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ORIGINAL CONTRIBUTION Adjunctive Risperidone Treatment
for Antidepressant-Resistant Symptoms
of Chronic Military Service–Related PTSD
A Randomized Trial
John H. Krystal, MD Context Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-
Robert A. Rosenheck, MD approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD).
Joyce A. Cramer, BS Objective To determine efficacy of the second-generation antipsychotic risperi-
Jennifer C. Vessicchio, MSW done as an adjunct to ongoing pharmacologic and psychosocial treatments for veter-ans with chronic military-related PTSD.
Karen M. Jones, MS Design, Setting, and Participants A 6-month, randomized, double-blind, placebo-
Julia E. Vertrees, PharmD controlled multicenter trial conducted between February 2007 and February 2010 at 23 Rebecca A. Horney, BA Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 werediagnosed with military-related PTSD and had ongoing symptoms despite at least 2 ad- Grant D. Huang, MPH, PhD equate SRI treatments, and 247 contributed to analysis of the primary outcome measure.
Christopher Stock, PharmD Intervention Risperidone (up to 4 mg once daily) or placebo.
for the Veterans Affairs Cooperative Main Outcome Measures The Clinician-Administered PTSD Scale (CAPS) (range,
Study No. 504 Group 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale(MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and der (PTSD) is among the Results Change in CAPS scores from baseline to 24 weeks in the risperidone group was
most common and disabling −16.3 (95% CI, −19.7 to −12.9) and in the placebo group, −12.5 (95% CI, −15.7 to −9.4); psychiatric disorders among the mean difference was 3.74 (95% CI, −0.86 to 8.35; t=1.6; P=.11). Mixed model analy- military personnel serving in combat sis of all time points also showed no significant difference in CAPS score (risperidone: mean, theaters.1-3 Antidepressants are the pre- 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean dominant pharmacotherapy for PTSD.
difference, 2.73; 95% CI, −0.74 to 6.20; P=.12). Risperidone did not reduce symptomsof depression (MADRS mean difference, 1.19; 95% CI, −0.29 to 2.68; P=.11) or anxiety Two serotonin reuptake inhibitors (HAMA mean difference, 1.16; 95% CI, −0.18 to 2.51; P=.09; patient-rated CGI mean (SRIs), sertraline and paroxetine, have difference, 0.20; 95% CI, −0.06 to 0.45; P=.14; observer-rated CGI mean difference, 0.18; Food and Drug Administration ap- 95% CI, 0.01 to 0.34; P=.04), or increase quality of life (SF-36V physical component mean proval for the treatment of PTSD based difference, −1.13, 95% CI, −2.58 to 0.32; P=.13; SF-36V mental component mean dif- on multicenter trials.4-7 Within the De- ference, −0.26; 95% CI, −2.13 to 1.61; P=.79). Adverse events were more common with partment of Veterans Affairs (VA), 89% risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% of veterans diagnosed with PTSD and vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively.
treated with pharmacotherapy are pre- Conclusion Among patients with military-related PTSD with SRI-resistant symp-
scribed SRIs.8 However, SRIs appear to toms, 6-month treatment with risperidone compared with placebo did not reduce PTSD be less effective in men than in women4 and less effective in chronic PTSD than Trial Registration Identifier: NCT00099983
in acute PTSD.9,10 Thus, it may not be surprising that an SRI study in veter-ans produced negative results.11 Author Affiliations and Members of the Veterans Af-
fairs Cooperative Study No. 504 Group are listed at
(SGAs) are commonly used medica- the end of this article.
tions for SRI-resistant PTSD symp- Corresponding Author: John H. Krystal, MD, VA Con-
For editorial comment see p 549.
necticut Healthcare System (151-D), 950 Campbell Ave, toms, despite limited evidence support- West Haven, CT 06516 ([email protected]).
2011 American Medical Association. All rights reserved.
JAMA, August 3, 2011—Vol 306, No. 5 493
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER ing this practice.12,13 In 2007, PTSD was to screening; had clinical or labora- would be engaged if study medica- the most common off-label diagnosis tory evidence (levels of aspartate ami- tions were ineffective. These alterna- within the VA associated with an anti- notransferase, alanine aminotransfer- tive treatments enabled some patients psychotic prescription.14 In 2009, ase, bilirubin, blood urea nitrogen, or to remain as participants for the full 6 86 852 veterans diagnosed with PTSD creatinine) of hepatic or renal compro- months of randomized treatment (19.9%) received an antipsychotic pre- mise; had a medical disorder that might (eTable 1, available at http://www.jama scription and 81 279 of these prescrip- increase the risks of risperidone treat- .com). There were no significant dif- tions (93.6%) were for SGAs.14 There ment (insulin-dependent diabetes) or ferences across groups in the fre- are substantial safety concerns associ- complicate interpretation of study re- quency with which these adjunctive ated with SGAs, particularly risks for sults (epilepsy, dementia); had a his- medications from particular classes weight gain and extrapyramidal mo- tory of intolerance of antipsychotics; at- were initiated during the clinical trial.
tempted suicide or assaulted someone Patients participated in a feedback The current study evaluated whether in the prior year; or had an impending program that was designed to en- risperidone, an SGA, when added to an legal incarceration. Although ongoing hance adherence to prescribed medi- ongoing pharmacotherapy regimen pharmacotherapy was allowed, pa- cations.18,19 Medication was provided in would be more effective than placebo tients receiving SGAs, serotonergic bottles with microelectronic monitor for reducing chronic military-related (5HT2) receptor antagonists (cypro- caps (MEMS; AARDEX Group, Union PTSD symptoms among veterans whose heptadine, methysergide, trazodone), City, California) that recorded the date symptoms did not respond to at least ␣1 receptor antagonists (prazosin), and and time of each opening and showed 2 adequate SRI treatments. To our ␣2 receptor agonists/antagonists the number of hours elapsed since the knowledge, this study is the first large (clonidine, guanfacine, mirtazapine) previous opening. The Medication Us- trial of a pharmacotherapy aimed at SRI- were excluded initially.
age Skills for Effectiveness feedback sys- resistant PTSD symptoms.
Race and ethnicity of the partici- tem,18 in which data on the previous pants were determined by self-reports month's dosing were shown to pa- with concurrence by the rater.
tients at each visit, encouraged pa- Patients were eligible if they were at tients to take medication daily by train- least 18 years old, participated in a ing them to develop and use reminders military combat theater, met diagnos- The human subjects subcommittees of that supported medication adherence.
tic criteria for military service–related the VA Cooperative Studies Program chronic PTSD on the basis of a struc- and each participating VA Medical Cen- Randomization and Treatment
tured interview for making psychiatric ter approved this study. All patients Patients were recruited initially from 20 diagnoses according to the Diagnostic gave written informed consent prior to VA Medical Centers over a 2-year pe- and Statistical Manual of Mental Disor- study entry. An independent data safety riod. To address low recruitment rates ders (Fourth Edition) (DSM-IV),16 had monitoring board monitored patient and other issues, 8 sites were discon- a Clinician-Administered PTSD Scale safety throughout the study.
tinued and 6 sites were added during (CAPS) score greater than 50,17 had a Patients were randomized to re- the course of the study. A total of 26 clinical history of intolerance of or ceive double-blinded 6-month treat- sites were approved by the human sub- nonresponse to 2 or more antidepres- ment with risperidone or matched pla- jects subcommittee to enroll patients sants, and had an inadequate response cebo. Study medication (risperidone 1 into the study. In addition, the recruit- to 2 adequate SRI treatments (mini- mg or matching placebo) was initi- ment period was extended by 6 months, mum of 4 weeks of pharmacotherapy ated at a dose of 1 tablet orally at bed- and patients who had initially been con- each). Other eligibility criteria time and increased by 1 tablet per week sidered ineligible to participate in the included having a fixed address within to a dose of 3 tablets at bedtime. After study because they were receiving cer- 50 miles of the research site or con- participants received study medica- tain drugs (trazodone ⱕ100 mg, ne- firmed transportation for all visits, tion for 4 weeks, investigators who were fazodone ⱕ100 mg, quetiapine ⱕ25 using an acceptable method of birth blinded to study medication status and mg, and mirtazapine ⱕ30 mg) were al- control (female patients), and giving were treating patients had the option lowed if the drugs were prescribed for written informed consent.
of further increasing the dose by 1 tab- at least 3 months prior to screening and Patients were excluded if they met let (1 mg), providing medications were prescribed at the current dose for at least lifetime diagnostic criteria for bipolar well tolerated and a dose increase was 1 month. A total of 83 patients (42 in disorder or schizophrenia; required an- the risperidone group, 41 in the pla- tipsychotic medication for the treat- Prior to study entry, patients and cebo group) who were ultimately en- ment of psychosis; met diagnostic cri- their primary mental health care clini- rolled in this study had received at least teria for dependence on a substance cians developed a treatment plan that 1 of these medications. Secondary other than nicotine in the 30 days prior would not violate study protocol and analyses testing the effect of broaden- 494 JAMA, August 3, 2011—Vol 306, No. 5
2011 American Medical Association. All rights reserved.
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER ing the study entry criteria did not find Figure 1. Recruitment Flowchart in Clinical Trial of Risperidone Treatment for Military
any effects on the findings for the prin- Service–Related Posttraumatic Stress Disorder cipal outcome measures.
Randomized assignment of patients 367 Patients assessed for eligibility to treatment groups was conducted bythe Cooperative Studies Program Co- ordinating Center (Perry Point, Mary- land). Calls requesting randomizationwent to a central location on the day the patient was deemed eligible andready to start medication. Separate ran- 147 Randomized to receive risperidone 149 Randomized to receive placebo domization schedules were generated 145 Received risperidone 147 Received placebo 2 Lost to follow-up 2 Lost to follow-up for each participating center, assign-ing equal numbers of patients to each 123 Completed study 124 Completed study of the groups. Block sizes of 2 and 4 22 Discontinued study 23 Discontinued study were used to balance assignments across 14 Missing source documentation 15 Missing source documentation groups and to prevent decoding of the 1 Unable to return for appointments 1 Unable to return for appointments system. Assignments were stratified within centers. Patients were evalu- 1 Other psychiatric problem 1 Lost to follow-up 1 Intolerant of burden of visits ated to ensure they met all eligibility cri- 1 Lack of effectiveness teria before a randomization code wasprovided. Treatment was initiated 123 Included in primary analysis 124 Included in primary analysis within a day of randomization.
Valid baseline data were collected for 267 patients; the primary outcome analysis included 247 patients forwhom a valid week-24 CAPS assessment was obtained.
Outcome Measures
The primary outcome measure for this
study was the total score on the 34-
sis (Positive and Negative Syndrome the improvement in PTSD symptoms item CAPS.20 This scale was adminis- Scale [PANSS]),23 the Veterans RAND from baseline to week-24 follow-up as tered by trained raters who were blind 36-Item Health Survey (SF-36V),24 the measured by the CAPS. A 2-tailed t test to the randomization status of pa- 26-item Boston Life Satisfaction Inven- was performed on these data using an tients at baseline and weeks 6, 12, and tory (BLSI),25 and a service utilization ␣=.05. This study was powered ini- 24. All raters underwent initial train- measure. At each visit, smoking was as- tially to detect a 9-point difference ing and credentialing to administer and sessed using the first 3 items of the Fag- between the treatment groups in the score the primary and secondary out- erstro¨m Scale,26 and alcohol consump- CAPS change score; assuming a 20% come measures. They also completed tion was evaluated using the timeline dropout rate and a power of 0.9, a target annual training and reliability checks follow-back method for the 90 days prior sample size of 205 patients per group was during the study to ensure that they met to study entry and the interval between required. In the absence of a validated at least 80% reliability of their mea- each visit.27 Motor adverse events asso- threshold for minimal important differ- surement; all raters eventually met this ciated with risperidone were assessed ence on the CAPS, the threshold of 9 reliability standard. Interrater reliabil- using the Barnes Akathisia Scale,28 the points was derived from data suggest- ity was assessed at 2 annual subse- Extrapyramidal Symptom Rating Scale,29 ing the following: (1) a 9-point decrease quent time points. All raters showed and the Abnormal Involuntary Move- would be predicted to produce clearly evi- 100% diagnostic accuracy at both ses- ment Scale.30 On all reported outcome dent changes in core PTSD symp- sions, and median scores were within measures except the SF-36V, higher toms31,32; (2) 9 points was estimated to 0.5 points and 3 points at the 2 annual scores reflect higher symptom levels. On be approximately 0.5 SD in severely the SF-36V, higher scores reflect higher symptomatic veterans with PTSD,33 and The CAPS provided an overall mea- quality of life.
across medical conditions score reduc- sure of PTSD symptom severity. Second- tions of 0.5 SD are generally found to be ary outcomes were assessed each time the a minimal important difference34; and (3) CAPS was administered: the observer- Data were collected and analyzed by the 9- to 10-point decreases would be rated and patient-rated Clinical Global VA Cooperative Studies Program. Base- expected to be associated with improve- Impression scale (CGI), the Montgom- line characteristics were compared with ments in measures of quality of life.35 ery-Asberg Depression Rating Scale ␹2 and t tests as appropriate.
The recruitment rate was lower than (MADRS),21 the Hamilton Anxiety Scale The primary outcome measure in this projected, with a total of 296 random- (HAMA),22 a scale used to rate psycho- study was the intent-to-treat analysis of ized patients rather than the targeted 410.
2011 American Medical Association. All rights reserved.
JAMA, August 3, 2011—Vol 306, No. 5 495
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER However, both the dropout rate and the covarying for baseline values and using symptoms associated with DSM- variance in the data were lower than pro- all available outcome data. The mod- IV-TR diagnostic criteria37—reexperi- jected, offsetting the effects of the ac- els initially had fixed effects for treat- encing, avoidance/numbing, and hy- tual sample size on the statistical power ment group and time. The interac- perarousal20—were analyzed separately of the study. Two hundred forty-seven tions between treatment and time effects with Bonferroni adjustments for mul- patients (123 per group, for purposes of were dropped because they were not tiple comparisons. Also, treatment ef- power calculation) completed the study.
significant in reported analyses. Site and fects on PTSD severity categories based Based on the original parameters for patient were treated as random ef- on the CAPS32 were analyzed using a study sample size, an ␣=.05, and the es- fects. Generalized least squares means 2-tailed ␹2 test. This analysis yielded an timated pooled 18.4 SD, this sample size of treatment effect were computed estimate of medication effects on re- provided 96.9% power to detect a 9-point within the SAS mixed linear models mission rates in this study as defined difference between the groups in the pri- procedures (MIXED and GLIMMIX) by a CAPS score of less than 20.38 mary outcome measure—ie, the differ- used to analyze outcome data (SAS In- A comparison of the treatment groups ence between baseline and week-24 stitute, Cary, North Carolina). These on retention in the study was based on CAPS scores.
least squares means are estimators of the survival analysis of time (days) receiv- In secondary and exploratory analy- treatment means that would be ex- ing study medication as measured from ses, the CAPS, its subscales, and all pected for a balanced design.
the day of randomization to the day of other continuous outcome measures In post hoc analyses, the severity of last dose. Survival curves for study re- were analyzed using mixed models,36 the 3 component clusters of PTSD tention were estimated for each treat-ment group with Kaplan-Meier meth-odology (SAS procedure LIFETEST), and Table 1. Baseline Demographic Data
treatment group comparisons were based on the log-rank test.
Age, mean (SD), y Of the 26 sites that were approved to enroll patients into the study, 23 sites Race/ethnicity, No. (%) enrolled patients from February 2007 White, not Hispanic to August 2009, with follow-up end- Black, not Hispanic ing in February 2010. A total of 367 pa- tients screened yielded 296 patients di- agnosed with military-related PTSD Weight, mean (SD), lbc with clinically significant SRI- Marital status, No. (%)d resistant PTSD symptoms who signed consent forms from 23 sites (FIGURE 1).
Valid diagnostic and primary out- come data were collected on 267 pa- tients randomized to receive risperi- done (n = 133) and placebo (n = 134) Living with partner Education, mean (SD), ye The study populations included se- Employment (current), No. (%)d verely ill patients, many of whom had disabilities related to long-standing mili- Irregular, part time tary-related PTSD (TABLE 1, TABLE 2,
and TABLE 3). The sample was pre-
dominately male (n = 258, 96.6%), Military history, No. (%) middle-aged (mean [SD] age, 54.4 WWI, WWII, Korea, Vietnam [10.7] years), non-Hispanic white Gulf War, Afghanistan, Iraq (n=177, 66.3%), and married (n=140, Balkans, other war 52.4%) or divorced (n = 60, 22.5%).
Most patients served during the Viet- Abbreviations: WWI, World War I; WWII, World War II.
a t Test.
nam war or earlier (n = 193, 72.3%) or b Fisher exact test.
c Data were missing for 13 patients.
the wars in Iraq and Afghanistan (n=63, d Data were missing or incorrect for 1 patient in the placebo group (0.4% of total patients).
23.6%). Their PTSD symptoms were at- e Data were missing for 2 patients.
tributed principally to direct participa- 496 JAMA, August 3, 2011—Vol 306, No. 5
2011 American Medical Association. All rights reserved.
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER tion in combat (n = 209, 78.3%). The Table 2. Disability and Service Utilization at Baselinea
majority of patients in this study also met lifetime diagnostic criteria for ma- jor depression (n=186, 69.7%) and life- VA disability pension, No. (%) time alcohol abuse or dependence (n = 167, 62.5%). Smaller numbers of patients were smokers (n = 88, 33.0%) Medical disability, No. (%) or met diagnostic criteria for other life- time substance abuse or dependence, Medical disability, mean (SD), %d antisocial personality disorder, or other Psychiatric disability, No. (%) Most patients in this study received VA service–connected disability com- Psychiatric disability , mean (SD), %e pensation (n = 223, 83.5%), of which Social Security pension, No. (%) 181 (81.2%) and 163 (73.1%) had psychiatric and medical disability, respectively. More than one-third of VA service use, No. (%) Outpatient mental health patients (n = 99, 37.1%) received a Social Security pension. Patients in Alcohol/drug abuse clinic this study received typical psychoso- Rehabilitation program cial treatments at the medical centers.
Readjustment counseling Based on data collected with a service Abbreviation: VA, Veterans Administration.
utilization measure, patients had a VA compensation and pension boards rule on the presence or absence of a VA service-connected disability. The dis- ability may be related to medical or psychiatric disorders. The extent of disability ranges from 0% to 100%.
received the following VA services in b Fisher exact test.
the month preceding study entry: 195 c t Test.
d Data were missing for 60 patients.
patients (74.1%) had received outpa- e Data were missing for 42 patients.
tient mental health treatment; 43patients (16.4%), case management;16 (6.1%), readjustment counseling; ious (mean [SD] HAMA score, 19.4 −12.9; placebo: −12.5; 95% CI, −15.7 and 15 (5.7%), addiction services.
[7.8]), with low levels of psychotic to −9.4; mean difference, 3.74; 95% CI, Less than 5% of the sample received symptoms (mean [SD] PANSS posi- −0.86 to 8.35; t = 1.6; P = .11). In the any other specified service. There tive symptom score, 11.6 [3.9]).
mixed model of CAPS total scores, the were no significant differences effect of medication was also not sig- between the groups in service utiliza- nificant (F1,253=2.30; P=.13), but symp- Rates of retention while receiving ran- tom scores decreased over time in both The patients in this study were domized treatment were high and did groups (F2,488=9.94; P⬍.001) (FIGURE 2
highly symptomatic at study baseline not differ by group (log-rank test and TABLE 4). Baseline CAPS score
despite long-standing individualized ␹21=0.71, P=.40) (eFigure 1). How- (F1, 253=257.67; P⬍.001), but not the pharmacologic treatments (mean ever, patients treated with placebo con- war in which the veteran served, was [SD] medications per patient: risperi- tinued receiving assigned medication on associated with higher CAPS score done, 3.09 [1.69]; placebo, 2.86 average approximately 1 week longer throughout the study. Neither effect in- [1.46]) (eTable 2 and eTable 3). There than patients treated with risperidone teracted significantly with medication were no significant differences in the (risperidone: median, 166.5 days; mean, group and controlling for their effects frequency with which medications 133.1 days; 95% confidence interval did not alter the findings.
other than SRIs were prescribed across [CI], 123.6-142.6 days; placebo: me- To further explore whether risperi- the groups prior to randomization or dian, 167.0 days; mean, 148.9 days; 95% done produced clinically significant in various combinations of medica- CI, 141.5-156.4 days; t = 2.59; Satter- changes on the CAPS, the distribution tions (eTable 4). Mean (SD) CAPS total thwaite df = 238.87; P = .01).
of patients in each treatment group was score at study entry was 78.2 (14.8), as- determined following a published cat- sociated with high levels of reexperi- egorization of PTSD status32 (0-19, encing (20.9 [6.4]), avoidance/ There were no significant effects of ris- asymptomatic/few symptoms; 20-39, numbing (31.5 [8.1]), and hyperarousal peridone treatment on the primary out- mild PTSD/subthreshold; 40-59, mod- (25.9 [4.9]) symptoms. Patients were come measure, the change in CAPS total erate PTSD/threshold; 60-79, severe significantly depressed (mean [SD] score from baseline to 24 weeks (ris- PTSD symptomatology; and ⬎80, ex- MADRS score, 23.4 [8.2]) and anx- peridone: −16.3; 95% CI, −19.7 to treme PTSD symptomatology). This 2011 American Medical Association. All rights reserved.
JAMA, August 3, 2011—Vol 306, No. 5 497
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER analysis did not reveal significant dif- In post hoc Bonferroni-adjusted not the CAPS avoidance/numbing ferences across treatment groups analyses (P = .02) of CAPS subscales (␹24=4.9; P=.30). This analysis also pro- using mixed regression models, ris- Assuming a 0.5-SD threshold for the vided information about the rate of re- peridone was associated with signifi- minimal clinically important differ- mission of patients in each group be- cantly reduced symptoms as mea- ence, the statistically significant find- cause a CAPS score of less than 20 is a sured by the CAPS reexperiencing ings for the CAPS subscales do not validated remission threshold.38 The meet this threshold. This suggests rate of remission in patients treated with d = 0.298) and the CAPS hyperarousal that although statistically significant, placebo (4%) did not differ signifi- subscale (treatment: F1,253 = 8.09, the changes on the CAPS scales cantly from patients treated with ris- P = .005, d = 0.318; treatment ⫻ week would not be recognized by many peridone (5%) (eFigure 2).
interaction: F2,486= 4.11, P = .02), but clinicians as meaningful.
Consistent with the CAPS findings, no medication effects on the observer- Table 3. Mental Health Conditions and Measures at Baseline
rated version (␹21=3.88, P=.049) or self- rated version (␹21=1.88, P=.17) of the CGI were significant after Bonferroni ad- justments for multiple comparisons (sig- PTSD symptom attribution nificance threshold: P=.008). Also there Direct participation in combat were no significant drug effects on anxi- Other combat-related events ety (HAMA score: F1,249=3.20, P=.08), Physical or sexual abuse depression (MADRS score: F1,248=2.02, Other event during military service P = .16), psychosis (PANSS positive symptom score: F1,250=0.43, P⬎.10), or quality of life (SF-36V physical compo- nent score: F1,248=2.24, P=.14).
Adverse events that occurred in at least 5% of the overall sample are reported in eTable 5. Overall, the rate of ad- verse events during treatment was low but appeared related to dosing of ris- peridone. The study protocol targeted No. of cigarettes per dayc a risperidone dose of 3 mg/day and al- lowed clinicians to increase the dose to Major depressionb,c 4 mg if indicated. With these instruc- tions, the modal medication dose was 4 mg for both groups. By the end of the study, patients randomized to receive placebo were receiving 3.35 mg of pla- cebo on average, suggesting that clini- cians were satisfied with the clinical Generalized anxiety disorderb,c progress of many patients treated with placebo. However, patients random- ized to risperidone were receiving on average a dose of 2.74 mg. This sug- gests, consistent with our clinical im- pressions, that adverse effects limited some patients from achieving the tar- get dose of 3 mg. This study was un- Antisocial personality disorderb able to determine whether adverse ef- fects limited the efficacy of risperidone, but perhaps these data suggest that fu- ture studies should explore doses lower than 3 mg of risperidone.
498 JAMA, August 3, 2011—Vol 306, No. 5
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RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER However, there were significantly Table 3. Mental Health Conditions and Measures at Baseline (continued)
more cases in the group treated with ris- peridone of self-reported weight gain(risperidone: n = 20, 15.3%; placebo: n=3, 2.3%), fatigue (risperidone: n=18, 13.7%; placebo: n=0), somnolence (ris- CAPS score, mean (SD) peridone: n = 13, 9.9%; placebo: n = 2, Part B (reexperiencing) 1.5%), and hypersalivation (risperi- Part C (avoidance/numbing) done: n=13, 9.9%; placebo: n=1, 0.8%) Part D (hyperarousal) (eTable 5). Risperidone did not in- PCL score, mean (SD) crease measured weight significantly Part B (reexperiencing)f 1,235 = 2.86, P = .09). Also, there were no significant effects of risperidone on Part C (avoidance/numbing) g the 3 measures of extrapyramidal symp- Part D (hyperarousal)h toms in this study, the Barnes Akathi- CGI, observer rated, mean (SD)f sia Scale, the Extrapyramidal Symp- MADRS, mean (SD)i tom Rating Scale, and the Abnormal Involuntary Movement Scale.
PANSS score, mean (SD)f Positive symptoms Negative symptoms In this study, there was no statistically significant difference between risperi- Pittsburgh Sleep Scale total score, done and placebo in reducing CAPS total scores when prescribed for 6 BLSI score, mean (SD)l months as an adjunct to SRIs and other SF-36V PCS score, mean (SD)m ongoing medication and psychosocial SF-36V MCS score, mean (SD)m treatments in a group of highly symp- Abbreviations: BLSI, Boston Life Satisfaction Inventory; CAPS, Clinician-Administered PTSD Scale; CGI, Clinical Global Impression; HAMA, Hamilton Anxiety Scale; MADRS, Montgomery-Asberg Depression Rating Scale; PANSS, Positive tomatic veterans with medication- and Negative Syndrome Scale; PCL, PTSD Checklist; PTSD, posttraumatic stress disorder; SF-36V PCS and MCS, resistant symptoms associated with Veterans RAND 36-Item Health Survey physical component subscale and mental component subscale.
a Fisher exact test.
chronic military-related PTSD. Com- b Based on lifetime DSM-IV diagnosis.
pared with placebo, risperidone pro- Data were missing or incorrect for 1 patient in the placebo group (0.4% of total patients).
d t Test.
duced only a 3.74-point greater reduc- e Data were missing for 13 patients.
f Data were missing for 1 patient.
tion from baseline in the CAPS total g Data were missing for 10 patients.
score. Thus, it is unlikely that clini- Data were missing for 7 patients.
i Data were missing for 2 patients.
cians could detect the magnitude of the j Data were missing for 3 patients.
k Data were missing for 23 patients.
risperidone effect over placebo that was l Data were missing for 18 patients.
observed in this study. In addition, ris- Data were missing for 4 patients.
peridone was not statistically superiorto placebo on any of the secondary out- tistically, these changes were smaller widespread prescription of trazodone, comes, including the observer- and self- than the 0.5-SD threshold used to de- a 5-HT2 receptor antagonist, for sleep rated versions of the Clinical Global Im- fine the minimal important difference impairment associated with PTSD.40 It pressions scale; quality of life (SF-36V in estimating the sample size for this is also consistent with the increasing or BLSI); and measures of depression study.34 Thus, it is questionable whether evidence of the efficacy of prazosin, an (MADRS), anxiety (HAMA), or para- the observed changes on these sub- ␣1 adrenergic receptor antagonist, for noia/psychosis (PANSS positive symp- scales would be detected clinically.
treating reexperiencing and hyper- tom subscale).
However, this study could not rule arousal symptoms of PTSD.41-43 Adverse events associated with ris- out the possibility that risperidone treat- The lack of efficacy of adjunctive ris- peridone were not serious. Post hoc ment addressed a real clinical need for peridone on CAPS total scores and analyses of the CAPS, adjusted for mul- some patients. The ability of risperi- global outcome measures in this study tiple comparisons, suggested that ris- done to reduce reexperiencing and hy- contrasts with positive findings from peridone was associated with a signifi- perarousal symptoms, such as dis- some smaller randomized trials4-11,44 but cant reduction in reexperiencing and rupted sleep and autonomic arousal, is is consistent with a study of SRI- hyperarousal symptoms associated with consistent with its ability to block resistant civilian PTSD.45 However, the PTSD with a small effect size. Al- 5-HT2A and ␣1 adrenergic receptors.39 lack of risperidone efficacy on avoid- though the findings were significant sta- This hypothesis is supported by the ance/emotional numbing symptoms 2011 American Medical Association. All rights reserved.
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RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER Table 4. Follow-up Assessment Outcomes Based on Least Squares Mean Estimates With All Available Data Up to 24 Weeksa
Mean (95% CI)
64.43 (61.98 to 66.89) 67.16 (64.71 to 69.62) 2.73 (−0.74 to 6.20) Part B (reexperiencing) 15.54 (14.58 to 16.49) 17.55 (16.60 to 18.50) 2.01 (0.66 to 3.37) Part C (avoidance/numbing) 27.98 (26.77 to 29.19) 26.93 (25.72 to 28.13) −1.05 (−2.76 to 0.66) Part D (hyperarousal) 20.99 (20.16 to 21.83) 22.70 (21.87 to 23.54) 1.71 (0.53 to 2.89) 15.80 (14.86 to 16.75) 16.97 (16.02 to 17.92) 1.16 (−0.18 to 2.51) 19.24 (18.19 to 20.29) 20.43 (19.39 to 21.48) 1.19 (−0.29 to 2.68) 104.62 (102.02 to 107.22) 104.30 (101.64 to 106.95) −0.32 (−4.04 to 3.40) 39.66 (38.63 to 40.68) 38.53 (37.50 to 39.55) −1.13 (−2.58 to 0.32) 33.80 (32.48 to 35.13) 33.55 (32.22 to 34.87) −0.26 (−2.13 to 1.61) 55.77 (54.24 to 57.30) 55.56 (54.03 to 57.09) −0.21 (−2.37 to 1.96) 31.69 (30.81 to 32.56) 31.80 (30.93 to 32.68) 0.12 (−1.12 to 1.35) Positive symptoms 10.65 (10.26 to 11.05) 10.85 (10.46 to 11.25) 0.20 (−0.35 to 0.75) Negative symptoms 13.45 (12.96 to 13.94) 12.88 (12.39 to 13.37) −0.57 (−1.26 to 0.13) CGI, patient rated 4.49 (4.30 to 4.67) 4.68 (4.50 to 4.86) 0.20 (−0.06 to 0.45) CGI, observer rated 4.32 (4.20 to 4.43) 4.49 (4.38 to 4.61) 0.18 (0.01 to 0.34) 211.86 (210.48 to 213.25) 210.18 (208.78 to 211.58) −1.68 (−3.66 to 0.29) Abbreviations: BLSI, Boston Life Satisfaction Inventory; CAPS, Clinician-Administered PTSD Scale; CGI, Clinical Global Impression; CI, confidence interval; HAMA, Hamilton Anxiety Scale; MADRS, Montgomery-Asberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale; PTSD, posttraumatic stress disorder; SF-36V PCS and MCS, Veterans RAND36-Item Health Survey physical component subscale and mental component subscale.
a For all outcomes, the treatment comparison was a linear contrast based on a mixed-effects model with site as a random effect and with autocorrelated repeated measures over time.
On all reported outcome measures except SF-36V, higher scores reflect higher symptom levels; higher scores on SF-36V reflect higher quality of life.
loss of data was discovered, the 29 pa- Figure 2. Change in CAPS Total Score During Treatment
tients were excluded from further analy- ses and enrollment was discontinued at both sites. At 1 of these sites, enroll- ment was later restarted with a new site investigator. Because our analyses con- trolled for clustering by study site, it is unlikely that the loss of patient data from these 2 sites would have biased the results, which were based only on pa- tient data from the 23 other study sites.
Follow-up Time, wk In addition, the study participants in these 2 sites were balanced with re- spect to treatment group (14 in the ris- CAPS indicates Clinician-Administered Posttraumatic Stress Disorder Scale. Error bars indicate 95% confi- peridone group and 15 in the placebo dence intervals.
group), so pre-existing biases werelikely to have been distributed equally and the relatively greater efficacy for hy- done would be a useful adjunct to treat- across treatment groups. Even after ex- perarousal or reexperiencing symp- ment in paranoid or psychotic patients cluding these 29 patients, our study had toms appear to be consistent with find- adequate statistical power to detect a ings of prior risperidone studies.12 This study has several limitations.
clinically meaningful benefit of risperi- Second-generation antipsychotics have This study did not achieve the prespeci- done, if a true benefit had existed.
been proposed as a treatment strategy fied sample size of 410 patients pro- Patient retention in the study was for paranoia or other psychotic symp- jected for this study. Further, source greater than expected and variance toms associated with PTSD.46,47 How- documentation for 29 patients was in- within the data was less than ex- ever, positive symptoms of psychosis advertently lost, invalidating their data.
pected. Based on the 247 patients who were at very low levels at baseline in this These 29 patients (9.8% of all random- completed the study and the prespeci- study. Thus, this study does not in- ized study participants) were enrolled fied factors in the power analysis, this form the question of whether risperi- at 2 of the original study sites. After the study had 96.6% power to detect a 500 JAMA, August 3, 2011—Vol 306, No. 5
2011 American Medical Association. All rights reserved.
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER 9-point difference in the ability of ris- spread prescription of risperidone to pa- Lilly and Company; for the respondent in Eli LillyCanada Inc v Novapharm Ltd and Minister of Health peridone and placebo to reduce CAPS tients with chronic SRI-resistant mili- respondent; and for the Patent Medicine Prices Re- total score during treatment, a change tary-related PTSD symptoms, and these view Board of Canada in the matter of Janssen Ortho that might be considered a minimal im- findings should stimulate careful re- Inc and "Risperdal Consta"; and being a testifying ex-pert in Jones ex rel the State of Texas v Janssen Phar- portant difference. However, even if the view of the benefits of these medica- maceutica et al. No other conflicts were reported.
full projected sample had been re- tions in patients with chronic PTSD.
Funding/Support: This study was supported by the Co-
operative Studies Program of the Department of Vet-
cruited, this study most likely would erans Affairs Office of Research and Development. Ris- not have yielded statistical signifi- Author Affiliations: Clinical Neuroscience Division, De-
peridone and matching placebo were donated to the partment of Veterans Affairs National Center for PTSD cance for the small differential change VA Cooperative Studies Program Clinical Research (Dr Krystal), and Psychiatry Service, VA Connecticut Pharmacy Coordinating Center (Albuquerque, New in CAPS total scores produced by ris- Healthcare System, West Haven (Drs Krystal and Mexico) by Ortho-McNeil Janssen Scientific Affairs.
Rosenheck and Mss Cramer and Vessicchio); Depart- peridone and placebo (3.74 points).
Ortho-McNeil Janssen Scientific Affairs also contrib- ment of Psychiatry, Yale University School of Medi- uted a total of $606 219 to the Baltimore Research and A second limitation is that study en- cine, New Haven, Connecticut (Drs Krystal and Rosen- Education Foundation on behalf of the VA Coopera- try criteria were relaxed because of re- heck and Mss Cramer and Vessicchio); Psychiatry tive Studies Program.
Services, Yale–New Haven Hospital, New Haven (Dr cruitment problems; patients were ac- Role of the Sponsors: The authors were responsible
Krystal); VA New England Mental Illness Research Edu- for the collection, management, and analysis of the cation and Clinical Center, West Haven (Dr Rosen- data and for the preparation of the manuscript and heck); VA Cooperative Studies Program Coordinat- prescriptions of low doses of com- its submission for publication. The funding sources did ing Center, Perry Point, Maryland (Mss Jones and not have a role in the collection, management, or analy- monly prescribed sleep medications, Horney); VA Cooperative Studies Program Clinical Re- sis of the data. The funding sources were provided with search Pharmacy Coordinating Center, Albuquer- particularly trazodone and quetiap- a draft of the paper, and they were invited to provide que, New Mexico (Dr Vertrees); Cooperative Studies input on the text. Representatives of Ortho-McNeil ine. Although adjusting for this effect Program Central Office, VA Office of Research andDevelopment, Washington, DC (Dr Huang); and Phar- Janssen Scientific Affairs attended 2 meetings where did not alter the findings with respect macy Department/Mental Health Service, VA Medi- the design of the study was discussed. Ortho-McNeil to the CAPS, including these patients cal Center, Salt Lake City, Utah (Dr Stock).
Janssen Scientific Affairs was not responsible for anddid not determine the final design of the study, did may have reduced the expected effects Author Contributions: Ms Jones had full access to all
of the data in the study and takes responsibility for
not collect or manage study data, did not draft the of risperidone in the current study.
the integrity of the data and the accuracy of the data manuscript, and did not have approval authority overthe content of the paper.
Third, it is not clear that the findings analysis.
Study concept and design: Krystal, Rosenheck, Cramer, Members of the Department of Veterans Affairs Co-
generalize to other SGAs, such as Jones, Vertrees.
operative Study No. 504 Group (in addition to the au-
olanzapine or quetiapine, that may have Acquisition of data: Rosenheck, Cramer, Vessicchio, thors): J. Canive, L. Calais, A. Smith, E. Nye, Albu- querque, New Mexico; E. Duncan, K. Skelton, R.
somewhat different clinical profiles in Analysis and interpretation of data: Krystal, Rosenheck, Bradley, K. Tabb, T. Sergent, M. Daugherty, E. Russ, PTSD.10 Fourth, it remains to be deter- Jones, Vertrees, Horney, Huang.
Atlanta, Georgia; N. Denny, K. Arnemann, J. Lauren-Rusnack, J. Schillac, Austin, Texas; S. Batten, L. Dixon, mined whether the findings general- Drafting of the manuscript: Krystal, Rosenheck, Huang.
Critical revision of the manuscript for important in- A. Santanello, L. Bell, J. Duncan, S. Carney, G. Ka- ize to women because the study popu- tellectual content: Krystal, Rosenheck, Cramer, vanagh, Baltimore, Maryland; P. Parker, K. McCall, S.
Rathmell, Birmingham, Alabama; D. Kaloupek, G.
lation was nearly entirely men. Analyses Vessicchio, Jones, Vertrees, Horney, Huang, Stock.
Statistical analysis: Krystal, Rosenheck, Jones, Horney.
Aguayo, D. Ryngala, A. Collins, Boston, Massachu- conducted to adjust for the effect of dif- Obtained funding: Krystal, Vertrees, Huang.
setts; M. Hamner, D. Agbor-Tabi, M. Timmerman, M.
fering combat theaters did not alter the Administrative, technical, or material support: Cramer, Brown, S. Robert, S. Coleman, Charleston, South Caro- Vessicchio, Jones, Vertrees, Huang, Stock.
lina; P. Fore, T. Tepper, J. Yount, Chicago, Illinois; E.
findings related to the primary out- Study supervision: Krystal, Vertrees, Huang.
Konicki, V. Nero, E. Smith, R. Huhra-Grassel, Cleve- come measure, but this study was not Conflict of Interest Disclosures: All authors have com-
land, Ohio; A. Suris, C. North, J. Whitman, E. Wiley, pleted and submitted the ICMJE Form for Disclosure Dallas, Texas; M. Hertzberg, R. Biddix, M. Becker, Dur- designed explicitly to explore the in- of Potential Conflicts of Interest. Dr Krystal reported ham, North Carolina; T. Grieder, C. Feigel, East Los teraction of combat theater and treat- having received research support from Janssen Re- Angeles, California; T. Vo, P. Wolf, Fargo, North Da- ment response. Fifth, this study evalu- search Foundation; having been a consultant to Ais- kota; R. Garza, C. Murphy, B. Melton, Houston, Texas; ling Capital, AstraZeneca, Brintnall and Nicolini, Bristol- E. Ahearn, C. Johnson, M. Mussey, T. Smith, Madi- Myers Squibb, Easton and Associates, Eli Lilly, F.
son, Wisconsin; D. David, J. Junco-Valladares, P. Slone, risperidone treatment, and the find- Hoffman LaRoche, Forest Laboratories, Gilead Sci- A. Giron, Miami, Florida; J. Westermeyer, M. Spring, ences, GlaxoSmithKline, Janssen, Lundbeck Re- A. Ferrier, Minneapolis, Minnesota; M. Eakin, A. Wol- ings may not generalize to risperidone search USA, Medivation, Merz Pharmaceuticals, MK kin, C. Woo, M. Kramer, New York, New York; R. Erh- prescribed by itself for the treatment of Medical Communications, Naurex, Pfizer, SK Hold- man, K. Marquez, A. Fornish, Philadelphia, Pennsyl- ings, Sunovion Pharmaceuticals, Takeda Industries, Te- vania; A. Khan, A. Zakai, H. Frank, J. Kikuchi, tragenex, and Teva Pharmaceutical Industries; hav- Providence, Rhode Island; C. Stock, L. Carpenter, S.
In summary, risperidone, the sec- ing patents for glutamatergic treatment of Plumb, S. Allen, C. Olsen, M. Greenwell, Salt Lake City, ond most widely prescribed SGA within neuropsychiatric disorders and intranasal administra- Utah; J. Casada, J. Polanco, T. Benson, San Antonio, tion of ketamine to treat depression (pending); hav- Texas; D. Baker, P. Shah, P. Gorman, T. Perin, A. Ke- VA for PTSD and the best data- ing served on the scientific advisory boards for Ab- lada, J. Cooley, J. Pittman, N. Madra, San Diego, Cali- supported adjunctive pharmaco- bott, Bristol-Myers Squibb, Eisai, Eli Lilly, Forest fornia; F. Schoenfeld, M. Schmitz, R. Coeshott, H. Q.
Laboratories, Lohocla Research Corporation, Mne- Tong, San Francisco, California; L. Davis, C. Garner, therapy for PTSD,12 did not reduce over- mosyne Pharmaceuticals, Naurex, Pfizer, and Shire; J. Newell, Tuscaloosa, Alabama; P. Hicks, S. Justice, all PTSD severity (CAPS total score), and being the editor of Biological Psychiatry and presi- B. Lippe, Waco, Texas; C. S. Saunders, D. Goldstein, dent elect of the American College of Neuropsycho- S. Ereshefsky, A. Melnick, M. Urbaitis, West Los An- produce global improvement (CGI pharmacology. Dr Rosenheck reported having re- geles, California; S. Affleck, M. Beam, E. Spence, D.
score), or increase quality of life (SF- ceived research support from Eli Lilly, Janssen Briones, S. Dixon, C. Howell, X. Lu, Perry Point, Mary- Pharmaceutica, Astra-Zeneca, and Wyeth Pharma- land; D. Conner, C. Haakenson, Albuquerque. Data 36V) in patients with chronic SRI- ceuticals; having been a consultant to GlaxoSmithKline, Monitoring Committee: T. Grieger, Falls Church, VA; resistant military-related PTSD symp- Bristol-Myers Squibb, Organon, Janssen Pharmaceu- D. Blake, Boise, ID; K. Dickerson, Baltimore; M. Thase, toms. Overall, the data do not provide tica, and Otsuka; having provided expert testimony Philadelphia; P. Harvey, Miami. Executive Commit- for the plaintiffs in UFCW Local 1776 and Participat- tee: K. Jones, Perry Point; J. Vertrees, Albuquerque; strong support for the current wide- ing Employers Health and Welfare Fund, et al v Eli M. Stein, San Diego; C. Stock, Salt Lake City; M. Hertz- 2011 American Medical Association. All rights reserved.
JAMA, August 3, 2011—Vol 306, No. 5 501
RISPERIDONE AND CHRONIC POSTTRAUMATIC STRESS DISORDER berg, Durham; E. Duncan, Atlanta; J. Gelernter, New posttraumatic stress disorder. Prog Neuropsychophar- vice, Alcohol, Drug Abuse, and Mental Health Ad- Haven, Connecticut. Planning Committee: D. Ci- macol Biol Psychiatry. 2009;33(2):169-180.
ministration, National Institute of Mental Health, Psy- raulo, D. Kaloupek, Boston; M. Stein, San Diego; G.
13. Pae CU, Lim HK, Peindl K, et al. The atypical an-
chopharmacology Research Branch; 1976:534-537.
Bartzokis, Los Angeles; A. Rasmusson, West Haven, tipsychotics olanzapine and risperidone in the treat- 31. Schnurr PP, Friedman MJ, Lavori PW, Hsieh FY.
Connecticut; J. Davidson, Durham; C. Marmar, San ment of posttraumatic stress disorder. Int Clin Design of Department of Veterans Affairs Coopera- Francisco; P. Lavori, Menlo Park, California; S. Berkow- tive Study No. 420. Control Clin Trials. 2001;22 itz, T. O'Leary, B. Schuster, Washington, DC; K. Jones, 14. Leslie DL, Mohamed S, Rosenheck RA. Off-label
J. Collins, C. Howell, Perry Point; J. Vertrees, Albu- use of antipsychotic medications in the Department 32. Weathers FW, Keane TM, Davidson JR. Clinician-
querque; D. Bradham, Baltimore; M. Friedman, White of Veterans Affairs health care system. Psychiatr Serv.
administered PTSD scale. Depress Anxiety. 2001; River Junction, Vermont.
Online-Only Material: The eTables and eFigures are
15. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis
33. Fontana A, Rosenheck R. Effectiveness and cost
available at
JM. Second-generation versus first-generation anti- of the inpatient treatment of posttraumatic stress Additional Contributions: We thank Frank Weathers,
psychotic drugs for schizophrenia. Lancet. 2009; disorder. Am J Psychiatry. 1997;154(6):758-765.
PhD, Department of Psychology, Auburn University, 34. Norman GR, Sloan JA, Wyrwich KW. Interpreta-
for providing CAPS training and rater certification. He 16. First MB, Spitzer RL, Gibbon M, Williams JBW.
tion of changes in health-related quality of life. Med did receive compensation for this contribution.
Structured Clinical Interview for the DSM-IV Axis I Disorders–Patient Edition (SCID-I/P): Version 2.0. 35. Lunney CA, Schnurr PP. Domains of quality of life
New York, NY: Biometrics Research Department, New and symptoms in male veterans treated for posttrau- York State Psychiatric Institute; 1996.
matic stress disorder. J Trauma Stress. 2007;20 17. Blake DD, Weathers FW, Nagy LM, Kaloupek DG,
1. Kulka RA, Schlenger WE, Fairbank J. Trauma and
Klauminzer GW, Charney DS. A clinician rating scale 36. Gueorguieva R, Krystal JH. Move over ANOVA.
the Vietnam War Generation. New York, NY: Bruner- for assessing current and lifetime PTSD: the CAPS-1.
Arch Gen Psychiatry. 2004;61(3):310-317.
Mazel; 1990.
Behav Ther. 1990;13:187-188.
37. American Psychiatric Association. Diagnostic and
2. Hoge CW, Castro CA, Messer SC, McGurk D,
18. Cramer JA, Rosenheck R. Enhancing medication
Statistical Manual of Mental Disorders. 4th ed, text Cotting DI, Koffman RL. Combat duty in Iraq and Af- compliance for people with serious mental illness.
revision. Washington, DC: American Psychiatric As- ghanistan, mental health problems, and barriers to care.
J Nerv Ment Dis. 1999;187(1):53-55.
sociation; 2000.
N Engl J Med. 2004;351(1):13-22.
19. Krystal JH, Cramer JA, Krol WF, Kirk GF, Rosenheck
38. Davidson JR. Remission in post-traumatic stress
3. Thomas JL, Wilk JE, Riviere LA, McGurk D, Castro
RA; Veterans Affairs Naltrexone Cooperative Study 425 disorder (PTSD). Int Clin Psychopharmacol. 2004; CA, Hoge CW. Prevalence of mental health prob- Group. Naltrexone in the treatment of alcohol lems and functional impairment among active com- dependence. N Engl J Med. 2001;345(24):1734- 39. Schotte A, Janssen PF, Gommeren W, et al. Ris-
ponent and National Guard soldiers 3 and 12 months peridone compared with new and reference antipsy- following combat in Iraq. Arch Gen Psychiatry. 2010; 20. Blake DD, Weathers FW, Nagy LM, et al. The de-
chotic drugs. Psychopharmacology (Berl). 1996; velopment of a Clinician-Administered PTSD Scale.
4. Brady K, Pearlstein T, Asnis GM, et al. Efficacy and
J Trauma Stress. 1995;8(1):75-90.
40. Mellman TA, Clark RE, Peacock WJ. Prescribing
safety of sertraline treatment of posttraumatic stress 21. Montgomery SA, Asberg M. A new depression
patterns for patients with posttraumatic stress disorder.
scale designed to be sensitive to change. Br J Psychiatry.
5. Davidson JR, Rothbaum BO, van der Kolk BA, Sikes
41. Raskind MA, Peskind ER, Hoff DJ, et al. A paral-
CR, Farfel GM. Multicenter, double-blind compari- 22. Hamilton M. The assessment of anxiety states by
lel group placebo controlled study of prazosin for son of sertraline and placebo in the treatment of post- rating. Br J Med Psychol. 1959;32(1):50-55.
trauma nightmares and sleep disturbance in combat traumatic stress disorder. Arch Gen Psychiatry. 2001; 23. Kay SR, Opler LA, Lindenmayer JP. The Positive
veterans with post-traumatic stress disorder. Biol and Negative Syndrome Scale (PANSS). Br J Psychia- 6. Marshall RD, Beebe KL, Oldham M, Zaninelli R. Ef-
try Suppl. 1989;(7):59-67.
42. Taylor FB, Lowe K, Thompson C, et al. Daytime
ficacy and safety of paroxetine treatment for 24. Hays RD, Sherbourne CD, Mazel RM. The RAND
prazosin reduces psychological distress to trauma spe- chronic PTSD. Am J Psychiatry. 2001;158(12): 36-Item Health Survey 1.0. Health Econ. 1993; cific cues in civilian trauma posttraumatic stress disorder.
Biol Psychiatry. 2006;59(7):577-581.
7. Tucker P, Zaninelli R, Yehuda R, Ruggiero L,
25. Smith AA, Niles BL, King L, King D. Psychomet-
43. Harpaz-Rotem I, Rosenheck RA. Tracing the flow
Dillingham K, Pitts CD. Paroxetine in the treatment ric properties of the Boston Life Satisfaction Inven- of knowledge. Arch Gen Psychiatry. 2009;66(4): of chronic posttraumatic stress disorder. J Clin tory among veterans with PTSD. Paper presented at: Annual Meeting of the International Society for Trau- 44. Pivac N, Kozaric´-Kovacic´ D. Pharmacotherapy of
8. Mohamed S, Rosenheck RA. Pharmacotherapy of
matic Stress Studies; December 2001; New Orleans, treatment-resistant combat-related posttraumatic stress PTSD in the US Department of Veterans Affairs. J Clin disorder with psychotic features. Croat Med J. 2006; 26. Heatherton TF, Kozlowski LT, Frecker RC,
9. Hertzberg MA, Feldman ME, Beckham JC, Kudler
Fagerstro¨m KO. The Fagerstro¨m Test for Nicotine 45. Rothbaum BO, Killeen TK, Davidson JR, Brady
HS, Davidson JR. Lack of efficacy for fluoxetine in PTSD.
Dependence. Br J Addict. 1991;86(9):1119-1127.
KT, Connor KM, Heekin MH. Placebo-controlled trial Ann Clin Psychiatry. 2000;12(2):101-105.
27. Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliabil-
of risperidone augmentation for selective serotonin 10. van der Kolk BA, Dreyfuss D, Michaels M, et al.
ity of a timeline method. Br J Addict. 1988;83 reuptake inhibitor-resistant civilian posttraumatic stress Fluoxetine in posttraumatic stress disorder. J Clin disorder. J Clin Psychiatry. 2008;69(4):520-525.
28. Barnes TR. A rating scale for drug-induced
46. Hamner MB, Faldowski RA, Ulmer HG, Frueh BC,
11. Friedman MJ, Marmar CR, Baker DG, Sikes CR,
akathisia. Br J Psychiatry. 1989;154:672-676.
Huber MG, Arana GW. Adjunctive risperidone treat- Farfel GM. Randomized, double-blind comparison of 29. Simpson GM, Angus JW. A rating scale for ex-
ment in post-traumatic stress disorder. Int Clin sertraline and placebo for posttraumatic stress disor- trapyramidal side effects. Acta Psychiatr Scand Suppl.
der in a Department of Veterans Affairs setting. J Clin 47. Hamner MB, Robert S. Emerging roles for atypi-
30. Guy W. ECDEU Assessment Manual for
cal antipsychotics in chronic post-traumatic stress 12. Berger W, Mendlowicz MV, Marques-Portella C,
Psychopharmacology. Rockville, MD: US Dept of disorder. Expert Rev Neurother. 2005;5(2):267- et al. Pharmacologic alternatives to antidepressants in Health, Education and Welfare, Public Health Ser- 502 JAMA, August 3, 2011—Vol 306, No. 5
2011 American Medical Association. All rights reserved.


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