I have another reason to suspect that the condition that psychiatrists refer to as treatment refractive schizophrenia is connected to endocrine dysfunction. The drug Clozapine is the drug of choice in this condition, usually arrived at by a crude process of elimination after administering the range of drugs available for the treatment of psychoses.

Dopamine has been the main suspect in schizophrenia for years but to date this has not been categorically confirmed. Nevertheless the main treatment for schizophrenia has been the drugs in the dopamine receptor antagonist class with some degree of success.

In treatment resistant forms of psychosis these drugs do not suppress the more florid symptoms which indicate two possibilities. The first is that the patient cannot metabolize these drugs due to deficiencies in cytochrome P450’s, the principal enzyme responsible for metabolizing anti-psychotic medication. It is logical that a poor or non-metabolizer will not benefit from drugs requiring P4502D6, P450IA2, P4502C or P4503A. All the current drugs in the psycho-pharmacopeia require these cytochromes for metabolism and apart from the possibility that the patient may be deficient, many other drugs interfere with the metabolism and pharmacokinetic properties.

The drug Clozapine is unusual in that it is a weak antagonist at D2 receptors. This casts some doubt on the dopamine theory as a cause of schizophrenia. Clozapine inhibits α-adrenoreceptors, muscarinic, 5-HT and histamine receptors. Risperidone is also a weak D2 antagonist and operates on 5-HT2 receptors.

The effect on 5-HT receptors is interesting in that elevation of cortisol after prolonged life stress may predispose a patient to mental illness by interfering with brain 5-HT function. This offers an alternative cause of psychotic episodes less reliant on dopamine levels. Endocrine disorders are associated with elevated cortisol. Plasma cortisol is increased in about half of patients with depression but this is not specific to any particular depressive disorder and occurs also in mania and schizophrenia.

Treatment refractive patients may not be suffering from classical dopamine related schizophrenia at all but their psychotic symptoms may be a result of an underlying endocrine dysfunction perhaps in the parathyroid or pituitary. It is hardly surprising that they would not respond to the classic psychiatric medications based on dopamine receptor antagonists.

You may as usual distribute this to as many people as you think may be interested and I am happy that you cite me as author. I am happy to join in any scientific debate on this subject with anyone interested.

Barry Turner – Senior Lecturer Lincoln University UK