Table 1.

PRISMA checklist

Title	#
Title	1	A systematic review titled: “Evidence-based Treatment for Depersonalisation-derealisation Disorder (DPRD)”.
Abstract
Structured summary	2	Background
		Depersonalisation-derealisation disorder (DPRD) is a distressing and impairing condition with a pathophysiology that is not well understood.
		Objectives
		A systematic review of randomised controlled pharmacotherapy and psychotherapy trials.
		Data sources
		Articles on DPRD published from January 1980 to August 2012. Searches were carried out on The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 8), MEDLINE, PsycINFO, the metaRegister of Controlled Trials database (mRCT), the National Institute of Health's Computer Retrieval of Information on Scientific Projects (CRISP) service, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP).
		Study eligibility criteria
		Randomised controlled trials (RCTs).
		Participants
		Individuals diagnosed with depersonalisation disorder (i.e. DSM-III-R, DSM-IV, ICD-9 or ICD-10) irrespective of age, in- or outpatient status, or presence of comorbidity.
		Interventions
		Pharmacotherapy (e.g. SSRIs), psychotherapy (e.g. behavioural modification and cognitive restructuring programs), somatic interventions (e.g. health education) and a blend of these modalities.
		Study appraisal methods
		Data extraction sheets were designed to enter specified data from each trial and risk of bias information was identified.
		Results
		Four RCTs (all within the duration of 12 weeks or less) met study criteria and were included (180 participants; age range 18–65 years). The four RCTs included two lamotrigine studies, one fluoxetine study and one biofeedback study. Evidence for the treatment efficacy of lamotrigine was found in one study (Cambridge Dissociation Scale (CDS): p < 0.001) with no evidence of effect for lamotrigine in the second study (CDS: p = 0.61 or Present State Examination (PSE): p = 0.17). Fluoxetine and biofeedback were not more efficacious than the control condition, although there was a trend for fluoxetine to demonstrate greater efficacy in those with comorbid anxiety disorder. The four studies had 'low' or 'unclear' risk of bias.
		Limitations
		There are a small number of studies with small samples. There are differences across trials in sample characteristics, and timing of interventions.
		Conclusion
		The limited data from randomised controlled trials on the pharmacotherapy and psychotherapy of DPRD demonstrates inconsistent evidence for the efficacy of lamotrigine, and no efficacy for other interventions. Additional research on this disorder is needed.
Introduction
Rationale	3	DPRD is not a rare condition. It occurred in 80% of psychiatric inpatients. A lifetime prevalence of depersonalisation and derealisation symptoms of 42 to 91% was reported in psychiatric settings. Given the growing interest in its pathogenesis, and the publication of a number of treatment trials, a systematic review of randomised controlled pharmacotherapy and psychotherapy trials is timely.
Objectives	4	Lack of awareness of DPRD may contribute to a high rate of misdiagnosis. With growing interest in the management of DPRD, we aimed at conducting a systematic review to determine the efficacy of medication, psychotherapy, somatic interventions and a combination of treatment modalities for depersonalisation-derealisation disorder, relative to placebo and other comparison groups.
Methods
Protocol and registration	5	This systematic search used Cochrane methods (http://www.cochrane.org).
Eligibility criteria	6	RCTs of pharmacotherapy, psychotherapy, somatic interventions and a blend of these modalities for the treatment of DPRD published from January 1980 to August 2012 in any language.
Information sources	7	Searches were carried out on The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 8), MEDLINE, PsycINFO, the metaRegister of Controlled Trials database (mRCT), the National Institute of Health's Computer Retrieval of Information on Scientific Projects (CRISP) service, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). The bibliographies of all identified trials were checked for additional studies and authors were contacted for published trials.
Search	8	For each database, the following search terms (in both American and British English) were used: “depersonalisation disorder” OR “derealisation disorder” OR “depersonalisation-derealisation disorder”, OR “depersonalisation syndrome” OR “derealisation syndrome” OR “depersonalisation-derealisation syndrome”, AND “drug” OR “pharmacotherapy” OR “medication” OR “treatment” OR “psychotherapy”, AND “randomised control trial”, OR “RCT”. The bibliographies of all identified trials were checked for additional studies and the authors were contacted for published trials. No restriction was placed on language and setting. Studies employing cross-over and parallel designs were potentially considered for inclusion.
Study selection	9	The criteria for selecting studies included (a) all RCTs of pharmacotherapy, psychotherapy, somatic interventions and a combination of treatments for DPRD, (b) all participants diagnosed with DPRD irrespective of age, in- or outpatient status, or presence of comorbidity, (c) all medication agents and non-pharmacological interventions, and (d) RCTs of all forms of psychotherapy. Both short- and long-term therapy were eligible for inclusion, as was group therapy in which cluster randomization designs were employed. Titles and abstracts were screened for face validity within the selected databases. Included, excluded and unclear studies were color coded, and the full text articles for each study were retrieved. After full text screening, studies were further included or excluded based on the study criteria for the review.
Data collection process	10	Study selection was completed by one of the authors (ES). Spreadsheet forms were designed for the purpose of recording descriptive information, summary statistics of the outcome measures, risk of bias data, and associated commentary (ES and TW). The reviewers contacted investigators by email in an attempt to obtain missing information. PRISMA guidelines were also followed to ensure that the methodology and reporting were comprehensive.
Data items	11	Aliyev and Aliyev 2011;Sierra et al. 2003;Simeon et al. 2004 and Schoenberg et al. 2012
		Participants
		All participants diagnosed with depersonalisation disorder according to the criteria of the Diagnostic and Statistical Manual (DSM-III-R or DSM-IV), or the International Classification of Diseases (ICD-9 or ICD-10) irrespective of age, in- or outpatient status, or presence of comorbidity.
		Interventions
		All medication agents and non-pharmacological interventions (e.g. selective serotonin reuptake inhibitors (SSRIs), anticonvulsants and opiate antagonists, temporo-parietal junction stimulation), and RCTs of all forms of psychotherapy (e.g. behavioural modification and cognitive restructuring programs, relaxation, gestalt, interpersonal, supportive therapies, mindfulness, acceptance and commitment therapy, compassion-focused therapy). Both short- and long-term therapy were eligible for inclusion, as was group therapy in which cluster randomisation designs were employed.
		Comparisons
		Where possible, planned treatment comparisons included:
		1. Pharmacotherapy versus placebo.
		2. Psychotherapy versus sham interventions or waiting list.
		3. Psychotherapy versus pharmacotherapy.
		4. Pharmacotherapy versus non-pharmacological interventions.
		Outcomes
		Diagnostics & baseline screening: all participants diagnosed with depersonalisation disorder according to the criteria of the Diagnostic and Statistical Manual (DSM-III-R, or DSM-IV), or the International Classification of Diseases (ICD-9, or ICD-10).
		Primary measures: Treatment response was reported if studies used the Clinical Global Impressions-Improvement subscale (CGI-I), a widely used categorical measure of treatment response in which responders are defined as having a change item score of 1 = "very much" or 2 = "much" improved (CGI), or by a 50% reduction reported by the Cambridge Depersonalization Scale. The effect of intervention on symptom severity was determined from standardised instruments such as the Cambridge Depersonalisation Scale, the Dissociative Experiences Scale (DES), or the Depersonalisation Severity Scale (DSS).
		Secondary measures: Depression was reported if studies provided data on the 17-item Hamilton Rating Scale for Depression (HRSD), the Beck Depression Inventory (BDI), or a similar scale. Anxiety was measured with the standard Hamilton Rating Scale for Anxiety (HRSA) the Beck Anxiety Inventory (BAI, or a similar scale. Symptom improvement in other anxiety disorders similarly employed customary “gold-standard” severity measures.
Risk of bias in individual studies	12	The overall risk of bias was evaluated as 'high’, 'low’ or 'unclear’ according to the five criteria stipulated by the Cochrane Handbook for Systematic Reviews of Interventions: random sequence generation, allocation concealment, blinding (performance bias and detection bias), blinding of outcome assessment, incomplete outcome data (attrition bias), and selective reporting (reporting bias).
Summary measures	13	Treatment response was reported if studies used the Clinical Global Impressions-Improvement subscale (CGI-I), a measure of treatment response in which responders are defined as having a change item score of 1 = "very much" or 2 = "much" improved (CGI), or by a 50% reduction reported by the Cambridge Depersonalization Scale (CDS). The effect of intervention on symptom severity was determined from standardized instruments such as the CDS, the Dissociative Experiences Scale (DES), or the Depersonalization Severity Scale.
Synthesis of results	14	Due to the clinically diverse nature of each trial, with different interventions used in different studies, the trials could not be meta-analysed.
Risk of bias across studies	15	All four studies were rated as having an “unclear” risk of bias for selective reporting, because there was no protocol available to determine if all outcomes were measured.
Additional analyses	16	N/A.
Results
Study selection	17	Records identified through database searching: n = 1296; Records excluded: n = 237, Reason: Duplicates; Title screening: n = 1059; Records excluded: n = 341, Reason: Not Depersonalisation/derealisation; Abstract screening: n = 718; Records excluded: n = 689, Reason: Not treatment articles or no outcome provided; Full-text articles assessed for eligibility: n = 29; Full-text articles excluded: n = 25, Reasons: Retrospective studies and open trials; Studies included in qualitative synthesis: n = 4.
Study characteristics	18	Medication
		● Aiyev 2011: Azerbaijani outpatients, single center, lamotrigine (25–300 mg/day), placebo comparison, 12 weeks, 80 randomised, mean age 37.7; 0% female, diagnostics: CDS.
		● Sierra et al. 2003: UK outpatients, single center, Lamotrigine (25–250 mg/day), placebo comparison, 12 weeks, 14 randomised, mean age 35.2, diagnostics: DSM-IV, PSE, CDS.
		● Simeon 2004: USA outpatients, single center, Fluoxetine (10–60 mg/day Eli Lilly); placebo comparison, 10 weeks, 54 randomised, mean age 36, 39% female, diagnostics: SCID-D.
		Psychotherapy
		● Schoenberg et al. 2012: UK outpatients, single center, electro-dermal biofeedback, sham electro-dermal biofeedback, 4 weeks (8 sessions), 32 randomised, mean age 35, 25% female, diagnostics: SCID-D.
Risk of bias within studies	19	Medication
		● Aliyev and Aliyev 2011: random sequence generation - low; allocation concealment - low; blinding (performance bias and detection bias) - low; blinding of outcome assessment - low; incomplete outcome data - low; selective outcome reporting - unclear.
		● Sierra et al. 2003: random sequence generation - low; allocation concealment - low; blinding (performance bias and detection bias) - unclear; blinding of outcome assessment - low; incomplete outcome data - low; selective outcome reporting - unclear.
		● Simeon et al. 2004: random sequence generation - low; allocation concealment - low; blinding (performance bias and detection bias) - unclear; blinding of outcome assessment - low; incomplete outcome data - low; selective outcome reporting - unclear.
		Psychotherapy
		● Schoenberg et al. 2012: random sequence generation - unclear; allocation concealment - low; blinding (performance bias and detection bias) - low; blinding of outcome assessment - low; incomplete outcome data - low; selective outcome reporting - unclear.
Results of individual studies	20	Medication
		● Simeon et al. 2004: Fluoxetine was not superior to placebo except for a clinically minimal but statistically significantly greater improvement in CGI–I score in the fluoxetine group. In participants with a comorbid diagnosis of depressive or anxiety disorder, those taking fluoxetine consistently tended to have better responses than those taking the placebo.
		● Sierra et al. 2003: A cross-over study among nine individuals suffering from DPRD comparing the lamotrigine with a placebo revealed following a 2-week washout that lamotrigine had no significant advantage over placebo when administered singularly for DPRD.
		● Aliyev and Aliyev 2011: 12 weeks of lamotrigine therapy resulted in a statistically significant difference in improvement in a lamotrigine group compared with that in the placebo group.
		Psychotherapy
		● Schoenberg 2012: While electro-dermal biofeedback did not help DPRD participants increase skin conductance response, real-time biofeedback resulted in lower state (but not trait) scores on the CDS. Biofeedback had no effect on DES, BDI or BAI scores, compared to sham biofeedback.
Synthesis of results	21	N/A
Risk of bias across results	22	There was no protocol available to determine if all outcomes were measured in the four selected studies. Risk of bias for selective reporting were rated as “unclear” for all included studies.
Additional analyses	23	N/A
Discussion
Summary of evidence	24	Data on lamotrigine for DPRD was inconsistent with one trial indicating that lamotrigine was not significantly better than placebo when applied as a singular treatment for DPRD, and one trial showing a statistically significant difference in improvement compared placebo. Fluoxetine was not demonstrated to be efficacious in treating depersonalization disorder. However, there was a tendency for depersonalization symptoms to improve in subjects with a comorbid anxiety disorder. Electro-dermal biofeedback was not effective in increasing SCR (a marker of emotional response) or in decreasing trait measures of depersonalization. However, SCR biofeedback did result in lower state scores on the CDS.
Limitations	25	We identified a small number of studies with small samples. There are differences across trials in sample characteristics and timing of interventions. Although we used a rigorous search methodology, we may have missed unpublished trials; there is, for example, a bias against the publication of negative studies.
Conclusions	26	There is inconsistent evidence to support the efficacy of lamotrigine in DPRD, with no evidence to support the efficacy of fluoxetine and biofeedback. Further research is necessary, particularly in light of the methodological differences between studies.
Funding
Funding	27	No funding was available for this review.