New emerging research is underscoring the role of stress in the schizophrenias. Richard Lewine (2005 “A contemporary appraisal of the role of stress in schizophrenia” in Handbook of Stress and the Brain: Part 2: Integrative and Clinical Aspects edited by T. Steckler, N.H. Kalin & J.M.H.M. Reul in 2005 for Elsevier) has presented an overview of research documenting the significant role of stress in the initiation and course of the schizophrenias. Research in Europe by investigators such as Jim van Os in the Netherlands has highlighted the etiologic salience of various psychosocial risk factors in the schizophrenias. At a biological level of analysis, much of the research has centered on the neuroendocrine system, particularly the limbic-hypothalamic-pituitary-adrenal axis (LHPA).

However, it should be noted that the LHPA is only one segregated system embedded within a multilevel system of functional connectivity which includes many neurotransmitter systems (including dopaminergic, glutamatergic, adrenergic, etc.), ionic and metabolic neurotransmission.

The link between hyperarousal of the LHPA and hippocampal functioning may explain the impaired neurocognitive functioning sometimes observed in chronic psychotic states. Horger and Roth (1996) reviewed data demonstrating that mesoprefrontal dopaminergic neurons (key neurons in traditional and current reductionistic perspectives on schizophrenia) are particularly vulnerable to stress, even at low levels. It is very likely that stress affects all areas of the brain, but particularly the prefrontal and temporal regions -- the very same neural regions implicated in schizophrenia research as dysfunctional. The fact that this linkage is not more frequently articulated or explored by many architects of the popular theories on the schizophrenias reminds me of the old metaphor that it is hard for fish to see the water that surrounds them.

Walker and Diforio (1997) calculated an average effect size of .60 for cortisol levels in persons with schizophrenia compared to controls. This effect size for persons with schizophrenia matches that for persons with affective disorders. It would not be stretching one’s speculative capacity too far to imagine the possibility that persons with schizophrenia may be coping with profound stress in particular kinds of ways which, although perhaps adaptive in the short term, e.g., salvaging self-esteem, may be quite self-defeating over the long-term, adding to their social isolation, alienation and sense of social defeat. The latter aspects contribute to the spiral towards further stress and anxiety and a profound sense of helplessness.

Some may hypothesize that the rise in cortisol is the result of the illness per se-epiphenomena of ‘having’ this illness schizophrenia. However, research has been conducted which demonstrates the rise in cortisol levels prior to psychotic relapse, implying that stress as indexed by glucocorticoid levels was a precursor and not a consequence of psychosis (Walker and colleagues, 1997, 2000, 2001). Walker et al (2001) observed that baseline cortisol levels correlated with symptom severity at follow-up. Developmentally, there is a correlation between average onset of psychotic disorders and a rise in cortisol levels during adolescence and young adulthood. Lewine (2005) concluded: “Overall, the evidence suggests that increased sensitivity of the HPA axis may be contributing to the onset and severity of psychotic symptoms” (p.294).

Brian Koehler PhD
New York University
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