Antipsychotic drug effects in schizophrenia: a review of longitudinal FMRI investigations and neural interpretations

Abstract

The evidence that antipsychotics improve brain function and reduce symptoms in schizophrenia is unmistakable, but how antipsychotics change brain function is poorly understood, especially within neuronal systems. In this review, we investigated the hypothesized normalization of the functional magnetic resonance imaging (fMRI) blood oxygen level dependent signal in the context of antipsychotic treatment. First, we conducted a systematic PubMed search to identify eight fMRI investigations that met the following inclusion criteria: case-control, longitudinal design; pre- and post-treatment contrasts with a healthy comparison group; and antipsychotic-free or antipsychotic-naive patients with schizophrenia at the start of the investigation. We hypothesized that aberrant activation patterns or connectivity between patients with schizophrenia and healthy comparisons at the first imaging assessment would no longer be apparent or "normalize" at the second imaging assessment. The included studies differed by analysis method and fMRI task but demonstrated normalization of fMRI activation or connectivity during the treatment interval. Second, we reviewed putative mechanisms from animal studies that support normalization of the BOLD signal in schizophrenia. We provided several neuronal-based interpretations of these changes of the BOLD signal that may be attributable to long-term antipsychotic administration.

Fig. 1

Dopamine (DA), via the D2 receptor (D2R), A) provides negative feedback through presynaptic autoreceptors, B) inhibits adenyl cyclase activity through G protein coupled receptors (GPRC), C) increases calcium (Ca++) concentration in astrocytes, and D) constricts the cerebral vasculature. Antipsychotics, via the D2 receptor, modulate all of these dopaminergic activities, which may affect the blood oxygen level dependent signal.