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

Phase 4

Completed

Conditions: Posttraumatic Stress Disorder

Interventions: Drug: Sertraline
Drug: Mirtazapine
Other: Sugar pill

Registration Number: NCT01178671

Lead Sponsor: Research Foundation for Mental Hygiene, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 38

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sertraline and Sugar pill	Sugar pill	Sertraline and Sugar pill for up to 24 weeks
Sertraline and Sugar pill	Sertraline	Sertraline and Sugar pill for up to 24 weeks
Sertraline and Mirtazapine	Mirtazapine	Flexible dose of both medications for up to 24 weeks
Sertraline and Mirtazapine	Sertraline	Flexible dose of both medications for up to 24 weeks

Primary Outcome Measures

Name	Time	Method
Time to Discontinuation of Study Treatment	up to 24 weeks
PTSD Severity	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).

Secondary Outcome Measures

Name	Time	Method
Adverse Effects	up to 24 weeks	as assessed by Side Effect Checklist
Sleep Quality	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).
PTSD Self-rated Severity	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	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).
Remission Status	up to 24 weeks	Remitter as defined by Clinician Administered Posttraumatic Stress Disorders Scale total score \<20 at endpoint
Alternative Measure of PTSD Severity	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)
Response Status	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
Sexual Functioning	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).