October 22, 2008

A Comparison of Clozapine (Clozaril) and Quetiapine (Seroquel) and How They Work in the Brain

Principal Investigators: Robert Kessler, PhD & Herbert Meltzer, PhD

This study, published in Neuropsychopharmacology in 2006, looked at how clozapine (Clozaril) and quetiapine (Seroquel) work to restore function in the brains of people with schizophrenia. Using a brain imaging method called PET that allows researchers to measure the occupancy of receptors for neurotransmitters by drugs, the researchers were able to determine how much each of these drugs blocked dopamine D2 receptors. This study showed that both of these drugs were effective despite occupying much fewer dopamine receptors compared to first generation drugs such as haloperidol or prolixin. This translates into fewer side effects that affect the motor system. Dr Meltzer’s research suggests that these drugs achieve their efficacy by blocking serotonin receptors, which drugs like haloperidol do not. (Kessler, et al, 2006).

Many researchers believe that people with schizophrenia produce more dopamine than is normal in a specific part of the brain called the limbic system (Cooper, 1996). This extra dopamine is believed to be responsible for the psychotic symptoms of the disease (Cooper, 1996). However, the cognitive deficits in schizophrenia (memory and attention impairment) may be related to too little dopamine in the higher centers of the brain, the cortex. 

Traditional antipsychotic drugs (i.e. holoperidol & chlorpromazine), block dopamine receptors in the limbic system – eliminating or reducing psychotic symptoms for many schizophrenics. However, blocking dopamine receptors in an area related to the limbic system affects a lot more of the body’s and brain’s functioning, leading to side-effects which are similar to Parkinson’s disease.

This study looked at some of the different sites that Seroquel and Clozaril (called typical antipsychotics) occupy in the brain. Seroquel and Clozaril both have a low incidence of motor side effects at clinically effective doses. This appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). In this study, the researchers found that clients receiving Seroquel at the regular doses (400mg or below) had lower levels of putamenal and temporal cortical DA D2r occupancy than those receiving Clozaril. When clients were given doses higher than 400mg of Seroquel, though, their response improved. (Kessler, et al, 2006).

These results may explain why at lower doses (i.e. 400mg a day or less), quetiapine has been found to be no more effective than typical antipsychotics (Conley et al, 2005). The authors suggest that preferential occupancy of cortical DA D2r, sparing of DA D2r occupancy in the substantia nigra, may contribute to the efficay of Clozaril and Seroquel. (Kessler, et al, 2006).

References
Conley RR, Kelly DL, Nelson MW, Richardson CM, Feldman S, Benham R et al (2005). Risperidone, quetiapine and fluphenazine in the treatment of patients with therapy-refractory schizophrenia. Clinical Neuropharmacology  28: 163–168.

Cooper, J.R., Bloom, F.E., & Roth, R.H. (1996). The biochemical basis of neuropharmacology. New York: Oxford University Press.

Kessler, R.M., Ansari, M.S., Riccardi, P., Li, R., Jayathilake, K., et al. (2006). Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine. Neuropsychopharmacology  31(9): 1991-2001.