Add-on Antipsychotic Promising for PTSD, Anxiety

Liam Davenport

March 05, 2018

NICE, France — Adding the antipsychotic risperidone (Risperdal, Janssen) to standard antidepressant therapy significantly improves outcomes in patients with posttraumatic stress disorder (PTSD) without causing additional adverse effects, new research suggests.

A meta-analysis of almost 400 patients showed that those who received risperidone as an add-on treatment not only experienced significant improvements in overall and key aspects of PTSD symptoms but also demonstrated significant reductions in anxiety scores compared to those who received placebo.

The drug, which has been known to have anxiolytic properties, improved outcomes despite being given at low doses.

"Our study suggests that the low dose of risperidone may be effective in the adjunctive treatment of PTSD, especially in the area of reexperiencing and hyperarousal," said study investigator Sirijit Suttajit, MD, Chiang Mai University, Thailand.

The findings were presented here at the European Psychiatric Association (EPA) 2018 Congress.

Conflicting Evidence

PTSD is associated with a number of psychiatric comorbidities and significant impairment in psychosocial functioning, Suttajit told conference attendees.

Moreover, up to 47% of PTSD patients fail to respond to treatment, "so we psychiatrists offer them antipsychotic medications, although the evidence is still controversial," she said, citing the risk for adverse effects associated with the drugs and the conflicting evidence of their effectiveness.

Because previous studies have suggested that adjunctive therapy with risperidone in conjunction with antidepressants may be beneficial in PTSD, the investigators systematically reviewed its efficacy and tolerability.

They searched the PubMed, PsychINFO, the Cochrane Central Register of Controlled Trials, the EU Clinical Trials Register, and the ClinicalTrials.gov databases for randomized controlled trials of risperidone vs placebo as an adjunctive treatment in PTSD.

Primary outcomes were changes in scores on the Clinician Administered PTSD Scale and the Patient Checklist for PTSD–Military Version.

Secondary outcomes included early study withdrawal; changes on the Clinical Global Impression–Severity (CGI-S) scale, the Clinical Global Impression–Improvement scale, and the Hamilton Anxiety Rating Scale (HAM-A); and the occurrence of adverse events.

Six studies were included in the meta-analysis, four of which were conducted in combat veterans and one in women only. Among the 387 total patients, most had been diagnosed with chronic PTSD and had received antidepressants and/or benzodiazepines.

The analysis showed that total PTSD scores were significantly lower for the group that received risperidone than for the group that received placebo (mean difference in average scores, -3.71; P = .02).

This difference was driven by significant reductions in reexperiencing scores (mean difference, -2.20; P = .0003) and hyperarousal scores (mean difference, -2.01; P = .002). There were no significant differences in avoidance/numbing scores (P = .50).

The investigators did find a significant difference in favor of risperidone over placebo in CGI-S scores (mean difference, -0.17) and HAM-A scores (mean difference, -1.62).

Importantly, these effects were achieved with an average daily dose of risperidone at the end of the study of just 2.05 to 2.5 mg/day.

There were no significant between-group differences in rates of early withdrawal and adverse events, including sedation, dry mouth, tremor, apathy, and extrapyramidal symptoms.

However, one study reported that the mean prolactin level increased by 26.2 ng/mL with risperidone, whereas it decreased by 1 ng/mL in the placebo group (P < .001).

This meta-analysis "supports the use of risperidone as adjunctive treatment in patients with PTSD," said Suttajit.

"The mechanism of risperidone might be due to the effect on serotonergic and dopaminergic systems, which has been implicated in chronic PTSD in preclinical models of stress response. Moreover, risperidone has affinity for alpha-adrenergic receptors, which has been shown to be dysregulated in PTSD," she added.

Asked by an audience member whether it is possible to determine when and for how long risperidone should be given to patients with PTSD, Suttajit pointed out that because the study was a meta-analysis and not a randomized controlled trial, they were unable to answer this question.

However, she noted that the studies were conducted in patients with chronic PTSD, "so most of them had PTSD for quite a long time, for many years."

"Obvious Hypothesis" Confirmed

Approached for comment, session chair Michel Benoit, MD, PhD, Centre Hospitalier Universitaire de Nice, France, said that the positive findings with risperidone were expected, because it is known to have anxiolytic properties.

Therefore, the study "kind of confirms the intuitive sense that it might well be useful in a condition that's very anxiety dependent," Benoit told Medscape Medical News. "I think it's good to see evidence that confirms what seems like an obvious hypothesis, but obviously, you don't know that without testing it."

However, he said that a notable aspect of the results is that they were largely driven by one large study that identified substantial differences in outcomes between the treatment groups. By contrast, the smaller trials that were included in the meta-analysis were less conclusive.

Benoit added that "trying to get a research methodology that definitively answers the question" is always a problem.

"The reason why it's difficult is because to replicate real-life conditions and real populations is enormously expensive, [and] there's no funding to do that kind of high-quality study," he said.

"The second point is a lot of research on medications is, at least initially, aimed at registering them as products that can be marketed. So it's not actually focused on whether they're useful for patient populations," said Benoit. "It's a commercial focus, rather than a scientific one, although there's an overlap."

He noted that because of this, the follow-up periods of studies are typically too short, or they have very selected populations, which, again, relates to the cost of conducting a definitive study.

"So what you see with this meta-analysis is, in effect, one larger paper and then some smaller papers. And although I've not looked at it myself, I suspect that if you look carefully at the papers, you'd find significant methodological issues with all of them," he said. That does not mean the findings are invalid, "but it just leaves a little bit of doubt.

"Having said that, the overall finding that risperidone may be useful in these patients makes sense, because risperidone has anxiolytic properties, and one should see that," he concluded.

The researchers and Dr Benoit have disclosed no relevant financial relationships.

European Psychiatric Association (EPA) 2018 Congress. Abstract OR0011, presented March 4, 2018.

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