Molecular imaging in schizophrenia spectrum disorders

In this chapter, we aim to shed light on the schizophrenia spectrum disorders using molecular imaging. Schizophrenia spectrum disorders consist primarily of the disorders with full-blown psychosis in their course and are grouped in the DSM-V category of schizophrenia and other psychotic disorders. The treatment of psychosis has been very successful in the era of psychopharmacology, starting with the discovery of the "neuroleptic" drug chlorpromazine (Largactil). The notion that the so-called typical antipsychotics bind to dopamine D2 and D3 receptors is one of the cornerstones of the dopamine hypothesis of schizophrenia (Davis et al., Am J Psychiatry 148:1474-1486, 1991). For more than a decade, this hypothesis has been the most influential hypothesis in schizophrenia research. It postulates that schizophrenia is a manifestation of a "hyperdopaminergic" state in some regions of the brain. The binding of antipsychotics to D2/D3 receptors can be directly visualized and quantified with dopamine receptor PET and SPECT ligands, such as [11C]-raclopride or [123I]-IBZM, respectively (Laruelle, Q J Nucl Med 42:211-221, 1998). Typical antipsychotics bind to D2/D3 receptors and displace these radiotracers from the postsynaptic receptors in the dopamine projection areas, such as the striatum, providing a unique way to quantify occupancy of these compounds to the D2/D3 receptors. In one of the first human studies with [11C]-raclopride, described that an occupancy of 70-80% of the D2/D3 receptors was sufficient for its antipsychotic effects while parkinsonistic effects were associated with much higher occupancies. The anti-dopaminergic effects in the striatum explain the major side effect of typical antipsychotics, i.e., parkinsonism. Very efficacious second-line or "atypical" antipsychotics appear to be less dependent on D2 blockade for clinical effect. The major example of this line of drugs is clozapine. Clozapine acts partly by its affinity for the postsynaptic 5HT2A receptor but has "pleiotropic" effects by affecting many other neurotransmitter receptors, hormone receptors, and inflammatory mediators. However, it was found that the newer "atypical" antipsychotics marketed after clozapine still bind for a large proportion to dopamine D2/D3 receptors, which contributes significantly to their antipsychotic efficacy. Despite the enormous progress in the development of antipsychotics, and growth of choice for the clinician to treat schizophrenia, the effect remains limited to a suppressive effect on the positive psychotic symptoms, like delusions and hallucinations. Antipsychotics do not cure the disease and have major metabolic side effects, like weight gain, increasing the risk for diabetes enormously. Therefore, more knowledge on the working mechanism and the discovery of alternative molecular pathways of treatment are needed. It is the aim of this chapter to translate molecular imaging in experimental models of schizophrenia and patients to better understand the etiopathogenesis of the clinical syndrome of schizophrenia. The ultimate aim is to design better prevention, care, and cure for schizophrenia by pinpointing to the molecular focus of the disease process.