Use of Antipsychotics in the Treatment of Post-Traumatic Stress Disorder

Abstract

Post-traumatic stress disorder (PTSD) is a severe and disabling psychiatric syndrome. With the advent of selective serotonin reuptake inhibitors (SSRIs), major strides have been made in the realms of pharmacotherapy. The multiplicity of symptom complex includes specific target symptoms, such as intrusiveness, aggression, sleep disturbances, and co-existing psychotic symptoms. Consequently, atypical antipsychotics gradually have been gaining ground in terms of adjunctive utilization. The purpose of this review is to look into the available evidence for their adjunctive use in this chronic disorder.

Introduction

Post-traumatic stress syndrome (PTSD) is a highly prevalent, yet poorly recognized syndrome¹ characterized by intense reaction (fear, horror, and helplessness) to extreme traumatic stressor. The key features include the following:

• Exposure to a traumatic event that is beyond normal experience

• Persistent intrusion of the traumatic scene or symbolic connotation through nightmares, flashbacks, visual or auditory illusions

• Persistent avoidance of situations related to the trauma which may include numbing, patchy amnesia, diminished interest, de-realization and depersonalization phenomena

• Persistent hyperarousal symptoms like hypervigilance, startle reflexes, anger, irritability, and insomnia

• Impairment of psychosocial and occupational spheres of the individual.

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR)² specified the syndrome as acute if symptoms are within three months of the trauma, chronic if symptoms occur between three and six months of the trauma, and delayed if the onset is at least six months after the stressor. While the symptom-complex of PTSD may be found in depression and anxiety disorders, it should also be borne in mind that PTSD coexists significantly with other psychiatric disorders. The National Comorbidity Survey (NCS) showed that 79 percent of women and 88 percent of men with PTSD had at least one other psychiatric diagnosis, and 49 percent of women and 59 percent of men had at least three concurrent diagnoses.³ Combat veterans diagnosed with PTSD and psychosis experience more positive symptoms, such as hallucinations, delusions, and violent thoughts, feelings, and behaviors, than participants with either disorder alone.^4,5 Infrequently, psychotic symptoms may be experienced including auditory, tactile, and visual hallucinations (Table 1). The presence of psychotic symptoms in individuals suffering from PTSD has lead some researchers to advocate the recognition of a variant of PTSD known as PTSD with psychotic features and its subsequent treatment with antipsychotic medication (Table 2).^6,7

Table 1.

Psychotic symptoms that may co-exist with PTSD

• Hallucinations (auditory, visual and tactile)

• Delusions

• Violent thoughts, feelings, and behaviors

Table 2.

Features of PTSD that may be ameliorated by antipsychotic drugs

• Intrusive thoughts

• Explosiveness

• Aggression

• Disturbed sleep patterns

• Flashbacks

The first line pharmacological approach involves the use of the selective serotonin reuptake inhibitors like sertraline (Zoloft) and paroxetene (Paxil). Other approaches include the use of buspirone (Buspar), tricyclic antidepressants like imipramine (Tofranil) and amitryptiline (Elavil), monoamine oxidase inhibitors like phenelzine (Nardil), and anticonvulsants like carbamazepine (Tegretol) and valproic acid (Depakote).⁸ There are a number of reports in which atypical antipsychotics have proved useful in the management of PTSD. While some studies demonstrate improvement in sleep patterns, with decreased frequency of nightmares, others show improvement in the frequency of flashbacks and intrusive thoughts. Some studies also show a global improvement across symptom clusters.⁹ Combat veterans with PTSD have been reported to have problems with impulsiveness, explosiveness, and aggression.¹⁰ These could respond to adjunctive use of traditional antipsychotics with the established line of treatment described above. The purpose of this article is to explore the evidence for the use of antipsychotics in the management of PTSD.

THE QUESTION: Is there Evidence for the Adjunctive Use of Antipsychotics in the Treatment of PTSD?

The Analysis. The primary-source literature was reviewed with use of a Pubmed Internet search (www.pubmed.com). Secondary source review articles and book chapters were also used. Other terms searched were PTSD, combat neurosis, stress disorder, and stress response. We also searched for evidence in abstracts and proceedings from prominent meetings. The type of evidence described in this article range from case reports, retrospective studies, open-labeled designs and randomized controlled clinical trials. The possible limitations and confounders to these were elucidated and recommendation was made based on the strength of the available evidence.

The Evidence

Quetiapine (Seroquel). In 2002, Adityanjee and Schulz¹¹ noted in their review that quetiapine may be a broad-spectrum agent with clinical usefulness in disease states other than schizophrenia. Later that year, Sattar, et al.,¹² described a case of a 49-year-old man whose PTSD symptoms improved on quetiapine. The patient had hitherto not responded to paroxetine. It was the first case published in the English language literature describing improvement in PTSD symptoms after treatment with quetiapine.

In 2003, Sokolski, et al.,¹³ described the effects of adjunctive quetiapine for treatment of refractory symptoms of combat-related PTSD. They restricted their analysis to patients with symptoms that had not responded to adequate therapy with two or more psychotropic medications prior to quetiapine. Results showed that the addition of quetiapine to ongoing therapy resulted in further symptomatic improvements in DSM-IV PTSD criterion B (re-experiencing) for 35 percent, criterion C (avoidance/numbing) for 28 percent, and criterion D (arousal) for 65 percent of study subjects. Low doses of quetiapine (mean=155±130mg) were associated with minimal side effects. The drawback to this study is the retrospective nature and the associated confounding variables.

Hamner, et al.,¹⁴ in 2003 described an open trial of adjunctive quetiapine treatment for patients with PTSD. Their six-week trial involved a starting dose of 25mg of quetiapine at bedtime with subsequent titration upwards based on tolerance and clinical response.

The outcome was measured with the Clinician Administered PTSD Scale (CAPS), Positive and Negative Symptom Scale (PANSS), the Hamilton Rating Scale for Depression, and the Clinical Global Impression Scale. Safety and tolerability evaluations included neurologic ratings, vital signs, and assessment of treatment-emergent side effects. Eighteen of 20 patients enrolled in the study completed six weeks of the open-label treatment. The dose range of quetiapine was 25mg to 300mg daily, with an average of 100±70mg daily. There was significant improvement in CAPS scores, from 89.8±15.7 to 67.5±21.0 (t=4.863, df=18, <0.005), and composite PANSS ratings from baseline to endpoint. General psychopathology (PANSS) and depressive symptoms (HRSD) were also reduced at the six-week end point. There were no serious adverse events and no clinically significant changes in vital signs or neurologic ratings.

Olanzapine (Zyprexa). In 2001, a 10-week pilot study by Butterfield, et al.,¹⁵ found that olanzapine fared no better than placebo in the treatment of PTSD symptoms. The study was double blind and randomized. There were 15 patients, of which 11 completed the study. Considering the methodology, the lack of difference in effect was postulated to be due to actual ineffectiveness of olanzapine or due to small sample size or high placebo response rate in certain forms of PTSD. An open label eight-week study in 2001 by Petty et al.,¹⁶ demonstrated that all PTSD outcome measures improved significantly during treatment. They concluded that olanzapine is useful in alleviating the symptoms of combat-induced PTSD. Jakovljevic, et al.,¹⁷ described a series of case reports whereby olanzapine augmentation improved treatment-resistant nightmares and insomnia in patients with combat-related PTSD. In a double-blind, randomized, placebo-controlled study with 19 SSRI-resistant PTSD patients, Stein, et al.,¹⁸ found that olanzapine augmentation was associated with statistically significantly greater reduction than placebo in specific measures of post-traumatic stress, depressive, and sleep disorder symptoms.

Risperidone (Risperdal). In 1999, Krashim and Oates¹⁹ published a case report where adjunctive use of risperidone ameliorated intrusive thoughts and emotional reactivity experienced by some PTSD patients. In 2000, another study published four case reports, whereby flashbacks improved secondary to the administration of risperidone in patients hospitalized for the treatment of physical trauma.²⁰ An eight-week, double-blind comparison of 0.5mg to 8mg per day of risperidone and placebo on women with PTSD related to childhood physical, sexual, verbal, and emotional abuse, showed that low-dosage risperidone is a safe and effective treatment for intrusive and hyperarousal symptoms.²¹ Despite the design, the authors raised some valid limitations of the study in terms of the small sample size, short duration, and that half of the sample were on other psychiatric medications. Another randomized, double-blind study by Monelly, et al.,²² suggested that low-dose risperidone administration reduces irritability and intrusive thoughts in combat-related PTSD. The dose range was between 0.5mg and 2mg per day of risperidone depending on response. One of the drawbacks to this study is that pre-randomization psychotropic regimens were continued. Bartozokis, et al.,²³ recruited 73 combat veterans with PTSD from a psychosocial treatment program and randomly assigned them to receive risperidone or placebo. Adjunctive risperidone was superior to placebo in all outcome measures including CAPS, Hamilton Anxiety Scale (HAS), Hamilton Depression Scale (HADS), and PANSS. They concluded that risperidone improved the psychiatric symptoms of PTSD even when overt psychosis was absent.

Other atypical antipsychotics. No study has been published yet on the possible effect of ziprasidone (Geodon) and aripiprazole (Abilify) on PTSD symptom clusters. Even though clozapine (Clozaril) is reserved for treatment resistant psychosis, Wheatley and his colleagues²⁴ investigated its usefulness in treatment-resistant abused adolescents detained in a secure environment who presented with chronic PTSD and psychotic symptoms. All participants had received at least two trials of conventional neuroleptic medication prior to starting clozapine. Efficacy was assessed by using single case methodology across six participants employing pre-dependent and post-dependent measures of psychiatric symptoms and behavioral observations. Subjective self-reports were also sought after treatment had been established. Evaluation of the data suggests that four of the participants demonstrated substantial improvements in psychiatric symptoms and behavioral presentation once a therapeutic dose of clozapine had been achieved. Questionnaire responses from five participants indicated that clozapine treatment was associated with a reduction in hallucinatory experiences. The most troubling side effects were those of excessive salivation, dizziness, and weight gain. Even though the findings suggest that clozapine may be effective in decreasing psychiatric symptoms and risk behaviors in traumatized adolescents presenting with psychotic symptoms, this might be a reduction in the intensity of psychotic experiences rather than core PTSD symptoms.

Any evidence for the use of traditional antipsychotics? There is a paucity of evidence for the use of typical antipsychotics in PTSD. In 1981, Hogben, et al.,²⁵ described five patients with traumatic war neurosis who had favorable therapeutic responses to phenelzine sulfate. These patients did not respond to multiple previous therapeutic trials including antipsychotics. In 2003, Manguno-Mire, et al.,²⁶ compared olanzapine with haloperidol in patients with combat PTSD with comorbid psychotic disorder. The mean dosage was 20mg/day for olanzapine and 10mg/day for haloperidol. They found that olanzapine was superior to haloperidol on the reference morbidity scales. The drawback to the study is the small sample size (n=15) and the possible confounder roles for the other medications, which were allowed and included hypnotics and benzodiazepines.

In 2004, Pivac and colleagues²⁷ compared olanzapine (atypical) and fluphenazine (typical) antipsychotics in an open-labeled study of 55 male war veterans with treatment-refractory, combat-related PTSD. The dose range of both medications was within 5mg to 10mg once or twice daily. Patients were evaluated at baseline and after three and six weeks of treatment, using Watson's PTSD scale, PANSS, Clinical Global Impression Severity Scale (CGI-S), Clinical Global Impression Improvement Scale (CGI-I), Patient Global Impression Improvement Scale (PGI-I), and Drug-Induced Extrapyramidal Symptoms Scale (DIEPSS).

To rule out confounders, patients' baseline data (age, duration of combat experience, and scores in all measurement instruments) were compared and found to be similar. However, after three and six weeks of treatment, olanzapine was significantly more efficacious than fluphenazine in reducing symptoms in PANSS (negative, general psychopathology subscale, supplementary items), Watson's PTSD (avoidance, increased arousal) subscales, CGI-S, CGI-I, and PGI-I scale. Both treatments affected similarly the symptoms listed in PANSS positive and Watson's trauma re-experiencing subscales. Also significantly, fluphenazine induced more extrapyramidal symptoms thus making the use of traditional antipsychotics an unattractive proposition.

Aukst-Margetic, et al.,²⁸ conducted a study using mepromazine (Levopromazine), a phenothiazine antipsychotic, to help to reduce sleep problems in patients with PTSD. It was prospective study with 21 in- and outpatients with severe PTSD. All of them had severe combat trauma-content nightmares, which remained persistent despite treatment with various psychoactive medications. The ongoing medications were continued while levopromazine was added adjunctively. Two patients dropped out while two of the remaining 21 did not improve on CAPS measures. However, all the 21 improved sleep prolongation. The limitation to the study is the methodological flaw in terms of small sample size, lack of control, and presence of concomitant medications.

Critique of the Evidence

Using well designed randomized controlled trials as the gold standard of evidence, the logical inference would be that the evidence for the adjunctive use of antipsychotics in PTSD is weak. Many of the studies described above have valid limitations ranging from the study design (case reports or open-labeled studies) to smallness of sample size and inability to remove confounders, such as concomitant use of other psychiatric medications. The studies have also generally focused on combat veterans who admittedly make up a large number of subjects with PTSD, even though the condition is being increasingly diagnosed in people who have experienced more commonplace non-combat–related traumas. It is not known if results from these populations can be validly extrapolated to a civilian population.

Conclusion

Based on the limitations of the studies described, our conclusion is that atypical antipsychotics may be useful in the treatment of PTSD with and without co-occurring psychosis. The side effect profile of traditional antipsychotics comparatively limits their use. When symptoms are very severe and exist with disorganized behavior and marked dissociative symptoms, low-dose atypical antipsychotic medication can be used adjunctively to the standard treatment. They may also be useful when targeted symptoms include explosiveness, aggression, and violent behavior. While we agree that there should be better designed studies, we would recommend that in the interim, clinical judgment should dictate whether or not to augment and which agents to use.