Open trial of citalopram in adults with post-traumatic stress disorder

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1 International Journal of Neuropsychopharmacology (2000), 3, Copyright 2000 CINP Open trial of citalopram in adults with post-traumatic stress disorder ARTICLE Soraya Seedat, Dan J. Stein and Robin A. Emsley Department of Psychiatry, University of Stellenbosch, P.O. Box 19063, Tygerberg 7505, Cape Town, South Africa Abstract The selective serotonin reuptake inhibitors (SSRIs) are rapidly emerging as preferred first-line drugs in the pharmacological management of post-traumatic stress disorder (PTSD). Citalopram, an SSRI with highly potent and selective serotonin reuptake inhibition, may be a useful agent for treating the intrusive, avoidance, and arousal symptoms that characterize PTSD. Fourteen adult subjects (12 with civilian-related post-traumatic stress disorder, and 2 with combat-related post-traumatic stress disorder) were entered into an 8 wk, openlabel, fixed-dose trial of citalopram, commencing with 20 mg d, and increasing to 40 mg d after 2 wk. Eleven subjects completed 8 wk treatment and were included in the data analysis. Based on the Clinician-Administered Post-traumatic Stress Disorder Scale (CAPS-2), there was significant reduction in all core PTSD symptoms (re-experiencing, hyperarousal, and avoidance) by week 8. Nine of the 11 completers were classified as responders on Clinical Global Impression Improvement scores. Secondary measures of depression (Montgomery Asberg Depression Rating Scale) and anxiety (Hamilton Anxiety Scale) also improved significantly by week 8. Citalopram was tolerated well, and there were no dropouts due to adverse effects. Data from this preliminary open trial suggests that citalopram, an SSRI, may be effective for reducing the key symptoms of PTSD, however, these findings need confirmation in double-blind, placebo-controlled trials. Received 24 November 1999; Reviewed 27 February 2000; Revised 16 March 2000; Accepted 21 March 2000 Key words: Post-traumatic stress disorder, citalopram, open trial. Introduction Post-traumatic stress disorder (PTSD) is a prevalent, trauma-specific anxiety disorder often characterized by high morbidity, chronicity, and co-morbidity (Kessler et al., 1995; Solomon and Davidson, 1997). The pathophysiology of PTSD is considered to involve dysfunction of several brain structures (amygdala, hippocampus, locus coeruleus) and dysregulation of serotonergic, noradrenergic, dopaminergic, opiate, and corticotropinreleasing-factor neurochemical systems (Charney et al., 1993). Because of the varied psychobiological disturbances, almost every class of psychotropic agent has been prescribed. The goals of any drug therapy in PTSD are 4-fold (Foa et al., 1999): (i) to control primary PTSD symptoms of intrusiveness, avoidance, numbing, and hyperarousal; Address for correspondence: Dr S. Seedat, Department of Psychiatry, University of Stellenbosch, P.O. Box 19063, Tygerberg 7505, Cape Town, South Africa. Tel.: (27) (21) Fax: (27) (21) sseedat gerga.sun.ac.za (ii) to reduce functional impairment and vulnerabilities to stress; (iii) to treat frequently occurring co-morbidities; (iv) to augment or potentiate non-pharmacological therapies (Connor and Davidson, 1998). However, much of our knowledge regarding the pharmacological management of PTSD derives from male combat veterans, and the pharmacotherapy of noncombat-related PTSD remains an under-researched area of study. Based on our current understanding and information gleaned from clinical trials (Davidson et al., 1998; Marshall et al., 1998; Connor et al., 1999; Rothbaum et al., 1996; van der Kolk et al., 1994), the selective serotonin reuptake inhibitors (SSRIs) have emerged as preferred first-choice drugs. While all the SSRIs are likely to provide some benefits, fluoxetine and sertraline have been the most rigorously tested in randomized controlled trials. Sertraline was recently approved by the Food and Drug Administration (FDA) as the first drug treatment for PTSD. The effectiveness of sertraline in PTSD treatment was established in two multicentre, placebo-controlled,

2 136 S. Seedat et al. 12-wk studies in a total of 385 adult out-patients (291 women and 94 men) with PTSD of mean duration of 12 yr. Sertraline was shown to be significantly more effective than placebo on change from baseline to endpoint on the Clinician-Administered PTSD Scale, and on Clinical Global Impression (severity and improvement) scores. The overall positive outcome in both trials appeared to derive from the 152 women on sertraline, with little effect seen in the male subgroups (Gottlieb, 1999; Henney, 2000). To date, there are no published open-label or controlled studies on the efficacy of citalopram in PTSD. Citalopram, a potent and highly selective inhibitor of serotonin reuptake (Hyttel et al., 1995), is an SSRI with known efficacy in major depressive disorder (Mendels et al., 1999) and panic disorder (Wade et al., 1997). Citalopram has been shown to be tolerated well in adult patients (Baldwin and Johnson, 1995), and has a low potential for drug interactions (Greenblatt et al., 1998). The objective of this small sample, open trial was to investigate the possible benefits of citalopram in PTSD. The authors hypothesized that overall PTSD symptoms would improve, and that the medication would be tolerated well. Methods Adults (18 yr and older) were recruited between January and September 1998 from psychiatry out-patient clinics, and newspaper magazine advertisements. The protocol for treatment was approved by the Ethics Committee of the University of Stellenbosch. Written informed consent was obtained from all subjects prior to study procedures. Subjects (n 14) met DSM-IV criteria for a current diagnosis of PTSD at study entry (American Psychiatric Association, 1994) as determined by the Structured Clinical Interview for DSM-IV (SCID-I) (First et al., 1995) and the Clinician-Administered PTSD Scale Diagnostic Version (CAPS-DX or CAPS-1) (Blake et al., 1995). The presence of co-morbid disorders was assessed using the SCID-I. Patients with alcohol and or other psychoactive substance abuse dependence disorders in the past 6 months, psychotic disorders, bipolar disorders, and serious medical disorders were excluded. In addition, patients who had previously received citalopram were excluded. Although 16 subjects were initially screened for participation, 2 were excluded on the basis of co-morbid alcohol dependence. There was a 2-wk washout phase for all patients on current benzodiazepines and or antidepressants [with the exception of fluoxetine (5-wk washout phase)]. Concomitant pharmacotherapy or psychotherapy was not allowed for the duration of the trial. However, supportive counselling was provided by the treating clinician. Symptoms were assessed at baseline and at fortnightly intervals by a single treating clinician. Symptom assessments for PTSD included the Clinician-Administered PTSD Scale Symptom Status Version (CAPS-SX or CAPS-2) (Blake et al., 1995), and the Clinical Global Impression of Severity and Improvement Scale (CGI) (Guy, 1976). Depression was rated using the Montgomery Asberg Depression Rating Scale (MADRS) (Montgomery and Asberg, 1979), and anxiety was rated using the Hamilton Anxiety Scale (HAMA) (Hamilton, 1959). Functional impairment was assessed with the patient-rated Sheehan Disability Scale (Sheehan, 1983). The dose of citalopram was initiated at 20 mg d for the first 2 wk, and then increased to 40 mg d after 2 wk (for weeks 3 8), if tolerated. Data analysis Paired t tests were used to assess statistical significance of symptom change from baseline over 8 wk treatment. Primary efficacy variables to monitor treatment response comprised the Clinician-Administered PTSD Scale (CAPS- 2) and the Clinical Global Impression Improvement Scale (CGI-I). All patients with CGI scores of 1 or 2 endpoint (8 wk) were classed as responders. To measure the timecourse of improvement, changes in CAPS-2 scores (global and subscale scores) were tested for statistical significance for each fortnightly rating vs. baseline using the paired t test. There were no missing values in the sample analysed. Results Description of sample Fourteen subjects were included, and 11 completed 8 wk of treatment. Three subjects dropped out after 2 wk (at weeks 3, 4 and 6, respectively) for non-compliance with visits, and were excluded from the analysis of data. There were 7 men and 7 women, with a mean age of 33.5 yr (range yr, median 33.5 yr). There were 7 Caucasian subjects, 2 Black subjects, and 5 subjects of mixed race. Marital status comprised: married (n 7), separated (n 1), single (n 6). Eleven subjects were employed, 2 were students, and 1 was unemployed (Table 1). All subjects met criteria for chronic PTSD (minimum duration of symptoms 3 months). The mean duration of PTSD symptoms at study entry was 38.6 months (range months, median 13 months). Only 2 subjects (both male) presented with combat-related PTSD. Civilian traumas included rape other sexual assault (n 5), physical assault or injury (n 5), torture (n 1), and witness

3 Citalopram treatment for post-traumatic stress 137 Table 1. demographic characteristics Co-morbid diagnoses (SCID-I) Age Marital Subject* (yr) status Occupation Current Lifetime 1 (M) 37 Married Engineer Dysthymic disorder Alcohol dependence 2 (M) 31 Married Computer software None Alcohol abuse specialist 3 (F) 33 Single Telephonist None None 4 (M) 26 Single Security guard None None 5 (M) 52 Married Quality controller None None 6 (F) 46 Separated Hospice worker MDD None 7 (F) 32 Married Sales None Antisocial PD representative 8 (M) 24 Single Driver None ADHD 9 (M) 35 Single Senior lecturer MDD None 10 (F) 34 Married Journalist MDD Bulimia nervosa 11 (F) 20 Single Scholar None None 12 (M) 38 Married Security guard None None 13 (F) 27 Single Scholar MDD None 14 (F) 34 Married Unemployed MDD Eating disorder NOS * M, male; F, female. MDD, major depressive disorder; PD, personality disorder; ADHD, attention deficit hyperactivity disorder; NOS, not otherwise specified p values and 4 0 and 6 0 and 8 4 and 8 Weeks Figure 1. Pattern of treatment response on CAPS item scores (sum of frequency and severity scores). Paired t tests for means, n 11, d.f. 10 (p values)., Re-experiencing;, avoidance;, hyperarousal. to extreme violence physical harm (n 1). Five subjects met criteria for current co-morbid major depression, and 1 subject met criteria for current dysthymic disorder, of post-traumatic onset. Lifetime diagnoses included past alcohol abuse and dependence (n 2), past bulimia nervosa (n 1), past attention deficit hyperactivity disorder (n 1), and a past eating disorder not otherwise specified (n 1). As regards past treatments for PTSD, none of the subjects had been in any formal psychotherapeutic treatment; 2 subjects had received previous single trials of other SSRIs (sertraline and fluoxetine, respectively) for less than 6 months, and 2 subjects had each received single trials of a tricyclic antidepressant (amitriptyline), for 3 months each. Overall outcome At week 8, 9 of the 11 completers were classed as responders on the CGI-I Scale, with 3 responders very much improved (CGI scores of 1) and 6 responders

4 138 S. Seedat et al Scores Week 0 Week 8 Figure 2. Paired two-sample for means (d.f. 9). For CAPS (total score), CAPS item scores, HAMA, MADRS and CGI (severity); p , Total CAPS; 2, hyperarousal; 3, avoidance; 4, MADRS and HAMA; 5, re-experiencing; 6, CGI-S. much improved (CGI scores of 2). The two nonresponders were minimally improved (CGI scores of 3) at endpoint. Paired two-sample for means showed significant differences between baseline and endpoint total CAPS scores (week 0, 77; week 8, 47.7; p ), as well as significant reduction in all three symptom cluster scores (re-experiencing, avoidance, hyperarousal) (Figure 2). There was a mean reduction of 29.3 points (38.0%) between baseline and endpoint total CAPS scores. Secondary measure analyses revealed statistically significant improvement, and clinical improvement on HAMA (week 0, 24.1; week 8, 15.9; p ) and MADRS (week 0, 24.8; week 8, 15.4; p ). However, the Sheehan Disability Scale indicated that subjects were significantly less impaired overall by week 8 (week 0, 19.1; week 8, 13.1; p 0.02), but improvement in individual domains (work, leisure, family) did not reach statistical significance. Time to response Improvement in total CAPS scores was not significant between weeks 0 and 2, but was significant between weeks 0 and 4 (week 0, 78.1; week 4, 58.1; p ). Improvement in hyperarousal symptoms (week 0, 29.4; week 4, 22.4; p 0.01) and re-experiencing symptoms was significant by week 4 (week 0, 19.5; week 4, 13.4; p 0.04), while improvement in avoidance symptoms reached significant levels by week 6 (week 0, 29.2; week 6, 18.4; p 0.01) (Figure 1). Side-effects Subjects were assessed for treatment-emergent sideeffects at each visit. Daytime sedation (n 5), nausea (n 4), headaches (n 2), dry mouth (n 2), and diarrhoea (n 2) were the side-effects most often reported. No subject dropped out because of side-effects. Discussion In recent years, serotonergic dysregulation has been postulated as an important aetiological factor in the response to extreme and traumatic stress, and the role of serotonin has been explored in animal model studies, pharmacologic challenge tests, clinical studies of paroxetine binding, and neuroimaging studies (Fichtner et al., 1994; Southwick et al., 1995). Results of open and controlled trials of the SSRIs, and drugs with serotonergic properties [e.g. tricyclic antidepressants, monoamine oxidase inhibitors, and reversible inhibitors of monoamine oxidase (RIMAs)], reinforce the hypothesis that modulation of serotonergic function in PTSD is of therapeutic benefit to both core and secondary PTSD symptoms (Petty et al., 1997). The findings of this study suggest that citalopram might be effective for reducing core symptoms in PTSD. In this mixed sample of civilian and combat trauma subjects with chronic PTSD (duration of symptoms 3 months), mean symptom reduction by week 8 was 38.0% (CAPS total score). This is comparable with findings of open trials (fluvoxamine, fluoxetine, and paroxetine) in civilian populations (Davidson et al., 1998; Marshall et al., 1998; van der Kolk et al., 1994), where observed symptom reduction was 40 50%. Overall improvement in PTSD symptoms was seen by week 4, and gains were sustained to week 8. This concurs with findings of other relatively small, SSRI trials (open and controlled), where large treatment effects have been observed at 4 6 wk (Marmar et al., 1996; van der Kolk et al., 1994). In a recent, larger-sample, double-blind, placebo-controlled study of fluoxetine in male combat veterans, onset of drug effect was observed as early as week 2 (Connor et al., 1999). Improvement in hyperarousal and intrusive symptoms was significant by week 4 (CAPS scores), and improvement in avoidance symptoms reached significance by

5 Citalopram treatment for post-traumatic stress 139 week 6. This is not altogether inconsistent with previous studies. In a recently published 12-wk, open trial of paroxetine in non-combat-related, chronic PTSD (Marshall et al., 1998), paroxetine produced rapid improvement in hyperarousal symptoms in responders (within 4 wk), while intrusive and avoidance symptoms improved more gradually over the 12 wk of treatment. Citalopram was effective in reducing concurrent depressive and anxiety symptoms (as measured by MADRS and HAMA, respectively), and was tolerated well at effective antidepressant dosages. Although the depressed sub-sample showed greater mean reduction in total CAPS scores at endpoint (mean 44 point reduction) as compared with the non-depressed sub-sample (mean 28.2 point reduction), this did not reach statistical significance (paired t tests for means). There were no dropouts due to adverse effects. Overall, adverse effects reported were mild, and of short duration (less than 4 wk). In conclusion, citalopram was safe and effective in treating core PTSD symptoms in this open trial of both civilian- and combat-related, chronic PTSD. Limitations of the trial include its small sample size, lack of placebo arm, lack of independent clinical evaluator (other than the treating clinician), and trial duration of less than 12 wk. With regard to duration of treatment, most SSRI trials have utilized a design of 8 12 wk for acute treatment of PTSD. Marshall et al. (1998) reported in their 12-wk, open trial of paroxetine, that all endpoint responders were identified as such by week 8, but suggested that gains in intrusive and avoidance symptoms might continue beyond 12 wk. More acute onset of drug effect has been observed with fluoxetine (Connor et al., 1999), where improvement in PTSD symptoms was seen as early as week 2, but further improvement continued up to week 12. Additional limitations include the lack of follow-up data after 8 wk, and the effects of discontinuation of medication. The findings of this trial should be replicated in larger, controlled, longer-term trials of citalopram, in civilian and combat PTSD populations. Acknowledgements This work is supported by the Medical Research Council Unit on Anxiety and Stress Disorders, and by a fellowship from the Lundbeck Institute of Psychiatry References American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: American Psychiatric Association. Baldwin D, Johnson F (1995). Tolerability and safety of citalopram. Review of Contemporary Pharmacotherapy 6, Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Gusman FD, Charney DS, Keane TM (1995). The development of a clinician administered PTSD scale. Journal of Traumatic Stress 8, Charney DS, Deutch AY, Krystal JH, Southwick SM, Davis M (1993). 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