Schizophrenia dopamine hypothesis

Overview
The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model attributing symptoms of schizophrenia (like psychoses) to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have DA-antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. The theory has been credited and proven as far too simplistic and has been rendered completely obsolete as a factor for causing Schizophrenia.

Introduction
Some researchers have suggested that dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition,alogia.

Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (Angel Dust), or excess steroids, or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D2 receptors in the high-affinity state for dopamine. This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical.

Evidence for the dopamine hypothesis
Some of the most obvious evidence for this theory is from the effect of drugs such as amphetamine and cocaine. These drugs (and others like them) increase levels of dopamine in the brain and can cause psychosis, particularly after large doses or prolonged use. This is often referred to as 'amphetamine psychosis' or 'cocaine psychosis', but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia. In fact, extensive reviews by Lieberman and by Curran highlight the fact that up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate or amphetamine or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.

Another important development was an accidental discovery that a group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, antagonized dopamine binding (particularly at receptors known as D2 dopamine receptors) and reduced positive psychotic symptoms.

This link was strengthened by experiments in 1970s which suggested that the affinity of antipsychotic drugs for the D2 dopamine receptor family seemed to be inversely proportional to their therapeutic dose. This correlation between the therapeutic doses of antipsychotics and their affinities for the dopamine D2 receptor (then called the "antipsychotic/dopamine receptor") was reported by Philip Seeman in 1975 and more recently in 2002. . There are no known exceptions to this correlation, as explained further below.

More recent experimental studies have shown that amphetamine increases the level and intensity of psychotic symptoms in people who already have, or are liable to psychosis. Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals.

Concurrently, those treated with dopamine enhancing Levodopa for Parkinson's disease can experience psychotic side effects mimicking the symptoms of Schizophrenia.

Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine related genes linked to psychosis in this way included COMT and DRD4.

Evidence against the dopamine hypothesis
Further experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D2 receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D2 occupancy of 60-70%. The only antipsychotic that occupies high levels of D2 receptors over 90% is aripiprazole, but this drug has both a D2-blocking component and a D2-stimulating component, and it is the D2-stimulating component that "internalizes" the D2 receptors in the nerve cells of patient, making it appear that there is more D2 occupancy than is really necessary to do the job of antipsychotic action.

Just as perplexing, although dopamine inhibiting medications modify dopamine levels within minutes, the associated improvement is usually not visible for at least several days, indicating that if nothing else, dopamine may not be directly responsible for the illness.

Similarly, a new generation of antipsychotic drugs (called the atypical antipsychotics) were found to be just as effective as older typical antipsychotic drugs in controlling psychosis despite the fact that they blocked fewer dopamine receptors. More recent work, however, has shown that antipsychotic drugs such as clozapine and quetiapine are loosely bound to the dopamine D2 receptor. These drugs, therefore, come off the D2 receptors over a period of 6 to 12 hours after ingestion, explaining why PET scanning finds these drugs to occupy somewhat lower levels of D2 receptors in patients. Earlier scanning of patients at about two hours after taking clozapine or quetiapine leads to the observation that their D2 receptors are occupied to the extent of 60% or 70%, the usual therapeutic level for all the antipsychotic drugs.

The blockade of serotonin (5-HT2) receptors does not contribute either to the antipsychotic action or to alleviating the Parkinsonism that can occur at high doses of antipsychotic medication.

The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine (also known as PCP or 'Angel Dust') and ketamine, both of which block glutamate (NMDA) receptors, are known to cause psychosis closely resembling schizophrenia, further suggesting that psychosis and schizophrenia cannot fully be explained in terms of dopamine function. However, as reported in 2005 and mentioned above, the sensitization of animals with PCP markedly increases the animal's behavioural sensitivity to dopamine and markedly increases the number of high-affinity D2 receptors in the brain (Seeman et al., Proc. Nat. Acad. Sci., USA 102:3513-3518, 2005), implying that the multiple psychosis pathways converge through D2High, the main common target for antipsychotic medications.

Similarly, there is now a great deal of evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in grey matter density in the frontal and temporal lobes. Such changes or lesions or injuries, especially when done at an early age or in utero can lead to behavioural dopamine supersensitivity, as noted above (Seeman et al., Proc. Nat. Acad. Sci., USA 102:3513-3518, 2005). It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations, lesions, and drug abuse.

Other evidence suggests that social and environmental factors are important in explaining how either schizophrenia, or specific episodes of psychosis, are triggered. This research has led people to argue that a purely biological explanation, without reference to social, cultural or environmental factors will never fully explain such phenomena. Such socio-economic-cultural factors can become highly stressful to certain individuals, such as immigrants, markedly altering their brain chemistry, including dopamine, and can be associated with increased risk to psychotic episodes.

Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as a deliberate and calculated simplification for the benefit of drug marketing. The fact remains that these antipsychotic medications are effective in the treatment of acute psychosis, because before their advent in 1952, severely psychotic individuals were untreatable and were housed in Bedlam-like back wards of mental hospitals. This no longer is the case.