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Pharmacological interventions

Ziprasidone monotherapy is ineffective for bipolar-associated anxiety Boadie W Dunlop Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, Georgia, USA; [email protected]

WHAT IS ALREADY KNOWN ON THIS TOPIC? Anxiety disorders are common among patients with bipolar disorder. Bipolar patients with anxiety disorders have poorer treatment outcomes, greater numbers of suicide attempts, higher rates of substance abuse and lower quality of life.1 Complicating treatment, standard antianxiety agents, such as antidepressants, may worsen the course of bipolar disorder, and there is conflicting evidence about antipsychotics. Some data support the use of quetiapine2 or olanzapine for the treatment of bipolar anxiety, while one trial found risperidone to be ineffective.3

WHAT NEXT IN RESEARCH? ▸ The negative effect of comorbid anxiety on long-term outcomes in bipolar disorder is very well established, yet little research has examined how bipolar anxiety is best treated.4 Possible future avenues include testing of structured psychotherapies for anxiety, low-dose antidepressants (limited to bipolar II disorder patients), or novel anxiolytics. ▸ The negative long-term effects of benzodiazepines for bipolar anxiety identified in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) trial5 should be prospectively assessed in a randomised trial with active comparator agents.

WHAT DOES THIS PAPER ADD? ▸ Ziprasidone treatment was ineffective compared with placebo in reducing anxiety symptoms. ▸ Ziprasidone was more poorly tolerated and led to significantly higher rates of early termination than placebo.

COULD THESE RESULTS CHANGE YOUR PRACTICES AND WHY? These results will not change my practice. In considering an antipsychotic to target bipolar anxiety, quetiapine and olanzapine have a substantially stronger evidence base for efficacy in anxiety disorders than ziprasidone. Although ziprasidone is safer in terms of adverse metabolic effects, and thus carries a certain appeal, the paucity of efficacy data for ziprasidone for anxiety, combined with the results from the current study, argue against its use for bipolar anxiety.

LIMITATIONS ▸ Generalisability of this study’s results is limited because patients were not on any mood stabiliser at the time of enrolment. Thus, whether ziprasidone added to an ongoing regimen of lithium or valproate would be helpful for anxiety, as was previously demonstrated with quetiapine,2 is unknown. ▸ Blinding was weak in this study, with 100% of the patients assigned to placebo correctly guessing their treatment assignment, which may have affected expectations of response. ▸ Sample size was small, though the observed effect sizes suggest that a larger sample would have been highly unlikely to find a different outcome. ▸ Akathisia, a known side effect of ziprasidone, is often associated with increased feelings of anxiety. The poor outcomes with ziprasidone may have stemmed in part from increased akathisia-related anxiety, but this possibility was not formally evaluated.

Competing interests BWD has received research support from AstraZeneca, Bristol-Myers Squibb, Forest, GlaxoSmithKline, Novartis and Otsuka. doi:10.1136/eb-2014-101894

REFERENCES 1. 2.

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Rakofsky JJ, Dunlop BW. Treating non-specific anxiety and anxiety disorders in patients with bipolar disorder: a review. J Clin Psychiatry 2011;72:81–90. Sheehan DV, Harnett-Sheehan K, Hdalgo RB, et al. Randomized, placebo-controlled trial of quetiapine XR and divalproex ER monotherapies in the treatment of the anxious bipolar patient. J Affect Disord 2013;145:83–94. Sheehan DV, McElroy SL, Harnett-Sheehan K, et al. Randomized, placebo-controlled trial of risperidone for acute treatment of bipolar anxiety. J Affect Disord 2009;115:376–85. Coryell W, Solomon DA, Fiedorowicz JG, et al. Anxiety and outcome in bipolar disorder. Am J Psychiatry 2009;166:1238–43. Perlis RH, Ostacher MJ, Miklowitz DJ, et al. Benzodiazepine use and risk of recurrence in bipolar disorder: a STEP-BD report. J Clin Psychiatry 2010;71:194–200.

Patients/participants Forty-nine adults with bipolar disorder and a co-occurring panic disorder or generalised anxiety disorder. All diagnoses were based on DSM-IV-TR criteria. Participants had to have at least moderately severe anxiety symptoms (defined as a CGI-21 Anxiety score ≥4) and no more than moderately severe bipolar symptoms (defined as CGI-BP score

Ziprasidone monotherapy is ineffective for bipolar-associated anxiety.

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