Antipsychotic Monotherapy Promising for Military PTSD

Pauline Anderson

July 21, 2016

Monotherapy with the atypical antipsychotic quetiapine (Seroquel, AstraZeneca Pharmaceuticals LP) is effective for the treatment of posttraumatic stress disorder (PTSD) among military veterans, results of a new randomized controlled study show.

"The primary outcome measure, the total CAPS [Clinician-Administered PTSD Scale] score, demonstrated significantly greater improvement in the quetiapine-treated group than in the placebo group," the authors, led by Mark B. Hamner, MD, professor of psychiatry, Medical University of South Carolina, Charleston, write.

The study was published online July 15 in the American Journal of Psychiatry.

Standard Treatment 'Iffy'

By and large, PTSD is treated with antidepressants such as sertraline (Zoloft, Pfizer Inc) and paroxetine (multiple brands), but the efficacy of these medications in the military population is "iffy," Dr Hamner told Medscape Medical News.

Dr Mark Hamner

In addition to depression, many veterans with PTSD have positive symptoms of psychosis, such as hallucinations, which might make them more refractory to treatment, he added.

Quetiapine is approved for the treatment of schizophrenia, bipolar disorder, and bipolar depression. It is a dibenzothiazapine derivative that antagonizes multiple receptors, including serotonin (5HT1A and 5HT2), dopamine (D2), histamine (H1), and adrenergic alpha 1 and alpha 2.

"It could be that this complex pharmacology is beneficial" for such a complex disorder as PTSD, said Dr Hamner.

The study included military service veterans, none of whom were on active duty, with PTSD at two sites.

After a 1-week, single-blind placebo lead-in phase that included 119 patients, nonresponders (those with less than a 30% reduction in CAPS total score) were randomly assigned to receive double-blind oral quetiapine (n = 42) or placebo (n = 38) for 12 weeks.

The mean age of study participants was 52 years. Most were male combat veterans. The treatment group and the placebo group were similar with regard to sex and race.

The mean total baseline CAPS score was also similar in the two groups (75.4 for quetiapine and 70.60 for placebo), although DSM-IV cluster B scores (reexperiencing) were higher in the treatment group.

The study medication was initiated at a dose of 25 mg at bedtime and was gradually titrated to 400 mg daily by the end of week 2, as tolerated. Further medication adjustments were allowed up to a maximum of 800 mg daily and a minimum of 50 mg.

The study excluded the use of antidepressants.

Of the patients in the treatment group, 31% dropped out; 53% of the placebo group discontinued the study.

At the end of the 12-week study, the quetiapine group demonstrated a greater drop in total CAPS scores, the primary outcome (mean, 53.85), than did the placebo group (mean, 65.66). The interaction between treatment and visit was significant (P = .02).

Good Signal

"There was a signal there that was as good as any signal that I've seen" in terms of this type of trial, said Dr Hamner. "From a research standpoint, it did show significant effects."

However, he noted that the patients "still had significant symptom burden at the end of trial," with CAP scores greater than 50. "So these were still very ill veterans."

Although there were too few women in the study to make a statistical comparison, on an individual basis, it appeared that their responses were similar to those of the men, said Dr Hamner.

The treatment group showed greater improvement than the placebo group on many of the secondary endpoints, including the CAPS reexperiencing subscale (P = .0004) and the hyperarousal subscale (P = .007).

However, there was no significant between-group difference on the avoidance/numbing (lack of emotion) subscale (P = .13) or the negative symptoms of the Positive and Negative Syndrome Scale (PANSS) scale.

Although the authors did not specifically analyze nightmares, Dr Hamner noted that the reexperiencing symptoms, which include nightmares, did improve more with quetiapine than with placebo. "We are planning further analyses and will certainly be looking at nightmares specifically," he said.

The lack of improvement in avoidance/numbing or PANSS negative symptoms is "a puzzle," said Dr Hamner. Psychotherapy that includes prolonged exposure therapy and that "encourages people to face triggers in the environment that may precipitate symptoms may be helpful, he added.

"In some ways, our data would support further research looking at combined therapies."

It also may take longer for negative or avoidance symptoms to improve, inasmuch as patients adopt healthier behaviors with improvement in reexperiencing and hyperarousal symptoms, say the authors.

The researchers also documented greater improvement in the treatment group on the Davidson Trauma Scale (P = .03) and on the Clinical Global Impressions Scale severity rating scale.

Improved Depression

The results suggest a greater improvement in depression, as measured by the Hamilton Depression Rating Scale. This, say the authors, is of particular interest because comorbid depression is common in patients with PTSD. No antidepressant medications were used in the study.

A "surprising" study finding was that although there seemed to be a better sleep response in the treatment group by week 4, this was later lost. This finding needs to be further investigated, the researchers note.

It could be that although the drug has a sedating effect at low doses (eg, 25 or 50 mg), at higher doses, it has less of a sleep effect, said Dr Hamner. "It may speak to core effect of this medication on PTSD symptoms that are beyond just sleep effects," he said.

The average quetiapine dose was 258 mg daily. The average dose of placebo was 463 mg daily. That the placebo dose was almost twice that of quetiapine "confirms the significance" of the finding that the treatment significantly improved total CAPS scores, say the authors. It implies "that clinicians continued to titrate the placebo to a higher dose due to lack of efficacy."

No patients dropped out of the quetiapine group because of lack of efficacy. Nine patients dropped out of the placebo group for this reason. "These results are remarkable, given the severity, chronicity, and difficult-to-treat nature of this population," the authors write.

Adverse events were generally mild and were consistent with the known safety profile of quetiapine. The most common side effects in the treatment group were dry mouth, somnolence, and sedation. Nine patients in the treatment group and three in the placebo group dropped out as a result of adverse effects.

There was no weight gain or worsening of diabetes in those who already had diabetes. However, with longer use, quetiapine has been associated with weight gain and metabolic effects, said Dr Hamner, adding that clinicians can monitor for these effects.

Dr Hamner stressed the importance of psychotherapy, which he said is a "cornerstone" of treatment for PTSD. He hopes that a trial can be organized that combines quetiapine with psychotherapy.

Although quetiapine proved effective for military veterans with PTSD, it is unclear whether it would have the same effect on nonmilitary PTSD patients. Dr Hamner pointed out that military veterans "tend to have higher symptom burden than civilian counterparts." The reason for this is unknown.

A take-home message from this study for psychiatrists is that quetiapine may be considered for patients who have failed standard treatments, such as antidepressants and psychotherapy, said Dr Hamner.

Legitimizes Use

Commenting on the findings for Medscape Medical News, Elspeth "Cam" Ritchie, MD, a retired military psychiatrist who now works for the Veterans Administration and who treats veterans with PTSD, shared her views on the study.

"This study is very important," because it helps to shed the pervasive view that soldiers who carry a weapon should not be taking an antipsychotic, said Dr Ritchie.

Clinicians, she said, have been using quetiapine off label to treat PTSD for some time. "This article sort of legitimizes what we have already been doing, because we have seen it work in patients."

The medication is sometimes used at a low dose to treat PTSD patients who experience trauma-induced nightmares, she said.

"We have been using it for nightmares for long time. This new study gives us more scientific evidence that what we have been doing is useful and acceptable."

The side effects of metabolic symptoms and weight gain are "legitimate concerns," but the drug is typically used at 25 mg to 50 mg a day, at at such doses, side effects might be minimal, she said.

Dr Hamner receives research support from Alkermes and Pfizer and has received research grant support or honoraria and/or has served as a consultant for Abbott, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen, Lundbeck, Organon, Otsuka, and Sanofi-Synthlabo. Dr Ritchie has disclosed no relevant financial relationships.

Am J Psychiatry. Published online July 15, 2016. Abstract

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