Dopamine hypothesis schizophrenia

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... 

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

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

However, the dopamine hypothesis does not account for some important observations. If an abnormality of dopamine physiology were solely responsible for the pathogenesis of schizophrenia, antipsychotic drugs would do a much better job in treating patients. As it is, they are only partially effective for most and ineffective for some patients. Moreover, there is evidence that diminished glutamatergic activity also plays a role in... 

In 1976, Ian Creese, David R. Burt, and Solomon H. Snyder of Johns Hopkins University in Baltimore, Maryland, reported that the most effective schizophrenia medications are the ones that have the strongest affinity for dopamine receptors. Researchers also discovered drugs that increased the amount of dopamine inadvertently caused schizophrenic symptoms in patients. These findings led to the dopamine hypothesis of schizophrenia—too much dopamine causes schizophrenia. 

Like the monoamine hypothesis of depression, such a simple hypothesis was appeaUng but, perhaps predictably, a Uttle too simple to be true. Further research using a technique known as positron emission tomography (PET) showed the relationship between dopamine and schizophrenia is more complex. PET detects radioactive emissions of certain isotopes these isotopes are incorporated into a molecule and injected into a patient. The machine measures the radioactivity with detectors positioned aroimd the body. PET lets researchers study the distribution of certain molecules in Uving tissue since, imUke autoradiography, the tissue is not sliced and treated chemically. The amoimt of radioactivity must be small, however, to avoid harming the human subjects. 

Dutch researcher Jacques van Rossum proposes the dopamine hypothesis of schizophrenia, which attributes the symptoms of the disease to an excess of dopamine. 

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. 

Another hypothesis (Crow, 1982) involves a division of schizophrenias into two types Type I corresponds to acute schizophrenia or schizophreniform disorder in which one observes more positive symptoms of hallucinations and delusions with a good prognosis and excellent response to neuroleptics... Type II represents chronic schizophrenia with affective flattening, poverty of speech and loss of drive, the so-called negative symptoms of schizophrenia. Type II patients respond less well to neuroleptics... (Snyder, 1982). Type I patients would fit into the dopamine hypothesis whereas a pathophysiological basis other than dopaminergic hyperactivity must be assumed for type II patients. However, as pointed out by Snyder (1982). "one should be cautious about drawing such a distinction. ... 

The dopamine hypothesis for schizophrenia was the first neurotransmitter-based concept to be developed but is no longer considered adequate to explain all aspects of schizophrenia. Nevertheless, it is still highly relevant to understanding the major dimensions of schizophrenia, such as positive and... 

After dopamine was identified as a neurotransmitter in 1959, it was shown that its effects on electrical activity in central synapses and on production of the second messenger cAMP by adenylyl cyclase could be blocked by antipsychotic drugs such as chlorpromazine, haloperidol, and thiothixene. This evidence led to the conclusion in the early 1960s that these drugs should be considered dopamine-receptor antagonists and was responsible for the dopamine hypothesis of schizophrenia described earlier in this chapter. The antipsychotic action is now thought to be produced (at least in part) by their ability to block dopamine in the mesolimbic and mesocortical systems. 

These findings have been incorporated into the dopamine hypothesis of schizophrenia. However, additional factors complicate interpretation of dopamine receptor data. For example, dopamine receptors exist in both high- and low-affinity forms, and it is not known whether schizophrenia or the antipsychotic drugs alter the proportions of receptors in these two forms. The fact that aripiprazole shows partial agonism at D2 and 5-HT1A receptors in preclinical studies suggests that the proportions of several receptors in their various affinity states may prove clinically important. 

Coyle JT Glutamate and schizophrenia Beyond the dopamine hypothesis. Cell Mol Neurobiol 2006 26 365. [PMID 16773445]... 

This chapter has provided a clinical description of psychosis, with special emphasis on the psychotic illness schizophrenia. We have explained the dopamine hypothesis of schizophrenia, which is the major hypothesis for explaining the mechanism for the positive symptoms of psychosis (delusions and hallucinations). 

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