Olanzapine monotherapy in posttraumatic stress

human psychopharmacology Hum. Psychopharmacol Clin Exp 2012; 27: 386–391. Published online 22 June 2012 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hup.2238

Olanzapine monotherapy in posttraumatic stress disorder: efficacy in a randomized, double-blind, placebo-controlled study Paul Carey1, Sharain Suliman1*, Keith Ganesan1, Soraya Seedat1 and Dan J. Stein1,2 1 2

MRC Research Unit on Anxiety Disorders, Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa Department of Mental Health and Psychiatry, University of Cape Town, Cape Town, South Africa

Objectives Although there have been important advances in the treatment of posttraumatic stress disorder (PTSD), many patients fail to respond to first-line pharmacotherapy. Limited evidence suggests that second generation antipsychotics may have a role to play as monotherapy in PTSD. Methods We undertook a randomized, placebo-controlled study using flexible-dose olanzapine monotherapy for 8 weeks in 28 adult male and female participants (mean age: 40.75 11.59 years) with non-combat related chronic PTSD. Data were analysed with repeated measures analysis of variance, using an intention to treat, last observation carried forward approach. Results The olanzapine group (n = 14) demonstrated significantly greater improvement on the Clinician Administered PTSD Scale from baseline to endpoint than the placebo group (n = 14) (F = 5.71, p = 0.018). Olanzapine was generally well tolerated, with no serious adverse events recorded. Substantial weight gain (6–10 kg) was, however, reported in 6/14 participants in the olanzapine group. Conclusions To our knowledge, this is the first controlled evidence of the efficacy of olanzapine monotherapy in an exclusively non-combat related chronic PTSD group. Despite the small sample size, these data suggest that olanzapine may have a role in the treatment of PTSD. These findings warrant replication in a larger sample. Copyright © 2012 John Wiley & Sons, Ltd. key words—olanzapine; posttraumatic stress disorder; randomized controlled trial

BACKGROUND Posttraumatic stress disorder (PTSD) is one of the most prevalent psychiatric disorders, with lifetime community estimates ranging from an average of 1.9% in European samples to 6.8% in the USA (Alonso et al., 2004; Kessler et al., 2005). PTSD is frequently associated with a chronic course as well as extensive comorbidity (Kessler et al., 2000; Alonso et al., 2004). There is growing recognition of the significant distress and disability associated with PTSD and the consequent importance of effective diagnosis and treatment (Kessler et al., 2000; Alonso et al., 2004). Fortunately, there have been significant advances in both the pharmacotherapy and psychotherapy of PTSD (Pratchett et al., 2011). The selective serotonin re-uptake inhibitors (SSRIs) and the serotonin–norepinephrine re-uptake inhibitors (SNRIs) are now accepted as firstline pharmacotherapy for PTSD (Asnis et al., 2004; Ursano et al., 2004; Stein et al., 2006; Marshall et al., *Correspondence to: S. Suliman, MRC Research Unit on Anxiety Disorders, Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa. Tel: +27 21 938 9020; Fax: +27 21 933 5790. E-mail: [email protected]

Copyright © 2012 John Wiley & Sons, Ltd.

2007; Pae et al., 2007). Unfortunately, up to 40% of participants in clinical trials fail to respond adequately to these agents (Rasmussen, 2006; Stein et al., 2006). There is therefore a need to explore alternative pharmacological interventions in PTSD. Given the involvement of the dopaminergic system in PTSD, there is a rationale for using antipsychotic treatments (Pae et al., 2008; Berger et al., 2009). Systematic reviews of existing clinical data provide some support for this view (Ipser et al., 2006), although not all data are consistent (Krystal et al., 2011). These inconsistencies perhaps partly reflect the study of heterogeneous populations, including combat veterans. There have been a number of trials using antipsychotics as augmentating agents but less work on these medications as monotherapy (Eidelman et al., 2000; Hamner et al., 2003; Monnelly et al., 2003; Reich et al., 2004; Bartzokis et al., 2005; Kozaric-Kovacic et al., 2005; Ipser et al., 2006; Berger et al., 2009). In the only double-blind placebo-controlled study of risperidone monotherapy of which we are aware, a significant improvement in PTSD symptoms in the treatment group was observed at the study endpoint (Padala et al., 2006). Received 21 November 2011 Accepted 23 May 2012

rct of olanzapine monotherapy for ptsd

Olanzapine has demonstrated efficacy in open-label (Jakovljevic et al., 2003) and placebo-controlled augmentation of SSRIs in treatment-refractory PTSD patients (Stein et al., 2002). As monotherapy in PTSD, the use of olanzapine is also supported by open-label evidence on symptom improvement (Petty et al., 2001). In the only published controlled study of olanzapine monotherapy in PTSD to date, the clinical response to olanzapine (n = 10) was indistinguishable from placebo (n = 5) on all efficacy measures, but the sample size was small (Butterfield et al., 2001). Here, we present the results of a double-blind placebo-controlled study of olanzapine monotherapy in non-combat related chronic PTSD. Our primary objective was to evaluate the efficacy and tolerability of olanzapine monotherapy compared with placebo in this population. METHODS Study setting and design We employed a randomized, placebo-controlled, doubleblind, parallel group, flexible-dose, 8-week study design. Potentially eligible participants were recruited through print advertisements and referrals from primary care clinics within a commutable distance from the trial centres. Men and women aged 18 years and over with DSM-IV, non-combat, chronic PTSD (PTSD symptoms of at least 3 months) were eligible to participate in the study if they (i) had a minimum score of 50 on the Clinician Administered PTSD Scale (CAPS) (Blake et al., 1995), (ii) were willing to provide written informed consent to their participation, and (iii) were free of disallowed psychotropic medication for a washout period of 5 days for all except fluoxetine (5 weeks) prior to randomization. Trauma types reflect the profile of trauma in South Africa (i.e. domestic violence and criminal violence; Williams et al., 2007).

Recruitment: N=39

Screening: N= 39

8 week visit (completion): N= 24

Figure 1.

387

Exclusion criteria included current major depressive disorder, a Montgomery Äsberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979) score ≥ 20 at baseline, and the presence of a significant suicide risk according to the clinical judgement of the investigator. Additional exclusion criteria included a substance use disorder within 6 months of randomization, a positive urine drug screen for illicit substances, a history of severe personality disorder (based on clinician judgement), a lifetime history of schizophrenia or other psychotic disorder, pregnant or breastfeeding women, women of child-bearing potential not willing to use contraception, an unstable medical condition, and unresolved clinically significant laboratory or electrocardiogram findings. Previous failure to respond to or intolerance of a second generation antipsychotic (SGA), failure of two or more trials of an SSRI or an SNRI given in adequate doses for an adequate duration, and initiation or change in psychotherapy within 8 weeks of screening receipt of electroconvulsive therapy in the 3 months before screening, participation in a clinical trial in the 6 months before screening, and finally an improvement of 2 or more points on the Clinical Global Impressions (CGI) severity score (Guy, 1976) from screening to randomization were also criteria for exclusion from participation. We screened 39 potentially eligible participants. Of these, 34 were eligible on the basis of clinical examination and fulfilled initial inclusion/exclusion criteria. Thirty-four participants were randomized to treatment. Of these, 24 completed the 8-week trial. In addition, we recorded at least one post-baseline assessment on another four participants. The study complied with International Conference on Harmonization Guidelines for Good Clinical Practice and was approved by the Committee for Human Research (Institutional Review Board) of the University of Stellenbosch as well as the Medicines Control Council of South Africa (national regulatory authority) (Figure 1).

Randomisation: N= 34

Early withdrawals: N=10 N=4 lost to follow-up N= 1 poor compliance N= 4 lack of efficacy N = 1 consent withdrawal

Flow chart of recruitment and retention


Hum. Psychopharmacol Clin Exp 2012; 27: 386–391. DOI: 10.1002/hup

388

p. carey

ET AL.

Assessments

Outcome measures and statistical analysis

Brief clinical screening for eligibility was followed by confirmation of a DSM-IV PTSD diagnosis using the Mini International Neuropsychiatric Interview (Sheehan et al., 1998). Severity of PTSD symptoms was assessed at baseline, week 4, and week 8 using the CAPS. Overall severity of PTSD was rated by clinicians at every study visit using the CGI (Guy, 1976). Depressive symptoms were measured using the MADRS (Montgomery and Asberg, 1979). Other patient rated measures included the Davidson Trauma Scale (DTS), a participant rated measure of PTSD symptoms severity (Davidson et al., 2002) and the Sheehan Disability Scale (SDS), a global measure of perceived functional impairment (Sheehan, 1983). Participants were assessed by clinicians at baseline, then weekly for the first 4 weeks and every 2 weeks thereafter, with these symptom measures, and with open-ended questions regarding tolerability. Following successful screening, eligible participants were randomly assigned to receive either olanzapine or placebo using a computer generated 10-number block randomization schedule.

The mean change from baseline to the week 8 endpoint on the CAPS was used as the primary outcome measure. By using an intent-to-treat sample, defined as all participants with at least one post-baseline CAPS assessment and a last observation carried forward (LOCF) approach, efficacy for olanzapine versus placebo was tested using repeated measures analysis of variance (RMANOVA). All tests were two-tailed with p-values of less than 0.05 considered significant. Response was defined as ≥50% improvement from baseline to the week 8 endpoint on the CAPS. CGI responders were defined as those with CGI-I scores of 2 (much improved) or 1 (very much improved) at week 8. Improvement on secondary outcome measures, including CAPS subscales, the DTS, and the SDS was also evaluated. Cohen’s d was used to calculate effect size (r). Frequencies of the most common adverse events were compared between groups using chi-square tests. These are tabled and reported if present in more than one subject in either of the study groups. RESULTS

Study treatment

Study population

Following the initial screening visit, eligible participants were given 1 week of single-blind placebo run-in to exclude early placebo responders. No participants met the criteria (≥2 point improvement on CGI severity rating) for withdrawal at the baseline visit. Following randomization, participants received 5 mg olanzapine or matching placebo for 1 week. This was followed by 7.5 mg for 1 week and then 10 mg for 2 weeks. If the response was satisfactory (CGI ≤ 2) and treatment was well tolerated at the end of week four, participants were maintained at that dose. However, if response was not satisfactory (CGI ≥ 3) but adequately tolerated, olanzapine/placebo was increased in 2.5 mg increments two weekly to a maximum dose of 15 mg. In cases of poor tolerability following a dose increase, a single dose reduction of 2.5 mg was permitted. Participants were not permitted to use any psychoactive medication other than the study drug during the course of the study. Non-psychoactive drugs at study entry and concomitant treatments during the study for unrelated conditions were permitted and recorded. Matching olanzapine/placebo was supplied by Eli Lilly and then packaged for individual participants by an independent contract pharmacist. Randomization codes were kept only by the contracted pharmacist. There was no instance of unblinding until after study closure and after data entry had been completed.

We obtained evaluable data for 28 participants (17 females, mean age of 41.53 (10.97) years and 11 males with a mean age of 39.55 (12.54) years). Of the 10 early withdrawals, four were lost to followup and one participant was withdrawn because of poor/erratic compliance at week 2. Of the remaining five participants, four were withdrawn because of lack of treatment efficacy or withdrawal of consent, and one was withdrawn at week 1 because of severe sedation (olanzapine group). No participants were withdrawn because of a serious adverse event.


Clinical outcomes Baseline total CAPS scores suggested that our population was severely ill (mean CAPS score > 75) with no baseline difference in severity between groups (p = 0.686). Fourteen participants were allocated to each of the olanzapine and placebo groups. RMANOVA demonstrated that for the primary outcome measure (CAPS total score), the olanzapine assigned group demonstrated a significantly greater improvement in PTSD symptoms (mean change = 35.86 19.85; 57.7% improvement) than the placebo group (mean change = 19.29 28.77; 23.7% improvement) from baseline to the week 8 endpoint using LOCF data (p = 0.018) (Table 1). In addition, we found that the olanzapine group demonstrated separation from placebo Hum. Psychopharmacol Clin Exp 2012; 27: 386–391. DOI: 10.1002/hup

rct of olanzapine monotherapy for ptsd Table 1.

Change in mean scores of measures from baseline to week 8

Measure (total score) CAPS total (136) Baseline Week 4 Week 8 % CAPS score reduced Symptoms clusters Re-experiencing (40) Baseline Week 4 Week 8 Avoidance (56) Baseline Week 4 Week 8 Hyper-arousal (40) Baseline Week 4 Week 8 DTS (136) Baseline Week 4 Week 8 % CAPS score reduced CGI severity (7) Baseline Week 8 CGI responders MADRS (60) Baseline Week 8 SDS (30) Baseline Week 8

Olanzapine

Placebo

(Mean, SD)

(Mean, SD)

p-value

Effect size, r

79.4 (16) 49.1 (27.2) 33.6 (28.2) 57.7%

81.6 (11.3) 73.21 (20.5) 62.3 (31.9) 23.7%

0.686 0.014* 0.018*

0.43

21.4 (6.9) 12.9 (8) 9.5 (8.7)

21.6 (5.1) 17.86 (10.7) 16.9 (10.3)

0.926 0.173 0.052

0.36

32.7 (7.1) 18.9 (12.1) 11.5 (12.3)

35.8 (5.3) 30.71 (8.1) 26.6 (13)

0.208 0.005** 0.004**

0.51

25.3 (5.5) 17.4 (8.6) 12.6 (9.1)

24.1 (5.2) 23.9 (5.4) 18.9 (9.9)

0.553 0.022* 0.092

0.31

75 (16.3) 54.8 (27.7) 37.9 (32) 51%

88.1 (22.5) 86.2 (22.3) 75.8 (34.5) 16%

0.088 0.003** 0.006**

0.5

4.7 (0.8) 2.9 (1.4) 11 (78.5%)

5 (0.8) 4.1 (1.3) 4 (28.5%)

0.356 0.027*

0.4

15.9 (4) 10.3 (6.8)

15.3 (2.9) 15.3 (9.8)

0.631 0.137

0.29

18.3 (7.1) 10.6 (6.9)

24.1 (4.2) 20.6 (7.4)

0.032* 0.004**

0.57

389

Consistent with findings on clinician-rated symptom measures, there was a significant baseline to endpoint effect on the DTS (patient-rated outcome measure of PTSD symptoms) (p = 0.006) and the SDS (a patientrated measure of disability) in the olanzapine group compared with the placebo group. There were no group differences in MADRS scores at baseline or at endpoint (Table 1). Safety and tolerability In general, olanzapine was well tolerated. There were no serious adverse events, and only one patient was withdrawn on account of poor tolerability (marked sedation) at week 1. Overall, sedation was the most commonly reported adverse effect, experienced by 11/14 in the olanzapine group and 5/14 in the placebo group. More participants in the olanzapine group reported increased appetite compared with the placebo group, and weight gain was reported in 100% of participants in the olanzapine group. One-third of participants in the placebo group demonstrated weight gain of between 1 and 5 kg compared with 57% in the olanzapine group. However, weight gain in the olanzapine group was substantial with the remaining 43% of participants experiencing weight gain of 6–10 kg compared with no participants in the placebo group experiencing this amount of weight gain. A full record of adverse events is provided in Table 2.

*p ≤ 0.05. **p ≤ 0.01.

DISCUSSION

by the end of week 4 (olanzapine: 9.29 mg 1.53; placebo: 9.82 mg 0.67; p = 0.014). At this time point, this dose had been maintained for a maximum of 2 weeks. In examining responder status, a proxy measure for the clinical significance of our finding, we found a significantly higher proportion of CAPS responders, defined as >50% reduction from baseline to endpoint in the olanzapine group (10/14) compared with placebo (3/14), with a Cohen’s d effect size of r = 0.43. Additionally, all responders were in remission (CAPS score of below 50) by week 8. For the CGI improvement scale at week 8, similar proportions were classified as either much or very much improved (11/14, olanzapine; 4/14, placebo) (Table 1). Treatment with olanzapine resulted in improvement in all three symptom clusters of PTSD on the CAPS; however, only improvement in avoidance and numbing was statistically significant at week 4 (p = 0.005), and this was maintained at week 8 (p = 0.004) (Table 1).

Our study is the first placebo-controlled study to demonstrate the efficacy of olanzapine monotherapy in PTSD in non-combat patients. Here, we demonstrate that olanzapine monotherapy in PTSD for 8 weeks is superior to placebo on measures of symptom severity rated by both clinicians and patients, with separation from placebo already seen at week 4. In general, olanzapine was well tolerated, but sedation and significant weight gain were reported in the majority of participants taking olanzapine. The statistical difference between olanzapine and placebo is also clinically relevant, with 71% of olanzapine versus 21% of placebo treated participants demonstrating a >50% reduction in CAPS scores. Furthermore, participants treated with olanzapine demonstrated a decrease in symptoms on all three symptom clusters of the CAPS (with those in the intrusion/experiencing domain just failing to reach statistical significance), a significant decrease in selfrated measures of PTSD symptoms, and a significant improvement in measures of impairment. Our study



390 Table 2.

p. carey

ET AL.

Adverse events (reported by >10% of study group) Olanzapine

Placebo

Symptoms

n, (%), [severity]

n, (%), [severity]

Weight gain at 8 weeks 0–5 kg 0–10 kg Mean Sedation

14 (100%) 8 (57%) 6 (43%) 5.6 (2.6) kg 5 (73%) [mild] 5 [moderate] 1 [severe] 7 (47%) 6 (40%) 5 (33%) 3 (20%) 3 (20%) 3 (20%) 3 (20%) 2 (13%) [mild] 2 (13%) [mild] 2 (13%) 2 (13%) 2 (13%) 2 (13%) 1 (7%)

5 (33%) 5 (33%) 0 (0%) 0.3 (3.9) kg 4 (33%) [mild] 1 [moderate] 0 [severe] 5 (33%) 1 (7%) 5 (33%) 0 (0%) 2 (13%) 1 (7%) 0 (0%) 3 (20%) [mild] 1 (7%) [moderate] 0 (0%) 0 (0%) 0 (0%) 1 (7%) 2 (13%)

Headache Increased appetite Upper respiratory tract infection Tremor Insomnia Muscle ache Diarrhoea Dizziness Dry mouth Skin rash Slurred speech Abdominal cramps Backache Increased anxiety

p-value

0.001** 0.000** 0.014* 0.362 0.023* 0.893 0.058 0.564 0.249 0.058 0.684 0.941 0.129 0.129 0.129 0.501 0.584

*p ≤ 0.05. **p ≤ 0.01.

also had a high response rate to medication and a low response to placebo. Our finding is in line with a recent systematic review of controlled data for the atypical antipsychotics risperidone and olanzapine, suggesting that they have potential to be effectively used in the treatment of PTSD (Ahearn et al., 2011). While our findings should still be interpreted with caution owing to the small sample, they nevertheless add to a body of accumulating evidence that support the use of the SGAs as a potentially useful strategy in the pharmacotherapy of PTSD (Pae et al., 2008; Canive et al., 2009). Recommended first-line treatments for PTSD still fall well short of the ideal with up to 40% of patients failing to respond adequately (Rasmussen, 2006). Our data are encouraging in that proportionately fewer patients (29%) were non-responders to olanzapine (Stein et al., 2002; Hamner et al., 2003; Pivac et al., 2004; Bartzokis et al., 2005; Kozaric-Kovacic et al., 2005; Pivac and Kozaric-Kovacic, 2006; KozaricKovacic and Pivac, 2007). Nonetheless, given the paucity of RCT data on SGAs as monotherapy, this should currently be considered as an augmentation strategy (Pae et al., 2008). In this study, olanzapine was generally well tolerated, but notable differences in side-effect profiles between the groups were observed. Arguably the most clinically relevant of these was the weight gain experienced by all of the participants in the olanzapine group, which was Copyright © 2012 John Wiley & Sons, Ltd.

significantly higher than that in the placebo group. This finding is in line with other studies (Butterfield et al., 2001; Petty et al., 2001; Stein et al., 2002) and therefore not unexpected. Sedation, also a well-documented sideeffect of olanzapine, was experienced by 73% of the treatment group compared with 33% in the placebo group (Pollack et al., 2006). This is also a concern in this outpatient population. Overall, despite the low rate of withdrawal for poor tolerance, some concern remains regarding the widespread use of olanzapine as monotherapy for PTSD owing to its acute sedative effects and the long-term risks associated with weight gain. Several limitations of this study should be emphasized. First, patients with comorbid severe depression were excluded, likely contributing to the failure to find significant differences on the MADRS scores after olanzapine versus placebo. On the other hand, this design has some strengths in that it is clear that the data are relevant to PTSD rather than merely relevant to the depression that is often seen as a comorbid condition in PTSD. Second, the inclusion of a reference group treated with an SSRI would have been useful. Nonetheless, in conclusion, this study demonstrates efficacy of olanzapine monotherapy over placebo in exclusively non-combat related chronic-type PTSD, with an onset of action within 4 weeks of treatment. Given the distress and impairment associated with PTSD, these findings are promising and support an existing literature on the potential value of SGAs in Hum. Psychopharmacol Clin Exp 2012; 27: 386–391. DOI: 10.1002/hup

rct of olanzapine monotherapy for ptsd

PTSD. Nevertheless, replication in larger samples and over longer treatment periods is required in order to assess fully the risk–benefit ratio of this medication for the treatment of PTSD. CONFLICT OF INTEREST The authors declare no conflicts of interest. ACKNOWLEDGEMENT Funding for this study was received from Eli Lilly.

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