Recommendations for second-line pharmacotherapy vary widely among recent reviews and treatment guidelines with a second antidepressant most often recommended for initial treatment failures. Despite a large, negative 6-month multicenter RCT of risperidone augmentation of antidepressants, some—but not all—treatment guidelines recommend atypical antipsychotic augmentation when antidepressants fail.11 None recommend atypical antipsychotic monotherapy or typical antipsychotics. Most specifically mention prazosin; one guideline recommends it in conjunction with focused CBT as the best initial treatment, while others recommend it as a second-line treatment.3-5,9
Most experts agree that patients with PTSD and persistent nightmares should not be regarded as treatment-refractory unless they have had an adequate trial of prazosin, which should be a minimum of 10 mg daily at bedtime, with additional daytime dosing in some patients. Prazosin may require careful titration over several months. Anticonvulsants are not supported by strong evidence, although some found the evidence for topiramate more convincing than others.6 I have seen benefit in some patients who have nightmares, although adverse effects are common.
One notable finding—unfortunately unchanged since Hamner and colleagues12 made the same observation in 2004—is that there is a dearth of evidence on lithium in PTSD, including no RCTs. This is unfortunate given associations between PTSD and suicidal behavior, anger dyscontrol, and impulsivity, which are potential targets for long-term lithium therapy. In my experience, both individuals with clear bipolar comorbidity and patients in whom bipolar NOS is more difficult to separate from severe PTSD may benefit.
D-cycloserine has been used as an augmentation strategy to enhance extinction in conjunction with exposure, with largely unimpressive, although complex, results. To date, it has not demonstrated efficacy in treatment-resistant PTSD.
Dunlop and colleagues13 developed the Emory Treatment Resistance Interview for PTSD (E-TRIP). It does not provide an algorithm for next-step treatment but allows the clinician to generate a numerical score for degree of treatment resistance in an individual based on failure of pharmacotherapies and psychotherapies, with RCT data supporting efficacy.
Table 1 addresses some of the complexities in assessing and managing treatment-resistant PTSD. The Case Vignettes also illustrate some of these points. Ms. A’s treatment consisted of psychoeducation about the nature of PTSD followed by prolonged exposure, as well as extensive cognitive-processing therapy that addressed “survivor guilt.” After nearly 2 years, she came to accept her child’s death; recovered from her self-blame; and her depression, hypervigilance, and avoidance improved. Sleep improved with trazodone once her avoidance and hypervigilance responded to exposure. Venlafaxine, 225 mg daily, provided more benefit than SSRIs.
Mr. B required systematic medication changes over 2 years, with a final regimen of 15 mg of prazosin and 30 mg of mirtazapine daily at bedtime plus 300 mg of sertraline and 50 µg of levothyroxine sodium daily (based on exacerbations of comorbid anergic depression correlated with high-normal thyroid-stimulating hormone levels of 3.5 to 4.5 mIU/L from a baseline of 1 to 2.4 mIU/L). With this regimen, nightmares stopped and he slept 7 to 8 hours for the first time in decades. The improvement in sleep and depression permitted in vivo exposure therapy that reduced first avoidance behavior and secondarily anger and hypervigilance. He has remained essentially well now for more than 3 years, even with current doses of 200 mg of sertraline, 15 mg of mirtazapine, and 5 mg of prazosin.
Dr. Koek is Staff Psychiatrist at the Sepulveda Ambulatory Care Center, VA Greater Los Angeles Healthcare System; Director of the Mood Disorders Clinic, UCLA/San Fernando Psychiatry Training Program; Clinical Professor, Department of Psychiatry and Bio-behavioral Sciences at the David Geffen School of Medicine at UCLA in Los Angeles; and Teaching Faculty at the Family Medicine Residency Program, Glendale Adventist Medical Center in Glendale, CA.
The author reports no conflicts of interest concerning the subject matter of this article.
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