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268 EFFECTS OF STRESSIn summary, it appears that there is a dynamic relation between circulating glucocorticoidsand hippocampal morphology. The specific neural mechanisms havenot been elucidated, nor do we know the time course for these events. But, asdescribed below, there may be critical developmental periods for these processes.The HPA-Hippocampal System and PsychosisFour general lines of investigation provide support for the hypothesis that dysregulationof the HPA axis is involved in the expression of vulnerability for psychosis(Walker & Diforio, 1997). First, behavioral studies have shown that clinicalsymptoms can be exacerbated by exposure to stress. Second, medical disorders(e.g., Cushing’s) that involve elevated levels of the “stress” hormone, cortisol,are associated with increased risk for psychosis. Third, unmedicated psychoticpatients manifest abnormalities in several aspects of the neural system that governscortisol release; namely, the hypothalamic-pituitary-adrenal (HPA) axis. Theseinclude an elevated rate of nonsuppression in response to dexamethasone challenge,heightened baseline cortisol (Muck-Seler et al., 2004; Ritsner et al., 2004), and apositive correlation between cortisol levels and symptom severity (Shirayama,Hashimoto, Suzuki, & Higuchi, 2002; Walder, Walker, & Lewine, 2000). Also, thefact that baseline cortisol is elevated in never-medicated, first-episode patientsindicates that elevated HPA activity precedes clinical onset (Ryan, Collins, &Thakore, 2003; Ryan, Sharifi, Condren, & Thakore, 2004). Lastly, among the mostcompelling evidence that the HPA system is implicated in schizophrenia are datashowing significant hippocampal volume reduction and structural abnormalities(Harrison, 2004). This is relevant to HPA function because, as described below,the hippocampus appears to play an important role in regulating the activity ofthe HPA axis (Altamura, Boin, & Maes, 1999).As noted, numerous studies of diagnosed schizophrenia patients have revealedsignificantly smaller hippocampal volumes when patients are compared to matchedcontrols (Harrison, 2004; Shenton, Dickey, Frumin, & McCarley, 2001). When effectsizes are compared across brain regions, hippocampal volume is characterized bythe largest diagnostic group difference. Other research suggests that reductions inhippocampal volume are present early in the illness, such that studies of young, firstonsetschizophrenia patients reveal hippocampal volume reductions (Seidman et al.,2003). These results parallel the evidence that memory deficits, a well-documentedconsequence of hippocampal impairment, are present in schizophrenia and spectrumdisorders (Antonova, Sharma, Morris, & Kumari, 2004).Further, twin studies indicate that both environmental and genetic factors contributeto hippocampal reductions in schizophrenia. The NIMH studies of discordantmonozygotic (MZ) twins revealed that the affected twins showed smaller brainvolumes than their healthy co-twins, but the hippocampal/amygdala complex wasmost markedly reduced in volume (Suddath, Christison, Torrey, Casanova, &Weinberger, 1990). Subsequent studies of discordant MZ twins have replicated