Reduced Subjective Response to Acute Ethanol Administration Among Young Men with a Broad Bipolar Phenotype

Abstract

Elevated lifetime prevalence rates of alcohol use disorders (AUDs) are a feature of bipolar disorder (BD). Individuals at-risk for AUDs exhibit blunted subjective responses to alcohol (low levels of response), which may represent a biomarker for AUDs. Thus, individuals atrisk for BD may exhibit low responses to alcohol. Participants were 20 unmedicated adult males who reported high rates of hypomanic experiences (bipolar phenotype participants; BPPs), aged 18 to 21 years, and 20 healthy controls matched on age, gender, IQ, BMI, and weekly alcohol intake. Subjective and pharmacokinetic responses to acute alcohol (0.8 g/kg) vs placebo administration were collected in a randomized, double-blind, cross-over, placebo-controlled, within-subjects design. BPP participants reported significantly lower subjective intoxication effects ('feel high': F ¼ 14.2, p ¼ 0.001; 'feel effects': F ¼ 8.1, p ¼ 0.008) across time, but did not differ in their pharmacokinetic, stimulant, or sedative responses. Paradoxically, however, the BPP participants reported significantly higher expectations of the positive effects of alcohol than controls. Our results suggest that unmedicated young males with previous hypomanic experiences exhibit diminished subjective responses to alcohol. These blunted alcohol responses are not attributable to differences in weekly alcohol intake, pharmacokinetic effects (eg, absorption rates), or familial risk of AUDs. These observations suggest that the dampened intoxication may contribute to the increased rates of alcohol misuse in young people at-risk for BD, and suggest possible shared etiological factors in the development of AUDs and BD.

Hypoactivation of the Ventral and Dorsal Striatum During Reward and Loss Anticipation in Antipsychotic and Mood Stabilizer-Naive Bipolar Disorder

“…Taken together with our previous findings of a reduced subjective response to acute ethanol among young adults with high rates of hypomanic experiences (Yip et al, 2012)-in conjunction with fMRI data demonstrating decreased BOLD response during the A2 phase among individuals family history positive for AUDs (Andrews et al, 2011)-these data suggest that blunted experiences of Abbreviation: FWE, family-wise error corrected. The dorsal and ventral striatum ROIs were defined using 9 mm spheres centering on the following coordinates: dorsal ROIs: left:…”

“…We previously demonstrated a reduced subjective psychostimulant response to acute ethanol administration among young men at increased risk for BD (Yip et al, 2012), which-as highlighted by Schuckit (2012)-was strikingly similar to the 'low level response' frequently observed among young adults family history positive for AUDs (eg, Schuckit and Smith, 1996;Schuckit, 2012). This low level of response in completely antipsychotic-naive subjects could reflect neurodevelopmental alterations-eg, in dopaminergic transmission (Bahi and Dreyer, 2012) or in white matter pathway development )-relating to the elevated rates of both substance and nonsubstance addictions observed across BD subtypes (Swann et al, 2005;Merikangas et al, 2007;Di Nicola et al, 2010;Swann, 2010).…”

“…This low level of response in completely antipsychotic-naive subjects could reflect neurodevelopmental alterations-eg, in dopaminergic transmission (Bahi and Dreyer, 2012) or in white matter pathway development )-relating to the elevated rates of both substance and nonsubstance addictions observed across BD subtypes (Swann et al, 2005;Merikangas et al, 2007;Di Nicola et al, 2010;Swann, 2010). From this perspective, altered neural processing of rewards may be a shared risk-factor between BD and addictive disorders (Yip et al, 2012). In the present study, we therefore tested the hypothesis of altered striatal activity among euthymic, antipsychotic-and mood stabilizer-naive young adults with BD.…”

“…Thus, based on our previous findings of blunted responses to acute ethanol among unmedicated individuals with high rates of hypomania (Yip et al, 2012), we hypothesized blunted VS activity during reward anticipation and outcome processing among euthymic-, antipsychotic-, and mood stabilizer-naive young adults with BD II/NOS.…”

Commentary on ‘Reduced Subjective Response to Acute Ethanol Administration Among Young Men with a Broad Bipolar Phenotype’

“…It is also possible that some of the same genes contribute to both AUDs or related endophenotypes and bipolarity (Schuckit et al, 2003). The latter hypothesis relates well to the paper by Yip et al (2012), whose data suggest that some of the link between a bipolar predisposition and adverse alcohol outcomes might operate through the low LR to alcohol. This commentary gives some additional background on LR and speculates about some implications of the Yip et al's results.…”