- Email: [email protected]
Schizophrenia: An extended etiological explanation
Medical Hypotheses Medical Hypmhcsrs (1994) 42, 1H-123 0 Longman GroupUK Ltd 1994
Schizophrenia: An Extended Etiological Explanation R. J. HOLDEN’, P. A. MOONEYt and J. C. NEWMAN (deceased) ‘Lakeview House, Shellhatbour Hospital, lllawarra Area Health Service, t?O, Box 52, She//ha&our Square, NSW, 2529, Australia, tDepartment of Applied Biomedical Science, Universiv of Tasmania at Launceston, l?O. Box 1214, Launceston 7250, Tasmania
Abstract - Schizophrenia has become an elusive medical conundrum since it was first described at the turn of the 19th century. Over time, a variety of causal hypotheses have been advanced to explain the spectrum of schizophreniform disorders. This etiological explanation outlines the relationship that obtains between smoking, schizophrenia, and impaired glycometabolism which also includes disruption to the dopaminergic and serotinergic pathways. A possible genetic explanation for this disruption will be identified which links mental illness to a locus of genes contained on the short arm of chromosome 11. These genes are all essential to normal glucose transport which positron emission tomography (PET) scans show is seriously abnormal in schizophrenia. Thus, a redefinition of schizophrenia as ‘cerebral diabetes’ will be proposed since this term implies a diabetic brain state consistent with PET scans of schizophrenic patients.
Schizophrenia, smoking, and smog The high prevalence of smoking among schizophrenic patients, 90% compared to 33% of the general population, is widely reported in the literature the reason for which is largely unknown (1). In addition, there is an interesting correlation between early onset schizophrenia, nicotine addiction, and prominent negative symptoms which are associated with decreased dopamine activity in the limbic system (2) and drug-induced Parkinsonism (3). It is also reported that schizophrenics who smoke require significantly higher doses of neuroleptics than non-smokers (4, 5) possibly due to the effect of nicotine on brain catecholamines. It has been found that nicotine activates the mesolimbocortical dopamine neurons in the ventral tegmental area (VTA) which may account for the relationship between early onset schizophre-
nia, negative symptoms and persistent hypofrontality. It is therefore hypothesized that smoking may restore the dynamics of the dopaminergic system in the VTA area (6). This conjecture is consistent with the increasing comorbidity of schizophrenia and polysubstance abuse (7, 8) in which nicotine and other illicit substances may reactivate the downregulated dopaminergic system in the schizophrenic brain. In rats, it has been found that withdrawal of ethanol, morphine, cocaine, and amphetamine results in a marked reduction of dopamine release in the mesolimbic area (9). At present, the dopamine hypothesis remains highly equivocal in that some studies associate schizophrenia with hyperactivity of dopaminergic transmission while others suggest a reduction of dopamine function (10, 11). However, despite this ambiguity, the action of neuroleptics is now better de-
Date received 12 August 1993 Date accepted 23 September 1993
115
116 fined. Antipsychotic medication targets the dopamine D2, D3 and D4 receptors, the current range of neuroleptics act on the D2 receptors which modify the positive symptoms of schizophrenia, while clozapine targets the D4 receptor which modifies the negative symptoms of schizophrenia (12). That the dopamine hypothesis has remained, thus far, equivocal may well be due to the action of heterocyclic amines (HCAs) on the dopamine receptors. Heterocyclic amines are potent carcinogenic mutagens which are found in petroleum fumes, cigarette smoke, azo food dyes (which comtaminate hard candies, soft drinks, and cordials), and broiled and fried meat and fish (13-15). It has recently been reported that cancer is the leading cause of death in Japan which coincides with a trend towards adopting Western diet and life-style (16). It has also been found that heterocyclic amines in cooked food, induce colon and mammary carcinomas in rats, lymphomas in mice, and liver cancer in monkeys (17). However, dietary induced cancer notwithstanding, a far more potent source of carcinogenic HCAs is petroleum fumes (which includes industrial pollution and motor vehicles exhaust emissions) and cigarette smoke. As previously mentioned, there is an extremely high correlation between early onset schizophrenia and smoking behaviour. Heterocyclic amines easily pass through the blood-brain barrier (BBB) and uptaken into the dopaminergic nerve terminals (18) and HCAs are known to inhibit the activity of tyrosine hydroxylase (TH) due to a reduction of affinity to the cofactor tetrahydrobiopterin (BH4) (19). HCAs have been shown to reversibly inhibit amino-acid-decarboxylase (AADC), TH and tryptophan hydroxylase (TPH) and are also noncompetitive inhibitors of BH4. TH activity represents the first step in dopamine biosynthesis from tyrosine while TFH is the first step in the biosynthesis of serotonin, and the AADC group of enzymes are also involved in the biosynthesis of dopamine and serotonin (20-22). BH4 functions as a co-factor for tyrosine and tryptophan hydroxylases. Thus, the presence of heterocyclic amines could represent the confounding variable responsible for the equivocal results with respect to the dopamine hypothesis and account for the high prevalence of smoking among schizophrenic sufferers due to the fact that nicotine reactivates dopaminergic neurotransmission, while heterocyclic amines block dopamine reuptake. It may also account for the higher doses of neuroleptic medication required by schizophrenic smokers compared to schizophrenic non-smokers. Another hypothesis favoured by psychiatry, in relation to schizophrenia, is the ‘geographical drift’ hypothesis which claims that the higher than expected
MEDICAL HYPOTHESES
incidence and prevalence of schizophrenia found in inner city areas can be explained by the supposed geographical drift of schizophrenics from rural and urban areas to the inner city. The ‘geographical drift’ hypothesis has recently been refuted by a Swedish study which shows that both the incidence and prevalence of schizophrenia is higher in inner city compared to urban and rural areas (23). This finding can be accounted for by the increased presence of HCAs in inner city areas from motor vehicle and industrial emissions acting in conjunction with high exposure to HCAs from smoking. Another theory advanced in the literature is the ‘recency hypothesis’ in which it is argued that schizophrenia is a comparatively recent disease that did not make its appearance until the early 1800s (24). Since this period also coincides with the beginning of the industrial revolution together with a correspondingly higher exposure to HCAs from industrial emissions, an increase in both prevalence and incidence of schizophrenia is consistent with the causal role HCAs may play in the etiology of schizophrenia. It has also been noted in the literature that despite excessive exposure to potentially carcinogenic substances, schizophrenics who smoke appear to enjoy a high protection against the development of lung cancer (25). Given that schizophrenics regularly smoke between 75 and 150 cigarettes per day the anticipated statistical incidence of lung cancer would be considerably higher than for the general population. This apparent immunity also extends to a lower than expected incidence of prostrate cancer (26) and it has been suggested that neuroleptics may modify the risk factors for developing lung, bladder, uterine cervix, and breast cancer (27). Recent research has implicated genetic changes in the initiation of cancers, specifically the oncogenes pertaining to the ras family (28). Watson et al (29) have demonstrated that elevated levels of the p21 byproduct of the H-ras oncogene is significantly implicated in the recurrence of, and death from, breast cancer. This is an important revelation in terms of understanding the genetic factors which may contribute to the pathogenesis of schizophrenia. The chromosome
11 link to schizophrenia
A study conducted among the Old Amish pedigree found that bipolar affective disorder was linked to DNA markers on the short arm of chromosome 11 (30) but subsequent studies have failed to confirm this finding (31, 32). In particular, a study conducted by Mitchell et al (33) considered the relationship between bipolar disorder to the 11~15 markers for H-ras,
SCHIZOPHRENIA: AN EXTENDED ETIOLOGICAL EXPLANATION
insulin and tyrosine hydroxylase but failed to find any association. Despite this finding, it is not without significance that the short arm of chromosome 11 contains DNA markers for the following genes: D2 dopamine receptor, tyrosine (Tyrase), tyrosine hydroxylase (TH) and the Harvey-ras-oncogene (34); the dopamine-4 receptor gene DRD4 maps on 11~15 (35); while tryptophan hydroxylase (TPH) is placed between DllS151 and DllS134 (36) all of which lie in close proximity to the markers for bipolar affective disorder originally claimed by Egeland et al. Elsewhere it has been argued that a continuum of liability exists between schizophrenia and the affective disorders (37). From a clinical perspective, endogenous depression is frequently masked by both mania and schizophrenia. The phenomenon of post-psychotic depression often appears following successful treatment of positive schizophrenia symptoms with phenothiazines, while depression has long been thought to underscore mania. It is therefore anticipated that the genetic abnormalities will be similar for each group of disorders. The other known genes carried on the short arm of Chromosome 11 are insulin and insulin growth factors 1 & 2 (IGF 1 & 2) (38) and each of these genes play an important role in glucose metabolism. In summary, the following genes contained on the short arm of chromosome 11 are: tyrosine and tryptophan hydroxylase, tyrosinase, IGF 1 & 2, insulin, dopamine D2 and D4 receptors, and the H-ras oncogene which produces the p21 by product. It has been demonstrated that the p21 is a GTP-binding protein, whose activity is negatively regulated by GTPaseactivating protein (39). Burgering et al (40) have shown that ~21 ras is an intermediate of the insulin signal transduction pathway involved in the regulation of gene expression and have found that elevated levels of receptor fibroblasts were associated with an increase in p21 GTP levels. The rate-limiting enzyme in BH4 biosynthesis is GTP-cyclohydrolase (GTPcycl) and it has been shown that decreased levels of GTPcycl reduced the availability of BH4. Furthermore, it appears that reduction of intracellular GTP levels significantly reduce BH4 biosynthesis (42). Thus, the GTP-binding p21 ras may ultimately not only affect insulin receptor activity but may also modulate the biosynthesis of BH4, thus exerting an indirect control over the enzymes, tyrosine and tryptophan hydroxylases. While TH is essential to the catecholamine and dopaminergic pathways, TPH is essential to the serotonergic pathway. All three pathways are seriously impaired in schizophrenia (43). BH4 is a complex pterin and cofactor of TH and is essential for the biosynthesis of DOPA and dopamine (44) and,
117 consequently, influences the turnover of both catecholamines (essential for glucose utilization) and serotonin. In addition, BH4 is essential for brain cells to produce monoamine neurotransmitters and low levels of BH4 have been associated with certain mental disorders (45). Some studies report that supplements of BH4 have improved outcomes in autism, juvenile Parkinsonism and phenylalanemia (46, 47). Thus, if levels of the by product p21 are reduced, then the activity of BH4, TH, and TPH will be seriously compromised along with the glucose metabolic, dopaminergic, and serotonergic pathways. Pterin metabolism has also been implicated in the genesis of depression. It has been found that patients with severe depression had a neopterin: biopterin (N:B) ratio which was significantly higher than the normal controls. ECT reduced the N:B ratio towards control values which implies that, in depression, there is a failure to convert neopterin to biopterin which reduces the availability of tetrahydrobiopterin. It was postulated that since the cofactor, BH4, is essential for noradrenaline, serotonin and dopamine formation, low levels of BH4 may exert a rate limiting control over monoamine synthesis thought to be implicated in depressive disorders (48). Furthermore, ECT not only increases the activity of BH4 but tyrosine hydroxylase as well, all of which serves to improve glucose transport into the cells (49). Weiner et al (50) have also confirmed that ECT increases TH and GTP cycle activity and BH4 levels in the locus ceruleus and hippocampus for up to 4 days after treatment. Thus, low levels of BH4 not only account for depression, but may also account for the rather interesting observation that cancer and schizophrenia appear to be mutually exclusive conditions. It is highly probable that reduced availability of BH4 is due to reduced levels of the p21 by product of the H-ras oncogene. Consequently, since cancer is associated with elevated levels of p21 and mental illness with reduced levels of p2 1, the perceived mutual exclusivity is explained. Abnormality of p21 levels may also explain the lack of genetic confirmation for the claimed association between bipolar disorder and the short arm of chromosome 11 since the mutation could occur at the level of transcription rather than with the H-ras gene itself. Reduced availability of BH4 will also downregulate the activity of tyrosine hydroxylase which promotes glucose metabolism in the neuron by means of facilitated diffusion. This lies in direct contrast to the astocytes where the insulin receptor (of which tyrosine kinase is a subunit (51, 52)), promotes glucose metabolism by means of active transport. Astrocytes constitute 60% of the brain mass and the end feet cover 95% of the blood-brain barrier (53).
118
MEDICAL HYPOTHFSES
Thus, the astrocyte functions as a buffer zone between the highly protected neuron and the blood-brain barrier, the recognition of which led to the postulation of a simple ‘functional triad’ that reflects the interdependence of the neuron, astrocyte and the bloodbrain barrier (Fig.) which is consistent with the recent identification of five glucose transporters (54). Of these five glucose transporters, GLUT- 1 specialises in the endothelial cells of the blood-brain barrier while GLUT-3 is active in the astrocytic glial cell (55). It is also postulated here that p2 1 may have the duel effect on both TH and insulin receptor functions by modulation of GTP availability for insulin signal transduction and BH4 biosynthesis.
To summarize, central glucose metabolism is adversely affected in a number ways: (i) HCAs inhibit the activity of tyrosine hydroxylase directly (19); (ii) HCAs inhibit the action of BH4 noncompetitively (20, 21); (iii) low levels of p21 inhibit the activity of BH4 which, in turn, inhibits the activity of tyrosine hydroxylase; (iv) low levels of BH4 negatively affects the turnover of catecholamines (essential for glucose utilization); (v) smoking leeches magnesium out of the cells which compromises the efficiency of the Na+/K+,Ca+, and Na/H+ pumps that drive glycometabolism (56). This means that the schizophrenic brain is in a diabetic state due to impoverished glucose uptake into the cells. For this reason the term
CHROMOSOME311 D4
Ins 1GFl lGF2
Fig. The physiological interaction of neuron, astrocytic glial cell and blood-brain barrier:the p21 gene-product (if defective) would interferewith the tyrosine and tryptophanhydroxylases (by inhibiting tetmhydrobiopterin(BH4)‘j.The functional integrity of the insulin receptormay be disturbedor impaired. This could result in the permeabilityof the blood brain barrier.
SCHIZOPHRENIA:
AN EXTENDED ETIOLOGICAL
EXPLANATION
‘cerebral diabetes’ has been proposed as a redefinition of mental illness which includes both schizophrenia and the affective disorders and this model has been extensively elaborated upon in relation to unipolar depression elsewhere (57). Such a redefinition is further supported by positron emission tomography (PET) scans which show a marked impairment of glucose metabolism in the cortical and subcortical areas of the brain (58). Reconceptualizing mental illness as ‘cerebral diabetes’ is particularly compelling once it is recognised that: (i) anecdotally, the incidence of diabetes among first degree relatives of the psychiatrically ill patients appears to be well over 50%; and (ii) the incidence of diabetes among patients with an affective disorder is 10%. This percentile is considerably higher than for the general population in relation to whom the incidence of diabetes is approximately 2% (59). Studies have reported mood changes with hyperglycaemia; brain glucose and fluid shifts in diabetes (60); and reduced glucose utilisation (61) and hyperinsulinaemia (62) in depressives. In addition, improved peripheral diabetic control has been obtained with ECT (63) while ‘insulin coma therapy’ was used in the affective disorders and schizophrenia with moderate success (64, 65). It is also not without significance that low doses of insulin have recently been found effective in the treatment of tardive dyskinesia (66). Thus, ‘cerebral diabetes’ as a model for serious mental disorders when conjoined with varying avenues of neurotoxic damage damage presents an attractive conceptual framework for understanding the etiology of mental illness and may serve to explain the ventricular enlargement observed on computed tomography scans (67, 68). Neurotoxicity and glycometabolism The N-methyl-D-asartate (NMDA) channel is one of three glutamate receptor subtypes (which includes AMPA and kainate receptors). It appears to mediate hypoglycemic, hypoxic, epileptic and toxin-related damage to the CNS (69, 70) and dopamine release in the striatum (71). This channel, which is highly permeable to Ca2+, is essential for excitatory synaptic transmission together with the plasticity that underlies memory and learning. Oxygen (e.g. hypoxia) and energy deficits (e.g. schizophrenia) can cause excitotoxicity or neuronal cell death through the activation of excitatory amino acid receptors (72, 73), while the pattern of neuronal damage in the cerebral cortex, consistent with that found in Huntington’s disease, is due to NMDA excitotoxic lesions (74). But the NMDA receptor channel can also initiate neuronal
119 dysfunction and death due to its role in the mediation of neurotoxicity. In response to neurotoxic damage that obtains from chronic alcohol exposure (or persistent exposure to heterocyclic amines), the NMDA receptors become hyperexcitable which initiates further toxicity due to an increase in intracellular calcium (75). This means that the neurotoxic damage caused by HCAs which systematically block dopamine reuptake, is compounded by the toxicity induced by an influx of intracellular calcium through increased NMDA receptor activation. It has also been reported that NMDA-type glutamate receptors are essential for the dopamine Dl-neurotensin interaction which is disrupted by drugs of abuse that mimic schizophrenic and paranoid-like symptoms (76). As previously stated, NMDA receptors are activated in response to hypoglycemic, hypoxic, epileptic and neurotoxic damage. Thus, with respect to schizophrenia, the NDMA receptors are liable to become hyperexcitable due to the compounding effect of hypoglycemia caused by impaired glycometabolism and neurotoxicity induced by heterocyclic amines. In response to NMDA receptor activation polamines, spermine and spermidine, are released into the extracellular space which causes longterm potentiation, synaptic plasticity and neurotoxicity (77). Capillary NMDA receptors are also involved in the regulation of blood-brain barrier and function, and polyamines are implicated in blood-brain barrier breakdown in response to cryogenic injury (78). Further, it has been reported that increased concentrations of polyamines are released in the brain in response to ischemia and brain trauma leading to excitotoxic neuronal death (79). In addition, the relationship between stress and subsequent decompensation with a serious mental disorder has long been noted but the biochemical pathway that mediates between these two events has remained elusive. Recent research indicates that the subjective experience of stress increases blood-brain barrier permeability (BBBP) (80-82) due to the release of histamines (83-86). Thus, sustained increase in blood-brain barrier permeability in response to stress exposes the organism to the risk of further neurotoxic damage, particularly from pervasive exposure to heterocyclic amines in food and air pollution. This means that emotional stress may well activate the capillary NMDA receptors, together with the release of polyamines and histamines, which would exacerbate blood-brain barrier permeability and/or breakdown. There is some empirical evidence to support this contention. Tyramine is a monoamine not normally considered capable of crossing the blood-brain barrier. In a study conducted by Swash et al (87) a
120 tyramine challenge was given to 15 epileptic patients using a double-blind placebo-controlled design and abnormal spike activity and sharp waves were subsequently monitored on an EEG. Since it is now known that epileptic abnormalities can activate the NMDA receptors which can compromise blood-brain barrier integrity, the mechanism of the tyramine response can now be elucidated. Conclusion The basic hypothesis being advanced here, is that when an underlying cerebral diabetic condition conjoins with the physiological consequences of stress, NMDA receptor hyperexcitability, and neurotoxic damage then schizophrenia will occur. It has been argued that the underlying cerebral diabetic condition arises from reduced levels of p21 which produces low availability of tetrahydrobioterin that, in turn, compromises the activity of tyrosine hydroxylase and tryptophan hydroxylase. This depressed activity negatively impacts on both dopaminergic and serotonergic neurotransmission as well as downregulating glycometabolism. When these endogenous events are conjoined with either emotional or organic stress, which compromises the integrity of the blood-brain barrier, and exposure to heterocyclic amines from either the food chain, air pollution or cigarette smoke, the brain is tipped over into a severe metabolic crisis which results in the presentation of what is commonly known. as schizophrenia. It is hoped that this causal model will provide not only profitable directions for future empirical research but also a viable model for future rehabilitation programs. While the stress component can be adequately addressed by a variety of psychoeducational programs, and the neurotoxicity from HCAs can be managed by dietary regulation and QUIT smoking campaigns, the underlying diabetic condition requires more sophisticated medical intervention. It has been found that, peripherally, vanadium compounds can reduce insulin resistance and improve insulin receptor binding, and they seem able to bypass the effect of the insulin receptor on intracellular messengers. It would seem, therefore, that this is one possible approach centrally (88). Neuronal activity depends on the activity of tyrosine hydroxylases, and tyrosine hydroxylase requires phosphorylation by four serine kinases for full activation. Anything which inhibits this process potentially inhibits full transmission capacity; the cofactor tetrahydrobiopterin is critical to both tyrosine and tryptophan hydroxylase and the heterocyclic amines reduce the efficiency of these hydroxylases. Therapeutically, it would seem possible that oral tetrahydrobiopterin may be used in depres-
MEDICAL HYPOTHESES
sion and schizophrenia as a means of compensating for reduced levels of ~21. The BH4 cofactor is very important because it is derived from the biosynthesis of GTP (the G-protein precursor) and it has already been used with some success in juvenile Parkinsons disease and autism (89). Recently, IGF infusions have been used for Down’s syndrome and in cases of refractory hyperinsulinism, successfully (90). It is proposed, therefore, from the above models, that IGF infusion might have therapeutic benefit in patients with unipolar depression and schizophrenia. Theoretically, IGF has the potential to bypass ‘insulin resistance’ in the CNS and, due to its stimulatory effects on oligodendrocyte myelination, it might also address some degree of neurotoxic damage. Thus, the therapeutic interventions that might be considered in the near future for the treatment of mental illness generally, and schizophrenia in particular, are magnesium and vanadium supplements, tetrahydrobiopterin, and IGF infusions. The future direction of empirical research points to investigation of the H-ras oncogene and its ~21 by product in conjunction with the activity of tetrahydropbiopterin. Acknowledgements 1 wish to pay tribute to my co-researcher, John C Newman, BSc, MB, BS, without whose collaboration this paper could not have been written. His untimely demise has been a sad loss both personally and professionally. We wish to thank Magda Heaslip for her assistance in the preparation of the computer generated diagram. We also wish to extend our gratitude to Mr John Layhe, Area Director of Nursing, Illawarra Area Health Service, for kindly funding the publication of this research.
References 1. Lohr J B, Flynn K. Smoking and schizophrenia. Schizophr Res 1992; 8: 93-102. 2. Sandyk R, Kay S R. Tobacco addiction as a marker of age at onset of schizophrenia. Int J Neurosci 1991; 27: 259-262. 3. Sandyk R, Kay S R. Drug induced parkinsonism: relationship to age of onset of schizophrenia. Funct Neurol 1991; 6: ISl157. 4. Goff D C, Henderson D C, Amico E. Cigarette smoking in schizophrenia: a relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149: 1189-1194. 5. Decina P, Caracci G, Sandik R, Berman W, Mukherjee S, Scapicchio P. Cigarette smoking and neuroleptic-induced parkinsonism. Biol Psychiatry 1990; 28: 502-508. 6. Svensson T H, Grenhoff J, Engberg G. Effect of nicotine on dynamic function of brain catecholamine neurons. Ciba Found Symp 1990; 152: 169-180. I. Amdt S, Tyrrell G, Flaum M, Andreasen N C. Comorbidity of substance abuse and schizophrenia: the role of pm-morbid adjustment. Psycho1 Med 1992; 22: 379-388. 8. Chen C, Balagh M, Bathija J, Howanitz E, Plutchik R, Conte H R. Substance abuse among psychiatric inpatients. Compr Psychiatry 1992; 33: 60-64. 9. Rossetti 2 L, Hmaiden Y, Gessa G L. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol,
SCHIZOPHRENIA:
AN EXTENDED
ETIOLOGICAL
EXPLANATION
morphine, cocaine and amphetamine abstinence in rats. Em J Pharmacol 1992; 221: 227-234. 10. Reynolds G P. Beyond the dopamine hypothesis. The neurochemical pathology of schizpophrenia. Br J Psychiatry 1989; 155: 305-316. 11. Wyatt R J, Kirch D G, DeLisi L N. Schizophrenia: biochemical, endocrine, and immunological studies. In Kaplan H I, &dock, B J, eds. Comprehensive Textbook of Psychiatry V. 5th ed. 1989. 12. Seeman P Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharrnacology 1992; 7: 261-284. 13. Chung K T, Stevens S E Jr, Cemiglia C E. The reduction of azo dyes by the intestinal microflora. Crit Rev Microbial 1992; 18: 175-190. 14. Lancaster F E, Lawrence J E Determination of total nonsulphonated aromatic amines in soft drinks and liquid chromatography. Food Addit Contam 1992; 9: 171-182. 15. Minami M, Takabashi T, Maruyama W, Takahashi A, Nagatsu T, Naoi M. Allosteric effect of tetrahydrobiopterin cofactors on tyrosine hydroxylase activity. Life Science 1992; SO: IS20. 16. Sugimura T. Multistep carcinogenesis: a 1992 perspective. Science 1992; 258: 603-607. 17. Wakabayashi K, Nagao M, Esumi H, Sugimura T. Foodderived mutagens and carcinogens. Cancer Res 1992; 52(7 Suppl): 2092s-2098s. 18. Minchin R F, Reeves P T, Teitel C H et al. N- and Oacetylation of aromatic and heterocyclic amine carcinogens by human monomorphic and polymorphic acetyltransferases expressed in COS-1 cells, Biochem Biophys Res Commun 1992; 185: 839-844. 19. Maruyama W, Minami M, Ota A et al. Reduction of enzymatic activity of tyrosine hydroxylase by heterocyclic amine, 3amino 1, 4-dimethyl-SH-pyrido (4,3-b) indole (Tip-P-l), was due to reduced affinity to a cofactor biopterin. Neurosci Lett 1991; 125: 85-88. 20. Ota M, Naoi M, Hamanaka T, Nagatsu T. Inhibition of human brain aromatic L-amino acid decarboxylase by cooked foodderived 3-amino-1-methyl-SH-pyrido (4,3-b) indole (Trp-P-2) and other heterocyclic amines. Neurosci Lett 1990; 116: 372378. 21. Naoi M, Hosoda S, Ota M, Takahashi, Nagatsu T. Inhibition of trytophan hydroxylase by food-derived carcinogenic heterocyclic amines, 3-amino-1-methyl-SH-pyrido (4,3-b) indole and 3-amino- 1,4-dimethyl-SH-pyrido (4,3-b) indole. Biochem Pharmacol 1991; 41: 199-203. 22. Naoi M, Takahashi T, lchinose H, Wakabayashi K, Sugimura T, Nagatsu T. Uptake of heterocyclic amines, Trp-P- 1 and TrpP-2, into clonal pheochromocytoma PCl2h cells by dopamine uptake system. Neurosci Lett 1989; 99: 317-322. 23. Lewis Cl, David A, Andrt%sson S, Allebeck P. Schizophrenia and city life. Lancet 1992; 340: 137-140. 24. Hare E. Schizophrenia as a recent disease. Br J Psychiat 1988; 153: 521-531. 25. Gopalaswamy A K, Morgan R. Smoking in chronic schizoohrenia. Br J Psvchiat 1986; 149: 523. 26. Mortensen P B: Neuroleptic medication and reduced risk of prostrate cancer in schizophrenic patients. Acta Psychiatr Scand 1992; 85: 390-393. 27. Mortensen P B. Neuroleptic treatment and other factors modifying cancer risk in schizophrenic patients. Acta Psychiatr Scand 1987; 75: 585-590. 28. Wogan G N. Molecular epidemiology in cancer risk assessment and prevention: recent progressand avenues for further research. Environ Health Perspect 1992; 98: 167-178.
121 29. Watson D M, Elton R A. Jack W J, Dixon J M, Chetty U, Miller W R. The H-ras oncogene product p21 and prognosis in human breast cancer. Breast Cancer Research Treat 1991; 17: 161-169. 30. Egeland J A, Gerhard D S, Pauls D L et al. Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 1987; 325: 783-787. 31. Law A, Richard C W 3rd, Cottingham Jr R W, Lathrop G M, Cox D R, Myers R M. Genetic linkage analysis of bipolar affective disorder in an Old Order Amish pedigree. Hum Genet 1992; 88: 562-568. 32. Mendlewicz J, Leboyer M, De Bruyn A et al. Absence of linkage between chromosome 11~15 markers and manicdepressive illness in a Belgian pedigree. Am J Psychiat 1991; 148: 1683-1687. 33. Mitchell P, Waters B, Morrison N, Shine J, Donald J. Eisman J. Close linkage of bipolar disorder to chromosome 11 markers is excluded in two large Australian pedigrees. J Affect Disord 1991; 21: 23-32. 34. Mendlewicz J. Sevy S, Mendelbaum K. Minireview: Molecular genetics in affective illness. Life Science 1993; 52: 231242. 35. Gelemter J, Kennedy J L, van To1H H, Civelli 0, Kidd K K. The D4 dopamine receptor (DRD4) maps to distal 1lp close to HRAS. Genomics 1992; 13: 208-210. 36. Nielsen D A, Dewan M, Goldman D. Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am J Hum Genet 1992; 51: 1366-1371. 37. Newman J C, Holden R J, Mooney P. The Psychoses, Schizophrenia and the Dementias: A Continuum of Liability? Med J Aust 1993; 158: 362. 38. Sten-Linder M, Wedell A, lselius L, Efendic S, Luft R, Luthman H. DNA polymorphisms in the human tyrosine hydroxylaselinsulin-like growth factor 11chromosomal region in relation to glucose and insulin responses. Diabetologia 1993; 36: 25-32. 39. Nori M, L’ Allemain G, Weber M J. Regulation of tetradecanoyl phorbol acetate-induced responses in NIH 3T3 cells by GAP, the GTPase-activating protein associated with p2lc-ras. Mol Cell Biol 1992; 12: 936-945. 40. Burgering B M, Medema R H, Maassen J A et al. Insulin stimulation of gene expression mediated by p2lra.s activation. The EMBO Journal 1991; 10: 1103-1109. 41. Katoh S, Sueoka T. Development of tetrahydrobiopterin and GTP cyclohydrolase in salivary glands of rats. lnt J Biochem 1986; 18: 131-135. 42. Hatakeyama K. Harada T, Kagamiyama H. IMP dehydrogenase inhibitors reduce intracellular tetrahydrobiopterin levels through reduction of intracellular GTP levels. Indications of the regulation of GTP cyclohydrolase I activity by restriction of GTP availability. J Biol Chem 1992; 267: 20734-20739. 43. Wyatt R J, Kirch D G, DeLisi L N. Schizophrenia: biochemical, endocrine, and immunological studies. In: Kaplan H I, Sadock B J, eds. Comprehensive Textbook of Psychiatry/V. 5th ed. 1989. 44. Jung W, Herken H. Inhibition of bioterin synthesis and DOPA production in PC-12 pheocbromocytoma cells induced by 6aminonicotinamide. Naunyn. Schmiedebergs. Arch Pharmacol 1989; 339: 424432. 45. Eto 1. Bandy M D, Butterworth C E Jr. Plasma and urinary levels of biopterin, neopterin. and related pterins and plasma levels of folate in infantile autism. J Autism Dev Disord 1992; 22: 295-308. 46. Dissing I C, Guttler F, Pakkenberg H et al. Tetrahydrobiopterin and Parkinson’s disease. Acta Neurol Stand 1989; 79: 493-
122 499. 41. Tanaka H, lshiiawa A, Ginns E I, Miyatake T, Tsuji S. Link-
48.
49.
50.
51.
52.
53. 54. 55.
56.
57. 58.
59. 60.
61. 62.
63. 64.
65. 66. 67.
68.
age analysis of juvenile parkinsonism to tyrosine hydroxylase gene locus on chromosome 11.Neurology 1991; 41: 719-722. Anderson D N, Ahou-Saleh M T, Collins 1 et al. Pterin metabolism in depression: an extension of the amine hypothesis and possible marker of response to ECT. Psycho1 Med 1992; 22: 863-869. Hashimoto R, O&i N, Ohta T, Kasahara Y, Kaneda N, Nagatsu T. Plasma tetrahydrobiopterin levels in patients with psychiatric disorders. Neuropsychobiology 1990-1991; 23: 140-143. Weiner N, Hossain M A, Masserano J M. The effects of electroconvulsive shock on catecholamine function in the locus ceruleus and hippocampus. J Neural Transm 1991; 34: (Suppl) 3-9. Hayashi H, Kamohara S, Nishioka Y et al. Insulin treatment stimulates the tyrosine phosphorylation of the alpha-type 85kDa subunit of phosphatidylinositol 3-kinase in vivo. J Biol Chem 1992; 267: 22575-22580. Gao Y. Keane N, Levine B A, Alejos R, Ellis L. Structural characterisation of substrate binding to human insulin receptor tyrosine kinase domain. Biochem Sot Trans 1992; 20: 2698. Pardridge W N. Advances in cell biology of blood-brain bartier transport. Semin Cell Biol 1991; 2: 419-426. Lienhard G E. Slot J W. James D E, Mueckler M M. How cells absorb glucose. Sci. Am 1992; 266: 34-39. Pardridge W M, Baodo R J, Farm1 C R. Brain-type glucose transporter (GLUT 1) is selectively localized to the blood brain barrier. J Biol Chem 1990; 265: 18035-18040. Newman J C, Amarasingham J L. The pathogenesis of eclampsia: The ‘magnesium ischaemia’ hypothesis. Med Hypoth 1993; 40: 250-256. Newman 3 C, Holden R J. The ‘cerebral diabetes’ paradigm for unipolar depression. Med Hypoth 1993; 41: 391-408. Wiesel F A. Glucose metabolism in psychiatric disorders: how can we facilitate comparisons among studies? J Neural Transm 1992; 37: (Suppl) I-18. Russell J D, Johnson G F S. Affective disorders, diabetes mellitus and lithium. Aust NZ J Psychiat 1981; 15: 349-353. Gonder-Federick L A, Cox D J, Bobbitt S A, Pennebaker J W. Mood changes associated with blood glucose fluctuations in insulin-dependent diabetes mellitus. Health Psychology 1989; 8: 45-59. Mendels J, Frazer A. Alterations in cell membrane activity in depression. Am J Psychiat 1974; 131: 1240-1246. Mueller P S, Henninger G R, McDonald R K. Intravenous glucose tolerance test in depression. Arch Gen Psychiat 1974; 131: 1240-1246. Fakhri 0, Fadhli A A, el Rawi R M. Effect of electroconvulsive therapy on diabetes mellitus. Lancet 1980; October 11: 775-777. Laqueur H P. insulin coma therapy. In: Berger P A, Brodie H, eds. American Handbook of Psychiatry, 2nd ed, Vol 5. New York: Basic Books Inc, 1986: 526-528. Ackner B, Oldham A J. Insulin treatment of schizophrenia. Lancet 1962; March 10: 504-506. Mouret J, Malika K, Le.moine, Sebert P. Low doses of insulin as a treatment of tardive dyskinesia: conjuncture or conjecture? Eur Neurol 1991; 31: 199-203. Weinberger D R, De Lisi L E, Terman G P, Targum S, Wyatt J. Computed tomography in schizophmniform disorder and other acute psychiatric disorders. Arch Gen Psychiatry 1982; 39: 778-783. Pearlson G D. Clinical correlates of lateral ventricular enlargement in bipolar affective disorder. Am J Psychiatry 1984; 141:
MEDICAL HYPOTHESES
253-256. 69. Kutsuwada T, Kashiwabuchi N, Mori H et al. Molecular diversity of the NMDA receptor channel. Nature 1992; 358: 3-l. 70. Usherwood P N, Blagbrough I S. Spider toxins affecting glutamate receptors: polyamines in therapeutic neurochemistry. Pharmacological Therapeutics 1991; 52: 245-268. 71. Martinez-Fong D, Resales M G, Gongora-Alfaro J L, Hemandez S, Aceves J. NMDA receptor mediates dopamine release in the striatum of unanesthetized rats as measured by brain microdialysis. Brain Res 1992; 595: 309-315. 72. Peruche B, Krieglstein J. Mechanisms of drug actions against neuronal damage caused by ischemia-an overview. Prog Neuropsychopharmocol Biol Psychiatry 1993; 17: 21-70. 13. Beal M E Mechanisms of excitotoxicity in neurologic diseases. FASEB J 1992; 6: 3338-3344. 74. Storey E, Kowall N M, Finn S F, Mazumk M F, Beal M F. The cortical lesion of Huntington’s disease: further neurochemical characterization, and reproduction of some histological and neurochemical features by N-methyl-D-aspartate lesions of rat cortex. Ann Neural 1992; 32: 526534. 75. Lovinger D M. Excitotoxicity and alcohol-related brain damage. Alcohol Clin Exp Res 1993; 17: 19-27. 76. Hanson G R, Singh N, Merchant K, Johnson M, Bush L, Gibb J W. Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms. Ann N Y Acad Sci 1992: 668: 165-172. 77. Fage D, Voltz C, Scatton B, Carter C. Selective release of spermine and spermidine from the rat striatumby N-methylD-aspartate receptor activation in vivo. J Neurochem 1992; 58: 2170-2175. 78. Koenig H, Trout J J, Goldstone A D, Lu C Y. Capillary NMDA receptors regulate blood-brain barrier function and breakdown, Brain Res 1992; 588: 297-303. 79. Lombardi G, Szekely A M, Bristol L A, Guidotti A, Manev H. Induction of omithine decarboxylase by N-methyl-D-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons. J Neurochem 1993; 60: 1317-1324. 80. Anagnostakis D, Messaritakis J, Damianos D, Mandyla H. Blood-brain barrier permeability in ‘healthy’ infected and stressed neonates. J Pediatrics 1992; 121: 291-294. 81. Sharma H S, Cervos-Navarro J, Dey P K. Increased bloodbrain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats. Neuroscience Research 1991; 10: 211-221. 82. Belova T I, Sudakov K V. Morphofunctional changes in brain neurons during emotional stress. Vestn Akad Med Nauk SSSR 1990; 2: 11-13. 83. Sharma H S, Nyberg F, Cervos-Navarro J, Dey P K. Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain ocdema and serotonin levels: an experimental study in conscious young rats. Neuroscience 1992; 50: 445-454. 84. Butt A M, Jones H C. Effects of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brainsurface microvessels. Brain Research 1992: 569: 100-105. 85. Boertje S B, Ward S, Robinson A. HZ-receptors mediate histamine-induced variations in the permeability of the bloodbrain barrier of rats. Res Commun Chem Path01 Pharmacol 1992; 76: 143-154. 86. Greenwood J. Mechanisms of blood-brain barrier breakdown. Neuroradiology 1991; 33: 95-100. 87. Swash M, Moffett A M, Scott D F. Tyramine activates the EEG in epileptic patients. Nature 1975; 258: 749. 88. Scimeca J C, Ballotti R, Filloux C, Van Obberghen E. lnsulin and orthovanadate stimulate multiple phosphotyrosine-
SCHIZOPHRENIA: AN EXTENDED ETIOLOGICAL EXPLANATION
containing serine kinases. Mol Cell Biochem 1992; 109: 139147. 89. Naruse H, Hayashi T. Takesada M, Nakane A, Yamazaki K. Metabolic changes in aromatic amino acids and monoamines in infantile autism and development of new treatment related
123 to the finding. No To Hattatsu 1989; 21: 181-189. 90. Usala A-L, Madigan T, Burguera B et al. Brief Report: Treatment of insulin-resistant diabetic ketoacidosis with insulin-like growth factor f in an adolescent with insulin-dependent diabetes. N Engl J Med 1992; 327: 853-857.
Schizophrenia: An Extended Etiological Explanation R. J. HOLDEN’, P. A. MOONEYt and J. C. NEWMAN (deceased) ‘Lakeview House, Shellhatbour Hospital, lllawarra Area Health Service, t?O, Box 52, She//ha&our Square, NSW, 2529, Australia, tDepartment of Applied Biomedical Science, Universiv of Tasmania at Launceston, l?O. Box 1214, Launceston 7250, Tasmania
Abstract - Schizophrenia has become an elusive medical conundrum since it was first described at the turn of the 19th century. Over time, a variety of causal hypotheses have been advanced to explain the spectrum of schizophreniform disorders. This etiological explanation outlines the relationship that obtains between smoking, schizophrenia, and impaired glycometabolism which also includes disruption to the dopaminergic and serotinergic pathways. A possible genetic explanation for this disruption will be identified which links mental illness to a locus of genes contained on the short arm of chromosome 11. These genes are all essential to normal glucose transport which positron emission tomography (PET) scans show is seriously abnormal in schizophrenia. Thus, a redefinition of schizophrenia as ‘cerebral diabetes’ will be proposed since this term implies a diabetic brain state consistent with PET scans of schizophrenic patients.
Schizophrenia, smoking, and smog The high prevalence of smoking among schizophrenic patients, 90% compared to 33% of the general population, is widely reported in the literature the reason for which is largely unknown (1). In addition, there is an interesting correlation between early onset schizophrenia, nicotine addiction, and prominent negative symptoms which are associated with decreased dopamine activity in the limbic system (2) and drug-induced Parkinsonism (3). It is also reported that schizophrenics who smoke require significantly higher doses of neuroleptics than non-smokers (4, 5) possibly due to the effect of nicotine on brain catecholamines. It has been found that nicotine activates the mesolimbocortical dopamine neurons in the ventral tegmental area (VTA) which may account for the relationship between early onset schizophre-
nia, negative symptoms and persistent hypofrontality. It is therefore hypothesized that smoking may restore the dynamics of the dopaminergic system in the VTA area (6). This conjecture is consistent with the increasing comorbidity of schizophrenia and polysubstance abuse (7, 8) in which nicotine and other illicit substances may reactivate the downregulated dopaminergic system in the schizophrenic brain. In rats, it has been found that withdrawal of ethanol, morphine, cocaine, and amphetamine results in a marked reduction of dopamine release in the mesolimbic area (9). At present, the dopamine hypothesis remains highly equivocal in that some studies associate schizophrenia with hyperactivity of dopaminergic transmission while others suggest a reduction of dopamine function (10, 11). However, despite this ambiguity, the action of neuroleptics is now better de-
Date received 12 August 1993 Date accepted 23 September 1993
115
116 fined. Antipsychotic medication targets the dopamine D2, D3 and D4 receptors, the current range of neuroleptics act on the D2 receptors which modify the positive symptoms of schizophrenia, while clozapine targets the D4 receptor which modifies the negative symptoms of schizophrenia (12). That the dopamine hypothesis has remained, thus far, equivocal may well be due to the action of heterocyclic amines (HCAs) on the dopamine receptors. Heterocyclic amines are potent carcinogenic mutagens which are found in petroleum fumes, cigarette smoke, azo food dyes (which comtaminate hard candies, soft drinks, and cordials), and broiled and fried meat and fish (13-15). It has recently been reported that cancer is the leading cause of death in Japan which coincides with a trend towards adopting Western diet and life-style (16). It has also been found that heterocyclic amines in cooked food, induce colon and mammary carcinomas in rats, lymphomas in mice, and liver cancer in monkeys (17). However, dietary induced cancer notwithstanding, a far more potent source of carcinogenic HCAs is petroleum fumes (which includes industrial pollution and motor vehicles exhaust emissions) and cigarette smoke. As previously mentioned, there is an extremely high correlation between early onset schizophrenia and smoking behaviour. Heterocyclic amines easily pass through the blood-brain barrier (BBB) and uptaken into the dopaminergic nerve terminals (18) and HCAs are known to inhibit the activity of tyrosine hydroxylase (TH) due to a reduction of affinity to the cofactor tetrahydrobiopterin (BH4) (19). HCAs have been shown to reversibly inhibit amino-acid-decarboxylase (AADC), TH and tryptophan hydroxylase (TPH) and are also noncompetitive inhibitors of BH4. TH activity represents the first step in dopamine biosynthesis from tyrosine while TFH is the first step in the biosynthesis of serotonin, and the AADC group of enzymes are also involved in the biosynthesis of dopamine and serotonin (20-22). BH4 functions as a co-factor for tyrosine and tryptophan hydroxylases. Thus, the presence of heterocyclic amines could represent the confounding variable responsible for the equivocal results with respect to the dopamine hypothesis and account for the high prevalence of smoking among schizophrenic sufferers due to the fact that nicotine reactivates dopaminergic neurotransmission, while heterocyclic amines block dopamine reuptake. It may also account for the higher doses of neuroleptic medication required by schizophrenic smokers compared to schizophrenic non-smokers. Another hypothesis favoured by psychiatry, in relation to schizophrenia, is the ‘geographical drift’ hypothesis which claims that the higher than expected
MEDICAL HYPOTHESES
incidence and prevalence of schizophrenia found in inner city areas can be explained by the supposed geographical drift of schizophrenics from rural and urban areas to the inner city. The ‘geographical drift’ hypothesis has recently been refuted by a Swedish study which shows that both the incidence and prevalence of schizophrenia is higher in inner city compared to urban and rural areas (23). This finding can be accounted for by the increased presence of HCAs in inner city areas from motor vehicle and industrial emissions acting in conjunction with high exposure to HCAs from smoking. Another theory advanced in the literature is the ‘recency hypothesis’ in which it is argued that schizophrenia is a comparatively recent disease that did not make its appearance until the early 1800s (24). Since this period also coincides with the beginning of the industrial revolution together with a correspondingly higher exposure to HCAs from industrial emissions, an increase in both prevalence and incidence of schizophrenia is consistent with the causal role HCAs may play in the etiology of schizophrenia. It has also been noted in the literature that despite excessive exposure to potentially carcinogenic substances, schizophrenics who smoke appear to enjoy a high protection against the development of lung cancer (25). Given that schizophrenics regularly smoke between 75 and 150 cigarettes per day the anticipated statistical incidence of lung cancer would be considerably higher than for the general population. This apparent immunity also extends to a lower than expected incidence of prostrate cancer (26) and it has been suggested that neuroleptics may modify the risk factors for developing lung, bladder, uterine cervix, and breast cancer (27). Recent research has implicated genetic changes in the initiation of cancers, specifically the oncogenes pertaining to the ras family (28). Watson et al (29) have demonstrated that elevated levels of the p21 byproduct of the H-ras oncogene is significantly implicated in the recurrence of, and death from, breast cancer. This is an important revelation in terms of understanding the genetic factors which may contribute to the pathogenesis of schizophrenia. The chromosome
11 link to schizophrenia
A study conducted among the Old Amish pedigree found that bipolar affective disorder was linked to DNA markers on the short arm of chromosome 11 (30) but subsequent studies have failed to confirm this finding (31, 32). In particular, a study conducted by Mitchell et al (33) considered the relationship between bipolar disorder to the 11~15 markers for H-ras,
SCHIZOPHRENIA: AN EXTENDED ETIOLOGICAL EXPLANATION
insulin and tyrosine hydroxylase but failed to find any association. Despite this finding, it is not without significance that the short arm of chromosome 11 contains DNA markers for the following genes: D2 dopamine receptor, tyrosine (Tyrase), tyrosine hydroxylase (TH) and the Harvey-ras-oncogene (34); the dopamine-4 receptor gene DRD4 maps on 11~15 (35); while tryptophan hydroxylase (TPH) is placed between DllS151 and DllS134 (36) all of which lie in close proximity to the markers for bipolar affective disorder originally claimed by Egeland et al. Elsewhere it has been argued that a continuum of liability exists between schizophrenia and the affective disorders (37). From a clinical perspective, endogenous depression is frequently masked by both mania and schizophrenia. The phenomenon of post-psychotic depression often appears following successful treatment of positive schizophrenia symptoms with phenothiazines, while depression has long been thought to underscore mania. It is therefore anticipated that the genetic abnormalities will be similar for each group of disorders. The other known genes carried on the short arm of Chromosome 11 are insulin and insulin growth factors 1 & 2 (IGF 1 & 2) (38) and each of these genes play an important role in glucose metabolism. In summary, the following genes contained on the short arm of chromosome 11 are: tyrosine and tryptophan hydroxylase, tyrosinase, IGF 1 & 2, insulin, dopamine D2 and D4 receptors, and the H-ras oncogene which produces the p21 by product. It has been demonstrated that the p21 is a GTP-binding protein, whose activity is negatively regulated by GTPaseactivating protein (39). Burgering et al (40) have shown that ~21 ras is an intermediate of the insulin signal transduction pathway involved in the regulation of gene expression and have found that elevated levels of receptor fibroblasts were associated with an increase in p21 GTP levels. The rate-limiting enzyme in BH4 biosynthesis is GTP-cyclohydrolase (GTPcycl) and it has been shown that decreased levels of GTPcycl reduced the availability of BH4. Furthermore, it appears that reduction of intracellular GTP levels significantly reduce BH4 biosynthesis (42). Thus, the GTP-binding p21 ras may ultimately not only affect insulin receptor activity but may also modulate the biosynthesis of BH4, thus exerting an indirect control over the enzymes, tyrosine and tryptophan hydroxylases. While TH is essential to the catecholamine and dopaminergic pathways, TPH is essential to the serotonergic pathway. All three pathways are seriously impaired in schizophrenia (43). BH4 is a complex pterin and cofactor of TH and is essential for the biosynthesis of DOPA and dopamine (44) and,
117 consequently, influences the turnover of both catecholamines (essential for glucose utilization) and serotonin. In addition, BH4 is essential for brain cells to produce monoamine neurotransmitters and low levels of BH4 have been associated with certain mental disorders (45). Some studies report that supplements of BH4 have improved outcomes in autism, juvenile Parkinsonism and phenylalanemia (46, 47). Thus, if levels of the by product p21 are reduced, then the activity of BH4, TH, and TPH will be seriously compromised along with the glucose metabolic, dopaminergic, and serotonergic pathways. Pterin metabolism has also been implicated in the genesis of depression. It has been found that patients with severe depression had a neopterin: biopterin (N:B) ratio which was significantly higher than the normal controls. ECT reduced the N:B ratio towards control values which implies that, in depression, there is a failure to convert neopterin to biopterin which reduces the availability of tetrahydrobiopterin. It was postulated that since the cofactor, BH4, is essential for noradrenaline, serotonin and dopamine formation, low levels of BH4 may exert a rate limiting control over monoamine synthesis thought to be implicated in depressive disorders (48). Furthermore, ECT not only increases the activity of BH4 but tyrosine hydroxylase as well, all of which serves to improve glucose transport into the cells (49). Weiner et al (50) have also confirmed that ECT increases TH and GTP cycle activity and BH4 levels in the locus ceruleus and hippocampus for up to 4 days after treatment. Thus, low levels of BH4 not only account for depression, but may also account for the rather interesting observation that cancer and schizophrenia appear to be mutually exclusive conditions. It is highly probable that reduced availability of BH4 is due to reduced levels of the p21 by product of the H-ras oncogene. Consequently, since cancer is associated with elevated levels of p21 and mental illness with reduced levels of p2 1, the perceived mutual exclusivity is explained. Abnormality of p21 levels may also explain the lack of genetic confirmation for the claimed association between bipolar disorder and the short arm of chromosome 11 since the mutation could occur at the level of transcription rather than with the H-ras gene itself. Reduced availability of BH4 will also downregulate the activity of tyrosine hydroxylase which promotes glucose metabolism in the neuron by means of facilitated diffusion. This lies in direct contrast to the astocytes where the insulin receptor (of which tyrosine kinase is a subunit (51, 52)), promotes glucose metabolism by means of active transport. Astrocytes constitute 60% of the brain mass and the end feet cover 95% of the blood-brain barrier (53).
118
MEDICAL HYPOTHFSES
Thus, the astrocyte functions as a buffer zone between the highly protected neuron and the blood-brain barrier, the recognition of which led to the postulation of a simple ‘functional triad’ that reflects the interdependence of the neuron, astrocyte and the bloodbrain barrier (Fig.) which is consistent with the recent identification of five glucose transporters (54). Of these five glucose transporters, GLUT- 1 specialises in the endothelial cells of the blood-brain barrier while GLUT-3 is active in the astrocytic glial cell (55). It is also postulated here that p2 1 may have the duel effect on both TH and insulin receptor functions by modulation of GTP availability for insulin signal transduction and BH4 biosynthesis.
To summarize, central glucose metabolism is adversely affected in a number ways: (i) HCAs inhibit the activity of tyrosine hydroxylase directly (19); (ii) HCAs inhibit the action of BH4 noncompetitively (20, 21); (iii) low levels of p21 inhibit the activity of BH4 which, in turn, inhibits the activity of tyrosine hydroxylase; (iv) low levels of BH4 negatively affects the turnover of catecholamines (essential for glucose utilization); (v) smoking leeches magnesium out of the cells which compromises the efficiency of the Na+/K+,Ca+, and Na/H+ pumps that drive glycometabolism (56). This means that the schizophrenic brain is in a diabetic state due to impoverished glucose uptake into the cells. For this reason the term
CHROMOSOME311 D4
Ins 1GFl lGF2
Fig. The physiological interaction of neuron, astrocytic glial cell and blood-brain barrier:the p21 gene-product (if defective) would interferewith the tyrosine and tryptophanhydroxylases (by inhibiting tetmhydrobiopterin(BH4)‘j.The functional integrity of the insulin receptormay be disturbedor impaired. This could result in the permeabilityof the blood brain barrier.
SCHIZOPHRENIA:
AN EXTENDED ETIOLOGICAL
EXPLANATION
‘cerebral diabetes’ has been proposed as a redefinition of mental illness which includes both schizophrenia and the affective disorders and this model has been extensively elaborated upon in relation to unipolar depression elsewhere (57). Such a redefinition is further supported by positron emission tomography (PET) scans which show a marked impairment of glucose metabolism in the cortical and subcortical areas of the brain (58). Reconceptualizing mental illness as ‘cerebral diabetes’ is particularly compelling once it is recognised that: (i) anecdotally, the incidence of diabetes among first degree relatives of the psychiatrically ill patients appears to be well over 50%; and (ii) the incidence of diabetes among patients with an affective disorder is 10%. This percentile is considerably higher than for the general population in relation to whom the incidence of diabetes is approximately 2% (59). Studies have reported mood changes with hyperglycaemia; brain glucose and fluid shifts in diabetes (60); and reduced glucose utilisation (61) and hyperinsulinaemia (62) in depressives. In addition, improved peripheral diabetic control has been obtained with ECT (63) while ‘insulin coma therapy’ was used in the affective disorders and schizophrenia with moderate success (64, 65). It is also not without significance that low doses of insulin have recently been found effective in the treatment of tardive dyskinesia (66). Thus, ‘cerebral diabetes’ as a model for serious mental disorders when conjoined with varying avenues of neurotoxic damage damage presents an attractive conceptual framework for understanding the etiology of mental illness and may serve to explain the ventricular enlargement observed on computed tomography scans (67, 68). Neurotoxicity and glycometabolism The N-methyl-D-asartate (NMDA) channel is one of three glutamate receptor subtypes (which includes AMPA and kainate receptors). It appears to mediate hypoglycemic, hypoxic, epileptic and toxin-related damage to the CNS (69, 70) and dopamine release in the striatum (71). This channel, which is highly permeable to Ca2+, is essential for excitatory synaptic transmission together with the plasticity that underlies memory and learning. Oxygen (e.g. hypoxia) and energy deficits (e.g. schizophrenia) can cause excitotoxicity or neuronal cell death through the activation of excitatory amino acid receptors (72, 73), while the pattern of neuronal damage in the cerebral cortex, consistent with that found in Huntington’s disease, is due to NMDA excitotoxic lesions (74). But the NMDA receptor channel can also initiate neuronal
119 dysfunction and death due to its role in the mediation of neurotoxicity. In response to neurotoxic damage that obtains from chronic alcohol exposure (or persistent exposure to heterocyclic amines), the NMDA receptors become hyperexcitable which initiates further toxicity due to an increase in intracellular calcium (75). This means that the neurotoxic damage caused by HCAs which systematically block dopamine reuptake, is compounded by the toxicity induced by an influx of intracellular calcium through increased NMDA receptor activation. It has also been reported that NMDA-type glutamate receptors are essential for the dopamine Dl-neurotensin interaction which is disrupted by drugs of abuse that mimic schizophrenic and paranoid-like symptoms (76). As previously stated, NMDA receptors are activated in response to hypoglycemic, hypoxic, epileptic and neurotoxic damage. Thus, with respect to schizophrenia, the NDMA receptors are liable to become hyperexcitable due to the compounding effect of hypoglycemia caused by impaired glycometabolism and neurotoxicity induced by heterocyclic amines. In response to NMDA receptor activation polamines, spermine and spermidine, are released into the extracellular space which causes longterm potentiation, synaptic plasticity and neurotoxicity (77). Capillary NMDA receptors are also involved in the regulation of blood-brain barrier and function, and polyamines are implicated in blood-brain barrier breakdown in response to cryogenic injury (78). Further, it has been reported that increased concentrations of polyamines are released in the brain in response to ischemia and brain trauma leading to excitotoxic neuronal death (79). In addition, the relationship between stress and subsequent decompensation with a serious mental disorder has long been noted but the biochemical pathway that mediates between these two events has remained elusive. Recent research indicates that the subjective experience of stress increases blood-brain barrier permeability (BBBP) (80-82) due to the release of histamines (83-86). Thus, sustained increase in blood-brain barrier permeability in response to stress exposes the organism to the risk of further neurotoxic damage, particularly from pervasive exposure to heterocyclic amines in food and air pollution. This means that emotional stress may well activate the capillary NMDA receptors, together with the release of polyamines and histamines, which would exacerbate blood-brain barrier permeability and/or breakdown. There is some empirical evidence to support this contention. Tyramine is a monoamine not normally considered capable of crossing the blood-brain barrier. In a study conducted by Swash et al (87) a
120 tyramine challenge was given to 15 epileptic patients using a double-blind placebo-controlled design and abnormal spike activity and sharp waves were subsequently monitored on an EEG. Since it is now known that epileptic abnormalities can activate the NMDA receptors which can compromise blood-brain barrier integrity, the mechanism of the tyramine response can now be elucidated. Conclusion The basic hypothesis being advanced here, is that when an underlying cerebral diabetic condition conjoins with the physiological consequences of stress, NMDA receptor hyperexcitability, and neurotoxic damage then schizophrenia will occur. It has been argued that the underlying cerebral diabetic condition arises from reduced levels of p21 which produces low availability of tetrahydrobioterin that, in turn, compromises the activity of tyrosine hydroxylase and tryptophan hydroxylase. This depressed activity negatively impacts on both dopaminergic and serotonergic neurotransmission as well as downregulating glycometabolism. When these endogenous events are conjoined with either emotional or organic stress, which compromises the integrity of the blood-brain barrier, and exposure to heterocyclic amines from either the food chain, air pollution or cigarette smoke, the brain is tipped over into a severe metabolic crisis which results in the presentation of what is commonly known. as schizophrenia. It is hoped that this causal model will provide not only profitable directions for future empirical research but also a viable model for future rehabilitation programs. While the stress component can be adequately addressed by a variety of psychoeducational programs, and the neurotoxicity from HCAs can be managed by dietary regulation and QUIT smoking campaigns, the underlying diabetic condition requires more sophisticated medical intervention. It has been found that, peripherally, vanadium compounds can reduce insulin resistance and improve insulin receptor binding, and they seem able to bypass the effect of the insulin receptor on intracellular messengers. It would seem, therefore, that this is one possible approach centrally (88). Neuronal activity depends on the activity of tyrosine hydroxylases, and tyrosine hydroxylase requires phosphorylation by four serine kinases for full activation. Anything which inhibits this process potentially inhibits full transmission capacity; the cofactor tetrahydrobiopterin is critical to both tyrosine and tryptophan hydroxylase and the heterocyclic amines reduce the efficiency of these hydroxylases. Therapeutically, it would seem possible that oral tetrahydrobiopterin may be used in depres-
MEDICAL HYPOTHESES
sion and schizophrenia as a means of compensating for reduced levels of ~21. The BH4 cofactor is very important because it is derived from the biosynthesis of GTP (the G-protein precursor) and it has already been used with some success in juvenile Parkinsons disease and autism (89). Recently, IGF infusions have been used for Down’s syndrome and in cases of refractory hyperinsulinism, successfully (90). It is proposed, therefore, from the above models, that IGF infusion might have therapeutic benefit in patients with unipolar depression and schizophrenia. Theoretically, IGF has the potential to bypass ‘insulin resistance’ in the CNS and, due to its stimulatory effects on oligodendrocyte myelination, it might also address some degree of neurotoxic damage. Thus, the therapeutic interventions that might be considered in the near future for the treatment of mental illness generally, and schizophrenia in particular, are magnesium and vanadium supplements, tetrahydrobiopterin, and IGF infusions. The future direction of empirical research points to investigation of the H-ras oncogene and its ~21 by product in conjunction with the activity of tetrahydropbiopterin. Acknowledgements 1 wish to pay tribute to my co-researcher, John C Newman, BSc, MB, BS, without whose collaboration this paper could not have been written. His untimely demise has been a sad loss both personally and professionally. We wish to thank Magda Heaslip for her assistance in the preparation of the computer generated diagram. We also wish to extend our gratitude to Mr John Layhe, Area Director of Nursing, Illawarra Area Health Service, for kindly funding the publication of this research.
References 1. Lohr J B, Flynn K. Smoking and schizophrenia. Schizophr Res 1992; 8: 93-102. 2. Sandyk R, Kay S R. Tobacco addiction as a marker of age at onset of schizophrenia. Int J Neurosci 1991; 27: 259-262. 3. Sandyk R, Kay S R. Drug induced parkinsonism: relationship to age of onset of schizophrenia. Funct Neurol 1991; 6: ISl157. 4. Goff D C, Henderson D C, Amico E. Cigarette smoking in schizophrenia: a relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149: 1189-1194. 5. Decina P, Caracci G, Sandik R, Berman W, Mukherjee S, Scapicchio P. Cigarette smoking and neuroleptic-induced parkinsonism. Biol Psychiatry 1990; 28: 502-508. 6. Svensson T H, Grenhoff J, Engberg G. Effect of nicotine on dynamic function of brain catecholamine neurons. Ciba Found Symp 1990; 152: 169-180. I. Amdt S, Tyrrell G, Flaum M, Andreasen N C. Comorbidity of substance abuse and schizophrenia: the role of pm-morbid adjustment. Psycho1 Med 1992; 22: 379-388. 8. Chen C, Balagh M, Bathija J, Howanitz E, Plutchik R, Conte H R. Substance abuse among psychiatric inpatients. Compr Psychiatry 1992; 33: 60-64. 9. Rossetti 2 L, Hmaiden Y, Gessa G L. Marked inhibition of mesolimbic dopamine release: a common feature of ethanol,
SCHIZOPHRENIA:
AN EXTENDED
ETIOLOGICAL
EXPLANATION
morphine, cocaine and amphetamine abstinence in rats. Em J Pharmacol 1992; 221: 227-234. 10. Reynolds G P. Beyond the dopamine hypothesis. The neurochemical pathology of schizpophrenia. Br J Psychiatry 1989; 155: 305-316. 11. Wyatt R J, Kirch D G, DeLisi L N. Schizophrenia: biochemical, endocrine, and immunological studies. In Kaplan H I, &dock, B J, eds. Comprehensive Textbook of Psychiatry V. 5th ed. 1989. 12. Seeman P Dopamine receptor sequences. Therapeutic levels of neuroleptics occupy D2 receptors, clozapine occupies D4. Neuropsychopharrnacology 1992; 7: 261-284. 13. Chung K T, Stevens S E Jr, Cemiglia C E. The reduction of azo dyes by the intestinal microflora. Crit Rev Microbial 1992; 18: 175-190. 14. Lancaster F E, Lawrence J E Determination of total nonsulphonated aromatic amines in soft drinks and liquid chromatography. Food Addit Contam 1992; 9: 171-182. 15. Minami M, Takabashi T, Maruyama W, Takahashi A, Nagatsu T, Naoi M. Allosteric effect of tetrahydrobiopterin cofactors on tyrosine hydroxylase activity. Life Science 1992; SO: IS20. 16. Sugimura T. Multistep carcinogenesis: a 1992 perspective. Science 1992; 258: 603-607. 17. Wakabayashi K, Nagao M, Esumi H, Sugimura T. Foodderived mutagens and carcinogens. Cancer Res 1992; 52(7 Suppl): 2092s-2098s. 18. Minchin R F, Reeves P T, Teitel C H et al. N- and Oacetylation of aromatic and heterocyclic amine carcinogens by human monomorphic and polymorphic acetyltransferases expressed in COS-1 cells, Biochem Biophys Res Commun 1992; 185: 839-844. 19. Maruyama W, Minami M, Ota A et al. Reduction of enzymatic activity of tyrosine hydroxylase by heterocyclic amine, 3amino 1, 4-dimethyl-SH-pyrido (4,3-b) indole (Tip-P-l), was due to reduced affinity to a cofactor biopterin. Neurosci Lett 1991; 125: 85-88. 20. Ota M, Naoi M, Hamanaka T, Nagatsu T. Inhibition of human brain aromatic L-amino acid decarboxylase by cooked foodderived 3-amino-1-methyl-SH-pyrido (4,3-b) indole (Trp-P-2) and other heterocyclic amines. Neurosci Lett 1990; 116: 372378. 21. Naoi M, Hosoda S, Ota M, Takahashi, Nagatsu T. Inhibition of trytophan hydroxylase by food-derived carcinogenic heterocyclic amines, 3-amino-1-methyl-SH-pyrido (4,3-b) indole and 3-amino- 1,4-dimethyl-SH-pyrido (4,3-b) indole. Biochem Pharmacol 1991; 41: 199-203. 22. Naoi M, Takahashi T, lchinose H, Wakabayashi K, Sugimura T, Nagatsu T. Uptake of heterocyclic amines, Trp-P- 1 and TrpP-2, into clonal pheochromocytoma PCl2h cells by dopamine uptake system. Neurosci Lett 1989; 99: 317-322. 23. Lewis Cl, David A, Andrt%sson S, Allebeck P. Schizophrenia and city life. Lancet 1992; 340: 137-140. 24. Hare E. Schizophrenia as a recent disease. Br J Psychiat 1988; 153: 521-531. 25. Gopalaswamy A K, Morgan R. Smoking in chronic schizoohrenia. Br J Psvchiat 1986; 149: 523. 26. Mortensen P B: Neuroleptic medication and reduced risk of prostrate cancer in schizophrenic patients. Acta Psychiatr Scand 1992; 85: 390-393. 27. Mortensen P B. Neuroleptic treatment and other factors modifying cancer risk in schizophrenic patients. Acta Psychiatr Scand 1987; 75: 585-590. 28. Wogan G N. Molecular epidemiology in cancer risk assessment and prevention: recent progressand avenues for further research. Environ Health Perspect 1992; 98: 167-178.
121 29. Watson D M, Elton R A. Jack W J, Dixon J M, Chetty U, Miller W R. The H-ras oncogene product p21 and prognosis in human breast cancer. Breast Cancer Research Treat 1991; 17: 161-169. 30. Egeland J A, Gerhard D S, Pauls D L et al. Bipolar affective disorders linked to DNA markers on chromosome 11. Nature 1987; 325: 783-787. 31. Law A, Richard C W 3rd, Cottingham Jr R W, Lathrop G M, Cox D R, Myers R M. Genetic linkage analysis of bipolar affective disorder in an Old Order Amish pedigree. Hum Genet 1992; 88: 562-568. 32. Mendlewicz J, Leboyer M, De Bruyn A et al. Absence of linkage between chromosome 11~15 markers and manicdepressive illness in a Belgian pedigree. Am J Psychiat 1991; 148: 1683-1687. 33. Mitchell P, Waters B, Morrison N, Shine J, Donald J. Eisman J. Close linkage of bipolar disorder to chromosome 11 markers is excluded in two large Australian pedigrees. J Affect Disord 1991; 21: 23-32. 34. Mendlewicz J. Sevy S, Mendelbaum K. Minireview: Molecular genetics in affective illness. Life Science 1993; 52: 231242. 35. Gelemter J, Kennedy J L, van To1H H, Civelli 0, Kidd K K. The D4 dopamine receptor (DRD4) maps to distal 1lp close to HRAS. Genomics 1992; 13: 208-210. 36. Nielsen D A, Dewan M, Goldman D. Genetic mapping of the human tryptophan hydroxylase gene on chromosome 11, using an intronic conformational polymorphism. Am J Hum Genet 1992; 51: 1366-1371. 37. Newman J C, Holden R J, Mooney P. The Psychoses, Schizophrenia and the Dementias: A Continuum of Liability? Med J Aust 1993; 158: 362. 38. Sten-Linder M, Wedell A, lselius L, Efendic S, Luft R, Luthman H. DNA polymorphisms in the human tyrosine hydroxylaselinsulin-like growth factor 11chromosomal region in relation to glucose and insulin responses. Diabetologia 1993; 36: 25-32. 39. Nori M, L’ Allemain G, Weber M J. Regulation of tetradecanoyl phorbol acetate-induced responses in NIH 3T3 cells by GAP, the GTPase-activating protein associated with p2lc-ras. Mol Cell Biol 1992; 12: 936-945. 40. Burgering B M, Medema R H, Maassen J A et al. Insulin stimulation of gene expression mediated by p2lra.s activation. The EMBO Journal 1991; 10: 1103-1109. 41. Katoh S, Sueoka T. Development of tetrahydrobiopterin and GTP cyclohydrolase in salivary glands of rats. lnt J Biochem 1986; 18: 131-135. 42. Hatakeyama K. Harada T, Kagamiyama H. IMP dehydrogenase inhibitors reduce intracellular tetrahydrobiopterin levels through reduction of intracellular GTP levels. Indications of the regulation of GTP cyclohydrolase I activity by restriction of GTP availability. J Biol Chem 1992; 267: 20734-20739. 43. Wyatt R J, Kirch D G, DeLisi L N. Schizophrenia: biochemical, endocrine, and immunological studies. In: Kaplan H I, Sadock B J, eds. Comprehensive Textbook of Psychiatry/V. 5th ed. 1989. 44. Jung W, Herken H. Inhibition of bioterin synthesis and DOPA production in PC-12 pheocbromocytoma cells induced by 6aminonicotinamide. Naunyn. Schmiedebergs. Arch Pharmacol 1989; 339: 424432. 45. Eto 1. Bandy M D, Butterworth C E Jr. Plasma and urinary levels of biopterin, neopterin. and related pterins and plasma levels of folate in infantile autism. J Autism Dev Disord 1992; 22: 295-308. 46. Dissing I C, Guttler F, Pakkenberg H et al. Tetrahydrobiopterin and Parkinson’s disease. Acta Neurol Stand 1989; 79: 493-
122 499. 41. Tanaka H, lshiiawa A, Ginns E I, Miyatake T, Tsuji S. Link-
48.
49.
50.
51.
52.
53. 54. 55.
56.
57. 58.
59. 60.
61. 62.
63. 64.
65. 66. 67.
68.
age analysis of juvenile parkinsonism to tyrosine hydroxylase gene locus on chromosome 11.Neurology 1991; 41: 719-722. Anderson D N, Ahou-Saleh M T, Collins 1 et al. Pterin metabolism in depression: an extension of the amine hypothesis and possible marker of response to ECT. Psycho1 Med 1992; 22: 863-869. Hashimoto R, O&i N, Ohta T, Kasahara Y, Kaneda N, Nagatsu T. Plasma tetrahydrobiopterin levels in patients with psychiatric disorders. Neuropsychobiology 1990-1991; 23: 140-143. Weiner N, Hossain M A, Masserano J M. The effects of electroconvulsive shock on catecholamine function in the locus ceruleus and hippocampus. J Neural Transm 1991; 34: (Suppl) 3-9. Hayashi H, Kamohara S, Nishioka Y et al. Insulin treatment stimulates the tyrosine phosphorylation of the alpha-type 85kDa subunit of phosphatidylinositol 3-kinase in vivo. J Biol Chem 1992; 267: 22575-22580. Gao Y. Keane N, Levine B A, Alejos R, Ellis L. Structural characterisation of substrate binding to human insulin receptor tyrosine kinase domain. Biochem Sot Trans 1992; 20: 2698. Pardridge W N. Advances in cell biology of blood-brain bartier transport. Semin Cell Biol 1991; 2: 419-426. Lienhard G E. Slot J W. James D E, Mueckler M M. How cells absorb glucose. Sci. Am 1992; 266: 34-39. Pardridge W M, Baodo R J, Farm1 C R. Brain-type glucose transporter (GLUT 1) is selectively localized to the blood brain barrier. J Biol Chem 1990; 265: 18035-18040. Newman J C, Amarasingham J L. The pathogenesis of eclampsia: The ‘magnesium ischaemia’ hypothesis. Med Hypoth 1993; 40: 250-256. Newman 3 C, Holden R J. The ‘cerebral diabetes’ paradigm for unipolar depression. Med Hypoth 1993; 41: 391-408. Wiesel F A. Glucose metabolism in psychiatric disorders: how can we facilitate comparisons among studies? J Neural Transm 1992; 37: (Suppl) I-18. Russell J D, Johnson G F S. Affective disorders, diabetes mellitus and lithium. Aust NZ J Psychiat 1981; 15: 349-353. Gonder-Federick L A, Cox D J, Bobbitt S A, Pennebaker J W. Mood changes associated with blood glucose fluctuations in insulin-dependent diabetes mellitus. Health Psychology 1989; 8: 45-59. Mendels J, Frazer A. Alterations in cell membrane activity in depression. Am J Psychiat 1974; 131: 1240-1246. Mueller P S, Henninger G R, McDonald R K. Intravenous glucose tolerance test in depression. Arch Gen Psychiat 1974; 131: 1240-1246. Fakhri 0, Fadhli A A, el Rawi R M. Effect of electroconvulsive therapy on diabetes mellitus. Lancet 1980; October 11: 775-777. Laqueur H P. insulin coma therapy. In: Berger P A, Brodie H, eds. American Handbook of Psychiatry, 2nd ed, Vol 5. New York: Basic Books Inc, 1986: 526-528. Ackner B, Oldham A J. Insulin treatment of schizophrenia. Lancet 1962; March 10: 504-506. Mouret J, Malika K, Le.moine, Sebert P. Low doses of insulin as a treatment of tardive dyskinesia: conjuncture or conjecture? Eur Neurol 1991; 31: 199-203. Weinberger D R, De Lisi L E, Terman G P, Targum S, Wyatt J. Computed tomography in schizophmniform disorder and other acute psychiatric disorders. Arch Gen Psychiatry 1982; 39: 778-783. Pearlson G D. Clinical correlates of lateral ventricular enlargement in bipolar affective disorder. Am J Psychiatry 1984; 141:
MEDICAL HYPOTHESES
253-256. 69. Kutsuwada T, Kashiwabuchi N, Mori H et al. Molecular diversity of the NMDA receptor channel. Nature 1992; 358: 3-l. 70. Usherwood P N, Blagbrough I S. Spider toxins affecting glutamate receptors: polyamines in therapeutic neurochemistry. Pharmacological Therapeutics 1991; 52: 245-268. 71. Martinez-Fong D, Resales M G, Gongora-Alfaro J L, Hemandez S, Aceves J. NMDA receptor mediates dopamine release in the striatum of unanesthetized rats as measured by brain microdialysis. Brain Res 1992; 595: 309-315. 72. Peruche B, Krieglstein J. Mechanisms of drug actions against neuronal damage caused by ischemia-an overview. Prog Neuropsychopharmocol Biol Psychiatry 1993; 17: 21-70. 13. Beal M E Mechanisms of excitotoxicity in neurologic diseases. FASEB J 1992; 6: 3338-3344. 74. Storey E, Kowall N M, Finn S F, Mazumk M F, Beal M F. The cortical lesion of Huntington’s disease: further neurochemical characterization, and reproduction of some histological and neurochemical features by N-methyl-D-aspartate lesions of rat cortex. Ann Neural 1992; 32: 526534. 75. Lovinger D M. Excitotoxicity and alcohol-related brain damage. Alcohol Clin Exp Res 1993; 17: 19-27. 76. Hanson G R, Singh N, Merchant K, Johnson M, Bush L, Gibb J W. Responses of limbic and extrapyramidal neurotensin systems to stimulants of abuse. Involvement of dopaminergic mechanisms. Ann N Y Acad Sci 1992: 668: 165-172. 77. Fage D, Voltz C, Scatton B, Carter C. Selective release of spermine and spermidine from the rat striatumby N-methylD-aspartate receptor activation in vivo. J Neurochem 1992; 58: 2170-2175. 78. Koenig H, Trout J J, Goldstone A D, Lu C Y. Capillary NMDA receptors regulate blood-brain barrier function and breakdown, Brain Res 1992; 588: 297-303. 79. Lombardi G, Szekely A M, Bristol L A, Guidotti A, Manev H. Induction of omithine decarboxylase by N-methyl-D-aspartate receptor activation is unrelated to potentiation of glutamate excitotoxicity by polyamines in cerebellar granule neurons. J Neurochem 1993; 60: 1317-1324. 80. Anagnostakis D, Messaritakis J, Damianos D, Mandyla H. Blood-brain barrier permeability in ‘healthy’ infected and stressed neonates. J Pediatrics 1992; 121: 291-294. 81. Sharma H S, Cervos-Navarro J, Dey P K. Increased bloodbrain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats. Neuroscience Research 1991; 10: 211-221. 82. Belova T I, Sudakov K V. Morphofunctional changes in brain neurons during emotional stress. Vestn Akad Med Nauk SSSR 1990; 2: 11-13. 83. Sharma H S, Nyberg F, Cervos-Navarro J, Dey P K. Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain ocdema and serotonin levels: an experimental study in conscious young rats. Neuroscience 1992; 50: 445-454. 84. Butt A M, Jones H C. Effects of histamine and antagonists on electrical resistance across the blood-brain barrier in rat brainsurface microvessels. Brain Research 1992: 569: 100-105. 85. Boertje S B, Ward S, Robinson A. HZ-receptors mediate histamine-induced variations in the permeability of the bloodbrain barrier of rats. Res Commun Chem Path01 Pharmacol 1992; 76: 143-154. 86. Greenwood J. Mechanisms of blood-brain barrier breakdown. Neuroradiology 1991; 33: 95-100. 87. Swash M, Moffett A M, Scott D F. Tyramine activates the EEG in epileptic patients. Nature 1975; 258: 749. 88. Scimeca J C, Ballotti R, Filloux C, Van Obberghen E. lnsulin and orthovanadate stimulate multiple phosphotyrosine-
SCHIZOPHRENIA: AN EXTENDED ETIOLOGICAL EXPLANATION
containing serine kinases. Mol Cell Biochem 1992; 109: 139147. 89. Naruse H, Hayashi T. Takesada M, Nakane A, Yamazaki K. Metabolic changes in aromatic amino acids and monoamines in infantile autism and development of new treatment related
123 to the finding. No To Hattatsu 1989; 21: 181-189. 90. Usala A-L, Madigan T, Burguera B et al. Brief Report: Treatment of insulin-resistant diabetic ketoacidosis with insulin-like growth factor f in an adolescent with insulin-dependent diabetes. N Engl J Med 1992; 327: 853-857.