Plasma dehydroepiandrosterone levels are strongly increased

Di seguito un mio articolo di qualche anno fa pubblicato su una rivista internazionale di settore che ci permette di entrare in  parte nel complesso e affascinante mondo delle neuroscienze, da tempo per me piattaforma di lavoro e di produzione scientifica preferenziale.

La malattia mentale è una malattia multifattoriale, genetica e ambientale. Il gruppo di lavoro che ha studiato le tematiche su riportate ha esperienze cliniche e di ricerca diversificate.


Carlo Caltagirone a,b, Giuseppina Bonaviri c,a,b, Gianfranco Spalletta a,b,*a


Laboratorio di Neurologia Clinica e Comportamentale, IRCCS Santa Lucia Foundation, Via Ardeatina, 306 00179 Rome, Italyb
Department of Neuroscience, Tor Vergata University of Rome, 00133 Rome, Italyc
General Direction and Department of Mental Health, ASL Frosinone, 03010 Frosinone, ItalyReceived 22 April 2004; received in revised form 8 July 2004; accepted 30 July 2004
Abstract
Dehydroepiandrosterone has been recently recognized as neuroactive steroid with several vital neurophysiological activities on
membrane receptors, such as
does also have an antiglucocorticoid effect. So far, the relevance of this neuroactive steroid to psychiatric disorders is not well
known. In this study, plasma levels of DHEA were determined with a highly sensitive and specific gas-chromatography/mass-spectrometry
method in 23 outpatients suffering from Diagnostic and Statistical Manual of Mental Disorders-IV schizophrenia compared
with 23 healthy control subjects matched for age and sex. Plasma levels of DHEA were found to be strongly elevated in the group of
schizophrenic patients (mean ± SD = 90.9 ± 61.4 nmol/l) compared to that of control subjects (mean ± SD = 24.0 ± 17.9 nmol/l)
and the difference was highly significant (
we divided the groups of schizophrenics and controls in subgroups of males (
df = 18,
mechanism of action in the brain involving genomic and non-genomic components. Therefore, its study may provide further
understanding of the pathophysiology of psychoses and open new avenues for their treatment.
N-methyl-D-aspartate, and c-aminobutyric acid receptors and on genomic androgen receptors. DHEAt = 5.018, df = 44, p < 0.0001). This statistically significant difference was also found whent = 4.536, df = 24, p = 0.0001) and females (t = 2.777,p = 0.0124). These results suggest that DHEA may have some role in the pathophysiology of schizophrenia due to its complex
2004 Elsevier Ltd. All rights reserved.Keywords:
Schizophrenia; Dehydroepiandrosterone; Neuroactive steroids; Pathophysiology; Gender1. Introduction
Dehydroepiandrosterone (DHEA) and its sulfate
derivative DHEAS in the past have been thought to
function merely as precursors for sex steroid synthesis
being produced by adrenal glands. Only recently they
have been recognized as neuroactive steroids (
et al., 2001
receptors, such as
and
the genomic androgen receptor (
the brain is not only the target tissue for neuroactive
steroids, but may itself de novo produce them
(therefore called neurosteroids) in glia cells and in neurons,
starting from cholesterol (
Schumacher et al., 2000
DHEA does also have an antiglucocorticoid effect by
inhibiting glucocorticoid induced enzyme activity and
antagonizing dexamethasone-induced suppression of
lymphocytes and thymic involution (
and Verkes, 2003
Baulieu). In fact, in the brain they interact with membraneN-methyl-D-aspartate (NMDA)c-aminobutyric acid (GABAA) receptors, and withLu et al., 2003). Moreover,Baulieu et al., 2001;).van Broekhoven).0022-3956/$ – see front matter
doi:10.1016/j.jpsychires.2004.08.005
 2004 Elsevier Ltd. All rights reserved.*
54225988.
Corresponding author. Tel.: +39 06 51501575/1568; fax: +39 06E-mail address:
www.elsevier.com/locate/jpsychires
Journal of Psychiatric Research 39 (2005) 267–273
g.spalletta@hsantalucia.it (G. Spalletta).J
OURNAL OFP
SYCHIATRICR
ESEARCHWhile many reports have demonstrated the effects of
DHEA on neural, endocrine, immune and metabolic systems
(
steroid to psychiatric disorders is still not well known.
Past scientific literature suggests a link between certain
psychotic states and DHEA levels. However, results from
these studies are conflicting. Indeed, on the one hand
abnormally high levels of DHEA have been identified
among severely psychotic male population (
1992
to occur as DHEA returned to its normal range using
standard low dose dexamethasone suppression (
1992
pointing to a possible utility of DHEA and
DHEAS as markers of psychosis in young schizophrenic
patients (
psychotic depression who are nonresponsive to electroconvulsive
treatment (
hand, other studies (
1972
DHEA diurnal rhythms (i.e., low levels in the morning,
but within the range of the controls for subsequent determinations)
in psychotic patients (
1979
and control subjects by means of plasma DHEA
measurements was 100% accurate, while cortisol, aldosterone,
DHEAS and testosterone did not provide such
a basis for discrimination (
correlations between low serum DHEA levels and higher
psychopathology ratings have been observed (
et al., 2001
no differences in DHEA levels between schizophrenic
and control subjects.
Controversial is also the use of DHEA in the pharmacotherapy
of schizophrenia. Before chlorpromazine,
DHEA had been used in young schizophrenics with
modest success in improving deficit symptoms. In particular,
DHEA, other sex hormones and some of their natural
and synthetic derivatives had been used in an
attempt to treat deficit symptoms of schizophrenia in
both sexes (
(
augmentation in the management of negative, depressive,
and anxiety symptoms of schizophrenia.
On the other hand, a potential for severe psychiatric
complications, such as mania, in conjunction with the
use of DHEA or prasterone, a DHEA analogue, has
been described. In fact, the use of DHEA in those under
age 35 may be especially risky, as endogenous DHEA
concentrations peak at age 20–30 years (
This datum has been confirmed by another case report
(
studies in schizophrenic patients used the radioimmunoassay
technique only. In reality, the gas-chromatography/
mass-spectrometry (GC/MS) is the most sensitive,
specific and accurate method for neuroactive steroid
determination (
one of the potential explanations of conflicting results.
Here, to further clarify a possible correlation between
DHEA and schizophrenia, we measured DHEA plasma
levels by means of GC/MS method, and compared schizophrenic
patients with healthy controls matched for age
and gender.
Bellino et al., 1995), the relevance of this neuroactiveHoward,). In particular, improvement in psychosis appearedHoward,). These data are strengthened by more recent investigations,Oades and Schepker, 1994) and in patients withMaayan et al., 2000). On the otherOertel et al., 1974; Tourney and Hatfield,) have described low DHEA levels or abnormalTourney and Erb,). Interestingly, the discrimination between schizophrenicErb et al., 1981). Furthermore,Harris). Finally, Brophy et al. (1983) have foundAlias, 2000). In addition, a recent reportStrous et al., 2003) described a possible role for DHEADean, 2000).Vacheron-Trystram et al., 2002). Unfortunately, pastAlomary et al., 2001) and this could be2. Materials and methods
2.1. Subjects, diagnostic assessment and symptom profile
In this study we included 23 right-handed subjects
with a DSM-IV schizophrenia diagnosis, all of whom
had been consecutively referred to an outpatient psychiatric
clinic. All the females tested were postmenopausal
or in the mid-luteal phase. The clinicians were free to use
conventional or atypical neuroleptics, and benzodiazepines
to control for psychiatric symptoms. They were
free to use any dosage and were blind to the aims of
the study. For purposes of subsequent analysis, all neuroleptic
dosages were converted to estimated equivalent
dosages of olanzapine by use of a standard table (
et al., 2003
between 18 and 65 years, no major medical or neurological
illness, no previous or present additional psychiatric
disorders or substance abuse disorder. At the assessment
point, all patients had been receiving stable oral doses of
psychotropic drugs for at least one month and were
studied during the phase of clinical stabilization (i.e.,
they were analyzed during the residual period). All the
subjects gave written informed consent after a full explanation
of the procedure of the study.
A trained clinical psychiatrist diagnosed DSM-IV
schizophrenia by using the Structured Clinical Interview
for DSM-IV Patient edition (SCID-P) (
1995
A second trained psychiatrist assessed the patients
Oquendo). Additional inclusion criteria were: ageSpitzer et al.,).psychopathology by using the Positive and Negative
Syndrome Scale (PANSS), which is a 30-item, 7-points
rating instrument for assessing psychiatric symptoms
in schizophrenia (
three scales (positive, negative and general psychopathology)
and five symptom clusters (anergia, thought
disturbance, activation, paranoid/belligerence and
depression). PANSS ratings were performed on the
same day of the SCID-P interview and were based on direct
assessment of the patient during the interview and
reports by the entire clinical staff. The psychiatrists
who compiled the SCID-P and the PANSS were not
aware of the DHEA data.
A group of 23 subjects, matched with the schizophrenic
patients for age and gender, were included as
control subjects. The Structured Clinical Interview for
DSM-IV NonPatient edition (SCID-NP) (
Kay, 1991). PANSS scoring producesSpitzer268
F. di Michele et al. / Journal of Psychiatric Research 39 (2005) 267–273et al., 1995
suffered from any mental disorder at the moment of
the evaluation or in the past.
) was administered to controls and nobody2.2. Determination of plasma dehydroepiandrosterone
levels
Plasma samples were obtained 1 h before psychometric
assessment at 12:00 a.m. and were quantified for
DHEA by using a combined GC/MS analysis, that profiles
and quantifies with high accuracy very small
amounts (fmol) of steroidal compounds (
1995; Kim et al., 2000
approximately 5000 dpm of [1,2,6,7]-
(87.6 Ci/mmol) (Amersham) were added to the
plasma to monitor recovery. After extraction with
3
isooctane and 90% methanol and separation of
the recovered 90% methanol material by chromatography
on C18 Amprep reverse-phase cartridges (Amersham).
Seven pmol of progesterone was added to the
eluate containing DHEA as an internal standard. The
eluate was lyophilized and derivatized with heptafluorobutyric
acid anhydride. Derivatized steroids were analyzed
using a Finnigan Trace GC/MS equipped with a
capillary column (HP-35MS: length 30 m, i.d. 0.25
mm, film thickness 0.25
negative ion chemical ionization mode (NCI) and the
ion at
[
relative abundance of other ion fragments was almost
negligible. The retention time was 23.4 + 0.025. The
recovery of tritiated steroid ranged from 80% to 90%.
The detection limit for the steroids studied was approximately
10 fmol. The intra-assay variation was lower
than the inter-assay variation and the ratio of the variances
did not reach the level of significance at
Cheney et al.,). Briefly, after blood centrifugation,3H-progesterone· 2 ml of ethyl acetate, delipidation by partition betweenlm). They were assayed in them/z (ratio of fragment mass [m] to atomic numberz]) 444 was monitored for DHEA identification. Thep
detection above reported.
The person who measured the DHEA plasma levels
was not aware of the subjects
< 0.05. The sensitivity was determined by the limit of diagnosis.2.3. Statistical analysis
Comparisons with respect to categorical and continuous
variables between schizophrenics and controls were
made by using the
correlation coefficient was used to assess the relationships
between continuous variables. Fisher
was used to determine the significance of
correlations The level of significance was set at
v2 test and Students t test. Pearsonss r to z transformationp < 0.05.3. Results
In
of the schizophrenic patients and control subjects
are indicated.
Table 1 the sociodemographic and clinical characteristicsTable 1
Sociodemographic, clinical and DHEA variables of 23 outpatients with schizophrenia and 23 control subjects
Characteristics Schizophrenics (
n = 23) Controls (n = 23) t or v2 pMean ± SD Mean ± SD
Age (year) 37.3 ± 9.5 39.6 ± 9.0
Age of onset (year) 24.5 ± 7.0 – – –
Duration of illness (year) 12.8 ± 7.4 – – –
Olanzapine equivalents (mg/day) 19.4 ± 16.4 – – –
Diazepam equivalents (mg/day) 9.1 ± 10.8 – – –
DHEA plasma level (nmol/l) (total group) 90.9 ± 61.4 24.0 ± 17.9 5.018 <0.0001
Males (
Females (
PANSS positive 25.2 ± 5.8 – – –
PANSS negative 26.9 ± 9.9 – – –
PANSS general psychopathology 58.4 ± 15.9 – – –
PANSS anergia 12.9 ± 4.9 – – –
PANSS thought disturbance 13.3 ± 4.5 – – –
PANSS activation 11.7 ± 3.5 – – –
PANSS paranoid/Belligerence 11.2 ± 2.9 – – –
PANSS depression 13.4 ± 3.8 – – –
0.844 0.4035n = 13 for each group) 110.7 ± 62.0 29.8 ± 16.9 4.536 0.0001n = 10 for each group) 65.3 ± 52.8 16.5 ± 17.0 2.777 0.0124n
Gender (males) 13 (56.5) 13 (56.5) 0.000 >0.9999
DSM-IV subtypes
Paranoid 14 (61) –
Disorganized 3 (13) –
Undifferentiated 5 (22) –
Residual 1 (4) –
DSM, Diagnostic and Statistical Manual of Mental Disorders; DHEA, dehydroepiandrosterone; PANSS, Positive and Negative Syndrome Scale.
(%) n (%)F. di Michele et al. / Journal of Psychiatric Research 39 (2005) 267–273
269In
and plasma DHEA levels of each individual schizophrenic
patients are indicated.
As expected, age and gender did not differ between
schizophrenics and controls.
Student
difference between schizophrenic patients and
control subjects existed for DHEA plasma levels.
This statistically significant difference was also found
when we divided the groups of schizophrenics and
controls in subgroups of males and females (see
1
levels compared with controls independently from
the gender.
Table 2 the neuroleptic drugs and dosages useds t test revealed that a statistically significantFig.). Thus, schizophrenics had higher DHEA plasmaTable 2
Neuroleptic drugs and dosages used and plasma DHEA levels in 23 outpatients with schizophrenia
Patients Neuroleptic drugs Dosages (mg/die) Olanzapine equivalents (mg/die) Plasma DHEA levels (nmol/l)
1 Olanzapine 10 10 (total = 15) 174.97
Haloperidol 2 5
2 Haloperidol 12 30 120.21
3 Olanzapine 5 5 91.45
4 Clozapine 100 8.3 65.37
5 Risperidone 4 13.3 215.12
6 Clozapine 450 37.5 26.27
7 Risperidone 4 13.3 25.09
8 Haloperidol 25 62.5 43.24
9 Olanzapine 10 10 17.16
10 Olanzapine 10 10 (total = 15) 24.24
Haloperidol 2 5
11 Olanzapine 10 10 12.05
12 Olanzapine 10 10 75.28
13 Haloperidol 3 7.5 167.90
14 Haloperidol 6 15 (total = 23.3) 171.90
Fluphenazine 2.5 8.3
15 Risperidone 4 13.3 104.79
16 Risperidone 4 13.3 73.24
17 Haloperidol 6 15 58.92
18 Fluphenazine 3 10 70.39
19 Haloperidol 9 22.5 194.96
20 Thioridazine 100 5 84.75
21 Clozapine 200 16.7 82.82
22 Olanzapine 15 15 (total = 23.3) 152.30
Fluphenazine 2.5 8.3
23 Haloperidol 27 67.5 39.30
DHEA, dehydroepiandrosterone.
Fig. 1. Plasma dehydroepiandrosterone (DHEA) levels (mean ± SE) in male and female patients with schizophrenia and control subjects matched
for age and gender.
270
F. di Michele et al. / Journal of Psychiatric Research 39 (2005) 267–273Results of correlation analysis evidenced that there
was no relationship between DHEA plasma levels and
olanzapine equivalents (
entire group of schizophrenics. Also, when we divided
patients who were treated with typical neuroleptics only
(
only (
of typical and atypical neuroleptics (
levels did not correlate with olanzapine equivalents
in any of the three individual groups. Interestingly, a
strong negative correlation (
clozapine dosages and DHEA plasma levels in the group
of patients treated with clozapine only (
benzodiazepine dosages, a negative correlation which
approached statistical significance (
r = 0.160; p = 0.4699) in then = 9) from those who were treated with atypical neurolepticn = 12) and who were treated with a mixturen = 2), DHEA plasmar = 0.833) existed betweenn = 3). As forr = 0.409;p
DHEA plasma levels.
Results of the correlation analyses between DHEA
plasma levels and PANSS scores and subscores revealed
that there were negative relationships (Pearson
between
significant, between all symptom clusters here
measured, except depression, and DHEA plasma levels.
= 0.0521) existed between diazepam equivalents ands r ranged0.221 and 0.043), although non statistically4. Discussion
Our results have shown significantly higher DHEA
plasma levels in schizophrenic subjects compared with
healthy controls, both in males and females. This datum
is in line with those of recent studies performed in young
schizophrenic patients (
patients with severe psychosis (
patients with psychotic depression who are nonresponsive
to electroconvulsive treatment (
2000
performed between the late 1970s and the early 1980s
(
1972; Tourney and Erb, 1979
this discrepancy, we have used, for the first time in schizophrenia,
a very highly sensitive and specific GC/MS
technique. Therefore, we believe that our results may
add new relevant scientific information in this field.
Thus, it is conceivable that DHEA levels may serve as
a potential biological marker of psychosis.
One limitation of the study may be represented by
the neuroleptic and benzodiazepine treatment of the
schizophrenics included. Nevertheless, we found a
non significant negative correlation between DHEA
plasma levels and psychopharmacological treatment
dosages (i.e., olanzapine and diazepam equivalents),
indicating that treatment at most could reduce DHEA
concentrations. This suggests that untreated patients
may have even higher DHEA levels in comparison with
treated patients. Therefore, it would be possible to exclude
in our sample study that elevated DHEA plasma
levels may be the consequence of typical antipsychoticinduced
hyperprolactinemia stimulating the adrenal
cortex to secrete DHEA (
et al., 1977
study (
the atypical antipsychotic clozapine, but not haloperidol,
decreases rat brain DHEA and DHEAS levels.
To better understand the role of antipsychotics, we also
individually correlated dosages of the two different
treatments, that is typical and atypical antipsychotics,
with DHEA levels but no statistically significant relationship
was found. However, in accordance with
Oades and Schepker, 1994), inHoward, 1992) and inMaayan et al.,), while it is in contrast with results from studiesErb et al., 1981; Oertel et al., 1974; Tourney and Hatfield,). In order to clarifyOseko et al., 1986; Vermeulen). Interestingly, in a very recent preclinicalNechmad et al., 2003) it has been shown thatNechmad et al. (2003)
taking clozapine only, the dosages correlated negatively
with DHEA concentrations. Thus, to definitely exclude
any possible treatment interference, investigations on
drug-naive schizophrenic patients are certainly
required.
In our study, the elevation of DHEA concentrations
was higher in male patients than in females, resembling
the physiological trend, where DHEA concentrations
show sex differences, being lower in females than males
(
If elevated DHEA levels play some role in the pathophysiology
of psychosis is a key issue to be addressed.
The case report evidence (
et al., 2002
complications in conjunction with the use of DHEA
or prasterone, an analogue of DHEA, is in favor of this
hypothesis. Nevertheless, it is difficult to formulate a
pathophysiological model, considering that the molecular/
genetic mechanisms of DHEA have not yet been
established. Furthermore, it is not clear if all the effects
attributed to DHEA are mediated by DHEA or by its
metabolites.
It is known that the neurosteroids DHEA and
DHEAS, other than exerting genomic effects via the
androgen receptor (
their effects via non-classic steroid hormone receptors,
binding GABA
1984; Majewska et al., 1986; Puja et al., 1990
neurosecretion mediated by NMDA receptors,
via
1995
possibly acting as a glucocorticoid antagonist or reducing
intracellular calcium concentration after elevated
NMDA exposure (
the final effect of DHEA and DHEAS on neurotransmission
is controversial.
In fact, in primary cultures of mouse embryonic neocortical
neurons, DHEA rapidly increased free intracellular
calcium via activation of NMDA receptors, at
concentrations normally found in the brain (
and Mellon, 1998
(
with DHEA can accentuate the actions of glutamate
, we found that in three patientsBirkenhager-Gillesse et al., 1994).Dean, 2000; Vacheron-Trystram) of a potential for severe psychiatricLu et al., 2003), mediate some ofA receptors (Harrison and Simmonds,) and modulatingr-receptor (Bergeron et al., 1996; Monnet et al.,). Furthermore, DHEA has a neuroprotective effectKimonides et al., 1998). However,Compagnone). Electrophysiological evidenceBergeron et al., 1996) suggests that acute treatmentF. di Michele et al. / Journal of Psychiatric Research 39 (2005) 267–273
271potentiating the NMDA response selectively and dosedependently,
via
reversed by neuroleptics. On the other hand, longer term
treatment (6–8 h) of DHEA at 10–100 nM has proved
to prevent or reduce the neurotoxic actions in the hippocampus
of NMDA both in vitro and in vivo or -amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
and kainic acid in vitro (
it seems that DHEA is a neuromodulator with a
bimodal action on the NMDA receptors. Taken into
consideration the glutamatergic hypothesis of schizophrenia
(i.e., a deficit in activity at NMDA receptors
associated with psychotic states (
may interpret our data by inferring that high DHEA levels
found in schizophrenia might be responsible for a
chronic overstimulation of NMDA receptors, via
with a consequent down-regulation of the
NMDA receptors.
Furthermore, it is interesting to note that a possible
involvement of
densities in the limbic structures as well as in motorrelated
areas in the pathogenesis of schizophrenia has
been suggested (
et al., 1998
to create compounds with affinity for
without affinities for dopamine receptors having an antipsychotic
profile (
further strengthened the hypothesis that high DHEA
levels may have a pathophysiological role in schizophrenia.
We can exclude the opposite hypothesis that high
DHEA levels represent a mechanism to counteract the
reversing effect of neuroleptics on its NMDA receptors
modulation, via
a negative correlation between drug dosages and DHEA
plasma levels.
Also, it must be noted that DHEA possesses intrinsic
androgenic activity that is potentially independent of
metabolic conversion to other androgens, and that it
can affect gene function through the androgen receptor
(
reported excess sharing of alleles by male sibling pairs
with schizophrenia, at a triplet repeat marker within
the androgen receptor gene, indicating that mutations
at or near this gene may be a risk factor for males. This
provides support for the hypothesis that the androgen
receptor may be one of the factors contributing to the
development of schizophrenia.
Although, it is difficult to draw final conclusions, due
to the complexity of the mechanisms of action of DHEA
in the brain, which certainly imply a ‘‘cross-talk’’ cellular
signaling system that involves both nongenomic and
genomic components, our findings underlie a possible
role for DHEA in the regulation of neural transmission
and a possible involvement in the pathophysiology of
schizophrenia. Therefore, further extended studies are
required to better understand the real meaning of neuroactive
steroids in psychosis and for new potential therapeutic
approaches in this field.
r-receptor. Interestingly, this effect isKimonides et al., 1998). Therefore,Millan, 2000)), werreceptor,r-receptors, which is present in highDebonnel and de Montigny, 1996; Ishiguro). Indeed, many efforts have been spentr-receptors andTakahashi et al., 1999). It is, therefore,r-receptors. This is because we foundLu et al., 2003). Interestingly, Crow et al. (1993) haveReferences
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