Molecular imaging of schizophrenia: Neurochemical findings in a heterogeneous and evolving disorder

Abstract

The past four decades have seen enormous efforts placed on a search for molecular markers of schizophrenia using positron emission tomography (PET) and single photon emission computed tomography (SPECT). In this narrative review, we cast a broad net to define and summarize what researchers have learned about schizophrenia from molecular imaging studies. Some PET studies of brain energy metabolism with the glucose analogue FDGhave have shown a hypofrontality defect in patients with schizophrenia, but more generally indicate a loss of metabolic coherence between different brain regions. An early finding of significantly increased striatal trapping of the dopamine synthesis tracer FDOPA has survived a meta-analysis of many replications, but the increase is not pathognomonic of the disorder, since one half of patients have entirely normal dopamine synthesis capacity. Similarly, competition SPECT studies show greater basal and amphetamine-evoked dopamine occupancy at post-synaptic dopamine D2/3 receptors in patients with schizophrenia, but the difference is likewise not pathognomonic. We thus propose that molecular imaging studies of brain dopamine indicate neurochemical heterogeneity within the diagnostic entity of schizophrenia. Occupancy studies have established the relevant target engagement by antipsychotic medications at dopamine D2/3 receptors in living brain. There is evidence for elevated frontal cortical dopamine D1 receptors, especially in relation to cognitive deficits in schizophrenia. There is a general lack of consistent findings of abnormalities in serotonin markers, but some evidence for decreased levels of nicotinic receptors in patients. There are sparse and somewhat inconsistent findings of reduced binding of muscarinic, glutamate, and opioid receptors ligands, inconsistent findings of microglial activation, and very recently, evidence of globally reduced levels of synaptic proteins in brain of patients. One study reports a decline in histone acetylase binding that is confined to the dorsolateral prefrontal cortex. In most contexts, the phase of the disease and effects of past or present medication can obscure or confound PET and SPECT findings in schizophrenia.