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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.

 

ISSUE 21, December 2013 — Guest Commentator: Sanjay J. Mathew, MD, Baylor College of Medicine, Houston, TX

 

 

Luradisone Monotherapy in the Treatment of Bipolar I Depression: A Randomized, Double-Blind, Placebo-Controlled Study

Loebel A, Cucchiaro J, Silva R, et al
Am J Psychiatry. 2013 Oct 30. doi:10.1176/appi.ajp.2013.12070984. [Epub ahead of print].


Objective
: The authors evaluated the efficacy and safety of lurasidone in the treatment of patients with major depressive episodes associated with bipolar I disorder.

Methods:
• Patients were randomly assigned to double-blind treatment with lurasidone 20–60 mg/day (n=166), 80–120 mg/day (n=169), or placebo (n=170) for 6 weeks.
• Primary endpoint was change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS).
• Secondary endpoint was depression severity score on the Clinical Global Impressions scale for bipolar illness (CGI-BP).

Results: Lurasidone treatment significantly reduced mean MADRS total scores at week 6 for both treatment groups compared with placebo (Table). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores for both treatment groups compared with placebo. Both lurasidone groups also experienced significant improvements compared with placebo in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were similar in all groups. The most frequent adverse events associated with lurasidone were nausea, headache, akathisia, and somnolence. Minimal changes in weight, lipids, and measures of glycemic control were observed with lurasidone.


 Outcomes


Lurasidone 20–60 mg/day


Lurasidone 80–120 mg/day

 

Placebo

Reduction in MADRS total scores

-15.4; effect size 0.51

-15.4; effect size 0.51

-1.7; effect size 0.50

Reduction in CGI-BP depression severity scores

-1.8; effect size 0.61

-1.7; effect size 0.50

-1.1

Discontinuation rates (due to adverse events)

6.6%

5.9%

6.5%

Conclusion: Monotherapy with lurasidone in the dosage range of 20–120 mg/day significantly reduced depressive symptoms in patients with bipolar I depression. Lurasidone was well tolerated, with few changes in weight or metabolic parameters.

Clinical Commentary
Lurasidone, an atypical antipsychotic, was approved by the FDA for bipolar I depression as monotherapy and as adjunctive therapy with lithium or valproate in July 2013. Two 6-week Phase 3 studies in patients with a depressive episode in bipolar I were recently published: a monotherapy study (the subject of this paper) and an adjunctive study (to lithium or valproate).   Both a low-dose regimen (20–60 mg/day) and a high-dose regimen (80–120 mg) were more effective than placebo. The effect size was moderate, with a number needed to treat for response =5. Tolerability appeared to be very acceptable, with a low drop-out rate, and minimal impact on weight, lipids, and glycemic control. There was a modest dose-related increase in prolactin levels, most notably in female participants. Multiple secondary endpoints found significant benefits in anxiety, quality of life, and self-reported depressive symptoms. Overall, this appears to be a well-conducted study and found a convincing benefit of lurasidone monotherapy for the acute treatment of depression in bipolar I disorder. A limitation was the lack of comparison to quetiapine, which is generally considered the atypical antipsychotic most effective for bipolar depression. Given its putative advantage over quetiapine in metabolic side effects and weight gain, this will be an essential comparative study in order to evaluate the relative position of lurasidone among the available approved options for bipolar depression. Another limitation was the restriction of the study sample to BP I; information on its efficacy in BP II will be required.

 

 

Lanicemine: A Low Trapping NMDA Channel Blocker Produces Sustained Antidepressant Efficacy with Minimal Psychotomimetic Adverse Effects  

Sanacora G, Smith MA, Pathak S, et al
Molecular Psychiatry advance online publication; October 15, 2013; doi:10.1038/mp.2013.130.


Objective
: Ketamine, an N-methyl-D-aspartate receptor (NMDAR) channel blocker, has been found to induce rapid and robust antidepressant-like effects in rodent models and in treatment-refractory depressed patients. However, the marked acute psychological side effects of ketamine complicate the interpretation of both preclinical and clinical data. Moreover, the lack of controlled data demonstrating the ability of ketamine to sustain the antidepressant response with repeated administration leaves the potential clinical utility of this class of drugs in question.

Method: This study utilized quantitative electroencephalography (qEEG) to objectively align doses of a low-trapping NMDA channel blocker, AZD6765 (lanicemine), to that of ketamine.

Results: This study demonstrated the potential for NMDA channel blockers to produce antidepressant efficacy without psychotomimetic and dissociative side effects. Furthermore, using placebo-controlled data, we show that the antidepressant response to NMDA channel blockers can be maintained with repeated and intermittent drug administration.

Conclusion: Together, these data provide a path for the development of novel glutamatergic-based therapeutics for treatment-refractory mood disorders.

Clinical Commentary
The study is the first large placebo-controlled study of repeated intravenous infusions of a NMDA receptor blocker for patients with treatment-resistant major depressive disorder.  Lanicemine is a “low trapping” NMDA receptor channel blocker devoid of many of the psychotomimetic side effects observed with classic NMDA receptor antagonists such as ketamine. The study is important from a broader drug development perspective in that it attempts to use a biomarker—gamma band EEG—to assess target engagement and help guide dose-response. A potential advantage of lanicemine over ketamine is the concept of "low trapping" within the NMDA channel pore. This theoretically preserves use-dependent channel block under normal physiological conditions. The idea is that low trapping will bias NMDA receptor channel block to targeted regions such as cortical interneurons with high tonic activity (in other words, the drug will target the areas most critical for mood while not impacting NMDAR related to side effects and toxicity). Clinically, this translates to less impact on psychological side effects, and in fact the clinical trial study reported very few dissociative symptoms. The drug also appears to have less of an impact on hemodynamics than ketamine.

 

 

Relapse Following Successful Electroconvulsive Therapy for Major Depression: A Meta-Analysis

Jelovac A, Kolshus E, McLoughlin DM, et al
Neuropsychopharmacology. 2013;38(12):2467-2474.


Objective
: High rates of early relapse following electroconvulsive therapy (ECT) are typically reported in the literature. Current treatment guidelines offer little information to clinicians on the optimal nature of maintenance therapy following ECT. The aim of this study was to provide a systematic overview of the existing evidence regarding post-ECT relapse.

Methods:
• A keyword search of electronic databases was performed for studies on relapse rates in responders to an acute course of ECT for a major depressive episode.
• Studies appeared in the peer-reviewed literature before January 2013; meta-analyses were performed where appropriate.
• Thirty-two studies with up to 2 years' duration of follow-up were included.

Results: In modern era studies of continuation pharmacotherapy, more than half of patients relapsed by 12 months following successful initial treatment with ECT, with the majority relapsing within the first 6 months (Table). The 6-month relapse rate was similar in patients treated with continuation ECT. In randomized controlled trials, antidepressant medication halved the risk of relapse compared with placebo in the first 6 months.

Maintenance Post-ECT

Relapse at 6 Months

Relapse at 12 Months

Continuation pharmacotherapy

37.7% (95% CI, 30.7-45.2%)

51.1% (95% CI, 44.7-57.4%)

Continuation ECT

37.2% (95% CI, 23.4-53.5%)

 

Antidepressant

Risk ratio=0.49 (95% CI, 0.39-0.62; P<.0001)

 

Conclusion: Despite continuation therapy, the risk of relapse within the first year following ECT is substantial, with the period of greatest risk being the first 6 months. The largest evidence base for efficacy in post-ECT relapse prevention exists for tricyclic antidepressants. Published evidence is limited or non-existent for commonly used newer antidepressants or popular augmentation strategies. Maintenance of well-being following successful ECT needs to be improved.

Clinical Commentary
There is currently no consensus as to what constitutes the ideal post-ECT relapse prevention strategy. This report is an important meta-analysis of a troubling clinical situation; namely, the substantial rates of relapse following an acute course of ECT. The data suggest that over the first 6 months following successful treatment ECT, up to half of patients relapse, despite continuation medication or continuation ECT. Somewhat surprisingly, we still do not have adequate data regarding the continuation benefit of newer antidepressant medications beyond the tricyclics (most available data is for imipramine and amitriptyline). An important limitation is that the meta-analysis is not able to answer whether continuation ECT or continuation pharmacotherapy is preferred post-ECT response. This report is an urgent call for more research in this critical area.

 

 

Preventing Depressive Relapse and Recurrence in Higher-Risk Cognitive Therapy Responders: A Randomized Trial of Continuation Phase Cognitive Therapy, Fluoxetine, or Matched Pill Placebo

Jarrett RB, Minhajuddin A, Gershenfeld H, et al.
JAMA Psychiatry. 2013;70(11):1152-60. doi: 10.1001/jamapsychiatry.2013.1969.


Objective
: Strategies to improve the course of recurrent major depressive disorder have great public health relevance. To reduce the risk of relapse/recurrence after acute phase cognitive therapy (CT), a continuation phase model of therapy may improve outcomes. This study aimed to test the efficacy of continuation phase CT (C-CT) and fluoxetine for relapse prevention in a pill placebo (PBO)-controlled randomized trial and compare the durability of prophylaxis after discontinuation of treatments.


Methods:

• A sequential, 3-stage design as follows: (1) Acute phase: all patients received 12 weeks of CT; (2) Experimental phase: responders at higher risk were randomized to C-CT, fluoxetine, or PBO for 8 months; and (3) Longitudinal: patients received posttreatment follow-up for 24 months.

• The study was held in two university-based specialty clinics.

• 523 adults with recurrent MDD began acute phase CT; 241 higher-risk responders were randomized and 181 subsequently entered follow-up.

• Cognitive therapy responders at higher risk for relapse were randomized to receive 8 months of C-CT (n=86), fluoxetine (n=86), or PBO (n=69).

• Main outcomes and measures included survival analyses of relapse/recurrence rates, as determined by blinded evaluators using DSM-IV criteria and the Longitudinal Interval Follow-up Evaluation.


Results
: As predicted, the C-CT or fluoxetine groups were significantly less likely to relapse than the PBO group across 8 months. Relapse/recurrence rates for C-CT and fluoxetine were nearly identical during the 8 months of treatment, although C-CT patients were more likely to accept randomization, stayed in treatment longer, and attended more sessions than those in the fluoxetine and PBO groups. Contrary to prediction, relapse/recurrence rates following the discontinuation of C-CT and fluoxetine did not differ.

Conclusions: Relapse risk was reduced by both C-CT and fluoxetine in an enriched randomization sampling only CT responders. The preventive effects of C-CT were not significantly more durable than those of fluoxetine after treatment was stopped, suggesting that some higher-risk patients may require alternate longer-term interventions.

Clinical Commentary
This study is the largest study of relapse prevention after acute phase CT in depression published to date. Patients with MDD who responded to acute phase CT but were at higher risk of relapse or recurrence due to a slow or incomplete remission were randomized to continuation phase fluoxetine, C-CT, or placebo. This report shows for the first time that an antidepressant medication can reduce the risk of relapse or recurrence of depression in patients who initially received and responded to a course of psychotherapy. Somewhat surprisingly, while relapse risk was reduced by both modalities, there were no differences between the active conditions in the durability of response following termination of treatment. 

 

 

Topiramate for the Treatment of Cocaine Addiction: A Randomized Clinical Trial
Johnson BA, Ait-Daoud N, Wang XQ, et al
JAMA Psychiatry. 2013 Oct 16. doi: 10.1001/jamapsychiatry.2013.2295. [Epub ahead of print]

 

Objective: No medication has been established as an efficacious treatment for cocaine dependence. We hypothesized that dual modulation of the mesocorticolimbic dopamine system by topiramate, a glutamate receptor antagonist and γ-aminobutyric acid receptor agonist, would result in efficacious treatment for cocaine dependence compared with placebo. This study aimed to determine the efficacy of topiramate vs placebo as a treatment for cocaine dependence.

Methods:
• This was a double-blind, randomized, placebo-controlled, 12-week trial.
• Participants included 142 cocaine-dependent adults in clinical research facilities at the University of Virginia between November 22, 2005, and July 25, 2011.
• Treatment interventions included topiramate (n=71) or placebo (n=71) in escalating doses from 50 mg/d to the target maintenance dose of 300 mg/d in weeks 6 to 12, combined with weekly cognitive-behavioral treatment.
•  For the efficacy period, weeks 6 to 12, the primary outcome was the weekly difference from baseline in the proportion of cocaine nonuse days; the secondary outcome was urinary cocaine-free weeks, and exploratory outcomes included craving and self- and observer-rated global functioning on the Clinical Global Impression scales.

Results: Using an intent-to-treat analysis, topiramate was more efficacious than placebo at increasing the weekly proportion of cocaine nonuse days, irrespective of whether missing data were or were not imputed conservatively to the baseline value (Table). Topiramate also was associated, significantly more than placebo, with increasing the likelihood of urinary cocaine-free weeks as well as decreasing craving and improving observer-rated global functioning.

Efficacy Outcomes

Topiramate

Placebo

Statistical values

Weekly proportion of cocaine nonuse days
- missing data   imputed to baseline value
- missing data not imputed to baseline value

 

13.3%

8.9%

 

5.3%

3.7%

 

95% CI, 1.4%-14.6%; P=.02

95% CI, 0.2%-10.1%; P=.04

Urinary cocaine-free weeks

16.6%

5.8%

95% CI, 1.24-8.32; P=.02

Conclusion: Topiramate is more efficacious than placebo at increasing the mean weekly proportion of cocaine nonuse days and associated measures of clinical improvement among cocaine-dependent individuals.

Clinical Commentary
There are still no FDA-approved treatments for cocaine addiction. Topiramate, an anticonvulsant medication also approved for migraine prophylaxis, is commonly used off-label in psychiatry for alcohol use disorders and to capitalize on its anorectic properties. While topiramate was significantly more effective than placebo in increasing the weekly proportion of cocaine nonuse days and in increasing the likelihood of urinary cocaine-free weeks, the response rates were modest (although the effect size was 0.48 for nonuse of cocaine) and there was significant attrition during the trial. A slow dose escalation to a maximum of 300 mg may have attenuated potential cognitive side effects, which were greater than placebo but generally transient and non-interfering.

 


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