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Adial Pharmaceuticals, Inc. is filing an application for Fast Track with the US Food and Drug Administration (FDA) for its lead drug candidate, AD04.

Adial previously requested AD04, a therapeutic agent for the treatment of alcohol use disorder (AUD) in patients with target genotypes, be considered for the FDA expedited review program.

“We are working with our regulatory counsel to prepare our Fast Track submission after consultation with the FDA,” Adial’s CEO, William Stilley, said to the press “Following our submission, the FDA is expected to review the request and make a decision within 60 days.”

When a Fast Track application is reviewed, the submitted drug must demonstrate advantages over the currently available and approved therapy, thus meeting an unmet medical need. Advantages Adial believes AD04’s advantages include the following: 1) AD04 had a significant effect in patients with AUD who did not tolerate available therapy or failed to respond to said therapy; 2) AD04 saw a decrease in clinically significant toxicity of a common available therapy that often causes discontinuation of treatment; 3) AD04 has a safety and efficacy profile similar to that of available therapies, but is expected to enhance improvement in serious cases of AUD; 4) AD04 addresses the anticipated public health need.

“Adial’s correspondence and consultation with the FDA following its expedited review filing in September 2020, leads us to believe that AD04 qualifies for Fast Track consideration,” Adial’s Head of Regulatory, Jack Reich, PhD, commented to press. “I am confident Alcohol Use Disorder qualifies as a serious condition and that there is an unmet medical need, based on our communication with the FDA and as set forth in the FDA’s 

Guidance for Industry Expedited Programs for Serious Conditions—Drugs and Biologics

Cornel N. Stanciu, MD, MRO, had this to say: "You can look at the issue of pharmacotherapy for alcohol use disorders in two ways. On one hand, currently only 6% of those with an alcohol use disorder receive any of the FDA approved medications for relapse prevention, so we are not making use of what is available. On the other hand, addictionologists like myself need more tools to be able to tailor and personalize treatments for individual sufferers as one size does not fit all. This development presents a step forward towards a novel type of drug development to address an unmet medical need."

1. Adial Pharmaceuticals. Adial to file Fast Track application for AD04 with the FDA. News release. February 23, 2021. 

https://ir.adialpharma.com/press-releases/detail/112/adial-to-file-fast-track-application-for-ad04-with-the-fda

An alcohol use disorder treatment has 4 potential advantages over existing treatments.  

Hitting the Fast Track: Alcohol Use Disorder Treatment Filing with FDA

 of alcohol use disorders (AUD) with depression, one medication stood out as the most effective but is not widely used. The meta-analysis, which included 66 randomized controlled trials that tested 18 categories of medications in 5890 patients who had an AUD and either 

 or depressive symptoms, found that disulfiram was the most effective at reducing alcohol use across all comparisons.

Only 3 medications reached statistical significance for remission: disulfiram, anticonvulsants (carbamazepine, topiramate, tiagabine), and a naltrexone with a selective serotonin reuptake inhibitor (

). The odds ratio for remission was much higher with disulfiram, although the spread of the data was also wider as indicated by the standard deviations in the graph. This difference held up to sensitivity analysis, in which studies that might have skewed the results were removed.

For abstinence, only disulfiram and baclofen reached statistical significance. (Baclofen is a muscle relaxant with mixed results in AUD when studied independent of 

. It has no measurable reinforcing properties; there have been rare reports of baclofen abuse.) The odds ratio for days abstinent was higher for disulfiram compared with baclofen; this finding held up to sensitivity analysis (

, there were no clear winners. The noradrenergic medications appeared effective as a group, but this group included only venlafaxine and the non-US medication viloxazine. Nearly all efficacy was attributable to viloxazine, a norepinephrine reuptake inhibitor. Mirtazapine showed promise, but only in a secondary analysis of studies looking at full episodes of depression, rather than subsyndromal cases.

Although these studies cannot explain why disulfiram works well in depression, I will venture a guess from clinical experience. Patients with depression are often unable to take action on the things that are good for them, ie, bathing, eating healthy, and achieving sobriety. Although they want to stop drinking, they struggle with ruminative thoughts and never arrive at an executable plan. Disulfiram halts indecision, relieving them of the struggle. Patients are unlikely to drink on disulfiram because their actions are driven more by 

Disulfiram’s efficacy may not be unique to depression. The drug worked well in general AUD in prior analyses. In the 1930s, workers who were exposed to it at a rubber factory became sick after drinking alcohol. This led to the first clinical use in the 1940s and its FDA approval for alcohol cessation in 1951. However, only 200,000 individuals— about 1% of patients with AUD — take disulfiram in the US.

The reason for disulfiram’s decline may be due to its unique mechanism. Disulfiram induces an immediate hangover reaction when combined with alcohol. It blocks the enzyme that metabolizes acetaldehyde, the toxin responsible for alcohol’s hangover effect. With heavy drinking or high doses of disulfiram, this effect can be fatal. When disulfiram was first released, that effect was thought to be necessary, so patients were advised to drink. That practice ended when a few patients died, but it also left a stain on disulfiram’s reputation.

Oncologists do not withhold lifesaving medications because they are potentially toxic. Yet disulfiram appears underutilized, despite the fact that alcohol-related fatalities have soared to the No. 1 cause of death in middle-aged adults. Although fatalities are extremely rare with disulfiram, physicians may feel a greater weight of responsibility for those deaths than they do when patients die from 

. An oncologist, however, would not feel this way when a patient dies from 

 of disulfiram’s safety noted, “Deaths from the disulfiram-alcohol (ethanol) interaction have not been reported in recent years, possibly because the dosages used are lower than those used 40 years ago and patients with cardiac disease are now excluded from treatment.”

Today, most physicians prefer the lower dose of 250 mg/day. This produces a less toxic interaction with alcohol and works just as well as 500 mg/day. Actually, placebo worked just as well as disulfiram in the blinded studies because simply warning a patient that the interaction is toxic will help them achieve sobriety even when the pill is a placebo.

Patients must be alcohol free for 12 hours before starting disulfiram; the disulfiram-alcohol interaction persists for up to 2 weeks after stopping disulfiram. Disulfiram is contraindicated in severe 

 or heart failure, as there have been cases of sudden death after drug initiation. Relative contraindications include liver disease (disulfiram can elevate liver function tests, as can naltrexone), psychotic disorder (there are rare cases of psychosis or confusional states), and active alcohol use (in the past 12 hours). When used in absence of alcohol, common adverse effects include fatigue and headache. Check for drug interactions in the 

The bottom line seems pretty straightforward: Don’t overlook disulfiram, but know how to use it safely in 

is an instructor in clinical psychiatry at the Wake Forest School of Medicine and the director of the Mood Treatment Center in Winston-Salem, North Carolina. He is editor in chief of The Carlat Psychiatry Report and coeditor of the bipolar disorder section for

Efficacy of pharmacotherapeutics for patients comorbid with alcohol use disorders and depressive symptoms-a bayesian network meta-analysis

Safety issues concerning the use of disulfiram in treating alcohol dependence

Despite alcohol-related fatalities soaring to the No. 1 cause of death in middle-aged adults, this medication is often overlooked.

Underused Medication May Be Best Bet for Comorbid AUD and Depression

, half of full time college students aged 18 to 22 consumed alcohol this past month, and 33% of them engaged in binge drinking during this same time frame.

 as consumption of 5 or more standard drinks on 1 occasion for males, or 4 or more for females, bringing blood alcohol concentration to 0.08 grams of alcohol per deciliter or higher.

 These drinking patterns lead to serious health and safety risks, including death from unintentional injuries such as motor vehicle crashes,

 suicide attempts and other mental health issues, legal charges, and, over the long term, damage to the liver and other organs.

Academic performance is also compromised, with 1 in 4 students endorsing academic difficulties (ie, missing class or falling behind on assignments) due to alcohol consumption.

 to perform poorly on tests or projects compared to those who drink but do not binge (40% vs 7%) and 5 times more likely to have missed a class.

 Additionally, although not all who drink develop an addiction, consumption and especially binge drinking patterns are certainly preludes to developing an addiction, with approximately 9% of college students meeting criteria for alcohol use disorder.

 Lack of screening may also underestimate the magnitude of the problem.

Although most students arrive to college having already had some experience with alcohol, the first few weeks of freshman year are often a period of 

 and alcohol-related consequences. Social pressures and expectations during new-found independence, widespread availability and access to alcohol, an unstructured schedule with mounting 

, and lack of parental interactions all play a role. Alongside these stressors, many students have pre-existing personality traits that may account for the use and misuse of alcohol during college.

One of the “Big Five” higher order personality traits, neuroticism, defined by high emotional instability, depressed mood, low frustration tolerance, and anxiety, has been found to positively predict alcohol consumption,

 as well as being a predictor of alcohol use.

 As it pertains to the college population, only 1 previous study of 200 students evaluated the implications of personality types and found high neuroticism and low conscientiousness predicted more alcohol use and related problems.

In the study analyzed in this journal club, 

 aim to better understand the role of personality and neuroticism in college alcohol use/misuse among freshman, above and beyond the reported levels of stress. The starting hypothesis revolves around the notion that negative affect faces of neuroticism, and primarily depression, are more strongly associated with alcohol use and misuse than stress when accounting for other personality domains.

Do personality traits and neuroticism in particular predict 

 in matriculating college freshmen above and beyond reported levels of stress?

 Cross-sectional outpatient Institutional Review Board, an approved study with survey data collected from participants during the first 8 weeks of their first college semester.

211 female and 90 male matriculating college freshmen with an average age of 18.58 years (SD =0.39) from 2 campuses of a private university in the Southeastern United States, spanning both urban and rural areas.

Participants were recruited from the 2 campuses of a private university (urban n=193; rural n =110) at the start of the first semester through fliers posted around campus and during frequent in-person undergraduate events. They were administered an online survey of behavioral and health questionnaires, in addition to several 

. Most surveys were completed within 3 weeks of the study start, and participants received a $15 gift card for completion. The Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) and the Alcohol Use Disorders Identification Test (AUDIT) were used to assess alcohol use and misuse (

Endorsement of use 1 or more times on the ASSIST prompted the administration of the AUDIT, a 10-item questionnaire with a maximum score of 40, where the higher scores indicate more severe and hazardous, harmful, 

. Stress was assessed using the Perceived Stress Scale (PSS), a 14-item self-reported measure of stress with each stress symptom scored on a 4-point Likert scale, where 0 =never and 4=very often (maximum score of 56). Personality was assessed using the 44-item version of the Big Five Inventory (BFI), which measures 5 dimensions of personality (openness to experience, conscientiousness, extraversion, agreeableness, and neuroticism).

Ten facet traits were also calculated to assess more specific 

 within the 5 domains: for openness, aesthetics, and ideas; conscientiousness, order, and self-discipline; for extraversion, assertiveness, and activity; agreeableness, altruism, and compliance; and for neuroticism, anxiety, and depression.

 All analyses controlled for campus site (rural versus urban), sex, and individual week of study enrollment (as school obligations as potential stressors fluctuated between study weeks). The researchers examined partial correlations between predictions while controlling for covariates. They used multiple regression analysis to examine the conditional and joint effect of personality and stress on alcohol use and misuse.

Of the sample, 54% (or 164 individuals) endorsed 

 at least once in their lifetime. Descriptive statistics of all covariates were accounted for, and across covariates sex and week of study enrollment were only modestly associated with AUDIT scores (male gender and more weeks since college commencement somewhat associated with higher AUDIT scores), while site of the campus was not. Despite this, a t-test concluded that there were no gender differences between alcohol use and misuse (t(161) =-1.89, 

=.06). Among partial correlations, the participants’ AUDIT scoreswere positively correlated with PSS scores (

< .001), and negatively correlated with agreeableness (

 was significantly correlated with all the personality domain scores except for openness to experience.

Regression analyses provided less biased estimates of personality and stress on AUDIT. To elucidate the relationship between neuroticism, stress, and alcohol use and misuse (given the discrepancy between the partial correlation results and the multiple regression model), the neuroticism facets were explored as outcome measures. Analyses that used the neuroticism facets(depression or anxiety) in place of the 

domain found that neuroticism-depression was positively associated with higher AUDIT scores when accounting for PSS and domain-level Big Five personality traits (

Exclusion of all personality traits except for neuroticism-depression did not explain more variance in AUDIT (Adjusted 

 < .001). Interaction effects found that neuroticism as a domain moderated the relationship between PSS and AUDIT (

=0.001). This interaction was found to be unique. Neuroticism-depression score moderated the relationship between PSS and AUDIT-T (

< .001. At low levels of the depression facet, stress was negatively associated with alcohol use and misuse, but at high levels of the depression facet, stress was positively associated with alcohol use and misuse (

 supports the notion that neuroticism, and the neuroticism-depression facet specifically, appear to be the most robust predictors of alcohol use and misuse among incoming 

 and could serve as useful population risk indicators for campuses. At low levels of the depression facet, stress was negatively associated with alcohol use and misuse, but at high levels of the depression facet, stress was positively associated with alcohol use and misuse.

This study tested an interesting hypothesis: do personality traits—and neuroticism in particular—predict alcohol use and misuse in matriculating freshmen above and beyond reported levels of stress?

Investigators branched off previous studies exploring the roles of personality or stress on college drinking. They analyzed survey results data from Wave I of the MAPme Project, a longitudinal study of biobehavioral health and substance use during college. The findings showed that personality characteristics and stress play a significant role in the severity of problematic alcohol use and misuse, but that certain traits are more significantly associated with alcohol involvement than others. The neuroticism-depression facet was a better predictor of alcohol use and misuse than the neuroticism domain, and this facet accounted for unique variance even when controlling for stress and other personality facets and domains. Stress did not account for unique variance in harmful and hazardous alcohol use and misuse beyond personality traits.

1. When presented with highly stressful circumstances, individuals’ high neuroticism-depression predicts propensity to use and misuse alcohol.

2. People with high neuroticism-depression are likely to drink more when stressed, but for individuals with low neuroticism-depression, the trait seems to be protective with these individuals using and misusing alcohol at lower rates.

3. The BFI domains and faces seem to have a role in alcohol use/misuse, above stress levels. These could be used as screeners for population risk indicators among incoming freshmen.

1. This study was conducted using a primarily Caucasian group from a private university located in the Southeast US. Findings may not generalize to other diverse individuals with varied socioeconomic statuses. Although it encompassed both urban and rural participants, they were located in the same part of the country.

2. Overall, looking at the big picture, there was a fairly low numbers of reported 

 among the sample to confidently generalize findings.

3. The study included a greater proportion of women compared to men, which may have skewed the baseline starting characteristics and outcomes.

4. Compensation offered to participants may add external biases and contribute to participant selection and participation.

5. The authors used a single-domain,hear self-reported assessment of stress, associated with increased likelihood of response bias and social desirability bias. More comprehensive and objective measures of stress levels might include physiological assessment, such as 

, or cortisol measures that have shown be strongly associated with perceived stress.

6. Here the authors used the AUDIT-Total score, which confounds 

 and problematic alcohol use behaviors. As they note, while the study participants reported low alcohol use and misuse behaviors and were not well prepared to detect unique effects of these constructs, future research could expand on the present study by examining alcohol consumption and problems separately.

 is limited by its cross-sectional design. To best examine the relationship between stress and personality on alcohol use and misuse, future studies could take a longitudinal state-trait perspective, treating personality and neuroticism specifically as stable traits and stress as a state. Data from this sample will continue to be collected until the students graduate, allowing longitudinal examinations into alcohol use and misuse trajectories, and the associations between stress, personality traits, and hazardous and harmful alcohol use.

is assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for

TM. The author reports no conflicts of interest concerning the subject matter of this article.

1. US Department of Health and Human Services. Center for Behavioral Statistics and Quality, Substance Abuse and Mental Health Services Administration. 2019 National Survey on Drug Use and Health. Table 6.21B—Types of Illicit Drug, Tobacco Product, and Alcohol Use in Past Month among Persons Aged 18 to 22, by College Enrollment Status and Gender: Percentages, 2018 and 2019. Accessed February 5, 2021. 

https://www.samhsa.gov/data/sites/default/files/reports/rpt29394/NSDUHDetailedTabs2019/NSDUHDetTabsSect6pe2019.htm#tab6-21b

2. National Institute on Alcohol Abuse and Alcoholism. NIAAA council approves definition of binge drinking. 

https://pubs.niaaa.nih.gov/publications/Newsletter/winter2004/Newsletter_Number3.pdf

3. Hingson R, Zha W, Smyth D. Magnitude and trends in heavy episodic drinking, alcohol-impaired driving, and alcohol-related mortality and overdose hospitalizations among emerging adults of college ages 18-24 in the United States, 1998-2014. 

4. Hingson R, Heeren T, Winter M, Wechsler H. 

Magnitude of alcohol-related mortality and morbidity among U.S. college students ages 18-24: changes from 1998 to 2001

5. Wechsler H, Lee JE, Kuo M, et al. Trends in college binge drinking during a period of increased prevention efforts. Findings from 4 Harvard School of Public Health college alcohol study surveys: 1993-2001. 

The introduction of the heavy and frequent drinker: a proposed classification to increase accuracy of alcohol assessments in postsecondary educational settings

7. US Department of Health and Human Services. Center for Behavioral Statistics and Quality, Substance Abuse and Mental Health Services Administration. 2019 National Survey on Drug Use and Health. Table 6.23B—Alcohol Use Disorder in Past Year among Persons Aged 18 to 22, by College Enrollment Status and Demographic Characteristics: Percentages, 2018 and 2019. Accessed February 5, 2021. 

https://www.samhsa.gov/data/sites/default/files/reports/rpt29394/NSDUHDetailedTabs2019/NSDUHDetTabsSect6pe2019.htm#tab6-23b

8. Stanciu CN, Penders TM, Wuensch KL, et al. Underutilization of screening tools for alcohol use disorders – part I: results from survey of practices among North Carolina mental health providers and brief review of available instruments. 

. 2017;5(5):100282.Accessed February 5, 2021. 

https://www.longdom.org/open-access/underutilization-of-screening-tools-for-alcohol-use-disorderspart-iresults-from-survey-of-practices-among-north-carolina-mental-he-2329-6488-1000282.pdf

9. Allen MS, Vella SA, Laborde S. Health-related behaviour and personality trait development in adulthood. 

10. Cooper ML, Agocha VB, Sheldon MS. A motivational perspective on risky behaviors: the role of personality and affect regulatory processes. 

11. Loukas A, Krull JL, Chassin L, Carle AC. The relation of personality to alcohol abuse/dependence in a high-risk sample. 

12. Goldstein AL, Flett GL. Personality, alcohol use, and drinking motives: a comparison of independent and combined internal drinking motives groups. 

13. Ruiz MA, Pincus AL, Dickinson KA. NEO PI-R predictors of alcohol use and alcohol-related problems. 

14. Martin KP, Benca-Bachman CE, Palmer RHC. 

Risk for alcohol use/misuse among entering college students: The role of personality and stress

Are people with high "neuroticism-depression" likely to drink more than the average person when stressed? We may be getting closer to the answer. 

Neuroticism-Depression: What Is It and Does It Play a Role in College Drinking?

There is evidence for an increased prevalence of comorbid substance use disorders (SUDs) in patients with bipolar disorder (BD), even when 

 found that the lifetime prevalence of alcohol abuse or dependence in bipolar I and II disorder was 46% and 39%, respectively. A more 

 of 43,000 respondents found a 24% 12-month and 56% lifetime prevalence of any alcohol use disorders (AUD) in patients with bipolar I disorder.

 that comorbid AUD is associated with a more complicated illness course and poorer outcomes in patients with BD.

Most studies of comorbid BD and AUD have been retrospective, and few prospective studies have differentiated between bipolar I and II disorders. Using the COGA sample (Collaborative Study on Genetics in Alcoholism), 

 directly compared patients who had bipolar I and II disorders with and without comorbid alcohol dependence. These patients were assessed at baseline and then prospectively reinterviewed after 5 years.

COGA enrolls treatment-seeking probands with 

 (and their relatives) at 6 centers in the United States. Exclusion criteria are life-threatening medical disorders, repeated intravenous drug use, and an inability to speak English. Patients were interviewed at baseline, as well as after approximately 5 years using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). The SSAGA contains an assessment of 17 DSM-IV diagnoses, including BD, as well as the timing of symptom onset and remission.

Altogether, 228 participants with bipolar I disorder or bipolar II disorder were identified. One-hundred seventy-two patients had a comorbid diagnosis of alcohol dependence (N = 56 with bipolar II [Group 2] and 116 with bipolar I [Group 4]). Fifty-six individuals did not have 

 (N = 20 with bipolar II [Group 1] and N = 36 with bipolar I [Group 3]). One-hundred twenty-one (53%) of patients were reassessed at a mean of 5.7 years after the initial interview, including 13, 30, 17, and 61 patients in Groups 1, 2, 3, and 4, respectively. All participants were in a euthymic mood state at the time of the SSAGA interview. Between-group differences were evaluated using chi-square tests for categorical data and 1-way analysis of variance (ANOVA). Repeated-measures ANOVA was used to compare continuous variables over time.

At baseline, the mean age was 36 years; 52% were female, and 74% were Caucasian. Regarding patients with alcohol dependence, those with bipolar II disorder had a higher rate of alcohol-related liver disease than those with bipolar I disorder (10.7% versus 1.7%). Individuals with bipolar I disorder were significantly more likely to have had outpatient treatment than those with bipolar II disorder (48% versus 29%). Otherwise, there were no differences in age of onset of alcohol dependence, treatment, alcohol-related violence and physical problems, and other psychiatric comorbidity.

There were no significant differences in age of onset of mania/hypomania and depression between all groups. There were also no significant difference in the proportion of patients with lifetime suicidal ideation and suicide attempt between patient groups. However, 

 and comorbid alcohol dependence had a greater number of lifetime suicide attempts than patients without alcohol comorbidity (5 versus 1.5), although this finding was not statistically significant. Patients with bipolar I disorder and alcohol dependence had a significantly lower global assessment of functioning score (58) than the other groups (range 67-75).

During the 5-year follow-up, regarding patients with alcohol dependence, subjects with bipolar I disorder had a significantly higher prevalence of 

 than those with bipolar II disorder (31.1% versus 13.3%). Individuals with comorbid bipolar I disorder and AUD had a significantly higher prevalence of suicidal ideation (46% versus 10% to 29%) and suicide attempt (18% versus 0%) than the other groups. Patients with bipolar I disorder and alcohol dependence also had more affective symptoms and significantly lower global assessment of functioning score (59) than the other groups (range 62-77).

The authors concluded that individuals with bipolar I disorder and comorbid alcohol dependence had a worse course of mood illness. One limitation of the 

 include that the target of the COGA study was patients with alcohol dependence, and therefore only about one-quarter of the patients with BD did not have comorbid alcohol dependence. Another limitation is that almost half of the participants could not be re-interviewed after 5 years, and there is the potential for selective recall bias in those who were interviewed. A primary strength of the study is consideration of patients with bipolar I and bipolar II disorders, separately.

There is evidence from this prospective study that there is a more severe course of bipolar illness in patients with bipolar I disorder and comorbid alcohol dependence. These patients may require comprehensive treatment for psychiatric and SUDs in order to improve symptomatic and functional outcomes.

is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for 

The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.

Comorbidity of mental disorders with alcohol and other drug abuse: results from the epidemiologic catchment area (ECA) study

2. Grant BF, Stinson FS, Hasin DS, et al. 

Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National epidemiologic survey on alcohol and related conditions

Impact of substance abuse on the course and treatment of bipolar disorder

4. Preuss UW, Hesselbrock MN, Hesselbrock VM. 

A prospective comparison of bipolar I and iI subjects with and without comorbid alcohol dependence from the COGA dataset

Are there differences in the clinical course of bipolar I and bipolar II disorder with and without comorbid alcohol use disorder?

Don't Raise a Glass: Alcohol Dependence Complicates Bipolar Disorder

Alcohol abuse is often associated with cardiac arrythmia, blood clot disorders, diabetes, and hypertension. All of these are also associated with stroke. Gary Seale, PhD, talks more. 

is the director regional at the Centre for Neuro Skills in Galveston, Texas. 

Chronic issues with alcohol are often related to a myriad of symptoms associated with stroke. 

Alcohol Abuse and Stroke

Schizophrenia is associated with an increased prevalence of alcohol use disorder (AUD),

 which is also associated with relapse and 

 Adherence with (limited) treatment options for this patient population are suboptimal. Furthermore, patients with comorbid AUD are often excluded from pharmacologic trials in schizophrenia. Therefore, this represents an understudied and difficult-to-treat patient population.

Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), funded by the 

, was a large, long comparative series of trials of antipsychotics for the treatment of schizophrenia.

 As effectiveness trials, CATIE did not exclude patients with substance use comorbidity.

“Ms Norman” is in her 40s and has a longstanding history of 

 and severe AUD. She binges on alcohol episodically, with several months’ sobriety between periods of heavy drinking. Typically, within several weeks of alcohol cessation, she will experience an exacerbation of psychosis requiring inpatient psychiatric hospitalization. She previously lived independently and was able to have part-time employment. Following a recent illness exacerbation, she experienced a period of homelessness for several months, during which she continued to drink alcohol and dropped out of outpatient psychiatric treatment.

 reported on a post hoc analysis of the course of illness in patients with schizophrenia and AUD from the CATIE study. They assessed time to first and recurrent exacerbation, and risks of first and current hospitalization within the 5 years before study entry for patients with this comorbidity, compared with patients with schizophrenia only. They also compared treatment outcomes with olanzapine versus other antipsychotics in these 2 groups. The authors hypothesized that patients with schizophrenia plus AUD would have worse outcomes than patients with schizophrenia alone and, within each group, the advantages of olanzapine for exacerbations and hospitalizations would be retained.

Data for the study were obtained from the publicly available, limited-access CATIE study dataset from the NIMH. Briefly, CATIE was an 18-month, double-blind, randomized trial of perphenazine, olanzapine, quetiapine, risperidone, and ziprasidone in 1493 patients with schizophrenia. The primary end point was time to all-cause discontinuation.

Patients were categorized into schizophrenia and AUD and schizophrenia-only groups (based on DSM-IV criteria). The authors excluded 155 patients with nonalcohol substance-use disorders, except for marijuana use, which was permitted. Exacerbation was defined as hospitalization for psychopathology; more than a 25% or 15-point increase in baseline 

 (PANSS) total score, or significant worsening of key PANSS items; clinically significant aggression or suicidal/homicidal ideation; use of rescue medication; emergency department visit; discontinuation due to lack of efficacy; or arrest or incarceration. Times to first and recurrent exacerbations and hospitalizations were compared, including the reasons leading to exacerbations. In the schizophrenia and AUD group, exacerbations and hospitalizations were compared between patients taking olanzapine and those taking other antipsychotics. There were 303 (23%) participants in the 

 and AUD group and 1035 (77%) in the schizophrenia-only group. Patients with schizophrenia and AUD were significantly younger, had a lower body mass index, were more likely to be male, and had a greater number of hospitalizations in the year prior to study entry than those with schizophrenia only. There was little difference in the prevalence of marijuana use between the 2 groups.

Both the time to first exacerbation (median, 5.4 versus 6.4 months; HR, 1.20) and time to first hospitalization (HR, 1.63) were significantly shorter in the schizophrenia and AUD group than the schizophrenia-only group (

). A similar finding was observed for recurrent hospitalizations (HR, 1.60), although there was only a trend for between-group differences in recurrent exacerbations. More than half (61%) of patients with schizophrenia and AUD had an exacerbation, compared with 52% in the schizophrenia-only group, and the patients with schizophrenia and AUD were more likely to have an exacerbation resulting in hospitalization for psychopathology, due to aggression or suicidal/homicidal ideation, or arrest or incarceration.

Overall, perphenazine, quetiapine, risperidone, and ziprasidone were all associated with a significantly shorter time to first exacerbation compared with olanzapine (HRs, 1.81-2.80). A similar pattern of findings was observed for time to first hospitalization.

The authors concluded that patients with schizophrenia plus AUD had a poorer course of illness, with higher risk of disease progression, compared with patients with only schizophrenia. The investigators also found that olanzapine may be associated with longer time to first and recurrent exacerbations compared with other treatments in patients with schizophrenia and AUD comorbidity.

“Mr Greggs” is in his 30s with a history of chronic schizophrenia and severe AUD, as well as cannabis use disorder. He is currently serving a 1-year probation for a driving-while-impaired citation. He is adherent with monthly administration of a long-acting injectable antipsychotic but continues to drink alcohol and smoke marijuana regularly. He lives at home with his parents and is chronically unemployed. He has not had a psychiatric hospitalization in many years but remains precontemplative regarding the need for treatment for substance use disorder.

Strengths of the present study included the large number of subjects and the real-world design of the CATIE trial. Potential limitations included the post hoc nature of the analysis as well as the lack of generalizability of findings to patients with schizophrenia and other (nonalcohol) substance use disorders. Future trials are needed to identify effective treatment for this patient population.

Patients with schizophrenia with alcohol use disorder comorbidity versus those without have a worse course of illness, and olanzapine may be associated with a longer time to exacerbations versus other nonclozapine antipsychotics.

is professor, Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is the schizophrenia section chief for 

. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain & Behavior Research Foundation, and the Stanley Medical Research Institute.

1. Hartz SM, Pato CN, Medeiros H, et al; Genomic Psychiatry Cohort Consortium. Comorbidity of severe psychotic disorders with measures of substance use. 

2. Bradizza CM, Stasiewicz PR, Dermen KH. 

Behavioral interventions for individuals dually-diagnosed with a severe mental illness and a substance use disorder

3. Jones RM, Lichtenstein P, Grann M, Långström N, Fazel S. Alcohol use disorders in schizophrenia: a national cohort study of 12,653 patients. 

4. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. 

5. Pathak S, Jiang Y, DiPetrillo L, Todtenkopf MS, Liu Y, Correll CU. 

Course of psychosis in schizophrenia with alcohol use disorder: a post hoc analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness in Schizophrenia phase 1 study

Navigating the treatment options for comorbid schizophrenia and alcohol use

Schizophrenia and AUD

 of its kind, researchers discovered that young adults who combine alcohol and cannabis products experience fewer negative consequences when they avoid cannabis concentrate and consume a single kind of drink rather than multiple types of drinks.

The study examined day‐level influences of alcohol and cannabis combinations on consumption and consequences among young adults who used both. Responses from 274 college students aged 18 to 24 years who used both alcohol and cannabis were gathered using a smartphone application. About 5 short surveys per day over 54 days gathered data on types of alcohol consumed, types of cannabis, number of drinks or cannabis uses, and unwanted outcomes. Negative consequences were constituted as the following: hangover, nausea, vomiting, injury, driving under the influence, blackout, aggression, or unwanted sex.

The study honed in on 4 use categories in particular: dry cannabis leaf and beer; 2 cannabis products with 2 or more alcohol types; liquor with 2 cannabis products; and cannabis concentrate with 2 or more alcohol products. Using the statistical analysis from the gathered survey responses, researchers examined the associations and consequences of each of these combinations.

The most prevalent combination was leaf and beer, and the potentially most risky combination was 2 cannabis products with 2 or more alcohol types. Consumption of multiple alcohol products was likely to produce negative consequences though liquor was statistically riskier than wine or beer. Overall participants who combined alcohol and cannabis reported 1 or more these negative consequences on 1 in 3 study days. Those who used dry leaf and beer were unlikely to have negative consequences when compared with other combinations.

These findings suggest that shrewd choice of products may reduce potential risks.

1. Stevens AK, Aston ER, Gunn RL, et al. Does the Combination Matter? Examining the Influence of Alcohol and Cannabis Product Combinations on Simultaneous Use and Consequences in Daily Life. 

2. Research Society on Alcoholism. People who use alcohol and cannabis together may reduce risks by choosing certain products and combinations. News release. November 23, 2020. 

https://www.newswise.com/articles/people-who-use-alcohol-and-cannabis-together-may-reduce-risks-by-choosing-certain-products-and-combinations?sc=mwhr&xy=5013482

According to a recent study, certain product combinations of alcohol and cannabis may be less likely to cause negative consequences. 

Less Risky Than Believed: Alcohol and Cannabis Combinations 

Top Medications for Alcohol Use Disorders with Depression

One medication stood out as the most effective in a meta-analysis of alcohol use disorders with depression, but few patients are taking it.

Top Medications for Alcohol Use Disorders With Depression

 involving 2 million participants, people experiencing depression, anxiety disorder, or bulimia, are at heightened risk of excessive alcohol use.

Unhealthy alcohol use and psychiatric disorders frequently co‐occur, but understanding how the levels of alcohol consumption affect those with psychiatric disorders might provide valuable insight to health care providers. The study sought to learn more about these relationships.

Researchers used alcohol screenings from Kaiser Permanente Northern California (KPNC), an integrated healthcare delivery system, to collect data from a large, population‐based sample. More than 12 million alcohol screenings were conducted, which will help identify subgroups of patients with psychiatric disorders and co‐occurring unhealthy alcohol use.

Medical assistants asked 3 questions. One is a modified version of the National Institute on Alcohol Abuse and Alcoholism single‐item screening question used to determine whether the individual had drinking-heavy days: “How many times in the past 3 months have you had 5 or more drinks in a day?” The second and third are questions used to calculate average alcoholic drinks consumed per week: “On average, how many days per week do you have an alcoholic drink?” and “On a typical drinking day, how many drinks do you have?”

From these questions, patients were classified into 2 groups: low risk of alcohol abuse and unhealthy use. The unhealthy use class was further divided into subgroups: daily, where patients exceeded daily drinking limits; weekly, where patients exceeded weekly drinking limits; and both. Researchers then compared these answers to whether patients had a documented psychiatric disorder diagnosis, focusing on a list of 8 common psychiatric disorders: depression, bipolar disorder, anxiety disorder, obsessive compulsive disorder, schizophrenia, schizoaffective disorder, anorexia nervosa, and bulimia nervosa.

In the final sample of patients, it was found that the daily group was more likely to be male and aged 18 to 34 years old, while the weekly group was more likely to be female and aged 65 or older. The daily and weekly groups were more likely to have higher household incomes, greater than approximately $87,500. Those who reported no alcohol usage were more likely to be Asian, Native Hawaiian, or Pacific Islander. Those diagnosed with bipolar disorder or schizoaffective disorder were more likely to report no drinking, as well.

A diagnosis of depression, anxiety disorders, or bulimia may also indicate a heightened risk of excessive drinking. 

Alcohol Abuse