Predictors of Response to Augmentation With Ziprasidone (Geodon®) in Major Depressive Disorder

Predictors of Response to Augmentation With Ziprasidone (Geodon®) in Major Depressive Disorder : A 13-week, Double-Blind, Placebo-Controlled, Cross-Over Trial

The primary outcome of this study is to determine if predictors of response can select a population of patients with MDD that is effectively treatable by augmentation with ziprasidone.

Major depressive disorder (MDD) is a broad category, including many forms of depressive illness, including those with only a single major depressive episode, those with episodic recurrence with intervening well states, those with chronic depressive/anxious states without intervening euthymia, and those with manic symptoms that do not meet threshold definitions of full mania/hypomania.

In this heterogenous, large diagnostic definition, important groups of patients do not appear to respond well to antidepressants, and, conversely, based on observational studies, may respond well to neuroleptics. These predictors of response have begun to be identified and may serve to better design studies of neuroleptics in depressive illnesses.

Among these predictors of response in MDD are clinical features that are more similar to bipolar illness than unipolar depression. These include a family history of bipolar disorder, antidepressant-induced mania, highly recurrent depressive episodes (>5), atypical depression, early age of onset of depression (< age 20), failure to respond to antidepressants, and antidepressant tolerance (initial response followed by later loss of response).

The investigators propose to use these predictors to pick out patients that are more likely to respond to Geodon for MDD. This will be the first RCT of these predictors of depressive response applied to neuroleptics.

Study Overview

• Status: Completed
• Conditions: Depression; Bipolar Disorder
• Intervention / Treatment: Drug: Sugar pill; Drug: ziprasidone

Detailed Description

This will be a three-site, block randomized (1:1 ratio) double-blind, placebo-controlled prospective cross-over study with 50 subjects. Patients will be randomized to receiving ziprasidone-washout-placebo or placebo- washout-ziprasidone for 13-weeks.

Primary and Secondary and safety outcomes: The primary outcome measure will be change from baseline Montgomery-Asberg Depression Rating Scale (MADRS) score to end of treatment. Safety outcomes will be determined by spontaneously reported adverse events on the case report form.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18-70 years.
2. If female, nonpregnant/nonlactating
3. If a sexually active female of reproductive potential, must be using adequate contraception (i.e., oral contraceptives, barrier protection, or prior tubal ligation)
4. Currently meets DSM-IV criteria for a major depressive episode, non-psychotic.
5. Having at least 3 of the following criteria listed for predictors of depressive response to neuroleptics: a family history of bipolar disorder, antidepressant-induced mania, highly recurrent depressive episodes (>5), atypical depression, early age of onset of depression (< age 20), failure to respond to antidepressants, and antidepressant tolerance (initial response followed by later loss of response). Inadequate response to antidepressants is identified as follows: having a score of ≥14 on the 17-item HAMD or a CGI-S score of ≥ 3 after a retrospective confirmation of an adequate trial of a single antidepressant (defined as a ≥ 6-week trial of acceptable therapeutic dose [≥ 40 mg of fluoxetine, paroxetine or citalopram, 20 mg of escitalopram, 60 mg of duloxetine, 37.5 mg of paroxetine CR, 150 mg of sertraline, 100 mg of fluvoxamine, 225 mg of venlafaxine XR, 30 mg of mirtazapine, 300 mg of bupropion, 75 mg of nortriptyline, 20 mg of protriptyline, 100 mg of amitriptyline or imipramine)

Exclusion Criteria:

1. Bipolar depression
2. Sensitivity to or failure to respond to ziprasidone by history or ziprasidone use in previous 3 months
3. Active substance abuse or dependence in the previous 3 month
4. Psychotic disorders
5. Serious suicidality as evidenced by score of 3 or greater on suicide item of MADRS
6. Medically unstable as judged by study investigators
7. Lack of capacity to provide informed, written, consent to investigators
8. Previous diagnosed cardiac arrhythmias

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sugar pill; Patients are randomized to a sugar pill (placebo), added to their current medications.	Drug: Sugar pill; The once-daily total daily dose will be 80-160 mg/d of the sugar pill. Dosing will begin at 20 mg BID with an escalation strategy based on target symptoms and tolerability, with a target dose range of 80-160 mg/d. Dose escalations will occur by increments of 20-40 mg weekly.; Other Names: Placebo
Active Comparator: Ziprasidone; Patients are randomized to ziprasidone, added to their current medications.	Drug: ziprasidone; Ziprasidone will be administered as a pill. The once-daily total daily dose will be 80-160 mg/d of ziprasidone. Dosing will begin at 20 mg BID with an escalation strategy based on target symptoms and tolerability, with a target dose range of 80-160 mg/d. Dose escalations will occur by increments of 20-40 mg weekly.; Other Names: Geodon

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MADRS Improvement Over 6 Weeks	Montgomery Asberg Depression scale improvement was assessed in two 6 week crossover periods. Minimum score on MADRS is 0, the maximum is 60. Higher scores represent a worse outcome, i.e., greater severity of depressive symptoms. Scores of about 20 and above are generally seen as consistent with being in a full major depressive episode. No subscales were used or combined.	13 weeks (Two 6 week periods plus a one week washout)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictors of Bipolarity to Define the Study Population	The specific bipolarity predictors in patients with MDD were assessed.	13 weeks

Collaborators and Investigators

• Sponsor: Tufts Medical Center
• Collaborators: Duke University; University of South Carolina
• Investigators: Principal Investigator: Nassir Ghaemi, MD MPH, Tufts Medical Center; Principal Investigator: Ashwin Patkar, MD, Duke; Principal Investigator: Meera Narasimhan, MD, University of South Carolina; Principal Investigator: Prakash Masand, MD, Duke

Study record dates

Study Major Dates

• Study Start: February 1, 2010
• Primary Completion (Actual): December 1, 2011
• Study Completion (Actual): December 1, 2011

Study Registration Dates

• First Submitted: July 21, 2010
• First Submitted That Met QC Criteria: July 22, 2010
• First Posted (Estimate): July 23, 2010

Study Record Updates

• Last Update Posted (Actual): February 24, 2017
• Last Update Submitted That Met QC Criteria: February 21, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Depression; Bipolar Disorder; MDD; Major Depressive Disorder; BD; Major Depressive Disorder with Bipolar features
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Pathologic Processes; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Disease; Bipolar Disorder; Depressive Disorder, Major; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Agents; Dopamine Agents; Serotonin Antagonists; Dopamine Antagonists; Ziprasidone
• Other Study ID Numbers: 9238

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No