Department of Psychiatry, Mount Sinai School of Medicine, New York, New York, USA
Correspondence: Dr Daphne Simeon, Psychiatry, Box 1230, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA. Tel: +01 (212) 241 7477; fax: +01 (212) 427 6929; e-mail: daphne.simeon{at}mssm.edu
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ABSTRACT |
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Aims To investigate the efficacy of fluoxetine in the treatment of depersonalisation disorder.
Method Fifty-four people who met DSMIV criteria for depersonalisation disorder were recruited through newspaper advertisements, and 50 were randomised to a 10-week, double-blind trial of fluoxetine 1060 mg/day or placebo. Primary outcome measures were the Dissociative Experiences Scale Depersonalisation Factor, the Depersonalization Severity Scale and the Clinical Global Impression Improvement (CGII) scale.
Results Intention-to-treat analysis revealed that fluoxetine (mean dosage 48 mg/day) was not superior to placebo except for a clinically minimal but statistically significantly greater improvement in CGII score in the fluoxetine group prior to covarying for anxiety and depression (2.9 v. 3.6). Depersonalisation was significantly more likely to improve if comorbid anxiety disorder improved.
Conclusions Fluoxetine was not efficacious in treating depersonalisation disorder, despite the commonly reported clinical use of serotonin reuptake inhibitors for this condition.
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INTRODUCTION |
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METHOD |
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People with lifetime diagnoses of schizophrenia, schizoaffective disorder, bipolar disorder or organic mental disorder were excluded from the study, as were individuals with current substance use disorder or eating disorder. Lifetime Axis I disorders were assessed using the Structured Clinical Interview for DSMIV Axis I Disorders (First et al, 1995), and Axis II personality disorders were assessed with the Structured Interview for DSMIV Personality Disorders (Pfohl et al, 1995). Participants were allowed to enter the trial if they had been receiving psychotherapy for at least 3 months, but those who had recently begun psychotherapy or were receiving specialised treatment such as cognitivebehavioural therapy and hypnosis were excluded. Individuals with acute or unstable medical illnesses, as well as those with a history of seizure disorder or major head trauma, were also excluded. All participants had a normal baseline routine laboratory evaluation with negative urine toxicology screenings. Women of childbearing age were required to use an effective birth control method; pregnant and lactating women were excluded.
Design
The study was a double-masked, randomised, parallel, flexible-dosage
comparison of fluoxetine v. placebo for the treatment of
depersonalisation disorder. After a 2-week single-masked placebo run-in phase,
participants were randomised to receive identical-appearing fluoxetine or
placebo capsules. Participants were assigned to the fluoxetine or placebo
group by the institutions pharmacy on the basis of a standard
randomisation table, unknown to the investigators. Fluoxetine dosage was 10 mg
per day for the first week, flexibly increased to 20 mg, 40 mg or 60 mg per
day over the following 3 weeks, according to tolerability. The wide dosage
range was based on the previously anecdotally reported efficacy of higher
dosages (Hollander et al,
1990), but a dosage increase above 10 mg was not required if not
tolerated. No concomitant medication was allowed for the entire duration of
the trial.
Treatment visits occurred every 2 weeks, during which the treating psychiatrist (D.S.) evaluated clinical state, compliance and adverse effects, and adjusted the medication dose. Subsequently, the independent evaluator (O.G.), to whom participants had been requested to report all symptoms accurately but without references or attributions to medication, assessed the primary and secondary outcome measures.
Measures
The same measures were administered at each treatment visit. Three primary
outcome measures were used, in order to give a comprehensive picture of
patient-rated symptoms, clinician-rated symptoms and an overall clinical
impression.
Clinical Global Impression
The Clinical Global Impression scale (CGI;
Guy, 1976) is a standard
clinician-rated, seven-point scale; the severity scale (CGIS) was
applied at the initial visit, and the improvement scale (CGII) was
applied during all subsequent visits, specifically to rate change in
depersonalisation.
Dissociative Experiences Scale
The Dissociative Experiences Scale (DES;
Bernstein-Carlson & Putnam,
1993) is by far the most widely applied measure of dissociation,
having been used in over 250 research studies to date. It is a 28-item
self-report questionnaire of dissociative experiences: each item is scored at
10% intervals from 0% to 100%, and the total score is the mean of all items.
The DES has been shown to have good testretest reliability (intraclass
correlation coefficient 0.790.96), high internal consistency
(Cronbachs =0.95) and strong convergent, discriminant and
criterion validity. The DES has also been used as a state measure in treatment
settings, where patients are asked to rate their experience in the past week
only; in this context it has been shown to be sensitive to treatment change
(Ellason & Ross, 1997; Lubin et al, 1998;
Simeon et al, 2001).
Furthermore, factor analysis of the DES in people with depersonalisation
disorder has yielded three factors absorption, amnesia and
depersonalisation/derealisation (Simeon
et al, 1998b) and in our study we use a
depersonalisation score (DESDP) based on the particular factor analysis
(mean of DES items 7, 12, 13, 24 and 28).
Depersonalization Severity Scale
The Depersonalization Severity Scale (DSS;
Simeon et al, 2001)
is a six-item, clinician-administered scale of depersonalisation experiences
rated 03, applied to the past week, which takes into account both
symptom frequency and intensity. It has been found to have excellent
interrater reliability, moderate internal consistency, high convergent and
divergent validity, and to be sensitive to treatment change
(Simeon et al,
2001).
Secondary outcome measures
The following secondary outcome measures were clinician-administered at
each visit. Depression was measured using the 17-item Hamilton Rating Scale
for Depression (HRSD; Hamilton,
1960), and anxiety was measured with the standard Hamilton Rating
Scale for Anxiety (HRSA; Hamilton,
1959). Social phobia symptoms were measured with the Liebowitz
Social Anxiety Scale (LSAS; Heimberg
et al, 1999), a 25-item scale measuring both social
anxiety and consequent avoidance. Obsessivecompulsive symptoms were
measured using the YaleBrown Obsessive Compulsive Severity scale
(Goodman et al, 1989),
a ten-item scale that measures obsessions and compulsions The Panic Attack
Diary was a weekly subject-generated record of total number of panic attacks.
In addition to these scales, CGII scores were applied to all existent
comorbid disorders to measure treatment change in each.
Statistical analyses
An intention-to-treat analysis was performed, with last observation carried
forward for participants who did not complete the trial. For each of the three
primary outcome measures, two types of analyses of covariance (ANCOVAs) were
performed, one not controlling and the other controlling for depression and
anxiety variables. In the former ANCOVAs, baseline scores were used as the
only covariate. The latter ANCOVAs included six additional covariates in order
to control for baseline and treatment effects in anxiety, depression and
social anxiety, using baseline HRSD, HRSA and LSAS scores, as well as change
scores in these variables between baseline and week 10.
Obsessivecompulsive and panic attack symptom scores were not included
in the latter analyses because they were minimal (see
Table 3). Specifically for the
CGII analyses, the baseline CGIS score was used as the
covariate, and for the four people who did not reach the week 2 treatment
visit, a CGII score of 4 was assumed. For two treatment groups, each
consisting of 25 participants, to achieve a power of 0.80 in detecting group
differences with a two-tailed test at the 0.5 level of significance, the
effect size (difference between means divided by the common standard
deviation) would have to be 0.81 (Cohen,
1988).
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A categorical analysis of responders v. non-responders was
conducted using a 2 test, defined as a CGII score of 2
or 1, combined with a decrease of at least 30% in the two depersonalisation
symptom measures. Chi-squared tests were also used to compare demographic and
clinical characteristics of the two groups where appropriate, as well as
categorical treatment response in relation to the presence of Axis I or Axis
II disorders. For all 2x2
2 tests with an expected value
of less than 5 in any cell, continuity correction was employed. Independent
sample Students t-tests were used to compare demographic and
illness variables between the two groups where appropriate. All statistics are
two-tailed with a 0.5 level of significance.
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RESULTS |
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People withdrawing from the fluoxetine group were individually accounted for as follows: two persons before week 2, one to seek private treatment and one with worsening anxiety; three persons before week 4, one to attempt impregnation (CGII 5), one to seek private treatment (CGII 4) and one discontinued by the investigators for worsening depression (CGII 3); two persons did not return (without explanation) before week 8 (CGII 2 and 4); and two persons dropped out before the final visit, one who relocated (CGII 5) and one who did not return, without explanation (CGII 1). Withdrawals from the placebo group were individually accounted for as follows: two persons before week 2, one because of work schedule and one without an explanation; and two persons by week 4, one because of work schedule (CGII 4) and one non-compliant with treatment visits (CGII 4).
The demographic and illness characteristics of the 50 participants with DSMIV depersonalisation disorder who composed the intention-to-treat sample are given in Table 1. Current comorbidity is summarised in Table 2. It can be seen that the two study groups did not differ on any demographic or clinical variables. There was a trend toward more people with depressive disorders in the fluoxetine group and more people with anxiety disorders in the placebo group, which did not reach statistical significance.
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Treatment outcome
The six ANCOVA analyses of the three primary outcome variables revealed
that fluoxetine was not superior to placebo in treating depersonalisation,
with the exception of a statistically significant improvement in CGII
score when not covaried for depression and anxiety
(Table 3). The mean improvement
in CGI score with fluoxetine was clinically modest (2.9), although
statistically greater than the placebo mean improvement of 3.6. Bi-weekly
changes in the three primary outcome measures are shown in
Fig. 1. Finally, a categorical
analysis of responder status revealed a 24% response rate on fluoxetine
(n=6) and a 20% response rate on placebo (n=5)
(2 0.12, d.f.=1, P=0.73).
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Baseline anxiety and depression scores were modest (Table 3), probably accounting for the absence of a differential improvement in anxious and depressive symptoms during treatment between the two groups as a whole. However, if the participants who had a diagnosis of depressive or anxiety disorder are considered alone (Table 2), those taking fluoxetine consistently tended to have better responses than those taking the placebo, as defined by CGII scores of 2 or 1 for the particular disorder: 50% v. 0% for major depression, 75% v. 25% for dysthymia, 50% v. 40% for generalised anxiety disorder, 100% v. 25% for obsessivecompulsive disorder, 50% v. 40% for panic disorder and 33% v. 13% for social phobia.
Finally, we specifically examined the depersonalisation disorder
CGII score in relation to comorbidity, as this was the only primary
outcome variable to show differential improvement on fluoxetine, prior to
covarying for anxiety and depression. For the fluoxetine group, end-point
CGII score for depersonalisation disorder did not significantly differ
according to the presence or absence of clinical improvement (CGII) in
comorbid depressive disorders (2=5.07, d.f.=4,
P=0.28). However, end-point CGII for depersonalisation
disorder did marginally differ according to the presence or absence of
clinical improvement (CGII) in comorbid anxiety disorders
(
2=5.76, d.f.=2, P=0.06). In effect, of the nine
persons in the fluoxetine group who did have comorbid anxiety disorder, the
four who were anxiety disorder responders were all depersonalisation disorder
responders by CGII. Of the five whose anxiety disorder did not respond
to fluoxetine, only one was a depersonalisation disorder responder. Finally,
within the fluoxetine group, depersonalisation responder status did not
significantly differ in the presence or absence of personality disorder
(
2=0.00, d.f.=1, P=1.00).
Adverse events
Side-effects occurring at a frequency of at least 10% in at least one of
the two study groups included decreased appetite (36% fluoxetine, 4% placebo),
muscle stiffness or cramping (16% fluoxetine, 12% placebo), tremor (16%
fluoxetine, 0% placebo), nervousness (28% fluoxetine, 40% placebo), excitation
or hyperactivity (8% fluoxetine, 12% placebo), fatigue (48% fluoxetine, 16%
placebo), sedation (20% fluoxetine, 0% placebo), headaches (28% both groups),
diarrhoea (16% both groups), nausea (40% fluoxetine, 20% placebo), stomach
ache (12% both groups), urinary frequency (20% fluoxetine, 8% placebo),
palpitations (4% fluoxetine, 20% placebo), dizziness/lightheadedness (16% both
groups), blurry vision (12% fluoxetine, 8% placebo), sweating (16% fluoxetine,
12% placebo), insomnia (48% fluoxetine, 24% placebo), decreased libido (48%
fluoxetine, 20% placebo) and decreased sexual arousal (24% fluoxetine, 4%
placebo). Only one person from the fluoxetine group discontinued the trial
prematurely because of adverse effects, in this case heightened anxiety.
Therefore, to our knowledge, the greater withdrawal rate in the medication arm
was not due to adverse events.
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DISCUSSION |
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Both clinician-rated and self-rated dissociation scores showed a modest decline in both treatment groups, which was clinically not noteworthy and statistically no different. The statistically significant improvement in depersonalisation by CGII score in the fluoxetine group, before correction for depression and anxiety effects, was also not clinically significant, as the average improvement score was approximately 3, i.e. minimal change. Indeed, a number of the participants who experienced some improvement on fluoxetine expressed this effect in words, stating that their symptoms had not really changed, but that they seemed somehow to take less notice or be less bothered by them. The study finding of slight improvement in CGII score without notable improvement in depersonalisation symptom ratings on fluoxetine mirrors these subjective experiences.
Comorbidity and treatment outcome
It is possible that some alleviation of comorbid anxiety and depression
contributed to an overall more tolerable affective state, which led
participants to experience their depersonalisation as less troubling although
essentially unchanged. Indeed, a mediating effect of comorbid anxiety and
depression is suggested by the loss of statistically significant improvement
in CGII when covaried for baseline and change in anxiety and
depression, as well as by the greater improvement in anxiety disorders in
those whose depersonalisation responded to fluoxetine, compared with
non-responders.
The relationship of depersonalisation to anxiety and depression has been debated for decades, and it would be fair to say that the issue remains controversial. Earlier investigators eloquently described the relationship of depersonalisation to phobic anxiety (Roth, 1959), depression (Sedman, 1972) and obsessions (Torch, 1978). More recently, David and colleagues have favoured the view that depersonalisation disorder should be placed with the mood and anxiety disorders (Baker et al, 2003). An alternative view, however, is that extreme emotional states such as severe depression or anxiety are one type of traumatic stress, among many others, that may trigger depersonalisation in individuals with an underlying vulnerability; in some cases, the depersonalisation may become chronic and autonomous of the precipitating stressor (Simeon et al, 2003). The lack of responsiveness of depersonalisation to fluoxetine supports the latter concept, that depersonalisation disorder is a distinct dissociative disorder. Indeed, as long ago as the 1930s Mayer-Gross (1935) conceptualised depersonalisation as a universal preformed functional response of the brain to extreme stress.
Strengths and limitations of the study
Strengths of the study include the fluoxetine dosing and the trial
duration; the use of well-validated dissociation measures, both
clinician-rated and self-reported; the use of an independent evaluator masked
to adverse events and medication adjustment to conduct the clinical ratings;
and the stringent selection criteria for the participants with primary
DSMIV depersonalisation disorder. Limitations include the higher
withdrawal rate in the fluoxetine arm, and the medium size of the sample.
Implications for treatment
Our study suggests that first-line use of serotonin reuptake inhibitors for
the treatment of depersonalisation disorder is not indicated, except possibly
in selected individuals with troublesome anxiety or depression; in such
individuals, improved affective state might result in a somewhat better
tolerance of their dissociative symptoms. Although negative, the findings of
this study are important in light of the absence of any efficacious
pharmacotherapy for depersonalisation, and the common clinical practice of the
past decade of using serotonin reuptake inhibitors on the basis of promising
early anecdotal reports and the frequent presence of comorbid anxiety and
depression. In the future, investigating other classes of medications that may
have anti-depersonalisation effects may prove fruitful.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Baker, D., Hunter, E., Lawrence, E., et al
(2003) Depersonalisation disorder: clinical features of 204
cases. British Journal of Psychiatry,
182, 428
-433.
Bernstein-Carlson, E. & Putnam, F. W. (1993) An update on the Dissociative Experiences Scale. Dissociation, 6, 16 -27.
Cohen, J. (1988) Statistical Power Analysis for the Behavioral Sciences (2nd edn). Hillsdale, NJ: Lawrence Erlbaum.
Ellason, J. W. & Ross, C. A. (1997) Two-year follow-up of inpatients with dissociative identity disorder. American Journal of Psychiatry, 154, 832 -839.[Abstract]
Fichtner, C. G., Horevitz, R. P. & Braun, B. G. (1992) Fluoxetine in depersonalisation disorder [letter]. American Journal of Psychiatry, 149, 1750 -1751.
First, M. B., Spitzer, R. L., Gibbon, M., et al (1995) Structured Clinical Interview for DSMIV Axis I Disorders, Patient Version (SCIDP), version 2. New York: New York State Psychiatric Institute Biometrics Research.
Goodman, W. K., Price, L. H., Rasmussen, S. A., et al (1989) The YaleBrown Obsessive Compulsive Scale I. Development, use and reliability. Archives of General Psychiatry, 46, 1006 -1011.[Abstract]
Guy, W. (1976) ECDEU Assessment Manual for Psychopharmacology. Revised DHEW Pub. (ADM). Rockville, MD: National Institute for Mental Health.
Hamilton, M. (1959) The assessment of anxiety states by rating. British Journal of Medical Psychology, 32, 50 -55.
Hamilton, M. (1960) A rating scale for depression. Journal of Neurology, Neurosurgery and Psychiatry, 23, 56 -61.[Medline]
Heimberg, R. G., Horner, K. J., Juster, H. R., et al (1999) Psychometric properties of the Liebowitz Social Anxiety Scale. Psychological Medicine, 29, 199 -212.[CrossRef][Medline]
Hollander, E., Liebowitz, M. R., DeCaria, C., et al (1990) Treatment of depersonalization with serotonin reuptake blockers. Journal of Clinical Psychopharmacology, 10, 200 -203.[Medline]
Lubin, H., Loris, M., Burt, J., et al
(1998) Efficacy of psychoeducational group therapy in
reducing symptoms of posttraumatic stress disorder among multiply traumatized
women. American Journal of Psychiatry,
155, 1172
-1177.
Mayer-Gross, W. (1935) On depersonalization. British Journal of Medical Psychology, 15, 103 -126.
Pfohl, B., Blum, N. & Zimmerman, M. (1995) Structured Interview for DSMIV Personality Disorders (SIDPIV). Iowa City, IA: University of Iowa Department of Psychiatry.
Ratliff, N. B. & Kerski, D. (1995) Depersonalization treated with fluoxetine [letter]. American Journal of Psychiatry, 152, 1689 -1690.
Roth, M. (1959) The phobicanxiety depersonalization syndrome. Proceedings of the Royal Academy of Medicine, 52, 587 -595.
Sedman, G. (1972) An investigation of certain factors concerned in the aetiology of depersonalization. Acta Psychiatrica Scandinavica, 48, 191 -219.[Medline]
Sierra, M., Phillips, M. L., Krystal, J., et al (2003) A placebo-controlled, crossover trial of lamotrigine in depersonalization disorder. Journal of Psychopharmacology, 17, 103 -105.[CrossRef][Medline]
Simeon, D. (2004) Depersonalization disorder: a contemporary overview. CNS Drugs, 18, 343 -354.[Medline]
Simeon, D., Gross, S., Guralnik, O., et al (1997) Feeling unreal: 30 cases of DSMIIIR depersonalization disorder. American Journal of Psychiatry, 154, 1107 -113.[Abstract]
Simeon, D., Stein, D. J. & Hollander, E. (1998a) Treatment of depersonalization disorder with clomipramine. Biological Psychiatry, 44, 302 -303.[CrossRef][Medline]
Simeon, D., Guralnik, O., Gross, S., et al (1998b) The detection and measurement of depersonalization disorder. Journal of Nervous and Mental Disease, 186, 536 -542.[CrossRef][Medline]
Simeon, D., Guralnik, O. & Schmeidler, J. S. (2001) Development of a depersonalization severity scale. Journal of Traumatic Stress, 14, 341 -349.[CrossRef][Medline]
Simeon, D., Knutelska, M., Nelson, D., et al (2003) Feeling unreal: a depersonalization disorder update of 117 cases. Journal of Clinical Psychiatry, 64, 900 -907.
Steinberg, M. (1994) Structured Clinical Interview for DSMIV Dissociative Disorders (SCIDD), revised. Washington, DC: American Psychiatric Press.
Torch, E. M. (1978) Review of the relationship between obsession and depersonalization. Acta Psychiatrica Scandinavica, 58, 191 -198.[Medline]
World Health Organization (1992) Tenth Revision of the International Classification of Diseases and Related Health Problems (ICD10) . Geneva: WHO.
Received for publication August 6, 2003. Revision received December 23, 2003. Accepted for publication January 19, 2004.
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