Brain activation and subjective anxiety during an anticipatory anxiety task is related to clinical outcome during prazosin treatment for alcohol use disorder.

BACKGROUND: Higher levels of anxiety, negative affect, and impaired emotion regulation are associated with alcohol use disorder (AUD) and contribute to relapse and worse treatment outcomes. Prazosin, while typically used to treat post-traumatic stress disorder (PTSD) and other anxiety disorders, has shown promise for treating AUD. In order to better understand these underlying neural processes in individuals with AUD, our aims in this study were to measure brain activation during an anticipatory anxiety task before treatment to determine whether observed patterns supported previous work. We then aimed to measure the effects of prazosin on patients with AUD and explore whether greater baseline anticipatory anxiety (as measured by subjective and neural measures) predicts better treatment outcomes. METHODS: Thirty-four individuals seeking treatment for AUD participated in a six-week placebo-controlled study of prazosin and underwent an anticipatory anxiety task during fMRI scans at baseline and three weeks. Alcohol use over six weeks was measured. RESULTS: Greater levels of subjective anxiety and deactivation in posterior cingulate cortex (PCC) and ventromedial prefrontal cortex (vmPFC) were observed during high-threat stimuli compared to low-threat stimuli. Compared to placebo, prazosin reduced subjective anxiety to high-threat stimuli but there were no observed significant effects of prazosin on brain activation during the task. However, AUD patients with greater vmPFC deactivation during high threat relative to low threat and patients with low baseline anticipatory anxiety during the task had worse clinical outcomes on prazosin. CONCLUSIONS: Deactivation in PCC and vmPFC to high-threat stimuli replicated previous work and shows promise for further study as a marker for AUD. Although prazosin did not affect brain activation in the regions of interest during the anticipatory anxiety task, subjective levels of anxiety and brain activation in vmPFC predicted treatment outcomes in individuals with AUD undergoing treatment with prazosin, highlighting individuals more likely to benefit from prazosin than others.

Stroop-related cerebellar and temporal activation is correlated with negative affect and alcohol use disorder severity.

Impairment in cognitive control in alcohol use disorder (AUD) contributes to difficulty controlling alcohol use and, in many populations, difficulties with emotion regulation. However, the most reliable and robust marker of clinically-relevant deficits in cognitive control in AUD is unclear. Our aims were to measure relationships between BOLD signal during a Stroop task and AUD severity and change in BOLD signal and change in drinking over three weeks. We also aimed to explore the relationships between BOLD signal and subjective negative affect. Thirty-three individuals with AUD underwent a multisensory Stroop task during functional magnetic resonance imaging (fMRI), as well as a battery of neuropsychological tests and self-report assessments of negative affect and AUD severity. Greater activation in temporal gyrus and cerebellum during incongruent trials compared to congruent trials was observed, and percent signal change (incongruent minus congruent) in both clusters was positively correlated with AUD severity and self-reported negative affect. Neuropsychological task performance and self-reported impulsivity were not highly correlated with AUD severity. Hierarchical regression analyses indicated that percent signal change (incongruent minus congruent) in cerebellum was independently associated with negative affect after controlling for recent and chronic drinking. In a subset of individuals (n = 23) reduction in cerebellar percent signal change (incongruent minus congruent) was correlated with increases in percent days abstinent over 3 weeks. BOLD activation during this Stroop task may therefore be an important objective marker of AUD severity and negative affect. The potential importance of the cerebellum in emotion regulation and AUD severity is highlighted.

A Randomized, Placebo-controlled, Clinical Trial of Prazosin for the Treatment of Alcohol Use Disorder.

OBJECTIVES: The noradrenergic system plays an important role in the pathophysiology of alcohol use disorder (AUD). Medications in this class may reduce drinking. Our aims were to investigate this in a unique sample of individuals with AUD. METHODS: Thirty-six individuals with AUD were randomized to treatment with prazosin, an alpha-1 noradrenergic antagonist, or placebo, for 6 weeks (target daily dose 16 mg). Hierarchical linear modeling was used to examine the effect of treatment group on rate of change in primary (drinks per week [DPW]) and several secondary outcome measures. RESULTS: Prazosin did not significantly affect rate of reduction in alcohol use in the intent to treat sample (n = 36) compared with placebo, but did significantly increase the rate of reduction in DPW in an optimal treatment exposure subgroup (beta = -0.3; P = 0.01; event rate ratio 0.74; confidence interval 0.59, 0.93; n = 27). Poor adherence and tolerability may have contributed to null effects. Diastolic blood pressure (DBP) moderated the effects of treatment group on rate of reduction in drinks per drinking day, supporting previous work in doxazosin, another alpha-1 antagonist. Specifically, prazosin was associated with greater rates of reduction in drinking compared with placebo in individuals with high but not low DBP. CONCLUSIONS: Our findings do not support the clinical utility of prazosin for all treatment-seeking AUD, but post hoc analyses indicate that it might have some efficacy in individuals who can tolerate it. Further work exploring the clinical utility of DBP as a treatment matching variable, and defining optimal values using sensitivity and specificity analyses, is warranted.