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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 17, August 2013 — Guest Commentator: Terence E. Ketter, MD, Stanford School of Medicine Stanford, CA


Lithium in the Prevention of Suicide in Mood Disorders: Updated Systematic Review and Meta-Analysis

Cipriani A, Hawton K, Stockton S, Geddes JR.
Br Med J. 2013 (ePub).

Objective: To assess whether lithium has a specific preventive effect for suicide and self-harm in people with unipolar and bipolar mood disorders.


  • Systematic review and meta-analysis of randomized controlled trials comparing lithium with placebo or active drugs in long-term treatment of mood disorders.
  • Studies up to January 2013 were utilized.
  • The main outcomes were the number of people who completed suicide, engaged in deliberate self-harm, and died from any cause.

48 randomized controlled trials including 6,674 participants were included in the analysis. Lithium was more effective than placebo in reducing number of suicides and deaths from any cause, but not in preventing deliberate self-harm. In unipolar depression, lithium compared to placebo was associated with a reduced risk of suicide and number of total deaths.

Conclusions: Lithium was effective for reducing risk of suicide in people with mood disorders. Lithium’s antisuicidal effects appear at least in part mediated by reducing mood disorder relapse. However, additional mechanisms, such as reducing aggression and impulsivity, need to be considered.

Clinical Commentary
Psychiatric disorders in general, and mood disorders in particular, are associated with increased suicide risk. Aside from the notable exception of clozapine in schizophrenia, the role of psychotropics in suicide prevention remains to be established. This updated review extends data suggesting lithium’s efficacy in reducing the risk of suicide in people with mood disorders, including unipolar major depressive disorder. These data thus extend support for lithium’s role in the treatment of mood disorders to include a possible specific utility in people at risk for suicide. As such, combining lithium with psychosocial, educational, and means-reduction strategies could enhance efforts to prevent suicide in people with mood disorders.


Lithium Moderate-Dose Use for Bipolar Disorder (LiTMUS): A Randomized Comparative Effectiveness Trial of Optimized Personalized Treatment with and without Tolerable Doses of Lithium

Nierenberg AA, Friedman ES, Bowden CL, et al
Am J Psychiatry. 2013;170(1):102-110.

The authors investigated the comparative effectiveness of tolerable dosages of lithium as part of optimized personalized treatment (OPT).


  • 283 bipolar disorder outpatients were randomized to 6 months of single-blind (rater), flexible, moderate dosages (most often 600 mg/day) of lithium plus OPT or 6 months of OPT alone.
  • The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder–Overall Severity (CGI-BP-OS) and “necessary clinical adjustments” (medication adjustments per month).
  • Sustained remission (CGI-BP-OS score ≤2 for 2 months) and treatment with second-generation antipsychotics were also assessed.
  • The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.

Longer-term (6 months) treatment with lithium plus OPT was most often adequately tolerated, with only 21% of patients discontinuing lithium. However, the authors observed no statistically significant advantage of lithium (mean final serum concentration 0.47 mEq/L) plus OPT on CGI-BP-OS scores, necessary clinical adjustments, or proportion with sustained remission. However, fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).

Conclusions: In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

Clinical Commentary
This study addresses an important issue in the contemporary management of bipolar disorder – namely, the potential role of moderately-dosed lithium in combination with OPT. It is clear from this work that moderately-dosed lithium in combination with OPT had adequate tolerability. However, determining clinical effectiveness (i.e. integrating the efficacy and tolerability implications) of this approach is more complex. Specifically, although use of moderately-dosed lithium combined with OPT failed to yield significant improvements in efficacy outcomes, it did permit approximately 14% less use of second-generation antipsychotics. Thus, moderately-dosed lithium combined with OPT could prove to be a strategy worth exploring for bipolar disorder patients for whom avoiding second-generation antipsychotics is a priority.



Lurasidone Monotherapy for the Treatment of Bipolar I Depression: Results of a 6-Week, Double-Blind, Placebo-Controlled Study

Loebel A, Cucchiaro J, Silva R, et al
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Poster Session II. Bipolar Disorders, 15:138. doi: 10.1111/bdi.12084


Objective: To evaluate the efficacy and safety of lurasidone, flexibly dosed at 20­-60 mg/d or 80-120 mg/d, in the treatment of major depressive episodes in patients with bipolar I disorder without psychotic features.

Methods: 505 subjects with DSM-IV-TR bipolar I depression, with or without rapid cycling, with baseline MADRS score ≥20 were randomized to 6 weeks of once-daily, double-blind treatment with either lurasidone 20-60 mg/d, lurasidone 80-120 mg/d, or placebo.

Results: Lurasidone treatment resulted in significantly greater reduction in MADRS scores at Week 6 endpoint for both lurasidone 20-60 mg/d and lurasidone 80-120 mg/d versus placebo. Both lurasidone groups separated significantly from placebo from week 2 onward. Minimal changes in weight, lipids and measures of glycemic control were observed.


Lurasidone 20-60 mg/day

Lurasidone 80-120 mg/day


Responder rates*




Discontinuation rates due to adverse events
















*MADRS reduction ≥50%.

Conclusions: In this study, monotherapy with lurasidone, flexibly dosed at 20-60 mg/d or 80-120 mg/d, significantly reduced depressive symptoms in patients with bipolar I depression compared to placebo. Tolerability and safety of lurasidone was consistent with results of previous studies in schizophrenia.

Clinical Commentary
These data, along with those of a companion lurasidone adjunctive therapy (added to lithium or valproate) bipolar I depression study (Bipolar Disorders 2013;15(Suppl 1):137-8) were the basis for the recent United States Food and Drug Administration (US FDA) approval of lurasidone monotherapy and adjunctive therapy (added to lithium or valproate) for the treatment of bipolar I depression. This has great clinical significance, as it constitutes the first approval of a new medication for bipolar depression since 2006. Depression is the predominant abnormal mood state in bipolar disorder, and there were previously only two US FDA-approved treatments (olanzapine and fluoxetine combination and quetiapine monotherapy), both of which were similarly likely to yield harm (weight gain and sedation) and benefit (response). The approval of a treatment that is more than twice as likely to yield benefit (response) as harm (akathisia or nausea) provides an important new option for patients with bipolar I depression.



A Double-Blind, Placebo-Controlled, Multicenter Trial of Adjunctive Armodafinil for the Treatment of Major Depression Associated with Bipolar I Disorder

Ketter TA, Calabrese JR, Yang R, Frye MA.
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Poster Session I. Bipolar Disorders, 15:88. doi: 10.1111/bdi.1208


Objective: The objective of this study was to evaluate the efficacy and safety of armodafinil as an adjunctive therapy for major depression associated with bipolar I disorder.


  • Participants consisted of patients 18–65 years of age with bipolar I disorder currently experiencing a major depressive episode while taking 1 or 2 of the following medications: lithium, valproate, olanzapine, aripiprazole, risperidone, lamotrigine, or ziprasidone (only in combination with lithium or valproate).
  • Patients were randomized to armodafinil 150 mg/d, 200 mg/d, or placebo.
  • The primary outcome was the mean change from baseline to week 8 in the 30-item Inventory of Depressive Symptomatology–Clinician-rated (IDS-C30) total score.

433 patients were randomized to placebo, armodafinil 150 mg, or armodafinil 200 mg. Randomization to the 200 mg armodafinil group was discontinued early; data from this group were included in safety analyses only. There was a significantly greater IDS-C30 total score decrease at week 8 for the armodafinil 150 mg/d group compared with placebo.


Placebo (n=199)

Armodafinil 150 mg (n=201)

Armodafinil 200 mg (n=33)

IDS-C30 responders: Week 8

IDS-C30 responders: final visit






Weight gain ≥7%




Discontinuation due to adverse events
















Conclusions: Adjunctive armodafinil 150 mg/d significantly improved depressive symptoms compared with placebo in patients with a major depressive episode associated with bipolar I disorder. Safety data indicated that adjunctive armodafinil 150 mg/d was generally well tolerated.

Clinical Commentary
These data, like those from the above-mentioned lurasidone study, address an important unmet need in the management of bipolar I depression – the need for not only effective, but also well-tolerated, treatments. It is clear that armodafinil has tolerability that is superior to the first two treatments approved for bipolar depression (olanzapine and fluoxetine combination and quetiapine monotherapy). However, the clinical significance of this study depends on this finding being replicated, which is necessary for US FDA approval for bipolar I depression, and for armodafinil to become a substantive new option for patients with bipolar I depression.



Cariprazine Effects on YMRS Items: Results of a Pooled Analysis of 3 Randomized, Double-Blind, Placebo-Controlled Trials in Bipolar Mania

Keck PE, Zukin S, Lu K, Laszlovszky I, Durgam S.
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Poster Session I. Bipolar Disorders, 15:87. doi: 10.1111/bdi.1208

Objective: The second-generation antipsychotic cariprazine is a potent dopamine D3/ D2 receptor partial agonist with preferential binding to dopamine D3 receptors that has demonstrated efficacy in 3 randomized, double-blind, placebo-controlled trials in acute bipolar mania. This pooled analysis evaluated the effects of cariprazine on Young Mania Rating Scale (YMRS) single items to investigate efficacy across mania symptom domains.


  • Data were pooled from 3 cariprazine studies in patients with acute mania or mixed episodes associated with bipolar I disorder.
  • Cariprazine was flexibly dosed (3-12 mg/day) in 2 studies; the third study used a fixed/flexible dose design (3-6 mg/day, 6-12 mg/day).
  • Post hoc pooled analysis evaluated change from baseline to Week 3 in individual items of the YMRS using a mixed-effects model for repeated measures.

A total of 1,037 patients (cariprazine, n=608; placebo, n=429) who received at least 1 dose of study medication and had at least 1 post-baseline YMRS assessment were included in the analysis. In each of the three individual trials, cariprazine showed significant advantage versus placebo on YMRS total score improvement. Moreover, in the pooled analysis, cariprazine was significantly superior to placebo for improvement on all 11 individual YMRS items (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech, language, content, disruptive-aggressive behavior, appearance, and insight).

Conclusions: Cariprazine demonstrated efficacy on all 11 individual YMRS items (elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech, language, content, disruptive-aggressive behavior, appearance, and insight) in this pooled analysis. These results suggest that cariprazine has broad efficacy across symptoms in the treatment of acute mania associated with bipolar I disorder.

Clinical Commentary
These data extend the findings of three studies indicating cariprazine efficacy in acute mania, to indicate a broad spectrum of efficacy with respect to diverse individual symptoms of mania. The demonstrated utility of cariprazine in acute mania has led to the US FDA considering approval of cariprazine for acute mania. Should the US FDA approve cariprazine for this indication, this would have clinical impact in that cariprazine would be a new option for patients with bipolar I disorder with a current manic episode.



Antidepressant Use in Bipolar Disorder: International Society for Bipolar Disorder Task-Force Consensus Report

Vieta E, for the International Society for Bipolar Disorders Task-Force on Antidepressants in Bipolar Disorder.
In: 10th International Conference on Bipolar Disorder; June 13-16, 2013; Miami Beach, FL.
(2013), Symposiums. Bipolar Disorders, 15:12-13. doi: 10.1111/bdi.12079


Objective: The International Society for Bipolar Disorders Task-Force sought to develop consensus recommendations on the use of antidepressants in bipolar disorder.

Methods: The expert Task-Force iteratively developed consensus, using the Delphi method. Initial survey items were based on systematic review of the literature, and subsequent iterative surveys were performed to yield final recommendations.

Results: Evidence of efficacy and safety of antidepressants in bipolar disorder is limited and inconsistent. Well-designed, long-term trials of prophylactic benefits are scant. There is insufficient evidence for treatment benefits with antidepressants combined with mood-stabilizers. There is striking disparity between the very common clinical use of antidepressants in bipolar disorder, and the weak evidence-base to support such use. Risks for mood switches to hypomania, mania, and mixed-states are important concerns. Consensus was achieved for 12 statements regarding the use of antidepressants in bipolar disorder.

Conclusions: Due to data limitations, broad statements were not possible endorsing antidepressants in bipolar disorder. However, selective serotonin reuptake inhibitors (SSRIs) and bupropion may have lower manic switch rates than tricyclic antidepressants (TCAs) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) in adults. The frequency and severity of antidepressant-associated mood elevations appear greater in bipolar I disorder than bipolar II disorder patients. Thus, in bipolar I disorder patients antidepressants should only be used as adjuncts to antimanic medications.

Clinical Commentary
These data confirm a persistent unmet need in bipolar disorder research – namely, the need for definitive studies regarding the role of antidepressants in bipolar disorder. Thus, although antidepressants are very commonly used in patients with bipolar depression (perhaps due to their generally adequate somatic tolerability), evidence of their efficacy and safety (i.e. risk of mood elevation) is limited and inconsistent.


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