Combined Mirtazapine and SSRI Treatment of PTSD: A Placebo-Controlled Trial
Condition: Posttraumatic Stress Disorder
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Interventional
Phase: Phase 4

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.
    

Intervention name(s): Mirtazapine; Sertraline; Sugar pill
Intervention type(s): Drug; Drug; Other
Intervention description(s): Mirtazapine capsule, flexible dose of 15-45 mg/day for up to 24 weeks; Sertraline tablet, flexible dose of 25-200mg/day for up to 24 weeks; Sugar pill capsule, flexible dose of 1-3 per day, for up to 24 weeks
Other intervention name(s): Remeron; Zoloft; placebo
Intervention MeSH terms: Mirtazapine; Sertraline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: PTSD; trauma; anxiety disorder; medication; sertraline; mirtazapine; pharmacotherapy