Bridging Neuroscience and Clinical Assessment in a Patient with Alcohol Use Disorder, Anxiety, and Trauma

Abstract

This article presents a unique framework that combines insights from neuroscience with clinical assessment to evaluate individuals who have co-occurring alcohol use disorder, anxiety, and trauma. Through the use of a case study, the authors demonstrate the practical application of this framework and contextualize the relevant neurocircuitry associated with alcohol withdrawal, maladaptive fear and anxiety, and chronic stress. By integrating these perspectives, they provide a comprehensive approach for assessing and treating patients with complex psychiatric histories, particularly those presenting with anxiety symptoms, offering valuable insights for practitioners.

The past 2 decades of neuroscience research in preclinical and clinical models have significantly enhanced our understanding of the neurobiology of substance use disorders. Koob and Volkow^1-3 have summarized a large and growing body of literature and have proposed a 3-stage model of addiction, which progresses from binge/intoxication to withdrawal/negative affect and, finally, preoccupation/anticipation. While this 3-stage model has provided a critical neuroscience framework for guiding research, the utility of applying neuroscience-based frameworks to individual patients remains challenging. Kwako and colleagues⁴ recently proposed that this 3-stage model corresponds to clinically identifiable neurofunctional domains that can be used as a framework, and they demonstrated the utility of this framework in characterizing heterogeneity in a large sample of people with an alcohol use disorder (AUD).⁵

In this article, we describe how we applied a unique framework that combines insights from neuroscience with clinical assessment to evaluate a patient with co-occurring AUD, anxiety, and trauma. By examining the patient’s specific alterations in stress circuitry and emotional and motivational processing, we explored how this understanding informed the use of gabapentin as a treatment, leading to notable improvements in both the patient’s underlying anxiety and anxiety exacerbated by abstinence. By adopting a comprehensive approach that integrates neuroscience and clinical assessment, practitioners may identify and deliver more effective treatments for complex psychiatric conditions and improve patient outcomes.

CASE PRESENTATION

The patient, a 29-year-old female with a history of AUD and posttraumatic stress disorder (PTSD), presented to the emergency department with suicidal ideation (SI). The patient endorsed active SI with a plan to cut her wrists, and she requested psychiatric hospitalization. She reported drinking between 5 and 8 beers a day and frequently running out of her alprazolam prescription, which she used to try to relieve her suffering. The patient reported waking up with palpitations, racing thoughts, and “pure panic” almost daily, although it was uncertain whether she had previously experienced alcohol or benzodiazepine withdrawal. She also reported re-experiencing prior sexual abuse and that she was struggling to manage without the support of therapy. She also endorsed self-blame, guilt, and deficits in energy and concentration. Despite being prescribed 4 psychotropic medications, the patient stated, “They have me on medications but they’re not really working.”

Psychosocial History

The patient’s parents separated when she was 5 years old. Her father “had a lot of issues with drugs” and was physically abusive toward her mother. Soon after her parents’ separation, the patient recalled being taken away by her father to live in a “drug house” where she was repeatedly molested and sexually abused by her father and the “other men that came in and out.” She was eventually removed from this environment and returned to live with her mother and thereafter had a “pretty normal childhood.” The patient reported a history of self-harming behavior (cutting) and 1 previous suicide attempt while in high school that resulted in inpatient psychiatric treatment. She denied previous manic/hypomanic episodes although she noted impulsivity in the form of sexual promiscuity in the context of substance use. The patient started drinking alcohol recreationally at the age of 15 and “heavily” at the age of 22. In an effort to “get rid of [her] feelings,” the patient’s alcohol consumption escalated to six 12-ounce beers and between 2 and 3 shots of liquor a day. She also had a history of illicit drug use and stated that her recent cannabis use had “only made [her] more anxious”. Although the patient described most of these substances as allowing her to “escape,” she identified alcohol as her drug of choice.

Inpatient Hospital Course

The patient was admitted to the psychiatric hospital due to active SI and clinically significant distress in the context of severe alcohol and benzodiazepine misuse. She was monitored for withdrawal and treated with phenobarbital given her risk for a complicated alcohol withdrawal syndrome. Throughout her admission, the patient repeatedly identified anxiety as impairing her ability to focus her attention. She endorsed symptoms consistent with several DSM-5 disorders including PTSD, panic disorder, and generalized anxiety disorder; these symptoms were further complicated by acute withdrawal. In addition to unrelenting, disabling anxiety, she also reported depressed mood and depressive episodes that occurred without a trigger. She was desperate to change her medication regimen and was started on lithium to target suicidality, episodic lability, depressive episodes, and a history of impulsivity; prazosin to reduce nightmares and hyperarousal; and naltrexone to curb alcohol cravings. The patient’s anxiety and panic symptoms were not specifically targeted by these initial pharmacological interventions, although she did participate in group coping skills training for anxiety. She continued to struggle with high levels of anxiety and dysphoria, and her prazosin and lithium doses were increased to address these anxiety and mood symptoms, respectively. She tolerated oral naltrexone and transitioned to the long-acting injectable formulation before discharge. As her discharge date approached, the patient endorsed significant anxiety; she feared that she would decompensate because she was “not 100% ready” to leave the hospital. However, her anxiety was not perceived as severe enough to warrant a continued inpatient level of care, and she was discharged with follow-up in the resident outpatient addiction clinic.

Outpatient Clinic Management

The patient presented to her outpatient intake appointment 1 week after discharge. She reported medication adherence and denied depressive symptoms, SI, or substance use. However, she did note ongoing anxiety and racing thoughts. No medication changes were made at this visit as the patient indicated her preference to implement the coping skills she had recently learned. However, the patient presented in distress at her 1-month follow-up visit. She reported poor quality of life in the context of high levels of anxiety and insomnia and requested assistance, fearing relapse and further decompensation.

DISCUSSION

Advances in neuroscience research have shed light on neurobiological mechanisms of psychiatric disorders and facilitated the integration of psychological concepts and environmental factors within a brain disease model.⁶ In this article, we applied a unique framework to elucidate the neurobiological factors contributing to the patient’s symptoms and to guide treatment selection.

Alcohol Withdrawal Neurobiology

Withdrawal from alcohol produces an aversive, stress-like state.¹ Following a reduction or discontinuation of alcohol, individuals with heavy or prolonged use may experience heightened negative affect or hyperkatifeia,⁷ which includes symptoms such as anxiety, stress, irritability, emotional pain, and dysphoria.⁸ These negative emotional symptoms were not only observed in the patient during her inpatient detoxification, but they also complicated her outpatient treatment and increased her risk of relapse.

Chronic alcohol use disrupts the balance of several neurotransmitter systems. Alcohol is a central nervous system depressant that enhances inhibitory tone and inhibits excitatory tone via alterations in γ-aminobutyric acid (GABA)⁹ and glutamate.¹⁰ Long-term consumption of alcohol triggers compensatory and negative feedback mechanisms, which upregulate the excitatory, glutamatergic system. An increasing amount of alcohol is therefore required to achieve its inhibitory effects, and abrupt cessation results in a state of brain hyperexcitability. Thus, the withdrawal period is mediated by decreased GABA-ergic and increased glutamatergic transmission, and several downstream and independent neurochemical alterations, most notably a reduction in serotonin (5-HT) and elevations in dopamine (DA), norepinephrine (NE), and corticotropin-releasing factor (CRF).¹¹

Chronic alcohol use leads to neuroadaptations of the reward and stress systems thought to underlie the experience of alcohol withdrawal.² Downregulation of signaling in the nucleus accumbens (NAcc), a central reward region, counters the rewarding effects of alcohol.³ When alcohol use abruptly stops, the system’s alcohol-mediated adaptations of reduced levels of DA,¹² 5-HT, and GABA¹³ now result in negative mood, anhedonia, and amotivation. In parallel, enhanced recruitment of stress circuits in the extended amygdala¹⁴ trigger aversive symptoms such as dysphoria and anxiety. The extended amygdala consists of several structures, of which the central nucleus of the amygdala and the bed nucleus of the stria terminalis are of particular importance to human stress-related diseases.¹⁵ During both acute withdrawal and prolonged abstinence, elevated levels of CRF, NE, and dynorphin are observed in the extended amygdala.² These neuroadaptations, therefore, produce a stress-like state marked by negative affect and heightened anxiety that not only lasts from weeks to years, but also drives negative reinforcement processes (ie, alcohol consumption that serves to remove the discomfort experienced during abstinence) responsible for craving and relapse. Thus, the anxiety that the patient experienced was likely exacerbated by neuroadaptations due to chronic alcohol use.

Alterations in Threat Processing

The patient’s anxiety and PTSD reflect abnormal function of threat processing and response. The rapid detection and avoidance of threat is crucial for survival; fear serves as an alerting signal to draw attention to impending threats.¹⁶ However, when fear becomes frequent, excessive, or occurs in response to non-threatening events, it is maladaptive and leads to anxiety disorders. Anxiety disorders involve alterations in the threat-processing circuitry—an area in which psychiatry has made great progress as a result of translational research.¹⁷ Findings from rodent and non-human primate studies show that fear, defined as a specific and brief response to an external, immediate threat, is mediated by the amygdala.¹⁵ These studies also showed that sustained response to an unknown threat or internal conflict, thought to reflect anxiety, is mediated by the bed nucleus of the stria terminalis.¹⁸ Other key neural substrates involved in threat processing include regions of the prefrontal cortex such as the ventral medial prefrontal cortex,^19-21 which has critical roles in emotion regulation and fear extinction, and the dorsal anterior cingulate cortex,²² which is involved in fear expression and conflict detection. Human neuroimaging studies confirm that these brain regions have altered function and connectivity in panic disorder, generalized anxiety disorder, and PTSD.^15,23,24 We would expect that similar patterns of brain region involvement and activity were present in our patient, and this knowledge allows us to better understand her presenting symptoms. The patient’s crippling fear—superimposed upon chronic anxiety—may be rooted in disrupted functioning of brain regions and networks that interpret and respond to threat or danger.

Separating fear and anxiety into a 2-system framework has clinical utility.¹⁷ First, this approach recognizes the inherent complexity involved in emotional processing. As illustrated by this case, fear and anxiety often overlap and occur together; however, our patient’s subjective experiences of these emotions not only differed based on their context or cue, but also produced a diverse array of symptoms. Second, a 2-system framework allows us to better understand the physiological and behavioral symptoms displayed by the patient and anticipate the symptoms with which she may continue to struggle. Third, as we will demonstrate later, this approach helps inform and guide selection of treatments to include pharmacologic agents and behavioral interventions that engage both networks.

The Impact of Chronic Stress

Early life adversity, such as the sexual abuse and physical neglect that our patient endured, activates and alters neural networks implicated in the stress response system.²⁶ In response to stress, the amygdala signals the hypothalamus, which activates the sympathetic nervous system, leading the adrenal glands to release NE.²⁶ NE is involved in the fight-or-flight response and contributes to the physiological manifestations of anxiety, such as elevated heart rate and restlessness. The hypothalamus also triggers the hypothalamic-pituitary-adrenal axis to secrete CRF, which signals the downstream release of glucocorticoids such as cortisol.^18,27 CRF and cortisol are implicated in the subjective feelings of anxiety and anxiety-like behaviors, such as avoidance and startle reactivity.²⁸ Long-term stress leads to dysregulation of these responses, providing a mechanism for the development of psychiatric disturbances such as affective and anxiety disorders.²⁹

Traumatic stressors impact the function of the limbic system—a set of structures involved in emotional processing and memory formation including the amygdala, hippocampus, and dorsolateral prefrontal cortex (dlPFC).³⁰ The amygdala plays a central role in processing emotions and contributes to memory formation by assigning emotional significance to experiences.³¹ The hippocampus is responsible for encoding new memories—a process that is especially sensitive to stress.³² Dysregulation of the memory encoding process due to trauma or chronic stress can lead to overgeneralization of new contexts or cues and inappropriately trigger a stress response. The dlPFC regulates the activity of the limbic system via established connections to the amygdala and hippocampus.³⁰ As such, the dlPFC modulates affective and motivated behaviors and influences reinforcement learning.³³ Toxic stress from complex trauma impairs the functioning of the dlPFC, disrupting the ability to regulate one’s emotional state and stress response. The patient’s adverse childhood experiences likely resulted in a pathologic stress response system, disrupting healthy brain development and contributing to her maladaptive fear and anxiety.

Translating Neuroscience into Clinical Practice

Conceptualizing this case through 3 different neuroscience lenses enhanced our ability to understand the patient’s psychiatric symptoms and identify specific targets to guide the selection of personalized treatments. During her 1-month follow-up visit, the patient reported severe anxiety, likely a chronic symptom exacerbated by her abstinence. Given the neurobiology of alcohol withdrawal and maladaptive anxiety, the dysregulation of GABA likely played a significant role in the manifestation of many of her symptoms. For these reasons, the patient was started on gabapentin, a medication that is commonly prescribed off-label for anxiety and has shown promise for the treatment of AUD.³⁴ Gabapentin’s mechanisms of action include increasing GABA-ergic activity, decreasing glutamatergic tone, and inhibiting the release of NE and DA,¹¹ thereby targeting the patient’s symptoms of elevated anxiety, depressed mood, and sleep disturbance. The patient noted improvements in anxiety and sleep upon initiating gabapentin, although she continued to experience daytime anxiety and alcohol cravings, for which the dose of gabapentin was further titrated. At her return visit, the patient reported “zero anxiety” and that she felt “better than I have for a long time.” During subsequent visits, brief interventions incorporating principles of acceptance, mindfulness, and exposure therapy were delivered to build tolerance for anxiety. By challenging faulty predictions about the presence of anxiety and reducing avoidance of these symptoms, the patient was able to reframe negative automatic thoughts and regain control over her life.

CONCLUSIONS

In this article, we presented a unique framework that combined insights from neuroscience with clinical assessment to evaluate an individual patient with co-occurring AUD, anxiety, and trauma. We examined the neurobiology of 3 key clinical components, providing an integrative and comprehensive approach to enhance our understanding and characterization of the patient’s anxiety symptoms. A prominent theme identified in this case was the role of the extended amygdala and its dysfunction in contributing to pathology. The patient’s history of abuse and neglect predisposed her to experience maladaptive fear and anxiety. Heightened anxiety, coupled with alterations in threat and reward processing, likely contributed to a neurobiologically-based vulnerability to substance use. While alcohol initially dampened the patient’s elevated anxiety levels and overactive threat response, the development of an AUD over time complicated her anxiety and impaired her ability to regulate distress (Figure 1). By considering the neurobiological underpinnings of the patient’s conditions, we were able to tailor the treatment approach to target the specific mechanisms driving her symptoms. This approach reduced her debilitating fear and chronic anxiety, allowing her to engage in educational, motivational, and relapse-prevention interventions. By recognizing the interplay between neurobiology and clinical symptoms, practitioners can provide more effective and personalized treatments, ultimately improving outcomes for patients facing complex psychiatric conditions.

FIGURE 1. Neurobiological Pathways Linking Trauma, Anxiety, and Alcohol Use Disorder in the Patient.

A history of complex trauma predisposed the patient to experience maladaptive levels of fear and anxiety. Heightened anxiety, coupled with alterations in stress circuitry and threat processing, likely contributed to a neurobiologically-based vulnerability to alcohol use. While alcohol initially mitigated her elevated anxiety levels and overactive threat response, the development of an alcohol use disorder over time complicated her anxiety and impaired her ability to regulate distress. With chronic alcohol use, an upregulated stress response occurs in the context of alcohol withdrawal, and over time, allostatic changes in the reward system result in a reduced response to alcohol itself.

Purple = predisposing factors; red = clinical symptoms; blue = neurobiological concepts CRH indicates corticotropin-releasing factor; GABA, γ-aminobutyric acid; NAcc, nucleus accumbens