Occupancy of Striatal and Extrastriatal Dopamine D2/D3 Receptors by Olanzapine and Haloperidol

Abstract

There have been conflicting reports as to whether olanzapine produces lower occupancy of striatal dopamine D 2 /D 3 receptor than typical antipsychotic drugs and preferential occupancy of extrastriatal dopamine D 2 /D 3 receptors. We performed [18 F] fallypride PET studies in six schizophrenic subjects treated with olanzapine and six schizophrenic subjects treated with haloperidol to examine the occupancy of striatal and extrastriatal dopamine receptors by these antipsychotic drugs. [18 F] setoperone PET studies were performed in seven olanzapine-treated subjects to determine 5-HT 2A receptor occupancy. Occupancy of dopamine D 2 /D 3 receptors by olanzapine was not significantly different from that seen with haloperidol in the putamen, ventral striatum, medial thalamus, amygdala, or temporal cortex, that is, 67.5-78.2% occupancy; olanzapine produced no preferential occupancy of dopamine D 2 /D 3 receptors in the ventral striatum, medial thalamus, amygdala, or temporal cortex. There was, however, significantly lower occupancy of substantia nigra/VTA dopamine D 2 /D 3 receptors in olanzapine-treated compared to haloperidol-treated subjects, that is, 40.2 vs 59.3% (p ¼ 0.0014, corrected for multiple comparisons); in olanzapine-treated subjects, the substantia nigra/VTA was the only region with significantly lower dopamine D 2 /D 3 receptor occupancy than the putamen, that is, 40.2 vs 69.2% (po0.001, corrected for multiple comparison). Occupancy of 5-HT 2A receptors was 85-93% in the olanzapine-treated subjects. The results of this study demonstrated that olanzapine does not produce preferential occupancy of extrastriatal dopamine D 2 /D 3 receptors but does spare substantia nigra/VTA receptors. Sparing of substantia nigra/VTA dopamine D 2 /D 3 receptor occupancy may contribute to the low incidence of extrapyramidal side effects in olanzapine-treated patients.

Asenapine Increases Dopamine, Norepinephrine, and Acetylcholine Efflux in the Rat Medial Prefrontal Cortex and Hippocampus

“…As reported by Schotte et al (1996), these agents, including clozapine, risperidone, 9-hydroxyrisperidone (paliperidone), olanzapine, pipamperone, quetiapine, sertindole, ziprasidone, and zotepine, also have higher occupancy in the rat cortex and striatum of 5-HT 2A than D 2 receptors, respectively, at all but the highest doses studied. PET studies are also consistent with the view that at clinically relevant doses, those agents, which are direct acting antagonists of D 2 receptors, have higher occupancy of D 2 than 5-HT 2A receptors (Goyer et al, 1996;Nyberg et al, 1999;Gefvert et al, 2001;Kessler et al, 2005). Aripiprazole, a partial D 2 receptor agonist, has a higher D 2 than 5-HT 2A receptor occupancy at clinical doses, but, nevertheless, has a weak functional effect to inhibit D 2 receptor stimulation (Mamo et al, 2007).…”

Occupancy of Striatal and Extrastriatal Dopamine D2 Receptors by Clozapine and Quetiapine

“…The quetiapine study (Stephenson et al, 2000) used the same methodology criticized by Olsson (Olsson and Farde, 2001). In a study of olanzapine-treated schizophrenic patients, we have reported no preferential occupancy of cortical DA D 2 r but sparing of nigral DA D 2 r occupancy using the same methods utilized here (Kessler et al, 2005).…”

“…The substantia nigra can be stereotactically localized in the ventral midbrain 9-14 mm below the ACPC line (Schaltenbrand and Wahren, 1977) and can be easily visualized in the midbrain on PET [ 18 F]fallypride scans (see Figure 2). The amygdala can be easily visualized in the anteromedial temporal lobe on MRI scans just anterior to the tip of the temporal horn of the lateral ventricle and deep to the uncus (Kessler et al, 2005); stereotactically, the amygdala is localized approximately 6-20 mm below the ACPC line, from 12 to 28 mm lateral to the midline, and from 2 to 12 mm behind the plane of the anterior commissure (Schaltenbrand and Wahren, 1977). To decrease partial voluming from the striatum, regions of interest for the amygdala were drawn on the MRI images from 10 to 16 mm below the plane of the ACPC.…”

ITI-007 demonstrates brain occupancy at serotonin 5-HT2A and dopamine D2 receptors and serotonin transporters using positron emission tomography in healthy volunteers

“…For example, risperidone shows no or little separation between 5-HT 2A and D 2 RO, depending on the dose, with ≥78 % occupancy of 5-HT 2A receptors and ≥75 % occupancy of D 2 receptors at a 6 mg/day dose and approximately 83 % 5-HT 2A RO and 72 % D 2 RO at a dose of 3 mg/day Nyberg et al 1999). Olanzapine also shows little separation between 5-HT 2A RO (68-78 %) and striatal D 2 RO (85-93 %; Kessler et al 2005). These atypical antipsychotic drugs with relatively high striatial D 2 RO elevate prolactin levels (Bushe et al 2008) and can induce extrapyramidal motor side effects (extrapyramidal symptoms (EPS)) at therapeutic doses (Rummel-Kluge et al 2012).…”