The dopamine model was the predominant theory of biological causation during the late twentieth century. This theory hypothesized that schizophrenia is caused by abnormal dopaminergic activity in the brain.
Dopamine neurons are located in a number of different brain regions. In the basal ganglia, these nerve cells help to regulate motor functioning. In areas of the limbic and reticular systems, dopamine neurons appear to play an important role in emotional control and the screening of stimuli.
The dopamine model holds that the basic physiological pathology involves primarily overactive or hyper-reactive dopamine neurons. The excessive dopamine activity can lead to behavioral agitation, a failure to adequately screen stimuli, and disorganization of perception and thought.
This theory is supported by two observations: The first is that the potency of antipsychotic drugs has correlated closely with their ability to bind to and block the postsynaptic dopamine (D2) receptors in the mesolimbic system.
The second observation is that drugs that increase dopamine activity (such as amphetamines) can produce a paranoid psychosis similar to paranoid schizophrenia and, if given to schizophrenic patients, amphetamines may exacerbate psychotic symptoms.
Dopamine Model Has Been Modified
Although the dopamine model has merit, the basic theory has been modified to help explain some clinical data and fill in some theoretical gaps. One of the strongest stimuli has been the finding that clozapine, although effective in the treatment of schizophrenia, is only a weak D2 blocker, because it is a reversible antagonist.
On the other hand, it is a fairly potent 5-HT2A and 5-HT2C (serotonin) antagonist. The 5-HT blocking ability appears to correlate with its effectiveness against negative symptoms. This has also been the case with second-generation antipsychotics. (Note that second-generation antipsychotics were formerly called atypical antipsychotics).
Also, it has been shown that clozapine does significantly decrease dopaminergic activity in the mesolimbic area (despite the lack of D2 blockade) but not in the nigrostriatal tracts (thus the lack of extrapyramidal effects).
What emerges is the following picture: In schizophrenia, there is hyperdopaminergic activity in the mesolimbic tracts that is associated with positive symptoms. In addition, there is decreased activity in the prefrontal cortex associated with negative symptoms. The exact relationship between these phenomena is not fully understood at this time.
It has been suggested that hypofunction of the glutamate neurons, which interconnect the four main areas shown to be abnormal in schizophrenia (prefrontal cortex, mesolimbic, striatum/nucleus acumbens, and medial temporal lobe), may be the underlying pathophysiology. The different neurochemical basis dictates alternative treatment approaches: the use of second-generation antipsychotics.
Another theory was proposed nearly 60 years ago as the phencyclidine (PCP) model of schizophrenia. This was based on the discovery that PCP exerts its effect by blocking the action of glutamate at the N-methyl-D-aspartate (NMDA) receptor in the brain.
Further contemporary evidence from studies of another NMDA antagonist, ketamine, also support the influence of the role of glutamate in schizophrenia. The advantage of this model is that PCP and ketamine, unlike amphetamines, induces negativism and apathy in addition to disorganized thinking.
It is hypothesized that, in schizophrenia, there is a primary dysregulation of the glutamate system resulting in cognitive deficits and that the dopaminergic hyperactivity, and resultant positive symptoms, are secondary phenomena. Even though the glutamate hypothesis of schizophrenia was broached nearly 60 years ago, it remains one of the more popular and researched theories of schizophrenia today.
*This article is based on Dr. Moore’s latest book “Handbook of Clinical Psychopharmacology for Therapists” published by New Harbinger Press and co-authored by John Preston, John O’Neal, and Mary Talaga.
Preston, J., O’Neal, J., Talaga, M., & Moore, B. A. (in press). Handbook of Clinical Psychopharmacology for Therapists-Ninth Edition. Oakland, CA: New Harbinger Press.