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Tales of the Clinic: The Art of Psychiatry

, we discuss a patient who was construed as difficult to manage by multiple standards and elicited strong feelings from the treatment team. Ms Grant is a 29-year-old female with a history of alcohol use disorder (AUD) and complicated alcohol withdrawal. This case presentation spans 4 years and highlights the importance of behavior shaping and personality trait management to achieve stability. The focus is treating patients who are at risk of being perceived as “less than likeable, disruptive, and uncooperative.”

, Ms Grant describes her life as wrought with chronic anxiety and depression, with a frequent desire to self-medicate with alcohol. Her story includes multiple rehabilitation programs, inpatient psychiatric hospitalizations, and suicide attempts in the context of alcohol use. Borderline and antisocial traits seemed to influence her clinical presentation. She became well-known to the clinic and hospital staff for one incident that involved her throwing a shoe directly at a police officer’s face.

Social and family history was significant for intergenerational 

, involving her mother, father, and maternal grandfather. Ms Grant relates fond memories of her father, yet reports a childhood dominated by physical abuse and neglect, with the notable absence of her mother. She struggled in school and had suspensions and behavioral problems. Ms Grant became pregnant at 17 years of age and dropped out of school. Her partner left during her pregnancy, so she had to stay with her father.

Substance use and psychiatric history started early, with her first drink during her high school freshman year. She describes peers and boyfriends, whom she shared drinks with, as the support system she never got from family. She abstained from alcohol with her first pregnancy but developed postpartum depression and relapsed when her child turned 5 months old. The stressors of raising her child alone exacerbated feelings of 

. Family support was limited, and her romantic relationships did not last long because of alcohol-associated behaviors. Ms Grant had her second child at the age of 20 while in a verbally and physically abusive relationship. Child protective services were involved. When she was 26, her two children were taken away and placed under a cousin’s care; the relationship ended as well.

Her treatment course included striking, intense episodes of intoxication with agitation and suicidality. One involved being verbally aggressive towards employees and customers while intoxicated at a gas station. In the emergency department, declarations of suicidal ideations, a blood alcohol level > 300 mg/dl and a history of complicated withdrawals led to inpatient hospitalization. She was discharged back to outpatient care, having consistently denied suicidality when no longer intoxicated, and declined transfer to a rehabilitation program at the time.

The second incident involved being caught stealing a wallet from another patient in the clinic. Ms Grant denied the theft despite confrontation, so police were called. The police asked to search Ms Grant’s backpack, but she escalated, cursed, and swung at the officers. This led to a physical scuffle in the psychiatrist’s office, that ultimately culminated in Ms Grant sustaining scratches and bruises. She was handcuffed, brought into police custody for refusing to comply with the search, and subsequently charged and incarcerated for a week.

The psychiatrist felt ongoing empathy for the patient struggling with anxiety and alcohol use disorder who had no one else for support. At the same time, it was a difficult decision on whether to continue treatment following the 

. Despite a strong desire to maintain a working relationship that had lasted for years, there was a sense of disappointment, and even anger, towards the dishonest and illegal behaviors that directly affected other patients. There were concerns about the potential for further covert theft or altercations if she were to continue treatment in the clinic. In addition, the psychiatrist had vivid, uncomfortable memories of the office scuffle.

Yet, Ms Grant, just like many with co-occurring disorders, was at very high risk of acute decompensation with perceived abandonment, which cessation of treatment would have been to her. The psychiatrist considered evaluating the decision-making process from a harm-reduction approach. If Ms Grant were to no longer receive treatment in the clinic, she would likely decompensate, with possible increases in aggressive, antisocial behaviors, and substance use. The psychiatrist felt sharing and processing this case with other colleagues was helpful, especially regarding countertransference.

Another consideration was that Ms Grant, as a woman, faced unique challenges to obtaining substance use treatment. 

Women are less likely to seek treatment for AUD

, and multiple barriers have been identified among women compared to men, including gender stereotype roles and societal expectations, even though women are more predisposed to medical complications from alcohol use.

 Women face gaps in employment, economic challenges, and more parental responsibilities compared to men.

 Along with logistic barriers to treatment including transportation issues, limited childcare resources and insurance, and fear of losing children to child protective services, women are more likely than men to attribute alcohol use disorder to character flaws rather than to genetic disposition.

 With these pressures and beliefs, the fact that women have lower rates of substance use treatment compared to men is unsurprising.

Fortunately, recent research indicates that the gender gap of AUD has been narrowing,

 with studies indicating higher satisfaction in women-only treatment programs. Ongoing challenges include limited access to these types of programs and the necessity of further research to identify the effects on engagement and response to treatment.

Ultimately, considering all these factors, the psychiatrist decided to allow Ms Grant to continue clinic treatment, despite reservations from the clinical staff. They worked through these feelings of anger towards Ms Grant, which was helpful not only for a sense of closure for the psychiatrist and to help promote setting treatment boundaries, but also to help Ms Grant identify the consequences of her actions through behavioral chain analysis. It also helped to visualize that despite all that had happened, Ms Grant was doing “the best that she could,” relying on her limited coping skills, unfortunately stunted by 

. This step is essential to avoid judging the patient from a moral standpoint, where maladaptive or disruptive behaviors are viewed as entirely volitional. With this approach, work was able to resume, with her goals largely revolving around maintaining employment to regain custody of her children, and maintaining her current relationship.

The treatment team and Ms Grant’s deeper understanding of her own motivations and 

 served as a catalyst towards treatment adherence and sobriety. She had chronic difficulty trusting and building new relationships, including those with mental health providers. This issue could be compounded by the concept that patients with substance use disorder (SUD) and personality disorders have often encountered judgmental stances and behaviors, even if subtle or unconscious, from healthcare providers. Bias against patients with SUD, legal histories, and personality disorders can occur easily, especially when the patient is perceived to be “behaving badly.”

Organizationally, clinics are rarely set up with enough support to manage severe personality pathology and navigate psychosocial stressors stemming from complex addiction histories. As the development of AUD is complex and multifactorial, treatment is variable and has to incorporate multiple contributing factors including psychological factors, genetics, personality traits, traumatic events, and family dynamics.

 Research indicates some benefits of regular attendance of Alcoholics Anonymous meetings, but this may not be a treatment that works for everyone.

 Project MATCH, sponsored by the National Institute on Alcohol Abuse and Alcoholism compared 3 different types of therapies and found some positive results with each therapy modality, implying that multiple therapeutic approaches can be utilized in addition to medications.

Support for treating physicians and therapists is essential, as patient relapses and failed treatment trials can contribute to feelings of helplessness, anger, and frustration for both patient and treatment provider

 Identifying this in our own self, as well as any subconscious biases, may provide the space to combat the reactions that come with our countertransference and redirect attention towards meeting the patient’s needs

On a biological level, typologies and classifications have been developed to further classify the development and presentations of 

. Ms Grant’s family history, early onset of alcohol use, and history of legal problems correspond with Cloninger type II alcoholism, which has increased genetic predisposition compared to type I.

Cloninger type I alcoholism is typically associated with adult-onset and harm-avoidance behaviors. Differences in personality traits may underscore drinking motivation; type I alcoholism associates alcohol use with anxiety reduction, while type II corresponds to sensation-seeking behaviors. Neurobiological differences between alcoholism subtypes (serotonin levels, monoamine oxidase activities) are also known. However, the type II subset, under the Stockholm study, was found more commonly in men compared to women, whereas type I affects both genders equally. Identifying topology helps clinicians conceptualize a patient’s presentation, anticipate treatment needs, and may help guide medication selection. For example, off-label use of ondansetron works better for early-onset.

 Patients treated with sertraline may respond better if they have less severe AUD.

Personalized treatment plans work best and should include medication in conjunction with psychotherapy. Naltrexone has the benefit of different routes of administration; intramuscular formulation leads to improved compliance/better outcomes compared to oral. Acamprosate, a hepatically safe option, can help increase time to relapse; however, 3 times daily administration may deter adherence. Disulfiram, an example of aversive therapy, can provide physical discomfort to curb drinking, but effectiveness is limited by poor compliance and risk of induced hepatitis/psychosis. Of note, Ms Grant had already tried all of the FDA-approved options for AUD treatment with little success or tolerability.

Thus, off-label medication was considered. Off-label medications for AUD mirror our understanding of the neurobiology of alcohol use. Varenicline (effects on nicotinic acetylcholine receptor), baclofen (GABA receptors), and ondansetron (serotonin 5-HT

 receptor antagonist), are just a few of the many suggested potential treatments given the complex effect of alcohol on the neural pathways.

 Ms Grant was eventually started on topiramate as further studies report improvement of drinking outcomes and quality of life with adjunct therapy with topiramate compared to placebo.

 The addition of topiramate, with an off-label indication, helped reduce Ms Grant’s cravings and days of heavy drinking. The risks of inadequate treatment of AUD, including frequent rehospitalizations, emergency room visits, and further hepatic injury from drinking, were considered much more dire than off-label potential side effects.

The efficacy of selective serotonin reuptake inhibitors for cravings has been sparse, and use for AUD does not follow American Psychiatric Association guidelines; however, studies have also indicated that patients with mental health conditions are more vulnerable to substance use. It is not uncommon to have a comorbid mental health disorder and substance use. Depressive and anxiety symptoms can also stem from alcohol use.

In addition, research indicates that the chronic use of alcohol, repeat periods of abstinence, and withdrawal results in changes in the prefrontal–striatal–limbic (PSL) circuit, which plays a significant role in emotion regulation, decision making, and modulating reward and stress.

 Therefore, the role of antidepressants on serotonin may have potential effects on obsessional thoughts and impulsivity with chronic alcohol use.

 Open discussions with patients regarding current availability of medications and setting realistic expectations of the effects of medications may mitigate the frustrations arising from continued cravings, a common complaint in SUD patients, and counteract the belief that medications alone lead to remission.

When a patient walks out of the office, one question lingers, 

? This may especially be the case in AUD treatment. AUD is complex, multifactorial, and treatment includes taking into consideration biological, psychological, and socioenvironmental factors. We must gently process and elicit the details of one’s life that they might be the most shameful of, in order to address the deeper underlying issues. Identifying our own defenses and countertransference can potentially improve the therapeutic alliance. The presence of personality disorders can also provide an additional challenge while balancing limited resources and constraints a patient may also have that prevent them from utilizing these options. Thankfully, in addition to off-label options, there are 3 FDA approved medications to treat AUD, though they remain woefully underused. 

There are many patients with stories like Ms Grant; however, with prodding, patience, and exploration, positive outcomes can be achieved. Lastly, systemic and organizational structures ought to take into account the complex treatment needs for SUD, and thoughtfully target resources.

Three years after the office scuffle, the outlook has been much brighter; Ms Grant has found stable and supportive housing and has been in remission from alcohol use for the past 2 years. She lives with her husband and cat and attends online 12-step groups. She clearly recalls the struggles she went through during treatment and uses that to prevent her from drinking again. While her past struggles may have been a reason to abandon hope, she is grateful that neither she, nor her psychiatrist, gave up. Her psychiatrist also realizes that while complex cases can be challenging, they also include the most meaningful work and lead to the most personal growth and satisfaction.

psychiatry resident at the Baylor College of Medicine.

is an associate professor and addiction-boarded faculty at Harris Health System in the Menninger Department of Psychiatry and Behavioral Sciences at Baylor College of Medicine.

1. Agabio R, Pisanu C, Luigi Gessa G, Franconi F. 

Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication?

3. Epstein EE, Menges D. Women and addiction. In: McCrady BS, Epstein EE (eds). 

4. Lale R, Sklar M, Wooldridge J, Sarkin A. 

Gender congruence moderates beliefs about the causes of alcohol dependence and major depression.

Treatment interventions for women with alcohol use disorder.

Psychodynamic psychiatry in Clinical Practice

7. Cloninger CR, Sigvardsson S, Bohman M. 

Type I and type II alcoholism: an update.

8. Johnson BA, Roache JD, Javors MA, et al. 

Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial.

Sertraline in the treatment of co‐occurring alcohol dependence and posttraumatic stress disorder. 

Anticraving therapy for alcohol use disorder: a clinical review.

11. Johnson BA, Ait-Daoud N, Akhtar FZ, Ma JZ. 

Oral topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial.

Neuroplasticity and predictors of alcohol recovery.

Treating patients who may be perceived as “unlikeable” can be difficult. 

To Treat or Not to Treat? The Conundrum of Likeability

Precision medicine took another step forward as Adial Pharmaceuticals announced their intent to enter the genetic testing market. The news comes after the company received a Notice of Allowance from the US Patent and Trademark Office related to use of their genetic diagnostic panel in combination with their lead product, 

“This new patent related to the use of our genetic diagnostic panel in combination with AD04 for the treatment of AUD and OUD is a major milestone as we believe genetic evaluation of patients can be used to identify individuals that may benefit from AD04. We have been utilizing the genetic panel covered by this patent in our ongoing ONWARD™ Phase 3 trial, and, given this patent allowance, we anticipate that genetic diagnostics are expected to be an important segment of our commercial strategy going forward,” Adial’s CEO, William Stilley, said in a statement to the press. “Our view that AUD has a solid nexus in genetics is fundamental to the premise of the successful Phase 2B trial of AD04 conducted at the University of Virginia and our ONWARD™ Phase 3 trial of AD04 currently underway in Europe. And, it is consistent with Adial’s premise that the presence of certain genetics is expected to substantially influence whether an individual suffering from AUD or OUD would likely respond to treatment with AD04.”

 is a genetically targeted therapeutic agent for the treatment of AUD. The drug is designed to reduce cravings thereby reducing alcohol intake. patients curb their drinking. The oral medication will not require abstinence before or during treatment. To date, it has shown positive safety and tolerability profiles.

Once issued, the patent is anticipated to provide market exclusivity for the AD04 genetic diagnostic test. With this in mind, Adial plans to enter the genetic testing market as a stand-alone commercial business line and market the genetic diagnostic panel as a Companion Diagnostic Test to AD04. Approximately one-third (33%) of AUD patients are expected to respond to treatment with AD04.

In addition to the benefits for patients, the resulting efficacy may also realize cost savings to the health care industry. “Market research conducted by Adial indicates a willingness among payors to reimburse a genetic companion diagnostic test, and this may allow Adial to provide patients personalized, precision medicine and also potentially provide dramatic cost savings to payors,” Stilley said further.

1. Adial Pharmaceuticals. Adial Pharmaceuticals plans to enter genetic testing market following allowance of US Patent for genetic diagnostic test. News release. June 22, 2021. Accessed June 22, 2021. 

https://ir.adialpharma.com/press-releases/detail/122/adial-pharmaceuticals-plans-to-enter-genetic-testing-market

2. Adial Pharmaceuticals. Technology. Accessed June 22, 2021. 

Adial’s AD04 for the treatment of alcohol use disorder received a Notice of Allowance from the US Patent and Trademark Office. 

Patent Brings Psychiatry One Step Closer to Precision Medicine

The Acting Administrator of the Drug Enforcement Administration has removed samidorphan (3-carboxamido-4-hydroxy naltrexone) and its salts from the schedules of the Controlled Substances Act.

Samidorphan, a chemical entity that is structurally similar to naltrexone, was a schedule II controlled substance, as it can be derived from opium alkaloids.

One psychiatrist and clinical investigator in favor stated that, “…samidorphan counters weight gain associated with clinical use of olanzapine as antipsychotic medication and this combination product offers significant advancement relative to olanzapine alone…”

Review of scientific and medical evaluations of samidorphan, as well as the recommendation to decontrol samidorphan from the US Department of Health and Human Services, bolstered this decision.

This action effectively removes regulatory controls and any administrative, civil, or criminal sanctions for controlled substances on samidorphan.

1. Drug Enforcement Administration. Schedules of controlled substances: removal of samidorphan from control. 

https://www.federalregister.gov/documents/2021/04/19/2021-07884/schedules-of-controlled-substances-removal-of-samidorphan-from-control

The Drug Enforcement Administration has freed this formerly schedule II controlled substance. 

Samidorphan: Scheduled Substance No More

Binge drinking is defined 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 

 from unintentional injuries such as motor vehicle crashes,

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

Perhaps not surprisingly, national surveys have found that half of full-time 

 aged 18 to 22 years consumed alcohol in the previous month, and one-third engaged in binge drinking.

 In addition to the previously noted negative impacts, 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 and projects compared with those who drink but do not binge (40% vs 7%) and are 5 times more likely to miss a class.

 Although not all individuals who drink develop an addiction, consumption and especially binge drinking patterns are often preludes to 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.

The first few weeks of freshman year are often a period of heavy drinking and alcohol-related consequences. Social pressures and expectations during new-found independence, widespread availability and access to alcohol, unstructured schedules with mounting academic pressure, and lack of parental interactions all play a role. Alongside these stressors, many students have preexisting personality traits that may account for the use and misuse of alcohol during college.

Neuroticism, 1 of the 5 higher order personality traits, is defined by high emotional instability, depressed mood, low frustration tolerance, and anxiety. It also has been found to positively predict alcohol consumption (social intake within recommended parameters)

 and alcohol use (intake beyond recommended parameters that can lead to addiction).

 Only 1 previous study of 200 college students evaluated the implications of personality types; that study found high neuroticism and low conscientiousness predicted more 

aimed 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 revolved around the notion that negative affect faces of neuroticism, and primarily 

, are more strongly associated with alcohol use and misuse than stress when accounting for other personality domains.

 conducted a cross-sectional outpatient study, which was approved by the Institutional Review Board. Survey data was collected from participants during the first 8 weeks of their first college semester. Participants included 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. Students were recruited via fliers posted on campus and during frequent in-person undergraduate events.

Data was acquired via online surveys of behavioral, health questionnaires, and cognitive assessments. Most surveys were completed within 3 weeks of the study initiation, 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 for which the higher scores indicate more severe and hazardous, harmful, excessive alcohol use/misuse. 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 personality characterization within the 5 domains: openness, aesthetics, and ideas; conscientiousness, order, and self-discipline; extraversion, assertiveness, and activity; agreeableness, altruism, and compliance; and neuroticism, anxiety, and depression.

Analyses controlled for campus site (rural vs urban), sex, and individual week of study enrollment (school obligations as potential stressors fluctuated between study weeks). The investigators 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 use of 

 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); 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, P = .06). Among partial correlations, the participants’ AUDIT scores were positively correlated with PSS scores (r = .17, P = .003) and neuroticism (r =.31, P < .001), and negatively correlated with agreeableness (r = −.12, P = .031). Stress 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 

 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 neuroticism domain found that neuroticism-depression was positively associated with higher AUDIT scores when accounting for PSS and domain-level 5 personality traits (β = .23, P = .028; adjusted R

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

= .10, F (5, 152) = 4.56, P < .001). Interaction effects found that neuroticism as a domain moderated the relationship between PSS and AUDIT (β = .16, P = .040; adjusted R

 = .12, F (10, 146) = 3.16, P = 0.001). This interaction was found to be unique. Neuroticism-depression score moderated the relationship between PSS and AUDIT-T (β = .18, P = .020; adjusted R

 = .14, F(11, 145) = 3.22, P < .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 (

This study supports the notion that neuroticism, and specifically the neuroticism-depression facet, appear to be the most robust predictors of alcohol use and misuse among incoming freshmen and could serve as useful population risk indicators. At low levels of the depression facet, stress was negatively associated with 

 and misuse; at high levels of the depression facet, however, stress was positively associated with alcohol use and misuse.

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. Those findings showed that personality characteristics and 

 play a significant role in the severity of problematic alcohol use and misuse, but 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.

Unfortunately, this study had a number of limitations. Due to issues with the sample population, the findings may not generalize to other student populations. This study was conducted using a primarily Caucasian group from a private university located in the southeast US, without ensuring varied socioeconomic statuses. Similarly, although the sample encompassed both urban and rural participants, they were located in the same part of the country. The study also included a greater proportion of women compared to men, which may have skewed the baseline starting characteristics and outcomes.

Other issues can impact the findings. For instance, there were fairly low numbers of reported alcohol use among the sample to confidently generalize findings. Compensation offered to participants may add external biases and contribute to participant selection and participation.

The authors used a single-domain, 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 skin conductivity, heart rate, or cortisol measures that have shown be strongly associated with perceived stress.

The study employed the AUDIT-Total score, which confounds alcohol consumption and problematic alcohol use behaviors. The study participants reported low alcohol use and misuse behaviors, but the tool was not well prepared to detect unique effects of each of these constructs. Thus, future research could expand on this study by examining alcohol consumption and problems separately.

This study 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.

Fortunately, 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.

So what does this mean for clinical practice? When presented with highly stressful circumstances, high neuroticism-depression in individuals predicts propensity to use and misuse alcohol. Similarly, people with high neuroticism-depression are likely to drink more when stressed, but low neuroticism-depression seems to be protective, with these individuals using and misusing alcohol at lower rates. Finally, 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.

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

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

An earlier version of this article appeared online on February 10, 2021, under the title Neuroticism-Depression: What Is It and Does It Play a Role in College Drinking? and has since been updated for print. -Ed

1. 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

2. 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. 

3. 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. 

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

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

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

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Although college drinking develops into an addiction, overconsumption and especially binge drinking patterns are often preludes to alcohol use disorder, with approximately 1 in 10 students meeting criteria for AUD.

Exploring the Link Between Neuroticism-Depression and College Drinking

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.

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.

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

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Samidorphan: Scheduled Substance No More

Exploring the Link Between Neuroticism-Depression and College Drinking

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

Underused Medication May Be Best Bet for Comorbid AUD and Depression

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

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

Alcohol Abuse and Stroke

Schizophrenia and AUD