Projektdetaljer
Beskrivelse
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 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 were included, who were not antipsychotic-naïve.
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.
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. Then 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.
Our results suggest that frontal cortical 5-HT2AR is involved in the pathophysiology of schizophrenia.
Furthermore, the study supports that the 5-HT2AR has a therapeutic role in the treatment of positive symptoms, at least in subgroups of patients.
• Psykiatrisk Center Glostrup
• Afdeling for Hjerne- og Nervesygdomme
• Clinical Intervention and Neuropsychiatric Schizophrenia Research/Center for Neuropsykiatrisk Skizofreniforskning
• Periode:
Finansiel støtte:
The Danish Medical Research Council
Copenhagen Hospital Cooperation Research Council
Copenhagen University Hospital, Bispebjerg
The University of Copenhagen, Faculty of Health Sciences
The Copenhagen Council Research Foundation
The Gangsted Foundation
The Lundbeck Foundation
A nonrestricted grant from Astra Zeneca
towards lower frontal cortical 5-HT2AR binding in schizophrenia patients 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 were included, who were not antipsychotic-naïve.
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.
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. Then 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.
Our results suggest that frontal cortical 5-HT2AR is involved in the pathophysiology of schizophrenia.
Furthermore, the study supports that the 5-HT2AR has a therapeutic role in the treatment of positive symptoms, at least in subgroups of patients.
• Psykiatrisk Center Glostrup
• Afdeling for Hjerne- og Nervesygdomme
• Clinical Intervention and Neuropsychiatric Schizophrenia Research/Center for Neuropsykiatrisk Skizofreniforskning
• Periode:
Finansiel støtte:
The Danish Medical Research Council
Copenhagen Hospital Cooperation Research Council
Copenhagen University Hospital, Bispebjerg
The University of Copenhagen, Faculty of Health Sciences
The Copenhagen Council Research Foundation
The Gangsted Foundation
The Lundbeck Foundation
A nonrestricted grant from Astra Zeneca
| Status | Afsluttet |
|---|---|
| Effektiv start/slut dato | 1/01/07 → 31/12/11 |