Abstracts: Psychopharmacology: Evidence and Treatments
A Review of Ketamine in Affective Disorders: Current Evidence of Clinical Efficacy, Limitations of Use, and Pre-Clinical Evidence on Proposed Mechanisms of Action
J Affect Disord 2014; 156:24‒35 (Copyright © 2014, reprinted with permission from Elsevier)
Background: Recent research has seen low-dose ketamine emerge as a novel, rapid-acting antidepressant. Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, leads to effects on the glutamatergic system and abnormalities in this neurotransmitter system are present in depression. This article aims to 1) review the clinical literature on low-dose ketamine as a rapid-acting antidepressant in affective disorders, 2) provide a critical overview of the limitations of ketamine and research attempts to overcome these, 3) discuss the proposed mechanisms of action of ketamine, and 4) point toward future research directions. Methods: The electronic database PubMed, Web of Science, and Science Direct were searched using the keywords: ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, bipolar depression, suicidal ideation, ECT, and mechanism of action. Results: The literature demonstrates evidence supporting a rapid-acting antidepressant effect of low-dose intravenous ketamine in major depressive disorder, in bipolar depression, and in depression with suicidal ideation. There are mixed results as to whether ketamine leads to a reduction in time to remission in patients undergoing ECT. Efforts to unravel ketamine's therapeutic mechanism of action have implicated the mammalian target of rapamycin (mTOR)-dependent synapse formation in the rat prefrontal cortex, eukaryotic elongation factor 2 phosphorylation (p-eEF2) and glycogen synthase kinase (GSK-3). Ketamine's limiting factors are the transient nature of its antidepressant effect and concerns regarding abuse, and research efforts to overcome these are reviewed. Conclusions: Current and future research studies are using ketamine as a promising tool to evaluate the glutamatergic neurotransmitter system to learn more about the pathophysiology of depression and develop more specific rapid-acting antidepressant treatments.
Lurasidone as Adjunctive Therapy With Lithium or Valproate for the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study
Am J Psychiatry 2014; 171:169‒177
Objective: Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. Methods: Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. Results: Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (−17.1 versus –13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (−1.96 versus –1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates because of adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. Conclusions: In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.
Clinical Assessment of Lurasidone Benefit and Risk in the Treatment of Bipolar I Depression Using Number Needed to Treat, Number Needed to Harm, and Likelihood to be Helped or Harmed
J Affect Disord 2014; 155:20‒27 (Copyright © 2014, reprinted with permission from Elsevier)
Background: Prior to recent Food and Drug Administration (FDA) approval of lurasidone for treatment of bipolar depression, there were only two approved treatments for this condition (quetiapine and olanzapine-fluoxetine combination), and these were as likely to provide therapeutic benefit as adverse effects. We assessed the efficacy, safety, and tolerability of lurasidone for major depressive episodes associated with bipolar I disorder, using number needed to treat (NNT, for benefits), number needed to harm (NNH, for harms), and likelihood of being helped or harmed (LHH, ratio of NNH to NNT, for trade-offs between benefits versus harms). Methods: Data were collected from two 6-week multicenter, randomized, double-blind, placebo-controlled, flexibly-dosed acute bipolar I depression studies, one using lurasidone monotherapy at 20–60 mg/day or 80–120 mg/day, and the other using lurasidone 20–120 mg/day adjunctive to lithium or valproate. The NNT or NNH was calculated for lurasidone versus placebo for the following dichotomous outcomes: response [≥50% reduction from baseline on Montgomery Asberg Depression Rating Scale (MADRS) total score]; remission (final MADRS total score ≤12); discontinuation because of an adverse event (AE); weight gain ≥7% from baseline; incidence of spontaneously reported AEs; and incidence of total cholesterol ≥240 mg/dL, low-density lipoprotein cholesterol ≥160 mg/dL, fasting triglycerides ≥200mg/dL, and glucose ≥126 mg/dL post-baseline. Results: NNT versus placebo for response was 5 for lurasidone monotherapy (both dose ranges) and 7 for adjunctive therapy. NNT versus placebo for remission for lurasidone monotherapy was 6 for 20–60 mg/day and 7 for 80–120 mg/day and 7 for adjunctive lurasidone. NNH versus placebo for discontinuation due to an AE for lurasidone monotherapy was 642 for 20–60 mg/day and –181 for 80–120 mg/day, and for adjunctive lurasidone was –54 (negative NNH denotes an advantage for lurasidone). Lurasidone was not associated with any clinically meaningful mean weight or metabolic changes compared with placebo; NNH versus placebo for weight gain ≥7% was 29 for 20–60 mg/day and 5550 for 80–120 mg/day and 42 for adjunctive lurasidone. The three most frequently occurring AEs with the largest difference in incidence for lurasidone versus placebo were nausea, akathisia, and somnolence, with NNH values for lurasidone versus placebo ranging from 11 (nausea with lurasidone monotherapy 80–120 mg/day) to 130 (somnolence with lurasidone monotherapy 20–60 mg/day). LHH was substantially and consistently >1 (indicating benefit being more likely than harm) when contrasting response or remission versus AEs or weight gain. Additional studies, including longer-term and open-label, “real world” data are needed to confirm the results reported here. Conclusions: NNT, NNH, and LHH help quantify relative benefits (efficacy) and harms (side effects), thus, placing lurasidone findings in research studies into clinical perspective. Lurasidone, compared with other treatments approved for bipolar depression, yielded comparable benefits (all had single-digit NNT versus placebo for response or remission), and less risk of harm (double-digit or greater NNHs with lurasidone compared with single-digit NNHs for sedation with quetiapine and for ≥7% weight gain with olanzapine-fluoxetine combination), and thus, a substantially more favorable LHH (> or >>1) with lurasidone monotherapy and adjunctive therapy, compared with quetiapine and olanzapine-fluoxetine combination (LHH<or ∼1).
The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders
Am J Psychiatry 2013; 170:1249‒1262
Objective: The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders. Methods: An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder. Results: There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder. Conclusions: Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
Am J Psychiatry 2013; 170:1134‒1142
Objective: Ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression. Methods: This was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared with an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Results: The ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points [95% confidence interval (CI) 3.20‒12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio 2.18; 95% CI 1.21‒4.14), with response rates of 64% and 28%, respectively. Conclusions: Ketamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
Common Genetic Variation and Antidepressant Efficacy in Major Depressive Disorder: A Meta-Analysis of Three Genome-Wide Pharmacogenetic Studies
Am J Psychiatry 2013; 170:207‒217
Objective: Indirect evidence suggests that common genetic variation contributes to individual differences in antidepressant efficacy among individuals with major depressive disorder, but previous studies may have been underpowered to detect these effects. Methods: A meta-analysis was performed on data from three genome-wide pharmacogenetic studies [the Genome-Based Therapeutic Drugs for Depression (GENDEP) project, the Munich Antidepressant Response Signature (MARS) project, and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study], which included 2,256 individuals of Northern European descent with major depressive disorder, and antidepressant treatment outcomes were prospectively collected. After imputation, 1.2 million single-nucleotide polymorphisms were tested, capturing common variation for association with symptomatic improvement and remission after up to 12 weeks of antidepressant treatment. Results: No individual association met a genome-wide threshold for statistical significance in the primary analyses. A polygenic score derived from a meta-analysis of GENDEP and MARS participants accounted for up to approximately 1.2% of the variance in outcomes in STAR*D, suggesting a weakly concordant signal distributed over many polymorphisms. An analysis restricted to 1,354 individuals treated with citalopram (STAR*D) or escitalopram (GENDEP) identified an intergenic region on chromosome 5 associated with early improvement after 2 weeks of treatment. Conclusions: Despite increased statistical power accorded by meta-analysis, the authors identified no reliable predictors of antidepressant treatment outcome, although they did identify modest, direct evidence that common genetic variation contributes to individual differences in antidepressant response.
Comparative Efficacy and Acceptability of Antimanic Drugs in Acute Mania: A Multiple-Treatments Meta-Analysis
Lancet 2011; 378:1306‒1315 (Copyright © 2011, reprinted with permission from Elsevier)
Background: Conventional meta-analyses have shown inconsistent results for efficacy of pharmacological treatments for acute mania. We did a multiple-treatments meta-analysis, which accounted for both direct and indirect comparisons, to assess the effects of all antimanic drugs. Methods: We systematically reviewed 68 randomized controlled trials (16,073 participants) from Jan. 1, 1980, to Nov. 25, 2010, which compared any of the following pharmacological drugs at therapeutic dose range for the treatment of acute mania in adults: aripiprazole, asenapine, carbamazepine, valproate, gabapentin, haloperidol, lamotrigine, lithium, olanzapine, quetiapine, risperidone, topiramate, and ziprasidone. The main outcomes were the mean change on mania rating scales and the number of patients who dropped out of the allocated treatment at 3 weeks. Analysis was done by intention to treat. Results: Haloperidol [standardized mean difference (SMD) –0.56 (95% CI –0.69 to –0.43)], risperidone [−0.50 (–0.63 to –0.38)], olanzapine [−0.43 (–0.54 to –0.32)], lithium [−0.37 (–0.63 to –0.11)], quetiapine [−0.37 (–0.51 to –0.23)], aripiprazole [−0.37 (–0.51 to –0.23)], carbamazepine [−0.36 (–0.60 to –0.11)], asenapine [−0.30 (–0.53 to –0.07)], valproate [−0.20 (–0.37 to –0.04)], and ziprasidone [−0.20 (–0.37 to –0.03)] were significantly more effective than placebo, whereas gabapentin, lamotrigine, and topiramate were not. Haloperidol had the highest number of significant differences and was significantly more effective than lithium [SMD –0.19 (95% CI –0.36 to –0.01)], quetiapine [−0.19 (–0.37 to 0.01)], aripiprazole [−0.19 (–0.36 to –0.02)], carbamazepine [−0.20 (–0.36 to –0.01)], asenapine [−0.26 (–0.52 to 0.01)], valproate [−0.36 (–0.56 to –0.15)], ziprasidone [–0.36 (–0.56 to –0.15)], lamotrigine [−0.48 (–0.77 to –0.19)], topiramate [−0.63 (–0.84 to –0.43)], and gabapentin [−0.88 (–1.40 to –0.36)]. Risperidone and olanzapine had a very similar profile of comparative efficacy, being more effective than valproate, ziprasidone, lamotrigine, topiramate, and gabapentin. Olanzapine, risperidone, and quetiapine led to significantly fewer discontinuations than did lithium, lamotrigine, placebo, topiramate, and gabapentin. Conclusions: Overall, antipsychotic drugs were significantly more effective than mood stabilizers. Risperidone, olanzapine, and haloperidol should be considered as among the best of the available options for the treatment of manic episodes. These results should be considered in the development of clinical practice guidelines.
Combining Medications to Enhance Depression Outcomes (CO-MED): Acute and Long-Term Outcomes of a Single-Blind Randomized Study
Am J Psychiatry 2011; 168:689‒701
Objective: Two antidepressant medication combinations were compared with selective serotonin reuptake inhibitor monotherapy to determine whether either combination produced a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment. Methods: The single-blind, prospective, randomized trial enrolled 665 outpatients at six primary and nine psychiatric care sites. Participants had at least moderately severe nonpsychotic chronic and/or recurrent major depressive disorder. Escitalopram (up to 20 mg/day) plus placebo, sustained-release bupropion (up to 400 mg/day) plus escitalopram (up to 20 mg/day), or extended-release venlafaxine (up to 300 mg/day) plus mirtazapine (up to 45 mg/day) was delivered (1:1:1 ratio) by using measurement-based care. The primary outcome was remission, defined as ratings of less than 8 and less than 6 on the last two consecutive applications of the 16-item Quick Inventory of Depressive Symptomatology–Self-Report. Secondary outcomes included side effect burden, adverse events, quality of life, functioning, and attrition. Results: Remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks. The remission rates were 38.8% for escitalopram-placebo, 38.9% for bupropion-escitalopram, and 37.7% for venlafaxine-mirtazapine, and the response rates were 51.6%−52.4%. The mean number of worsening adverse events was higher for venlafaxine-mirtazapine (5.7) than for escitalopram-placebo (4.7). At 7 months, remission rates (41.8%−46.6%), response rates (57.4%−59.4%), and most secondary outcomes were not significantly different. Conclusions: Neither medication combination outperformed monotherapy. The combination of extended-release venlafaxine plus mirtazapine may have a greater risk of adverse events.
Atypical Antipsychotic Augmentation in Major Depressive Disorder: A Meta-Analysis of Placebo-Controlled Randomized Trials
Am J Psychiatry 2009; 166:980‒991
Objective: The authors sought to determine by meta-analysis the efficacy and tolerability of adjunctive atypical antipsychotic agents in major depressive disorder. Methods: Searches were conducted of MEDLINE/PubMed (1966 to January 2009), the Cochrane database, abstracts of major psychiatric meetings since 2000, and online trial registries. Manufacturers of atypical antipsychotic agents without online registries were contacted. Trials selected were acute-phase, parallel-group, double-blind controlled trials with random assignment to adjunctive atypical antipsychotic or placebo. Patients had nonpsychotic unipolar major depressive disorder that was resistant to prior antidepressant treatment. Response, remission, and discontinuation rates were either reported or obtained. Data were extracted by one author and checked by the second. Data included study design, number of patients, patient characteristics, methods of establishing treatment resistance, drug doses, duration of the adjunctive trial, depression scale used, response and remission rates, and discontinuation rates for any reason or for adverse events. Results: Sixteen trials with 3,480 patients were pooled using a fixed-effects meta-analysis. Adjunctive atypical antipsychotics were significantly more effective than placebo [response: odds ratio (OR) =1.69, 95% confidence interval (CI)=1.46–1.95, z=7.00, N=16, p <0.00001; remission: OR=2.00, 95% CI=1.69–2.37, z=8.03, N=16, p <0.00001]. Mean ORs did not differ among the atypical agents and were not affected by trial duration or method of establishing treatment resistance. Discontinuation rates for adverse events were higher for atypical agents than for placebo (OR=3.91, 95% CI=2.68–5.72, z=7.05, N=15, p <0.00001). Conclusions: Atypical antipsychotics are effective augmentation agents in major depressive disorder but are associated with an increased risk of discontinuation due to adverse events.
