Quetiapine for treatment of refractory symptoms of combat-related post-traumatic stress disorder

Military Medicine, Jun 2003 by Sokolski, Kenneth N, Denson, Thomas F, Lee, Robert T, Reist, Christopher

To assess the effects of adjunctive quetiapine for treatment of refractory symptoms of combat-related post-traumatic stress disorder (PTSD), charts of Vietnam veterans with war-connected PTSD who had been prescribed quetiapine were reviewed. Only patients with symptoms that had not responded to adequate therapy with two or more psychotropic medications prior to quetiapine treatment were analyzed. Addition of quetiapine to ongoing therapy resulted in further symptomatic improvements in DSM-IV PTSD criterion B (re-experiencing) for 35%, criterion C (avoidance/numbing) for 28%, and criterion D (arousal) for 65% of study subjects. Low doses of quetiapine (mean = 155 or - 130 mg) were associated with minimal side effects. These results, although retrospective, suggest that augmentative quetiapine may benefit some refractory symptoms of PTSD in combat veterans.

Introduction

Combat-related post-traumatic stress disorder (PTSD) is among the most refractory psychiatric conditions .1-4 A number of studies have suggested that while some of the symptoms related to combat trauma improve following selective serotonin reuptake inhibitors,5-9 bupropion,10 nefazodone,2 or anticonvulsants,11 these agents often have little impact on the most disturbing symptoms of combat veterans, including insomnia, nightmares, and flashbacks. A double-blind, placebo-controlled study demonstrated efficacy for fluoxetine in civilian PTSD but failed to detect any benefits in patients with war-related trauma.12 Open-label nefazodone reduced intrusive recollections, avoidance, numbing, and hyperarousal in a small number of combat veterans with PTSD but provided limited improvement in sleep disturbance or depression.13,14 Similarly, a noncontrolled study of fluvoxamine improved intrusion, avoidance, and arousal in Vietnam combat veterans but worsened sleep quality and disturbing dreams.15 In an open-label trial of valproate, hyperarousal was decreased in 11 of 14 Vietnam combat veterans, however patients reported increased nightmares and had worsening sleep architecture.16 The onset of beneficial effects in these studies was generally between 4 and 12 weeks.

Frequent flashbacks of traumatic events, withdrawal from others, recurrent awakenings, threatening vivid dreams, nighttime panic attacks, and thrashing movements are among the most disruptive and refractory symptoms experienced by Vietnam combat veterans.3,4,15,17,18 Ongoing lack of sleep often results in worsening depression, paranoia, exhaustion, diminished concentration, withdrawal from others, increased fears after sunset, and an overall decline in the ability to function. The rates of psychosis in such patients may be more than 40%, including ideas of reference and auditory hallucinations related to battle situations.19-21 As a consequence of these persistent symptoms, clinicians often resort to combinations of various agents including antidepressants, mood stabilizers, and antipsychotics in an attempt to provide relief for these patients. Several case studies have reported improvements in treating combat veterans with adjunctive antipsychotic medications including thioridazine,22 risperidone,23-25 olanzapine,26 and clozapine;27 however, these anecdotal reports are limited to a few subjects who were not demonstrated to be refractory to other medications. A recent placebo-controlled study reported improvements on the arousal (D subscale) but not the re-experiencing or avoidance subscales (B and C) of the clinician-administered PTSD scale in Vietnam combat veterans with PTSD who were randomized to adjunctive risperidone.28,29

Although the addition of quetiapine to existing psychotropic regimens has been reported to benefit patients with refractory anxiety or mood disorders,30,31 its use in PTSD has received little attention. Quetiapine is unique among novel antipsychotic agents in that it exhibits potent histaminergic (H^sub 1^) blockade at low doses and similar to other atypicals demonstrates in vivo antagonism of [alpha]^sub 1^-adrenergic and 5-HT^sub 2A^ receptors.32-34 Such a profile may be of particular benefit to combat veterans with PTSD where prominent disturbances in sleep architecture17 as well as adrenergic and serotonergic neurotransmission35 have been reported.

Given the large number of Vietnam combat veterans with PTSD treated in our facility, it was decided to undertake a review of all medication-resistant cases who had been treated with adjunctive quetiapine over an 18-month study period. The object of this retrospective review was to evaluate the effectiveness and tolerabiliry of quetiapine added to ongoing therapy, particularly for the most refractory symptoms of insomnia, nightmares, agitation, and depression. A secondary goal was to characterize the dosage range at which beneficial effects might be noted.

Methods

Subjects

Records were reviewed for all outpatient Vietnam combat veterans diagnosed by DSM-FV36 criteria with PTSD who initiated treatment with quetiapine during an 18-month study period (March 2000-September 2001). Subjects considered for the study were those who had persistent symptoms of PTSD prior to receiving quetiapine, despite treatment for at least 60 days with a minimum of 40 mg (fluoxetine equivalent) of a selective serotonin reuptake inhibitor or an equivalent dose of a tricyclic antidepressant plus one or more of the following medications: sodium divalproex (serum level > or = 75 [mu]g/mL), trazodone (> or =200 mg), mirtazapine (15-30 mg), nefazodone (> or =200 mg), or an antipsychotic (> or =3 mg of risperidone or equivalent). Patients were under the care of 12 outpatient staff psychiatrists at the Veteran Affairs Health Care System (Long Beach, California) who made treatment decisions based on standard psychiatric practice. The decision to prescribe quetiapine was the choice of an individual psychiatrist and not influenced by study objectives.