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Member Since 16 Nov 2008
Offline Last Active Feb 10 2011 02:23 PM

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In Topic: New clinical trial for treatment of DP

10 February 2011 - 02:16 PM



1. Introduction

Neither medications nor psychotherapy have been shown to be
effective for DPD (Sierra, 2008), prompting exploration of other
treatment modalities.
In one case high-frequency repetitive Transcranial Magnetic
Stimulation (rTMS) to left dorsolateral prefrontal cortex (DLPFC)
improved DPD symptoms (Jiménez-Genchi, 2004). However, excitatory
rTMS to DLPFC may not be optimal given reports of increased
activity in prefrontal cortex (Phillips and Sierra, 2003), and evidence
for involvement of other brain regions in DPD (Simeon et al., 2000).
Importantly, DPD patients showed increased glucose metabolism in
temporal, parietal, and occipital areas, suggesting abnormalities along
auditory, somatosensory, and visual processing pathways, as well as
in areas responsible for an integrated body schema.
Using evoked potential mapping, Blanke et al. (2005) demonstrated
bilateral temporo-parietal junction (TPJ) activation when healthy
volunteers imagined themselves in position and visual perspective
that generally are reported by people experiencing spontaneous “out
of body experiences (OBEs).” Applications of single-pulse TMS to TPJ
impaired mental transformation of one's own body and had no effect
for imagined spatial transformations of external objects. This suggests
that TPJ has a crucial role in the conscious experience of the normal
self, and mediates spatial unity of self and body, process impaired in
dissociative conditions.
We present results of the first trial testing the effects of inhibitory
low-frequency rTMS administered to TPJ in DPD patients. We
hypothesized that right-side stimulation would be more effective
because excitation of this site by electrical stimulation induced OBEs
(Blanke et al., 2002). At the same time, since bilateral involvement has
been reported, we allowed partial responders and nonresponders to
right-side stimulation to cross over to left TPJ stimulation. Subjects
were informed that either right or left-sided stimulation might be

2. Methods
This open-label cross-over study consisted of two phases: (1) 3 weeks of right TPJ
rTMS, (2) 3 more weeks of right TPJ rTMS for full responders, who showed 50%
improvement on the Cambridge Depersonalization Scale (CDS), our primary outcome
measure, by the end of phase 1, or 3 more weeks of right or left TPJ rTMS for partial
responders, who showed at least 25% decrease on the CDS, or 3 more weeks of left TPJ
rTMS for non-responders to phase 1.
Twelve right-handed outpatients (9 male; age 33.6±12.9 years) who met DSM-IVTR
criteria for DPD entered the study. DPD age of onset was 33.6±12.9 years and illness
duration was 9.8±12 years. Participants were recruited from the Brain Behavior Clinic
of Columbia Psychiatry and the Depersonalization and Dissociation Program of Mount
Sinai and Beth Israel Medical Centers in New York. Two patients were unmedicated and
10 had their concomitant medications (e.g. Serotonin Reuptake Inhibitors, Anticonvulsants,
Atypical Antispychotics, and Benzodiazepines) at stable doses for at least
2 months prior to rTMS and throughout the trial. Two patients met criteria for Major
Depressive Disorder, 3 for Generalized Anxiety Disorder, and 1 for Panic Disorder.
Nobody else met criteria for any other axis I and/or II disorders by using the Structured
Clinical Interview (SCID-I and II) for the DSM-IV. Individuals with a history of seizure or
head trauma were excluded. All patients gave written informed consent, and the protocol was approved by the New York State Psychiatric Institute/Columbia University
rTMS was administered with the MAGSTIM super-rapid stimulator (Magstim
Company, Ltd., Whitland, U.K.) using a vacuum cooled 70-mm figure-8 coil. Stimulation
parameters were 1-Hz, 30 min train (1800 pulses/day) at 100% of resting motor
threshold (EMG-determined, and repeated weekly). The coil was positioned over the
right and left TPJ, between T4/P4 and T3/P3 respectively, according to the 10–20
International EEG System.
Symptoms were rated at baseline and after each week by observer- and selfreported
scales. Clinician-Administered Dissociative States Scale (CADSS), Hamilton
Depression and Anxiety Rating Scales (HDRS and HARS), and Clinical Global
Impression-Severity (CGI-S) were administered by a psychiatrist not involved in the
treatment, while CDS, Dissociation Evaluation Scale (DES), Beck Depression Inventory
(BDI–II), Zung Self-rating Anxiety Scale (Zung-SAS), and Patient Global Impression
(PGI) were filled in by patients. The primary efficacy measure was the CDS, a
comprehensive 29-item scale inquiring about subjective experiences associated with
depersonalization symptoms (Sierra and Berrios, 2000).
Statistical analyses were performed using SPSS library, 13.0 version. Chi-Square
and Student t-test were applied to compare demographic and clinical data. Repeatedmeasures
analysis of variance (ANOVA), with adjustments for non-sphericity, was
applied to evaluate time-dependent effects of rTMS on depersonalization (CDS, CADSS
and DES), depression (HDRS-24, BDI), anxiety (HARS, Zung-SAS), and clinical global
impression severity scores (CGI-S, PGI), followed by LSD post-hoc tests. Pearson's
correlations were applied to examine the relationship between depression/anxiety and
DPD symptoms.

3. Results

All 12 patients completed phase 1, with no adverse events. Four
patients dropped out after phase 1 because subjectively they did not
feel any benefit from rTMS.
At 3 weeks (end of phase 1) the entire sample response rate was
50% (6 out of 12). Specifically 4 patients were classified as full
responders and 2 as partial responders. All responders, except for 1,
who experienced a partial response and wanted to be crossed over to
the left TPJ rTMS, entered phase 2 to test whether additional right TPJ
stimulation would improve further their symptoms. After 6 weeks
(end of phase 2), response rate was still 50%, with the same
responders as at the end of phase 1. Of the 3 who were switched to
left TPJ rTMS, 1 remained a partial responder and 2 were classified as
Responders did not significantly differ from nonresponders in
demographics, number of concurrent axis I disorders, baseline clinical
ratings, or with regard to their daily dose of Benzodiazepines.
Specifically, 2 of the 6 responders were on lorazepam equivalent dose
of 4 mg/d, and 3 of the 6 non-responderswere on lorazepam equivalent dose of 3 mg/d. Responders significantly differ from nonresponders in
DPD symptoms age of onset (29.8±9 versus 17.7±3 years)whichwas
significantly younger in nonresponders (t=−3.13, df=6.01,
Clinical measures from baseline to week 6 are presented in Table 1.
Repeated-measures ANOVA revealed a significantmain effect of timeon
depersonalization and dissociation (CDS, CADSS and DES), depression
(HDRS-24), anxiety (HARS), and global impression (CGI-S) at the end of
phase 1. On average, the entire sample showed a 24% reduction in CDS
total scores after 3 weeks of right TPJ rTMS.
After 6 weeks of rTMS repeated-measures ANOVA revealed a
significant main effect of time on depersonalization and dissociation
(CDS, CADSS and DES), depression (HDRS-24 and BDI–II), anxiety
(HARS and Zung-SAS), and global impression (CGI-S and PGI). Time
by group interactions were examined to determine which of these
improvements were related to 6 weeks of right TPJ stimulation versus
3 weeks of right TPJ plus 3 weeks of left TPJ rTMS. The only significant
time by group interactions were seen with CDS and CGI-S (Table 1).
The group that received 6 weeks of right TPJ rTMS (n=5)
demonstrated a significant decrease (F=7.87, df=6, p=0.000) in
symptom severity (CGI-S changed from severe to mild-borderline)
with a significant (F=8.81, df=6, p=0.000) 68% reduction in CDS
scores from the beginning to the end of the treatment. Post-hoc
analyses revealed that from week 3 to week 6 there was a significant
improvement in CDS total scores by an additional 35% (p=0.021).
The group (n=3) that received 3 weeks of left TPJ rTMS after right TPJ
rTMS showed no change in symptoms severity (F=2.69, df=6,
p=0.068) and only 7% improvement in CDS scores (F=0.94, df=6,
In responders, depression (HDRS and BDI-II) and anxiety (HARS
and Zung-SAS) changes from baseline were not correlated with CDS
changes after treatment. CDS and CADSS changes from baseline to
treatment completion were highly intercorrelated (r=0.961,

4. Discussion

This first open-label cross-over study suggests that low-frequency
rTMS to the right TPJ may show therapeutic promise in DPD, if
substantiated by future sham-controlled trials. Likely, rTMS produced
a clinically significant improvement of DPD symptoms by dampening
down TPJ hyperactivity.
Improvements in depression and anxiety were also seen. While it
is possible that improvements in DPD symptoms could be secondary
to non-specific antidepressant or anxiolytic effects, CDS changes were
not correlated with changes in depression and anxiety. Although
rTMS to the right parietal cortex (precisely to P4 according to the
international 10–20 EEG system) has been shown to have a partial
antidepressant and anxiolytic effect in patients with Major Depression
(Schutter et al., 2009), there is no evidence from the literature that
stimulating over right TPJ can produce an antidepressant or anxiolytic
effect. Moreover TPJ is not a region typically implicated in depression
circuitry (Mayberg, 2003). For this reason, we believe that changes in
HDRS and HARS might be secondary to DPD symptoms improvement,
but our sample may have been underpowered to see this association.
Limitations of this study are the open-label design and the small
sample size. Arguing against this bias is that nonresponders and 1
partial responder to right TPJ rTMS, once crossed over to left TPJ rTMS,
did not show any significant improvement in DPD symptoms. But
without a sham condition we cannot rule out a placebo response.
Making placebo response less likely is that DPD patients are
recognized to have a low placebo response (Simeon et al., 2004),
and that our patients had been ill for long periods of time (the illness
duration was 9.8±12 years) and had tried many treatments
previously (6.6±4.1), without success. In addition, while placebo
responses are usually transitory, the clinical improvement we found
was gradually progressive, continuing until the sixth week of
treatment. A naturalistic follow-up after the end of rTMS will be
necessary to establish the long-term clinical stability.
Another limitation is the allowance of concomitant medications.
Concomitant medications were held at stable doses for 2 months prior
to study entry, and throughout rTMS, so it would be difficult to explain
improvements as resulting from medications alone. However, rTMS
and medications might have a synergistic effect.

The authors thank the staff of the Columbia Brain Behavior Clinic, including Lis
Bernhardt, Linda Fitzsimmons, Austin Harrison, and Nancy Turret. Funding support for
the study has been provided by the Frontier Fund of the Department of Psychiatry at
Columbia University, and the Columbia Division of Brain Stimulation and Therapeutic

Austin Harrison
Lab Manager & Clinical Coordinator
Columbia University
Department of Psychiatry
Division of Brain Stimulation and Therapeutic Modulation
(212) 543-5765, phone
(212) 543-4340, fax