SUMMARYAntipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D 2 dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [ 11 C]-raclopride has been the most widely used for binding to the D 2 /D 3 -dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65-80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D 2 -occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs. PrologueOver the last 50 years, antipsychotic drugs have been widely used to treat psychotic disorders such as schizophrenia. The drugs were discovered empirically, and initially the mechanism of action (MoA) was entirely unknown. In the mid 60s it was suggested that antipsychotic drugs work through blockade of dopamine receptors [1,2]. A few years later, the advent of radioligand binding techniques [3] and the availability of 3H-labeled radioligands allowed for direct studies of antipsychotic drug binding to neuroreceptors. For a series of antipsychotic drugs, a close correlation was subsequently demonstrated between affinity for dopamine receptors in vitro and antipsychotic potency in man [4,5]. The results provided strong support for the view that the antipsychotic effect is mediated by blockade of dopamine receptors.The existence of two distinct dopamine receptors-the D 1 and the D 2 receptors-were later proposed on the basis of pharmacological observations [6]. It was soon demonstrated that antipsychotic drugs bind primarily to the D 2 receptor subtype [7]. In addition, no correlation could be dem...
Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [¹¹C]AZ10419369 is a novel 5-HT(1B) receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [¹¹C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect.
The BPND of [(11)C]AZ10419369 is highly reproducible in cortical regions and satisfactory in subcortical projection areas. The variability in the RN is higher. Thus larger sample sizes or larger divergences are required to assess a potential difference between subjects or between experimental conditions in this region.
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