"Neuroimaging in Psychiatry"
Hans Rasmussen, PhD, Center for Neuropsychiatric Schizophrenia Research, Psychiatric Center Glostrup.

Post-mortem investigations and the receptor affinity profile of atypical antipsychotics have
implicated the serotonin 2A receptors (5-HT2AR) in the pathophysiology of schizophrenia. Most
post-mortem studies point towards lower frontal cortical 5-HT2AR binding in schizophrenia patients
as compared to healthy controls. However, in vivo studies of 5-HT2AR binding report conflicting
results, presumably because sample sizes have been small or because schizophrenia patients who
were not antipsychotic-naïve were included. Furthermore, the relationships between 5-HT2AR
binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear. Finally,
there are no in vivo studies of 5-HT2AR in first episode antipsychotic-naïve schizophrenia patients
before and after sustained treatment with an atypical antipsychotic compound rendering the
relationship between 5-HT2AR occupancy and treatment effect unknown.
First we assessed in vivo brain 5-HT2AR binding potentials in antipsychotic-naïve first episode
schizophrenia patients and matched healthy controls, and examined possible associations with
psychopathology, memory, attention and executive functions. The participants were 30 patients and
30 matched healthy control subjects.
The patients were subsequently treated with the atypical antipsychotic compound quetiapine for 6
months in flexible doses according to their clinical need.
Secondly, we measured 5-HT2AR occupancy in the same patients after 6 months of quetiapine
treatment and explored the relationship with quetiapine and its active metabolite nor-quetiapine
plasma levels, dose and the treatment effect. Fifteen patients completed the follow-up PET scan.
The main outcome measure was in vivo 5-HT2AR binding as measured using positron emission
tomography (PET) and the 5-HT2AR-specific radioligand, [18F]altanserin, in a bolus infusion steady
state model. Psychopathology was assessed using the Positive and Negative Syndrome Rating Scale
(PANSS) and both patients and controls underwent a neuropsychological test battery. After the
treatment period 5-HT2AR occupancy was determined from an occupancy plot of the regional
distribution volumes in the unblocked and the partially blocked condition. Treatment effect was
defined as the difference between PANSS scores at baseline and PANSS scores at the follow-up
scan.
At baseline schizophrenia patients had significantly lower 5-HT2AR binding in frontal cortex than
control subjects. A significant negative correlation was observed between frontal cortical 5-HT2AR
binding and positive psychotic symptoms in the male patients. No correlations were found between
cognitive functions and 5-HT2AR binding.
At follow up we found a one site binding hyperbolic relationship between 5-HT2AR occupancy,
quetiapine dose and plasma concentration. Furthermore, the data revealed a modest effect on
positive symptoms up until a 5-HT2AR occupancy level of approximately 60 %, after which a
considerable increase in efficacy was found. The mean dose of quetiapine was 383 mg in the
present study, corresponding to a 5-HT2AR occupancy of 64 %. This occupancy level is in the
middle range of 60-70 % where we found quetiapine to exert the highest reduction in the positive
symptoms. The mean dose is in the lower part of the recommended dose-range of quetiapine (300-
800 mg). As such this study provides support for using low doses of quetiapine in first episode
schizophrenia patients.
Our results suggest that frontal cortical 5-HT2AR are involved in the pathophysiology of
schizophrenia. Furthermore, the study supports that the 5-HT2AR has an important therapeutic role
in the treatment of positive symptoms with quetiapine and suggests that measurements of quetiapine
plasma concentrations provide guidance in terms of dosing and 5-HT2AR blockade.



ADDIN REFMGR.REFLIST Reference List

1.     Rasmussen H, Erritzoe D, Andersen R, Ebdrup BH, Aggernaes B, Oranje B, Kalbitzer J, Madsen J, Pinborg LH, Baare W, Svarer C, Lublin H, Knudsen GM,