Combined Mirtazapine and SSRI Treatment of PTSD: A Placebo-Controlled Trial

• ClinicalTrials.gov Identifier: NCT01178671
• Recruitment Status: Completed
• First Posted: August 10, 2010
• Results First Posted: February 29, 2016
• Last Update Posted: April 8, 2016
• Sponsor: Research Foundation for Mental Hygiene, Inc.
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Franklin Schneier, Research Foundation for Mental Hygiene, Inc.

Tracking Information

• First Submitted Date: July 29, 2010
• First Posted Date: August 10, 2010
• Results First Submitted Date: December 8, 2015
• Results First Posted Date: February 29, 2016
• Last Update Posted Date: April 8, 2016
• Study Start Date: July 2010
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 2, 2016)

• PTSD Severity [ Time Frame: up to 24 weeks ]
  PTSD severity will be measured by the Clinician-Administered Posttraumatic Stress Disorder Scale, from 0 (least severe) to 136 (most severe).
• Time to Discontinuation of Study Treatment [ Time Frame: up to 24 weeks ]

Original Primary Outcome Measures (submitted: August 9, 2010)

• Change in PTSD severity as measured by the Clinician-Administered PTSD Scale [ Time Frame: 12 weeks ]
• Duration of time in treatment [ Time Frame: 24 weeks ]

Current Secondary Outcome Measures (submitted: April 2, 2016)

• Alternative Measure of PTSD Severity [ Time Frame: up to 24 weeks ]
  as measured by the Short Posttraumatic Stress Disorder Rating Interview, which rates severity of PTSD from 0 (least severe) to 32 (most severe)
• PTSD Self-rated Severity [ Time Frame: up to 24 weeks ]
  as measured by the PTSD Checklist which rates severity of PTSD from 17 (least severe) to 85 (most severe).
• Depression Severity [ Time Frame: up to 24 weeks ]
  as measured by the 17-item Hamilton Rating Scale for Depression, which rates severity of depression on a scale from 0 (least depression) to 50 (greatest depression).
• Response Status [ Time Frame: up to 24 weeks ]
  Responders defined by Clinician Administered Posttraumatic Stress Disorder Scale total score decreased by at least 30% compared with baseline and Clinical Global Impression improvement score of =1 or 2 at endpoint
• Remission Status [ Time Frame: up to 24 weeks ]
  Remitter as defined by Clinician Administered Posttraumatic Stress Disorders Scale total score <20 at endpoint
• Adverse Effects [ Time Frame: up to 24 weeks ]
  as assessed by Side Effect Checklist
• Sleep Quality [ Time Frame: up to 24 weeks ]
  as measured by Pittsburgh Sleep Quality Index, which rates severity of impairment in sleep quality from 0 (least impaired) to 21 (most impaired).
• Sexual Functioning [ Time Frame: up to 24 weeks ]
  as measured by Arizona Sexual Experiences Scale, which rates impairment in sexual functioning from 5 (least impaired) to 30 (most impaired).

Original Secondary Outcome Measures (submitted: August 9, 2010)

• Change in PTSD severity as measured by the Short PTSD Rating Interview [ Time Frame: 12 weeks ]
• Change in self-rated PTSD severity as measured by the PTSD Checklist [ Time Frame: 12 weeks ]
• change in depression as measured by the 17-item Hamilton Rating Scale for Depression [ Time Frame: 12 weeks ]
• Response status as defined by decrease on CAPS of at least 30% compared with baseline and Clinical Global Impression improvement score of =1 or 2 [ Time Frame: 12 weeks ]
• Adverse effects as assessed by Side Effect Checklist [ Time Frame: 12 weeks ]
• Change in Sleep Quality as measured by Pittsburgh Sleep Quality Index [ Time Frame: 12 weeks ]
• Change in sexual functioning as measured by Arizona Sexual Experiences Scale [ Time Frame: 12 weeks ]
• Change in PTSD severity as measured by the Clinician Administered PTSD Scale [ Time Frame: 24 weeks ]
• Change in PTSD severity as measured by the Short PTSD Rating Interview [ Time Frame: 24 weeks ]
• self-rated PTSD severity as measured by the PTSD Checklist [ Time Frame: 24 weeks ]
• Depression as measured by the 17-item Hamilton Rating Scale for Depression [ Time Frame: 24 weeks ]
• Response status as defined by decrease on CAPS of at least 30% compared with baseline and Clinical Global Impression improvement score of =1 or 2 [ Time Frame: 24 weeks ]
• Remission status, defined by CAPS <20 at treatment end [ Time Frame: 12 weeks ]
• Remission status, defined by CAPS <20 at treatment end [ Time Frame: 24 weeks ]
• Adverse effects as assessed by Side Effect Checklist [ Time Frame: 24 weeks ]
• Change in Sleep Quality as measured by Pittsburgh Sleep Quality Index [ Time Frame: 24 weeks ]
• Change in sexual functioning as measured by Arizona Sexual Experiences Scale [ Time Frame: 24 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Combined Mirtazapine and SSRI Treatment of PTSD: A Placebo-Controlled Trial
• Official Title: Combined Mirtazapine and Selective Serotonin Reuptake Inhibitor (SSRI) Treatment of Post-traumatic Stress Disorder (PTSD)

Brief Summary

The overall goal of this study is to examine the efficacy of the combination of mirtazapine and sertraline in the treatment of posttraumatic stress disorder (PTSD). Sertraline is FDA-approved for PTSD, but it is often not fully effective. The combination of mirtazapine and serotonin reuptake inhibitors like sertraline has appeared highly effective in a related disorder -- depression.

In this study, sixty patients with chronic PTSD will be randomized to treatment with either sertraline + mirtazapine or sertraline + placebo for 12 weeks. Patients who show at least a minimal response after 12 weeks will continue for another 12 weeks on the same treatment.

Detailed Description

This double-blind randomized controlled trial was conducted from January 2011 to February 2014. To acquire a diverse sample, outpatients were recruited at an academic medical center and at a private mental health clinic with primarily Spanish-speaking patients. A single team of investigators conducted the trial at both settings. Individuals with chronic PTSD were randomly assigned to 24 weeks of double-blind treatment with sertraline plus mirtazapine or sertraline plus placebo. This study was conducted in compliance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and the standards established by an Institutional Review Board and by the National Institutes of Health. Informed consent was obtained from participants after the nature of the procedures was explained.

Participants Participants were adults ages 18-75, referred by clinicians or responding to advertisements. After a preliminary telephone screening, eligibility was determined by clinical interview and confirmed by structured interview with trained raters using the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM-IV Axis I Disorders -- Patient Edition. Participants had a principal Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnosis of chronic PTSD of at least moderate severity (CAPS score ≥50), and English or Spanish fluency. Bilingual clinicians treated and assessed individuals with Spanish language preference. Exclusion criteria were significant suicidal ideation; lifetime psychotic disorder, bipolar disorder, organic mental disorder, or seizure disorder; alcohol or substance use disorder in the past 3 months; unstable medical illness; history of traumatic brain injury of greater than moderate severity; pregnancy or nursing; unwillingness to use contraception (for women of childbearing potential); prior nonresponse to sertraline or combined treatment, or intolerance of sertraline or mirtazapine); and psychotropic medication use during the prior 2 weeks (4 weeks for monoamine oxidase inhibitors or fluoxetine), except that zolpidem for insomnia was allowed up to three times per week during the week prior to randomization; psychotherapy initiated within 3 months before randomization. Concomitant psychotropic medications were not permitted during the study.

Randomization and Blinding Randomization used randomly permuted blocks stratified by patient language preference (English vs. Spanish), implemented by the data manager who had no patient contact. Mirtazapine 15 mg capsules or matching placebo capsules were packaged by a pharmacist with no patient contact. Patients were reminded at each visit with the independent evaluator (IE) to not discuss medication or adverse events, and allocations were concealed from all research personnel throughout each patient's participation.

Treatments A single psychiatrist saw each patient for medication management, with an initial visit of 45 minutes and subsequent 30 minute visits weekly for two weeks, biweekly through week 12, then at 4-week intervals. At each visit the psychiatrist assessed clinical improvement and adverse events. Mirtazapine/placebo was initiated at 30 mg (two capsules) at bedtime for four weeks, after which patients without significant adverse events and with persistent PTSD symptoms had dose increased to a maximum of 45 mg/day. Dose could be decreased for intolerable adverse events, to a minimum of 15mg/day. Sertraline was initiated at 25 mg/day for four days, then increased as tolerated to 50 mg/day for the remainder of Week 1, 100 mg/day for Weeks 2-4, 150 mg/d for Weeks 5-6, and then 200 mg/day. Dosage could be decreased as clinically indicated to a minimum of 50 mg/day. Compliance was assessed with patient diaries and pill counts.

Patients who prematurely discontinued study medication were encouraged to return for all assessments through week 24.

• Study Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Posttraumatic Stress Disorder

Intervention

• Drug: Mirtazapine
  Mirtazapine capsule, flexible dose of 15-45 mg/day for up to 24 weeks
  Other Name: Remeron
• Drug: Sertraline
  Sertraline tablet, flexible dose of 25-200mg/day for up to 24 weeks
  Other Name: Zoloft
• Other: Sugar pill
  Sugar pill capsule, flexible dose of 1-3 per day, for up to 24 weeks
  Other Name: placebo

Study Arms

• Experimental: Sertraline and Mirtazapine
  Flexible dose of both medications for up to 24 weeks
  Interventions:

  • Drug: Mirtazapine
  • Drug: Sertraline
• Active Comparator: Sertraline and Sugar pill
  Sertraline and Sugar pill for up to 24 weeks
  Interventions:

  • Drug: Sertraline
  • Other: Sugar pill

• Publications *: Schneier FR, Campeas R, Carcamo J, Glass A, Lewis-Fernandez R, Neria Y, Sanchez-Lacay A, Vermes D, Wall MM. COMBINED MIRTAZAPINE AND SSRI TREATMENT OF PTSD: A PLACEBO-CONTROLLED TRIAL. Depress Anxiety. 2015 Aug;32(8):570-9. doi: 10.1002/da.22384. Epub 2015 Jun 26.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 20, 2015): 38
• Original Estimated Enrollment (submitted: August 9, 2010): 60
• Actual Study Completion Date: June 2014
• Actual Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Current primary diagnosis of chronic PTSD
• Fluent in English or Spanish

Exclusion Criteria:

• Past or current schizophrenia, schizoaffective disorder, organic mental disorder, bipolar disorder, or antisocial personality disorder.
• Substance abuse of dependence diagnosis in past 3 months
• Suicidal ideation or behavior in past 6 months that poses a significant danger.
• Medical illness that could significant increase risk of sertraline and mirtazapine treatment or assessment of response
• History of traumatic brain injury of greater than mild severity
• History of seizure disorder (except febrile seizure in childhood)
• Currently taking medication which has been effective for patient's PTSD.
• Inability to tolerate or unwillingness to accept a drug-free period prior to beginning the study for certain psychiatric medications.
• History of inability to tolerate sertraline or mirtazapine or inadequate response to an adequate trial of combined treatment.
• Pregnancy, lactation; for women of childbearing potential, not using an effective birth control method.
• Current cognitive-behavioral therapy. Any psychotherapy initiated within 3 months of beginning this study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01178671
• Other Study ID Numbers: R34MH091336( U.S. NIH Grant/Contract ); R34MH091336 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Franklin Schneier, Research Foundation for Mental Hygiene, Inc.
• Study Sponsor: Research Foundation for Mental Hygiene, Inc.
• Collaborators: National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Franklin Schneier, MD; New York State Psychiatric Institute

• PRS Account: Research Foundation for Mental Hygiene, Inc.
• Verification Date: April 2016