AJHP RESIDENTS EDITION  Posttraumatic stress disorder

AJHP RESIDENTS EDITION

Pharmacotherapy for posttraumatic stress disorder at a Veterans Affairs facility Tracie M. Kobayashi, Meeta Patel, and Megan Lotito

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osttraumatic stress disorder (PTSD) is a complex, multifaceted anxiety disorder common among military veterans. Within the Department of Veterans Affairs (VA) healthcare system, the number of veterans receiving care for PTSD increased from around 170,000 in 1999 to approximately 500,000 in 2009.1 The VA–Department of Defense (DoD) Clinical Practice Guideline for Management of Post-Traumatic Stress recommends selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) as first-line pharmacotherapies for this disorder (Figure 1).2 The SSRIs and SNRIs are proven to be effective for reducing the three core PTSD symptom clusters: reexperiencing, avoidance, and hyperarousal. The VA–DoD guideline recommends trials of two different SSRIs or SNRIs before proceeding to second-line pharmacotherapeutic strategies. The recommended duration of monotherapy is at least 8–12 weeks, which is considered adequate to allow for a sufficient response time. According to the guideline, other medication options for the treatment of PTSD include mirtazapine, nefazodone, tricyclic

Purpose. Results of a study of psychotropic prescribing patterns in a Veterans Affairs (VA) population with posttraumatic stress disorder (PTSD) are presented. Methods. VA prescription records were reviewed to identify veterans with PTSD at a large VA healthcare center and evaluate their medication regimens for conformance with a VA practice guideline that calls for the use of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) as first-line therapies for PTSD; the VA guideline does not recommend second-generation antipsychotics (SGAs) and benzodiazepines for PTSD symptom control. The primary objective was to determine if veterans with PTSD who were receiving an SGA had first received SSRI or SNRI therapy in accordance with VA recommendations.

antidepressants, and phenelzine; however, these medications are considered second-line therapies. In 2009, approximately 65% of veterans with PTSD received treatment with an SSRI or an SNRI within the VA system.3 Aside from these medications, second-generation antipsychotics (SGAs) and benzodiazepines are often used, but neither class

Tracie M. Kobayashi, Pharm.D., BCPS, is Clinical Pharmacist, Veterans Affairs Pacific Islands Health Care System, Honolulu, HI; when this study was conducted, she was Postgraduate Year 1 Pharmacy Resident, Veterans Affairs Southern Nevada Healthcare System, Las Vegas. Meeta Patel, Pharm.D., CDE, BCPS, is Director of Pharmacy Education and Training; and Megan Lotito, Pharm.D., BCPP,

Results. Among 308 veterans who met the inclusion criteria, the average number of SSRI or SNRI agents prescribed prior to initiation of SGA therapy was 0.88. Only 19.8% of patients (n = 61) had been prescribed 2 SSRI or SNRI agents, with 48.4% of patients (n = 149) having received 1 agent. All evaluated courses of SSRI and SNRI therapy prior to SGA initiation were of sufficient duration (range, 5–30 months), and mean adherence rates were >80%. Current or past benzodiazepine use was documented in about 55% of patients (n = 170). Conclusion. SSRIs and SNRIs were underutilized for the treatment of PTSD at the study site in patients receiving an SGA. The current use of benzodiazepines in these patients was lower than a reported national average for VA patients. Am J Health-Syst Pharm. 2015; 72(suppl 1):S11-5

is recommended for PTSD treatment in the VA–DoD guideline.2 According to the VA–DoD guideline, SGAs are not effective for PTSD monotherapy.2 Several small trials have evaluated their efficacy as adjuncts to antidepressant therapy and have found some benefit.4-6 However, a study to determine the efficacy of adjunctive risperidone therapy in

is Psychiatric Pharmacy Specialist, Veterans Affairs Southern Nevada Healthcare System, Las Vegas. Address correspondence to Dr. Kobayashi ([email protected]). The authors have declared no potential conflicts of interest. DOI 10.2146/ajhp150095

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Tracie M. Kobayashi, Pharm.D., BCPS, is a clinical pharmacist at VA Pacific Islands Health Care System. She received her doctor of pharmacy degree from the Oregon State University–Oregon Health & Science University College of Pharmacy in 2012. Dr. Kobayashi completed an ASHP-accredited residency in ambulatory care at the VA Southern Nevada Healthcare System in 2013.

patients receiving an SSRI or SNRI revealed that risperidone use, compared with placebo use, was not associated with a reduction in PTSD symptoms but was associated with an increase in adverse events.7 As a result of this study, the VA–DoD guideline recommends against the use of SGAs as an adjunct to SSRI or SNRI treatment for patients with PTSD.2 Despite the limited evidence supporting the use of SGAs in the treatment of PTSD, they are commonly used off label for this indication.8 The current literature does not support the use of benzodiazepines to reduce the core PTSD cluster symptoms, yet patients with PTSD often receive these medications for symptoms such as anxiety and insomnia,2,9,10 raising concerns about the potential for the use of these medications to result in long-term harms such as tolerance and physiological dependence. Although the use of benzodiazepines in veterans S12

with PTSD has decreased over the past decade, the frequency of use remains above 30%.2,8 The primary objective of the study described here was to determine if veterans at one VA facility system with diagnosed PTSD who were receiving an SGA had first been treated with an SSRI or an SNRI. The secondary objective was to evaluate current and prior benzodiazepine use in the study population. The VA Southern Nevada Healthcare System (VASNHS) is located in Las Vegas and provides healthcare services to over 65,000 enrolled veterans. Outpatient services are provided at primary care clinics located throughout the Las Vegas metropolitan area. In addition, VASNHS recently opened a new medical center that houses 90 inpatient beds and a 120-bed skilled nursing unit. Methods The study was a retrospective chart review–based investigation conducted at VASNHS. The study was approved by the VA Loma Linda Healthcare System institutional review board and received no funding. Patient data were extracted from the Veterans Integrated Service Network 22 Mental Health Academic Detailing Portal developed by the VA Academic Detailing Service. This dashboard is a real-time user interface that links to the electronic medical record at VASNHS. It is an online tool used to identify patients or subsets of patients receiving mental health medications who may benefit from clinical review or intervention. The population of interest in our study consisted of patients with diagnosed PTSD, without selected other comorbid psychiatric conditions (i.e., psychosis, schizophrenia, and bipolar disorder), and currently receiving an SGA. First-generation antipsychotics were excluded from the study because the focus of the most recent research on PTSD has centered on SGAs. A list of patients

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who met these criteria was obtained from the dashboard on January 10, 2013. Each patient’s mental health medication history profile was reviewed using the Medication History Portal within the dashboard. Data collection included SGA use (medication name, average dose, prescriber, date of initiation), SSRI and SNRI use (medication name; average dose; date of initiation; duration of therapy; and adherence rate, calculated as the medication possession ratio [MPR], or cumulative days of supply received divided by cumulative days elapsed during a specified time period) prior to initiation of the SGA, and current and past use of benzodiazepines. The dashboard was programmed to automatically calculate the MPR for each medication. The MPR is a measure commonly used for determining medication adherence.11 The primary outcome measure was the percentage of eligible patients—those with a diagnosis of PTSD but without selected other psychiatric conditions and currently prescribed an SGA—who had been treated with one or two SSRIs or SNRIs. The secondary outcome was the percentage of patients who had been treated with a benzodiazepine. Results Three hundred twenty-eight VASNHS patients were initially identified as meeting the study inclusion criteria. Of these patients, 308 were included in the study. Twenty patients were excluded for the following reasons: insufficient data to calculate the MPR for an SSRI or SNRI (n = 2), current use of a first-generation antipsychotic (n = 6), and inability to access the medication history profile on the dashboard (n = 12). The mean number of SSRIs and/ or SNRIs prescribed before SGA initiation was 0.88 per patient; only 19.8% of patients (61 of 308) had been treated with two different agents (as recommended in the VA–

AJHP RESIDENTS EDITION  Posttraumatic stress disorder

DoD guideline). About half of the patients (149 of 308 [48.4%]) had received only 1 SSRI or SNRI. Overall, 210 of 308 patients (68.2%) had received 1 or 2 SSRIs or SNRIs before initiation of SGA therapy; the most commonly prescribed medications were citalopram and sertraline, followed by fluoxetine, venlafaxine, paroxetine, duloxetine, and escitalopram (Table 1). The mean SSRI and SNRI trial durations ranged from 5 months when venlafaxine was used in the first course of therapy to 30 months when duloxetine was used in the first

commonly prescribed SGA, followed by risperidone, olanzapine, and ziprasidone (Table 2). Fifty-four patients (17.5%) were currently receiving a benzodiazepine, and 116 patients (37.7%) had been prescribed a benzodiazepine in the past. Overall, current or past benzodiazepine use was documented in 55.2% of patients (n = 170) in the population studied.

or second course. On average, adherence for all SSRIs and SNRIs was greater than 80% during both first and second courses (Table 1). Mental health providers accounted for 245 (79.5%) of the 308 SGA prescriptions, while 32 (10.4%) and 31 (10.1%) were prescribed by primary care practitioners and PTSD specialists, respectively. Quetiapine, at an average daily dose of 214 mg orally, was the most commonly prescribed SGA (n = 151) and accounted for 49.0% of the SGA prescriptions. Aripiprazole was the second most

Discussion Our study aimed to determine if patients receiving an SGA for the

Figure 1. Summary of Veterans Affairs–Department of Defense recommendations on stepped-care treatment of posttraumatic stress disorder.2 SSRI = selective serotonin reuptake inhibitor, SNRI = serotonin–norepinephrine reuptake inhibitor, TCA = tricyclic antidepressant.

Initial Treatment

Step I

Step II

Step III

Psychotherapy or SSRI or SNRI

Switch to another SSRI or SNRI and/or psychotherapy

Add psychotherapy and/or switch to mirtazapine

Switch to alternative step II or toTCA, nefazodone, or phenelzine Add psychotherapy

Add prazosin for sleep disturbances or nightmares

Table 1.

Use of Serotonin Reuptake Inhibitors and Serotonin–Norepinephrine Reuptake Inhibitors in Patients With Posttraumatic Stress Disorder Receiving a Second-Generation Antipsychotic Medication No. (%) Patients

Medication First course (n = 210) Citalopram Escitalopram Fluoxetine Paroxetine Sertraline Duloxetine Venlafaxine Second course (n = 61) Citalopram Fluoxetine Paroxetine Sertraline Duloxetine Venlafaxine

Mean Daily Dose (mg)

Mean Treatment Duration (mo)

Mean Adherence Rate (%)



76 (36.2) 1 (0.5) 30 (14.3) 7 (3.3) 77 (36.7) 1 (0.5) 18 (8.6)

42.8 20.0 37.5 32.9 169.7 120.0 221.8

15 6 17 13 16 30 5

88 92 87 93 90 100 88



17 (27.9) 7 (11.5) 5 (8.2) 22 (36.1) 4 (6.6) 6 (9.8)

48.6 38.3 44.0 139.0 82.5 275.5

16 23 18 10 30 18

86 91 99 83 96 86

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treatment of PTSD had been treated in accordance with the recommendations in the VA–DoD guideline. We found that fewer than 20% of veterans had received treatment with two different SSRIs or SNRIs and that the average number of SSRIs or SNRIs used was 0.88 per patient. However, approximately two thirds of patients had received at least 1 SSRI or SNRI; mean trial durations allowed for a sufficient response time, and mean adherence rates were greater than 80%. Of note, the mean daily citalopram dose was higher than 40 mg, a finding likely explained by patients taking relatively high dosages before the Food and Drug Administration’s (FDA’s) 2011 recommendation that daily doses not exceed 40 mg.12 The alarmingly small proportion of study patients who had been treated with 2 SSRIs or SNRIs identifies an area in the pharmacologic management of PTSD where pharmacists can intervene. Reeducating providers about the evidence-based treatment guidelines for PTSD will help to ensure optimal care for veterans with this disorder. Due to a lack of evidence of efficacy, SGAs cannot be recommended for PTSD monotherapy and should not be used as adjunctive therapies for PTSD.2 In our population, quetiapine was the most commonly prescribed SGA, accounting for nearly 50% of the SGA prescriptions. At VASNHS, initiation of SGA therapy is restricted to mental health provid-

ers, so it was not surprising that these providers accounted for the majority of the SGA prescriptions in the study population. Primary care providers (who are permitted to renew SGA prescriptions for patients continuing therapy) accounted for a small percentage of SGA prescriptions, as did providers specializing in treating patients with PTSD. The VA–DoD guideline discourages the use of benzodiazepines for the treatment of PTSD due to a lack of evidence of benefit and because of the potential for tolerance or dependence.2 In our population, approximately 18% of patients had an active prescription for a benzodiazepine. These results were encouraging, as it was estimated in a 2012 study that the frequency of benzodiazepine use among veterans nationwide remained greater than 30%.1 Providing education about the potential detrimental effects of benzodiazepines may help to achieve further reductions in the number of patients receiving benzodiazepines in our population. Our study had several notable limitations. First, our results do not take into account that patients might have been treated with SSRIs or SNRIs outside of our facility, as the dashboard used to collect medication-use data is specific to VASNHS. Therefore, unless patients only received care from VASNHS, we cannot be sure that the medication history obtained was comprehensive.

Table 2.

Use of Second-Generation Antipsychotic Medications in Patients With Posttraumatic Stress Disorder (n = 308) No. (%) Patients

Medication Aripiprazole Olanzapine Quetiapine Risperidone Ziprasidone hydrochloride

S14



65 (21.1) 9 (2.9) 151 (49.0) 59 (19.2) 24 (7.8)

Mean Daily Dose (mg) 8.7 11.7 214.0 2.0 94.4

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Second, we did not exclude patients with a diagnosis of depression from the study. Several SGAs, including aripiprazole, olanzapine, and quetiapine, are approved by FDA for use as adjuncts to antidepressant therapy in patients with treatmentresistant depression; we did not account for such SGA use in our study. Third, we were unable to include all initially identified patients in the study population, mainly due to insufficient medicationuse data; because of these exclusions, the results of our study do not necessarily reflect the experience of all patients with PTSD at VASNHS. Conclusion SSRIs and SNRIs were underutilized for the treatment of PTSD at VASNHS in patients receiving an SGA. The current use of benzodiazepines in these patients was lower than a reported national average for VA patients. References 1. Lund BC, Bernardy NC, Alexander B et al. Declining benzodiazepine use in veterans with posttraumatic stress disorder. J Clin Psychiatry. 2012; 73:292-6. 2. Veterans Health Administration, Department of Defense. VA/DoD clinical practice guideline for management of post-traumatic stress, version 2.0 (October 2010). www.healthquality. va.gov/guidelines/MH/ptsd/cpg_PTSDFULL-201011612.pdf (accessed 2015 Feb 24). 3. Bernardy NC, Lund BC, Alexander B et al. Prescribing trends in veterans with posttraumatic stress disorder. J Clin Psychiatry. 2012; 73:297-303. 4. Bartzokis G, Lu PH, Turner J et al. Adjunctive risperidone in the treatment of chronic combat-related posttraumatic stress disorder. Biol Psychiatry. 2005; 57:474-9. 5. Hamner MB, Deitsch SE, Brodrick PS et al. Quetiapine treatment in patients with posttraumatic stress disorder: an open trial of adjunctive therapy. J Clin Psychopharmacol. 2003; 23:15-20. 6. Stein MB, Kline NA, Matloff JL. Adjunctive olanzapine for SSRI-resistant combat-related PTSD: a double-blind, placebo-controlled study. Am J Psychiatry. 2002; 159:1777-9. 7. Krystal JH, Rosenheck RA, Vessicchio JC et al. Adjunctive risperidone treatment for antidepressant-resistant symptoms

AJHP RESIDENTS EDITION  Posttraumatic stress disorder

of chronic military service–related PTSD. JAMA. 2011; 306:493-502. 8. Leslie DL, Mohamed S, Rosenheck RA. Off-label use of antipsychotic medications in the Department of Veterans Affairs health care system. Psychiatr Serv. 2009; 60:1175-81. 9. Gelpin E, Bonne O, Peri T et al. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry. 1996; 57:390-4. 10. Braun P, Greenberg D, Dasberg H et al. Core symptoms of posttraumatic stress disorder unimproved by alprazolam treatment. J Clin Psychiatry. 1990; 51:236-8. 11. Andrade SE, Kahler KJ, Frech F et al. Methods for evaluation of medication adherence and persistence using automated databases. Pharmacoepidemiol Drug Saf. 2006; 15:565-74. 12. Food and Drug Administration. FDA drug safety communication: abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide) (updated March 28, 2012). www.fda.gov/ Drugs/DrugSafety/ucm269086.htm (accessed 2015 Feb 24).

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Pharmacotherapy for posttraumatic stress disorder at a Veterans Affairs facility.

Results of a study of psychotropic prescribing patterns in a Veterans Affairs (VA) population with posttraumatic stress disorder (PTSD) are presented...
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