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 antipsychoticnaïve 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.

Hemodynamic response function abnormalities in schizophrenia during a multisensory detection task

“…First, although we examined the impact of medication use, motor‐side effects and smoking status in regards to our findings, we cannot entirely rule‐out their effects on neurovascular coupling, the vasculature and hence the HRF [Friedman et al, ; Leyba et al, ; Roder et al, ]. For example, certain antipsychotic medications (e.g., olanzapine and risperidone) result in cardiovascular abnormalities in both preclinical and human studies [Aboul‐Fotouh and Elgayar, ; Leung et al, ], which may directly affect the HRF [Abbott et al, ; Roder et al, ]. Similarly, HRF may also be influenced by other disease‐related changes to perfusion, metabolism, structure volume loss, neurochemical, or a combination of any of these factors, all of which would impact on current findings.…”

Neurobiology of Cognitive Remediation Therapy for Schizophrenia: A Systematic Review

“…Unfortunately, few imaging studies of pharmacologically induced cognitive changes exist. Importantly, the existing studies share important limitations in the wide effects of antipsychotics on the brain, which may confound neural changes relevant to cognition with changing symptoms or side-effects (76). Relevant findings include reduced default-mode negative modulation and increased connectivity in the ventral medial PFC during n -back tasks (77), as well as increased activity in the sensory and ventrolateral PFC, and decreased activation in the DLPFC, striatum, and thalamus during visually guided eye saccades (78).…”

“…Relevant findings include reduced default-mode negative modulation and increased connectivity in the ventral medial PFC during n -back tasks (77), as well as increased activity in the sensory and ventrolateral PFC, and decreased activation in the DLPFC, striatum, and thalamus during visually guided eye saccades (78). These studies report both neural normalization and denormalization, which may be influenced by cognitive or motor side-effects of the treatments, as well as a general effect of antipsychotics on the BOLD response (76). These confounders should be considered when comparing pharmacological treatment and CRT for cognitive deficits, though they may both provide evidence for the role of prefrontal changes in cognitive improvement.…”

Altered connectivity between striatal and extrastriatal regions in patients with schizophrenia on maintenance antipsychotics: an [18F]fallypride PET and functional MRI study

“…Previous studies have shown that dopaminergic antagonism generally alters BOLD signal and functional connectivity in healthy subjects, depending on the task paradigms and regions investigated (Abler, Erk, & Walter, ; Brassen et al, ; Honey et al, ; Tost et al, ). These changes are considered to be due to modifications of neuronal activity and cerebral vascular function (Abbott, Jaramillo, Wilcox, & Hamilton, ; Rӧder, Dieleman, van der Veen, & Linden, ). In addition, although the data are limited, studies with unmedicated patients with schizophrenia have also reported decreased or increased large‐scale functional networks (Guo et al, ; Kraguljac et al, ; Lui et al, ).…”