol. 2018;32:397-407.
15. Ehrich E, Turncliff R, Du Y, et al. Evaluation of opioid modulation in major depressive disorder. Neuropsychopharmacol. 2015;40:1448-1455.
16. Fava M, Memisoglu A, Thase ME, et al. Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. Am J Psychiatry. 2016;173:499-508.
17. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry. 2014;71:1381-1391.
18. Uher R, Tansey KE, Dew T, et al. An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. Am J Psychiatry. 2014;171:1278-1286.
19. Papakostas GI, Shelton RC, Zajecka JM, et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014;75:855-863.
20. Raison CL, Rutheford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.
21. Rosenblat JD, McIntyre RS. Efficacy and tolerability of minocycline for depression: a systematic review and meta-analysis of clinical trials. J Affect Disord. 2018;227:219-225.
22. Drevets WC, Zarate CA Jr, Furey ML. Antidepressant effects of the muscarinic cholinergic antagonist scopolamine: a review. Biol Psychiatry. 2013;73:1156-1163.
23. Furey ML Pietrini P, Haxby JV, et al. Selective effects of cholinergic modulation on task performance during selective attention. Neuropsychopharmacol 2008; 33:913-923.
24. Kanes S, Colquohoun H, Grunduz-Bruce H, et al. Brexanolone (SAGE-547 injection) in post-partum depression: a randomised controlled trial. Lancet. 2017;390:480-489.
25. Colle R, de Larminat D, Rotenberg S, et al. Pioglitazone could induce remission in major depression: a meta-analysis. Neuropsychiatr Dis Treat 2016;13: 9-16.
26.Yang CC, Barrós-Loscertales A, Pinazo D, et al. State and training effects of mindfulness meditation on brain networks reflect neuronal mechanisms of its antidepressant effect. Neural Plast. 2016;2016:9504642.
27. Koch JM, Hinze-Selch D, Stingele K, et al. Changes in CREB phosphorylation and BDNF plasma levels during psychotherapy of depression. Psychother Psychosom. 2009;78:187-192.
28. ECNP Neuroscience Applied. Neuroscience-based Nomenclature. https://www.ecnp.eu/research-innovation/nomenclature.aspx. Accessed June 6, 2018.