Neuropsychopharmacology. 2010 Feb 3;
Authors: McClure MM, Harvey PD, Goodman M, Triebwasser J, New A, Koenigsberg HW, Sprung LJ, Flory JD, Siever LJ
Cognitive deficits observed in schizophrenia are also frequently found in individuals with other schizophrenia spectrum disorders, such as schizotypal personality disorder (SPD).
Dopamine appears to be a particularly important modulator of cognitive processes such as those impaired in schizophrenia spectrum disorders.
In a double-blind, placebo-controlled clinical trial, we administered pergolide, a dopamine agonist targeting D(1) and D(2) receptors, to 25 participants with SPD and assessed the effect of pergolide treatment, as compared with placebo, on neuropsychological performance.
We found that the pergolide group showed improvements in visual-spatial working memory, executive functioning, and verbal learning and memory.
These results suggest that dopamine agonists may provide benefit for the cognitive abnormalities of schizophrenia spectrum disorders.
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Traditionally, it has been thought that excessive dopamine signaling is the primary contributing factor toward the development of schizophrenia. Though more recently, it has been recognized that schizophrenia has a complex pathophysiology.
The typical antipsychotic medications primarily block dopamine D2 receptors. They are useful in reducing positive psychotic symptoms such as hallucinations and delusions. But they also impair cognitive function.
The atypical antipsychotic medications block dopamine receptors but also block serotonin 2A presynaptic receptors. They also have a multitude of other mechanisms of action both possibly good and possibly bad. Serotonin 2A presynaptic receptors, interestingly, are primarily located in the frontal cortex – an area affected by schizophrenia in causing cognitive dysfunction. By blocking serotonin 2A presynaptic receptors on dopamine-releasing neurons, dopamine signaling is enhanced. The sum of dopamine receptor blockade and serotonin 2A presynaptic receptor blockade on dopamine-releasing neurons in the frontal cortex is an increase in dopamine signaling. This increase in dopamine signaling is itself sufficient to reduce positive psychotic symptoms (as exhibited by pure serotonin 2A receptor antagonists). But the increase in frontal cortex dopamine signaling also improves cognitive function.
This article is interesting in the use of a dopamine agonist, Pergolide, in improving cognitive function in schizophrenia spectrum disorders. It proves the concept.
Interestingly, some patients with schizophrenia, who also abuse amphetamines, have reported reduction in psychotic symptoms with amphetamine use. The increase in dopamine signaling may explain this.
Years ago, there were rumors, additionally, of a study showing amphetamine reducing psychotic symptoms. However, ethical reasons ruled out publishing this article.
The treatment, however, with a dopamine agonist or amphetamine, has to be taken with great care. The problem is that the increase in dopamine signaling with these substances is not localized, as with a serotonin 2A antagonist. The increase in dopamine signaling in the mesolimbic dopamine system, for example, may increase the risk of psychosis. Precipitating psychosis is thus the risk when using these medications, as indicated in the prescribing information. The risks versus benefits of this treatment needs to be carefully considered.
Interestingly, it is important to check what physical health problems a patient may have. Many times, I find patients with schizophrenia being treated by their psychiatrist with an antipsychotic and their primary care physician with a dopamine agonist (e.g. Requip or Mirapex) for restless legs syndrome or Parkinsonism with both physicians unaware of the other’s treatment and potential side effects and interactions. The patient’s psychotic illness may be free of acute psychotic symptoms but I wonder if the risk of psychosis was assessed or if the treatments even makes sense given the simultaneous use of a dopamine antagonist and a dopamine agonist.
And on another example, I have a patient, who has both schizophrenia and attention deficit/hyperactivity disorder, inattentive type. He is fully symptom free of schizophrenia with an atypical antipsychotic but could not function academically or occupationally until I treated him also with methylphenidate. He is doing very well and has been stable for years with treatment.