Lack of Efficacy for Fluoxetine in PTSD: A Placebo

Annals of Clinical Psychiatry, Vol. 12, No. 2, 2000

Lack of Efficacy for Fluoxetine in PTSD: A Placebo Controlled Trial in Combat Veterans Michael A. Hertzberg, M.D.,1–3 Michelle E. Feldman, B.A.,2 Jean C. Beckham, Ph.D.,1,2 Harold S. Kudler, M.D.,1,2 and Jonathan R. T. Davidson, M.D.1,2

Background: Fluoxetine and placebo were studied in a population of combat veterans with severe, chronic PTSD. Methods: Twelve male veterans with PTSD were enrolled in a 12 week double-blind evaluation of fluoxetine and placebo. Mean fluoxetine dose at endpoint (week 12) was 48 mg/day with a range of 10 mg to 60 mg. Results: One fluoxetine patient responded (17%) and two of the six placebo patients responded (33%). Conclusions: Fluoxetine patients did not show a greater response than placebo patients in this small sample of male combat veterans with severe, chronic PTSD. Fluoxetine has displayed an efficacious response in controlled studies of patients with PTSD who were predominantly female, suffered civilian (noncombat) traumas, and were overall experiencing less severe PTSD. The reasons for the low response rate to fluoxetine in our study is unknown and will await further study examining variables other than symptoms that might influence outcome, such as gender, comorbidity, prior treatment history, trauma type, severity and chronicity. KEY WORDS: fluoxetine; placebo; PTSD; veterans.

INTRODUCTION

treatment of PTSD (8,9), but there remains no definitive pharmacotherapy for PTSD. Several drug classes have been reported to be beneficial in treating PTSD symptoms including antidepressant drugs, adrenergic agonists and antagonists, mood stabilizing drugs, and atypical neuroleptics (10–15). Controlled trials with amitriptyline (16) phenelzine, and imipramine (17) with male combat veterans did show clear but modest efficacy for PTSD symptoms. Brofaromine showed significant positive effect for PTSD over placebo in a European study of patients with noncombat and combat trauma (18) while showing no significant difference with placebo in a population of US combat veterans (19). The SSRIs are commonly used as first line treatment for PTSD, yet there have only been a small number of published controlled studies of these agents with PTSD patients. To date, there have been two published controlled studies with fluoxetine (20, 21), while one other has been presented at a meeting (Nagy LM, Southwick SM, Charney DS: Placebocontrolled trial of fluoxetine in PTSD. Poster presentation, International Society for Traumatic Stress

PTSD is a chronic and distressing condition, with significant morbidity. It is estimated that 13% to 17% of Vietnam veterans suffer from current PTSD with an additional 11% experiencing many of the symptoms of PTSD but not meeting full DSM criteria (1). In the general population of the USA, 60% of people will experience at least one traumatic event in their lifetime, with approximately 8–10% developing PTSD (2). Survival analyses have indicated that more than one third of people with lifetime PTSD fail to recover even after many years (3). Several biologic models have been proposed as contributing to PTSD, with significant recent attention given to alterations in the serotonergic system (4–7). Fluoxetine was the first SSRI to be used in the 1

Duke University Medical Center, Department of Psychiatry, Durham, NC 27710. 2 Durham Veterans Affairs Medical Center, Durham, NC 27705. 3 To whom correspondence should be addressed at Durham VAMC, 116A, 508 Fulton Street, Durham, NC 27705.

101 1040-1237/00/0600-0101$18.00/1  2000 American Academy of Clinical Psychiatrists

102 Studies, 12th Annual Meeting, San Francisco, CA November 11, 1996). Likewise, two controlled studies with sertraline have only been presented at meetings (Davidson J, van der Kolk B, Brady K, Rothbaum B, Sikes C, Farfel G: Double-blind comparison of sertraline and placebo in patients with PTSD. Abstract at the European College of Neuropsychopharmacology Congress, Vienna, Austria Sept. 13-17, 1997; and Amital D, Zohar J, Kotler M, Bleich A, Nrdovnik H, Nevo A, Lane RM: A placebo-controlled pilot study of sertraline in PTSD. Abstract in Proceedings of the 152nd Annual Meeting of the American Psychiatric Association, Washington DC, May 18, 1999). In general, these controlled studies have shown both sertraline and fluoxetine to be of clinical benefit over placebo in study populations of predominately female, noncombat subjects. Three of the studies with predominantly male, combat veterans did not show a significant benefit of either sertraline or fluoxetine in the treatment of veterans, whereas one study from Israel reported a positive, although modest effect for sertraline over placebo in combat veterans. In contrast, multiple open trials with the SSRI’s have reported clinical efficacy in the treatment of combat veterans with PTSD (9,22–27). We present the results of a small double-blind study of fluoxetine and placebo in male combat veterans with severe, chronic PTSD. Often, negative trials do not become published, so the present study should be a beneficial report adding to our knowledge of treating PTSD. Our results are discussed in relation to previous studies, our study’s limitations and suggestion for further research.

Hertzberg, Feldman, Beckham, Kudler, and Davidson view for PTSD (SIP) (28). Comorbid diagnoses were determined by the Structured Clinical Interview for DSM-III-R (SCID) (29). The Combat Exposure Scale (CES) was also completed by all participants. (30) After random allocation to treatment, patients were seen at end of weeks 1, 2, 3, 4, 6, 8, 10, and 12 after receiving study medication. Symptoms were assessed at each visit using the self-rated Davidson Trauma Scale (DTS) (31), the Sheehan Disability Scale (SDS) (32), the clinician administered SIP and the physician administered Duke Global Rating for PTSD Scale (Duke) (33). The Duke measures severity and improvement for each of the three PTSD symptom domains (reexperiencing, avoidance/ numbing, and hyperarousal), as well as overall PTSD severity. Final Duke improvement scores were used as the basis for distinguishing treatment responders (Duke of 1 ⫽ very much improved; 2 ⫽ much improved) and nonresponders (Duke ⬎ 2). Patients were randomized to a double-blind treatment with fluoxetine or placebo in a 1:1 ratio. Placebo and fluoxetine were provided by Eli Lilly Co. No concomitant psychotropic medications were permitted. After an initial drug-free period, patients received study medication as follows: 10 mg/day for 1 week, then 20 mg/day for 2 weeks, then dosages were increased 10 mg/day every week until achieving a maximal response, reaching a maximum dosage of 60 mg/day or upon developing dose-limiting side effects. Mean fluoxetine dose at endpoint (week 12) was 48 mg/day with a range of 10 mg to 60 mg. Somatic symptoms during treatment were assessed using a 34-item checklist rated on a 4-point Likert scale (16). Patients completed this checklist at baseline and each subsequent visit.

METHODS RESULTS Patients were recruited from the PTSD outpatient treatment program at the Durham Veterans Affairs Medical Center. Twelve male Vietnam war veterans with chronic PTSD were enrolled in a 12week double-blind randomized evaluation of fluoxetine and placebo. The study protocol received approval from the Durham VAMC IRB. All patients provided informed consent. Support was provided by Eli Lilly Co. in the form of supplying all study medication, both fluoxetine and placebo. All patients were evaluated with a medical and psychiatric history, laboratory studies and ECG. All patients met DSM-IV criteria for a primary diagnosis of PTSD based on clinical interview and the Structured Inter-

Six patients received fluoxetine and 6 received placebo. Mean age was 46 years (range 44–48 years). Forty two percent (42%) were Caucasian and 58% were African-American. Five of 12 (2 placebo and 3 fluoxetine) patients were service connected for PTSD (i.e., receiving disability payment for PTSD from the VA). All 12 served in Vietnam with moderate to heavy combat exposure as scored on the Combat Exposure Scale (CES) (mean of 28 and range of 16 to 40). There were no significant differences between the groups for compensation status, age, or ethnic minority status, type, chronicity or severity of trauma. Current comorbid secondary diagnoses based on

Fluoxetine vs. Placebo in Combat-Related PTSD SCID criteria for the 12 patients were as follows: 8 with major depression, 4 with simple phobia, 2 with OCD, and 1 with alcohol and marijuana dependence. Lifetime comorbid diagnoses based on SCID criteria for the 12 patients were as follows: 10 with major depression, 7 with alcohol dependence, 4 with cannabis dependence, 2 with opiod dependence, 2 with sedative dependence, 1 with stimulant, cocaine, or hallucinogen dependence, 4 with simple phobia, 3 with OCD, 1 with GAD, and one with bulemia. Four of 6 placebo patients and 2 of 6 fluoxetine patients were psychotropic drug naive. The other 6 patients had all received prior unsuccessful treatment with one or more antidepressants. One of the six fluoxetine patients did not complete the study because of medication side effects. He experienced activation symptoms and dropped out at the end of week two on a dose of 10 mg/day. All the other patients completed the full 12 weeks of the study. Based on the Duke, one fluoxetine patient was very much improved for a 17% response rate, while 2 of 6 placebo patients were much improved for a 33% response rate. None of the placebo patients obtained very much improvement. No significant differences were demonstrated for pre- and post-treatment means of fluoxetine vs. placebo patients on either the DTS, SDS or SIP (see Table 1). Other than the one patient who did not complete the study, fluoxetine was generally well tolerated with the most troubling side effect being difficulty having an erection.

DISCUSSION Fluoxetine patients did not show a greater response than placebo patients in this small sample of male combat veterans with severe, chronic PTSD. This is consistent with a controlled study of fluoxetine by van der Kolk and colleagues, which reported significant improvement compared to placebo in non-

103 combat-related PTSD but not in combat veterans with PTSD (21). While patients were treated to a dose of 60 mg/day, the mean dose was 40 mg/day, somewhat lower than in our study and the trial lasted only 5 weeks compared to 12 weeks in our present study. Davidson et al. have presented results of a multicenter randomized double-blind study of sertraline vs. placebo in predominantly female patients with civilian traumas wih sertraline treated patients exhibiting signiflcantly greater improvement than placebo patients (Davidson J, van der Kolk B, Brady K, Rothbaum B, Sikes C, Farfel G: Double-blind comparison of sertraline and placebo in patients with PTSD. Abstract at the European College of Neuropsychopharmacology Congress, Vienna, Austria Sept. 13–17, 1997). Connor and colleagues have also reported positive results for fluoxetine in a double blind randomized trial of fluoxetine in predominantly female population of patients with PTSD following civilian traumas (20). The magnitude of the placebo response noted in some studies of psychiatric patients (34) is of interest, as is the response to placebo that has been reported in controlled studies of antidepressants in the treatment of PTSD (35). Davidson and colleagues have reviewed several controlled placebo trials of antidepressants in the treatment of PTSD and found placebo response rates generally higher in civilian trauma samples (28–62%) compared to combat trauma studies (19–33%) (35). Our sample showed a placebo response rate of 33%. These apparent differences in placebo rates between civilian and combat trauma populations still require further validation. Of further interest is a recent publication reporting on the pooled data of six separate open trials of PTSD treatment with nefazodone encompassing 92 total patients including both male and female patients and combat and civilian traumas (36). Response rates were clearly better in the population of

Table 1. Data for Fluoxetine Patients vs. Placebo (Mean ⫹ SD) b

Fluoxetine patients (n ⫽ 6)a Placebo patients (n ⫽ 6) a

DTS at Baseline

DTS at Week 12

SDSc at Baseline

SDS at Week 12

SIPd at Baseline

SIP at Week 12

106 ⫾ 27

103 ⫾ 23

24 ⫾ 7

24 ⫾ 6

48 ⫾ 9

47 ⫾ 8

111 ⫾ 12

102 ⫾ 26

27 ⫾ 4

25 ⫾ 5

43 ⫾ 10

42 ⫾ 11

One fluoxetine patient dropped out of study at end of week 2 (see text). DTS ⫽ Davidson Trauma Scale. c SDS ⫽ Sheehan Disability Scale. d SIP ⫽ Structured Interview for PTSD. b

104 younger, female, civilian trauma patients compared to the relatively older, predominantly male combat veterans. Younger age, female sex and civilian traumas all were found to predict a response to treatment with nefazodone and a small subset of male patients with civilian trauma was found to have responded better than male combat veterans, but not as well as female civilian trauma victims. Thus, a greater improvement in PTSD for women over men with nefazodone treatment for PTSD was observed. Whether or not this finding will be replicable and generalizable will need to await future studies. Whether women with PTSD respond better than men to serotonergic drugs remains unexplored. Indeed, there is very little definitive research on gender differences in psychopharmacology (37). A recent PET scanning study demonstrated a markedly lower rate of serotonin synthesis in the brains of normal subject women than in men (38). The low response rate to placebo and SSRI/5HT2 antagonist drugs in combat veterans may be reflective of subjects who enter clinical trials in the VA population. For example the mean baseline DTS in our subjects was substantially higher compared to the civilian subjects in the controlled trial of fluoxetine by Connor et al. (108 ⫾ 21 vs. 77 ⫾ 22) (20). Differences in responders vs. non responders could also be due to differences in trauma type and/or severity; PTSD symptom duration and/or severity (49); comorbidity status (40, 41, 42); prior treatment history; and potentially but less likely confounding compensation and disability issues (43). The demonstrated efficacy of two tricyclic drugs and an MAO-I, however, suggest that more broad spectrum (i.e., nonselective) antidepressants with catecholamine effects might be useful in PTSD in this population. While improvement in PTSD symptoms has been reported in several open trials of fluoxetine treatment of male and female patients with both combat and noncombat traumas, no controlled trials including the present study have yet demonstrated any significant benefit for fluoxetine treatment of male combat veterans with chronic PTSD. Even though our study was small, given the literature on antidepressant treatment of combat veterans with PTSD, we do not believe a larger sample would have provided positive results. The reasons for the low response rate to fluoxetine in our study of combat veterans with PTSD is unknown and will await further study examining variables other than symptoms that might influence outcome, such as gender, comorbid-

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