Bipolar Disorder, Alcohol Drinking, Alcohol Use Disorder
Conditions
Brief summary
Alcohol use disorders (AUDs) affect up to 60% of individuals with bipolar disorder during their lifetime-a rate 3 to 5 times higher than what occurs in the general population. The mechanisms that contribute to elevated rates of comorbidity are not known. Early identification in individuals with bipolar disorder who are at risk for AUDs could inform novel intervention strategies and improve life-long outcomes. The primary objective of this protocol is to use alcohol administration procedures and functional MRI techniques to investigate subjective response to alcohol, compared to placebo, and relationship with functional responses of, and connectivity among, brain regions in ventral prefrontal emotional networks in young adults with bipolar disorder and healthy comparison young adults. Baseline clinical and structural MRI assessments will be completed in 30 bipolar and 30 healthy young adults (21-26 years of age, 50% women). Then, following standard beverage administration procedures, participants will complete within-person, counter-balanced, fMRI scans and complete measures of subjective response to alcohol while under the influence of alcohol or placebo. Specifically, individual differences in the experience of stimulating, sedative, and anxiolytic effects of alcohol (measured with self-report surveys) and individual differences in neural responses to alcohol within ventral prefrontal emotional networks will be investigated and differences in bipolar disorder compared to healthy participants assessed. Functional MRI scans during a continuous performance task with emotional and neutral distractors (CPT-END) and at rest will be collected while under the influence of alcohol and placebo and compared. Experience of stimulating, sedative, and anxiolytic effects of alcohol from self-report survey data and neural responses to emotional stimuli while under the influence of alcohol compared to placebo will be the primary data outcomes assessed. Additionally, associations between subjective and neural response to alcohol and drinking patterns will be explored (secondary outcomes). The primary endpoint of the study will be after completion of both alcohol and placebo beverage conditions.
Detailed description
A total of 60 bipolar and healthy comparison subjects (n=30 per group, 21-26 years of age, 50% women, with no history of a moderate/severe AUD) will be recruited from the greater Austin area. Once recruited and enrolled, subjects will undergo detailed structured clinical evaluations to verify inclusion and exclusion criteria, comprehensive assessment of alcohol and other drug use history, and cognitive testing, followed by structural MRI assessments. Following standard beverage administration procedures, they will then complete measures of subjective response to alcohol and fMRI scans while under the influence of alcohol or a placebo condition (counter-balanced). For each participant the first beverage session assignment (whether the participant is given alcohol or the placebo beverage first) will be randomized. Alcohol and placebo sessions will occur within 3 days of each other. FMRI assessments will include a continuous performance task with emotional and neutral distractors (CPT-END) and a resting state scan. For both the alcohol and the placebo beverage conditions, the protocol will be the same. The beverage administration sessions will occur in a private room at the University of Texas at Austin in the Imaging Research Center. The table in the testing room will be wiped down with alcohol prior to the participant's arrival (olfactory cue). Study staff will use an algorithm to calculate individual alcohol doses based on the participants' age, sex, height, and weight. Participants fast from food for 4 hours prior to their session. Before beginning consumption of their beverages, they will eat a weight-adjusted, 1 calorie per pound snack of pretzels. While participants eat their pretzels, study staff will mix beverages in front of participants. Vodka and placebo (decarbonated tonic water) will be stored in absolute vodka bottles, measured out, and combined with mixer in front of participants. Mixed drinks will be poured into glasses that have been sitting face down with rims soaking in vodka. Prior to giving the beverage to the participant, all drinks will get an alcohol floater (squirt of absolute vodka on top of the drink). Participants will be given 20 minutes to orally consume two beverages (10 minutes per beverage). Following oral consumption and a 10 minute absorption period, breathalyzer tests will be conducted to identify a .06g% ascending limb breath alcohol concentration (BrAC). Self-report of subjective response to alcohol will be collected and participants will immediately enter the scanner and complete the fMRI scan (acquisition parameters are identical during alcohol and placebo conditions). BrAC will be tracked after the MRI scan and subjective response to alcohol collected again at peak BrAC and at descending BrAC of .06g%. Consistent with NIAAA guidelines for human alcohol studies, BrAC readings will continue every 30 minutes until participants are below 0.04% at which time they will be escorted home. During the placebo condition, participants will be given false BrAC readings. False BrAC readings given to participants during the placebo session will be based on the average BrACs we record during the alcohol sessions. The average time participants stay in the laboratory will be the same for the placebo and alcohol beverage conditions. Participants are debriefed after completing all sessions and the need for deception to ensure the placebo-controlled alcohol session will be explained.
Interventions
OTHERalcohol beverage
Participants will be provided alcohol during study visits and changes in behavior/neural activity after consuming alcohol will be examined.
OTHERPlacebo beverage
placebo beverage conditions.
Sponsors
University of Texas at Austin
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 26 Years
Healthy volunteers
Yes
Inclusion criteria
Inclusion criteria for all participants: * between 21 and 26 years of age * having consumed at least 4 (men) or 3 (women) drinks on a single occasion over the last year * euthymic at the time of study Inclusion criteria for bipolar disorder participants: \- Meeting Diagnostic and Statistical Manual-5 Research Version (DSM-V-RV) diagnostic criteria for bipolar disorder, confirmed by structured interview
Exclusion criteria
For all subjects
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | up to 1 week | Participants fill out self-report surveys \[specifically the Subjective Effects of Alcohol Scale (SEAS)\] on how they feel when they arrive to their beverage administration sessions (alcohol and placebo sessions). They then feel out the same self-report surveys on how intoxicated they feel during their beverage sessions (alcohol and placebo). Changes in how intoxicated they feel is calculated for both the alcohol and placebo condition (compared to how they felt pre-beverage). 4 subscores are calculated by summing individual items: positive valence/positive arousal (stimulation), SEAS positive valence/negative arousal (anxiolytic), negative valence/negative arousal (aggression/agitation), and negative valence/negative arousal (sedative effects). Summed subscores on the SEAS range between 0 and 40. Change scores can therefore range between -40 and 40 (post-beverage compared to pre-beverage feelings). Scores greater than 0 on any one subscale indicates feeling more effects of alcohol. |
| Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | up to 1 week | Neural responses to emotional stimuli during the alcohol and placebo sessions were modeled. Fisher transformed correlation coefficients between regions of interest while viewing emotional stimuli (compared to squares) were calculated for each beverage session and data extracted for posthoc analysis. Values represent change scores in correlation coefficients during each beverage session. |
Countries
United States
Participant flow
Recruitment details
60 participants were recruited.
Pre-assignment details
Participants were randomly assigned to receiving placebo first or alcohol beverage session first.
Participants by arm
| Arm | Count |
|---|---|
| BD Alcohol First, Then Placebo Participants will be dosed to a 0.08g% blood alcohol concentration on alcohol day and then on a following day was dosed to \<.01 blood alcohol concentration (placebo day). | 15 |
| TD Alcohol First, Then Placebo Participants will be dosed to a 0.08g% blood alcohol concentration on alcohol day and then on a following day was dosed to \<.01 blood alcohol concentration (placebo day). | 13 |
| BD Placebo First, Then Alcohol Participants were dosed to \<.01 blood alcohol concentration (placebo day) for their first beverage, and then on a following day were dosed to a 0.08g% blood alcohol concentration (alcohol day). | 13 |
| TD Placebo First, Then Alcohol Participants were dosed to \<.01 blood alcohol concentration (placebo day) for their first beverage, and then on a following day were dosed to a 0.08g% blood alcohol concentration (alcohol day). | 13 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | placebo manipulation issue | 1 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | BD Alcohol First, Then Placebo | TD Alcohol First, Then Placebo | BD Placebo First, Then Alcohol | TD Placebo First, Then Alcohol | Total |
|---|---|---|---|---|---|
| Age, Continuous | 23.3 years STANDARD_DEVIATION 1.8 | 22.1 years STANDARD_DEVIATION 1.3 | 23.5 years STANDARD_DEVIATION 1.7 | 22.9 years STANDARD_DEVIATION 1.3 | 22.9 years STANDARD_DEVIATION 1.6 |
| Race/Ethnicity, Customized Asian | 0 Participants | 3 Participants | 2 Participants | 5 Participants | 10 Participants |
| Race/Ethnicity, Customized Hispanic | 4 Participants | 3 Participants | 7 Participants | 3 Participants | 17 Participants |
| Race/Ethnicity, Customized More than one race | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Nonhispanic White | 10 Participants | 6 Participants | 3 Participants | 4 Participants | 23 Participants |
| Sex: Female, Male Female | 11 Participants | 8 Participants | 9 Participants | 7 Participants | 35 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 4 Participants | 6 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 15 | 0 / 13 |
| other Total, other adverse events | 0 / 15 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 15 | 0 / 13 |
| serious Total, serious adverse events | 0 / 15 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 13 | 0 / 15 | 0 / 13 |
Outcome results
Primary
Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares)
Neural responses to emotional stimuli during the alcohol and placebo sessions were modeled. Fisher transformed correlation coefficients between regions of interest while viewing emotional stimuli (compared to squares) were calculated for each beverage session and data extracted for posthoc analysis. Values represent change scores in correlation coefficients during each beverage session.
Time frame: up to 1 week
Population: Analysis was completed prior to study completion.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: alcohol | -0.04 Change scores in correlation coefficient | Standard Error 0.02 |
| BD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: placebo | 0.001 Change scores in correlation coefficient | Standard Error 0.02 |
| BD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: alcohol | -0.006 Change scores in correlation coefficient | Standard Error 0.03 |
| BD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: placebo | -0.06 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: placebo | -0.0003 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: alcohol | -0.05 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: placebo | -0.002 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Alcohol First, Then Placebo | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: alcohol | 0.03 Change scores in correlation coefficient | Standard Error 0.02 |
| BD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: alcohol | 0.01 Change scores in correlation coefficient | Standard Error 0.02 |
| BD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: placebo | 0.05 Change scores in correlation coefficient | Standard Error 0.01 |
| BD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: placebo | -0.014 Change scores in correlation coefficient | Standard Error 0.03 |
| BD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: alcohol | 0.002 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: placebo | 0.003 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: placebo | -0.006 Change scores in correlation coefficient | Standard Error 0.02 |
| TD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Insula:sgACC functional connectivity: alcohol | 0.05 Change scores in correlation coefficient | Standard Error 0.03 |
| TD Placebo First, Then Alcohol | Change in Functional Coupling Between Regions of Interest During Viewing of Emotional Stimuli (Neural Responses While Viewing Emotional Stimuli Were Contrasted Against Neural Responses When Viewing Squares) | Left NAc:vmPFC functional connectivity: alcohol | -0.02 Change scores in correlation coefficient | Standard Error 0.03 |
Comparison: Power analysis suggests this sample size (n = 23 with bipolar disorder, n = 24 healthy comparison participants), at an alpha = 0.05, provides \> 80% statistical power to detect a within subject effect size (ES) d ≥ 0.6 in both subgroups and a between group ES d ≥ 0.8 in this fMRI analysis.p-value: <0.004Mixed Models Analysis
Primary
Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking)
Participants fill out self-report surveys \[specifically the Subjective Effects of Alcohol Scale (SEAS)\] on how they feel when they arrive to their beverage administration sessions (alcohol and placebo sessions). They then feel out the same self-report surveys on how intoxicated they feel during their beverage sessions (alcohol and placebo). Changes in how intoxicated they feel is calculated for both the alcohol and placebo condition (compared to how they felt pre-beverage). 4 subscores are calculated by summing individual items: positive valence/positive arousal (stimulation), SEAS positive valence/negative arousal (anxiolytic), negative valence/negative arousal (aggression/agitation), and negative valence/negative arousal (sedative effects). Summed subscores on the SEAS range between 0 and 40. Change scores can therefore range between -40 and 40 (post-beverage compared to pre-beverage feelings). Scores greater than 0 on any one subscale indicates feeling more effects of alcohol.
Time frame: up to 1 week
Population: Excluded participants with placebo manipulation issues. One TD participant was excluded because they later revealed a past depressive episode.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: alcohol session | 7.3 score on a scale | Standard Error 1.2 |
| BD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: placebo session | 4.1 score on a scale | Standard Error 1.1 |
| BD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: alcohol session | -1.4 score on a scale | Standard Error 1.6 |
| BD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: placebo session | 1.7 score on a scale | Standard Error 0.98 |
| TD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: placebo session | 2.3 score on a scale | Standard Error 0.98 |
| TD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: alcohol session | -5.3 score on a scale | Standard Error 0.9 |
| TD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: placebo session | -0.42 score on a scale | Standard Error 0.47 |
| TD Alcohol First, Then Placebo | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: alcohol session | 3.6 score on a scale | Standard Error 1 |
| BD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: alcohol session | 7.1 score on a scale | Standard Error 2.1 |
| BD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: placebo session | 5.3 score on a scale | Standard Error 1.8 |
| BD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: placebo session | -2.3 score on a scale | Standard Error 0.97 |
| BD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: alcohol session | 15.4 score on a scale | Standard Error 2.3 |
| TD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: placebo session | -2.96 score on a scale | Standard Error 4.7 |
| TD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: placebo session | 3.3 score on a scale | Standard Error 1.1 |
| TD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/positive arousal: alcohol session | 6.3 score on a scale | Standard Error 1.3 |
| TD Placebo First, Then Alcohol | Level of Intoxication (Subjective Response) on Each Condition Day After Drinking Relative to How They Felt When Arriving to the Lab on That Respective Day )Prior to Drinking) | SEAS positive valence/negative arousal: alcohol session | 0.9 score on a scale | Standard Error 1.4 |
p-value: <0.05Mixed Models Analysis