Posttraumatic stress disorder (PTSD) is a trauma- and stress-related disorder that causes substantial harm to patients and their families. Though serotonin reuptake inhibitors (SRIs) are effective in reducing PTSD symptoms, most will have an inadequate response to them. This often leads to the addition of other classes of medication (augmentation), such as other types of antidepressants, atypical antipsychotics, or prazosin (an α1 adrenoreceptor antagonist typically used to lower blood pressure). However, these augmenting medications have not been as well studied for use with PTSD, and several have potentially harmful metabolic and cardiovascular side effects. As no trials have directly compared the benefits and risks of these medications in PTSD, patients and providers are left in a challenging position when trying to make treatment decisions.
To use Veterans Health Administration electronic records data to compare mental health and metabolic/cardiovascular outcomes in patients with PTSD taking an SRI who are prescribed 4 augmenting medication categories: (1) atypical antipsychotics, (2) mirtazapine, (3) prazosin, and (4) tricyclic antidepressants. Specifically, our aims were as follows: To compare the impact of augmenting medications on the following mental health outcomes: –. PTSD symptoms (primary outcome; measured with the PTSD Checklist [PCL]). –. Psychiatric hospitalizations and psychiatric emergency department (ED) visits. –. Suicidal ideation (measured through mandatory Veterans Affairs [VA] screens). To compare the impact of augmenting medications on the following metabolic and cardiovascular outcomes: –. Weight (primary outcome). –. Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride levels. –. Blood glucose and hemoglobin A(HbA). –. Blood pressure. –. Incident diagnoses of obesity, dyslipidemia, diabetes, and hypertension. –. Use of medications to treat metabolic risk factors. –. Cardiovascular and cerebrovascular disease events. –. All-cause mortality. To examine variations in the risks and benefits of augmenting medications in specific demographic subgroups: –. Female veterans. –. Iraq and Afghanistan veterans. –. Veterans aged ≥65 years.
We constructed a cohort of 872 324 VA patients who received a diagnosis of PTSD from January 1, 2007-December 31, 2015, and who did not have a comorbid diagnosis of bipolar disorder or a psychotic disorder. We further restricted the sample to those taking an SRI who filled a new prescription for 1 of the 4 groups of augmenting medications for at least 60 days in a period of 120 days. We considered the date of starting this new augmenting medication as time “index date.” We then compared changes in several mental health outcomes from the year before the year following the index date. Our primary mental health outcome was change in PTSD symptoms as measured by the PCL. We also evaluated changes in ED visits and hospitalizations for mental health problems as well as changes in rates of suicidality. For metabolic and cardiovascular outcomes, we evaluated changes in weight, total cholesterol, HbA, glucose, LDL cholesterol, HDL cholesterol, triglycerides, and blood pressure. We also compared rates of incident diagnoses of obesity, diabetes, dyslipidemia, and hypertension, as well as the use of medications to treat these conditions in the postindex year. Finally, we evaluated incident cardiovascular disease events and all-cause mortality in the postindex year. We also examined heterogeneity in these effects by sex, age, and era of military service. To control for potential confounding in this observational design, we adjusted for potentially confounding covariates as well as for propensity score weighting. We conducted numerous sensitivity analyses to test our conclusions.
We found that patients had statistically significant but clinically small improvements in their PTSD symptoms after receiving augmenting medications, and the effect was largely similar across classes (antipsychotics: −0.79 points on the PCL [score range, 17-85]; 95% CI, −1.04 to −0.54 points; mirtazapine: −0.77 points; 95% CI, −1.06 to −0.49 points; prazosin: −1.09 points; 95% CI, −1.28 to −0.91 points; tricyclics: −0.93 points; 95% CI, −1.41 to −0.44). We observed more dramatic reductions in rates of ED visits and hospitalizations for mental health conditions (antipsychotics: −3.15 visits/100 person-years; 95% CI, −3.80 to −2.51 visits/100 person-years; mirtazapine: −2.80 visits/100 person-years; 95% CI, −3.46 to −2.14; prazosin: −2.78 visits/100 person-years; 95% CI, −3.28 to −2.29; tricyclics −1.58 visits/100 person-years; 95% CI, −2.42 to −0.75) and in rates of suicidal ideation (antipsychotics: −2.63%; 95% CI, −3.41% to −1.85%; mirtazapine: −1.87%; 95% CI, −2.72% to −1.02%; prazosin: −2.64%; 95% CI, −3.25% to −2.03%; tricyclics: −1.07%; 95% CI, −2.39% to 0.26%). When we further evaluated the time course of these changes, it was apparent that medications were started after increases in symptoms, hospitalizations, and suicidal thoughts were seen on a population level. Following initiation of the medication, levels then returned to baseline but generally did not continue to improve beyond the baseline level. Changes in mental health outcomes tended to be similar across the 4 augmenting medication classes. We observed adverse metabolic effects that were most notable for mirtazapine, followed by antipsychotics; these effects were minimal with prazosin. Metabolic changes tended to be most dramatic for outcomes that were not as responsive to medications, such as weight and triglycerides. Rates of use of new medications or intensification of existing regimens to treat metabolic outcomes were also very high, which may have obscured the impact of the augmenting medications. We also found, relative to prazosin, that the other medications were associated with increased risk of incident cardiovascular disease risk factors and event diagnoses, as well as all-cause mortality. The effects on mental health and metabolic outcomes were generally similar across subgroups. However, we found that adverse metabolic changes were more dramatic in female and younger (aged <65 years) veterans.
Our findings suggest that the use of medications to augment SRI treatment in patients with PTSD may lead to mental health benefits, particularly in those who have a flare in symptoms or in patients with more severe illness or who are otherwise unstable. This may come at a cost of worsening metabolic parameters, particularly for those prescribed mirtazapine or antipsychotics. Therefore, patients should be closely monitored for both symptom and functional improvement as well as metabolic impact. It will be important to confirm these findings with randomized clinical trials given the observational nature of our study.
These analyses are based on observational data, and therefore, we cannot conclude that the associations between the medications and outcomes are causal. In addition, though we remained powered to detect small effects, PTSD symptom outcomes were available for a minority (18%) of the sample.
