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Venlafaxine pegged as first-line PTSD therapy: VA/DoD calls it the best-supported option among SNRIs; mirtazapine rises to second-line status.

TUCSON, ARIZ. -- The most recent set of treatment guidelines for posttraumatic stress disorder also are the first ever to boost venlafaxine to first-line status as "strongly recommended" alongside the well-established selective serotonin reuptake inhibitors.

Another milestone in the Veterans Affairs/Department of Defense PTSD treatment guidelines released in late 2010 is that mirtazapine has risen in status to second-line therapy in response to recent mounting evidence of efficacy.

Earlier PTSD treatment guidelines still in place--including the 2007 Australian guidelines, the 2005 British Association for Psychopharmacology guidelines, and the Canadian treatment guidelines--list mirtazapine as third-line therapy to be reserved for seriously treatment-resistant cases. Venlafaxine is generally classified as second- or third-tier therapy in these earlier guidelines, Dr. Gerardo Villarreal noted at meeting.

The new Veterans Affairs /Department of Defense (VA/DoD) evidence-based guidelines strongly recommend that all adults with PTSD be offered pharmacotherapy with a first-line agent. That means either an SSRI, for which the strongest evidence of benefit exists for sertraline, paroxetine, and fluoxetine, or a serotonin norepinephrine reuptake inhibitor (SNRI), among which venlafaxine has the strongest supporting evidence, said Dr. Villarreal, a psychiatrist at the University of New Mexico, Albuquerque, and the New Mexico VA Health Care System.

The guidelines also strongly recommend offering all patients trauma-focused psychotherapy that includes elements of exposure and/or cognitive structuring, or stress inoculation training.

The VA/DoD report advises pursuing monotherapy with one of the recommended medications for at least 8 weeks, provided the drug is tolerated. If at that point there's no improvement, the recommendation is to either increase to the maximum tolerated dose, switch to another recommended drug, or augment with a second agent.

Atypical antipsychotic agents are recommended as add-on therapy; the guidelines note that the strongest evidence is for risperidone. Dr. Villarreal said his personal practice is to reserve the second-generation antipsychotic agents for the most severe cases, including those involving psychosis or severe dissociation, because of the significant metabolic and other side effects accompanying use of these drugs.

Other recommended second-tier medications for PTSD, in addition to mirtazapine and adjunctive atypical antipsychotics, include the tricyclic antidepressants, nefazodone, prazosin when prescribed for sleep problems or nightmares, and monoamine oxidase inhibitors.

The VA/DoD guidelines specifically do not recommend benzodiazepines, tiagabine, guanfacine, valproate, or topiramate. None of these drugs has demonstrated evidence of benefit.

The guidelines panel provided a lengthy list of drugs for which to date there is deemed insufficient evidence to support a treatment recommendation in PTSD: trazodone, atypical antipsychotics as monotherapy, conventional antipsychotics, buspirone, bupropion, nonbenzodiazepine hypnotics, lamotrigine, gabapentin, clonidine, propranolol, and prazosin as monotherapy.

The VA/DoD list of "insufficient evidence" medications is seen as a nod toward the Institute of Medicine (IOM), which in October 2007 released an influential review of the research evidence on PTSD treatments. The report concluded that the strongest evidence of efficacy is for exposure-based therapies, and that there is also some evidence for cognitive restructuring, teaching of coping skills, and eye movement desensitization and reprocessing.

But as for pharmacotherapy, the quality of the studies up to that point was so flawed that the IOM panel concluded that no evidence-based medication exists for the treatment of PTSD.

"I'm told there were some dissenting opinions on the committee, but that was the consensus," Dr. Villarreal commented.

He noted that most of the numerous PTSD treatment guidelines recommend SSRIs as first-line therapy. Indeed, the only two Food and Drug Administration-approved treatments for the disorder are the SSRIs sertraline and paroxetine, although Dr. Villarreal said that in his experience, the efficacy of SSRIs is probably a class effect.

"I would say the SSRIs are helpful, but it's really a modest response, not a dramatic response," he said. "You rarely see remission of symptoms."

That is why the various treatment guidelines list so many second- and third-tier drug options, and also why there are so many ongoing studies evaluating the efficacy of non-SSRIs in PTSD.

Although the VA/DoD guidelines recommend venlafaxine as the best-supported option among the SNRIs, which together with the SSRIs are considered first-line agents, Dr. Villarreal noted that last year saw publication of two highly promising albeit open-label studies of duloxetine in PTSD.

He was lead investigator in one of the studies, in which 20 severely affected military veterans with a mean baseline Clinician-Administered PTSD Scale (CAPS) score of 80 were placed on duloxetine at a mean daily dosage of 81 mg for 12 weeks. Nine were deemed responders based on at least a 20% improvement in CAPS total score. All CAPS subscales improved, including sleep and depression measures.

The really striking thing was the speed of response: Most of the improvement occurred by week 2, he reported.

Five of the 20 patients dropped out of the study, 3 because of side effects, which included diarrhea, constipation, and nausea. Two patients developed tachycardia, which resolved in one with a reduction in the duloxetine dose from 60 to 30 mg/day. The other tachycardic patient dropped out of the study (Psychopharmacol. Bull. 2010;43:26-34).

The other recent duloxetine study was a Yale University naturalistic study involving 21 men with combat-related, refractory PTSD and comorbid major depressive disorder who were placed on duloxetine at 60-120 mg/day.

Twenty patients completed the 8-week trial. They showed significant improvement both in PTSD symptoms, including nightmares, and in major depression symptoms (Pharmacopsychiatry 2010; 43:45-9).

Summing up recent results with other classes of medications, Dr. Villarreal said the findings with anticonvulsants have been disappointing save for one small promising randomized trial of lamotrigine in veterans, which yielded a 50% response rate, twice that of placebo.

Studies of propranolol for the prevention of PTSD in individuals at high risk also have been generally disappointing.

The antiadrenergic agent prazosin is gaining increasing use in PTSD on the strength of several positive studies, including one that showed efficacy comparable to that of quetiapine but with far fewer side effects.

Dr. Villarreal is an investigator in an ongoing clinical trial in which male veterans are titrated fairly quickly to 20 mg/day of prazosin with regular blood pressure monitoring for possible hypotension.

Four years ago, the Department of Veterans Affairs did a survey and found 60% of prescribing of atypical antipsychotic agents were off label--and 42% were for PTSD. The pendulum has swung away since then in response to increased appreciation of the drugs' metabolic and other side effects.

Yet Dr. Villarreal was a coinvestigator in an as-yet unpublished multicenter, randomized, placebo-controlled trial of quetiapine monotherapy for PTSD that he said yielded "very impressive findings."

The study included 80 veterans. Those randomized to quetiapine received a mean daily dosage of 258 mg, with a range of 50-800 mg. They experienced a threefold greater decrease in CAPS scores than placebo-treated controls as well as a significant improvement on the Positive and Negative Syndrome Scale. "It was a very remarkable finding. I've continued to follow these patients, and some of them have continued on quetiapine after the study. In fact, in some patients it has been difficult to try to get them off of it," according to the psychiatrist.

When a member of the audience asked how long to treat patients for PTSD, Dr. Villarreal replied that the number of long-term studies has been few, so the minimum duration of an effective course of therapy really is not known.

But PTSD is a chronic condition, and his severely affected patients essentially are on medications for life.

He said he strongly encourages his patients to get into a program of exposure-based therapy, which he has found to be quite helpful in reducing polypharmacy.

Dr. Villarreal said he had no relevant financial disclosures.

The treatment guidelines strongly recommend that all patients with posttraumatic stress disorder receive trauma-focused psychotherapy in addition to pharmacotherapy with a first-line agent.


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Title Annotation:PSYCHIATRY
Author:Jancin, Bruce
Publication:Internal Medicine News
Date:Apr 1, 2011
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