Schizophrenia hypothesis

Pilowsky, LS, Costa, DC and Eli, PJ (1992) Clozapine single photon emission tomography and the D2 dopamine receptor blockade hypothesis of schizophrenia. Lancet 340 199-202. 

Carlsson, A. (1988). The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology, 1(3), 179-86. 

Schizophrenia is a chronic, complex psychiatric disorder affecting approximately 1% of the population worldwide. The chronic nature of the illness, in addition to the early age of onset, results in direct and indirect health care expenditures in the U.S., which amount to approximately 30 to 64 billion dollars per year [4]. It is perhaps the most devastating of psychiatric disorders, with approximately 10% of patients committing suicide. The dopamine hypothesis of schizophrenia postulates that overactivity at dopaminergic synapses in the central nervous system (CNS), particularly the mesolimbic system, causes the psychotic symptoms (hallucinations and delusions) of schizophrenia. Roth and Meltzer [5] have provided a review of the literature and have concluded a role for serotonin as well in the pathophysiology and treatment of schizophrenia. The basic premise of their work stems from the known interaction between the serotonergic and dopaminergic systems. 

The D2 antagonist activity of current antipsychotics led to the "dopamine hypothesis," which states that the pathophysiology of schizophrenia is due to excessive dopaminergic neurotransmission and dysfunctional D2 signaling [6]. This hypothesis has prevailed for nearly 60 years however, it falls short as a complete explanation due to the deficiencies current antipsychotics exhibit against negative and cognitive symptoms. 

The dopamine hypothesis has dominated schizophrenia research for over 40 years 880... 

Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia. The hypothesis that hypofunction of a subpopulation of NMDA receptors contributes to the pathophysiology of schizophrenia has gained considerable support over the last decade (see Fig. 54-1). The dissociative anesthetics including phencyclidine (PCP) and ketamine when introduced clinically 40 years ago were noted to produce a syndrome that was difficult to distinguish from schizophrenia. These agents act as noncompetitive open-channel blockers of the NMDA receptor. 

Determining the underlying rationale for studying a neuroreceptor system, e.g. the dopamine hypothesis for cocaine abuse and schizophrenia ... 

These results suggest that the taxon is overinclusive It includes 28% of low-risk participants—instead of the 10% predicted by Meehl s theory—and misses some cases that later become symptomatic. This might mean that the identified taxon is not isomorphic with specific genetic liability for schizophrenia and reflects a construct that is overlapping, but not identical to, the genetic risk factor. Another explanation is that the DSM criteria for schizophrenia and spectrum conditions may be too broad. Tyrka et al. (1995) proposed this hypothesis and estimated that at least two-thirds of the misses (symptomatic cases not assigned to the taxon) can be accounted for by errors in the taxon classification scheme, but the remaining misses are due to... 

Woolley and Shaw24 have recently put forth an interesting and worthy hypothesis that schizophrenia may be due to interference with the functioning of serotonin in the brain. This newly discovered hormone-like substance may be an important key. The evidence on which the hypothesis is based is that various chemically related substances (antagonists), notably lysergic acid diethylamide, produce, when given to well individuals, conditions which in some cases closely resemble schizophrenia. 

Seeman P. (1987). Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse. 

The term schizophrenia was introduced by the Swiss physician Eugen Bleuter to replace the earlier term dementia praecox. It derives from the two Greek words schism, a split , and phren, the mind , to indicate the apparent splitting of the mind. One part remains in touch with reality whereas the other part is out of touch. It is, however, characterised by its symptoms rather than by biological markers. The current hypothesis to account for the most... 

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

The 1960 s and 1970 s saw several other hypotheses proposed and dis-proven. The monoamine oxidase (MAO) deficiency hypothesis was based on the observation of diminished activity of platelet MAO-B in schizophrenia, although this was likely to be an artifact of drug treatment and the small deficits could not, in any case, account for changes in monoamine transmitters. Other hypotheses relating to, among other transmitter molecules, noradrenaline and enkephalin/endorphin have also been proposed. Each of these have had propo-... 

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