Ziprasidone Augmentation of Escitalopram for Major Depressive Disorder: Cardiac, Endocrine, Metabolic, and Motoric Effects in a Randomized, Double-Blind, Placebo-Controlled Study.
To examine motoric, cardiovascular, endocrine, and metabolic effects of adjunctive ziprasidone in adults with major depressive disorder (MDD) and prior nonresponse to 8 weeks of open-label escitalopram.



A multicenter, parallel, randomized, double-blind, placebo-controlled trial was conducted at 3 US academic medical centers from July 2008 to October 2013. Recruited were 139 outpatients with persistent DSM-IV MDD following an 8-week open-label trial of escitalopram. Subjects were then randomized to adjunctive ziprasidone (escitalopram + ziprasidone, n = 71) or placebo (escitalopram + placebo, n = 68) for 8 additional weeks. Cardiac and metabolic measures were obtained at each treatment visit. Barnes Akathisia Scale and Abnormal Involuntary Movement Scale (AIMS) scores were also obtained. Changes in outcome measures for each treatment group were compared by independent-samples t test.



A trend toward significance (P = .06) in corrected QT interval (QTc) increase was observed for ziprasidone (mean [SD] = 8.8 [20.2] milliseconds) versus placebo (-0.02 [25.5] milliseconds). Ziprasidone-treated patients had a significantly greater increase in global akathisia scores (P = .01) and significant weight increase (mean [SD] = 3.5 [11.8] kg, or 7.7 [26.1] lb) compared to placebo (1.0 [6.4] kg, or 2.2 [14.1] lb) (P = .03). No significant changes in AIMS scores were observed for either treatment group.



Adjunctive ziprasidone, added to escitalopram, led to a greater weight gain and greater but modest akathisia compared to placebo. The effect of ziprasidone on QTc showed a trend toward significance, and therefore caution should be used in the administration of ziprasidone. While ziprasidone augmentation in patients with MDD appears safe, precautions should be taken in practice, specifically regular monitoring of electrocardiogram, weight, extrapyramidal symptoms, and involuntary movements.



ClinicalTrials.gov identifier: NCT00633399​​.
Massachusetts General Hospital, One Bowdoin Sq, 6th Floor, Boston MA 02114. dmischoulon@partners.org.|Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
David
D
Mischoulon
Department of Psychiatry, University of Alabama, Birmingham, Alabama, USA.
Richard C
RC
Shelton
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
Lee
L
Baer
Department of Psychiatry & Psychology, Mayo Clinic, Rochester, Minnesota, USA.
William V
WV
Bobo
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
Laura
L
Curren
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
Maurizio
M
Fava
Depression Clinical and Research Program, Massachusetts General Hospital, Boston, Massachusetts, USA.
George I
GI
Papakostas
D000293:Adolescent; D000328:Adult; D000368:Aged; D017109:Akathisia, Drug-Induced / Q000209:etiology*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D015283:Citalopram / Q000008:administration & dosage / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects*; D015430:Weight Gain / Q000187:drug effects*; D055815:Young Adult
D014150:Antipsychotic Agents; D015283:Citalopram; D010879:Piperazines; D017367:Selective Serotonin Reuptake Inhibitors; D013844:Thiazoles; C092292:ziprasidone