Häfner H, an der Heiden W, Behrens S, Gattaz WF, Hambrecht M, Löffler W et al. Causes and consequences of the gender difference in age at onset of schizophrenia. Schizophr Bull 24: 99-113

Schizophrenia Research Unit, Central Institute of Mental Health, Mannheim, Germany.
Schizophrenia Bulletin (Impact Factor: 8.45). 01/1998; 24(1):99-113. DOI: 10.1093/oxfordjournals.schbul.a033317
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The ABC (age, beginning, course) schizophrenia study was commenced in 1987 to generate and test hypotheses about pathogenic aspects of schizophrenia. One of the main branches of the study focused on how gender influences the age distribution of onset, symptomatology, illness behavior, and early course in schizophrenia. Proceeding from one of the rare, strikingly deviating, consistent findings--the gender difference in age at first admission--we launched a systematic search for explanations by generating and testing hypotheses in a series of substudies. We moved from the epidemiological to the neurobiological and finally to the clinical level. The present article is an attempt to provide a brief overview of the individual stages of the ABC study and the different levels of investigation involved in formulating and testing the estrogen hypothesis in animal experiments and in demonstrating its applicability to human schizophrenia. From these results, three hypotheses were formulated and tested on data from an ABC study sample of 232 first-episode cases of schizophrenia. The analyses described here represent the latest stages of the ABC study.

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    • "Abnormal brain development at adolescence may play an important role in the emergence of psychopathology. Adolescence is a critical period for manifestation of mental illness, in particular schizophrenia, but also bipolar illness and depression (Christie et al. 1988; Hafner 2003; Hankin et al. 1998). Adolescent males are more prone to schizophrenia (Abel et al. 2010; Hafner 2003; Hafner et al. 1998), and young people with decreased tolerance of normal stress during adolescence are at an increased risk of transition to psychotic mental illness (Yung et al. 2005). "
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    ABSTRACT: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount. In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain. Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness.
    Psychopharmacology 01/2014; 231(8). DOI:10.1007/s00213-013-3415-z · 3.88 Impact Factor
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    • "However, when estrogen levels decline around menopause, women display a second peak in the incidence of schizophrenia , which is absent in men (Riecher-Rossler and Hafner, 1993; Hafner et al., 1998; Abel et al., 2010). In the premenopausal period, female patients generally tend to fare better than their male counterparts , displaying a less severe course of symptoms, with a superior response to antipsychotic (AP) treatment and better social outcome (Seeman, 1983, 1996; Hafner et al., 1998; Salem and Kring, 1998; Hafner, 2003; Abel et al., 2010; Markham, 2011). Also, symptom variability during the menstrual cycle has been reported. "
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    ABSTRACT: Background: Bone mineral density (BMD), as an indicator of cumulative estrogen exposure, may be reduced in female patients with psychotic disorder (van der Leeuw et al., 2013), possibly reflecting reduced cerebral exposure to estrogen and alterations in neuroprotective effects. To the degree that BMD is a marker of cumulative (endogenous) estrogen exposure, we hypothesized that BMD would be positively associated with cerebral gray and white matter indices. Methods: Dual X-ray absorptiometry (DEXA) and magnetic resonance (MRI) scans were acquired in fourteen female patients diagnosed with a psychotic disorder. BMD was expressed in total BMD (g/cm(2)), Z- and T-scores. Cerebral cortical thickness (CT) (as indicator of gray matter status) and fractional anisotropy (FA) (as indicator of white matter integrity) were measured and served as the dependent variables in multilevel random regression models. BMD measures were the independent variables. Results: Femoral BMD measures were positively associated with CT at trend significance (total BMD: B=0.266, 95% CI: -0.019-0.552, p=0.067; Z-score: B=0.034, 95% CI: 0.001-0.067, p=0.046; T-score: B=0.034, 95% CI: 0.000-0.068, p=0.052). There were no significant associations between femoral BMD measures and FA. Conclusions: The data suggest that in women with psychotic disorder, alterations in the neuroprotective effect of estrogen (as measured by BMD) impact cortical gray matter, but not white matter integrity. These findings merit further investigation and, if replicated, would lend support to the estrogen hypothesis of schizophrenia.
    Schizophrenia Research 10/2013; 150(1-1):114-20. DOI:10.1016/j.schres.2013.07.033 · 3.92 Impact Factor
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    • "The protective effect of estrogen in schizophrenia is well researched and is hypothesised to be the result of its neuroleptic-like effect on the dopamine system (19, 60-63). Dopamine overproduction is a pathophysiological feature of the illness and estrogen appears to blunt this effect by reducing dopamine receptor sensitivity and increasing the threshold for vulnerability (64, 65). Interestingly, neurocognitive and mood impairments are features of schizophrenia and other severe mental illnesses characterised by abnormalities in dopaminergic and serotonergic activity (66-75). "
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    ABSTRACT: Schizophrenia is a debilitating and pervasive mental illness with devastating effects on many aspects of psychological, cognitive and social wellbeing. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting that estrogen plays a "protective" role . Adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminisation, however, clinical trials using estrogen to treat prostate cancer, bone density loss and even aggression in men with dementia or traumatic brain injury, show estrogen to be a safe and effective therapy. Findings do, however, suggest that further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted. The development of the new estrogen compounds - Selective Estrogen Receptor Modulators (SERMs) which do not cause feminisation - opens up the possibility of using a different type of estrogen for a longer period of time at higher doses. Estrogen could therefore prove to be an important component in the treatment of psychotic symptoms in men with schizophrenia. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilised to address concerns unique to the care of men with schizophrenia.
    International Journal of Endocrinology and Metabolism 07/2013; 11(3):129-136. DOI:10.5812/ijem.6615
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