A 6 Week Randomized Double-Blind Placebo-Controlled Trial of Ziprasidone for the Acute Depressive Mixed State

Abstract

ObjectiveTo examine the efficacy of ziprasidone vs. placebo for the depressive mixed state in patients with bipolar disorder type II or major depressive disorder (MDD).Methods73 patients were randomized in a double-blinded, placebo-controlled study to ziprasidone (40-160 mg/d) or placebo for 6 weeks. They met DSM-IV criteria for a major depressive episode (MDE), while also meeting 2 or 3 (but not more nor less) DSM-IV manic criteria. They did not meet DSM-IV criteria for a mixed or manic episode. Baseline psychotropic drugs were continued unchanged. The primary endpoint measured was Montgomery- Åsberg Depression Rating Scale (MADRS) scores over time. The mean dose of ziprasidone was 129.7±45.3 mg/day and 126.1±47.1 mg/day for placebo.ResultsThe primary outcome analysis indicated efficacy of ziprasidone versus placebo (p = 0.0038). Efficacy was more pronounced in type II bipolar disorder than in MDD (p = 0.036). Overall ziprasidone was well tolerated, without notable worsening of weight or extrapyramidal symptoms.ConclusionsThere was a statistically significant benefit with ziprasidone versus placebo in this first RCT of any medication for the provisional diagnostic concept of the depressive mixed state.Trial RegistrationClinicaltrials.gov NCT00490542

Treatment of mixed features in bipolar disorder

“…Only 1 study was a primary RCT assessing treatment of depression with mixed features (using ziprasidone) a priori, while the remaining studies were post-hoc analyses assessing the efficacy of lurasidone, olanzapine, and the olanzapine-fluoxetine combination (OFC). [13][14][15][16][17] Three studies assessed the efficacy of treatment of manic/hypomanic episodes with mixed features with 2 post-hoc analyses assessing olanzapine and asenapine for mania with mixed features and 1 RCT assessing adjunctive quetiapine for hypomania with mixed features. [18][19][20] Treatment of mania with mixed features…”

“…13,16,17 One RCT showed antidepressant efficacy for ziprasidone in the acute treatment of a MDE with mixed features in subjects with BD-II or MDD, with a greater antidepressant effect in subjects with BD-II. 14 Taken together, SGAs show great promise for alleviating symptoms of both mania and depression in BD with mixed features. The preliminary efficacy of SGAs in mixed features comports with findings assessing treatments of DSM-IV-TR-defined mixed episodes.…”

“…Of interest, 3 of the studies predated the publication of the DSM-5. [13][14][15] The results of these studies are discussed herein and are summarized in Table 2.…”

“…[9][10][11][12] Given the relative recency of this new nosological entity (May 2013), only a limited number of studies has directly examined the efficacy of treatments for mood states with DSM-5-defined mixed features. [13][14][15][16][17][18][19][20][21][22] Further, to date, only the Florida Medicaid Guidelines have specifically addressed the treatment of mixed features. 23 At the current time, inadequate evidence exists to adequately inform evidencebased treatment guidelines for mixed features in BD, as randomized controlled trials (RCTs) assessing the efficacy of various treatments specifically for BD mood episodes with mixed features have yet to be conducted.…”

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…The third‐line options include monotherapy with divalproex (level 4)258, 459, 461,462, 463, 464, 465, 466 fluoxetine (mainly for patients with pure depression) (level 3)467, 468, 469 tranylcypromine (level 3),278 or ziprasidone (solely for patients with depression and mixed hypomania) (level 3) 470, 471. Adjunctive agomelatine (level 4),472 bupropion (level 4)276 eicosapentaenoic acid (EPA) (level 4),473, 474, 475 N ‐acetylcysteine (level 4),476 pramipexole (level 3),274 or thyroid hormones (level 4)272 may also be considered.…”