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.
Dr. Gerardo Villarreal
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 the annual psychopharmacology review sponsored by the University of Arizona.
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 in Dr. Villarreal’s 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’s 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.