Journal of Trauma & Dissociation

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The Treatment of Depersonalization-Derealization

Disorder: A Systematic Review

Sici Wang, Sisi Zheng, Francis Xiaitan Zhang, Rui Ma, Sitong Feng, Mingkang
Song, Hong Zhu & Hongxiao Jia

To cite this article: Sici Wang, Sisi Zheng, Francis Xiaitan Zhang, Rui Ma, Sitong Feng,
Mingkang Song, Hong Zhu & Hongxiao Jia (2024) The Treatment of Depersonalization-
Derealization Disorder: A Systematic Review, Journal of Trauma & Dissociation, 25:1, 6-29, DOI:
10.1080/15299732.2023.2231920

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JOURNAL OF TRAUMA & DISSOCIATION
2024, VOL. 25, NO. 1, 6–29
https://doi.org/10.1080/15299732.2023.2231920

The Treatment of Depersonalization-Derealization

Disorder: A Systematic Review
Sici Wang BMed a,b†, Sisi Zheng MD, PhD a,c†, Francis Xiaitan Zhang MSc d,
Rui Ma B.Sca,c, Sitong Feng MSc a,c, Mingkang Song BMed a,c, Hong Zhu MD ,
a,c

and Hongxiao Jia MD, PhD a,c

a
The National Clinical Research Center for Mental Disorders & Beijing Key Laboratory of Mental
Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, China; bDongzhimen Hospital,
Beijing University of Chinese Medicine, Beijing, China; cAdvanced Innovation Center for Human Brain
Protection, Capital Medical University, Beijing, China; dDepartment of Computer Science, Durham
University, Durham, UK

ABSTRACT ARTICLE HISTORY

Depersonalization-derealization disorder (DPD) is characterized by Received 18 October 2022
persistent or recurrent experiences of detachment from oneself Accepted 26 April 2023
and surroundings, as well as a sense of unreality. Considering the KEYWORDS
inadequacy of current research on treatment, we performed Depersonalization;
a systematic review of the available pharmacotherapies, neuromo- dissociative disorders;
dulations, and psychotherapies for DPD. The systematic review pharmacotherapy;
protocol was based on PRISMA 2020 guidelines and pre- neuromodulation;
registered. The PubMed, Web of Science, PsycINFO, Embase, the psychotherapy
Cochrane Library, Scopus, and ScienceDirect databases were
searched from inception to June 2021. All treatments for DPD and
all study types, including controlled and observational studies as
well as case reports, were assessed. Of the identiped 17,540 studies,
41 studies (four randomized controlled trials, one non-randomized
controlled trial, 10 case series, and 26 case reports) involving 300
participants met the eligibility criteria. We identiped 30 methods
that have been applied independently or in combination to treat
DPD since 1955. The quality of these studies was considered. The
relationship between individual dilerences, such as symptoms,
comorbidities, history, and duration since onset, and treatment
elects was explored. The results suggest that a series of treatments,
such as pharmacotherapies, neuromodulation, and psychothera-
pies, could be considered in combination. However, the quality and
quantity of studies were generally low considering the high pre-
valence of DPD. The review concludes with suggestions for future
research and an urgent call for more high-quality research.

Introduction
Depersonalization disorder/depersonalization-derealization disorder (DPD) is
a mental disorder that, according to the Diagnostic and Statistical Manual of

CONTACT Hong Zhu zhuhong@ccmu.edu.cn; Hongxiao Jia jhxlj@ccmu.edu.cn The National Clinical
Research Center for Mental Disorders & Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital
Medical University, Beijing100088, China
†
Sici Wang and Sisi Zheng have contributed equally to this work and share first authorship.
This article has been republished with minor changes. These changes do not impact the academic content of the article.
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15299732.2023.2231920
© 2023 Beijing Anding Hospital, Capital Medical University
 JOURNAL OF TRAUMA & DISSOCIATION 7

Mental Disorders 5th (DSM-5) and International Classification of Diseases 11th

(ICD-11), is characterized by feeling unreal or detached from oneself or one’s
surroundings, as suggested by metaphors like “I seem to be living in a dream” or “I
am just like a machine, like a robot”. Depersonalization or derealization symptoms
are common, affecting 8.7% of 13,182 participants in the Gutenberg health study
(Schlax et al., 2020), 11.9% of 3,809 surveyed students aged 12–18 year in German
in 2011 (Michal et al., 2015), and 19.1% of 1008 adults in a phone survey in the US
(Aderibigbe et al., 2001). If the symptoms are persistent or affect social functioning
it can become a disorder, with prevalence rates reported as high as 0.95% in
a cohort of 3,275 participants in the UK and 1.9% in a sample of 1,287 members of
the general population in Germany (Lee et al., 2012; Michal et al., 2016) Incidence
is accompanied by damage to individuals’ life and work, mainly due to increased
suicidal ideation and related mental stress (Michal et al., 2010; Solano et al., 2016),
elevated depression and anxiety symptoms (Schlax et al., 2020), association with
first-rank symptoms of schizophrenia-spectrum psychoses (Humpston et al.,
2020), and impaired cognition (attentional and perceptual systems) (Guralnik
et al., 2000, 2007), which also poses a tremendous burden on society. With recent
developments in psychopathology and neuroimaging, therapeutic treatments for
DPD have undergone a transformation and expansion from operative therapy to
pharmacotherapies, psychotherapies, and neuromodulation.
Given the incidence and economic burden of DPD, there is urgent need for
effective treatment measures. However, there is a lack of clinical guidance for
treating DPD. For example, a previous systematic review of DPD treatment
identified only four randomized controlled trials (RCTs), one of which was
later retracted (Somer et al., 2013). Another systematic review concentrated on
transcranial magnetic stimulation (TMS), but had issues with duplicates and
missing data (Orrù et al., 2021). A 2017 article provided clinical guidance for
assessment and measurement in the form of a narrative review – rather than
a systematic review – of treatment (E. C. M. Hunter et al., 2017). Due to the
limitations of previous systematic reviews, it is hard to develop guidelines for
DPD treatment, which limits appropriate clinical decision-making for DPD.
A complete review is important for DPD given its approximately 1%
incidence. To robustly review different types of clinical interventions
(Gurevitch et al., 2018), we gathered as much evidence as possible for this
systematical review and provide clear descriptions of the interventions (e.g.,
dose, add-on treatment, efficacy). Considering that individual differences (e.g.,
psychological trauma, affective temperament, and biological changes) might
be associated with patients’ behavior, emotion, and outcomes (Baldessarini
et al., 2017), case reports and case series that provide detailed information
(e.g., history of trauma, family details, and treatment) were combed to inspire
future studies. In addition, this review carefully evaluated the quality of extant
studies. In response to the identified issues and deficiencies, we offer some
suggestions for future research.
8 S. WANG ET AL.

Overall, this review examines clinical evidence for various methods along
with their curative and side effects to develop a clear landscape of DPD
healthcare, inform appropriate treatment options, and develop robust
research.

Method
This systematic review adhered to PRISMA 2020 guidelines and followed
a predetermined published protocol (Page et al., 2021). Details of the systema-
tic review protocol were registered on PROSPERO.

Search strategy
To gather articles for this review, we searched the PubMed, Web of Science,
PsycINFO, Embase, the Cochrane Library, Scopus, and ScienceDirect data-
bases from inception to June 2021. The named databases were searched using
combinations of two key concepts from MeSH, namely: depersonalization
(such as depersonali#ation, dereali#ation) and treatment (such as treatment*,
therap*, drug, pharmacotherap*, chemotherap*, psychotherap*, CBT, EMDR,
hypno*, cognitive behavior*, NIBS, noninvasive brain stimulation, ECT,
rTMS, transcranial magnetic stimulation*, tDCS, cathodal stimulation). The
within-concept subject headings and keywords were combined with the “OR”
command, while the two search strings were combined with the “AND”
command in each database. The complete search strategy is provided in
Table S1.
We also combed through the references sections of relevant review articles
to identify any relevant studies. The corresponding authors were contacted to
obtain additional data, when required.

Inclusion and exclusion criteria

The inclusion criteria were as follows: studies where participants were assessed
using at least one diagnostic basis for DPD, including the ICD or DSM, or
diagnosis by a specific clinical institution or physician. Any single or com-
bined ethical intervention was accepted when compared with another kind of
treatment, usual care, placebo, or none. Response to therapies should be
recorded using standardized rating scales, clinical interviews, or self-report.
Studies using electroencephalogram (EEG), magnetic resonance imaging
(MRI), and other measurements were considered. We included case reports,
case series, RCTs, and quasi-experimental studies. Only studies written in
English were included.
Studies were excluded when participants had DPD symptoms secondary
to organic brain disorders and other diseases (e.g., epilepsy, schizophrenia
 JOURNAL OF TRAUMA & DISSOCIATION 9

spectrum disorders, depressive disorders, anxiety disorders, substance-

related and addictive disorders, etc.). Therapeutic methods that do not
meet current ethical norms were also excluded. Moreover, studies where
the outcomes were not quantified or described, retracted articles, and
studies lacking full text (where the authors could not be contacted) were
excluded.

Study selection
After summarizing the retrieved articles and references to critical reviews,
results with the same author and similar titles were confirmed by reading the
complete text and excluded. All remaining studies were reviewed by the lead
authors (WS and ZS) who read the study titles to exclude any nonrelevant
articles based on the criteria listed above. All reviews/studies deemed poten-
tially relevant were read in full and independently judged against the inclusion
and exclusion criteria by two reviewers (WS and ZS). When necessary, dis-
putes were resolved by consensus and consultation with a third reviewer (FS).
Hand searches of the references from all included reviews/studies were per-
formed to identify studies missed by the bibliographic searches. The corre-
sponding authors of the papers were contacted to request additional
information if needed.

Data extraction, synthesis, and presentation

Considering the differences between studies, case reports, case series, and
controlled studies, the studies are presented separately in two tables.
Information about participants, interventions, comparisons, and outcomes
were extracted. We adopted the Cochrane (Higgins et al., 2019) for RCTs,
the methodological index for non-randomized studies (MINORS) (Slim et al.,
2003), the JBI critical appraisal tool (JBI) (Munn et al., 2020) for case series,
and M. H. Murad’s methodological quality and synthesis approach for case
reports (MHM) (Murad et al., 2018) to assess studies. We compared the
effectiveness of different treatments and one treatment using different doses
and/or frequencies, and identified the efficacy evaluation tools used and study
quality. The specific symptoms and comorbidities were summarized in
another table.

Results
A total of 40 citations, including 41 studies with 300 participants, were
identified by the PRISMA 2020 guidelines, as illustrated in Figure 1.
10 S. WANG ET AL.

Figure 1. Prisma.

Study characteristics and methodological quality

The 14 articles that included more than three cases, which are recorded in
Table 1, involved a total of 273 participants and were published between 1982
Table 1. Studies involving more than three participants.
Gender Mean Mean months of Disease Diagnosis Form of Quality
Authors, year N (M/F) age illness subtype basis Study type therapy Treatment score
(Nuller, 1982) 15 6/9 35 N/A 1 3 Case series 1 clozapine 2/10
(Nuller, 1982) 42 8/34 18–67 2–18 1 3 Case series 1 phenazepam 2/10
(E. Hollander et al., 1990) 8 3/5 30·3 N/A 1 2 Case series 1 fluoxetine or fluvoxamine 5/10
(Simeon, Guralnik, et al., 8 2/6 30·1 N/A 1 2 Crossover RCT 1 clomipramine vs 7/21
1998) desipramine
(Nuller et al., 2001) 14 5/9 32 N/A 1 1 Crossover controlled 1 naloxone 17/24
trial
(Sierra et al., 2001) 11 NA NA 24–180 1 1 Case series 1 lamotrigine with SSRIs 7/10
(Sierra et al., 2003) 14 8/6 35·2 24–120 1 1 Crossover RCT 1 lamotrigine 19/21
(Simeon et al., 2004) 50 29/21 35·7 212·4 1 1 RCT 1 fluoxetine 19/21
(E. C. M. Hunter et al., 2005) 21 17/4 38·0 144·0 3 3 Case series 3 CBT 7/10
(Simeon & Knutelska, 2005) 14 12/2 30·9 N/A 1 3 Case series 1 naltrexone 7/10
(Sierra et al., 2006) 32 19/13 37·1 145·2 1 1 Case series 1 lamotrigine with SSRIs 8/10
(H. E. Hollander, 2009) 8 N/A NA N/A 1 1 Case series 3 EMDR 2/10
(Mantovani et al., 2010) 12 9/3 33·6 9·8 1 1 Case series 2 rTMS 7/10
(Jay et al., 2014) 17 13/4 37·5 164·0 3 3 RCT 2 rTMS 7/21
(Jay et al., 2016) 7 5/2 36·1 232·8 3 1 Case series 2 rTMS 7/10
JOURNAL OF TRAUMA & DISSOCIATION
11
12 S. WANG ET AL.

and 2016. Nine of these articles were about pharmacotherapy, followed by

three about neuromodulation, and two about psychotherapy. The diagnostic
criteria for DPD varied from physician judgment to DSM 5 criteria. The study
type also varied from case reports to single-arm studies and crossover or
simple controlled trials, with improving research quality. The sample sizes of
these 14 studies averaged 18.2, with the largest study involving 50 individuals.
Differences were reported for effectiveness, which may relate to the use of
different assessment methods.
To objectively understand the status quo of DPD research, the quality of
studies was evaluated using the Cochrane, MINORS, JBI, or MHM
approaches, as shown in Figure 2. For the four RCTs, the Cochrane results
were not satisfactory, mainly due to attrition bias, performance bias, and
detection bias. Since these four studies used the Clinical Global Impression
Scale (CGI) (Busner & Targum, 2007), Dissociative Experiences Scale (DES)
(Carlson & Putnam, 1993), Cambridge Depersonalization Scale (CDS) (Sierra
& Berrios, 2000) and other tools to evaluate efficacy, it is difficult to compare
the results further. One non-RCT assessed by MINORS showed deficiencies in
patient inclusion, sample size estimation, and statistical analysis. The quality of
the 10 case series evaluated by JBI was generally low, lacking clear inclusion
criteria, valid methods for the condition measured, complete or consecutive
inclusion of participants, and clear reporting of the presenting site(s)/clinic(s)
demographic information. The shortcomings of the 26 case reports evaluated

Figure 2. Quality of case series (JBI) and RCT (Cochrane).

 JOURNAL OF TRAUMA & DISSOCIATION 13

by MHM related to causality, meaning that studies cannot provide a clear

explanation of the relationship between the treatment methods and results.
Disease subtype: 1=depersonalization; 2=derealization; 3=depersonaliza-
tion and derealization. Diagnosis basis:1=DSM-4 (R,TR), 2=DSM-3-R, 3=doc-
tors’ judgment; Form of therapy: 1=Pharmacotherapy, 2=Neuromodulation,
3=Psychotherapy, 4=Operation; NA, not applicable; SSRIs, selective serotonin
reuptake inhibitors; CBT, Cognitive Behavioral Therapy; EMDR, eye move-
ment desensitization and reprocessing; rTMS, repetitive Transcranial
Magnetic Stimulation

Treatment for DPD

Early studies involving lobotomy (Freeman et al., 1942), hallucinogens like

mescaline (Guttmann & Maclay, 1936), and medically induced convulsions
(Schilder, 1939) were excluded, leaving a total of 30 treatment methods in 40
studies covering the period 1955–2021. These methods are reported in Table 2.
Treatment: SSRIs, selective serotonin reuptake inhibitors; rTMS, repetitive
transcranial magnetic stimulation; TPJ, temporo-parietal junction; VLPFC,
ventrolateral prefrontal cortex; DLPFC, dorsolateral prefrontal cortex; CBT,
Cognitive Behavioral Therapy; EMDR, eye movement desensitization and
reprocessing; MBCT, Mindfulness-Based Cognitive Therapy.
Assessment: CGI: Clinical Global Impressions Scale; DES: Dissociative
Experiences Scale; PSE, Present State Examination; CDS, Cambridge
Depersonalization Scale; BDI, Beck Depression Inventory; HRSA, Hamilton
Rating Scale for Anxiety; YBOCS, Yale-Brown Obsessive Compulsive Severity
scale; SADS-L, Schedule for Affective Disorders and Schizophrenia-Lifetime
version; SPECT, Single Photon Emission Computed Tomography.Effect: dif-
ferent evaluation methods were used for independent case reports and multi-
case studies: the former for the degree of change in a single patient, while the
latter for the proportion of positive reactions (the former: 1=invalid, 2=partly
improved or scores of CDS or other scales for DPD dropped 20%-50%,
3=significantly improved or scores of CDS or other scales for DPD dropped
50%-80%, 4=completely improved or scores of CDS or other scales for DPD
dropped more than 80%). Specific manifestation: N=numbing, S=unreality of
self, and R=unreality of surroundings.Specific psychological symptom:
DD=Depressive Disorders, AD=Anxiety Disorders, OCRD=Obsessive-
Compulsive and Related Disorders, SSRD=Somatic Symptom and Related
Disorders.Quality: Cochrane is for randomized controlled trials, MINORS is
for non-randomized controlled trials, JBI is for case series, and MHM is for
case reports. MHM, Tool for evaluating the methodological quality of case
reports by Mohammad Hassan Murad.
Twenty-eight studies including 229 participants used drugs as the major
therapy. These drugs included include mood stabilizers (lamotrigine, as an
 14

Table 2. Treatment for DPD.

Specific
Number of Specific psychological
Treatment Author, year participants Dose Second treatment Assessment EUect manifestation symptoms Side eUect Study type Quality Score
Pharmacotherapies
Antidepressants
Fluoxetine (E. Hollander 7 5-80mg/d none self report 85.7% (6/ A, N, R, S, T AD, DD, OCRD insomnia Case series JBI 5/10
et al., 1990) 7)
S. WANG ET AL.

(Simeon et al., 50 10-60mg/day not allowed CGI, DES No N/A AD, DD, TSRD, fatigue, RCT Cochrane 19/
2004) carryover SSRD,PD insomnia, 21
eUect decreased libido,
et al.
(Fichtner et al., 1 20mg/d none self report 2 N, S, A, R AD N/A Case report TEMQCR 6/8
1992)
(E. Hollander 1 80mg/d none self report 4 N, S, A, R SSRD, OCRD, DD N/A Case report MHM 7/8
et al., 1992)
(RatliU & Kerski, 1 20mg/d Alprazolam self report 2 N, S, A AD,DD N/A Case report MHM 6/8
1995)
Fluvoxamine (E. Hollander 1 300mg/d Clomipramine self report 1 A, S, R OCRD none Case series JBI 5/10
et al., 1990)
Clomipramine (Simeon, 7 250 mg/d not allowed CGI 28·6% (2/ N/A DD, AD, OCRD sedation, weight RCT Cochrane 7/21
Guralnik, 7) gain
et al., 1998)
Desipramine (Simeon, 6 250 mg/d not allowed CGI 16.7% (1/ N/A DD, AD, OCRD N/A RCT Cochrane 7/21
Guralnik, 6)
et al., 1998)
(Noyes et al., 1 200mg/d none self report 3 N, S, R AD, DD Drowsiness, dry Case MHM 7/8
1987) mouth and report
constipation
Paroxetine (Ströhle et al., 1 40 mg/d none self report 2 N/A none restlessness, Case report MHM 7/8
2000) sleep
disturbances
Venlafaxine (Preve et al., 1 112·5mg/d none CDS 4 S DD, AD, OCRD none Case report MHM 6/8
2011)
Antiepileptics
Lamotrigine (Sierra et al., 11 250mg/d SSRIs only PSE, DES 54·5% (6/ N/A AD none Case series JBI 7/10
2001) 11)
(Sierra et al., 14 250mg/d none PSE, CDS, DES, BDI No N/A N/A dizziness, muscle RCT Cochrane 19/
2003) carryover aches, nausea 21
eUect
(Continued)
Table 2. (Continued).
Specific
Number of Specific psychological
Treatment Author, year participants Dose Second treatment Assessment EUect manifestation symptoms Side eUect Study type Quality Score
(Sierra et al., 32 25-600mg/d unlimited CDS, DES 56·3% N/A N/A nausea, diarrhea, Case series JBI 8/10
2006) (18/32) visual
disturbance,
tremor and
cognitive
impairment
(Rosagro- 1 100mg/d Sertraline, CDS, DES 3 S, R AD, OCRD, DD, N/A Case report MHM 6/8
Escámez Clomipramine BPD
et al., 2011)
(Salgado et al., 1 200mg/d none CDS 2 N, S AD, DD N/A Case report MHM 6/8
2012)
Clonazepam (Stein & Uhde, 1 1mg/d Carbamazepine SADS-L 4 R none N/A Case report MHM 7/8
1989)
(Sachdev, 2002) 1 3mg/d Citalopram self report 4 N, R, S, A DD, OCRD N/A Case report MHM 7/8
(J. V. Weber 1 1mg/d none CDS 3 N, S, R AD, DD, TSRD, N/A Case report MHM 7/8
et al., 2018) SSRD
Phenazepam (Nuller, 1982) 42 3–30 mg/d none self report 59.5% N/A AD N/A Case series JBI 2/10
(25/42)
Carbamazepine (Stein & Uhde, 1 1200mg/d none SADS-L 1 N/A N/A panic attacks Case report MHM 7/8
1989)
Antipsychotics
Clozapine (Nuller, 1982) 15 150–600 mg/ none self report 60·0%(9/ N/A AD, DD perculiar Case series JBI 2/10
day 15) confusion, loss
orientation
Quetiapine (Mancini-Marie 1 700mg/d none CDS, DES 2 N N/A N/A Case report MHM 7/8
et al., 2004)
Opioid receptor antagonists
Naloxone (Nuller et al., 14 1.6–10 mg i.v. benzodiazepine depersonalization 71.4% N/A DD, AD none non- Minors 17/
2001) scale (10/14) randomised 24
controlled trial
Naltrexone (Simeon & 14 100-250mg/d baseline treatment CGI, CDS, DES N/A N/A sedation, fatigue, Case series JBI 7/10
JOURNAL OF TRAUMA & DISSOCIATION

Knutelska, et al.
2005)
(Continued)
15
 16

Table 2. (Continued).
Specific
Number of Specific psychological
Treatment Author, year participants Dose Second treatment Assessment EUect manifestation symptoms Side eUect Study type Quality Score

Others
Methylphenidate (Foguet et al., 1 54mg/d baseline treatment self report 4 N/A DD N/A Case report MHM 4/8
2011)
Mixed (S. R. Weber, 1 20mg/d baseline treatment CDS 2 N/A N/A N/A Case report MHM 5/8
S. WANG ET AL.

amphetamine 2020)
salts
Neuromodulations
rTMS (TPJ) (Mantovani et al., 12 1Hz, 1800 lorazepam CDS, DES 50% (6/ N/A DD, AD N/A Case series JBI 7/10
2010) pulses (100% 12)
MT)
(Jay et al., 2014) 9 1Hz, 900 pulses baseline treatment CDS, DES, skin 55.6% (5/ N/A DD, AD “twitching or RCT Cochrane 7/21
(110% MT) conduction 9) jerking”
sensations,
headache,
divculties
concentrating
(Rachid, 2017) 1 1Hz, 1800 Paroxetine CDS 3 N, S, R, T DD N/A Case report MHM 7/8
pulses (100% +Trazodone
MT) +Lamotrigine
rTMS (VLPFC) (Jay et al., 2014) 8 1Hz, 900 pulses baseline treatment CDS, DES, skin 62.5% (5/ N/A DD, AD “drunk-like” RCT Jadad 5/5
(110% MT) conduction 8) feelings,
headache,
divculties
concentrating
(Jay et al., 2016) 7 1Hz, 900 pulses baseline treatment CDS, DES 85.7% (6/ N/A AD headache, pain Case series JBI 7/10
(110% MT) 7) above left eye
rTMS (DLPFC) (Jiménez-Genchi, 1 20Hz Clomipramine CDS, BDI, SPECT 3 N, S, R DD N/A Case report MHM 7/8
2004)
(Karris et al., 1 1-10Hz, 3000 Bupropion CDS, HRSA 3 N, S, R DD N/A Case report MHM 7/8
2017) pulses (110%
MT)
ECT (Ordas & Ritchie, 1 12 sessions Fluoxetine self report 2 S DD, SSRD, PD mild short-term Case report MHM 7/8
1994) memory loss
(Continued)
Table 2. (Continued).
Specific
Number of Specific psychological
Treatment Author, year participants Dose Second treatment Assessment EUect manifestation symptoms Side eUect Study type Quality Score

Psychotherapies
CBT (E. C. M. Hunter 21 13 sessions baseline treatment PSE, DES, CDS 29% (6/ N/A AD,DD none Case series JBI 7/10
et al., 2005) 21)
EMDR (H. E. Hollander, 8 20 sessions not limited self report 2 N/A AD none Case series JBI 2/10
2009)
vis-à-vis therapy (Rosen, 1955) 1 70 sessions none self report 2 S, R, A none N/A Case report MHM 5/8
Supportive (McKellar, 1978) 1 2 weeks none self report 4 S, R N/A N/A Case report MHM 3/8
therapy
Behaviour (Sookman & 2 20–50 sessions Flooding treatment self report 3, 4 S, R, A, T AD, OCRD N/A Case report MHM 5/8
therapy Solyom, 1978)
Directive therapy (Blue, 1979) 1 6 sessions none self report 4 A, S, R SSRD N/A Case report MHM 6/8
Family therapy (Dollinger, 1983) 1 16 weeks none self report 4 A, R N/A N/A Case report MHM 7/8
Dynamic
psychotherapy (Ballard et al., 1 12 sessions none self report 4 R, S, A AD N/A Case report MHM 6/8
1992)
MBCT (Mishra et al., 1 24 sessions Paroxetine CDS 3 N, S, R, A AD none Case report MHM 7/8
2021)
JOURNAL OF TRAUMA & DISSOCIATION
17
18 S. WANG ET AL.

adjunct to selective serotonin reuptake inhibitors (SSRIs), 25–600 mg/day,

etc.), SSRIs (fluoxetine, 5–80 mg/day, etc.), tricyclic antidepressants (clomi-
pramine, 250 mg/day, etc.), benzodiazepines (clonazepam, 1–3 mg/day, etc.),
antipsychotics (clozapine, 150–600 mg/day, etc.), opioid receptor antagonists
(naltrexone, 100–250 mg/day, etc.), and other medications. Most of these 19
drugs showed positive evidence on scales such as the CDS and DES. Sedation,
nausea, fatigue, and dizziness were consistently reported as side effects.
Lamotrigine and fluoxetine attracted great concern. The former proved
to be effective for DPD as an adjunct to SSRIs in an open trial (Sierra et al.,
2001) and a retrospective study (Sierra et al., 2006), while a placebo-
controlled crossover trial (Sierra et al., 2003) did not support beneficial
effects as a sole medication. The latter showed no obvious effect in a RCT
(Simeon, 2004), contradicting the results of a previous case series (E.
Hollander et al., 1990).
Forty participants from eight studies were treated by neuromodulation.
Repetitive transcranial magnetic stimulation (rTMS) has been a research
focus since 2004, mainly using a figure-of-eight coil held tangentially to the
scalp of the head with the handle pointing backward from the midline at 45° to
stimulate specific positions at a frequency of 1 Hz and 800 to 1800 pulses
per session. The stimulus positions were always set to the temporo-parietal
junction (TPJ), ventrolateral prefrontal cortex (VLPFC), and dorsolateral
prefrontal cortex (DLPFC). According to the scale measurements, patients
improved in terms of DPD as well as comorbidities such as anxiety disorders,
depressive disorders, and suicidal thoughts. Some patients experienced side
effects of rTMS, such as mild headaches. Electroconvulsive therapy (ECT) was
also applied in a case report (Ordas & Ritchie, 1994) without the desired result.
Nine studies involving 37 participants focused on psychotherapies, espe-
cially cognitive behavioral therapy (CBT) and eye movement desensitization
and reprocessing (EMDR). Of note, 29% of 21 participants did not meet the
DPD diagnostic criteria after an average of 13 CBT sessions (E. C. M. Hunter
et al., 2005). It was reported that simultaneous use of psychotherapies can
improve the overall condition of patients. However, the side effects were not
mentioned.
Four randomized controlled studies have focused on the therapeutic effects
of fluoxetine, lamotrigine, desipramine, clomipramine, and rTMS on deper-
sonalization (Jay et al., 2014; Sierra et al., 2003; Simeon et al., 2004; Simeon,
Guralnik, et al., 1998). No significant efficacy was found for fluoxetine and
lamotrigine (Sierra et al., 2003; Simeon et al., 2004). With “much improved” or
“very much improved” in the CGI results as effective, the effectiveness of
desipramine and clomipramine was 16.7% and 28.6% (Simeon, Guralnik,
et al., 1998). Using a 25% reduction in CDS-S score as effective, rTMS
stimulation of TPJ and VPLFC brain regions was 55.6% and 62.5% effective
(Jay et al., 2014).
 JOURNAL OF TRAUMA & DISSOCIATION 19

Table 3. Main symptoms of DPD and co-morbid mental disorders.

Symptoms Specific manifestations
Unreality of self detachment from body (robotic); observe oneself as another (float)
Unreality of surroundings detachment from surroundings; things were unreal; living in a fog/a dream/a
strange world/a parallel world
Numbing inability to feel emotions
Perceptual alterations visual, olfactory, auditory, spatial, and proprioceptive distortions
Temporal disintegration time distortions; déjà vu experiences
Others dizziness; headache; suicide thoughts or attempt; mind emptiness; mind fullness;
decline of concentration, cognition, judgment, and capability; socially
withdrawn
Co-morbid mental disorders Specific psychological symptoms
Depressive disorders depressed mood, persistent depressive disorder, major depressive disorder
Anxiety disorders social phobia, agoraphobia, specific phobia, panic attack, panic disorder,
generalized anxiety disorder
Obsessive-compulsive and obsessive-compulsive disorder, obsessive-compulsive personality traits
related disorders
Somatic symptom and related somatic symptom disorder, illness anxiety disorder, conversion disorder
disorders
Personality disorders paranoid personality disorder, schizoid personality disorder, narcissistic
personality disorder, borderline personality disorder
Trauma-and stressor-related posttraumatic stress disorder
disorders

Symptoms of DPD
To make deep use of the available information, we summarized the character-
istics of the patients from 26 case reports. The specific clinical information is
listed in Table S2, including symptoms, accompanying diseases, personality,
trauma history, family history, and treatment history. The main manifesta-
tions of DPD symptoms and detailed comorbidities are sorted based on Sierra
(Munn et al., 2020; Sierra et al., 2005) and the DSM-5, as shown in Table 2.
Main symptoms of DPD and co-morbid mental disorders were summarized
in Table 3. Unreality of self is the most common symptom of DPD (24 times),
followed by unreality of the surroundings (23 times), and numbing (13 times).
Most participants had other mental disorders: almost half had anxiety dis-
orders or depressive disorders, while one-third had obsessive-compulsive and
related disorders. Notably, all showed a sensitive and perfectionist personality
when dispositions were reported. Histories of psychological trauma, substance
abuse, and family abuse were common, too.
The symptoms were extracted from the Cambridge Depersonalization
Scale. The co-morbid mental disorders were extracted from DSM-5. The
specific manifestations and psychological symptoms were summarized from
the literatures.

Discussion
There are problems with previous systematic and narrative reviews of DPD
treatment, such as the singularity of the research field, low quantity and quality
of included studies, and an early publication time (E. C. M. Hunter et al., 2017;
20 S. WANG ET AL.

Orrù et al., 2021; Somer et al., 2013). This review has performed an updated
search of the relevant databases and assessed the methodological quality of the
identified studies.
Considering the quality and quantity of evidence, medication is the main
treatment for DPD. Drugs currently used to treat DPD include antidepres-
sants, antiepileptics, antipsychotics, opioid receptor antagonists, etc. Serotonin
reuptake blockers play a mediating role in serotonergic dysregulation, which is
a possible mechanism for DPD. Serotonergic effects and pharmacokinetic/
pharmacodynamic interactions between lamotrigine and SSRIs have been
considered in multiple mental disorders (Dursun & Deakin, 2001; Normann
et al., 2002; Southam et al., 1998), suggesting a link between glutamate, GABA,
and the serotonergic system (Sanacora et al., 2002). Hypoalgesia (Moroz et al.,
1990) and low cortisol levels (Nuller et al., 2001) in patients with DPD indicate
a possible role of the opioid system. Naloxone and naltrexone also help with
dissociation on a larger scale (Bohus et al., 1999; Glover, 1993), which may be
related to augmentation of cortisol production.
Neuromodulation is another promising therapeutic option, particularly
with the TPJ and VLPFC being in the spotlight. Possible causes for DPD
include fronto-limbic imbalance, hyperactivity of prefrontal structures and
hypoactivation of limbic regions (Lemche et al., 2008; Medford et al., 2006;
Phillips et al., 2001; Sierra & Berrios, 1998), and altered functional connectiv-
ity, can be explained by TPJ imbalance (E. Hollander et al., 1992; Locatelli
et al., 1993; Sierk et al., 2018). The VLPFC plays a role in physical and social
pain, emotional attribution (Vucurovic et al., 2020), object recognition
(Romanski & Chafee, 2021), and representation and integration of auditory
and visual stimuli (Romanski, 2012), which correlates with DPD symptoms
such as numbing, unreality of surroundings, and perceptual alterations. TMS
as a noninvasive brain stimulation technique that can modify the underlying
neural activity (Kluger & Triggs, 2007; Rossini & Rossi, 2007), resulting in
a decrement in cortical excitability when at low frequency (1 Hz) (Chen et al.,
1997). This method has been applied to stimulate the TPJ and VLPFC for the
treatment of DPD. Meanwhile, TMS in healthy individuals can induce illu-
sions or perception of self, disrupted mental transformation of the body
(Blanke et al., 2005), proprioceptive abilities (Tsakiris et al., 2008) and resolu-
tion of intersensory conflicts (Papeo et al., 2010).
Studies on psychotherapy are empirical without a mature paradigm. From
a cognitive behavioral perspective, transient depersonalization symptoms
could be exacerbated and perpetuated by a maintenance cycle resulting from
catastrophic misinterpretations of serious mental illness (E. C. Hunter et al.,
2003), which could be a path to chronic DPD. Models of panic (Clark, 1986)
and health anxiety (Warwick & Salkovskis, 1990) can provide similar evidence
for DPD treatment. From the perspective of the nervous system, inhibited
thalamic activity due to excessive suppression by the medial PCF and anterior
 JOURNAL OF TRAUMA & DISSOCIATION 21

cingulate could explain some characteristics of DPD patients (Critchley et al.,

2002; Frewen & Lanius, 2006). Dysfunctional breathing patterns, as repre-
sented by breath-holding, were associated with EMDR to reverse sensory and
cognitive numbing and recover a sense of familiar self, ultimately addressing
the core DPD symptoms (H. E. Hollander, 2009).
Previous studies cannot provide satisfactory evidence supporting clinical
treatment. First, according to the Cochrane, MINORS, JBI, and MHM
assessment results, the quality of studies was not high. Most trials did not
report adequate information about the outcomes. It should be noted that
double-blinding is difficult when using psychotherapy or rTMS. Second,
incomplete outcome data indicate that an effect may be more likely to be
overestimated from a “per-protocol” analysis compared with “ITT” analysis
of the same trials (Porta et al., 2007). Third, a lack of information in the
original studies prevented us from quantifying outcomes such as adverse
events. Finally, outcomes were measured with various rating scales, result-
ing in strong heterogeneity. Therefore, future researchers should carry out
methodological evaluation of trial design and result evaluation to support
research on DPD.
Furthermore, the design of clinical trials should be improved. The choice of the
control and blinding should be carefully considered. In a study of the potential
role of the VLPFC in DPD, researchers used the TPJ as an active control, since TPJ
stimulation could be therapeutically beneficial for patients but through an unre-
lated mechanism to that under investigation (Jay et al., 2014). The stimulus
scheme should be described in detail to ensure that the trial is reproducible. The
combination of drugs, starting dose, maximum dose, schedule of dose escalation,
and duration of the dose should be fully described. For rTMS, it is recommended
that the coil be placed according to the standard international 10–20 EEG system
of electrode placement.
The method of evaluating efficacy should be further standardized.
CGI has been used to quantify results since it was first published in
1976, although it has been criticized for inconsistency, unreliability, and
poor specificity (Bech, 1981; Beneke & Rasmus, 1992; Forkmann et al.,
2011). DES – especially its depersonalization subscale – is sensitive to
the detection of DPD (Daphne Simeon et al., 2003; Simeon, Guralnik,
et al., 1998). Compared with DES, which covers dissociative diseases, the
subsequently published CDS shows better selectivity and captures the
clinical aspects of DPD in a comprehensive manner (Sierra & Berrios,
2000). CDS has state and trait versions (CDS-S and CDS-T), the latter
of which helps with diagnosis and the former clarifies the patient’s
status as a percentage to assess the “here and now” rates of patients.
A partial responder means a 25% or more reduction in CDS-S score,
whereas a full responder means a 50% or more reduction (Jay et al.,
2016; Mantovani et al., 2010). Therefore, the percentage change in CDS
22 S. WANG ET AL.

score from baseline to the end of the trial can be used to assess
treatment efficacy.
In summary, this study has highlighted the low volume of studies and small
sample sizes in research relative to the high prevalence of DPD. Moreover,
heterogeneity among the studies hinders disease research. As DPD is a stressor
to society and a burden to 1% of the population without a knowledgeable doctor
or guidelines, there is a need for research focused on identifying and combining
evidence-based strategies to treat DPD through robust designs that aid symp-
tom alleviation and healing.

Limitations
This review is subject to several limitations. First, the identified studies were not of
high quality and lacked sufficient information. The quantity of evidence is not
enough to support a robust conclusion. Additionally, conflicts of interest of
evidence were not analyzed, which may give rise to present biased data, resulting
in low robustness of the conclusion. The number of studies focusing on the
combination of different types of treatment is insufficient to confirm robust
combination strategies.

Conclusion
Relative to previous studies, this review has advanced our understanding of
DPD research in terms of both breadth and depth. By comprehensively evaluat-
ing previous clinical studies in this area, we have provided a reference for future
clinical trial designs and guideline writing. We summarized the existing treat-
ment methods and proposed three strategies as references: collaborative treat-
ment strategies, personalized therapeutic schedules, and expectations for high-
quality research. Meanwhile, we made a summary of the main manifestations
and comorbidities of DPD, which can construct the characteristics of DPD to
a supplementary diagnostic basis, and provide clues to the relationship between
symptom propensity, comorbidity propensity, and treatment effectiveness.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The sponsor had no influence on designing the study, collection of data, analysis, or inter-
pretation of data, as well as no experience writing reports or deciding whether to submit the
article for publication.
 JOURNAL OF TRAUMA & DISSOCIATION 23

ORCID
Sici Wang BMed http://orcid.org/0000-0003-1643-4076
Sisi Zheng MD, PhD http://orcid.org/0000-0002-1575-6877
Francis Xiaitan Zhang MSc http://orcid.org/0000-0003-0228-6359
Sitong Feng MSc http://orcid.org/0000-0003-1819-9241
Mingkang Song BMed http://orcid.org/0000-0001-8146-1543
Hong Zhu MD http://orcid.org/0000-0003-4964-1610
Hongxiao Jia MD, PhD http://orcid.org/0000-0002-4924-1388

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