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-naïve 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.

Dysfunctional insular connectivity during reward prediction in patients with first-episode psychosis

“…41 This result corresponds to conclusions from a recent review that the BOLD signal in speci c neural regions normalizes over the course of antipsychotic treatment 42 and to a recent resting-state fMRI study showing that antipsychotic-induced improvement of psychotic symptoms was accompanied by increased functional connectivity among striatal regions, the ACC and the anterior insula. 12 The antipsychotic effect in treated patients can perhaps be explained by the underlying structure as well, given that insular and ACC volumes increase with increasing antipsychotic exposure in psychotic patients.…”

Involvement of amygdala–prefrontal dysfunction in the influence of negative emotion on the resolution of cognitive conflict in patients with schizophrenia

“…First, effects of medications were not ruled out. Antipsychotic drug effects in schizophrenia may include global brain functions and connectivity (Abbott, Jaramillo, Wilcox, & Hamilton, 2013; Kraguljac et al., 2015). In particular, antipsychotics could alter neural activity and functional connectivity of the amygdala (Rasetti et al., 2009) and different antipsychotics could have different effects on amygdala activity during emotional processing (Surguladze et al., 2011).…”

Increased orbitofrontal cortex activation associated with “pro-obsessive” antipsychotic treatment in patients with schizophrenia

“…18 A recent review of differential effects of antipsychotic medication concluded that lower dopaminergic receptor affinity and moderate to high serotonergic affinity is associated with greater activation of the prefrontal cortex. However, unexpectedly, clozapine appeared to cause a decrease in prefrontal activation in most studies.…”

“…17 In fact, an increasing number of studies have documented the effects of SGA treatment on neural functions. 18 These studies mostly focused on the recovery of altered frontocortical activation patterns, showing normalization of the blood oxygen level-dependent (BOLD) signal with antipsychotic treatment. 18 To elucidate differential effects of pharmacologic profiles, imaging investigations directly comparing different antipsychotic agents are needed.…”

“…18 These studies mostly focused on the recovery of altered frontocortical activation patterns, showing normalization of the blood oxygen level-dependent (BOLD) signal with antipsychotic treatment. 18 To elucidate differential effects of pharmacologic profiles, imaging investigations directly comparing different antipsychotic agents are needed. Röder and colleagues 19 and Liemburg and colleagues 20 recently reviewed the limited number of fMRI studies that used this approach, and they concluded that depending on the extent of blockade of the dopamine D2 receptor, SGAs might differentially influence the BOLD signal.…”