Original Research Key Words: asenapine, posttraumatic stress disorder, augmentation, atypical antipsychotic
An Open Label Pilot Study of Adjunctive Asenapine for the Treatment of Posttraumatic Stress Disorder
By Patricia Pilkinton, Carlos Berry, Seth Norrholm, Al Bartolucci, Badari Birur, Lori L. Davis ABSTRACT ~
Objective: Selective serotonin reuptake inhibitors (SSRIs) remain the firstline treatment for posttraumatic stress disorder (PTSD). However, adjunctive atypical antipsychotics are often used to target residual or refractory symptoms. Asenapine is a novel atypical antipsychotic that possesses a high serotonin (5-HT2A) to dopamine (D2) affinity ratio and alpha-adrenergic antagonism, which may be advantageous in treating PTSD. This pilot study aimed to identify the therapeutic potential of asenapine as an adjunctive treatment for PTSD. Method: Eighteen subjects initiated treatment in this single-site prospective, open-label, 12-week trial of flexibly-dosed asenapine in Veterans with PTSD who had not responded to an adequate course of treatment with an SSRI, venlafaxine, or mirtazapine. Subjects remained on their antidepressant medication and were started on adjunctive asenapine 5 mg sublingual at bedtime, which was gradually titrated to a maximum of 10 mg twice per day, as tolerated. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS) for DSM-IV. Results: Fifteen subjects finished at least 4 weeks and eleven completed the 12 week study. There was a significant and clinically meaningful decrease in CAPS from baseline (77.56 ± 14.48) to week 4 (48.7 ± 30.6), and to week 12 (35.3 ± 19.7). Six participants experienced adverse events possibly related to asenapine; however, only three participants discontinued early due to related adverse events. Conclusion: This pilot study demonstrated that adjunctive treatment with asenapine may provide additional benefit to some patients experiencing residual PTSD symptoms in spite of optimal antidepressant therapy. A larger efficacy study may be warranted. Psychopharmacology Bulletin. 2016;46(2):8–17.
Drs. Pilkinton, MD, Berry, MD, and Davis, MD, Tuscaloosa Veterans Affairs Medical Center, Tuscaloosa, Alabama, University of Alabama School of Medicine, Birmingham, AL. Dr. Norrholm, PhD, VA Medical Center, Emory University, Department of Psychiatry, Atlanta, GA. Dr. Bartolucci, PhD, University of Alabama at Birmingham, Birmingham, AL. Dr. Birur, MD, University of Alabama School of Medicine, Birmingham, AL. To whom correspondence should be addressed: Dr. Patricia Pilkinton, MD. Veterans Affairs Medical Center, 3701 Loop Road East, Tuscaloosa, Alabama, USA 35404. Phone: 205-554-3819; Fax: 205-554-2877; E-mail: [email protected]
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Intoduction Posttraumatic Stress Disorder (PTSD) is now recognized as a common and increasingly complex mental disorder with serious physical, emotional, and economic sequelae.1 PTSD affects up to 7.8% of the general population, with higher prevalence in individuals exposed to traumatic events such as abuse, violent conflict, war, and disaster.2 One study3 of US combat infantry units found that approximately 20% of those who served in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) reported symptoms consistent with PTSD. In addition to the core symptoms of re-experiencing, avoidance, and hyperarousal, many individuals with PTSD experience associated substance use, depressive, psychotic, and anxiety disorders.4 Ongoing PTSD symptomatology is associated with lower quality of life, greater problems with physical health, and increased use of health and social services.5 Selective serotonin reuptake inhibitors (SSRIs), noradrenergic/specific serotonergic antidepressants (NaSSAs), and serotonin norepinephrine reuptake inhibitors (SNRIs), continue to be the mainstay of treatment for individuals with PTSD.6 Many patients experience troubling residual PTSD symptoms even after optimal dosing,7 and start adjunctive medications. Studies utilizing atypical antipsychotics comprise the bulk of the evidence on adjunctive treatment of PTSD.8 Many,9–12 but not all,13 studies have shown improvement in overall PTSD symptoms, with greater gains in specific PTSD symptom clusters. Asenapine is a sublingually administered atypical antipsychotic with FDA approval for treatment of schizophrenia and bipolar disorder at doses up to 10 mg twice per day.14 While similar to other atypicals in its 5HT2A:D2 affinity ratio, asenapine has higher affinity for serotonergic, alpha 1, and 2 adrenergic receptors,15 all of which are implicated in the symptomatology of PTSD.16 Asenapine behaves as a partial agonist at the 5HT1a receptor17 which may help further ameliorate anxiety and mood symptoms. Asenapine appears to be metabolically neutral and has lower propensity to cause weight gain, prolactin elevation, or QTc prolongation than most atypical antipsychotics.18 Given asenapine’s mechanism of action and favorable side effect profile, we conducted an open label pilot study of adjunctive asenapine in the treatment of PTSD.
9 Pilkinton, Berry, Norrholm, et al.
Materials and Methods The study protocol was approved by the Institutional Review Board of the Tuscaloosa Veterans Affairs Medical Center and all participants signed an informed consent prior to participation in the study protocol. This is a prospective, 12-week, single-site, pilot study of adjunctive P sychopharmacology B ulletin : Vol. 46 · No. 2
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asenapine in Veterans with the diagnosis of PTSD who experienced an inadequate response to an acceptable antidepressant at a clinically appropriate dose level. Participant Recruitment Participants were recruited from the outpatient and residential programs of a Veterans Administration Medical Center through in-house advertisement flyers, provider referral, and outreach events. Potential participants underwent initial screening for eligibility followed by informed consent. Consenting participants underwent full eligibility assessment including diagnostic evaluation and assessment using the MINI Neuropsychiatric Interview,19 clinical evaluation, treatment and medication history, physical examination and basic laboratory studies. The origin of the index trauma was not limited to military service. 10 Pilkinton, Berry, Norrholm, et al.
Inclusion/Exclusion Criteria Veterans of any race or gender, ages 19 through 65, who had been treated with an adequate dose of allowed antidepressant for . 8 weeks and had ongoing symptoms of PTSD, were recruited for the study. PTSD symptom severity was assessed by a trained clinician using the ClinicianAdministered PTSD Scale – DSM IV (CAPS).20 Ongoing PTSD symptomatology was defined as a CAPS score of • 45 using DSM IV criteria. The following antidepressant medications were considered acceptable: citalopram (40–60 mg/day), escitalopram (20–40 mg/day), fluoxetine (40–60 mg/day), sertraline (150–200 mg/day), venlafaxine/venlafaxine XR (150–225 mg/day), and mirtazapine (30–60 mg/day). Participants taking paroxetine and fluvoxamine were excluded due to potential drugdrug interactions. Participants currently taking other psychotropic medications with serotonergic, dopaminergic, and alpha-adrenergic effects such as trazodone, bupropion, antipsychotics, buspirone, or prazosin could elect to undergo wash-out of the prohibited medication or were excluded from the study. Subjects were excluded from the study if they met any of the following criteria: a lifetime history of bipolar I, schizophrenia, schizoaffective, or cognitive disorder, those with active substance abuse or dependence (aside from nicotine and caffeine), clinically significant or unstable medical condition that would pose an undue risk, pregnancy or planned pregnancy during the study, breastfeeding, unwillingness to use study recommended contraception, clinically significant laboratory abnormalities, active suicidality or homicidality, current participation in an evidence based treatment for PTSD, allergy or other contraindication to the use of asenapine.
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Study Medication Participants meeting study inclusion/exclusion criteria were started on asenapine 5 mg sublingually twice daily. During the follow-up visits, asenapine was increased, as tolerated, to 10 mg twice daily by week 8 of the study. Face-to-face assessments were conducted at baseline, week 4, 8, and 12 (or end of treatment) and telephone follow-up at weeks 2, and 6. Study Assessments At baseline and weeks 4, 8, and 12 (or end of treatment), the following clinician-rated or self-report assessments were completed: CAPS, Clinical Global Impression (CGI),21 16-item Quick Inventory of Depressive Symptomatology—Self Report (QIDS-SR),22 Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q),23 PTSD Checklist (PCL), 24 and Brief Psychiatric Rating Scale (BPRS).25 Medication side effects were measured with self-report Frequency, Intensity, and Burden of Side Effects Rating (FIBSER)26 and clinician-administered Abnormal Involuntary Movement Scale (AIMS),27 Barnes Akathisia Scale (BAS)28 and the Simpson-Angus Scale (SAS).29 Clinical interview was conducted to identify adverse events, reconcile concomitant medications, and reinforce proper study medication administration.
11 Pilkinton, Berry, Norrholm, et al.
Statistical Analysis Comparisons to baseline were performed using paired t-tests. Overall change in values from baseline to week 12, including weeks 4 and 8, were done using a simple one-way analysis of variance. Because the sample size was small, p-values for the paired t-test and one-way results were recalculated using the signed rank test and Kruskal Wallis procedure, respectively. The statistical software used was SAS version 9.3, Cary, N.C. Results Thirty-one Veterans signed consent to participate in the study and after initial screening, 18 were eligible and initiated treatment with adjunctive asenapine. For the 13 Veterans who did not start medication, 7 were screen failures and 4 withdrew consent due to change in residence, and 2 were not on the appropriate antidepressant doses. Fifteen (83.3%) finished at least 4 weeks and eleven (61.1%) completed the 12-week study. Early drop-out was due to adverse events (n = 3), lost to follow-up (n = 2), participant withdrew due to nonresponse (n = 1), and relocation (n = 1). P sychopharmacology B ulletin : Vol. 46 · No. 2
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Demographics and Baseline Characteristics The following demographics describe the 18 participants who started study medication. Participants came from all branches of US military with the exception of the US Coast Guard and had time in service ranging from 2 to 21 years (average 8.4 ± 7.9 years). The traumatic events arose from military non-combat (n = 8), military combat (n = 3), combined military combat/noncombat (n = 4), civilian (n = 2) and civilian sexual assault (n = 1). The average length of PTSD was 18.8 ± 14 years with the most recent being 1 year and most distant being 47 years. Mean age of the participants was 48.3 ± 11.9 years and ranged from 33–68 years. Three participants were females and 15 were males; 33% were Caucasian, 61% were African-American, and one listed race as “other.” Based on the MINI, 72% of subjects met criteria for current major depressive disorder and 50% met criteria for past year substance use disorder in current remission. 12 Pilkinton, Berry, Norrholm, et al.
Clinical Outcomes There was a significant and clinically meaningful decrease in total CAPS score from baseline (77.56 ± 14.48) to week 4 (48.7 ± 30.6) and to week 12 (35.3 ± 19.7) as shown in Figure 1 and Table 1. The PCL, QIDS-SR, BPRS, and CGI scales also showed significant and clinically meaningful improvements (Table 1). Q-LES-Q showed little change over the 12-week course. Seven of the 18 (39%) participants met definition of remission (CAPS • 45) and ten of the 18 (56%) of the participants met definition of response (decrease in CAPS by 30% from baseline). Study Medication For all subjects, the maximum average dose of asenapine was 13.6 ± 6.4 mg/d. For those completing the 12-week study, the maximum average dose of asenapine was 15.9 ± 4.9 mg/d. Side Effects and Safety Monitoring Evaluation of abnormal movements was conducted using the AIMS, BARS and SAS. The scores were essentially zero from baseline to endpoint. Weight was measured at each visit and body mass index (BMI) calculated. The mean BMI was 31.0 ± 4.6 at baseline and 31.8 ± 4.10 at week 12.
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Adjunctive Asenapine for PTSD FIGURE 1
Change in Clinician Administered PTSD Scale (CAPS) Total Score and Subscores for CAPS-B (Re-Experiencing Symptoms), CAPS-C (Avoidance and Emotional Numbing) and CAPS-D (Hyperarousal) From Baseline Over Time (Weeks) in Veterans with Diagnosis of Posttraumatic Stress Disorder Treated with Open Label Asenapine Augmentation
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Eight participants experienced an adverse event (AE). Six participants had AE’s possibly related to asenapine, of which four stopped medication due to AE: one had sedation with syncope on day 1 (5 mg/d), one had severe agitation on day 4 (5 mg/d), one had weight gain and sedation at week 4 (5 mg/d), and one had sedation and severe extrapyramidal side effects (20 mg/d) at week 12. Two subjects continued the medication after AE: one participant experienced transient headache, fatigue, and gastrointestinal upset at 10mg/d and the other experienced sedation at 10 mg/d which improved with dose reduction. As unrelated AE’s, one participant had a sinus infection and one participant was hospitalized on the psychiatric unit in the month following study exit and was not on asenapine at the time.
13 Pilkinton, Berry, Norrholm, et al.
Discussion In this open-label pilot study, adjunctive asenapine was shown to be effective in reducing symptoms of PTSD in a diverse group of U.S. Veterans. The addition, asenapine contributed to a reduction in PTSD symptomatology in all symptom clusters (re-experiencing, avoidance/numbing, and hyperarousal) with the greatest response in re-experiencing cluster and least response in the avoidance/emotional numbing symptom cluster. This is consistent with other studies30 that note lower medication response in other sub-symptoms. It has been suggested that different P sychopharmacology B ulletin : Vol. 46 · No. 2
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14
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77.6 (14.5) 19.9 (5.7) 32.2 (9) 25.4 (5) 57.3 (12.2) 28.9 (13.6) 4.8 (1) 14.3 (4.1)
BASELINE
48.7 (30.6) 10.9 (10.9) 21.9 (13.4) 15.9 (9) 46.2 (14.1) 16.7 (10) 3.5 (0.8) 11.3 (6.3)
46.5 (22.8) 10.3 (7.6) 20 (9.6) 16.2 (7.8) 37.8 (14.2) 15.0 (7.2) 3.4 (1.1) 7.6 (4.5)
MEAN (SD) SCORES WEEK 4 WEEK 8
35.3 (19.7) 7.8 (6.6) 16.6 (10.1) 10.8 (7.4) 41.5 (14.7) 12.9 (6.9) 3 (1.1) 6.7 (4.1)
WEEK 12
–27.8 (19.1) –8.6 (8.7) –9.9 (7) –9.3 (6.9) –18.2 (15) –13.4 (8) –1.5 (1.7) –5.9 (6.9)
–39 (18.4) –11.1 (8.2) –13.3 (10.3) –14.6 (7.6) –14.5 (9.8) –15.5 (9.3) –1.9 (1.3) -6.8 (4.4)
MEAN (SD) CHANGE OVER TIME WEEK 8 WEEK 12
–31 (27.9) –9.2 (10.8) –11.3 (12.4) –10.5 (8.1) –13.9 (11.7) –15.7 (9.7) –1.8 (0.7) –3.5 (6.5)
WEEK 4
f
9.3 6.5 5.7 9.8 5.3 6.8 9.7 6.7
P
,.0001 .0009 .0021 ,.0001 .003 .0006 ,.0001 .0007
Abbreviations: SD, Standard Deviation; CAPS, Clinician Administered PTSD Scale for DSM-IV; CAPS-B, PTSD re-experiencing symptoms; CAP-C, PTSD avoidance and emotional numbing symptoms; CAP-D, PTSD hyperarousal symptoms; PCL, PTSD Checklist for DSM-IV; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression for Severity; QIDS-SR, 16-item Quick Inventory of Depressive Symptomatology – Self Report.
CAPS-Total CAPS-B CAPS-C CAPS-D PCL BPRS CGI-S QIDS-SR
RATING SCALE
Symptom Ratings During Adjunctive Asenapine Treatment for Posttraumatic Stress Disorder
TABLE 1
Adjunctive Asenapine for PTSD
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neural mechanisms and pathways underlie the development of avoidance and numbing behaviors,31 thus limiting their responsiveness to traditional medication therapies. Alternately, avoidance and emotional numbing symptoms may reflect a behavioral adaptation used by the patient to manage re-experiencing and hyperarousal symptoms. While the majority of improvement occurred within the first 4 weeks, additional benefits were noted through week 12 on the CAPS and PCL measures. This is consistent with other studies of time to response32 and suggests that shorter trials may have failed to capture the full response to medication. The vigorous response noted in this study in the first 4 weeks could be attributed to the synergistic effects of the index antidepressant and asenapine when compared to initiating medication in a treatment-naïve patient. Clinically significant responses were also noted in comorbid depressive symptoms as measured by the QIDS-SR. Asenapine is active at several 5HT receptor subtypes which might account for improvement in depressive symptoms in this study. Studies of atypical antipsychotics or aripiprazole augmentation in the treatment of major depression have yielded positive results.33,34 In this study, asenapine demonstrated a favorable side effect profile, with minimal weight gain and only one participant experiencing extrapyramidal side effects while at the 20 mg/day dose. The study population is consistent with the population of patients presenting for treatment at a Veterans Affairs Medical Center. We attempted to simulate a typical outpatient treatment setting by recruiting a naturalistic sample of US Veterans presenting for treatment. By enrolling a wide spectrum of participants with regards to index antidepressant, age, index trauma, and symptom duration we were attempting to achieve generalizable results. By doing so, it may have impacted our ability to detect which patients would be most likely to benefit from this augmentation approach. Since our study population had high rates of comorbid depression, and residual symptoms even after optimized antidepressant treatment, they may represent a more refractory subgroup than many single drug studies. This study was limited by both the small number of subjects enrolled and its open-label design. The small number of subjects also limits our ability to determine if asenapine augmentation has greater efficacy with specific antidepressants. The open-label design may introduce bias into the reporting and rating of symptoms.
15 Pilkinton, Berry, Norrholm, et al.
Conclusion In conclusion, the findings of this study support consideration of asenapine in the treatment of refractory PTSD. A larger double-blind, P sychopharmacology B ulletin : Vol. 46 · No. 2
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placebo-controlled study is warranted to further define its role in the medication management of PTSD. D Acknowledgement Financial support for this study provided through an investigator initiated study grant from Merck, Sharp & Dohme Corp. and Forest Research Institute, Inc. We acknowledge the outstanding clinical research coordination of Anita Davis. We are grateful for the administrative support of the Tuscaloosa VA Research and Development Service. Conflicts of Interests Dr. Davis has served as a consultant for Tonix, Otsuka, Lundbeck, and Brackett. 16 Pilkinton, Berry, Norrholm, et al.
Trial Registration clinicaltrials.gov Identifier: NCT01587118. Disclosure Opinions herein are those of the individual authors and the contents do not represent the views of the Department of Veterans Affairs or the United States Government. References 1. Goldstein RB, Smith SM, Chou SP, et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the national Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016 Epub ahead of print 22 Apr 2016. 2. Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048–1060. 3. Hoge CW, Castro CA, Messer SC, et al. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med. 2004;351(1):13–22. 4. Ohayon MM, Shapiro CM. Sleep disturbances and psychiatric disorders associated with posttraumatic stress disorder in the general population. Compr Psychiatry. 2000;41:469–478. 5. Tuerk PW, Wangelin B, Rauch SA, et al. Health service utilization before and after evidence-based treatment for PTSD. Psychol Serv. 2013;10:401–409. 6. Institute of Medicine (IOM). Treatment of posttraumatic stress disorder: an assessment of the evidence. Washington, DC: The National Academic Press, 2008. 7. Hamner MB, Robert S, Frueh BC. Treatment-resistance posttraumatic stress disorder: strategies for intervention. CNS Spectr. 2004;9:740–752. 8. Ahearn EP, Juergens T, Cordes T, et al. A review of atypical antipsychotic medications for posttraumatic stress disorder. Int Clin Psychopharmacol. 2011;26:193–200. 9. Padala PR, Madison J, Monnahan M, et al. Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women. Int Clin Psychopharmacol. 2006;21:275–280.
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Adjunctive Asenapine for PTSD 10. Hamner MB, Faldowski RA, Ulmer HG, et al. Adjunctive risperidone treatment in post-traumatic stress disorder: A preliminary controlled trial of effects on comorbid psychotic symptoms. Int Clin Psychopharmacol. 2003;18:1–8. 11. Butterfield MI, Becker ME, Connor KM, et al. Olanzapine in the treatment of posttraumtic stress disorder. A pilot study. Int Clin Psychopharmacol. 2001;16(4):197–203. 12. Bartzokis G, Lu PH, Turner J, et al. Adjunctive risperidone in the treatment of chronic combat-related PTSD. Biol Psych. 2004;57:474–479. 13. Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressantresistant symptoms of chronic military service-related PTSD: a randomized trial. JAMA. 2011; 306:493–502. 14. McIntyre RS, Cohen M, Zhao J, et al. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double blind, placebo controlled trial. J Affect Disord. 2010;122:27–38. 15. Bishara D and Taylor D. Asenapine monotherapy in acute treatment of both schizophrenia and bipolar I disorder. Neuropsychiatric Disease and Treatment. 2009;5:493–490. 16. Bremner JD, Southwick SM, Charney DS. The neurobiology of posttraumatic stress disorder: An integration of animal and human research. In: Saigh PA, Bremner JD, eds. Posttraumatic Stress Disorder: A Comprehensive Text. Boston: Allyn and Bacon, 1999;103–143. 17. Shahid M, Walker GB, Zorn SH, et al. Asenapine: a novel psychopharmacologic agent with a unique receptor signature. J Psychopharmacol. 2009;23:65–73. 18. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo and risperdone controlled trial. J Clin Psychiatry. 2007;68(1):1492–1500. 19. Sheehan DV, Lecrubier Y, Harnett Sheehan K, et al. The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability. European Psychiatry. 1997;12:232–241. 20. Blake DD, Weathers FW, Nagy LM, et al. The development of a Clinician-Administered PTSD Scale. J Trauma Stress. 1995;8:75–90. 21. Guy W.ECDEU – Assessment manual for psychopharmacology. Washington: National Institute of Mental Health (Ed.), 1976. 22. Rush AJ, Trividi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psych. 2003;54:573–583. 23. Endicott J, Nee J, Harrison W, et al. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull. 1993;29:321–326. 24. Weathers FW, Litz BT, Herman DS, et al. The PTSD Checklist (PCL): Reliability, validity, and diagnostic utility. Proceedings of the Annual Conference of the International Society for Traumatic Stress Studies; 1993 Oct 25; San Antonio, TX. 25. Overall JE and Gorham DR. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacol Bulletin. 1993;24:97–99. 26. Wisniewski SR, Rush AJ, Balasubramani GK, et al. Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract. 2006;12:71–79. 27. Munetz MR and Benjamin S. How to examine patients using the Abnormal Involuntary Movement Scale. Hospital and Community Psychiatry. 1988;39:1172–1177. 28. Banes T. A rating scale for drug induced akathisia. British Journal of Psychiatry. 1989;154:672–676. 29. Wang S, et al. Asenapine, Blonanserin, Iloperidone, Lurasidone, and Sertindole: Distinctive Clinical Characteristics of 5 Novel Atypical Antipsychotics. Clin Neuropharmacol. 2013;36:223–238. 30. Han C, Lee SJ, Patkar AA, et al. The potential role of atypical antipsychotics for the treatment of posttraumatic stress disorder. J Psychiatric Res. 2014;56:72–81. 31. Blomhoff S, Beinvang I, Malt UF. Event-related potentials to stimuli with emotional impact in posttraumatic stress patients. Biol Psychiatry. 1998;44:1045–1053. 32. Stein DJ, Pederson R, Rothbaum BO, et al. Onset of activity and time to response on individual CAPS-SX17 items in patients treated for post-traumatic stress disorder with venlafaxine ER: a pooled analysis. Int J Neuropsychopharm. 2009;12:23–31. 33. Zhou X, Keitner GI, Qin B, et al. Atypical antipsychotic augmentation for treatment-resistant depression: A systematic review and network meta-analysis. Int J Neuropsychopharm. 2015;18(11):1–10. 34. Han C, Wang SM, Kwak KP, et al. Aripiprazole augmentation versus antidepressant switching for patients with major depression: A 6-week, randomized, rater-blinded, prospective study. J Psychiatr Res. 2015;66–67:84–94.
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By Patricia Pilkinton, Carlos Berry, Seth Norrholm, Al Bartolucci, Badari Birur, Lori L. Davis ABSTRACT ~
Objective: Selective serotonin reuptake inhibitors (SSRIs) remain the firstline treatment for posttraumatic stress disorder (PTSD). However, adjunctive atypical antipsychotics are often used to target residual or refractory symptoms. Asenapine is a novel atypical antipsychotic that possesses a high serotonin (5-HT2A) to dopamine (D2) affinity ratio and alpha-adrenergic antagonism, which may be advantageous in treating PTSD. This pilot study aimed to identify the therapeutic potential of asenapine as an adjunctive treatment for PTSD. Method: Eighteen subjects initiated treatment in this single-site prospective, open-label, 12-week trial of flexibly-dosed asenapine in Veterans with PTSD who had not responded to an adequate course of treatment with an SSRI, venlafaxine, or mirtazapine. Subjects remained on their antidepressant medication and were started on adjunctive asenapine 5 mg sublingual at bedtime, which was gradually titrated to a maximum of 10 mg twice per day, as tolerated. The primary outcome measure was the Clinician Administered PTSD Scale (CAPS) for DSM-IV. Results: Fifteen subjects finished at least 4 weeks and eleven completed the 12 week study. There was a significant and clinically meaningful decrease in CAPS from baseline (77.56 ± 14.48) to week 4 (48.7 ± 30.6), and to week 12 (35.3 ± 19.7). Six participants experienced adverse events possibly related to asenapine; however, only three participants discontinued early due to related adverse events. Conclusion: This pilot study demonstrated that adjunctive treatment with asenapine may provide additional benefit to some patients experiencing residual PTSD symptoms in spite of optimal antidepressant therapy. A larger efficacy study may be warranted. Psychopharmacology Bulletin. 2016;46(2):8–17.
Drs. Pilkinton, MD, Berry, MD, and Davis, MD, Tuscaloosa Veterans Affairs Medical Center, Tuscaloosa, Alabama, University of Alabama School of Medicine, Birmingham, AL. Dr. Norrholm, PhD, VA Medical Center, Emory University, Department of Psychiatry, Atlanta, GA. Dr. Bartolucci, PhD, University of Alabama at Birmingham, Birmingham, AL. Dr. Birur, MD, University of Alabama School of Medicine, Birmingham, AL. To whom correspondence should be addressed: Dr. Patricia Pilkinton, MD. Veterans Affairs Medical Center, 3701 Loop Road East, Tuscaloosa, Alabama, USA 35404. Phone: 205-554-3819; Fax: 205-554-2877; E-mail: [email protected]
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Intoduction Posttraumatic Stress Disorder (PTSD) is now recognized as a common and increasingly complex mental disorder with serious physical, emotional, and economic sequelae.1 PTSD affects up to 7.8% of the general population, with higher prevalence in individuals exposed to traumatic events such as abuse, violent conflict, war, and disaster.2 One study3 of US combat infantry units found that approximately 20% of those who served in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) reported symptoms consistent with PTSD. In addition to the core symptoms of re-experiencing, avoidance, and hyperarousal, many individuals with PTSD experience associated substance use, depressive, psychotic, and anxiety disorders.4 Ongoing PTSD symptomatology is associated with lower quality of life, greater problems with physical health, and increased use of health and social services.5 Selective serotonin reuptake inhibitors (SSRIs), noradrenergic/specific serotonergic antidepressants (NaSSAs), and serotonin norepinephrine reuptake inhibitors (SNRIs), continue to be the mainstay of treatment for individuals with PTSD.6 Many patients experience troubling residual PTSD symptoms even after optimal dosing,7 and start adjunctive medications. Studies utilizing atypical antipsychotics comprise the bulk of the evidence on adjunctive treatment of PTSD.8 Many,9–12 but not all,13 studies have shown improvement in overall PTSD symptoms, with greater gains in specific PTSD symptom clusters. Asenapine is a sublingually administered atypical antipsychotic with FDA approval for treatment of schizophrenia and bipolar disorder at doses up to 10 mg twice per day.14 While similar to other atypicals in its 5HT2A:D2 affinity ratio, asenapine has higher affinity for serotonergic, alpha 1, and 2 adrenergic receptors,15 all of which are implicated in the symptomatology of PTSD.16 Asenapine behaves as a partial agonist at the 5HT1a receptor17 which may help further ameliorate anxiety and mood symptoms. Asenapine appears to be metabolically neutral and has lower propensity to cause weight gain, prolactin elevation, or QTc prolongation than most atypical antipsychotics.18 Given asenapine’s mechanism of action and favorable side effect profile, we conducted an open label pilot study of adjunctive asenapine in the treatment of PTSD.
9 Pilkinton, Berry, Norrholm, et al.
Materials and Methods The study protocol was approved by the Institutional Review Board of the Tuscaloosa Veterans Affairs Medical Center and all participants signed an informed consent prior to participation in the study protocol. This is a prospective, 12-week, single-site, pilot study of adjunctive P sychopharmacology B ulletin : Vol. 46 · No. 2
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asenapine in Veterans with the diagnosis of PTSD who experienced an inadequate response to an acceptable antidepressant at a clinically appropriate dose level. Participant Recruitment Participants were recruited from the outpatient and residential programs of a Veterans Administration Medical Center through in-house advertisement flyers, provider referral, and outreach events. Potential participants underwent initial screening for eligibility followed by informed consent. Consenting participants underwent full eligibility assessment including diagnostic evaluation and assessment using the MINI Neuropsychiatric Interview,19 clinical evaluation, treatment and medication history, physical examination and basic laboratory studies. The origin of the index trauma was not limited to military service. 10 Pilkinton, Berry, Norrholm, et al.
Inclusion/Exclusion Criteria Veterans of any race or gender, ages 19 through 65, who had been treated with an adequate dose of allowed antidepressant for . 8 weeks and had ongoing symptoms of PTSD, were recruited for the study. PTSD symptom severity was assessed by a trained clinician using the ClinicianAdministered PTSD Scale – DSM IV (CAPS).20 Ongoing PTSD symptomatology was defined as a CAPS score of • 45 using DSM IV criteria. The following antidepressant medications were considered acceptable: citalopram (40–60 mg/day), escitalopram (20–40 mg/day), fluoxetine (40–60 mg/day), sertraline (150–200 mg/day), venlafaxine/venlafaxine XR (150–225 mg/day), and mirtazapine (30–60 mg/day). Participants taking paroxetine and fluvoxamine were excluded due to potential drugdrug interactions. Participants currently taking other psychotropic medications with serotonergic, dopaminergic, and alpha-adrenergic effects such as trazodone, bupropion, antipsychotics, buspirone, or prazosin could elect to undergo wash-out of the prohibited medication or were excluded from the study. Subjects were excluded from the study if they met any of the following criteria: a lifetime history of bipolar I, schizophrenia, schizoaffective, or cognitive disorder, those with active substance abuse or dependence (aside from nicotine and caffeine), clinically significant or unstable medical condition that would pose an undue risk, pregnancy or planned pregnancy during the study, breastfeeding, unwillingness to use study recommended contraception, clinically significant laboratory abnormalities, active suicidality or homicidality, current participation in an evidence based treatment for PTSD, allergy or other contraindication to the use of asenapine.
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Study Medication Participants meeting study inclusion/exclusion criteria were started on asenapine 5 mg sublingually twice daily. During the follow-up visits, asenapine was increased, as tolerated, to 10 mg twice daily by week 8 of the study. Face-to-face assessments were conducted at baseline, week 4, 8, and 12 (or end of treatment) and telephone follow-up at weeks 2, and 6. Study Assessments At baseline and weeks 4, 8, and 12 (or end of treatment), the following clinician-rated or self-report assessments were completed: CAPS, Clinical Global Impression (CGI),21 16-item Quick Inventory of Depressive Symptomatology—Self Report (QIDS-SR),22 Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q),23 PTSD Checklist (PCL), 24 and Brief Psychiatric Rating Scale (BPRS).25 Medication side effects were measured with self-report Frequency, Intensity, and Burden of Side Effects Rating (FIBSER)26 and clinician-administered Abnormal Involuntary Movement Scale (AIMS),27 Barnes Akathisia Scale (BAS)28 and the Simpson-Angus Scale (SAS).29 Clinical interview was conducted to identify adverse events, reconcile concomitant medications, and reinforce proper study medication administration.
11 Pilkinton, Berry, Norrholm, et al.
Statistical Analysis Comparisons to baseline were performed using paired t-tests. Overall change in values from baseline to week 12, including weeks 4 and 8, were done using a simple one-way analysis of variance. Because the sample size was small, p-values for the paired t-test and one-way results were recalculated using the signed rank test and Kruskal Wallis procedure, respectively. The statistical software used was SAS version 9.3, Cary, N.C. Results Thirty-one Veterans signed consent to participate in the study and after initial screening, 18 were eligible and initiated treatment with adjunctive asenapine. For the 13 Veterans who did not start medication, 7 were screen failures and 4 withdrew consent due to change in residence, and 2 were not on the appropriate antidepressant doses. Fifteen (83.3%) finished at least 4 weeks and eleven (61.1%) completed the 12-week study. Early drop-out was due to adverse events (n = 3), lost to follow-up (n = 2), participant withdrew due to nonresponse (n = 1), and relocation (n = 1). P sychopharmacology B ulletin : Vol. 46 · No. 2
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Demographics and Baseline Characteristics The following demographics describe the 18 participants who started study medication. Participants came from all branches of US military with the exception of the US Coast Guard and had time in service ranging from 2 to 21 years (average 8.4 ± 7.9 years). The traumatic events arose from military non-combat (n = 8), military combat (n = 3), combined military combat/noncombat (n = 4), civilian (n = 2) and civilian sexual assault (n = 1). The average length of PTSD was 18.8 ± 14 years with the most recent being 1 year and most distant being 47 years. Mean age of the participants was 48.3 ± 11.9 years and ranged from 33–68 years. Three participants were females and 15 were males; 33% were Caucasian, 61% were African-American, and one listed race as “other.” Based on the MINI, 72% of subjects met criteria for current major depressive disorder and 50% met criteria for past year substance use disorder in current remission. 12 Pilkinton, Berry, Norrholm, et al.
Clinical Outcomes There was a significant and clinically meaningful decrease in total CAPS score from baseline (77.56 ± 14.48) to week 4 (48.7 ± 30.6) and to week 12 (35.3 ± 19.7) as shown in Figure 1 and Table 1. The PCL, QIDS-SR, BPRS, and CGI scales also showed significant and clinically meaningful improvements (Table 1). Q-LES-Q showed little change over the 12-week course. Seven of the 18 (39%) participants met definition of remission (CAPS • 45) and ten of the 18 (56%) of the participants met definition of response (decrease in CAPS by 30% from baseline). Study Medication For all subjects, the maximum average dose of asenapine was 13.6 ± 6.4 mg/d. For those completing the 12-week study, the maximum average dose of asenapine was 15.9 ± 4.9 mg/d. Side Effects and Safety Monitoring Evaluation of abnormal movements was conducted using the AIMS, BARS and SAS. The scores were essentially zero from baseline to endpoint. Weight was measured at each visit and body mass index (BMI) calculated. The mean BMI was 31.0 ± 4.6 at baseline and 31.8 ± 4.10 at week 12.
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Adjunctive Asenapine for PTSD FIGURE 1
Change in Clinician Administered PTSD Scale (CAPS) Total Score and Subscores for CAPS-B (Re-Experiencing Symptoms), CAPS-C (Avoidance and Emotional Numbing) and CAPS-D (Hyperarousal) From Baseline Over Time (Weeks) in Veterans with Diagnosis of Posttraumatic Stress Disorder Treated with Open Label Asenapine Augmentation
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Eight participants experienced an adverse event (AE). Six participants had AE’s possibly related to asenapine, of which four stopped medication due to AE: one had sedation with syncope on day 1 (5 mg/d), one had severe agitation on day 4 (5 mg/d), one had weight gain and sedation at week 4 (5 mg/d), and one had sedation and severe extrapyramidal side effects (20 mg/d) at week 12. Two subjects continued the medication after AE: one participant experienced transient headache, fatigue, and gastrointestinal upset at 10mg/d and the other experienced sedation at 10 mg/d which improved with dose reduction. As unrelated AE’s, one participant had a sinus infection and one participant was hospitalized on the psychiatric unit in the month following study exit and was not on asenapine at the time.
13 Pilkinton, Berry, Norrholm, et al.
Discussion In this open-label pilot study, adjunctive asenapine was shown to be effective in reducing symptoms of PTSD in a diverse group of U.S. Veterans. The addition, asenapine contributed to a reduction in PTSD symptomatology in all symptom clusters (re-experiencing, avoidance/numbing, and hyperarousal) with the greatest response in re-experiencing cluster and least response in the avoidance/emotional numbing symptom cluster. This is consistent with other studies30 that note lower medication response in other sub-symptoms. It has been suggested that different P sychopharmacology B ulletin : Vol. 46 · No. 2
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14
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77.6 (14.5) 19.9 (5.7) 32.2 (9) 25.4 (5) 57.3 (12.2) 28.9 (13.6) 4.8 (1) 14.3 (4.1)
BASELINE
48.7 (30.6) 10.9 (10.9) 21.9 (13.4) 15.9 (9) 46.2 (14.1) 16.7 (10) 3.5 (0.8) 11.3 (6.3)
46.5 (22.8) 10.3 (7.6) 20 (9.6) 16.2 (7.8) 37.8 (14.2) 15.0 (7.2) 3.4 (1.1) 7.6 (4.5)
MEAN (SD) SCORES WEEK 4 WEEK 8
35.3 (19.7) 7.8 (6.6) 16.6 (10.1) 10.8 (7.4) 41.5 (14.7) 12.9 (6.9) 3 (1.1) 6.7 (4.1)
WEEK 12
–27.8 (19.1) –8.6 (8.7) –9.9 (7) –9.3 (6.9) –18.2 (15) –13.4 (8) –1.5 (1.7) –5.9 (6.9)
–39 (18.4) –11.1 (8.2) –13.3 (10.3) –14.6 (7.6) –14.5 (9.8) –15.5 (9.3) –1.9 (1.3) -6.8 (4.4)
MEAN (SD) CHANGE OVER TIME WEEK 8 WEEK 12
–31 (27.9) –9.2 (10.8) –11.3 (12.4) –10.5 (8.1) –13.9 (11.7) –15.7 (9.7) –1.8 (0.7) –3.5 (6.5)
WEEK 4
f
9.3 6.5 5.7 9.8 5.3 6.8 9.7 6.7
P
,.0001 .0009 .0021 ,.0001 .003 .0006 ,.0001 .0007
Abbreviations: SD, Standard Deviation; CAPS, Clinician Administered PTSD Scale for DSM-IV; CAPS-B, PTSD re-experiencing symptoms; CAP-C, PTSD avoidance and emotional numbing symptoms; CAP-D, PTSD hyperarousal symptoms; PCL, PTSD Checklist for DSM-IV; BPRS, Brief Psychiatric Rating Scale; CGI-S, Clinical Global Impression for Severity; QIDS-SR, 16-item Quick Inventory of Depressive Symptomatology – Self Report.
CAPS-Total CAPS-B CAPS-C CAPS-D PCL BPRS CGI-S QIDS-SR
RATING SCALE
Symptom Ratings During Adjunctive Asenapine Treatment for Posttraumatic Stress Disorder
TABLE 1
Adjunctive Asenapine for PTSD
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neural mechanisms and pathways underlie the development of avoidance and numbing behaviors,31 thus limiting their responsiveness to traditional medication therapies. Alternately, avoidance and emotional numbing symptoms may reflect a behavioral adaptation used by the patient to manage re-experiencing and hyperarousal symptoms. While the majority of improvement occurred within the first 4 weeks, additional benefits were noted through week 12 on the CAPS and PCL measures. This is consistent with other studies of time to response32 and suggests that shorter trials may have failed to capture the full response to medication. The vigorous response noted in this study in the first 4 weeks could be attributed to the synergistic effects of the index antidepressant and asenapine when compared to initiating medication in a treatment-naïve patient. Clinically significant responses were also noted in comorbid depressive symptoms as measured by the QIDS-SR. Asenapine is active at several 5HT receptor subtypes which might account for improvement in depressive symptoms in this study. Studies of atypical antipsychotics or aripiprazole augmentation in the treatment of major depression have yielded positive results.33,34 In this study, asenapine demonstrated a favorable side effect profile, with minimal weight gain and only one participant experiencing extrapyramidal side effects while at the 20 mg/day dose. The study population is consistent with the population of patients presenting for treatment at a Veterans Affairs Medical Center. We attempted to simulate a typical outpatient treatment setting by recruiting a naturalistic sample of US Veterans presenting for treatment. By enrolling a wide spectrum of participants with regards to index antidepressant, age, index trauma, and symptom duration we were attempting to achieve generalizable results. By doing so, it may have impacted our ability to detect which patients would be most likely to benefit from this augmentation approach. Since our study population had high rates of comorbid depression, and residual symptoms even after optimized antidepressant treatment, they may represent a more refractory subgroup than many single drug studies. This study was limited by both the small number of subjects enrolled and its open-label design. The small number of subjects also limits our ability to determine if asenapine augmentation has greater efficacy with specific antidepressants. The open-label design may introduce bias into the reporting and rating of symptoms.
15 Pilkinton, Berry, Norrholm, et al.
Conclusion In conclusion, the findings of this study support consideration of asenapine in the treatment of refractory PTSD. A larger double-blind, P sychopharmacology B ulletin : Vol. 46 · No. 2
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placebo-controlled study is warranted to further define its role in the medication management of PTSD. D Acknowledgement Financial support for this study provided through an investigator initiated study grant from Merck, Sharp & Dohme Corp. and Forest Research Institute, Inc. We acknowledge the outstanding clinical research coordination of Anita Davis. We are grateful for the administrative support of the Tuscaloosa VA Research and Development Service. Conflicts of Interests Dr. Davis has served as a consultant for Tonix, Otsuka, Lundbeck, and Brackett. 16 Pilkinton, Berry, Norrholm, et al.
Trial Registration clinicaltrials.gov Identifier: NCT01587118. Disclosure Opinions herein are those of the individual authors and the contents do not represent the views of the Department of Veterans Affairs or the United States Government. References 1. Goldstein RB, Smith SM, Chou SP, et al. The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the national Epidemiologic Survey on Alcohol and Related Conditions-III. Soc Psychiatry Psychiatr Epidemiol. 2016 Epub ahead of print 22 Apr 2016. 2. Kessler RC, Sonnega A, Bromet E, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048–1060. 3. Hoge CW, Castro CA, Messer SC, et al. Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care. N Engl J Med. 2004;351(1):13–22. 4. Ohayon MM, Shapiro CM. Sleep disturbances and psychiatric disorders associated with posttraumatic stress disorder in the general population. Compr Psychiatry. 2000;41:469–478. 5. Tuerk PW, Wangelin B, Rauch SA, et al. Health service utilization before and after evidence-based treatment for PTSD. Psychol Serv. 2013;10:401–409. 6. Institute of Medicine (IOM). Treatment of posttraumatic stress disorder: an assessment of the evidence. Washington, DC: The National Academic Press, 2008. 7. Hamner MB, Robert S, Frueh BC. Treatment-resistance posttraumatic stress disorder: strategies for intervention. CNS Spectr. 2004;9:740–752. 8. Ahearn EP, Juergens T, Cordes T, et al. A review of atypical antipsychotic medications for posttraumatic stress disorder. Int Clin Psychopharmacol. 2011;26:193–200. 9. Padala PR, Madison J, Monnahan M, et al. Risperidone monotherapy for post-traumatic stress disorder related to sexual assault and domestic abuse in women. Int Clin Psychopharmacol. 2006;21:275–280.
P sychopharmacology B ulletin : Vol. 46 · No. 2
PB-Pilkinton.indd 16
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Adjunctive Asenapine for PTSD 10. Hamner MB, Faldowski RA, Ulmer HG, et al. Adjunctive risperidone treatment in post-traumatic stress disorder: A preliminary controlled trial of effects on comorbid psychotic symptoms. Int Clin Psychopharmacol. 2003;18:1–8. 11. Butterfield MI, Becker ME, Connor KM, et al. Olanzapine in the treatment of posttraumtic stress disorder. A pilot study. Int Clin Psychopharmacol. 2001;16(4):197–203. 12. Bartzokis G, Lu PH, Turner J, et al. Adjunctive risperidone in the treatment of chronic combat-related PTSD. Biol Psych. 2004;57:474–479. 13. Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressantresistant symptoms of chronic military service-related PTSD: a randomized trial. JAMA. 2011; 306:493–502. 14. McIntyre RS, Cohen M, Zhao J, et al. Asenapine in the treatment of acute mania in bipolar I disorder: a randomized, double blind, placebo controlled trial. J Affect Disord. 2010;122:27–38. 15. Bishara D and Taylor D. Asenapine monotherapy in acute treatment of both schizophrenia and bipolar I disorder. Neuropsychiatric Disease and Treatment. 2009;5:493–490. 16. Bremner JD, Southwick SM, Charney DS. The neurobiology of posttraumatic stress disorder: An integration of animal and human research. In: Saigh PA, Bremner JD, eds. Posttraumatic Stress Disorder: A Comprehensive Text. Boston: Allyn and Bacon, 1999;103–143. 17. Shahid M, Walker GB, Zorn SH, et al. Asenapine: a novel psychopharmacologic agent with a unique receptor signature. J Psychopharmacol. 2009;23:65–73. 18. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo and risperdone controlled trial. J Clin Psychiatry. 2007;68(1):1492–1500. 19. Sheehan DV, Lecrubier Y, Harnett Sheehan K, et al. The validity of the Mini International Neuropsychiatric Interview (MINI) according to the SCID-P and its reliability. European Psychiatry. 1997;12:232–241. 20. Blake DD, Weathers FW, Nagy LM, et al. The development of a Clinician-Administered PTSD Scale. J Trauma Stress. 1995;8:75–90. 21. Guy W.ECDEU – Assessment manual for psychopharmacology. Washington: National Institute of Mental Health (Ed.), 1976. 22. Rush AJ, Trividi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report (QIDS-SR): a psychometric evaluation in patients with chronic major depression. Biol Psych. 2003;54:573–583. 23. Endicott J, Nee J, Harrison W, et al. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull. 1993;29:321–326. 24. Weathers FW, Litz BT, Herman DS, et al. The PTSD Checklist (PCL): Reliability, validity, and diagnostic utility. Proceedings of the Annual Conference of the International Society for Traumatic Stress Studies; 1993 Oct 25; San Antonio, TX. 25. Overall JE and Gorham DR. The Brief Psychiatric Rating Scale (BPRS): recent developments in ascertainment and scaling. Psychopharmacol Bulletin. 1993;24:97–99. 26. Wisniewski SR, Rush AJ, Balasubramani GK, et al. Self-rated global measure of the frequency, intensity, and burden of side effects. J Psychiatr Pract. 2006;12:71–79. 27. Munetz MR and Benjamin S. How to examine patients using the Abnormal Involuntary Movement Scale. Hospital and Community Psychiatry. 1988;39:1172–1177. 28. Banes T. A rating scale for drug induced akathisia. British Journal of Psychiatry. 1989;154:672–676. 29. Wang S, et al. Asenapine, Blonanserin, Iloperidone, Lurasidone, and Sertindole: Distinctive Clinical Characteristics of 5 Novel Atypical Antipsychotics. Clin Neuropharmacol. 2013;36:223–238. 30. Han C, Lee SJ, Patkar AA, et al. The potential role of atypical antipsychotics for the treatment of posttraumatic stress disorder. J Psychiatric Res. 2014;56:72–81. 31. Blomhoff S, Beinvang I, Malt UF. Event-related potentials to stimuli with emotional impact in posttraumatic stress patients. Biol Psychiatry. 1998;44:1045–1053. 32. Stein DJ, Pederson R, Rothbaum BO, et al. Onset of activity and time to response on individual CAPS-SX17 items in patients treated for post-traumatic stress disorder with venlafaxine ER: a pooled analysis. Int J Neuropsychopharm. 2009;12:23–31. 33. Zhou X, Keitner GI, Qin B, et al. Atypical antipsychotic augmentation for treatment-resistant depression: A systematic review and network meta-analysis. Int J Neuropsychopharm. 2015;18(11):1–10. 34. Han C, Wang SM, Kwak KP, et al. Aripiprazole augmentation versus antidepressant switching for patients with major depression: A 6-week, randomized, rater-blinded, prospective study. J Psychiatr Res. 2015;66–67:84–94.
17 Pilkinton, Berry, Norrholm, et al.
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