Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions

Abstract

Standard-of-care biological treatment of schizophrenia remains dependent upon antipsychotic medications, which demonstrate D receptor affinity and elicit variable, partial clinical responses via neural mechanisms that are not entirely understood. In the striatum, where D receptors are abundant, antipsychotic medications may affect neural function in studies of animals, healthy volunteers, and patients, yet the relevance of this to pharmacotherapeutic actions remains unresolved. In this same brain region, some individuals with schizophrenia may demonstrate phenotypes consistent with exaggerated dopaminergic signaling, including alterations in dopamine synthesis capacity; however, the hypothesis that dopamine system characteristics underlie variance in medication-induced regional blood flow changes has not been directly tested. We therefore studied a cohort of 30 individuals with schizophrenia using longitudinal, multi-session [O]-water and [F]-FDOPA positron emission tomography to determine striatal blood flow during active atypical antipsychotic medication treatment and after at least 3 weeks of placebo treatment, along with presynaptic dopamine synthesis capacity (ie, DOPA decarboxylase activity). Regional striatal blood flow was significantly higher during active treatment than during the placebo condition. Furthermore, medication-related increases in ventral striatal blood flow were associated with more robust amelioration of excited factor symptoms during active medication and with higher dopamine synthesis capacity. These data indicate that atypical medications enact measureable physiological alterations in limbic striatal circuitry that vary as a function of dopaminergic tone and may have relevance to aspects of therapeutic responses.

Cerebral blood flow in striatal regions is associated with apathy in patients with schizophrenia

“…Previous research has suggested an influence of antipsychotic medication on striatal rCBF. 52,63,67,68 While we did not observe an association between striatal rCBF and antipsychotic dose, we cannot exclude a potential effect of antipsychotic medication. Thus, future studies should include nonmedicated patients and patients taking first-generation antipsychotics to generalize the relationship between apathy and striatal activity to these populations.…”

Inflammation and Negative Symptoms of Schizophrenia: Implications for Reward Processing and Motivational Deficits

“…As expected in a heterogeneous syndrome such as schizophrenia and given the complex circuit-dependent actions of neurotransmitters, some studies (150,151), have demonstrated that individuals with treatment resistant schizophrenia, who may have persistent negative symptoms (16, 152), may have decreased dopamine synthesis capacity. This is further supported by recent evidence that phase of illness and antipsychotic medications may alter dopaminergic tone by increasing presynaptic dopamine capacity (153). As such, there may be heterogeneity in dopamine signaling pathways such that the underlying hyperdopaminergic state in subcortical regions, which was long thought to be the field's understanding of dopamine signaling in patients with schizophrenia (154), may only be present in a subgroup of patients.…”

Approaches to neuromodulation for schizophrenia

“…Results relating changes in rCBF in VS to improvement in symptoms were less consistent (table 1). 12 25 However, one investigation went on to demonstrate that this rCBF change in VS was associated with presynaptic dopamine synthesis capacity in the VS 12. Clearly striatal modulation is warranted and regulation of striatal dopamine has been described as an ascending, feedforward spiral of information flow (figure 2).…”