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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 2  |  Page : 92-96

Testosterone and schizophrenia: A clinical review


1 Clinical Psychologist, Desousa Foundation and Minds Foundation, Mumbai, Maharashtra, India
2 Department of Psychiatry, Lokmanya Tilak Municipal Medical College, Mumbai, Maharashtra, India

Date of Submission02-Sep-2019
Date of Decision03-Oct-2019
Date of Acceptance14-Oct-2019
Date of Web Publication18-Dec-2019

Correspondence Address:
Dr. Sagar Karia
Department of Psychiatry, 2nd Floor, New OPD Building, Lokmanya Tilak Municipal Medical College and GH, Sion, Mumbai - 400 022, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aip.aip_54_19

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  Abstract 


The relationship between testosterone and psychiatric disorders has been a long-standing one. The sex difference in schizophrenia has triggered to better understand the role that testosterone plays in the unfolding and clinical presentation of this psychotic disorder. DHEA and testosterone are found to influence dopaminergic, glutamatergic and GABAergic neurotransmission systems that are believed to play a role in the pathophysiology of schizophrenia. The onset of schizophrenia in males, most frequently encountered during adolescence, is also characterized by an increase in testosterone levels. Some studies have also observed lower testosterone levels in adult males with schizophrenia (or psychosis) compared to healthy controls.

Keywords: Psychosis, schizophrenia, testosterone


How to cite this article:
Lodha P, Karia S. Testosterone and schizophrenia: A clinical review. Ann Indian Psychiatry 2019;3:92-6

How to cite this URL:
Lodha P, Karia S. Testosterone and schizophrenia: A clinical review. Ann Indian Psychiatry [serial online] 2019 [cited 2020 Feb 28];3:92-6. Available from: http://www.anip.co.in/text.asp?2019/3/2/92/273382




  Introduction Top


Schizophrenia is a neurodevelopmental disorder affecting approximately 1% of the population. Beginning in adolescence, schizophrenia typically causes a dramatic, lifelong impairment in social and occupational functioning. It is characterized by negative symptoms such as impaired motivation, drop in spontaneous speech, and social withdrawal; positive symptoms such as delusions and hallucinations; and cognitive symptoms such as disturbance in speech, attention, and thought, eventually impairing the person's capability to communicate with others. Hormones have an effect on physiology, emotions, cognition, and behavior, without the necessity for conscious input or control.[1]

The relationship between testosterone and psychiatric disorders has been a long-standing one.[2],[3] Epidemiologically, it is a well-documented fact that schizophrenia has an earlier onset among males than females. However, the biological mechanism has not been studied adequately to understand it clearly. Indeed, there are studies showing earlier age of schizophrenia onset, worse premorbid functioning and less favorable long-term outcomes, higher rates of treatment resistance, and more frequent subtle neurodevelopmental brain abnormalities in male patients.[4] The sex difference in schizophrenia has triggered to better understand the role that testosterone plays in the unfolding and clinical presentation of this psychotic disorder. Dehydroepiandrosterone (DHEA) and its metabolite (DHEA sulfate [DHEA-S]) are adrenal steroid precursors in the synthesis of testosterone. DHEA and testosterone are found to influence dopaminergic, glutamatergic, and GABAergic neurotransmission systems that are believed to play a role in the pathophysiology of schizophrenia.[5] Overall, all the three neuroactive steroids – DHEA, DHEA-S, and testosterone – are found to have some implications in schizophrenia. [Figure 1] shows pathways of testosterone action.
Figure 1: Depicting pathways of testosterone action

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  Testosterone and Schizophrenia Top


The possibility of a link between schizophrenia and gonadal activity is not new. It was pioneeringly found by Kraepelin in 1881.[6],[7] The following period from 1910 to 1930 saw various reports reflecting the conviction that various endocrine systems played an important role in the pathogenesis of schizophrenia.

Later, it was Reiss et al who cited the more intriguing observations telling us about the long-recognized relationship between onset of puberty and onset of schizophrenia,[8] relationships between the menstrual cycle and psychotic symptoms in women, the association of androgen administration, certain androgen-secreting tumors, and high urinary 17-ketosteroid excretion with paranoid symptoms,[8] and the occurrence of a hypogonadal syndrome in some male schizophrenic patients.

Schizophrenia has a slightly higher prevalence in men, with about three of five men getting affected.[9] In men with schizophrenia, symptoms tend to be more pronounced and less treatment responsive. It is also a recurring epidemiological incidence to find that men experience earlier onset of the illness as compared to women.

The onset of schizophrenia in males, most frequently encountered during adolescence, is also characterized by an increase in testosterone levels.[10] However, males expressing prodromal symptoms have been found to show lower testosterone levels than healthy males.[11] Some studies have also observed lower testosterone levels in adult males with schizophrenia (or psychosis) compared to healthy controls.[12] Women with schizophrenia tend to experience less severe psychotic symptoms during periods of high estrogen release such as during pregnancy and experience symptom exacerbation during times of low estrogen such as during postpartum and menopause.[13] Men with schizophrenia display increases in negative symptom severity with lower testosterone levels.[14] Furthermore, studies have shown that exogenous testosterone supplementation may reduce negative symptoms in men with schizophrenia [15] and that exogenous estrogen supplementation is associated with a reduction in psychotic symptoms in women with schizophrenia and possibly in men.[16]


  Testosterone And first-Episode Psychosis Top


Only one study summarized that in individuals with a first-episode psychosis (FEP), baseline DHEA and DHEA-S levels were significantly higher in schizophrenia patients than in controls.

These findings invoke interest to study the association between aggression and testosterone levels. It has been speculated that a neurosteroid response to the first onset of psychosis may develop which may be associated with a reduction in various adverse clinical features including aggression. Such a putative mechanism may become desensitized with the onset of chronic illness. This idea corresponds to a certain degree to our results and again stresses the importance of the first psychotic episode and the period after it when the positive symptoms are reduced.[17]

Previous studies that have evaluated the relationship between the serum levels of testosterone and schizophrenia have not shown consistent results.[15],[18],[19] However, with respect to the psychopathology of schizophrenia, limited recent studies have shown that there might be a consistent relationship between the serum levels of androgen, especially the level of testosterone, and negative symptoms in male patients with schizophrenia.[2],[16] However, some authors have suggested that drug-induced extrapyramidal symptoms and depressive symptoms occurring in the course of this illness may confound the negative symptoms. Therefore, because these symptoms may be shared or combined, clinicians and researchers have had difficulty differentiating between them because of overlapping clinical criteria.


  Testosterone and Schizophrenia Symptomatology Top


It is well known that serotonin receptor modulation is suggested to alleviate negative and cognitive symptoms,[20] whereas dopamine receptor dysregulation is associated with positive symptoms in schizophrenia.[21] Glutamatergic activity has been linked to positive, negative, and cognitive symptoms.[22] One of the developmental perspectives suggests that the greater deterioration of serotonin and dopamine receptors among males is a neurodevelopmental risk factor for schizophrenia such as prenatal/neonatal genotypic or environmental insults, or abnormal synaptic pruning in the brain during adolescence, resulting in earlier onset of illness, more brain abnormalities and chronicity, and poorer neurocognitive and psychosocial functioning,[23] whereas the social perspective hypothesizes the earlier onset of schizophrenia among males, at a critical period where social and cognitive skills develop.

Several researchers have outlined a negative relationship between the serum testosterone levels and the severity of negative symptoms and cognitive deficits in patients with schizophrenia,[2],[24] suggesting that lower levels of testosterone may severe the negative symptoms and cognitive deficits. However, of the evidence available, correlations are much more evident in males with dominant-negative (versus positive) symptoms.[2],[16]

It has been found that lower levels of testosterone is correlated with negative symptoms in patients with schizophrenia, thereby leaving ground for hypothesizing the possible effects of testosterone treatment in outcomes of schizophrenia. However, double-blind, placebo-controlled, randomized clinical trials conducted to understand the possible success of testosterone and DHEA failed to produce treatment outcomes for schizophrenia. Success was reported only in one study that studied the efficacy of testosterone as an augmentation strategy in terms of improving negative symptoms.[15] Studies measuring the levels of testosterone, DHEA, and DHEA-S have provided mixed findings, and thus, it is difficult to generalize their results and personalize add-on treatments. Overall, low testosterone therapy (or testosterone replacement therapy [TRT]) though has shown to report euphoric sensation, higher confidence, and energy, the effects have reported to wear off within 2 weeks. Many patients who have taken TRT have also reported symptoms such as irritability, aggression, impulsivity, criticism toward others, self-centeredness, depression, and personality changes. Thus, TRT does not stand as a promising intervention and calls for greater research to understand longitudinal ramifications and possibilities with the treatment.[25]

The theory proposing the protective role of estrogen and progesterone along with the role of testosterone and its precursors (DHEA and DHEA-S) has received great amount of attention, especially in relation to understanding the course and severity of schizophrenia. It has been proposed that estrogen may provide some degree of protection for females from risk for schizophrenia, resulting in less severe psychopathology and dysfunction and better outcomes,[26] whereas low levels of testosterone have been linked to negative symptoms in males. However, these findings remain inconclusive.

Research on testosterone and its role in schizophrenia has studied the role of free testosterone (total testosterone), DHEA levels, and DHEA-S levels in either prodromal phase of schizophrenia, FEP, or stable multiepisode schizophrenia (sMES). According to a systematic review,[4] 34 studies (1742 patients with schizophrenia and 1604 controls), females with sSME showed higher levels of total testosterone, whereas males with sSME showed lower levels of total testosterone. One of the plausible explanations is provided with the reason of antipsychotic-induced hyperprolactinemia which has adverse effects on males. DHEA-S levels were found to be higher in FEP and controls. Total testosterone and DHEA-S were found to be in FEP and acute relapse.

With testosterone, there is equivalent evidence for lower levels [27] or no differences [16],[28] for adult male patients versus controls. However, in the same single study with high-risk youth described above, lower levels of testosterone were found in adolescent males with prodromal symptoms compared to controls.[29] Testosterone levels in female patients have been less evaluated, but there are reports of higher levels compared to controls.[26]

Testosterone assists the regulation of hippocampal neuroplasticity, enhancement of neurotrophin expression, neurogenesis, neuroregeneration, and protection against apoptosis and beta-amyloid toxicity. However, it offers minimal protection against glutamate-induced neurotoxicity [30] and does not protect against dopamine depletion induced by several neurotoxins. This lower degree of neuroprotective effects (which has been found to be lesser compared to estrogen) may explain the more prominent neuroanatomical abnormalities and severer illness and dysfunction observed in male patients with schizophrenia.[31] DHEA-S has also shown to provide better neuroprotective role than testosterone.


  Role of Dehydroepiandrosterone in Schizophrenia Top


DHEA is the most abundant steroid hormone in the human body. Nonetheless, its physiological significance, mechanisms of action, and possible roles in human disease are not well understood.[32] Large-scale enthusiasm for DHEA as a potential neuropsychiatric therapy in schizophrenia started in the late 1980s through the mid-1990s, and preclinical data with few controlled clinical trials renewed hopes for therapeutic potential in schizophrenia.[33]

Correlational studies have suggested a relationship between endogenous concentrations of DHEA and depression, anxiety spectrum disorders, posttraumatic stress disorder, schizophrenia, and dementia. DHEA concentrations often decrease nonspecifically with chronic illness, and this may confound studies examining differences in DHEA concentrations in clinical populations, since the lowered hormone concentrations may reflect chronic medical illness, rather than having diagnostic specificity or direct pathophysiologic significance.[34]

Schizophrenia is linked to alterations in DHEA in many studies but with findings in both directions, i.e., elevations and abnormally low concentrations. In a small study comparing 13 acutely exacerbated patients with paranoid schizophrenia with matched controls, the schizophrenic group had lower serum DHEA and higher serum DHEA-S concentrations, although these differences were not statistically significant.[35]

Several recent studies have found elevated plasma and serum DHEA concentrations in medicated patients with schizophrenia.[17] In a study of first-episode unmedicated patients with schizophrenia, schizophrenia patients had higher serum concentrations of both DHEA compared to matched controls.[36] It was postulated that in the first episode of schizophrenic psychosis, increased DHEA concentrations serve as a protective or compensatory factor and that DHEA concentrations diminish later in the course of chronic illness.[37] In a study that examined tissue concentrations of DHEA in postmortem brain specimens, patients with schizophrenia had higher concentrations of DHEA in the posterior cingulate and parietal cortex compared to matched controls.[38]

Schizophrenia is a heterogeneous disease with multiple symptom profiles and comorbidities. Correlations were found between lower serum DHEA concentrations and the presence of negative symptoms, greater duration of illness and age of onset of illness, length of hospitalization and severity of illness, cognitive impairment, depression, anger and hostility, and anxiety.[39],[40],[41],[42],[43]


  Neuroimaging and Insights in Testosterone and Its Role in Schizophrenia Top


Functional imaging studies provide evidence that circulating testosterone levels influence neural processing in schizophrenia which has differential effects that depend on both task demands and brain region activated. Impaired social functioning in patients with schizophrenia may be related to brain hypoactivation in response to facial emotion processing in frontal and limbic systems.[44] It has been reported that inferior frontal gyrus activity was positively correlated to peripheral testosterone levels in men with schizophrenia during a facial emotion identification task.[45] Conversely, we also reported that circulating testosterone levels were inversely related to brain activation in the middle frontal gyrus and left insula during an emotional response inhibition task in men with schizophrenia.[46] There has been a hypothesis that optimal levels of testosterone are needed to benefit neural processing in cognitive and affective circuitry in men with schizophrenia. Furthermore, abnormal activity in frontal-striatal circuits during reward processing is considered to underlie the negative symptoms of schizophrenia.[47] Collectively, these studies implicate testosterone in the modulation of the neural substrates of symptoms and cognition in men with schizophrenia.


  Testosterone and Schizophrenia – major Indian Studies Top


In a pilot study in ten adult male patients with schizophrenia, five with predominantly positive symptoms (Group I) and five with predominantly negative symptoms (Group II) were compared to ten healthy matched controls. No significant differences in serum levels of testosterone, DHEA-S, estradiol, and cortisol were found between patients as a whole and controls, using radioimmunoassay. Testosterone and DHEA-S levels were lower in Group II patients than in Group I.[48]

Indian researchers have been part of the most comprehensive Cochrane review on testosterone and schizophrenia done way back in 2007.[49] In a study on patients with FEP, serum testosterone levels were correlated with suicidality, and it was seen that baseline mean serum testosterone levels did not differ between pre- and posttreatment levels. Both levels were lower than normal limits set by the laboratory (18–144 mmol/ml). On assessment, changes in testosterone levels showed a positive correlation with baseline scores on the positive symptom subscale of the positive and negative syndrome scale (PANSS). Suicidality scores failed to show a relation to changes in testosterone levels.

Testosterone levels in patients with first-episode schizophrenia in the early phase may be lower than normal limits and may remain low even after 6 months of treatment with antipsychotics. Positive symptoms were found to be significantly associated with change in pre- and posttreatment levels of testosterone.[50]


  Future Research Needs Top


Where there are research findings that show evidence for high and low levels of testosterone in patients with schizophrenia and reports of higher levels and no difference of testosterone between patients and healthy controls, it does leave a scope for further research to find the definite role of testosterone levels in schizophrenia. Various studies done on testosterone and schizophrenia delineate the repercussions on worsening negative symptoms and cognitive deficits in males, as opposed to females and healthy controls (however, most findings have been inconclusive). Although testosterone therapy has not been applauded much except for finding success in one study (Ko et al., 2008), estrogen therapy has also been considered. A study by Weickert et al. (2017) showed improvements in cognitive symptoms of patients with schizophrenia when they were put on an adjunctive raloxifene treatment (as compared to those on placebo). Steroid 5-alpha reductase has also found to be a putative therapeutic agent for schizophrenia (Paba et al., 2011). This is suggestive of the potential in understanding the role of testosterone antagonists such as finasteride and estrogen agonists such as raloxifene to bring about better treatment outcomes in schizophrenia. Testosterone and estrogen, thus, have the potential to serve as the future era of biomarker-driven precision medicine in schizophrenia treatment outcomes. Another theory that can be questioned supposedly is the noted surge of testosterone during the 7th month of pregnancy, where the fetus is suddenly surged with the testosterone. It demands a clarification whether the lower levels of testosterone in the prenatal condition can serve as an additional risk factor for the increased vulnerability to schizophrenia in the adolescent stage of the males.[32] So far, either the prodromal or FEP phase of the illness has been studied to understand the links between sex hormones and schizophrenia. There is a need for longitudinal studies to document the effects of testosterone (and estrogen) from the prodromal phase to schizophrenia in remission among males and females to understand and study the various other factors that can affect the course of illness in an individual.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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