Schizophrenia serotonin hypothesis

It became known in the same year (1954) that the substance reserpine, derived from the Indian plant Rauxcolfia serpentina, had antipsychotic effects similar to those of chlorpromazine This finding was of interest for two reasons the molecular structure of reserpine has some similarity to that of serotonin and LSD and it was found that reserpine liberates serotonin from presynaptic stores in the CNS and thus produces a short-lived excess supply of functionally available serotonin at the synapse. In the context of a serotonin hypothesis of schizophrenia, it could be postulated that the antipsychotic effect of reserpine was due to its ability to liberate serotonin presynaptically and make it functionally available. However, despite its scientific appeal, the serotonin hypothesis of schizophrenia did not last long because it was in conflict with both psychopathological and pharmacological findings ... 

Despite its relatively fast and thorough rebuttal, the serotonin hypothesis of schizophrenia was fruitful in two respects it gave rise to the development of sensitive serotonin assay methods and proof that serotonin does occur in the brain (Carlsson, 1987) and it served as the prototype for other simple and thus readily testable biochemical hypotheses of mental illnesses. Interest in serotonin has been reawakened in recent years in relation to the mechanism of action of some antipsychotics (see below) however, this development had little to do with the serotonin hypothesis of schizophrenia in its original version. 

Although the serotonin hypothesis of schizophrenia was formulated at approximately the same time as the discovery of the first neuroleptics, it had no direct connection with the pharmacological propraties of these drugs. The situation is different in the case of the dopamine hypothesis because all known neuroleptics have some inhibitory action on dopaminergic neurons, even though they vary considerably with regard to other pharmacological effects. 

Meltzer, H.Y. Clinical studies on the mechanism of action of clozapine the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology 99, 518-527, 1989. 

Among the above-listed abnormalities in schizophrenia, neurotransmitter abnormalities (especially the dopamine/serotonin hypothesis of schizophrenia) are widely accepted as directly inducing or at least mediating certain symptoms of the disorder. The major empirical observations concerning the role of abnormal neurotransmitter functioning in schizophrenia are as follows. 

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. 

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. 

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. 

In 1954, i.e. about 2 years after the discovery of chlorpromazine in Europe, two American biochemists (Woolley and Shaw) published the hypothesis that schizophrenia and similar psychoses could be based on a disturbance of serotoninergic neurotransmission in the brain. This hypothesis was supported by some facts that had become known shortly beforehand the spectacular psychotropic actions of LSD (lysergic acid diethylamide), which can trigger disturbances in perception, thought and feelings as well as hallucinations in healthy subjects (Stoll, 1947) and the serotonin-antagonistic effects of LSD, i.e. its ability to block the actions of serotonin in various pharmacological tests. 

Several studies have discussed the relationship between serum cholesterol and suicide, violence, anxiety disorders, depressive disorders, and schizophrenia [1-3]. Some of these papers suggested that low or lowering cholesterol levels could cause or worsen depressive symptoms and increase the risks of suicide and violence death. There are many reports that discussed the relationships between the lipid profiles, depression, and suicide from the viewpoints of decreased serotonergic transmission on suicide behavior [4, 5], lower serum cholesterol and serotonin levels [6, 7], serum cholesterol levels and polymorphism in the promoter region of the serotonin transporter gene for depression and suicide [8-10], low serum cholesterol and suicide risk [11, 12], and serotonergic receptor function [13, 14]. These studies supported the hypothesis that reduced cholesterol levels resulted in reduced central serotonin transmission. 

It may be concluded that despite the importance of the dopamine hypothesis of schizophrenia in serving to unify the mechanism of action of both typical and atypical neuroleptics, it is apparent that some serotonin receptor subtypes, and glutamate receptors of the NMDA subtype, may also play a crucial role. 

Keywords Schizophrenia Major depression Thl/Th2 balance Pro-inflammatory cytokines NMDA hypothesis Glutamate Serotonin Tryptophan Kynurenine Kynurenic acid HPA axis... 

Serotonin. Even before the dopamine hypothesis of schizophrenia became established, a role for overactive serotonin neu-... 

Noting the structural resemblance of serotonin to the hallucinogenic indoles dimethyl tryptamine (DMT) and bufotenin, researchers proposed that psychotic symptoms were caused by these or similar compounds generated in schizophrenics by the abnormal transmethylation of endogenous indoleamines (21). Unfortunately, studies were unable to confirm increases in methylated indole amines in the plasma or CSF of schizophrenic patients versus controls (22). The transmethylation hypothesis is also questioned by the recognition that LSD-induced psychosis differs significant ways from the signs and symptoms of schizophrenia (23). 

The dopamine hypothesis of schizophrenia posits that such symptoms arise because of a functional excess of dopaminergic activity in the CNS. The notion is based on the facts that drugs that activate DA receptors may cause psychotic symptoms and those that block DA receptors often have antipsychotic actions. However, drugs used for schizophrenia do not remedy all symptoms they are not curative, and some newer agents appear to be effective in many patients, even though they do NOT act as antagonists at brain DA receptors but may modify serotonin functions. 

Psilocybin is rapidly dephosphorylated in the body to psilocin, an agonist of serotonin (5-hydroxytryptamine [S-HTJja) receptors. The stimulating of 5-HT receptors by hallucinogenic drugs has given rise to the hypothesis that schizophrenia maybe caused by an imbalance in the metabolism of 5-HT. Depressive and catatonic states in schizophrenic patients are thought to be the result of 5-HT deficiency. 

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