|Year : 2012 | Volume
| Issue : 3 | Page : 181-185
Dehydroepiandrosterone sulfate and testosterone levels correlate with negative symptoms in male patients with schizophrenia
Haitham M. Hashim, Mohmed G. Negm
Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig, Egypt
|Date of Submission||30-Jan-2012|
|Date of Acceptance||15-Apr-2012|
|Date of Web Publication||4-Jun-2014|
Haitham M. Hashim
Department of Psychiatry, Faculty of Medicine, Zagazig University, Zagazig
Source of Support: None, Conflict of Interest: None
Clinical studies have shown greater sex differences in symptoms of schizophrenia, with men having more negative symptoms than women, which may be related to the action of the reproductive hormones.
The aim of this study was to determine the relationship between negative symptoms and the plasma levels of testosterone and dehydroepiandrosterone sulfate (DHEAS) in male patients with schizophrenia.
Participants and methods
The participants were 50 male patients with chronic schizophrenia. The psychopathology of the patients was assessed using the Positive and Negative Syndrome Scale (PANSS). The Calgary Depression Scale for Schizophrenia (CDSS) and the Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) were also used to exclude the effects of depression or drug-induced extrapyramidal symptoms.
The PANSS negative scores showed a significant inverse correlation with the serum testosterone levels without a correlation with serum DHEAS.
This study indicates that testosterone but not DHEAS may play an important role in the severity of negative symptoms in male patients with schizophrenia.
Keywords: dehydroepiandrosterone sulfate, negative symptoms, schizophrenia, testosterone
|How to cite this article:|
Hashim HM, Negm MG. Dehydroepiandrosterone sulfate and testosterone levels correlate with negative symptoms in male patients with schizophrenia. Egypt J Psychiatr 2012;33:181-5
|How to cite this URL:|
Hashim HM, Negm MG. Dehydroepiandrosterone sulfate and testosterone levels correlate with negative symptoms in male patients with schizophrenia. Egypt J Psychiatr [serial online] 2012 [cited 2021 Feb 24];33:181-5. Available from: http://new.ejpsy.eg.net/text.asp?2012/33/3/181/133913
| Introduction|| |
The diagnosis of schizophrenia is currently made using criterion-based systems, including positive (e.g. hallucinations and delusions) and negative (e.g. a volition and alogia) symptoms (Shirayama et al., 2002).
The correlation between negative symptoms and loss of social function among schizophrenics has been increasingly recognized. The diagnosis of schizophrenia has therefore shifted toward the presence of negative symptoms (Akhondzadeh et al., 2006).
Sex differences have been reported in schizophrenia and involve various aspects of the disease. The existence of sex differences in these areas strongly suggests a vital role played by gonadal hormones; the observations of an association between age of onset and reproductive age led some researchers to suggest an important pathogenic role of both estrogen and testosterone, and their interactions with neurotransmitters’ system in specific brain regions (Goldstein, 1988; Goldstein and Tsuang, 1990).
Dehydroepiandrosterone (DHEA) and its sulfate conjugate (DHEAS) are neurosteroids that mediate several neurotransmitter systems coupled to ion channels, such as γ-aminobutyric acid (GABAA), N-methyl-D-aspartate (NMDA), and sigma receptors (Wen et al., 2001).
DHEA metabolism has been reviewed recently; briefly, DHEA sulfotransferase catalyzes the transformation of DHEA into DHEAS (Falany et al., 1995). Androstenedione is synthesized from DHEA by 3h-hydroxysteroid dehydrogenase/D5–D4 isomerase and from progesterone through 17-OH-progesterone by 17a-hydroxylase and 17,20-lyase (Rupprecht, 2003). The conversion of androstenedione into testosterone is catalyzed by 17h-hydroxysteroid dehydrogenase (King et al., 1999). Previous studies investigating DHEA blood levels in concentrations in psychosis or schizophrenia have reported either low (Harris et al., 2001), elevated (Di Michele et al., 2005), or no differences in DHEA levels (Ritsner et al., 2004) compared with matched healthy controls. In addition, they have unaltered (Mason et al., 1988; Markianos et al., 1999) or significantly lower serum testosterone levels, especially among patients treated with high-dose first-generation antipsychotic agents (Rinieris et al., 1989; Kaneda and Fujii, 2000; Kaneda, 2003), and in male schizophrenia patients before and during treatment, but not after recovery (Taherianfard and Shariaty, 2004). The inconsistencies in the findings published may be because of the wide clinical variability, small sample sizes, or differences in the age and duration of illness of patients (Cleare et al., 2004). The majority of studies do not report repeat data on serum DHEA and their key metabolites in patients compared with healthy controls over time controlling for confounding factors.
Although there exist a few studies on the relationship between the plasma levels of testosterone and negative symptoms in patients with schizophrenia, the exact role of reproductive hormones in the pathophysiology of the schizophrenia is still emerging (Seeman, 1996; Shirayama et al., 2002; Akhondzadeh et al., 2003; Goyal et al., 2004).
The goals of this study were to determine whether alterations in serum DHEAS and testosterone occur in treated chronic schizophrenia patients compared with healthy controls and to evaluate the relationship between the plasma level of testosterone and DHEAS and the severity of negative symptoms in patients with chronic schizophrenia.
| Participants and methods|| |
Two groups of patients were invited to participate in the study.
A total of 50 patients were recruited from among consecutive attenders of the psychiatric inpatient department and outpatient clinics of Zagazig University Hospitals from April 2010 to March 2011, with a diagnosis of schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV).
All patients had chronic schizophrenia, defined as having symptoms of schizophrenia for at least 2 years before recruitment.
Their psychiatric symptoms were stable before the examination, and their doses of antipsychotic medications and other concomitant psychotropic medications such as benzodiazepines, antiparkinsonian agents, mood stabilizers, and/or hypnotics were fixed for at least 2 weeks before participation in this study.
The patients were considered symptomatically stable if there had been no appreciable change in their psychotic symptoms during the 4 weeks before participation in this study, irrespective of the severity of their symptoms.
They had no abnormal medical findings as evidenced by assessment of medical histories and physical examinations and no other chronic medical illness, substance abuse (including anabolic steroids), or substance dependence in the past year.
Patients with a BMI less than 20 kg/m2 or more than 30 kg/m2, those with drug-induced extrapyramidal symptoms, and depressed patients were excluded.
An equal number of apparently healthy men, matching the recruited patients as much as possible in terms of age, and with no history of treatment for any neuropsychiatric disorder were recruited.
An informed consent was obtained from all the participants after the procedures had been fully explained. The study was approved by the ethical committee of the institution.
Clinical assessment: semistructured interview
Participants were subjected to a semistructured psychiatric interview, using a specially designed interview derived from the Psychiatric Department sheet of Zagazig University.
The semistructured interview included a full psychiatric sheet, which allowed each patient to receive a psychiatric diagnosis at the end of the interview, during which the DSM-IV-TR (American Psychiatric Association, 2000) diagnosis of a schizophrenia disorder was confirmed.
The following scales were administered:
Positive and Negative Syndrome Scales (PANSS) (Kay et al., 1987): This is a 30-item, psychopathology rating scale, based on a semistructured clinical interview. The scale was designed to measure positive and negative schizophrenic symptoms, and related variables such as cognitive, affective, and social functioning. It has been evaluated rigorously from a psychometric perspective and has been used widely in several clinical studies. The scale yields five scores: a positive symptom score, a negative symptom score, a general psychopathology score, a total score, and a composite score.
The Calgary Depression scale for Schizophrenia (Addington et al., 1990): The Calgary Depression scale for Schizophrenia (CALG) is used to assess the mood state of schizophrenic patients. The patients were asked about (a) depression (his mood over the last 2 weeks), (b) hopelessness (how do you see the future), (c) self-depreciation, (d) guilty ideas of reference, (e) pathological guilt, (f) morning depression, (g) early awakening, (h) suicide, and (i) observed depression (on the basis of interviewers’ observations). These items were described according to the severity (absent, mild, moderate, and severe).
The Drug-induced Extrapyramidal Symptoms Scale (DIEPSS) (Inada, 1996): The DIEPSS, which consists of eight individual items and one global item, was used to assess treatment-emergent extrapyramidal symptoms.
The eight individual items include (1) gait, (2) bradykinesia, (3) sialorrhea (increased salivation), (4) muscle rigidity, (5) tremor, (6) akathisia, (7) dystonia, and (8) dyskinesia. The global item is overall severity. Extrapyramidal syndromes, as measured by the DIEPSS, were grouped into four categories: (a) parkinsonism, (b) akathisia, (c) dystonia, and (d) dyskinesia.
The parkinsonism syndrome consisted of DIEPSS items 1–5. The akathisia, dystonia, and dyskinesia syndromes consisted of DIEPSS items 6, 7, and 8, respectively. The severity of each item was rated from 0 (normal) to 4 (severe).
The patients filled in a questionnaire consisting of nine comprehensive questions aimed to detect typical symptoms of parkinsonism including akathisia, dystonia, and dyskinesia.
Body mass index
BMI a statistical measure of the weight of an individual scaled according to height, sometimes referred to as body weight index. It is defined as the individual’s body weight divided by the square of their height.
Patients with a BMI below 18.5 kg/m2 were categorized as underweight, 18.5–24.9 kg/m2 were categorized as normal, 25.0–29.9 kg/m2 were categorized as overweight, and at least 30 kg/m2 were categorized as obese according to the WHO classification.
Ten milliliters of blood sample was collected in a tube to determine the levels of total testosterone and DHEAS. Blood samples for the hormone estimation were collected from 8:00 to 9:00 a.m. The sera were prepared and stored at −20πC until the time of analysis. Testosterone and DHEAS were assayed by a radioimmunoassay.
Data were statistically described in terms of mean±SD, frequencies (number of cases), and percentages when appropriate. A comparison of the quantitative variables between the study groups was performed using the Student t-test for independent samples. For comparison of categorical data, the χ2-test was carried out. The exact test was used when the expected frequency was less than 5. The correlation between various variables was determined using the Pearson moment correlation equation for a linear relation in normally distributed variables and the Spearman rank correlation equation for non-normal variables. P values less than 0.05 were considered statistically significant. All statistical calculations were carried out using computer programs Microsoft Excel 2007 (Microsoft Corporation, New York, USA) and statistical package for the social science (SPSS Inc., Chicago, Illinois, USA) version 15 for Microsoft Windows.
| Results|| |
The sociodemographic and clinical characteristics of the patients and the control group are presented in [Table 1]. Because of the selection procedures, the patients and the controls were comparable in terms of age, BMI, and education. [Table 1] also shows that there was a statistically significant difference between the group of patients and the control individuals in the level of serum testosterone hormone, but there were no statistically significant differences in the DHEAS level. [Table 1] indicates that the mean age at onset of the disease was 19.4±3.4 years (range between 15 and 28 years) and the duration of illness was 9.3±61 years (range between 2 and 23 years); the mean values of the PANSS score were as follows: total 84.8±12.6, positive 20.6±4.7, negative 22.1±4.5, and psychopathology 41.8±7.3.
|Table 1: Sociodemographic and clinical characteristics of the patients and the control group|
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[Table 2] shows that there was no statistically significant difference between the serum testosterone level and the age of the patients, age at onset, BMI, and duration of illness, but there was a statistically significant difference in the PANSS score. The PANSS negative scores showed a significant inverse correlation with the serum testosterone level (r=−0.481, P<0.001) and there was no significance difference between the DHEAS level and the age of the patients, age at onset, BMI, duration of illness, and the PANSS negative score.
|Table 2: Correlation between serum testosterone, dehydroepiandrosterone sulfate, and other parameters|
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[Table 3] shows the correlation between serum testosterone and the DHEAS level and the severity of negative symptoms, and indicates that there was a highly significant negative correlation between the severity of different negative symptoms and serum testosterone level as, when testosterone decreases, the severity of negative symptoms increases, but there was no correlation between negative symptoms and the serum level of DHEAS.
|Table 3: Correlation between serum testosterone and dehydroepiandrosterone sulfate level and the severity of negative symptoms|
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| Discussion|| |
The results of this study indicate that in medicated male patients with chronic schizophrenia, compared with healthy controls, the serum concentration of testosterone was found to be increased, but the DHEAS level was normal, and that the serum total testosterone level is inversely correlated with negative symptoms. Moreover, there was no any correlation between testosterone and DHEAS or between DHEAS and the clinical characteristics of the patients. Decreased serum testosterone levels among our patients have also been reported by Ko et al., 2007, who found strongly decreased serum testosterone levels in a group of 35 male inpatients with schizophrenia, and the serum testosterone level was inversely correlated with negative symptoms in male patients with chronic schizophrenia. These findings suggest that lower total and free testosterone levels may reflect more severe negative symptoms in male patients with schizophrenia.
Our results are also supported by the finding reported by Akhondzadeh et al. (2006). The results of this study are in agreement with previous studies reporting the relationship between gonadal hormones and negative symptoms in male patients with chronic schizophrenia (Shirayama et al., 2002; Goyal et al., 2004).
With respect to DHEAS (sulfate conjugate of DHEA), some studies have reported low DHEA levels in schizophrenic patients compared with healthy controls (Harris et al., 2001); however, other studies have not reported any differences between patients with schizophrenia and normal controls (Brophy et al., 1983; Ritsner et al., 2004, 2006). Another study reported higher DHEAS levels in young male patients with schizophrenia (Oades and Schepker, 1994) and higher DHEAS levels in first-episode schizophrenia patients (Strous et al., 2004). Plasma levels of DHEA were found to be strongly elevated in a group of schizophrenic patients compared with that of control individuals as reported by Di Michele et al. (2005).
However, Goyal et al. (2004) reported that both serum testosterone and DHEAS levels were lower in a patient group with predominantly negative symptoms than in a patient group with predominantly positive symptoms.
Previous studies investigating DHEA and testosterone blood levels in psychosis or schizophrenia have reported either low DHEA (Harris et al., 2001), elevated DHEA (Di Michele et al., 2005), or no differences in DHEA levels (Ritsner et al., 2004) compared with matched healthy controls. DHEAS levels have been reported to be elevated (Strous et al., 2004) or in the control range (Ritsner et al., 2004).
In addition, unaltered (Markianos et al., 1999) or significantly lower serum testosterone levels have been reported (Kaneda, 2003). The inconsistencies in published findings may be because of the wide clinical variability, small sample sizes, or differences in the age and duration of illness of patients (Cleare et al., 2004). The majority of studies have not reported repeat data on serum DHEA and their key metabolites in patients compared with healthy controls.
Many factors affect serum androgen levels as serum testosterone levels decrease with age, starting from the fifth decade of life (Gray et al., 1991). Maximal values of circulating DHEAS are attained between the ages of 20 and 30 years (Orentreich et al., 1984); the serum testosterone level has a diurnal variation, with the highest values at 8:00 a.m. and the lowest values in the late afternoon (Bremner et al., 1983); adiposity, as assessed by the BMI, is a negative determinant of serum testosterone levels (Zumoff et al., 1990).
Therefore, to reduce the effects of these factors on androgen levels, we recruited young male schizophrenic patients aged between 20 and 39 years, taking blood samples between 8:00 and 9:00 a.m., and excluded patients who were obese, that is, those with a BMI of over 30 kg/m2 in this study.
Previous studies have reported controversial results on the relationship between serum testosterone level and negative symptoms in male schizophrenia patients.
However, these previous studies provide possible explanations for the role of testosterone in the negative symptoms of schizophrenia through its effects on receptors of gonadal hormones that are concentrated in hypothalamic and limbic systems involved in perception, cognition, and behavior (Stevens, 2002).
Testosterone modulates the action of various neurotransmitters and neuropeptides (Białek et al., 2004) and through the neuroprotective or neurotrophic actions of testosterone on motor and autonomic neurons (Białek et al., 2004).
This study had some limitations. First, we did not measure other related hormone levels, including the gonadotropin-releasing hormone, luteinizing hormone, adrenocorticotropic hormone, prolactin, cortisol, and estradiol, and thus we did not identify their associations with testosterone and DHEAS levels. Second, the number of participants in this study was small; therefore, a larger sample size is recommended for further studies.
Finally, all patients included in our study received antipsychotic drugs; therefore, it is recommended that in further studies, patients who are not under any treatment be studied in order to exclude the effect of those drugs on the level of serum hormones.
However, this study indicates that testosterone but not DHEAS may play an important role in the severity of negative symptoms in male patients with schizophrenia.
| Conclusion|| |
There is a need to determine the serum total testosterone hormone level in male schizophrenia patients with predominantly negative symptoms as it may reflect an associative relationship of testosterone with the severity of negative symptoms in male schizophrenic patients.
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[Table 1], [Table 2], [Table 3]
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