International Journal of Psychiatry in Clinical Practice
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study Ulrich Frommberger, Rolf-Dieter Stieglitz, Elisabeth Nyberg, Harald Richter, Ulrike Novelli-Fischer, Jorg Angenendt, Rocco Zaninelli & Mathias Berger To cite this article: Ulrich Frommberger, Rolf-Dieter Stieglitz, Elisabeth Nyberg, Harald Richter, Ulrike Novelli-Fischer, Jorg Angenendt, Rocco Zaninelli & Mathias Berger (2004) Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study, International Journal of Psychiatry in Clinical Practice, 8:1, 19-23 To link to this article: http://dx.doi.org/10.1080/13651500310004803
Published online: 13 Sep 2010.
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International Journal of Psychiatry in Clinical Practice 2004
Volume 8
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Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study ULRICH FROMMBERGER1, ROLF-DIETER STIEGLITZ1, ELISABETH NYBERG1, HARALD RICHTER1, ULRIKE NOVELLI-FISCHER1, JO¨RG ANGENENDT1, ROCCO ZANINELLI2 AND MATHIAS BERGER1 1
Department of Psychiatry, University of Freiburg, Hauptstr. 5, D-79104 Freiburg, Germany and 2GlaxoSmithKline, Neuroscience Clinical Development, Philadelphia, PA, USA
Antidepressants and cognitive-behavioural therapy (CBT) have been reported to decrease severity of psychopathology in PTSD-patients. To date, no study has been carried out which compares psychopharmacological and psychotherapeutic treatments. In a randomized pilot study, PTSD-patients were treated either with paroxetine or CBT. Diagnoses were made by structured clinical interviews (ADIS, CAPS). The duration of treatment was 3 months; the paroxetine dosage was 10 50 mg; exposure and cognitive restructuring were the main elements in cognitivebehavioural therapy. Twenty-one patients were included. Drop-outs in both groups occurred within the first 2 weeks. Paroxetine and CBT significantly decreased PTSD-symptoms (CAPS) as well as concurrent depression (MADRS) after 3 months treatment. At 6 month follow-up, symptoms of PTSD had slightly increased in the paroxetine group and further decreased in the cognitive-behavioural therapy group. (Int J Psych Clin Pract 2004; 8: 19 23)
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Correspondence Address Ulrich Frommberger, MD, Klinik an der Lindenho¨he, Bertha von Suttner Str. 1, D-77654 Offenburg, Germany Tel: /(49) 781 9192201 Fax: /(49) 781 9192231 E-mail: [email protected]
Received 2 June 2000; revised 22 May 2002; accepted for publication 19 June 2002
Keywords posttraumatic stress disorder paroxetine follow-up
INTRODUCTION
C
ivilian traumatic events such as accidents, sexual and non-sexual violence often occur in our society.1 Immediately following the trauma or with delay individuals may respond by exhibiting a variety of symptoms indicative of stress reaction. In most patients symptom frequency and intensity decrease within days or weeks. However, a substantial minority develop chronic and debilitating symptoms of posttraumatic stress disorder (PTSD). According to DSM-IV,2 PTSD is a condition which develops after severe trauma with symptoms of (1) reexperiencing the traumatic event, (2) avoiding thoughts, feelings or situations which remind of the trauma, (3) hyperarousal with tension, nervousness or sleep disturbances. Posttraumatic stress
treatment cognitive-behavioural therapy (CBT)
disorder is often associated with major depression, which can complicate the course and increase the severity of the illness. Epidemiological data1 reveal that 5% of the male and 10% of the female US population have a lifetime diagnosis of PTSD. Although a number of published studies indicate that both pharmacotherapy3 11 and psychotherapy12,13 can be effective treatments for PTSD, to date no study has compared these two treatment approaches (for reviews, see Refs. 14 /17). Cognitive-behavioural therapy (CBT) with prolonged exposure in sensu and exposure in vivo has been shown to be effective in rape victims,12,13 but there is very limited information about the efficacy of this treatment for other types of civilian traumas, e.g. for accident victims. In DOI: 10.1080/13651500310004803
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U Frommberger et al
addition, exposure therapy is limited in its availability to PTSD patients. Despite its general efficacy the challenges of exposure therapy can lead to a worsening of psychopathology18 in single patients. Tricyclic antidepressants (amitriptyline, imipramine) or MAO inhibitors (phenelzine) have shown significant but only limited efficacy on PTSD symptoms.19 21 However, side effects of these medications may negatively effect patients’ compliance. The more recently developed selective serotonin reuptake inhibitors (SSRIs) are better tolerated due to a more favorable side effect profile and are safer in overdose than the older compounds. For the SSRIs fluoxetine,5,22 sertraline3,4,6 9 and paroxetine10,11 efficacy in decreasing PTSD symptoms and good tolerability have been shown in controlled studies. The SSRI paroxetine has been demonstrated to be one of the more versatile drugs of this class and is currently registered in the US and several European countries for the treatment of depression, panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder and PTSD.10,11 In this pilot study we evaluated the efficacy, tolerability and safety of paroxetine and cognitive-behavioural therapy in the treatment of PTSD with comorbid depression. We compared these treatments after 3 months and after a 6month follow-up period.
METHODS DESIGN This study was an open, randomized, parallel-group comparison of paroxetine and CBT. The treatment duration was 12 weeks. Cognitive-behavioural therapy was conducted by clinical psychologists who had been trained onsite by Edna Foa (E.N., H.R.) and who were supervised by an experienced CBT therapist (J.A.). The psychopharmacological treatment was conducted by a senior psychiatrist who was also the principal investigator (U.F.). Paroxetine dosing began at 10 mg/day for 1 week and from the beginning of week 2 could be increased weekly by 10-mg increments at the discretion of the investigator according to clinical response and tolerability. The maximum individual dosage of paroxetine ranged from 20 to 50 mg (mean 28 mg). Medication management included thorough psychoeducation regarding the nature of the disorder and strategies for dealing with side-effects. Elements of exposure were omitted from the drug treatment in order to differentiate clearly between both treatment approaches. Cognitive-behavioural therapy was based on the structured manual of Foa et al,12 comprising psychoeducation, behavioural assessment, relaxation training, stress inoculation training, exposure in sensu (prolonged exposure) and in vivo as well as cognitive restructuring. CBT and medication-management sessions were conducted weekly. Upon completion of the 12-week treatment period, patients could elect to continue paroxetine or unstructured (not
manualized) CBT. A follow-up assessment was conducted 6 months after the end of treatment.
PATIENTS Patients were recruited from a specialized outpatient PTSD treatment center. Patients 18 years and older fulfilling DSMIII-R criteria for chronic PTSD were randomized to either paroxetine or cognitive-behavioural therapy. The patients also met the diagnosis of major depressive episode (n /6 in the paroxetine group; n /5 in the CBT group), dysthymia (n /2 in the paroxetine group; n /2 in the CBT group) or did not meet the criteria for a depressive disorder although they exhibited depressive symptoms (n /2 in the CBT group). Patients were excluded if they were pregnant or suffered from severe illness or injuries which are contraindications for drug or behavioural therapy treatment. Patients were also excluded if they had suicidal ideation, had abused alcohol or drugs in the last 6 months prior to the study, had a history of schizophrenia or bipolar disorder or had received treatment with SSRIs or MAO inhibitors 6 weeks prior to study entry. The study was carried out at the Department of Psychiatry of the University of Freiburg, Germany. All patients signed written informed consent; the study was approved by the local ethics committee.
ASSESSMENTS The following diagnostic and efficacy measures were employed: the Clinician Administered PTSD Scale (CAPS-1 and CAPS-2)23 for diagnosis and severity of PTSD, the German version of the Anxiety Disorders Inventory Schedule ADIS24 for lifetime psychiatric diagnoses. In PTSD, depressive and anxiety symptoms often are difficult to distinguish from each other. We therefore chose two separate clinician-rated instruments to measure depressive and anxiety symptoms, the Montgomery Asberg Depression Rating Scale (MADRS)25 and the Hamilton Rating Scale for Anxiety (HAMA).26 Patient-rated instruments were the Posttraumatic Stress Scale PSS (27,28) and the Beck Depression Inventory BDI (29). A record was provided for the assessment of all spontaneous reports of adverse symptoms due to paroxetine. Laboratory testing at baseline and during treatment as well as weekly examinations of side effects were used to monitor the tolerability and safety of paroxetine. All efficacy assessments were performed at baseline, weeks twelve and at 6-month follow-up.
STATISTICS Group differences at the 12-week endpoint were calculated by ANOVA (two-factor design with repeated measures). The data of the patients who discontinued were excluded from analysis. Due to missing data, the number of patients at each measure varied from five to eight patients in each of the
Paroxetine versus CBT in PTSD
groups. All analyses were performed using Statistical Package for the Social Sciences (SPSS), Version 6.1.3.
RESULTS
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PATIENTS Twenty-one patients were included in the study (10 patients CBT, 11 patients paroxetine). In the paroxetine group the mean age was 44.09/18.8 years, and there were seven male and four female patients. In the behavioural therapy group the mean age was 41.29/9.3 years with two male and eight female patients. The difference in age between both groups was not significant (t (19) /0.74, P /0.46). The most frequent traumatic events were serious accidents, sexual or non-sexual violence. The mean time since the index trauma was the same in both treatment groups: 349/35 months in the paroxetine group, 349/25 months in the cognitivebehavioural group, respectively.
21
Improvement in PTSD symptoms was demonstrated by changes in the CAPS at 3 months. At 6-month follow-up, in the paroxetine group the scores of the CAPS, MADRS, PSS and BDI had increased relative to the 12-week endpoint. This appeared due to the occurrence of adverse life events in two patients (CAPS: from 36.1 to 53.6; MADRS: from 9.5 to 19.8; PSS from 25.1 to 26.0; BDI from 18.5 to 19.0). Due to the small number of patients in this pilot study, these two relapses had a significant influence on the follow-up data. Those paroxetine patients who did not relapse continued to improve during follow-up. All patients in the CBT group showed continued reduction in CAPS, MADRS and PSS scores (CAPS: from 34.8 to 23.0; MADRS: from 13.4 to 12.0; PSS: from 15.0 to 13.9). Because of the small size of the sample at 6-month follow-up (n /5 in the paroxetine group and n /8 in the CBT group), only descriptive statistics were performed for this assessment. From the end of the structured treatment until the follow-up assessment, all of the paroxetine and CBT patients had a continuous treatment at a 2-weekly or monthly basis. The treatment consisted in clinical or symptom management but no exposure therapy.
EFFICACY At the 3-month endpoint, relative to baseline symptoms of PTSD as measured by the CAPS and the PSS decreased significantly (P /0.001) in both treatment groups (Table 1). Table 1 also shows that there were significant reductions in depressive (MADRS) and anxiety (HAMA) symptoms (P / 0.001). The improvement in depressive symptoms is reflected more by the changes in the clinician-rated MADRS (P /0.001) than in the patient-rated BDI (P /0.05). No statistically significant differences were observed between the treatment groups in any of the efficacy ratings. Nonetheless, the improvement in PTSD symptomatology as assessed by the patient-rated PSS was twice as great in the cognitivebehavioural therapy group than in the paroxetine group.
TOLERABILITY
AND
SAFETY
No significant adverse events due to treatment with paroxetine occurred in laboratory tests (e.g. white blood cell count, liver enzymes), ECG or EEG. In the paroxetine group, three patients discontinued the study within the first 2 weeks of treatment due to nervousness, agitation, headache, nausea, dizziness or blurred vision. Two patients in the CBT group dropped out due to an increase of anxiety before the first exposure session despite a thorough explanation of the treatment rationale. Most paroxetine patients did not spontaneously report adverse events, and those who exhibited side effects (agitation, headache, nausea, fatigue, abnormal
Table 1 Analysis of variance: PTSD symptomatology and depression Pre
CAPS PSS HAMA MADRS BDI
Par BT Par BT Par BT Par BT Par BT
Analysis of variance
Post
Mean
SD
Mean
SD
‘Groups’
‘Time’
‘Groups /Time’
65.0 70.5 34.1 34.5 28.5 27.6 25.0 25.6 25.2 19.1
13.4 7.2 9.8 4.3 8.8 12.3 9.0 12.7 11.8 9.5
36.1 34.8 25.1 15.0 14.1 16.6 9.5 13.4 18.5 11.6
12.1 15.0 11.6 5.3 7.0 10.7 5.8 12.9 15.2 7.2
Ns
***
Ns
Ns
***
**
Ns
***
Ns
Ns
***
Ns
Ns
*
Ns
Factor 1 ‘groups’: Par; paroxetine; BT, behaviour therapy, BT. Factor 2 ‘time’: Pre, Pre-test. Post, Post Test; interaction: groups /time. Ns, P /0.10; **P 5/0.10; *P 5/0.05; ***P 5/0.001.
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ejaculation, breast swelling, irregular menstrual period) tolerated these because of the benefits of the drug on symptoms of PTSD or depression. In two patients, 10 mg paroxetine over 12 weeks was sufficent to relieve symptoms substantially. In three patients with severe comorbid depression, a marked response occurred shortly after the dosage was increased to 40 mg. During the follow-up period, two patients in the paroxetine group relapsed following re-exposure to reminders of the trauma or loss of a significant other.
DISCUSSION Any conclusions from this pilot study are limited because of the small number of patients, the lack of a placebo control group, and the lack of an independent status of the raters (the therapists were the raters). Nonetheless, the results of this pilot study should serve to encourage controlled comparative studies with larger sample sizes. In this randomized pilot study we showed that paroxetine and cognitive-behavioural therapy significantly decreased symptoms of posttraumatic stress disorder and major depression by 3 months. These results confirm the findings of placebo-controlled studies on the efficacy of SSRIs3,7,9,11,22 and cognitive-behavioural therapy12 in patients suffering from chronic PTSD. The efficacy of the SSRI fluoxetine has been reported to be better in a civilian patient sample than in combat veterans.22 Recently published studies of the effects of sertraline and paroxetine in the treatment of PTSD were also carried out in predominantly civilian patient samples. Our patients had been confronted exclusively with civilian traumas including non-sexual violence. Thus our data support the notion that chronic psychological sequelae of civilian traumas can be treated successfully either with a SSRI or with cognitive-behavioural therapy. In this pilot study of the direct comparison of these two treatments, the reduction of symptoms is similar for both approaches. At 6-month follow-up the groups differed probably only because two patients in the paroxetine group
showed a substantial increase of PTSD symptoms and depression due to new adverse life events. It may be speculated that cognitive-behavioural therapy and its focus on coping strategies would have been more helpful for these patients than drugs as prophylactic treatment modality. Paroxetine and behaviour therapy were well tolerated by three-quarters of the patients. In our clinical opinion, thorough psychoeducation is as essential for compliance with CBT as it is with psychopharmacotherapy. The results of this study are supported by the results from the meta-analysis of controlled treatment studies in PTSD of Van Etten and Taylor,16 who reported substantial effect sizes for both SSRIs and CBT, as well as a possibly more favourable long-term outcome for psychotherapy than for medication treatment. Our results might favour cognitive-behavioural therapy, too, because of its better outcome at follow-up. This notion is supported by an expert consensus guideline rating on the treatment of PTSD.30 In conclusion, future studies should focus on comparing under more controlled conditions the efficacy not only of CBT and pharmacotherapy but also of combinations of these approaches in the treatment of PTSD.31
ACKNOWLEDGEMENTS This investigator-initiated study was supported by SmithKline-Beecham, Munich.
KEY POINTS . Paroxetine and cognitive-behavioural therapy (CBT) equally reduce symptoms in PTSD-patients . Symptoms of anxiety, depression and PTSD decrease during both treatments . Six-month follow-up indicates maintained improvement in most patients, with somewhat greater effect of CBT
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de Clercq M, Hoyois PH, Lim-Cow C, Vermeiren E (1999) Openlabel study of fluoxetine in civilian post-traumatic stress disorder. Poster presented at the XI World Congress of Psychiatry, 6 /11 August 1999, Hamburg. Davidson J, Londborg P, Pearlstein T, Rothbaum B, Brady K, Farfel GM (2000) Sertraline and posttraumatic stress disorder: results of 24 weeks of open-label sertraline, followed by a 28-week discontinuation study. Poster presented at the 13th ECNP Congress , 9 /13 September 2000, Mu¨nchen. Davidson JRT, Rothbaum BO, van der Kolk BA, Sikes CR, Farfel GM (2001) Multicenter, double-blind comparison of sertraline and placebo in the treatment of posttraumatic stress disorder. Arch Gen Psychiatry 58: 485 /92.
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Davidson JRT, Kudler HS, Smith RD, Mahorney SL, Lipper S, Hammet E, Saunders WB, Cavenar JO Jr (1990) Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry 47: 259 /66. Kosten TR, Frank JB, Dan E, McDouble CJ, Giller EL (1991) Pharmacotherapy for posttraumatic stress disorder using phenelzine or imipramine. J Nerv Ment Dis 179: 366 /70. Shestatzky M, Greenberg D, Lerer B (1988) A controlled trial of phenelzine in posttraumatic stress disorder. Psychiatry Res 24: 149 /55. Van der Kolk BA, Dryfuss D, Michaels M, Shera D, Berkowitz B, Fisler R, Saxe G (1994) Fluoxetine in Posttraumatic Stress Disorder. J Clin Psychiatry 55: 517 /22. Blake DD, Weathers FW, Nagy LM, Kaloupek DG, Klauminzer G, Charney DS, Keane TM (1990) A clinician rating scale for assessing current and lifetime PTSD: the CAPS-1. Behavior Ther 13: 187 /8. DiNardo PA, Barlow DH (1988) Anxiety Disorders Interview Schedule /Revised (ADIS-R). State University of New York, Albany, NY (German Version: Diagnostisches Interview bei Psychischen Sto¨rungen DIPS, Margraf et al 1991, Springer, Berlin). Montgomery SA, Asberg M (1979) A depression rating scale designed to be sensitive to change. Br J Psychiatry 139: 382 /9. Hamilton M (1960) Diagnosis and rating of anxiety. In: Lader MH (ed) Studies on anxiety. Br J Psychiatry (Special Publication) 3: 76 / 9. Foa EB, Riggs DS, Dancu CV, Rothbaum BO (1993) Reliability and validity of a brief instrument for assessing Post-Traumatic Stress Disorder. J Traumatic Stress 6: 459 /73. Stieglitz R-D, Frommberger U, Foa E, Berger M (2001) Evaluation of the German Version of the PTSD Symptom Scale (PSS). Psychopathology 34: 128 /33. Beck AT, Steer RA, Garbin MG (1988) Psychometric properties of the Beck Depression Inventory: Twenty-five years later. Clin Psychol Rev 8: 77 /100. Foa EB, Davidson JRT, Frances A (eds) (1999) The Expert Consensus Guideline Series. Treatment of Posttraumatic Stress Disorder. J Clin Psychiatry 60 (Suppl. 16). Ballenger JC, Davidson JRT, Lecrubier Y, Nutt DJ, Foa E, Kessler RC, McFarlane A, Shalev A (2000) Consensus statement on posttraumatic stress disorder from the international consensus group on depression and anxiety. J Clin Psychiatry 61 (Suppl. 5): 60 /6.
ISSN: 1365-1501 (Print) 1471-1788 (Online) Journal homepage: http://www.tandfonline.com/loi/ijpc20
Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study Ulrich Frommberger, Rolf-Dieter Stieglitz, Elisabeth Nyberg, Harald Richter, Ulrike Novelli-Fischer, Jorg Angenendt, Rocco Zaninelli & Mathias Berger To cite this article: Ulrich Frommberger, Rolf-Dieter Stieglitz, Elisabeth Nyberg, Harald Richter, Ulrike Novelli-Fischer, Jorg Angenendt, Rocco Zaninelli & Mathias Berger (2004) Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study, International Journal of Psychiatry in Clinical Practice, 8:1, 19-23 To link to this article: http://dx.doi.org/10.1080/13651500310004803
Published online: 13 Sep 2010.
Submit your article to this journal
Article views: 91
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ijpc20 Download by: [NUS National University of Singapore]
Date: 09 November 2015, At: 00:00
# 2004 Taylor & Francis
International Journal of Psychiatry in Clinical Practice 2004
Volume 8
Pages 19 /23
19
Downloaded By: [informa internal users] At: 15:12 7 September 2010 Downloaded by [NUS National University of Singapore] at 00:00 09 November 2015
Comparison between paroxetine and behaviour therapy in patients with posttraumatic stress disorder (PTSD): A pilot study ULRICH FROMMBERGER1, ROLF-DIETER STIEGLITZ1, ELISABETH NYBERG1, HARALD RICHTER1, ULRIKE NOVELLI-FISCHER1, JO¨RG ANGENENDT1, ROCCO ZANINELLI2 AND MATHIAS BERGER1 1
Department of Psychiatry, University of Freiburg, Hauptstr. 5, D-79104 Freiburg, Germany and 2GlaxoSmithKline, Neuroscience Clinical Development, Philadelphia, PA, USA
Antidepressants and cognitive-behavioural therapy (CBT) have been reported to decrease severity of psychopathology in PTSD-patients. To date, no study has been carried out which compares psychopharmacological and psychotherapeutic treatments. In a randomized pilot study, PTSD-patients were treated either with paroxetine or CBT. Diagnoses were made by structured clinical interviews (ADIS, CAPS). The duration of treatment was 3 months; the paroxetine dosage was 10 50 mg; exposure and cognitive restructuring were the main elements in cognitivebehavioural therapy. Twenty-one patients were included. Drop-outs in both groups occurred within the first 2 weeks. Paroxetine and CBT significantly decreased PTSD-symptoms (CAPS) as well as concurrent depression (MADRS) after 3 months treatment. At 6 month follow-up, symptoms of PTSD had slightly increased in the paroxetine group and further decreased in the cognitive-behavioural therapy group. (Int J Psych Clin Pract 2004; 8: 19 23)
/
/
Correspondence Address Ulrich Frommberger, MD, Klinik an der Lindenho¨he, Bertha von Suttner Str. 1, D-77654 Offenburg, Germany Tel: /(49) 781 9192201 Fax: /(49) 781 9192231 E-mail: [email protected]
Received 2 June 2000; revised 22 May 2002; accepted for publication 19 June 2002
Keywords posttraumatic stress disorder paroxetine follow-up
INTRODUCTION
C
ivilian traumatic events such as accidents, sexual and non-sexual violence often occur in our society.1 Immediately following the trauma or with delay individuals may respond by exhibiting a variety of symptoms indicative of stress reaction. In most patients symptom frequency and intensity decrease within days or weeks. However, a substantial minority develop chronic and debilitating symptoms of posttraumatic stress disorder (PTSD). According to DSM-IV,2 PTSD is a condition which develops after severe trauma with symptoms of (1) reexperiencing the traumatic event, (2) avoiding thoughts, feelings or situations which remind of the trauma, (3) hyperarousal with tension, nervousness or sleep disturbances. Posttraumatic stress
treatment cognitive-behavioural therapy (CBT)
disorder is often associated with major depression, which can complicate the course and increase the severity of the illness. Epidemiological data1 reveal that 5% of the male and 10% of the female US population have a lifetime diagnosis of PTSD. Although a number of published studies indicate that both pharmacotherapy3 11 and psychotherapy12,13 can be effective treatments for PTSD, to date no study has compared these two treatment approaches (for reviews, see Refs. 14 /17). Cognitive-behavioural therapy (CBT) with prolonged exposure in sensu and exposure in vivo has been shown to be effective in rape victims,12,13 but there is very limited information about the efficacy of this treatment for other types of civilian traumas, e.g. for accident victims. In DOI: 10.1080/13651500310004803
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addition, exposure therapy is limited in its availability to PTSD patients. Despite its general efficacy the challenges of exposure therapy can lead to a worsening of psychopathology18 in single patients. Tricyclic antidepressants (amitriptyline, imipramine) or MAO inhibitors (phenelzine) have shown significant but only limited efficacy on PTSD symptoms.19 21 However, side effects of these medications may negatively effect patients’ compliance. The more recently developed selective serotonin reuptake inhibitors (SSRIs) are better tolerated due to a more favorable side effect profile and are safer in overdose than the older compounds. For the SSRIs fluoxetine,5,22 sertraline3,4,6 9 and paroxetine10,11 efficacy in decreasing PTSD symptoms and good tolerability have been shown in controlled studies. The SSRI paroxetine has been demonstrated to be one of the more versatile drugs of this class and is currently registered in the US and several European countries for the treatment of depression, panic disorder, obsessive-compulsive disorder, social phobia, generalized anxiety disorder and PTSD.10,11 In this pilot study we evaluated the efficacy, tolerability and safety of paroxetine and cognitive-behavioural therapy in the treatment of PTSD with comorbid depression. We compared these treatments after 3 months and after a 6month follow-up period.
METHODS DESIGN This study was an open, randomized, parallel-group comparison of paroxetine and CBT. The treatment duration was 12 weeks. Cognitive-behavioural therapy was conducted by clinical psychologists who had been trained onsite by Edna Foa (E.N., H.R.) and who were supervised by an experienced CBT therapist (J.A.). The psychopharmacological treatment was conducted by a senior psychiatrist who was also the principal investigator (U.F.). Paroxetine dosing began at 10 mg/day for 1 week and from the beginning of week 2 could be increased weekly by 10-mg increments at the discretion of the investigator according to clinical response and tolerability. The maximum individual dosage of paroxetine ranged from 20 to 50 mg (mean 28 mg). Medication management included thorough psychoeducation regarding the nature of the disorder and strategies for dealing with side-effects. Elements of exposure were omitted from the drug treatment in order to differentiate clearly between both treatment approaches. Cognitive-behavioural therapy was based on the structured manual of Foa et al,12 comprising psychoeducation, behavioural assessment, relaxation training, stress inoculation training, exposure in sensu (prolonged exposure) and in vivo as well as cognitive restructuring. CBT and medication-management sessions were conducted weekly. Upon completion of the 12-week treatment period, patients could elect to continue paroxetine or unstructured (not
manualized) CBT. A follow-up assessment was conducted 6 months after the end of treatment.
PATIENTS Patients were recruited from a specialized outpatient PTSD treatment center. Patients 18 years and older fulfilling DSMIII-R criteria for chronic PTSD were randomized to either paroxetine or cognitive-behavioural therapy. The patients also met the diagnosis of major depressive episode (n /6 in the paroxetine group; n /5 in the CBT group), dysthymia (n /2 in the paroxetine group; n /2 in the CBT group) or did not meet the criteria for a depressive disorder although they exhibited depressive symptoms (n /2 in the CBT group). Patients were excluded if they were pregnant or suffered from severe illness or injuries which are contraindications for drug or behavioural therapy treatment. Patients were also excluded if they had suicidal ideation, had abused alcohol or drugs in the last 6 months prior to the study, had a history of schizophrenia or bipolar disorder or had received treatment with SSRIs or MAO inhibitors 6 weeks prior to study entry. The study was carried out at the Department of Psychiatry of the University of Freiburg, Germany. All patients signed written informed consent; the study was approved by the local ethics committee.
ASSESSMENTS The following diagnostic and efficacy measures were employed: the Clinician Administered PTSD Scale (CAPS-1 and CAPS-2)23 for diagnosis and severity of PTSD, the German version of the Anxiety Disorders Inventory Schedule ADIS24 for lifetime psychiatric diagnoses. In PTSD, depressive and anxiety symptoms often are difficult to distinguish from each other. We therefore chose two separate clinician-rated instruments to measure depressive and anxiety symptoms, the Montgomery Asberg Depression Rating Scale (MADRS)25 and the Hamilton Rating Scale for Anxiety (HAMA).26 Patient-rated instruments were the Posttraumatic Stress Scale PSS (27,28) and the Beck Depression Inventory BDI (29). A record was provided for the assessment of all spontaneous reports of adverse symptoms due to paroxetine. Laboratory testing at baseline and during treatment as well as weekly examinations of side effects were used to monitor the tolerability and safety of paroxetine. All efficacy assessments were performed at baseline, weeks twelve and at 6-month follow-up.
STATISTICS Group differences at the 12-week endpoint were calculated by ANOVA (two-factor design with repeated measures). The data of the patients who discontinued were excluded from analysis. Due to missing data, the number of patients at each measure varied from five to eight patients in each of the
Paroxetine versus CBT in PTSD
groups. All analyses were performed using Statistical Package for the Social Sciences (SPSS), Version 6.1.3.
RESULTS
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PATIENTS Twenty-one patients were included in the study (10 patients CBT, 11 patients paroxetine). In the paroxetine group the mean age was 44.09/18.8 years, and there were seven male and four female patients. In the behavioural therapy group the mean age was 41.29/9.3 years with two male and eight female patients. The difference in age between both groups was not significant (t (19) /0.74, P /0.46). The most frequent traumatic events were serious accidents, sexual or non-sexual violence. The mean time since the index trauma was the same in both treatment groups: 349/35 months in the paroxetine group, 349/25 months in the cognitivebehavioural group, respectively.
21
Improvement in PTSD symptoms was demonstrated by changes in the CAPS at 3 months. At 6-month follow-up, in the paroxetine group the scores of the CAPS, MADRS, PSS and BDI had increased relative to the 12-week endpoint. This appeared due to the occurrence of adverse life events in two patients (CAPS: from 36.1 to 53.6; MADRS: from 9.5 to 19.8; PSS from 25.1 to 26.0; BDI from 18.5 to 19.0). Due to the small number of patients in this pilot study, these two relapses had a significant influence on the follow-up data. Those paroxetine patients who did not relapse continued to improve during follow-up. All patients in the CBT group showed continued reduction in CAPS, MADRS and PSS scores (CAPS: from 34.8 to 23.0; MADRS: from 13.4 to 12.0; PSS: from 15.0 to 13.9). Because of the small size of the sample at 6-month follow-up (n /5 in the paroxetine group and n /8 in the CBT group), only descriptive statistics were performed for this assessment. From the end of the structured treatment until the follow-up assessment, all of the paroxetine and CBT patients had a continuous treatment at a 2-weekly or monthly basis. The treatment consisted in clinical or symptom management but no exposure therapy.
EFFICACY At the 3-month endpoint, relative to baseline symptoms of PTSD as measured by the CAPS and the PSS decreased significantly (P /0.001) in both treatment groups (Table 1). Table 1 also shows that there were significant reductions in depressive (MADRS) and anxiety (HAMA) symptoms (P / 0.001). The improvement in depressive symptoms is reflected more by the changes in the clinician-rated MADRS (P /0.001) than in the patient-rated BDI (P /0.05). No statistically significant differences were observed between the treatment groups in any of the efficacy ratings. Nonetheless, the improvement in PTSD symptomatology as assessed by the patient-rated PSS was twice as great in the cognitivebehavioural therapy group than in the paroxetine group.
TOLERABILITY
AND
SAFETY
No significant adverse events due to treatment with paroxetine occurred in laboratory tests (e.g. white blood cell count, liver enzymes), ECG or EEG. In the paroxetine group, three patients discontinued the study within the first 2 weeks of treatment due to nervousness, agitation, headache, nausea, dizziness or blurred vision. Two patients in the CBT group dropped out due to an increase of anxiety before the first exposure session despite a thorough explanation of the treatment rationale. Most paroxetine patients did not spontaneously report adverse events, and those who exhibited side effects (agitation, headache, nausea, fatigue, abnormal
Table 1 Analysis of variance: PTSD symptomatology and depression Pre
CAPS PSS HAMA MADRS BDI
Par BT Par BT Par BT Par BT Par BT
Analysis of variance
Post
Mean
SD
Mean
SD
‘Groups’
‘Time’
‘Groups /Time’
65.0 70.5 34.1 34.5 28.5 27.6 25.0 25.6 25.2 19.1
13.4 7.2 9.8 4.3 8.8 12.3 9.0 12.7 11.8 9.5
36.1 34.8 25.1 15.0 14.1 16.6 9.5 13.4 18.5 11.6
12.1 15.0 11.6 5.3 7.0 10.7 5.8 12.9 15.2 7.2
Ns
***
Ns
Ns
***
**
Ns
***
Ns
Ns
***
Ns
Ns
*
Ns
Factor 1 ‘groups’: Par; paroxetine; BT, behaviour therapy, BT. Factor 2 ‘time’: Pre, Pre-test. Post, Post Test; interaction: groups /time. Ns, P /0.10; **P 5/0.10; *P 5/0.05; ***P 5/0.001.
22
U Frommberger et al
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ejaculation, breast swelling, irregular menstrual period) tolerated these because of the benefits of the drug on symptoms of PTSD or depression. In two patients, 10 mg paroxetine over 12 weeks was sufficent to relieve symptoms substantially. In three patients with severe comorbid depression, a marked response occurred shortly after the dosage was increased to 40 mg. During the follow-up period, two patients in the paroxetine group relapsed following re-exposure to reminders of the trauma or loss of a significant other.
DISCUSSION Any conclusions from this pilot study are limited because of the small number of patients, the lack of a placebo control group, and the lack of an independent status of the raters (the therapists were the raters). Nonetheless, the results of this pilot study should serve to encourage controlled comparative studies with larger sample sizes. In this randomized pilot study we showed that paroxetine and cognitive-behavioural therapy significantly decreased symptoms of posttraumatic stress disorder and major depression by 3 months. These results confirm the findings of placebo-controlled studies on the efficacy of SSRIs3,7,9,11,22 and cognitive-behavioural therapy12 in patients suffering from chronic PTSD. The efficacy of the SSRI fluoxetine has been reported to be better in a civilian patient sample than in combat veterans.22 Recently published studies of the effects of sertraline and paroxetine in the treatment of PTSD were also carried out in predominantly civilian patient samples. Our patients had been confronted exclusively with civilian traumas including non-sexual violence. Thus our data support the notion that chronic psychological sequelae of civilian traumas can be treated successfully either with a SSRI or with cognitive-behavioural therapy. In this pilot study of the direct comparison of these two treatments, the reduction of symptoms is similar for both approaches. At 6-month follow-up the groups differed probably only because two patients in the paroxetine group
showed a substantial increase of PTSD symptoms and depression due to new adverse life events. It may be speculated that cognitive-behavioural therapy and its focus on coping strategies would have been more helpful for these patients than drugs as prophylactic treatment modality. Paroxetine and behaviour therapy were well tolerated by three-quarters of the patients. In our clinical opinion, thorough psychoeducation is as essential for compliance with CBT as it is with psychopharmacotherapy. The results of this study are supported by the results from the meta-analysis of controlled treatment studies in PTSD of Van Etten and Taylor,16 who reported substantial effect sizes for both SSRIs and CBT, as well as a possibly more favourable long-term outcome for psychotherapy than for medication treatment. Our results might favour cognitive-behavioural therapy, too, because of its better outcome at follow-up. This notion is supported by an expert consensus guideline rating on the treatment of PTSD.30 In conclusion, future studies should focus on comparing under more controlled conditions the efficacy not only of CBT and pharmacotherapy but also of combinations of these approaches in the treatment of PTSD.31
ACKNOWLEDGEMENTS This investigator-initiated study was supported by SmithKline-Beecham, Munich.
KEY POINTS . Paroxetine and cognitive-behavioural therapy (CBT) equally reduce symptoms in PTSD-patients . Symptoms of anxiety, depression and PTSD decrease during both treatments . Six-month follow-up indicates maintained improvement in most patients, with somewhat greater effect of CBT
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