Abstract
Robyn J. Holden, Corrections Health Service, Silverwater, NSW, Australia, and Irwin S. Pakula, University of Wollongong, Wollongong, NSW, Australia:
In an epidemiology study, conducted by Holden [1], it was found that the prevalence of diabetes among the first-degree relatives of schizophrenic patients was twice that of the general population, while the prevalence rates for rheumatoid arthritis and carcinoma was three times that of the general population. All of these conditions are associated with an elevation of either tumour necrosis factor-alpha (TNF-α) or interferon-gamma (IFN-γ). In insulin-dependent diabetes mellitus (IDDM) [2], non-insulin dependent diabetes mellitus (NIDDM) [3], rheumatoid arthritis [4] and carcinoma [5], [6], TNF-α is elevated; while in schizophrenia, IFN-γ is elevated [7]. TNF-α and IFN-γ influence, either directly or indirectly, insulin secretion [8], [9] as well as the synthesis of acetylcholine (ACh) [10], dopamine [10] and serotonin [11]. Both TNF −α and IFN-γ inhibit follicle-stimulating hormone (FSH)-induced aromatase activity [12], [13], and increase indoleamine-2,3-dioxygenase (IDO) activity [11]; while TNF-α inhibits the activity of certain key enzymes such as protein tyrosine phosphatase (PTPase) [14] and protein tyrosine kinase (PTKase) [3].
When TNF-α (200–2000 U/mL) is mildly elevated insulin secretion is increased; however, at higher concentrations (> 2000 U/mL) T N Fα i n h i b i t s insulin secretion [8]. Similarly, elevated IFN-γ (1000 U/mL) results in a 20% decrease in glucose-induced insulin release, while the synergistic effect of IFN-γ (1000 U/mL), TNF-α (1000 U/mL), and IL-1[.beta] (50 U/mL) causes an 80% decrease in islet insulin content [9].
One shared symptom of IDDM and schizophrenia is hallucinatory experiences that result from central hypoglycaemic episodes. It has been found that mild hypoglycaemia causes functional impairment of the inferior colliculus in the brainstem [15]. The inferior colliculus processes auditory and visual information which coincides with very high rates of glucose consumption [15]. Thus, mild central hypoglycaernia interferes with auditory and visual information processing and may contribute to the hallucinatory experiences common to both conditions.
TNF-α and IFN-γ also inhibits FSH-induced activity of aromatase [12], [13], the enzyme that converts androgens to oestrogen. Oestrogen, in turn, stimulates the activity of choline acetyltransferase (ChAT), the enzyme that synthesises ACh [10]. Thus, sustained elevation of either TNF-α or IFN-γ can lead to a TNF-α IFN-γ induced inhibition of ChAT and, hence, ACh. Since ACh is involved in cognitve performance [10] and fine motor movement, reductions in oestrogen availability may lead to pyramidal cell dysfunction in both of these conditions. Deterioration in cognitive performance is a known complication in chronic schizophrenia, while memory and learning deficits, resulting from hyperglycemic and hypoglycemic episodes, have been observed in diabetes [16], [17].
Since TNF-α and IFN-γ exert a bi-phasic effect on insulin and PTPase [18], we hypothesise that IFN-γ may also exert a bi-phasic effect on FSH-induced aromatase activity. Thus, mild elevation of IFN-γ would increase FSH-induced aromatase activity, which would increase oestrogen availability and dopamine, a neurobiological state associated with the positive symptoms of schizophrenia. However, as IFN-γ increases further, FSH-induced aromatase activity is inhibited leading to reductions in oestrogen, dopamine and ACh, which may culminate in pyramidal cell dysfunction.
Elevated TNF-α and IFN-γ also increase IDO activity which degrades tryptophan down the kynurenine pathway to produce quinolinic acid [11]. This means that any increase in IDO activity could induce a serotonin deficiency, since tryptophan is degraded into quinolinic acid at the expense of serotonin. Reduced serotonin is associated with depression and, depression is a recognised complication of IDDM, NIDDM and carcinoma [19]. Furthermore, depression frequently follows recovery from the acute phase of schizophrenia, referred to as post-psychotic depression.
TNF-α also influences the activity of certain key enzymes involved in energy metabolism and immunological regulation, enzymes that play a major role in the pathophysiology of IDDM, NIDDM and carcinoma. In IDDM, mild elevation of TNF-α increases the activity of PTPase, which activates the pathway leading to overexpression of major histo-compatibility complex (MHC) class I molecules on the cell surface [18]. In NIDDM, TNF-α inhibits the activity of PTKase on the insulin receptor which results in insulin resistance [3]. In carcinoma, high elevation of TNF-α inhibits the activity of PTPase, which inhibits the pathway leading to low expression of MHC class I molecules on the cell surface [18]. In both IDDM and carcinoma, disruption of PTPase activity has serious immunological and metabolic consequences. It is our contention that understanding the effect of TNF-α and IFN-γ on insulin secretion together with certain key enzymes, is also the key to understanding the pathophysiology of these perplexing immunological conditions, and may aid in the understanding of some of the phenomenology of schizophrenia.