Increased Dopamine Transmission in Schizophrenia: Relationship to Illness Phases

 
M. LaRuelle, A. Abi-Dargham, R. Gil, L. Kegeles, and R. Innis

Biological Psychiatry 46: 56-72, 1999.

 

The aim of this study was to further establish a disregulation of dopamine in schizophrenic patients, as well as see if this disregulation was more present at specific episodes within the disease.  In vivo results of competition for endogenous dopamine and administered radioligands have been demonstrated in rodents (Inoue et al. 1991; Kohler et al 1981; Ross 1991), nonhuman primates (Carson et al 1997; Dewey et al 1993; LaRuelle et al 1997) and recently humans (Breier et al 1997; LaRuelle et al 1996).  This study combines the results of previous PET and SPECT results (Abi-Dargham et al., 1998, LaRuelle et al., 1996) with new subjects, all who were off neuroleptic treatment for at least 21 days and some who were drug naïve.  [¹²³I] IBZM was used in this SPECT imaging procedure similarly to the already reviewed SPECT imaging study.  Exacerbation of symptoms was also scored on the Positive and Negative Symptom Scale (PANSS).  

Schizophrenic patients again showed elevation of amphetamine-induced elevation in IBZM displacement, indicating an increase in dopamine release.  The amphetamine administration also produced an increase in positive symptoms as scored on the positive subscale of the PANSS.  A large portion of the patients experienced a worsening of symptoms (47%, 16 of 34 subjects), while 14 (41%) had no change and 4 (12%) had improvement in positive symptoms.  Patients who experienced a worsening on symptoms had a higher IBZM displacement compared to the subjects who had no change or improved (24% + 12.4% compared to 10.9% + 10.8%), which was statistically significant.  This indicates that a portion of schizophrenic patients may have a disregulation of dopamine leading to their symptomology, while others may be due to other factors.  So, while the dopamine hypothesis appears to be applicable to a subset of schizophrenic patients, not all achieve the same results after amphetamine administration, possibly indicating an alternate cause to their behaviors.

Negative symptoms were affected following amphetamine administration, but in the opposite direction.  Slight improvements were found and severity of symptoms was a good predictor of improvement following amphetamine.  Although results were only a trend and not statistically significant, data leads to the idea that the positive and negative symptoms may be a result of opposite disregulation of dopamine levels. 

Previous medication exposure or extended duration did not increase the amphetamine effect, while both drug free and naïve patients had significant IBZM displacement compared to controls. 

A difference was found within patients with schizophrenia.  Those patients who were experiencing an exacerbation of the illness had larger IBZM displacement compared to patients in remission (23.7 + 13.2% versus 10.5 + 9.7%).  Additionally, IBZM displacement was not different between patients in remission and controls.  A non-significant increase in positive symptoms was noted in patients during exacerbation compared to remission, but this was only a trend. 

A couple of strong results were found in this study.  Further evidence for dopamine disregulation was noted compared to controls.  IBZM displacement was higher in schizophrenic patients, indicating a larger increase in dopamine release.  A novel finding was that the dopamine disregulation is more prevalent during a relapse into schizophrenic symptoms than when a patient is in a period of remission.  This may be due to variations in dopamine receptor density or dopamine production and release depending on the period of disease a patient is currently experiencing.  This finding may lead to new treatment strategies for schizophrenia, especially during periods of remission