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By Robyn Holden


Major Depression is associated with diurnal variation of mood, loss of energy, loss of libido, loss of appetite and early morning waking. The current treatment for Major Depression is the administration of Electroconvulsive Therapy (ECT). A biochemical explanation of the depressive symptoms and the effectiveness of ECT will be addressed later in the discussion.

In the first article on Anxiety, the interaction between the inflammatory cytokines, glucose transporters and insulin was discussed. In major depression the biochemical pathway becomes a little more complicated. Now we have to enter the world of neuropeptides that play a decisive role in many neuropsychiatric conditions. Psychiatrists frequently tell their patients that they are unwell due to a chemical in balance in the brain. But this explanation of psychiatric disorders explains absolutely nothing at all. We need to know what chemicals are involved and also what effect these chemicals have on the brain. We now know that the interplay between the inflammatory cytokines, glucose transporters and insulin play a significant role. But now we must add neuropeptides to the mix.

First, cholecystokinin (CCK) is a satiety peptide the elevation of which leads to a loss of appetite. It has, therefore been postulated that CCK is elevated in major depression given that a loss of appetite is one of the leading symptoms. It has also been found that patients with major depression had reduced expression of somatostatin (SOM), a peptide that regulates spontaneous motor activity in the basal ganglia, rapid eye movement (REM) sleep and stimulates appetite. It is noted that reduced physical activity is another marked symptom of major depression. But of all the neuropeptides the opioid peptide beta-endorphin is downregulated in melancholic patients that directly correlates with feelings of worthlessness, self-reproach and excessive guilt. Finally, neuropeptide Y (NPY) is also downregulated in major depression. NPY is a powerful anxiolytic, thus, reduced concentrations of NPY contributes to high levels of anxiety and loss of appetite found in depression.

In summary, Interleukin-1b (IL-1beta), Interrleukin-6 (IL-6) and Interferon-gamma (IFN-gamma) are all elevated in major depression while Interleulin-2 (IL-2) is downregulated. The action of IL-2 is complicated, but for the purpose of this discussion, IL-2 induces the release of Tumour (TNF-alpha) followed by (IFN-gamma) and (IL-6). Moderate elevation of TNF-alpha and IFN-gamma both inhibit insulin secretion that results in reduced energy metabolism in the brain. Positron Emission Topography (PET) Scans of depressed patients have consistently shown persistent hypofrontality (impaired frontal cortical function) in the brain that’s induced by the inhibition of brain insulin. At this juncture it should be made clear that medicine, has for decades asserted that the brain is an insulin INDEPENDENT organ. In this series of articles on mental illness the exact opposite contention is advanced. Insulin is crucially important for healthy brain metabolism, a fact that’s supported by innumerable scientific studies as well as PET Scans. Elevation of IL-6 in major depression explains another leading depressive symptom, namely, the diurnal variation of mood. Here, the patient’s mood is mildly elevated in the morning but deteriorates as the day wears on. It has been found in a study that IL-6 is also elevated in the morning and declines as the day progresses reaching its lowest point in the evening.


The Glucose Transporters (GLUT 1 and 3) each have a specific role in a specific area of the brain. GLIUT-1 is expressed in the basal ganglia and thalamus while GLUT-3 is expressed in the frontal cortex. Insulin influences the activity of the glucose transporters and, therefore, plays a critical role in energy metabolism as well as brain neurotransmission. The particular areas of the brain most likely to be deleteriously affected are those that rely on GLUT-3 with respect to the frontal cortex and GLUT-1 with respect to the basal ganglia and thalamus. It is therefore hypothesised that the inhibition of GLUT-3 may explain persistently impaired function of the frontal cortex found in PET Scans of patients with major depression. An inhibition of GLUT-1 also explains the basal ganglia deficits of decreased activity, disrupted cognition and flattened affect associated with major depression.

Apart from the Glucose Transporters, the cytokines IFN-gamma and IL-1beta as well as the neuropeptides beta-endorphin and NYP all influence brain insulin secretion. It has been found that acute intravenous administration of beta-endorphin induces an acute release of insulin leading to hyperglycaemia in brain cells. Conversely, a slow infusion of beta-endorphin inhibits insulin secretion leading to hypoglycaemia of brain cells. Both NPY and SOM are downregulated in major depression. It is now known that ECT upregulates SOM while ECT and lithium carbonate upregulates NPY. While the neuropeptides were initially thought to regulate the digestive system, it is now known that the primary role of the neuropeptides is to modulate immune functions. ‘Neuropeptides are only synthesised in immune cells which is why the causal interaction between neuropeptides and cytokines is so intricate.


It has been hypothesised that bacterial or viral infections, vehicle emissions, industrial emissions and pesticides such as Agent Orange and Roundup can induce many psychiatric disorders including major depression. The author conducted an epidemiological study into the comparative prevalence of diabetes mellitus, rheumatoid arthritis and cancer in first degree relatives of schizophrenic patients compared to the prevalence rates of these conditions in the general population. It was found that the prevalence of the above conditions were 2-3 times higher than that in the general population. This could well be due to the incapacity to produce antibodies to each of the inflammatory cytokines that is genetically transmitted resulting in any one of a number of autoimmune disorders, including psychiatric disorders. Administration of antibodies to the inflammatory cytokines, known to be implicated in psychiatric disorders, maybe a line of research well worth pursuing.


Robyn J Holden, Irwin Pakula and Phyllis A Mooney (1997). (A neuroimmunological model of schizophrenia and major depression: A Review. ) Human Psychopharmacology. Vol 12. 177-20.

Panerai, A. E. and Sacerdote, P. (1993). ( Brain and gut neuropeptides in peripheral blood mononuclear cells. ) Journal of Physiology, 87,283-289.

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