SPECT imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects

M.  LaRuelle, A. Abi-Dargham, C. H. Van Dyck, R. Gil, C. D. D’Souza, J. Erdos, E. McCance, W. Rosenblatt, C. Fingado, S. S. Zoghbi, R. M. Baldwin, J. P. Seibyl, J. H. Krystal, D. S. Charney, and R. B. Innis

Proc. Natl. Acad. Sci. USA
93:9235–9240, August 1996

The dopamine hypothesis suggests a disregulation of dopamine systems in schizophrenia, but until this study the disregulation could not be shown.  In this study, 15 patients with schizophrenia and 15 control patients (those without schizophrenia or other psychotic conditions) were given amphetamine.  The effects of amphetamine were visualized using a procedure called SPECT.  This procedure allows doctors and researchers to view specific activities of a person’s organ, including the brain.  A chemical, called a radiotracer, is injected into the patient and as the radioactive element breaks down, it emits gamma waves, which are similar to X-rays.  These emitted gamma waves allow for the SPECT machine to visualize where the radioactive chemical is in a living patient, and the researchers can make inferences based on the emitted waves. 

In this study, [¹²³I] IBZM, the radiotracer, was injected into the blood stream prior to amphetamine administration.  This chemical binds to D₂ dopamine receptors, the same receptor that endogenous (released from the body) dopamine will bind to.  [¹²³I] IBZM competitively binds to these receptors, meaning that one [¹²³I] IBZM molecule will try to bind to the receptor the same as dopamine will.  A decrease in the binding of the radiotracer to the D₂ receptor will show an increase in dopamine binding to those same receptors.  The schizophrenic and control groups did not differ in factors like the amount of [¹²³I] IBZM injected, amount of [¹²³I] IBZM in the blood, or the initial amounts of D₂ receptors.  Despite these similarities, amphetamine’s effect on [¹²³I] IBZM binding was decreased more in patients with schizophrenia when compared to controls.  This means that more dopamine was binding to the receptors in these patients, indicating an increased dopamine release in response to amphetamine. 

Positive psychotic symptoms, one of the main symptoms seen in patients with schizophrenia, were increased in six of the 15 patients.  Controls showed no psychotic symptoms.  Additionally, the patients with schizophrenia who experienced worsening of positive symptoms also showed a larger reduction in [¹²³I] IBZM levels. 

These results may indicate abnormal functioning of the dopamine system in patients with schizophrenia. Increased dopamine binding, which was also correlated with increased positive psychotic symptoms, gives evidence supporting the dopamine hypothesis.  This is the first of many steps needed to strongly show the influence of dopamine in schizophrenia.  One limitation of this study is that all of the patients had previously received treatment for schizophrenia.  Many of these treatments can lead to increases in receptor numbers, which may skew the results in the schizophrenic patients.  A study including drug-naïve patients (those that have never taken antipsychotic medication) could further strengthen the results from this study.