Clinical molecular imaging of schizophrenia

The aim of this thesis was to examine pathophysiology and antipsychotic treatment of schizophrenia by using positron emission tomography (PET).

The high affinity radioligand [11C]FLB 457 was used for determination of dopamine D2 receptor binding in the thalamus and the cortex of nine drug-naïve patients with schizophrenia and eight control subjects. The D2 receptor binding was significantly lower in the right medial thalamus in the patient group.

With the moderate affinity radioligand [11C]raclopride, the D2 receptor binding in the striatum and the thalamus was determined in eighteen drug-naïve patients with schizophrenia and seventeen control subjects. In concordance with previous studies, no significant group differences were found in the D2 receptor binding in the striatum. However, in the right thalamus the D2 receptor binding was significantly lower in patients, thus confirming the preliminary results from the study using [11C]FL13 457. Taken together, these results indicate pathology of the thalamus, a brain region with widespread connections to regions implicated in schizophrenia.

Despite a relatively low D2 receptor occupancy the atypical drug clozapine is efficacious also in patients that do not respond to classical antipsychotics. It has been suggested that 5HT2A receptor antagonism may be an important mechanism underlying the atypical properties of clozapine. In this thesis, the selective 5HT2A receptor antagonist M100907 was used for treatment of two patients with schizophrenia. The results indicate that clinical treatment with M100907 is well tolerated and that the dosage was sufficient to induce high 5HT2A receptor occupancy in the frontal cortex. M100907 can thus be proposed as a suitable tool for evaluation of 5HT2A receptor antagonism in schizophrenia.

Other authors have suggested that the clinical superiority of clozapine is related to a preferential effect in limbic and cortical dopaminergic systems. This hypothesis of regional selectivity was examined in seven patients with schizophrenia. Striatal D2 receptor occupancy was determined with [11C]raclopride whereas [11C]FLB 457 was used for the determination of D2 receptor occupancy in the thalamus and in the cortex. In the haloperidol-treated patients the D2 receptor occupancy was relatively high and similar in all regions, whereas in the clozapine-treated patients the D2 receptor occupancy was relatively low, and of the same magnitude in all regions. The hypothesis of regional selectivity was thus not supported.

Based on previous PET studies an optimal interval for D2 receptor occupancy during antipsychotic treatment has been suggested. A therapeutic window for serum drug concentration has been reported for the classical antipsychotic drug perphenazine. In the present thesis, the relationship between these intervals was examined in six patients. It could be concluded that the suggested interval for serum perphenazine concentration coincides with the optimal interval for central D2 receptor occupancy.

List of scientific papers

I. Talvik-Lotfi M, Nyberg S, Nordstrom AL, Ito H, Halldin C, Brunner F, Farde L (2000). High 5HT2A receptor occupancy in M100907-treated schizophrenic patients. Psychopharmacology. 148(4): 400-3.
https://pubmed.ncbi.nlm.nih.gov/10928313

II. Talvik M, Nordstrom AL, Nyberg S, Olsson H, Halldin C, Farde L (2000). No support for regional selectivity in clozapine-treated patients: a PET study with [(11)C]raclopride and [(11)C]FLB 457. Am J Psychiatry. 158(6): 926-30.
https://pubmed.ncbi.nlm.nih.gov/11384901

III. Talvik M, Nordstrom AL, Olsson H, Halldin C, Farde L (2003). Decreased thalamic D2/D3 receptor binding in drug-naïve patients with schizophrenia. INJP. [Accepted]

IV. Talvik M, Nordstrom AL, Okubo Y, Olsson H, Borg J, Halldin C, Farde L (2003). D2 receptor binding in drug-naïve patients schizophrenia examined with [(11)C]raclopride and PET. [Manuscript]

V. Talvik M, Nordstrom AL, Jucaite A, Cervenka S, Larsen NE, Farde L (2003). A crossvalidation study of the relationship between central D2 receptor occupancy and serum perphenazine concentration. [Submitted]