Quetiapine Augmentation for Treatment-resistant PTSD

A Placebo-controlled Trial of Adjunctive Quetiapine for Refractory PTSD

The purpose of this study is to compare the response of veterans with PTSD without an optimal response to paroxetine to quetiapine augmentation versus placebo.

Study Overview

• Status: Completed
• Conditions: Stress Disorders, Post-Traumatic; Combat Disorders
• Intervention / Treatment: Drug: Open Label (OL) Paroxetine; Drug: Placebo; Drug: Quetiapine

Detailed Description

This is a two-site study designed to evaluate the efficacy and safety of quetiapine augmentation of paroxetine treatment in veterans with PTSD who have failed to respond to paroxetine treatment.

In Phase I, eligible patients will take open-label paroxetine (up to 60 mg daily) for 8 weeks. Patients who are refractory (less than 30% reduction in CAPS scores or a minimum CAPS score of 50 at week 8) and have PTSD symptoms of at least moderate severity on CGI-S will be eligible for the second phase. In Phase II, patients will continue taking open-label paroxetine and will be randomized to the addition of quetiapine (up to 800 mg daily) or placebo for 8 weeks in a double-blind fashion.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • Birmingham VA Medical Center
    • Tuscaloosa, Alabama, United States, 35404
      • Tuscaloosa VAMC
  • South Carolina
    • Charleston, South Carolina, United States, 29401-5799
      • Ralph H. Johnson

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Veteran age 18 to 75.
• Competent to give informed consent.
• Meeting DSM-IV criteria for PTSD.
• Minimal CAPS score of 50 at baseline.
• If female of childbearing potential, patient must have a negative pregnancy test and, if sexually active, be using a medically approved contraceptive method.

• Patients who have not taken psychiatric medications within 1 week prior to study entry (except fluoxetine [5 weeks])

  • monoamine oxidase inhibitors (MAOIs [4 weeks])
  • depot neuroleptics [4 weeks])
  • or any investigational drug within 30 days prior to study enrollment.

• To be eligible for Phase II

  • patients must be refractory to paroxetine in Phase I, as defined by less than 30% reduction in CAPS scores or a minimum CAPS score of 50 at week 8
  • must have PTSD symptoms at least moderate severity on CGI-S
  • and must have been compliant with study medicine in Phase I, as defined by taking at least 80% of prescribed doses.

Exclusion Criteria:

• History of sensitivity to paroxetine or quetiapine.
• Failure to respond to a prior adequate therapeutic trial i.e. minimum of 8 weeks at maximum tolerated dose of paroxetine (up to 60 mg daily) or quetiapine (up to 800 mg daily).

• Women who are

  • breast-feeding
  • pregnant
  • expect to become pregnant during the course of the study
  • or are sexually active and are not using a medically acceptable method of birth control.

• Presence of clinically significant hepatic

  • cardiovascular
  • or other medical conditions that may prevent safe administration of paroxetine or quetiapine
  • or any other clinically significant unstable medical conditions.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Arm 1: Open Label (OL) Paroxetine; Open-label Paroxetine In Phase I, eligible participants will take open-label (OL) Paroxetine (up to 60 mg) daily for 8 weeks. Participants who are refractory (less than 30% reduction in CAPS scores or a minimum CAPS of 50 at week 8) and have PTSD symptoms of at least moderate severity on CGI-S will be eligible for Phase II.	Drug: Open Label (OL) Paroxetine; Open-label Paroxetine; Other Names: Paxil
Placebo Comparator: Arm 2 OL Paroxetine + DB Placebo; In Phase II, participants will continue taking open label paroxetine and will be randomized to the addition of placebo for 8 weeks in a double-blind (DB) fashion.	Drug: Open Label (OL) Paroxetine; Open-label Paroxetine; Other Names: Paxil; Drug: Placebo; Double-blind placebo taken with OL paroxetine; Other Names: sugar pill
Experimental: Arm 3: OL Paroxetine + DB Quetiapine; In Phase II, participants will continue taking open label paroxetine and will be randomized to the addition of quetiapine (up to 800 mg daily) for 8 weeks in a double blind fashion.	Drug: Open Label (OL) Paroxetine; Open-label Paroxetine; Other Names: Paxil; Drug: Quetiapine; Double-blind quetiapine taken with OL paroxetine; Other Names: Seroquel

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Clinician-Administered PTSD Scale for DSM-IV Total Score.	The Clinician-Administered PTSD Scale for DSM-IV (CAPS) is described in the National Center for PTSD Instruction Manual (November 2000) as a semi-structured clinical interview designed to assess the seventeen symptoms for Post Traumatic Stress Disorder (PTSD) outlined in the DSM-IV, along with five associated features. Ratings are made on a 5 point continuum from the lowest frequency or intensity to the highest. Total CAPS score is a summed score that ranges from 0 to 136 where 0 is asymptomatic and higher scores equal more severe PTSD symptomatology. Also, a change in total CAPS score of 15 points was proposed as clinically significant change.	From baseline (week 8) to endpoint (week 16 or termination)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in CGI-I	Clinical Global Impressions Scale and Global Improvement Subscales (CGI-I) is a 7-point scale which was used to assess overall improvement. The scores range from 1 to 7, with 1 indicating very much improved and 7 indicating very much worse.	From Baseline (week 8) to Endpoint (week 16 or termination)
Change in Mean PANSS Total and Subscores From Baseline to Endpoint	Positive and Negative Symptom Scale (PANSS). A 30-item clinician administered rating scale for which positive, negative and general subscales are scored from 30 to 210 with a higher scores indicating greater severity of symptoms.	Baseline (week 8) to Endpoint (week 16 or termination)
Change in Total Mean Hamilton Rating Scale for Depression (HAMD) Scores	Hamilton Rating Scale for Depression (HAMD) was used as a measure of depression. Scoring is based on a 17-item scale. Eight items are scored on a 5 point scale from 0= not present to 4= severe. The scoring is based on the first 17 items. Scores of 0-7 normal, 8-13 is mild depression, 14-18 moderate depression, 19-22 severe depression and 23 and above very severe depression; the maximum score being 52 on the 17-point scale.	From Baseline (week 8) to Endpoint (week 16 or Termination)
Change in Total Mean Davidson Trauma Scale (DTS)	The DTS is a 17-item self-rated scale that measures the frequency and the severity of DSM-IV PTSD symptoms. Items are rated on 5-point frequency (0 = "not at all" to 4 = "every day") and severity scales (0 = "not at all distressing" to 4 = "extremely distressing"). The DTS yields a frequency score (ranging from 0 to 68), severity score (ranging from 0 to 68), and total score (ranging from 0 to 136). A higher score indicates higher frequency and severity. It can be used to make a preliminary determination about whether the symptoms meet DSM criteria for PTSD. Scores can also be calculated for each of the 3 PTSD symptom clusters (i.e., B, C, and D).	From Baseline (week 8) to Endpoint (week 16 or Termination)
Change in Mean Q-LES-Q Score From Baseline to Endpoint.	Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) a self-rated 14-item questionnaire designed to assess the degree of enjoyment and satisfaction of various aspects of daily functioning. Each question is rated on a 5-point scale with scores ranging from "1 = very poor" to "5 = very good". The minimum raw score on the Q-LES-Q-SF is 14, and the maximum score is 70. A lower score indicates worsening and a higher score indicates better quality of life.	From Baseline (week 8) to Endpoint (week 16 or termination)
Change in Mean Scores of Pittsburgh Sleep Quality Index (PSQI) From Baseline to Endpoint.	The PSQI is one of the most frequently used self-rated sleep questionnaire. Total score ranging from 0 to 21. Higher scores are representing worse sleep quality.	From Baseline (week 8) to Endpoint (week 16)
Change in Mean Sheehan Disability Scale (SDS) Scores From Baseline to Endpoint.	The SDS is a brief 3-item questionnaire that was used as a self-report to assess the degree to which psychiatric symptoms have disrupted the patient's work, family/home responsibilities, and social life. Score ranging from 0 (no impairment) to 30 (most severe).	Baseline (week 8) to Endpoint (week 16 or termination)
Change in Arizona Sexual Experience Scale (ASEX)	The ASEX is a brief 5-item rating scale that assesses five global aspects of sexual dysfunction. Score is 5 and the maximum score is 30. Lower scores indicate more positive sexual experiences.	From Baseline (week 8) to Endpoint (week 16 or termination)

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Collaborators: AstraZeneca
• Investigators: Principal Investigator: Mark B Hamner, MD BS, Ralph H. Johnson VA Medical Center

Publications and helpful links

General Publications

• Weathers FW, Keane TM, Davidson JR. Clinician-administered PTSD scale: a review of the first ten years of research. Depress Anxiety. 2001;13(3):132-56. doi: 10.1002/da.1029.

Helpful Links

• The National Center for PTSD is part of the US Department of Veterans Affairs

Study record dates

Study Major Dates

• Study Start: January 1, 2006
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): May 1, 2009

Study Registration Dates

• First Submitted: February 13, 2006
• First Submitted That Met QC Criteria: February 13, 2006
• First Posted (Estimate): February 15, 2006

Study Record Updates

• Last Update Posted (Actual): October 16, 2019
• Last Update Submitted That Met QC Criteria: September 26, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: Stress Disorders, Post-Traumatic; Treatment resistant; Atypical Antipsychotics; Quetiapine; Paroxetine; Treatment refractory; Controlled Trial
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Trauma and Stressor Related Disorders; Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Combat Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Serotonin Uptake Inhibitors; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Paroxetine; Quetiapine Fumarate
• Other Study ID Numbers: CLIN-006-04F

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No