Schizophrenia: reproductive hormones and the brain.

OBJECTIVE: Onset of schizophrenia occurs during the reproductive period in more than 80% of those affected. The author reviews neuroendocrine and physiologic events that occur in the basal forebrain at the initiation of and throughout the reproductive period and proposes their possible relationship to the onset of schizophrenia. METHOD: The neuroendocrine changes that occur in specific areas of the anterior basal forebrain during the reproductive period are reviewed and analyzed in relation to reported anatomic, molecular, and biochemical pathologies of schizophrenia. RESULTS: The reproductive period is associated with development of regular pulsatile release in the brain and bloodstream of gonadotropic releasing hormones from the hypothalamus, luteinizing and follicle stimulating hormones from the pituitary, and gonadal hormones from the ovaries and testes. In addition to being concentrated in the hypothalamus, brain receptors for gonadotropic and gonadal hormones are concentrated in specific subcortical forebrain nuclei of the limbic system that project to the thalamus and to cortical and subcortical structures that subserve perception, cognition, and behavior. CONCLUSIONS: There is a flood of estrogen and testosterone to the brain and body during puberty and throughout the reproductive period. To avoid hyperexcitability and seizures, the surge of these excitatory hormones must be counterbalanced by appropriate inhibitory factors. Excessive focal inhibition may be induced by increased release of or increased receptors for one or more inhibitory transmitters, e.g., dopamine, serotonin, and gamma-aminobutyric acid in the anterior basal forebrain. Further investigation of the physiology and pathology of this brain region, where abnormal electrical activity was recorded from individuals with schizophrenia many years ago and where dopamine D(2) and dopamine D(3) receptors targeted by the most effective antipsychotic agents are maximally expressed, could lead to greater understanding of the critical pathophysiology for development of schizophrenia.

Disentangling the pathology of schizophrenia and paraphrenia.

With increasing longevity, the number of older schizophrenic patients is growing. Previous criteria used the age of symptom onset to differentiate between the late manifestations of early-onset schizophrenia and late-onset schizophreniform disorders. Current DSM-IV or ICD 10 nomenclatures do not differentiate between early- and late-onset schizophrenia. Many decades of repeated failures to provide for distinguishing neuropathological findings have prompted narrower definition criteria. Since psychotic or schizophreniform symptoms in old age may be a manifestation of Alzheimer's disease, we attempted to base a distinction between both early- and late-onset schizophrenia on the presence of degenerative changes. This study examined the brains of 64 schizophrenic patients and 18 controls immunocytochemically for tau and amyloid staining. We divided patients according to their ages at the onset of symptoms: <40, >40. Using Braak's classification, we assessed the presence of neurofibrillary pathology. Stages III and IV were observed in 11.1% (2/18) of controls, 36.7% (11/30) of early-onset schizophrenics (<40) and 58.8% (20/34) of late-onset (>40) schizophrenics (chi2=11.39, P =0.003). Stages V and VI (definite Alzheimer's disease) did not significantly differ among groups (chi2=3.6, P =0.165). Astrocytes, subependymal and fibroblastic, also exhibited tau-positive tangles. Chi-square analysis of the data revealed a significant association between tau-positive glial tangles and Braak staging ( P =0.002). Amyloid deposits were sparse in comparison to tau-related changes. The restricted limbic tauopathy not only affected a majority of patients with late-onset schizophrenia (19 female: 1 male among positive cases) ( P =0.048) but also appeared in one-third of those elderly schizophrenic patients whose symptom onset occurred before 40 years of age (8 female: 3 male among positive cases) ( P =0.048). The resultant changes define a type of neuronal cytoskeletal disruption that alters the flow of information through the hippocampus and provides a useful clinico-pathological correlate to a group of patients until recently diagnosed as schizophrenic.