Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue8.2000:
Basal Plasma Dehydroepiandrosterone Sulfate Level: A
Possible Predictor for Response to Electroconvulsive
Therapy in Depressed Psychotic Inpatients
Rachel Maayan, Yana Yagorowski, Daniel Grupper, Mordechai Weiss,
Biana Shtaif, Mahmoud Abou Kaoud, and Abraham Weizman
Background: Dehydroepiandrosterone (DHEA) and its
sulfate derivative DHEAS are neuroactive steroids. In the
brain, they interact with g-aminobutyric acid (GABAA)
receptors, which are involved in the regulation of anxiety
and mood. The relevance of circulatory neurosteroids to
psychiatric disorders and biological treatment is
unknown.
Methods: Basal plasma levels of cortisol, DHEA, and
DHEAS and the DHEAS–DHEA ratio were determined in
17 psychiatric inpatients before and after six electroconvulsive (ECT) therapy sessions, and all changes were
statistically analyzed. For baseline values, 25 healthy
individuals served as control subjects. Severity of depression and psychosis in the patients was measured with the
Hamilton Depression Rating Scale (HDRS) and the Brief
Psychiatric Rating Scale, respectively.
Results: Both basal and post-ECT levels of cortisol,
DHEA, and DHEAS were significantly higher in the
patients than in the control subjects. DHEAS levels in
responding patients were higher at completion of treatment than at baseline. Patients defined as ECT nonresponders (change in HDRS , 30% from before treatments) exhibited elevated basal DHEAS levels compared
with ECT responders.
Conclusions: Markedly elevated basal DHEAS levels
(mean 1 2 SD of control value) are associated with
resistance to ECT and may serve as a potential predictive
marker of nonresponsiveness to ECT in depressed patients. Biol Psychiatry 2000;48:693–701 © 2000 Society
of Biological Psychiatry
Key Words: Dehydroepiandrosterone (DHEA), DHEAS,
neurosteroids, electroconvulsive therapy (ECT), depression, GABAA receptor
From the Laboratory of Biological Psychiatry, Felsenstein Medical Research
Center, Tel Aviv (RM, BS, MAK, AW), Research Unit, Geha Psychiatric
Hospital, Beilinson Campus, Petah Tiqva (AW), Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv (AW), and Be’er Yaakov Mental Health Center,
Be’er Yaakov (YY, DG, MW), Israel.
Address reprint requests to Abraham Weizman, M.D., Geha Psychiatric Hospital,
PO Box 102, Petah Tiqva 49100, Israel.
Received August 27, 1999; revised February 9, 2000; accepted February 15, 2000.
© 2000 Society of Biological Psychiatry
Introduction
D
ehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are neuroactive steroids that are synthesized in situ within the brain, independent of their synthesis in the steroidogenic organs
(Baulieu 1991, 1992, 1997; Baulieu and Robel 1990;
Mellon 1994; Regelson and Kalimi 1994; Robel and
Baulieu 1995a, 1995b; Robel et al 1995). Some of the
neuroactive steroids have been found to interact with the
g-aminobutyric acid (GABA)-gated chloride ion channels
and may represent an important class of neuromodulators
that can rapidly alter central nervous system excitability
via nongenomic mechanisms (Baulieu and Robel 1996;
Deutsch et al 1992; Majewska 1992, 1995; Majewska et al
1986; Majewska and Schwartz 1987; McEwen 1991).
DHEA, but not DHEAS, is associated with antiaggressive
effects (Haug et al 1988). Researchers speculate that the
sedative effects of some neurosteroids are achieved via
direct or indirect enhancement of GABA-mediated chloride ion conductance (Majewska 1995; Regelson and
Kalimi 1994; Robel and Baulieu 1995a, 1995b; Young et
al 1996). They may act either by decreasing the level of
the GABAA antagonistlike pregnenolone sulfate (Robel
and Baulieu 1995b) or by increasing the level of the
GABAA agonistlike metabolites of progesterone (such as
di- and tetrahydro- progesterone) (Young et al 1996) or the
level of the DHEA metabolite androsterone (Majewska
1995).
In contrast to the GABA agonists, the neurosteroids
DHEA and DHEAS display allosteric antagonistic properties at GABAA receptors (Akiva et al 1991; Demirgoren
et al 1991; Majewska 1995; Majewska et al 1990; Spivak
1994); DHEAS appears to be the more potent (Baulieu and
Robel 1998). Alterations in the synthesis of the neurosteroids may result in GABA-mediated behavioral changes.
Neuroactive steroids were reported to be altered during
major depression in humans and to play a putative role in
the treatment of depression with antidepressants. A significant decrease in the plasma concentrations of 5a-preg0006-3223/00/$20.00
PII S0006-3223(00)00848-9
694
R. Maayan et al
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nan-3a-ol-20-one (3a,5a-THP) and 5b-pregnan-3a-ol20-one (3a,5b-THP), which are positive allosteric
modulators of the GABAA receptor, and a concomitant
increase in 5a-pregnan-3b-ol-20-one (3b,5a-THP), which
may act as a functional antagonist for GABA-agonistic
steroids, were reported in patients with major depression.
These alterations in the composition of neuroactive steroids were corrected following successful treatment with
various antidepressants. Pregnenolone, DHEA, progesterone, and 5a-pregnan-3,20-dione (5a-DHP) plasma concentrations were not altered by the antidepressants (Romeo et al 1998). The authors suggested that progesterone
metabolism is dysregulated during depression, possibly
resulting in a decreased GABA-ergic neurotransmission.
Electroconvulsive therapy (ECT) is one of the most
effective treatments for major depression (Avery and
Winokur 1977; Barton 1977; Lambourn and Gill 1978).
ECT is especially recommended for patients with psychotic depression and refractory major depression, as well
as for patients with schizophrenia with affective symptoms
(Avery 1993; Solan et al 1988). Usually six ECT treatments lead to a significant improvement. ECT, as a major
stressor, causes a rise in the stress hormones (Purdy et al
1991; Weizman et al 1987), which may be followed by a
corresponding increase in the steroids active at the
GABAA receptors. It is possible that in the brain, the in
situ glial synthesis of allopregnanolone and allotetrahydrodeoxycorticosterone, which are GABA-positive steroids,
may be heightened following ECT, and there may also be
changes in the levels of the GABA-negative steroids, such
as DHEAS and pregnenolone sulfate (for a review of brain
neurosteroids see Deutsch et al 1992). DHEA may be
involved in the termination of the stress response through
its putative anxiolytic activity (Melchior and Ritzmann
1994).
The role of neurosteroids in neuropsychiatric disorders
is still unknown. One can speculate that changes in the
levels of the neuroactive steroids and the ratio between
them and their sulfate derivatives (which have more potent
antagonistic activity) may be involved in the pathophysiology of stress states such as anxiety and depression.
Interestingly, Ferguson et al (1964) demonstrated 25 years
ago that ECT is associated with increased urinary DHEAS
excretion. The aims of our study were 1) to investigate the
influence of six sequential ECT sessions in drug-resistant
psychiatric patients on the plasma levels of DHEA and
DHEAS and the ratio between the free steroid and its
sulfate derivative (the corresponding weak and potent
GABAA antagonists) and 2) to assess whether one of these
parameters may predict clinical responsiveness to ECT.
We hypothesized that ECT will be associated with increases in plasma DHEA and/or DHEAS and cortisol
levels and that pretreatment high neurosteroid levels will
interfere with the response to ECT.
Methods and Materials
Study Population
The study population consisted of 17 hospitalized psychiatric
patients, seven men and 10 women, of mean age 40.4 6 3.1
years. Two patients had major depression with psychotic features, 10 had schizophrenia with comorbid depression (Siris
1995), and five were schizoaffective patients with current depressive signs and symptoms. The diagnoses of schizophrenia,
schizoaffective disorder, and major depression were established
according to the DSM-IV criteria using the Structured Clinical
Interview for DSM-IV—Patient Version (SCID-P; First et al
1995). The duration of the psychiatric disorders was 14.8 6 8.4
years. All were physically healthy with no infection or history of
drug or alcohol abuse. Six patients were receiving zuclopenthixol, three fluphenazine, four haloperidol, and four clothiapine; three patients also were being treated with carbamazepine,
three with clomipramine, and one with maprotiline. Patients were
maintained on the same drug treatment for at least 4 weeks, and
treatment regimen was not altered during the entire study period.
An independent psychiatrist recommended ECT according to
clinical judgment because of the patients’ drug resistance. For the
patients with psychotic depression, drug resistance was defined
as failure to respond to adequate trials with antipsychotics
combined with antidepressants (a heterocyclic antidepressant, a
selective serotonin reuptake inhibitor, or another class of antidepressant medication) before initiation of ECT (Prudic et al 1996).
The schizophrenic and schizoaffective patients were defined as
drug resistant if no satisfactory response was obtained following
at least three adequate trials with antipsychotics (Meltzer et al
1990) combined with antidepressants, without or with carbamazepine. For baseline comparison, 25 healthy age- and gendermatched control subjects (10 men, 15 women; mean age 38.5 6
2.7 years) were used. The control subjects were assessed by a
clinical interview according to the SCID guidelines (First et al
1995) and medical examination. The rates of cigarette smoking
were similar: 14 of 17 of the patients and 22 of 25 of the control
subjects were smokers. None of the patients or control subjects
used hormones. Both patients and control subjects were sampled
during the summer (June-August) to avoid seasonal variations
(Deslypere et al 1983).
The study was approved by the Be’er Yaakov Review Board
for Clinical Research, and informed consent was obtained from
all participants.
ECT Procedure
Unilateral ECT was administered according to D’Elia (1970),
between 7:00 and 8:00 AM with a brief-pulse ECT device
(MECTA SRI, Mecta Corporation, Lake Oswega, OR). One
stimulus electrode was placed over the nondominant frontotemporal area, and one was placed over the nondominant centroparietal scalp, just lateral to the midline vertex. Premedication
included atropine sulfate 0.5 mg IV, thiopental 2–3 mg/kg IV,
DHEAS and ECT
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and succinylcholine 0.5–1.0 mg/kg IV. Seizure duration was
monitored with a single-channel electroencephalograph (including electrodes placed over the contralateral hemisphere) and cuff
technique. Treatment was given twice weekly for a total of six
sessions. The starting charge of the ECT stimulus dosage (pulse
width 3 frequency (2) 3 train duration 3 current) was 48 mc;
this was increased gradually during the ECT course according to
the rise in seizure threshold, as described previously (Coffey et al
1995; Fink 1992; Sackheim et al 1987).
Clinical Assessments
The severity of the depressive, anxiety, and psychotic symptoms
was measured with the Hamilton Depression Rating Scale
(HDRS; Hamilton 1960), the Hamilton Anxiety Rating Scale
(HARS; Hamilton 1959), and the Brief Psychiatric Rating Scale
(BPRS; Overall and Gorham 1962). Clinical assessments were
performed 1 day before initiation of the ECT course and 1 day
after the sixth treatment. The rater (YY) was blind to the
laboratory measures, and the laboratory staff was blind to the
clinical data.
Figure 1. Effect of six electroconvulsive therapy (ECT) sessions
on depression, anxiety, and psychosis as assessed by various
psychiatric scales. HDRS, Hamilton Depression Rating Scale;
HARS, Hamilton Anxiety Rating Scale; BPRS, Brief Psychiatric
Rating Scale. *p , .0001 vs. pre–ECT-1.
Results
Clinical Effects of ECT
Hormone Determinations
Blood samples were obtained before and 20 min after the first
and sixth ECT session (ECT-1, ECT-6). Morning (7:00 to 8:00
AM) basal samples were collected concomitantly from the control
subjects. All hormone determinations were performed in the
same run to avoid interassay variability.
The levels of DHEA, DHEAS, and cortisol were determined
by commercial radioimmunoassay (RIA) kits, as follows:
• DHEA-DSL 9000 Active DHEA coated tube RIA kit
(Diagnostic Systems Laboratories, Webster, TX): sensitivity 0.02 ng/mL; specificity-cross-reactivity with DHEAS
0.88%, all others negligible; assay variability 10.2% between runs, 5.6 –10.6% within runs, according to level.
• DHEA-S-DSL-3500 Active DHEAS coated tube RIA kit
(Diagnostic Systems Laboratories): sensitivity 17 ng/mL;
specificity-cross-reactivity with DHEA 41%; assay variability 10% between runs, 6.3–9.4% within runs, according
to level.
• Cortisol-TKCO1 Coat-A-Count kit (Diagnostic Products
Corporation, Los Angeles): sensitivity 0.2 mg%; specificity-cross-reactivity: with prednisolone 76%, 11-deoxycortisol 11.4%, prednisone 2.3%, cortisone and corticosterone
1%, all others #0.3%; assay variability 4.0 – 6.4% between
runs, 3– 4.8% within runs, according to level.
Statistical Analysis
Analyses of variance (ANOVAs) with or without repeated
measures followed by the Student–Newman–Keuls post hoc test
were used for the evaluation of the hormonal data. The changes
in the HDRS, HARS, and BPRS scores were analyzed by
two-tailed Student’s paired t test. Correlation was analyzed by
Pearson’s correlation test. All results are expressed as means 6
SEMs.
As expected, the HDRS, HARS, and BPRS scores for the
whole group significantly decreased after completion of
the six ECT sessions: p , .0001 for all (Figure 1).
Hormone Effects of ECT
PATIENTS VERSUS CONTROL SUBJECTS. The patients had significantly higher levels of cortisol, DHEA,
and DHEAS than did the healthy control subjects both at
baseline and after the last session [F(4,90) 5 4.44, p 5
.0025; F(4,90) 5 3.16, p 5 .017; and F(4,90) 5 5.51, p 5
.005, respectively; Figures 2– 4]. No significant difference
was found in the DHEAS–DHEA ratio [F(4,90) 5 1.38,
p 5 .24, ns; Figure 5]. The patients did not have elevated
cortisol and DHEA compared with the controls subjects at
the pre–ECT-6 time point, and the DHEAS–DHEA ratio
did not differ significantly at the post–ECT-6 time point.
No correlation was found between the pretreatment level
of depression and DHEAS or DHEA levels (r 5 2.11 and
r 5 2.28, respectively, both ns).
PATIENT LEVELS BEFORE, DURING, AND AFTER ECT.
Cortisol and DHEA plasma levels remained unaltered
during the study period [F(67) 5 2.19, p 5 .1, ns, and
F(67) 5 0.30, p 5 .8, ns, respectively; Figures 2 and 3],
but DHEAS levels rose significantly from the beginning to
the end of treatment. Both pre– and post–ECT-6 DHEAS
levels were significantly higher than the pre– and post–
ECT-1 levels [F(67) 5 5.11, p 5 .003; Figure 4]. A
significant difference was also found in the DHEAS–
DHEA ratio [pre–ECT-6 vs. post–ECT-1, F(67) 5 3.44,
p 5 .02; Figure 5]. Because DHEA and/or DHEAS may
act as a cortisol antagonist (Hechter et al 1997), we
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2000;48:693–701
R. Maayan et al
Figure 2. Levels of serum cortisol before, during, and after electroconvulsive therapy (ECT). *p , .05 vs. control subjects. **p ,
.01 vs. control subjects.
assessed also possible alterations in DHEAS– cortisol and
DHEA– cortisol ratios, which were not affected significantly by the repeated ECT [F(67) 5 2.13, p 5 .11, ns,
and F(67) 5 2.36, p 5 .08, ns, respectively].
Relationship between Clinical Response and
Alterations in DHEAS
No statistically significant correlations were found between the changes in the severity of depressive, anxiety,
and psychotic symptoms (post–ECT-6 minus pre–ECT-1)
and the corresponding changes in DHEAS, DHEA, and
cortisol levels (correlations were 2.28, .29, and .11 for
depression; 2.14, .17, and .13 for anxiety and 2.11, .38,
and .29 for psychosis, all ns).
Because DHEAS was the only hormone altered significantly by ECT, we decided (post hoc) to evaluate the
possibility that pre-ECT DHEAS levels can predict a
positive clinical response to ECT. Patients were divided
Figure 3. Levels of serum dehydroepiandrosterone (DHEA) before, during, and after electroconvulsive therapy (ECT). *p , .05 vs.
control subjects.
DHEAS and ECT
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2000;48:693–701
697
Figure 4. Levels of serum dehydroepiandrosterone sulfate (DHEAS)
before, during, and after electroconvulsive therapy (ECT). *p , .05 vs
control subjects. **p , .01 vs. control subjects. #p , .05 vs. pre–
ECT-1. ##p , .01 vs. post–ECT-1
within “total.” 1p , .05 vs. post–
ECT-1.
into two groups by basal DHEAS levels. A cutoff point of
elevated DHEAS level was defined as a level higher than
the control mean 1 2 SD (.2200 ng/mL). Eight patients
were found to have a basal DHEAS above this cut-off
(5171 6 407 ng/mL), and nine patients a nonelevated basal
DHEAS level (1691 6 407 ng/mL). A positive clinical
response of the depressive, anxiety, and psychotic symptoms
to ECT was defined as a reduction of at least 30% from
baseline in the HDRS scores a day after ECT-6. This cutoff
for clinical response was chosen a priori because most of the
patients were chronic (mean duration of the psychiatric
disorders: 14.8 6 8.4 years), drug-resistant psychotic patients
with depression who are difficult to treat. Accordingly, eight
of the nine patients with a nonelevated basal DHEAS level
responded to the ECT treatment as opposed to only one of the
eight patients with an elevated level (Fisher’s exact test: p ,
.005, odds ratio 5 56, 95% confidence interval 2.9 –1072.4).
Such a relationship was not found for either anxiety or
psychotic symptom response to ECT (Fisher’s exact test:
HARS, p 5 .13, ns; BPRS, p 5 .29, ns). The patient
subgroups with high and normal baseline DHEAS levels did
not differ significantly in their ECT-induced changes in
Figure 5. Serum dehydroepiandrosterone sulfate (DHEAS)/dehydroepiandrosterone (DHEA) ratio before, during, and after electroconvulsive therapy (ECT). *p , .05 vs. post–ECT-1.
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2000;48:693–701
DHEAS levels [1188 6 449 vs. 662 6 485 ng/mL; t(15) 5
0.77, p 5 .45, ns].
Discussion
The major findings of this study are that ECT induces an
elevation in DHEAS plasma levels and that nonelevated
basal DHEAS levels are associated with a clinically
relevant response (improvement . 30%) of depressive
symptoms (as assessed by the HDRS) to ECT, at least
following six repeated ECT treatments. In addition, we
demonstrated that cortisol, DHEAS, and DHEA basal
levels are higher in drug-resistant psychotic depressed
patients than in healthy control subjects.
Our finding of elevated basal plasma levels of DHEA
and DHEAS in psychiatric patients is in accordance with
earlier studies. Hansen et al (1982) reported high basal
DHEA levels in psychotic depressed patients, and Tollefson et al (1990) found elevated 24-hour urinary DHEAS
levels in nonpsychotic patients with major depression. In a
more recent study, however, Romeo et al (1998) failed to
demonstrate altered DHEA in 11 hospitalized patients
with severe major depression. Furthermore, other researchers reported on reduced DHEA and/or DHEAS
levels or DHEA and/or DHEAS– cortisol ratios in depressed patients (Berr et al 1996; Goodyer et al 1998;
Herbert 1998; Osran et al 1993). Our results regarding the
effect of ECT are in agreement with Ferguson et al (1964)
who demonstrated that ECT increased urinary DHEAS
levels. It is of note that DHEA and/or DHEAS show
increased concentrations both in blood and in the brain
following acute stress (Zinder and Dar 1999). Thus, the
pretreatment elevated DHEA and/or DHEAS levels in the
patients may be related to stress of hospitalization, and the
increase obtained immediately after ECT may be related to
the stress of the iatrogenic convulsions or to ECT
premedication.
The increase in neuroactive steroid levels during depression may act to attenuate the depression-associated
overactivity of the hypothalamic-pituitary-adrenal (HPA)
axis (Wolf et al 1997), as well as the severity of the
depressive symptoms (Wolkowitz et al 1995, 1997b). It is
of note that DHEA has been successfully tested as an
antidepressant (Reus 1997; Wolkowitz et al 1997a, 1997b,
1999) and may act as an endogenous antidepressant.
Furthermore, the antidepressant responses to DHEA treatment were directly correlated with treatment-induced increases in plasma DHEAS (Wolkowitz et al 1997b).
Previous studies have demonstrated that depression is
associated with a decrease in cerebrospinal fluid (CSF)
and plasma levels of the GABA-agonistic neurosteroids
3a,5a-tetrahydroprogesterone (THP, allopregnanolone),
and 3a,5b-THP (Romeo et al 1998; Uzunova et al 1998),
R. Maayan et al
which occurs concomitantly with an increase in plasma
levels of 3b,5a-THP, but not DHEA. Furthermore, in one
study, CSF levels of allopregnanolone correlated negatively with the severity of depression as assessed by the
HDRS, and successful antidepressant therapy led to normalization of both the CSF and plasma content of the
GABA-active neurosteroids (Romeo et al 1998; Uzunova
et al 1998). Based on preclinical and clinical studies, these
authors suggested that the antidysphoric and anxiolytic
profiles of selective serotonin reuptake inhibitors may be
related to their ability to increase brain allopregnanolone
availability (Guidotti and Costa 1998; Uzunov et al 1996).
Unfortunately the role of the balance between neurosteroids with GABA-agonistic and antagonistic activity
were not assessed in nonpsychotic and psychotic depressed patients.
To the best of our knowledge, the involvement of
DHEA or DHEAS in psychosis complicated by depression
or in the response of the depressive symptoms of psychotic
patients to ECT has not yet been investigated. Because
both DHEA and DHEAS are GABAA antagonists, although DHEAS is a more potent inhibitor of the GABAgated chloride ion channel function (Baulieu and Robel
1998; Deutsch et al 1992; Majewska et al 1990; Paul and
Purdy 1992) and because DHEA may act as a functional
antagonist for GABA-agonistic neurosteroids (Prince and
Simmonds 1992; Romeo et al 1998), an elevation in their
circulatory levels could lead to an increase in anxiety,
dysphoria, aggression, or psychosis (Howard 1992; Sands
1954). Moreover, as shown here, a high basal DHEAS
plasma level is a predictor of poor response to ECT,
whereas a normal-range DHEAS level before treatment,
and its persistence following ECT, is associated with a
good response (at least following six repeated ECTs).
Nevertheless, it is possible that the ECT-induced increase
in DHEAS is associated with attenuated GABA activity
and increased release of brain serotonin (Abadie et al
1993). In addition, the activity of DHEAS at the Nmethyl-D-aspartate and sigma receptors, as well as possible neurosteroid-related adaptation of NMDA receptors,
may also be relevant to the antidepressive effect of ECT
(Maurice et al 1997; Reddy et al 1998; Reddy and
Kulkarni 1997; Skolnick et al 1996). Unfortunately, we
did not assess the plasma levels of GABA-agonistic
steroids in our study, so we cannot rule out the possibility
of a disequilibrium of neuroactive steroids, that is, increase in GABA-antagonists and decrease in GABAagonists before ECT treatment and an impact of ECT on
such balance. Moreover, the relationship between high
circulatory levels of DHEAS and brain neurosteroid biosynthesis and content is as yet unclear. Furthermore, the
relationship between neurosteroids and depressive symptoms may be complex because no significant correlation
DHEAS and ECT
was found in our study population between the changes in
DHEAS levels and changes in depression scores. Nonetheless, a recent study (Heinz et al 1999) has demonstrated
in abstinent alcoholics negative correlations between
DHEAS plasma concentrations and both self-rated depression and observer-rated depression scores. In addition, the
ratio of DHEAS to cortisol concentrations was also negatively correlated with depression scores.
In conclusion, depression in drug-resistant psychotic
inpatients is associated with high levels of the putative
allosteric GABAA receptor antagonist DHEAS as compared with healthy controls, and a markedly elevated
(mean 1 2 SD of control levels) basal level of this
neurosteroid is a predictor of resistance to ECT. The
relationship between elevated DHEAS levels, other
GABA-active neurosteroids, depression, anxiety and psychosis, as well as the clinical response to antidepressants,
anxiolytics, and ECT, merit further investigation. Our data
should be considered as preliminary pilot data and should
inspire more rigorous studies in homogeneous psychiatric
populations.
We are grateful for the editorial and secretarial help of Gloria Ginzach
and Hanni Penn.
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Possible Predictor for Response to Electroconvulsive
Therapy in Depressed Psychotic Inpatients
Rachel Maayan, Yana Yagorowski, Daniel Grupper, Mordechai Weiss,
Biana Shtaif, Mahmoud Abou Kaoud, and Abraham Weizman
Background: Dehydroepiandrosterone (DHEA) and its
sulfate derivative DHEAS are neuroactive steroids. In the
brain, they interact with g-aminobutyric acid (GABAA)
receptors, which are involved in the regulation of anxiety
and mood. The relevance of circulatory neurosteroids to
psychiatric disorders and biological treatment is
unknown.
Methods: Basal plasma levels of cortisol, DHEA, and
DHEAS and the DHEAS–DHEA ratio were determined in
17 psychiatric inpatients before and after six electroconvulsive (ECT) therapy sessions, and all changes were
statistically analyzed. For baseline values, 25 healthy
individuals served as control subjects. Severity of depression and psychosis in the patients was measured with the
Hamilton Depression Rating Scale (HDRS) and the Brief
Psychiatric Rating Scale, respectively.
Results: Both basal and post-ECT levels of cortisol,
DHEA, and DHEAS were significantly higher in the
patients than in the control subjects. DHEAS levels in
responding patients were higher at completion of treatment than at baseline. Patients defined as ECT nonresponders (change in HDRS , 30% from before treatments) exhibited elevated basal DHEAS levels compared
with ECT responders.
Conclusions: Markedly elevated basal DHEAS levels
(mean 1 2 SD of control value) are associated with
resistance to ECT and may serve as a potential predictive
marker of nonresponsiveness to ECT in depressed patients. Biol Psychiatry 2000;48:693–701 © 2000 Society
of Biological Psychiatry
Key Words: Dehydroepiandrosterone (DHEA), DHEAS,
neurosteroids, electroconvulsive therapy (ECT), depression, GABAA receptor
From the Laboratory of Biological Psychiatry, Felsenstein Medical Research
Center, Tel Aviv (RM, BS, MAK, AW), Research Unit, Geha Psychiatric
Hospital, Beilinson Campus, Petah Tiqva (AW), Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv (AW), and Be’er Yaakov Mental Health Center,
Be’er Yaakov (YY, DG, MW), Israel.
Address reprint requests to Abraham Weizman, M.D., Geha Psychiatric Hospital,
PO Box 102, Petah Tiqva 49100, Israel.
Received August 27, 1999; revised February 9, 2000; accepted February 15, 2000.
© 2000 Society of Biological Psychiatry
Introduction
D
ehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) are neuroactive steroids that are synthesized in situ within the brain, independent of their synthesis in the steroidogenic organs
(Baulieu 1991, 1992, 1997; Baulieu and Robel 1990;
Mellon 1994; Regelson and Kalimi 1994; Robel and
Baulieu 1995a, 1995b; Robel et al 1995). Some of the
neuroactive steroids have been found to interact with the
g-aminobutyric acid (GABA)-gated chloride ion channels
and may represent an important class of neuromodulators
that can rapidly alter central nervous system excitability
via nongenomic mechanisms (Baulieu and Robel 1996;
Deutsch et al 1992; Majewska 1992, 1995; Majewska et al
1986; Majewska and Schwartz 1987; McEwen 1991).
DHEA, but not DHEAS, is associated with antiaggressive
effects (Haug et al 1988). Researchers speculate that the
sedative effects of some neurosteroids are achieved via
direct or indirect enhancement of GABA-mediated chloride ion conductance (Majewska 1995; Regelson and
Kalimi 1994; Robel and Baulieu 1995a, 1995b; Young et
al 1996). They may act either by decreasing the level of
the GABAA antagonistlike pregnenolone sulfate (Robel
and Baulieu 1995b) or by increasing the level of the
GABAA agonistlike metabolites of progesterone (such as
di- and tetrahydro- progesterone) (Young et al 1996) or the
level of the DHEA metabolite androsterone (Majewska
1995).
In contrast to the GABA agonists, the neurosteroids
DHEA and DHEAS display allosteric antagonistic properties at GABAA receptors (Akiva et al 1991; Demirgoren
et al 1991; Majewska 1995; Majewska et al 1990; Spivak
1994); DHEAS appears to be the more potent (Baulieu and
Robel 1998). Alterations in the synthesis of the neurosteroids may result in GABA-mediated behavioral changes.
Neuroactive steroids were reported to be altered during
major depression in humans and to play a putative role in
the treatment of depression with antidepressants. A significant decrease in the plasma concentrations of 5a-preg0006-3223/00/$20.00
PII S0006-3223(00)00848-9
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nan-3a-ol-20-one (3a,5a-THP) and 5b-pregnan-3a-ol20-one (3a,5b-THP), which are positive allosteric
modulators of the GABAA receptor, and a concomitant
increase in 5a-pregnan-3b-ol-20-one (3b,5a-THP), which
may act as a functional antagonist for GABA-agonistic
steroids, were reported in patients with major depression.
These alterations in the composition of neuroactive steroids were corrected following successful treatment with
various antidepressants. Pregnenolone, DHEA, progesterone, and 5a-pregnan-3,20-dione (5a-DHP) plasma concentrations were not altered by the antidepressants (Romeo et al 1998). The authors suggested that progesterone
metabolism is dysregulated during depression, possibly
resulting in a decreased GABA-ergic neurotransmission.
Electroconvulsive therapy (ECT) is one of the most
effective treatments for major depression (Avery and
Winokur 1977; Barton 1977; Lambourn and Gill 1978).
ECT is especially recommended for patients with psychotic depression and refractory major depression, as well
as for patients with schizophrenia with affective symptoms
(Avery 1993; Solan et al 1988). Usually six ECT treatments lead to a significant improvement. ECT, as a major
stressor, causes a rise in the stress hormones (Purdy et al
1991; Weizman et al 1987), which may be followed by a
corresponding increase in the steroids active at the
GABAA receptors. It is possible that in the brain, the in
situ glial synthesis of allopregnanolone and allotetrahydrodeoxycorticosterone, which are GABA-positive steroids,
may be heightened following ECT, and there may also be
changes in the levels of the GABA-negative steroids, such
as DHEAS and pregnenolone sulfate (for a review of brain
neurosteroids see Deutsch et al 1992). DHEA may be
involved in the termination of the stress response through
its putative anxiolytic activity (Melchior and Ritzmann
1994).
The role of neurosteroids in neuropsychiatric disorders
is still unknown. One can speculate that changes in the
levels of the neuroactive steroids and the ratio between
them and their sulfate derivatives (which have more potent
antagonistic activity) may be involved in the pathophysiology of stress states such as anxiety and depression.
Interestingly, Ferguson et al (1964) demonstrated 25 years
ago that ECT is associated with increased urinary DHEAS
excretion. The aims of our study were 1) to investigate the
influence of six sequential ECT sessions in drug-resistant
psychiatric patients on the plasma levels of DHEA and
DHEAS and the ratio between the free steroid and its
sulfate derivative (the corresponding weak and potent
GABAA antagonists) and 2) to assess whether one of these
parameters may predict clinical responsiveness to ECT.
We hypothesized that ECT will be associated with increases in plasma DHEA and/or DHEAS and cortisol
levels and that pretreatment high neurosteroid levels will
interfere with the response to ECT.
Methods and Materials
Study Population
The study population consisted of 17 hospitalized psychiatric
patients, seven men and 10 women, of mean age 40.4 6 3.1
years. Two patients had major depression with psychotic features, 10 had schizophrenia with comorbid depression (Siris
1995), and five were schizoaffective patients with current depressive signs and symptoms. The diagnoses of schizophrenia,
schizoaffective disorder, and major depression were established
according to the DSM-IV criteria using the Structured Clinical
Interview for DSM-IV—Patient Version (SCID-P; First et al
1995). The duration of the psychiatric disorders was 14.8 6 8.4
years. All were physically healthy with no infection or history of
drug or alcohol abuse. Six patients were receiving zuclopenthixol, three fluphenazine, four haloperidol, and four clothiapine; three patients also were being treated with carbamazepine,
three with clomipramine, and one with maprotiline. Patients were
maintained on the same drug treatment for at least 4 weeks, and
treatment regimen was not altered during the entire study period.
An independent psychiatrist recommended ECT according to
clinical judgment because of the patients’ drug resistance. For the
patients with psychotic depression, drug resistance was defined
as failure to respond to adequate trials with antipsychotics
combined with antidepressants (a heterocyclic antidepressant, a
selective serotonin reuptake inhibitor, or another class of antidepressant medication) before initiation of ECT (Prudic et al 1996).
The schizophrenic and schizoaffective patients were defined as
drug resistant if no satisfactory response was obtained following
at least three adequate trials with antipsychotics (Meltzer et al
1990) combined with antidepressants, without or with carbamazepine. For baseline comparison, 25 healthy age- and gendermatched control subjects (10 men, 15 women; mean age 38.5 6
2.7 years) were used. The control subjects were assessed by a
clinical interview according to the SCID guidelines (First et al
1995) and medical examination. The rates of cigarette smoking
were similar: 14 of 17 of the patients and 22 of 25 of the control
subjects were smokers. None of the patients or control subjects
used hormones. Both patients and control subjects were sampled
during the summer (June-August) to avoid seasonal variations
(Deslypere et al 1983).
The study was approved by the Be’er Yaakov Review Board
for Clinical Research, and informed consent was obtained from
all participants.
ECT Procedure
Unilateral ECT was administered according to D’Elia (1970),
between 7:00 and 8:00 AM with a brief-pulse ECT device
(MECTA SRI, Mecta Corporation, Lake Oswega, OR). One
stimulus electrode was placed over the nondominant frontotemporal area, and one was placed over the nondominant centroparietal scalp, just lateral to the midline vertex. Premedication
included atropine sulfate 0.5 mg IV, thiopental 2–3 mg/kg IV,
DHEAS and ECT
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695
and succinylcholine 0.5–1.0 mg/kg IV. Seizure duration was
monitored with a single-channel electroencephalograph (including electrodes placed over the contralateral hemisphere) and cuff
technique. Treatment was given twice weekly for a total of six
sessions. The starting charge of the ECT stimulus dosage (pulse
width 3 frequency (2) 3 train duration 3 current) was 48 mc;
this was increased gradually during the ECT course according to
the rise in seizure threshold, as described previously (Coffey et al
1995; Fink 1992; Sackheim et al 1987).
Clinical Assessments
The severity of the depressive, anxiety, and psychotic symptoms
was measured with the Hamilton Depression Rating Scale
(HDRS; Hamilton 1960), the Hamilton Anxiety Rating Scale
(HARS; Hamilton 1959), and the Brief Psychiatric Rating Scale
(BPRS; Overall and Gorham 1962). Clinical assessments were
performed 1 day before initiation of the ECT course and 1 day
after the sixth treatment. The rater (YY) was blind to the
laboratory measures, and the laboratory staff was blind to the
clinical data.
Figure 1. Effect of six electroconvulsive therapy (ECT) sessions
on depression, anxiety, and psychosis as assessed by various
psychiatric scales. HDRS, Hamilton Depression Rating Scale;
HARS, Hamilton Anxiety Rating Scale; BPRS, Brief Psychiatric
Rating Scale. *p , .0001 vs. pre–ECT-1.
Results
Clinical Effects of ECT
Hormone Determinations
Blood samples were obtained before and 20 min after the first
and sixth ECT session (ECT-1, ECT-6). Morning (7:00 to 8:00
AM) basal samples were collected concomitantly from the control
subjects. All hormone determinations were performed in the
same run to avoid interassay variability.
The levels of DHEA, DHEAS, and cortisol were determined
by commercial radioimmunoassay (RIA) kits, as follows:
• DHEA-DSL 9000 Active DHEA coated tube RIA kit
(Diagnostic Systems Laboratories, Webster, TX): sensitivity 0.02 ng/mL; specificity-cross-reactivity with DHEAS
0.88%, all others negligible; assay variability 10.2% between runs, 5.6 –10.6% within runs, according to level.
• DHEA-S-DSL-3500 Active DHEAS coated tube RIA kit
(Diagnostic Systems Laboratories): sensitivity 17 ng/mL;
specificity-cross-reactivity with DHEA 41%; assay variability 10% between runs, 6.3–9.4% within runs, according
to level.
• Cortisol-TKCO1 Coat-A-Count kit (Diagnostic Products
Corporation, Los Angeles): sensitivity 0.2 mg%; specificity-cross-reactivity: with prednisolone 76%, 11-deoxycortisol 11.4%, prednisone 2.3%, cortisone and corticosterone
1%, all others #0.3%; assay variability 4.0 – 6.4% between
runs, 3– 4.8% within runs, according to level.
Statistical Analysis
Analyses of variance (ANOVAs) with or without repeated
measures followed by the Student–Newman–Keuls post hoc test
were used for the evaluation of the hormonal data. The changes
in the HDRS, HARS, and BPRS scores were analyzed by
two-tailed Student’s paired t test. Correlation was analyzed by
Pearson’s correlation test. All results are expressed as means 6
SEMs.
As expected, the HDRS, HARS, and BPRS scores for the
whole group significantly decreased after completion of
the six ECT sessions: p , .0001 for all (Figure 1).
Hormone Effects of ECT
PATIENTS VERSUS CONTROL SUBJECTS. The patients had significantly higher levels of cortisol, DHEA,
and DHEAS than did the healthy control subjects both at
baseline and after the last session [F(4,90) 5 4.44, p 5
.0025; F(4,90) 5 3.16, p 5 .017; and F(4,90) 5 5.51, p 5
.005, respectively; Figures 2– 4]. No significant difference
was found in the DHEAS–DHEA ratio [F(4,90) 5 1.38,
p 5 .24, ns; Figure 5]. The patients did not have elevated
cortisol and DHEA compared with the controls subjects at
the pre–ECT-6 time point, and the DHEAS–DHEA ratio
did not differ significantly at the post–ECT-6 time point.
No correlation was found between the pretreatment level
of depression and DHEAS or DHEA levels (r 5 2.11 and
r 5 2.28, respectively, both ns).
PATIENT LEVELS BEFORE, DURING, AND AFTER ECT.
Cortisol and DHEA plasma levels remained unaltered
during the study period [F(67) 5 2.19, p 5 .1, ns, and
F(67) 5 0.30, p 5 .8, ns, respectively; Figures 2 and 3],
but DHEAS levels rose significantly from the beginning to
the end of treatment. Both pre– and post–ECT-6 DHEAS
levels were significantly higher than the pre– and post–
ECT-1 levels [F(67) 5 5.11, p 5 .003; Figure 4]. A
significant difference was also found in the DHEAS–
DHEA ratio [pre–ECT-6 vs. post–ECT-1, F(67) 5 3.44,
p 5 .02; Figure 5]. Because DHEA and/or DHEAS may
act as a cortisol antagonist (Hechter et al 1997), we
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R. Maayan et al
Figure 2. Levels of serum cortisol before, during, and after electroconvulsive therapy (ECT). *p , .05 vs. control subjects. **p ,
.01 vs. control subjects.
assessed also possible alterations in DHEAS– cortisol and
DHEA– cortisol ratios, which were not affected significantly by the repeated ECT [F(67) 5 2.13, p 5 .11, ns,
and F(67) 5 2.36, p 5 .08, ns, respectively].
Relationship between Clinical Response and
Alterations in DHEAS
No statistically significant correlations were found between the changes in the severity of depressive, anxiety,
and psychotic symptoms (post–ECT-6 minus pre–ECT-1)
and the corresponding changes in DHEAS, DHEA, and
cortisol levels (correlations were 2.28, .29, and .11 for
depression; 2.14, .17, and .13 for anxiety and 2.11, .38,
and .29 for psychosis, all ns).
Because DHEAS was the only hormone altered significantly by ECT, we decided (post hoc) to evaluate the
possibility that pre-ECT DHEAS levels can predict a
positive clinical response to ECT. Patients were divided
Figure 3. Levels of serum dehydroepiandrosterone (DHEA) before, during, and after electroconvulsive therapy (ECT). *p , .05 vs.
control subjects.
DHEAS and ECT
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697
Figure 4. Levels of serum dehydroepiandrosterone sulfate (DHEAS)
before, during, and after electroconvulsive therapy (ECT). *p , .05 vs
control subjects. **p , .01 vs. control subjects. #p , .05 vs. pre–
ECT-1. ##p , .01 vs. post–ECT-1
within “total.” 1p , .05 vs. post–
ECT-1.
into two groups by basal DHEAS levels. A cutoff point of
elevated DHEAS level was defined as a level higher than
the control mean 1 2 SD (.2200 ng/mL). Eight patients
were found to have a basal DHEAS above this cut-off
(5171 6 407 ng/mL), and nine patients a nonelevated basal
DHEAS level (1691 6 407 ng/mL). A positive clinical
response of the depressive, anxiety, and psychotic symptoms
to ECT was defined as a reduction of at least 30% from
baseline in the HDRS scores a day after ECT-6. This cutoff
for clinical response was chosen a priori because most of the
patients were chronic (mean duration of the psychiatric
disorders: 14.8 6 8.4 years), drug-resistant psychotic patients
with depression who are difficult to treat. Accordingly, eight
of the nine patients with a nonelevated basal DHEAS level
responded to the ECT treatment as opposed to only one of the
eight patients with an elevated level (Fisher’s exact test: p ,
.005, odds ratio 5 56, 95% confidence interval 2.9 –1072.4).
Such a relationship was not found for either anxiety or
psychotic symptom response to ECT (Fisher’s exact test:
HARS, p 5 .13, ns; BPRS, p 5 .29, ns). The patient
subgroups with high and normal baseline DHEAS levels did
not differ significantly in their ECT-induced changes in
Figure 5. Serum dehydroepiandrosterone sulfate (DHEAS)/dehydroepiandrosterone (DHEA) ratio before, during, and after electroconvulsive therapy (ECT). *p , .05 vs. post–ECT-1.
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2000;48:693–701
DHEAS levels [1188 6 449 vs. 662 6 485 ng/mL; t(15) 5
0.77, p 5 .45, ns].
Discussion
The major findings of this study are that ECT induces an
elevation in DHEAS plasma levels and that nonelevated
basal DHEAS levels are associated with a clinically
relevant response (improvement . 30%) of depressive
symptoms (as assessed by the HDRS) to ECT, at least
following six repeated ECT treatments. In addition, we
demonstrated that cortisol, DHEAS, and DHEA basal
levels are higher in drug-resistant psychotic depressed
patients than in healthy control subjects.
Our finding of elevated basal plasma levels of DHEA
and DHEAS in psychiatric patients is in accordance with
earlier studies. Hansen et al (1982) reported high basal
DHEA levels in psychotic depressed patients, and Tollefson et al (1990) found elevated 24-hour urinary DHEAS
levels in nonpsychotic patients with major depression. In a
more recent study, however, Romeo et al (1998) failed to
demonstrate altered DHEA in 11 hospitalized patients
with severe major depression. Furthermore, other researchers reported on reduced DHEA and/or DHEAS
levels or DHEA and/or DHEAS– cortisol ratios in depressed patients (Berr et al 1996; Goodyer et al 1998;
Herbert 1998; Osran et al 1993). Our results regarding the
effect of ECT are in agreement with Ferguson et al (1964)
who demonstrated that ECT increased urinary DHEAS
levels. It is of note that DHEA and/or DHEAS show
increased concentrations both in blood and in the brain
following acute stress (Zinder and Dar 1999). Thus, the
pretreatment elevated DHEA and/or DHEAS levels in the
patients may be related to stress of hospitalization, and the
increase obtained immediately after ECT may be related to
the stress of the iatrogenic convulsions or to ECT
premedication.
The increase in neuroactive steroid levels during depression may act to attenuate the depression-associated
overactivity of the hypothalamic-pituitary-adrenal (HPA)
axis (Wolf et al 1997), as well as the severity of the
depressive symptoms (Wolkowitz et al 1995, 1997b). It is
of note that DHEA has been successfully tested as an
antidepressant (Reus 1997; Wolkowitz et al 1997a, 1997b,
1999) and may act as an endogenous antidepressant.
Furthermore, the antidepressant responses to DHEA treatment were directly correlated with treatment-induced increases in plasma DHEAS (Wolkowitz et al 1997b).
Previous studies have demonstrated that depression is
associated with a decrease in cerebrospinal fluid (CSF)
and plasma levels of the GABA-agonistic neurosteroids
3a,5a-tetrahydroprogesterone (THP, allopregnanolone),
and 3a,5b-THP (Romeo et al 1998; Uzunova et al 1998),
R. Maayan et al
which occurs concomitantly with an increase in plasma
levels of 3b,5a-THP, but not DHEA. Furthermore, in one
study, CSF levels of allopregnanolone correlated negatively with the severity of depression as assessed by the
HDRS, and successful antidepressant therapy led to normalization of both the CSF and plasma content of the
GABA-active neurosteroids (Romeo et al 1998; Uzunova
et al 1998). Based on preclinical and clinical studies, these
authors suggested that the antidysphoric and anxiolytic
profiles of selective serotonin reuptake inhibitors may be
related to their ability to increase brain allopregnanolone
availability (Guidotti and Costa 1998; Uzunov et al 1996).
Unfortunately the role of the balance between neurosteroids with GABA-agonistic and antagonistic activity
were not assessed in nonpsychotic and psychotic depressed patients.
To the best of our knowledge, the involvement of
DHEA or DHEAS in psychosis complicated by depression
or in the response of the depressive symptoms of psychotic
patients to ECT has not yet been investigated. Because
both DHEA and DHEAS are GABAA antagonists, although DHEAS is a more potent inhibitor of the GABAgated chloride ion channel function (Baulieu and Robel
1998; Deutsch et al 1992; Majewska et al 1990; Paul and
Purdy 1992) and because DHEA may act as a functional
antagonist for GABA-agonistic neurosteroids (Prince and
Simmonds 1992; Romeo et al 1998), an elevation in their
circulatory levels could lead to an increase in anxiety,
dysphoria, aggression, or psychosis (Howard 1992; Sands
1954). Moreover, as shown here, a high basal DHEAS
plasma level is a predictor of poor response to ECT,
whereas a normal-range DHEAS level before treatment,
and its persistence following ECT, is associated with a
good response (at least following six repeated ECTs).
Nevertheless, it is possible that the ECT-induced increase
in DHEAS is associated with attenuated GABA activity
and increased release of brain serotonin (Abadie et al
1993). In addition, the activity of DHEAS at the Nmethyl-D-aspartate and sigma receptors, as well as possible neurosteroid-related adaptation of NMDA receptors,
may also be relevant to the antidepressive effect of ECT
(Maurice et al 1997; Reddy et al 1998; Reddy and
Kulkarni 1997; Skolnick et al 1996). Unfortunately, we
did not assess the plasma levels of GABA-agonistic
steroids in our study, so we cannot rule out the possibility
of a disequilibrium of neuroactive steroids, that is, increase in GABA-antagonists and decrease in GABAagonists before ECT treatment and an impact of ECT on
such balance. Moreover, the relationship between high
circulatory levels of DHEAS and brain neurosteroid biosynthesis and content is as yet unclear. Furthermore, the
relationship between neurosteroids and depressive symptoms may be complex because no significant correlation
DHEAS and ECT
was found in our study population between the changes in
DHEAS levels and changes in depression scores. Nonetheless, a recent study (Heinz et al 1999) has demonstrated
in abstinent alcoholics negative correlations between
DHEAS plasma concentrations and both self-rated depression and observer-rated depression scores. In addition, the
ratio of DHEAS to cortisol concentrations was also negatively correlated with depression scores.
In conclusion, depression in drug-resistant psychotic
inpatients is associated with high levels of the putative
allosteric GABAA receptor antagonist DHEAS as compared with healthy controls, and a markedly elevated
(mean 1 2 SD of control levels) basal level of this
neurosteroid is a predictor of resistance to ECT. The
relationship between elevated DHEAS levels, other
GABA-active neurosteroids, depression, anxiety and psychosis, as well as the clinical response to antidepressants,
anxiolytics, and ECT, merit further investigation. Our data
should be considered as preliminary pilot data and should
inspire more rigorous studies in homogeneous psychiatric
populations.
We are grateful for the editorial and secretarial help of Gloria Ginzach
and Hanni Penn.
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