Abstract
Adolf Meyer (1866-1950) did not see schizophrenia as a discrete disorder with a specific etiology but, rather, as a reaction to a wide variety of biopsychosocial factors. He may have been right. Today, we have evidence that gene mutations, brain injury, drug use (cocaine, amphetamine, marijuana, phencyclidine, and steroids), prenatal infection and malnutrition, social isolation and marginalization, can all result in the signs and symptoms of schizophrenia. This clinical picture is generally associated with supersensitivity to dopamine, and activates dopamine neurotransmission that is usually alleviated or blocked by drugs that block dopamine D2 receptors. While the dopamine neural pathway may be a final common route to many of the clinical symptoms, the components of this pathway, such as dopamine release and number of D2 receptors, are approximately normal in schizophrenia patients who are in remission. Postmortem findings, however, reveal more dimers of D1D2 and D2D2 receptors in both human schizophrenia brains and in animal models of schizophrenia. Another finding in animal models is an elevation of high-affinity state D2High receptors, but no radioactive ligand is yet available to selectively label D2High receptors in humans. It is suggested that synaptic dopamine supersensitivity in schizophrenia is an attempt at compensation for the original damage by heightening dopamine neurotransmission pathways (preparing the organism for fight or flight). The dopamine overactivity is experienced subjectively as overstimulation, which accounts for some of the clinical symptoms, with attempts at dampening down the stimulation leading to still other symptoms. Reaction and counter-reaction may explain the symptoms of schizophrenia.
Highlights
Most investigators acknowledge that there are many risk factors that contribute to schizophrenia
While all antipsychotics target the dopamine D2 receptor, the number of these receptors has been found to be approximately normal in the cerebral cortex of patients, as long as they have not been medicated with antipsychotics (Seeman, 2013a, in press)
In the schizophrenia thalamus, several reports show evidence that suggest that there may be fewer than normal presynaptic D2 receptors and fewer presynaptic terminals, as monitored by benzamide ligands (Buchsbaum et al, 2006; Kegeles et al, 2010; Talvik et al, 2003, 2006; Tuppurainen et al, 2006; Yasuno et al, 2004), especially in association with a genetic variant in the dopamine D2 receptor
Summary
Most investigators acknowledge that there are many risk factors that contribute to schizophrenia. Despite the impact of many different factors, the brain can react to them all to produce the signs and symptoms of schizophrenia, the specific experiential and behavioral expression of which can, and does, vary from patient to patient This common general reaction is associated with supersensitivity to dopamine (Lieberman et al, 1987; Seeman, 2011), and overactivity of dopamine neurotransmission, which is usually alleviated or blocked by drugs that block dopamine D2 receptors (Madras, 2013). While there is renewed interest in the hypoglutamate theory of psychosis based on the fact that glutamate antagonists such as phencyclidine and ketamine trigger psychosis, it is known clinically that haloperidol (which has high affinity for D2, but low affinity for glutamate receptors) effectively alleviates the psychosis secondary to phencyclidine or ketamine (Giannini et al, 1984–1985–2000) It is uncertain whether glutamate receptor agonists such as pomaglumetad methionil or LY404,039 have any antipsychotic efficacy. A four-week trial had little or no efficacy against positive symptoms or negative signs when compared to olanzapine (Kinon et al, 2011; Seeman, 2012a)
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