Abstracts: Emerging Therapies in Psychiatry
Ketamine for Rapid Reduction of Suicidal Thoughts in Major Depression: A Midazolam-Controlled Randomized Clinical Trial
Am J Psychiatry 2018; 175:327–335
OBJECTIVE: Pharmacotherapy to rapidly relieve suicidal ideation in depression may reduce suicide risk. Rapid reduction in suicidal thoughts after ketamine treatment has mostly been studied in patients with low levels of suicidal ideation. The authors tested the acute effect of adjunctive subanesthetic intravenous ketamine on clinically significant suicidal ideation in patients with major depressive disorder.
METHOD: In a randomized clinical trial, adults (N=80) with current major depressive disorder and a score≥4 on the Scale for Suicidal Ideation (SSI), of whom 54% (N=43) were taking antidepressant medication, were randomly assigned to receive ketamine or midazolam infusion. The primary outcome measure was SSI score 24 hours after infusion (at day 1).
RESULTS: The reduction in SSI score at day 1 was 4.96 points greater for the ketamine group compared with the midazolam group (95% CI=2.33, 7.59; Cohen's d=0.75). The proportion of responders (defined as having a reduction≥50% in SSI score) at day 1 was 55% for the ketamine group and 30% for the midazolam group (odds ratio=2.85, 95% CI=1.14, 7.15; number needed to treat=4.0). Improvement in the Profile of Mood States depression subscale was greater at day 1 for the ketamine group compared with the midazolam group (estimate=7.65, 95% CI=1.36, 13.94), and this effect mediated 33.6% of ketamine's effect on SSI score. Side effects were short-lived, and clinical improvement was maintained for up to 6 weeks with additional optimized standard pharmacotherapy in an uncontrolled follow-up.
CONCLUSIONS: Adjunctive ketamine demonstrated a greater reduction in clinically significant suicidal ideation in depressed patients within 24 hours compared with midazolam, partially independently of antidepressant effect.
Reprinted with permission from American Psychiatric Association Publishing.
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 2018; 175:620–630
OBJECTIVE: The authors compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of major depression, including suicidality, among individuals at imminent suicide risk.
METHOD: In a double-blind, multicenter, proof-of-concept study, 68 participants were randomly assigned to receive esketamine (84 mg) or placebo twice weekly for 4 weeks, in addition to comprehensive standard-of-care treatment. The primary efficacy endpoint was change in score from baseline to 4 hours after initial dose on the Montgomery-Åsberg Depression Rating Scale (MADRS). Clinician global judgment of suicide risk (from the Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25.
RESULTS: A significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 hours (least-square mean difference=−5.3, SE=2.10; effect size=0.61) and at ?24 hours (least-square mean difference=−7.2, SE=2.85; effect size=0.65), but not at day 25 (least-square mean difference=−4.5, SE=3.14; effect size=0.35). Significantly greater improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 hours (effect size=0.67), but not at 24 hours (effect size=0.35) or at day 25 (effect size=0.29). Between-group reductions in clinician global judgment of suicide risk scores were not statistically different at any time point. The most common adverse events among participants in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.
CONCLUSIONS: These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.
Reprinted with permission from American Psychiatric Association Publishing.
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
OBJECTIVE: Suicide is a public health crisis with limited treatment options. The authors conducted a systematic review and individualparticipant data meta-analysis examining the effects of a single dose of ketamine on suicidal ideation.
METHOD: Individual participant data were obtained from 10 of 11 identified comparison intervention studies that used either saline or midazolam as a control treatment. The analysis included only participants who had suicidal ideation at baseline (N=167). A one-stage, individual participant data, meta-analytic procedure was employed using a mixed-effects, multilevel, general linear model. The primary outcome measures were the suicide items from clinician-administered (the Montgomery-Åsberg Depression Rating Scale [MADRS] or the Hamilton Depression Rating Scale [HAM-D]) and self-report scales (the Quick Inventory of Depressive Symptomatology-Self Report [QIDS-SR] or the Beck Depression Inventory [BDI]), obtained for up to 1 week after ketamine administration.
RESULTS: Ketamine rapidly (within 1 day) reduced suicidal ideation significantly on both the clinician-administered and self-report outcome measures. Effect sizes were moderate to large (Cohen's d=0.48–0.85) at all time points after dosing. A sensitivity analysis demonstrated that compared with control treatments, ketamine had significant benefits on the individual suicide items of the MADRS, the HAM-D, and the QIDS-SR but not the BDI. Ketamine's effect on suicidal ideation remained significant after adjusting for concurrent changes in severity of depressive symptoms.
CONCLUSIONS: Ketamine rapidly reduced suicidal thoughts, within 1 day and for up to 1 week in depressed patients with suicidal ideation. Ketamine's effects on suicidal ideation were partially independent of its effects on mood, although subsequent trials in transdiagnostic samples are required to confirm that ketamine exerts a specific effect on suicidal ideation. Additional research on ketamine's long-term safety and its efficacy in reducing suicide risk is needed before clinical implementation.
Reprinted with permission from American Psychiatric Association Publishing.
Convergent Mechanisms Underlying Rapid Antidepressant Action
CNS Drugs 2018; 32:197–227
Traditional pharmacological treatments for depression have a delayed therapeutic onset, ranging from several weeks to months, and there is a high percentage of individuals who never respond to treatment. In contrast, ketamine produces rapid-onset antidepressant, antisuicidal, and antianhedonic actions following a single administration to patients with depression. Proposed mechanisms of the antidepressant action of ketamine include N-methyl-d-aspartate receptor (NMDAR) modulation, gamma aminobutyric acid (GABA)-ergic interneuron disinhibition, and direct actions of its hydroxynorketamine (HNK) metabolites. Downstream actions include activation of the mechanistic target of rapamycin (mTOR), deactivation of glycogen synthase kinase-3 and eukaryotic elongation factor 2 (eEF2), enhanced brain-derived neurotrophic factor (BDNF) signaling, and activation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors (AMPARs). These putative mechanisms of ketamine action are not mutually exclusive and may complement each other to induce potentiation of excitatory synapses in affective-regulating brain circuits, which results in amelioration of depression symptoms. We review these proposed mechanisms of ketamine action in the context of how such mechanisms are informing the development of novel putative rapid-acting antidepressant drugs. Such drugs that have undergone preclinical, and in some cases clinical, testing include the muscarinic acetylcholine receptor antagonist scopolamine, GluN2B-NMDAR antagonists (i.e. CP-101,606, MK-0657), (2R,6R)-HNK, NMDAR glycine site modulators (i.e. 4-chlorokynurenine, prodrug of the glycineB NMDAR antagonist 7-chlorokynurenic acid), NMDAR agonists [i.e., GLYX-13 (rapastinel)], metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists, GABAA receptor modulators, and drugs acting on various serotonin receptor subtypes. These ongoing studies suggest that the future acute treatment of depression will typically occur within hours, rather than months, of treatment initiation.
Copyright 2018. Reprinted with permission from Springer Nature.
Can Smartphone Mental Health Interventions Reduce Symptoms of Anxiety? A Meta-Analysis of Randomized Controlled Trials
J Affect Disord 2017; 218:15–22
BACKGROUND: Various psychological interventions are effective for reducing symptoms of anxiety when used alone, or as an adjunct to antianxiety medications. Recent studies have further indicated that smartphone-supported psychological interventions may also reduce anxiety, although the role of mobile devices in the treatment and management of anxiety disorders has yet to be established.
METHODS: We conducted a systematic review and meta-analysis of all randomized clinical trials (RCTs) reporting the effects of psychological interventions delivered via smartphone on symptoms of anxiety (subclinical or diagnosed anxiety disorders). A systematic search of major electronic databases conducted in November 2016 identified 9 eligible RCTs, with 1837 participants. Random-effects meta-analyses were used to calculate the standardized mean difference (as Hedges' g) between smartphone interventions and control conditions.
RESULTS: Significantly greater reductions in total anxiety scores were observed from smartphone interventions than control conditions (g=0.325, 95% C.I.=0.17–0.48, p<0.01), with no evidence of publication bias. Effect sizes from smartphone interventions were significantly greater when compared with waitlist/inactive controls (g=0.45, 95% C.I.=0.30–0.61, p<0.01) than active control conditions (g=0.19, 95% C.I.=0.07–0.31, p=0.003).
LIMITATIONS: The extent to which smartphone interventions can match (or exceed) the efficacy of recognized treatments for anxiety has yet to established.
CONCLUSIONS: This meta-analysis shows that psychological interventions delivered via smartphone devices can reduce anxiety. Future research should aim to develop pragmatic methods for implementing smartphone-based support for people with anxiety, while also comparing the efficacy of these interventions to standard face-to-face psychological care.
Copyright 2017. Reprinted with permission from Elsevier.
Investigational Drugs in Recent Clinical Trials for Treatment-Resistant Depression
Expert Rev Neurother 2017; 17:593–609
https://www.tandfonline.com/doi/full/10.1080/14737175.2017.1283217?scroll=top&needAccess=true
The authors describe the medications for treatment-resistant depression (TRD) in phase II/III of clinical development in the EU and USA and provide an opinion on how current treatment can be improved in the near future. Areas covered: Sixty-two trials were identified in US and EU clinical trial registries that included six investigational compounds in recent phase III development and 12 others in recent phase II clinical trials. Glutamatergic agents have been the focus of many studies. A single intravenous dose of the glutamatergic modulator ketamine produces a robust and rapid antidepressant effect in persons with TRD; this effect continues to remain significant for 1 week. This observation was a turning point that opened the way for other, more selective glutamatergic modulators (intranasal esketamine, AVP-786, AVP-923, AV-101, and rapastinel). Of the remaining compounds, monoclonal antibodies open highly innovative therapeutic options, based on new pathophysiological approaches to depression. Expert commentary: Promising new agents are emerging for TRD treatment. Glutamatergic modulators likely represent a very promising alternative to monoaminergic antidepressant monotherapy. We could see the arrival of the first robust and rapid acting antidepressant drug in the near future, which would strongly facilitate the ultimate goal of recovery in persons with TRD.
Synaptic Loss and the Pathophysiology of PTSD: Implications for Ketamine as a Prototype Novel Therapeutic
Curr Psychiatry Rep 2017; 19(10):74
PURPOSE OF REVIEW: Studies of the neurobiology and treatment of PTSD have highlighted many aspects of the pathophysiology of this disorder that might be relevant to treatment. The purpose of this review is to highlight the potential clinical importance of an often-neglected consequence of stress models in animals that may be relevant to PTSD: the stress-related loss of synaptic connectivity.
RECENT FINDINGS: Here, we will briefly review evidence that PTSD might be a “synaptic disconnection syndrome” and highlight the importance of this perspective for the emerging therapeutic application of ketamine as a potential rapid-acting treatment for this disorder that may work, in part, by restoring synaptic connectivity. Synaptic disconnection may contribute to the profile of PTSD symptoms that may be targeted by novel pharmacotherapeutics.
Copyright 2017. Reprinted with permission from Springer Nature.
Digital Cognitive Behavioral Therapy (dCBT) for Insomnia: A State-of-the-Science Review
Curr Sleep Med Rep 2017; 3(2):48–56.
PURPOSE OF REVIEW: Over the past decade, digital solutions have been developed to support the dissemination of Cognitive Behavioral Therapy (CBT). In this paper, we review the evidence for and implications of digital CBT (dCBT) for insomnia.
RECENT FINDINGS: We propose three categories of dCBT, which differ in the amount of clinician time needed, level of automatization, costs, and scalability: dCBT as support, guided dCBT, and fully automated dCBT. Consistent evidence has been published on the effectiveness of dCBT to address insomnia disorder, in a variety of populations, with effects extending into well-being. Important gaps in the literature are identified around moderators and mediators of dCBT, cost-effectiveness, and the implementation of dCBT.
SUMMARY: The evidence base for dCBT is rapidly developing and already suggests that dCBT for insomnia is effective. However, further science and digital innovation is required to realize the full potential of dCBT and address important clinical questions.
Reprinted with permission from the authors; http://creativecommons.org/licenses/by/4.0. No changes have been made to the abstract.
Synaptic Plasticity and Depression: New Insights From Stress and Rapid-Acting Antidepressants
Nat Med 2016; 22:238–249
Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.
Copyright 2016. Reprinted with permission from Springer Nature.
