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Updated: Jan 31, 2021

By R.J Holden ,RPN , Phd.


In the previous article on major depression the interplay between the inflammatory cytokines, glucose transporters, insulin and the neuropeptides were discussed. With respect to schizophrenia, the interaction between these entities also occurs but in a slightly different manner. When brain insulin is elevated, energy metabolism and neurotransmission is hyperactive resulting in the positive symptoms of schizophrenia. Conversely, when brain insulin is inhibited, energy metabolism and neurotransmission are hypoactive resulting in the negative symptoms of schizophrenia (1)


Wang and Lui (2) argued that the brain itself is capable of synthesizing insulin while Craft (3) identified the three brain areas where insulin receptors are most dense. These are the hypothalamus, hippocampus and olfactory bulb that also coincides with the areas most damaged in Alzheimer’s Disease.

Brain insulin increases the synthesis and release of dopamine (DA) and norepinephrine (NE). Psychiatry has long endorsed the hypothesis that elevated dopamine is the primary cause of decompensation in schizophrenia. However, while it is certainly the case that dopamine is elevated in positive schizophrenia, the hypothesis fails to acknowledge the role insulin and the inflammatory cytokines play in dopamine elevation.

Positron emission tomography (PET) scans have consistently shown impaired glucose utilization in the brains of patients with various neuropsychiatric disorders. It has been found that mild elevation of interleukin 1-beta (IL-1 beta) and/or tumour necrosis factor-alpha (TNF-alpha) increases insulin secretion while moderate to high levels of these cytokines inhibits insulin secretion. Thus, in psychiatric disorders in which more than one inflammatory cytokine is elevated, such as negative schizophrenia, glucose utilization is impaired. But this is further complicated by the fact that insulin also influences the opioid peptides that, in turn, influence the cytokines. This means there is a causal interaction between insulin, the cytokines and the opioid peptides that together effect energy metabolism and neurotransmission.


Cholecystokinin (CCK) is a satiety peptide and also a DA agonist. Thus, CCK is elevated in positive schizophrenia in which DA is overexpressed and downregulated in negative schizophrenia in which DA is under expressed. In addition to CCK, neuropeptide Y (NPY) also influences appetite but in the opposite direction to CCK. Elevated CCK and downregulated NPY both inhibit appetite. In positive schizophrenia CCK is elevated while neuropeptide Y (NPY) is downregulated thereby inhibiting appetite. In negative schizophrenia NPY is elevated and CCK is downregulated thereby increasing appetite which possibly accounts for the tendency of patients with negative schizophrenia to become overweight. Apart from stimulating the appetite, NPY also enhances memory and cognitive performance as well as possessing powerful anxiolytic properties.

In positive schizophrenia, the cytokines interleukin-2 (IL-2), interleukin-1 beta (IL-1 beta) interleukin-6 (IL-6) and interferon-gamma (IFN-gamma) are all elevated. IL-2 is a DA agonist and the effect of the typical neuroleptics is to downregulate IL-2 and thus, inhibit DA. In negative schizophrenia the atypical neuroleptics upregulate IL-2 and thus increase DA levels. As an aside, immunotherapy with interleukin-2 (IL-2) is frequently administered to patients with advanced carcinoma that often induces neuropsychiatric symptoms and delusional disorders. It has also been found that IL-2 rapidly induces the release of TNF-alpha followed by IFN-gamma and IL-6. IL-2 is also involved in IFN-gamma production both of which are produced by T-helper cells. Thus, IL-2 and IFN-gamma follow the same pattern of dysregulation. In positive schizophrenia these cytokines are both elevated while in negative schizophrenia they are both downregulated.

It has been found that interleukin-6 (IL-6) is elevated in both positive and negative schizophrenia. This is due to the observed gender bias that exists with respect to the relative age of onset between the sexes. Males tend to succumb to schizophrenia comparatively early in life. On the other hand, females increase their vulnerability during periods of natural estrogen decline such as: (i) during menstruation, (ii) during the post-partum period and (iii) post-menopausal period. On the other hand, females enjoy protection from a schizophrenic illness during pregnancy. This pattern of illness onset can be explained by the fact that estrogen is a powerful inhibitor of IL-6. Thus, during periods of high estrogen availability, IL-6 levels are suppressed while during periods of natural estrogen decline IL-6 is elevated. On the other hand, the estrogen content in males is deleteriously affected by elevated insulin that inhibits the activity of the enzyme aromatase. This inhibition of aromatase activity negatively influences the conversion of androgens to estrogen in male schizophrenics. This accounts for the gender difference with respect to the onset of schizophrenia (4).


Glucose transporter-1 (GLUT-1) is most abundant in the basal ganglia and the thalamus while glucose transporter-3 (GLUT-3) is most abundant in the frontal cortex. Consequently, if insulin is either overexpressed or downregulated in the brain it will have a direct impact on the basal ganglia, thalamus and frontal cortex resulting in a significant increase or decrease in glucose utilization in the brain. Thus, any cytokine or neuropeptide that disrupts insulin regulation will concomitantly disrupt the glucose metabolic pathway and neurotransmission of the brain. Inhibited function of GLUT-3 explains persistent hypofrontality, (impaired frontal cortical function) found on PET scans of patients with chronic schizophrenia. Similarly, inhibited function of GLUT-1 explains the basal ganglia deficits of decreased activity, disrupted cognition and flattened affect associated with chronic schizophrenia. Persistent elevation of IL-2 is an important feature of positive schizophrenia since IL-2 induces four-fold increase in the release of beta-endorphin. This is important because beta-endorphin modulates IL-2 production, IFN-gamma production and the synthesis of antibodies. Mild elevation of the inflammatory cytokines increases insulin secretion, found in positive schizophrenia. On the other hand, moderate elevation of the cytokines inhibits insulin secretion, found in negative schizophrenia. In positive schizophrenia, Il-2, beta-endorphin and IFN-gamma are all elevated and, conversely, downregulated in negative schizophrenia both of which leads to insulin dysregulation.

GLUT-1 and GLUT-3 are moderately expressed in the parietal cortex (5) an area that processes auditory and visual information. If the expression of glucose transporters increases in response to hyperglycaemia, it may cause hyperexcitability of these brain cells and induce auditory and/or visual hallucinations. Elevated IL-2 is known to give rise to delusional symptoms, hallucinations and delusions all of which are the hallmark of positive schizophrenia. It should also be noted that CCK and IL-2 are elevated in positive schizophrenia both being DA agonists. This explains why dopaminergic hyperactivity is associated with positive schizophrenia and dopaminergic hypoactivity is associated with negative schizophrenia. Finally, elevated CCK, beta-endorphin and downregulated NPY gives rise to the extreme levels of psychotic anxiety in positive schizophrenia while the opposite pattern occurs in negative schizophrenia.

The prominent symptoms of negative schizophrenia are social withdrawal, flattened affect, impaired attention, anhedonia (the inability to feel pleasure) and apathy. Weight gain and reduced psychotic anxiety are also associated with negative schizophrenia due to the elevation of NPY. In negative schizophrenia almost all the inflammatory cytokines and neuropeptides are downregulated (with the exception of NPY), thus, the expression of insulin and beta-endorphin are reduced. This then leads to an elevation of NPY thereby lowering anxiety and increasing appetite.


If it be the case that a bacterial or viral infection can induce schizophrenia in susceptible individuals, an obvious question to ask is: (i) what contributes to this susceptibility; and (ii) is this susceptibility genetically determined? The author, in an epidemiological study found that the prevalence of diabetes mellitus, rheumatoid arthritis and cancer was significantly higher among first degree relatives of schizophrenic patients compared with the prevalence rates for the general population. Consequently, it could well be that the lack of capacity to produce specific antibodies to each of the inflammatory cytokines is what runs in families prone to the development of autoimmune disorders including schizophrenia. Given that beta-endorphin modulates the synthesis of antibodies, the downregulation of beta-endorphin could well contribute to antibody suppression.


1. Holden, R.J., Pakula, I. S., Mooney, P. A. (1997).

A neuroimmunological model of schizophrenia and major

depression: a review. Human Psychopharmacology, Vol 12,


2. Wang, Q and Lu, Z. (1994). The presence and distribution of

insulin in rat brain and its relation to feeding. Chung Kuo et al,

16 (6), 434-437.

3. Craft, S., Dagogo-Jack, S. E., Wiethop, B. V., Murphy, C.,

Nevins, R. T., Fleischman, S., Rice, V., Newcomer, J. W., Cryer,

P. E. (1993). Effects of hypoglycaemia on memory and

hormone levels in dementia of the Alzheimer type: a

longitudinal study. Behavioural Neuroscience, 107, 926-940.

4. Holden, R. J. (1995). The estrogen connection: the

etiological relationship between diabetes, cancer, rheumatoid

arthritis and psychiatric disorders. Medical Hypothesis, 45,


5. Yano, H., Seino, Y., Inagaki, N., Hinokio, Y., Yamamoto, T.,

Yasuda, K., Masuda, K., Someya, Y. and Imura, H. (1991).

Tissue and species difference of the brain type glucose

transporter (GLUT-3). Biochemical and Biophysical Research

Communications, 174, 470-477.


I first met Dr. Phyllis Mooney (Biochemist) when working at the University of Tasmania and Dr. Irwin Pakula (Psychiatrist) when working in a conjoint appointment with the University of Wollongong and the Psychiatric Unit at Shellharbour Hospital.

When at Shellharbour Hospital I met a wonderful man, Dr John Newman, who taught me how to extract information from Medicine by a process of cross referencing a series of obscure scientific studies, in order to develop a workable hypothesis. To John Newman I am extremely grateful for, without his tutelage, these articles would never have been written.

Of all the psychiatric disorders, Schizophrenia is the most destructive on the lives of those who develop it. For males it usually means they can never marry, own a car, own a house, study or have a job. Their lives are totally consumed battling this terrible illness from their late teens onwards. During my entire career I felt driven to discover what caused this terrible condition. I started with the idea that schizophrenia was a diabetic brain state that I dubbed ‘cerebral diabetes’. From that point, with the considerable help from Medline, I tracked down the biochemical pathway that contributed to the development of schizophrenia.

People with schizophrenia suffer from brain hypoglycaemia. They have difficulty getting up in the morning and gravitate to eating and drinking high sugary food and drinks. For one patient this problem was so marked that he consumed 12 apple turnovers and cream in one sitting each day. In response to this problem, I developed a method of keeping their glycaemic levels evenly balanced during the day. I asked the patients to nibble on dates, figs, almonds and walnuts throughout the day. These dry fruits were chosen because they are rich in magnesium and magnesium assists with glucose uptake into the cells. The patients found that within one day their voices disappeared, they were better able to rise in the morning and voluntarily stopped consuming sugary food and drinks. So, feeling considerably better they were disposed to cooperate with the regimen. And this was the beginning of a very long journey.

R. Holden, Phd.

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