Avoiding anticholinergic burden in neuropsychiatric treatments comorbid with alcohol use disorderABSTRACT
Alcohol use disorder (AUD) frequently co-occurs with neuropsychiatric conditions such as insomnia, anxiety, depression, and psychosis. The management of these comorbidities requires careful pharmacological consideration, particularly the avoidance of drugs that either interact adversely with alcohol or possess a high potential for misuse. After these considerations, many of the medications left available for AUD—such as tricyclic antidepressants and certain first-generation antipsychotics—are associated with anticholinergic burden (ACB), a cumulative side effect linked to an elevated risk of dementia. Given that AUD is itself an independent risk factor for cognitive decline and dementia, the use of ACB-contributing medications in this population may further potentiate neurocognitive deterioration through the compounding of risk factors. While ACB-sparing pharmacotherapeutic approaches have been developed for cognitively vulnerable populations such as the elderly and patients with dementia, similar clinical decision-making tools are not available for AUD care. This review highlights the evidence on the cognitive effects of AUD and ACB independently, to justify that this combination of risk factors should be avoided. Furthermore, it delineates pharmacological agents that should be either avoided or preferentially considered, forming the basis for an ACB-sparing approach in the treatment of four common neuropsychiatric comorbidities in AUD: insomnia, anxiety, depression, and psychosis.
Keywords:
Cholinergic Antagonists; Alcoholism; Dementia; Cognitive dysfunction
RESUMEN
El trastorno por consumo de alcohol (TUA) frecuentemente coexiste con trastornos neuropsiquiátricos como insomnio, ansiedad, depresión y psicosis. El manejo de estas comorbilidades requiere una cuidadosa consideración farmacológica, en particular, evitar fármacos que interactúen negativamente con el alcohol o tengan un alto potencial de abuso. Además de estas consideraciones, muchos de los medicamentos disponibles para el TUA —como los antidepresivos tricíclicos y ciertos antipsicóticos de primera generación— se asocian con la carga anticolinérgica (CAC), un efecto secundario acumulativo vinculado a un mayor riesgo de demencia. Dado que el TUA es en sí mismo un factor de riesgo independiente para el deterioro cognitivo y la demencia, el uso de medicamentos que contribuyen a la CAC en esta población puede potenciar aún más el deterioro neurocognitivo, mediante la combinación de estos factores de riesgo. Si bien se han desarrollado enfoques farmacoterapéuticos que evitan la CAC para poblaciones cognitivamente vulnerables, como los ancianos y los pacientes con demencia, no existen herramientas similares para la toma de decisiones clínicas en el tratamiento del TUA. Esta revisión destaca la evidencia sobre los efectos cognitivos del TUA y la CAC de forma independiente, lo que justifica evitar esta combinación de factores de riesgo. Además, describe los agentes farmacológicos que deben evitarse o considerarse preferentemente, lo que sienta las bases para un enfoque que evite el CAC en el tratamiento de cuatro comorbilidades neuropsiquiátricas comunes al TCA: insomnio, ansiedad, depresión y psicosis.
Palabras-clave:
Antagonistas Colinérgicos; Alcoholismo; Demencia; Disfunción Cognitiva
GLOBAL HEALTH IMPACT OF ALCOHOL USE DISORDER
The global prevalence of AUD is estimated to range between 5.1 and 8.6% of the population, representing a significant burden on global health and contributing substantially to both morbidity and mortality1. In 2019 alone, alcohol consumption was responsible for 2.6 million deaths worldwide, accounting for 4.7% of all deaths2. Likewise, alcohol use also contributes to adverse social and economic consequences, such as a higher risk of accidents, productivity losses, and increased rates of crime and violence2.
DIFFICULTIES OF PHARMACOTHERAPY IN AUD PATIENTS
Current AUD therapy includes non-pharmacological treatments such as cognitive behavioral therapy (CBT) or psychosocial interventions. However, moderate to severe AUD cases require the prescription of AUD-specific medication. These medications may be prescribed as alcohol reduction and remission promoting (ARRP) therapy or as relapse prevention therapy. Only three medications have been approved by the Food and Drugs Administration (FDA) of the United States of America for treatment of AUD: naltrexone—a μ-opioid receptor antagonist, acamprosate—a GABAergic/glutaminergic modulator, and disulfiram—an alcohol-antagonizing drug. Naltrexone and acamprosate are considered first-line ARRP medications, while disulfiram is mainly prescribed as relapse prevention therapy during substance remission. In case of failure or restrictions with the FDA-approved options, gabapentin and topiramate—two anticonvulsant drugs—may also be prescribed off-label as second-line ARRP options, with topiramate preferred over gabapentin due to stronger available evidence. Finally, baclofen—a GABA receptor agonist used as a muscle relaxant—and ondansetron—a selective 5-HT3 serotonin receptor antagonizing antiemetic—may also be considered as third-line off-label ARRP medications3, 4, 5, 6.
Treating pathologies co-occurring with AUD frequently represents a significant challenge due to multiple restricting factors like drug-alcohol interactions, potentially reduced or impaired liver function, and the potential for cross-abuse. For instance, medications that enhance GABA type A receptors (GABAA) functions, such as benzodiazepines and benzodiazepine-like drugs (i.e., z-hypnotics), should be avoided in chronic treatments of AUD patients because GABAA receptors are one of the molecular targets of ethanol, increasing the risk of a toxicological synergy resulting in overdose5, 6, 7, 8. However, the convergence on this pharmacological target resulted in benzodiazepines emerging as the first-line treatment for alcohol withdrawal syndrome (AWS)5,6,9. Likewise, long-term prescription of benzodiazepines and z-hypnotics should be avoided in AUD due to their high potential for co-abuse8,10. Thus, pharmacotherapy of comorbid disorders like anxiety, panic disorder, and insomnia, often treated with benzodiazepines or z-hypnotics as main options, should discourage the prescription of these drug categories to AUD patients. Similarly, other drugs with high misuse potential, such as opioids, should be used cautiously due to the risk of cross-abuse with alcohol11. These types of restrictions mean that pharmacotherapy for AUD patients is inherently restrictive, especially for chronic treatments.
COGNITIVE EFFECTS OF AUD AND THE POTENTIALLY HARMFUL COMBINATION WITH ANTICHOLINERGIC DRUGS
Although the benefits of low alcohol consumption remain controversial, a recent meta-analysis found a non-linear, “J-shaped” relationship between alcohol consumption and cognitive dysfunction or dementia. While lower consumption levels reduce the overall risk of these conditions, higher intake (≥30 or ≥15 g of ethanol per day, respectively) increases the likelihood of developing cognitive dysfunction or dementia in a dose-dependent manner12. AUD also increases the risk of developing dementias such as Alzheimer’s disease and vascular dementia13,14. Additionally, prolonged and excessive alcohol consumption may lead to various neurological and neurodegenerative conditions, including Korsakoff syndrome, Wernicke’s encephalopathy, seizures, hepatic encephalopathy, and alcohol-related dementia15,16. All these factors highlight ethanol’s widespread and multidomain toxic effects on the central nervous system (CNS), establishing AUD as both a cause and a contributing factor in various neurological, neurodegenerative, and neurocognitive disorders.
Drugs that block muscarinic receptors (i.e., anticholinergics) also increase the risk of developing neurocognitive disorders, such as mild cognitive impairment (MCI) and dementia. This risk occurs through a long-term cumulative side effect commonly known as anticholinergic burden (ACB), which derives from blocking the essential role of muscarinic receptors in cognitive processes such as hippocampal-dependent memory encoding and retrieval17, 18, 19.
Identification of cumulative effects of anticholinergic drugs on cognition led to the development of ACB scales that serve as decision-making tools by identifying the offending medications while also providing an impact score for each one of them. Development of these scales began using in vitro muscarinic antagonism as the main ACB criteria, but they later moved to a more systematic approach by studying the drugs’ long-term cognitive effects through retrospective clinical studies20. Most ACB scales use a numeric score from 0 to 3, with score 0 meaning no cognitive adverse effects, score 1 being the drugs associated with mild cognitive impact, score 2 reflecting moderate deleterious effects, and score 3 reserved for drugs linked to the greatest cognitive function decline. For the purpose of this review, Table 1 shows a simplification of some of the latest ACB systematic reviews20, 21, 22. Table 1 shows drugs prescribed for some neuropsychiatric disorders that commonly co-occur with AUD by dividing them into two groups only: low or no anticholinergic properties (ACB scores 0 to 1) and moderate to high anticholinergic properties (ACB scores 2 to 3). This simplification of the ACB scales was chosen to simplify and streamline the relevant decision-making information.
Drugs used for the treatment of four neuropsychiatric disorders commonly co-occurring with AUD: insomnia, anxiety, depression, and psychosis. Drugs are separated on the basis of their anticholinergic properties into two columns: Low to no ACB scores (ACB scores 0 to 1), and medium to high ACB scores (ACB scores 2 to 3). ACB scores based on Pistorio et al.21 and Ramos et al.22.
Alongside the publication of ACB drug scales, ACB-sparing pharmacotherapy guidelines have also been developed with the intention of decreasing the impact of anticholinergic drugs on populations with neurocognitive vulnerability, such as the elderly, dementia patients, and human immunodeficiency virus (HIV)-positive individuals. In general, ACB-sparing approaches attempt to reduce this modifiable risk factor in vulnerable populations by deprescribing offending medications, while prioritizing drugs with the lowest ACB impact possible21,23, 24, 25.
Unlike the research available for other groups with neurocognitive vulnerability, like dementia patients and HIV-positive individuals, at present, no clinical or pre-clinical studies have examined the combined effects of AUD and ACB on cognitive decline. Nevertheless, the existing evidence clearly demonstrates that both AUD and ACB independently play a role in neurocognitive dysfunctions and are both independent risks for the development of dementia. These considerations warrant that preventing the co-occurrence of AUD and ACB is a reasonable and desirable strategy. Although different areas of pharmacotherapy for AUD patients (e.g., cardiovascular or hepatic pharmacology) would benefit from ACB-sparing pharmacotherapeutic guidelines, this review highlights that medical care of neuropsychiatric comorbidities is an area with ample potential to increase or reduce ACB in AUD patients.
The link between AUD and neuropsychiatric disorders is well established, as it is often challenging to determine whether mental health issues contribute to alcohol consumption or if alcohol use leads to mental health problems. This strong association is highlighted by the high comorbidity between AUD and various neuropsychiatric disorders, including schizophrenia, depression, anxiety, attention deficit and hyperactivity disorder, and post-traumatic stress disorder26. In fact, current medical guidelines recommend that AUD patients are initially evaluated for co-occurring neuropsychiatric disorders6. Moreover, anxiety and depression—the two most prevalent psychiatric disorders—are linked to increased alcohol consumption, potentially creating a vicious cycle that worsens both substance misuse and overall mental health outcomes27,28.
ACB-SPARING PHARMACOTHERAPY FOR DEPRESSION IN COMORBIDITY WITH AUD
Considerations, exclusions, and restrictions
ACB scales categorize all tricyclic antidepressants as agents with moderate to high anticholinergic potency, classifying them as unadvisable medications for chronic treatments in individuals with cognitive vulnerability (Table 1). Similarly, paroxetine is the only selective serotonin reuptake inhibitor (SSRI) classified under moderate ACB impact (Table 1), which warrants its use with caution.
Nefazodone, an atypical antidepressant with only mild ACB impact, should still be avoided in AUD patients due to hepatotoxicity concerns29,30. Similarly, trazodone, a serotonin antagonist and reuptake inhibitor antidepressant, has been associated with a concerning increase in alcohol intake and relapses, especially post-treatment. Therefore, trazodone should be ruled out as a treatment for depression in AUD patients31,32. However, further benefit-risk assessments are required for trazodone use in AUD patients, given that an extended-release form of this atypical antidepressant was reported to improve depressive symptoms, anxiety, sleep alterations, and alcohol cravings33.
Aggregated evidence shows that SSRIs should be used with caution in AUD patients before achieving alcohol cessation, as these antidepressants may increase alcohol intake5,34. While evidence on the effects of serotonin-norepinephrine reuptake inhibitors (SNRIs) on alcohol intake is limited, at least two recent reports show that this drug class may also lead to an unintended increase in alcohol consumption or decrease remission chances35,36. These considerations have led to the current discouragement of the outdated practice of prescribing antidepressants as ARRP therapy.
ACB-sparing options
After the aforementioned exclusions and restrictions, an ACB-sparing pharmacotherapy for the treatment of depression co-occurring with AUD would be left with very limited options. Fortunately, current AUD care guidelines still consider antidepressants such as SSRIs as viable options as long as they are combined with an accepted ARRP medication such as naltrexone5,6. For example, two clinical studies assessed the effect of combining sertraline plus naltrexone, and two more clinical studies analyzed the combination of citalopram/escitalopram plus naltrexone. Each of these reports shows that the combination of an SSRI and naltrexone is as effective as, or more effective than, naltrexone alone as ARRP therapy. Moreover, the combined data from these four studies show that the SSRI plus naltrexone combination is an effective ARRP therapy. In terms of depressive outcomes, each SSRI plus naltrexone combination was as effective as the respective SSRI alone37, 38, 39, 40, 41. Furthermore, naltrexone monotherapy or in combination with antidepressants reduces the risk of alcohol-related hospitalizations, while antidepressants alone do not42. Therefore, current evidence supports that antidepressants in combination with ARRP medications, more specifically an SSRI plus naltrexone, are able to reduce depressive symptoms, as well as other alcohol-related risks, while promoting alcohol reduction or remission.
Other ACB-sparing alternatives for the treatment of depression co-occurring with AUD include mirtazapine and bupropion (Table 1). The aggregated evidence provided by several small clinical studies using mirtazapine shows its effectiveness in improving depression symptomatology in AUD patients, while having no effect on alcohol intake outcomes43,44. Thus, mirtazapine may serve as an adjuvant to treat depression in AUD patients, but like other antidepressants, it should not be considered as an ARRP alternative. On the other hand, the available evidence evaluating bupropion—a norepinephrine-dopamine reuptake inhibiting antidepressant—for the treatment of depression in patients with AUD is very limited. A single retrospective study found bupropion to be ineffective in this population, as patients with AUD had lower odds of responding to the drug compared to depressed patients without AUD36. Although a small study using a combination of bupropion plus naltrexone showed effectiveness at reducing alcohol intake, it provided no evidence that this combination offers advantages over naltrexone alone, nor did the study assess depression in the patients45. For these reasons, more evidence is required to properly assess the effectiveness and safety of bupropion as an antidepressant in AUD.
Finally, it must be noted that adding non-pharmacological options, such as CBT, to AUD-specific pharmacotherapy has a modest but significant effect on the treatment of depression, as well as on alcohol intake outcomes36,46,47. Therefore, non-pharmacological interventions may be considered for AUD patients with depression or anxiety, instead of adding another drug to the central AUD pharmacotherapy, or as co-adjuvants to it.
Conclusions and further considerations
Antidepressants in general are ineffective ARRP options and should not be prescribed for that purpose. Likewise, SSRIs/SNRIs should not be prescribed as monotherapy for depression co-occurring with AUD due to the risk of increasing alcohol intake or relapse. However, the evidence supports the use of an SSRI plus naltrexone as effective on both therapeutic fronts (i.e., alcohol intake and depression). This combination eliminates the potentially detrimental effects of SSRI monotherapy in AUD patients. Paroxetine is the only SSRI excluded from these recommendations due to its moderate ACB score.
Mirtazapine may be used as monotherapy for depression in AUD patients in remission, but it should also be combined with an ARRP drug in patients who have not achieved remission.
CBT and other forms of psychotherapy interventions may be considered as non-pharmacological options to address depression in AUD patients.
ACB SPARING PHARMACOTHERAPY FOR ANXIETY IN COMORBIDITY WITH AUD
Considerations, exclusions and restrictions
All tricyclic antidepressants and hydroxyzine should be excluded from an ACB-sparing pharmacotherapy due to their moderate to high ACB scores (Table 1).
The treatment of anxiety co-occurring with AUD must avoid benzodiazepines, unless during alcohol withdrawal, due to reasons previously explained (i.e., toxicological synergy with ethanol and potential for cross-abuse).
SSRIs/SNRIs may be prescribed for their anxiolytic properties in patients with comorbid anxiety and AUD; however, as is the case with the treatment of depression, these drugs classes should be combined with naltrexone or other ARRP drug.
Although paroxetine is the only SSRI with evidence of effectiveness for social anxiety in comorbidity with AUD, it is also the only SSRI with a moderate ACB score. For that reason, paroxetine may still be considered as an option for anxiety that does not respond adequately to the ACB-sparing medications34,48.
ACB-sparing options
Buspirone—a serotonin 5-HT1A receptor partially agonistic anxiolytic—has gathered multiple independent reports showing its effectiveness as an anxiolytic in AUD. Meanwhile, some anticonvulsant medications prescribed off-label to AUD patients, including topiramate, pregabalin and gabapentin, are also effective anxiolytics that perform as well, or better than first-line benzodiazepines during alcohol withdrawal34,48.
Non-pharmacological approaches such as CBT also has modest beneficial effects in the treatment of anxiety co-occurring with AUD, while they also lead to improvements on alcohol outcomes36,46,47.
Conclusions and further considerations
Topiramate and gabapentin may be used as monotherapy for anxiety co-occurring with AUD regardless of achievement of remission, as they are considered second-line ARRP medications. Buspirone and pregabalin may also be considered for anxiety treatment in AUD patients, but there is not enough evidence to support their use as monotherapy in individuals who have not achieved alcohol remission.
SSRIs/SNRIs may be prescribed as anxiolytics in AUD, but they should be accompanied with naltrexone or another ARRP drug.
CBT and other forms of psychotherapy interventions may be considered as non-pharmacological options to address anxiety in AUD patients.
ACB-SPARING PHARMACOTHERAPY FOR PSYCHOSIS IN COMORBIDITY WITH AUD
Considerations, exclusions, and restrictions
Similar to the case of antidepressants, current AUD pharmacotherapy guidelines discourage the outdated practice of prescribing some antipsychotics (e.g., quetiapine) as ARRP therapy5,6.
Psychotic disorders and psychotic episodes may co-occur with AUD or arise due to alcohol consumption or its withdrawal. For example, prolonged and excessive alcohol exposure, as well as repeated AWS events, may cause alcohol-induced psychotic disorder (AIPD), a substance-induced syndrome characterized by multiple psychotic symptoms that may include hallucinations and delusions. However, diagnosing AIPD in intoxicated individuals is difficult due to the similarity and symptom overlap between psychosis and intoxication. Similarly, AIPD cannot be diagnosed during AWS, as this withdrawal stage may also cause psychotic symptomatology. Thus, the identifying characteristic of AIPD is its persistence, often for days or weeks, after alcohol cessation and AWS9,49,50.
Pharmacotherapy for psychotic disorders diagnosed independently of AUD depends on the primary psychosis disorder diagnosed (e.g., schizophrenia, bipolar disorder, etc.) and generally follows the therapeutic guidelines for that underlying condition. However, in the case of AIPD, there are no clear pharmacotherapy guidelines due to scarce evidence and some contradictory findings. For example, different studies report opposite results regarding the effectiveness of haloperidol vs. risperidone in AIPD. Nonetheless, evidence validates that AIPD pharmacotherapy must include antipsychotic drugs, as this substance-induced disorder responds to both typical and atypical antipsychotics49,50.
ACB-contributing antipsychotics have been identified, consisting mainly of typical (i.e., first-generation) antipsychotics, such as clozapine and chlorpromazine, among many others (Table 1). Also, an increase in the risk of alcohol relapses has been reported under treatment with flupentixol; therefore, this medication should be avoided in AUD51.
ACB-sparing therapeutic options
After the exclusions explained above, six ACB-sparing antipsychotics are left: cariprazine, brexpiprazole, lurasidone, haloperidol, risperidone, and aripiprazole. The most recently approved drugs in this subcategory, namely cariprazine, brexpiprazole, and lurasidone, have not been purposely and specifically studied among AUD patients. Therefore, their use in this population remains a case-by-case decision. Interestingly, a series of case reports have revealed cariprazine as potentially decreasing substance abuse, but these effects need to be confirmed through specific clinical trials52. Fortunately, haloperidol, risperidone, and aripiprazole have all been successfully used in the treatment of AIPD, demonstrating their effectiveness and safety in AUD patients49,50.
Conclusions and further considerations
Antipsychotics can be used to treat psychotic symptoms and disorders comorbid with AUD, but they do not represent a replacement for ARRP treatments.
Haloperidol, risperidone, and aripiprazole should represent the preferred options in an ACB-sparing therapeutic approach for the acute treatment of psychotic symptoms found in AUD patients, such as those related to AIPD. For chronic treatment of psychotic disorders, such as those that may have an independent origin to AUD or AWS (e.g., preexisting schizophrenia or bipolar disorder), haloperidol, risperidone, and aripiprazole should also represent the initial drug trial options if there are no limitations for their use.
Unfortunately, even after all these considerations, yet another layer of complexity must be considered since all antipsychotics may lead to drug-induced parkinsonism (DIP). Besides the need to prevent this adverse result in any patient treated with antipsychotic medications, DIP is of special concern in neurocognitively vulnerable individuals because it is likely to require treatment with strong anticholinergic drugs such as trihexyphenidyl or benztropine. Therefore, all antipsychotic medications, including haloperidol, risperidone, and aripiprazole, may end up contributing to ACB in an indirect manner53,54. For these reasons, any treatment with antipsychotic drugs in AUD patients should strategize to limit their use both in time and in dose, as well as include monitoring of extrapyramidal signs characteristic of DIP.
ACB-SPARING PHARMACOTHERAPY FOR INSOMNIA IN COMORBIDITY WITH AUD
Considerations, exclusions, and restrictions
AUD is commonly accompanied by insomnia and other sleep disorders, which can persist after alcohol cessation and may require therapeutic management. Regardless of the underlying cause, the first-line treatment for insomnia is not pharmacological but rather CBT. However, it is accepted that many patients will require medication as a coadjutant or in lieu of CBT. In these cases, the traditionally accepted pharmacotherapy with benzodiazepines and z-hypnotics remains severely restricted for reasons previously explained (i.e., toxicological synergy with ethanol and potential for cross-abuse). Likewise, a more recent generation of hypnotics, represented by a few orexin receptor antagonists (i.e., lemborexant, suvorexant, and daridorexant), should also be avoided in AUD, given that they are classified by the FDA as Schedule IV substances due to their potential for misuse55. Similarly, agomelatine, an antidepressant with melatonin agonism that is commonly used off-label as a sleep-inducing medication, should also be avoided in AUD due to hepatoxicity concerns56. Trazodone, an atypical antidepressant effective at treating sleep disturbances in AUD, should be considered with caution due to concerning but also contradicting evidence regarding an association with increased alcohol intake and relapse, as previously explained31, 32, 33,57.
Importantly, an ACB-sparing pharmacotherapeutic approach for insomnia should rule out all sleep aids based on antihistamines, such as diphenhydramine, doxylamine, and chlorpheniramine, due to their high ACB scores. The moderate-to-high ACB-score group also includes various miscellaneous medications that have been used off-label for insomnia, like doxepin, carbamazepine, quetiapine, and hydroxyzine (Table 1).
ACB-sparing options
There are a few ACB-sparing medications that have been reported as having different degrees of effectiveness in the treatment of insomnia and other sleep disturbances co-occurring with AUD. Out of this group, it should be noted that gabapentin is the medication with the most supporting evidence showing improvement of sleep parameters in AUD patients. Similarly, a couple of reports show modest effectiveness of acamprosate—a first-line ARRP medication—in reducing sleep onset and improving sleep outcomes in AUD patients57,58. Finally, a single large clinical trial (n=371) evaluating different outcomes on alcohol consumption, quality of life, and physical health of AUD patients treated with topiramate shows that this drug is effective at improving alcohol outcomes and sleep quality59.
As previously referenced, mirtazapine effectively and safely improves depression symptoms in comorbidity with AUD; therefore, mirtazapine’s drowsiness-inducing effect could potentially improve sleep quality in this population. Unfortunately, this effect has never been studied in AUD patients.
Finally, a single and very small case series study (n=5) showed that ramelteon—a melatonin receptor agonist—reduces time to sleep and improves sleep time in AUD patients60.
Conclusions and further considerations
CBT is the first-line treatment of insomnia regardless of alcohol misuse; however, there is no limitation on starting CBT in combination with medication. Pharmacotherapy is required if CBT alone fails to improve sleep outcomes. Likewise, pharmacotherapy alone may be considered as starting treatment if CBT is not feasible.
Considering that gabapentin, acamprosate, and topiramate are first- or second-line ARRP medications, all of these drugs may be considered as valuable monotherapy options to address alcohol misuse concomitant with insomnia.
Mirtazapine or ramelteon have been used safely in AUD patients, but their effectiveness as hypnotics in this population is very limited or non-existent. Therefore, these two drugs may be considered for cases in which other options have failed or are otherwise restricted.
In conclusion, protecting cognitive functions from modifiable risk factors is undoubtedly a goal worth pursuing, but it is especially important in the case of populations with recognized cognitive vulnerabilities. The discovery of ACB brought forth a life-long modifiable risk that must be considered in the medical care of vulnerable individuals. However, the effects of ACB on a vulnerable population like AUD patients have never been considered, let alone studied for their medical care. Nonetheless, our current understanding of both AUD and ACB strongly supports that protecting cognitive functions in AUD patients should include ACB-sparing efforts. Considering the inherent complexity of pharmacotherapy in AUD, it is essential to carefully evaluate alternative treatments that do not put cognitive functions at further risk. Fortunately, as this review reveals, despite the limitations and challenges in AUD medical care, there are ACB-sparing alternatives available for the treatment of four neuropsychiatric disorders that commonly co-occur with AUD. Furthermore, the ACB-sparing alternatives identified are all supported by clinical evidence as being safe and efficacious for the use proposed.
DATA AVAILABILITY STATEMENT
No new data were generated or analyzed in this study.
REFERENCES
-
1. Asrani SK, Mellinger J, Arab JP, Shah VH. Reducing the global burden of alcohol-associated liver disease: a blueprint for action. Hepatology. 2021;73(5):2039-50. https://doi.org/10.1002/hep.31583
» https://doi.org/10.1002/hep.31583 - 2. World Health Organization. Global status report on alcohol and health and treatment of substance use disorders. World Health Organization; 2024.
-
3. McPheeters M, O’Connor EA, Riley S, Kennedy SM, Voisin C, Kuznacic K, et al. Pharmacotherapy for alcohol use disorder: a systematic review and meta-analysis. JAMA. 2023;330(17):1653-65. https://doi.org/10.1001/JAMA.2023.19761
» https://doi.org/10.1001/JAMA.2023.19761 -
4. Carpenter JE, LaPrad D, Dayo Y, DeGrote S, Williamson K. An overview of pharmacotherapy options for alcohol use disorder. Fed Pract [Internet]. 2018 [Accessed March 30, 2025];35(10):48-58. Available at: https://pmc.ncbi.nlm.nih.gov/articles/PMC6248154/
» https://pmc.ncbi.nlm.nih.gov/articles/PMC6248154/ -
5. Wood E, Bright J, Hsu K, Goel N, Ross JWG, Hanson A, et al. Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder. Can Med Assoc J. 2023;195(40):E1364-79. https://doi.org/10.1503/cmaj.230715
» https://doi.org/10.1503/cmaj.230715 -
6. American Psychiatric Association. Practice guideline for the pharmacological treatment of patients with alcohol use disorder. American Psychiatric Association Publishing; 2018. https://doi.org/10.1176/appi.books.9781615371969
» https://doi.org/10.1176/appi.books.9781615371969 -
7. Arnedt JT. Insomnia in patients with a substance use disorder. In: Benca R, ed. Uptodate [Internet]. Waltham, MA: UpToDate; 2022 [Acessed 2025 Oct 16]. Available at: https://www.uptodate.com/contents/insomnia-in-patients-with-a-substance-use-disorder#:~:text=Insomnia
» https://www.uptodate.com/contents/insomnia-in-patients-with-a-substance-use-disorder#:~:text=Insomnia -
8. Schubert JR, Todd Arnedt J. Management of insomnia in patients with alcohol use disorder. Curr Sleep Med Rep. 2017;3(2):38-47. https://doi.org/10.1080/14656566.2019.1705279
» https://doi.org/10.1080/14656566.2019.1705279 -
9. Day E, Daly C. Clinical management of the alcohol withdrawal syndrome. Addiction. 2022;117(3):804-14. https://doi.org/10.1111/ADD.15647
» https://doi.org/10.1111/ADD.15647 -
10. Licata SC, Rowlett JK. Abuse and dependence liability of benzodiazepine-type drugs: GABAA receptor modulation and beyond. Pharmacol Biochem Behav. 2008;90(1):74-89. https://doi.org/10.1016/J.PBB.2008.01.001
» https://doi.org/10.1016/J.PBB.2008.01.001 -
11. Witkiewitz K, Vowles KE. Alcohol and opioid use, co-use, and chronic pain in the context of the opioid epidemic: a critical review. Alcohol Clin Exp Res. 2018;42(3):478-88. https://doi.org/10.1111/ACER.13594
» https://doi.org/10.1111/ACER.13594 -
12. Zarezadeh M, Mahmoudinezhad M, Faghfouri AH, Honarvar NM, Regenstein QR, Papatheodorou SI, et al. Alcohol consumption in relation to cognitive dysfunction and dementia: A systematic review and dose-response meta-analysis of comparative longitudinal studies. Ageing Res Rev. 2024;100:102419. https://doi.org/10.1016/j.arr.2024.102419
» https://doi.org/10.1016/j.arr.2024.102419 -
13. Wang G, Li DY, Vance DE, Li W. Alcohol use disorder as a risk factor for cognitive impairment. J Alzheimer’s Dis. 2023;94(3):899-907. https://doi.org/10.3233/JAD-230181
» https://doi.org/10.3233/JAD-230181 -
14. Hu Y, Korhonen K, Li P, Bobak M, Martikainen P, Bijlsma MJ. Association between alcohol use disorders and dementia in 262,703 dementia-free finnish adults: is cardiovascular disease a mediator? J Gerontol Series A. 2023;78(6):1045-52. https://doi.org/10.1093/gerona/glac252
» https://doi.org/10.1093/gerona/glac252 -
15. Rao R, Topiwala A. Alcohol use disorders and the brain. Addiction. 2020;115(8):1580-9. https://doi.org/10.1111/add.15023
» https://doi.org/10.1111/add.15023 -
16. Huang J, Ahmed IM, Wang T, Xie C. Beyond the liver. Clin Liver Dis. 2024;28(4):681-97. https://doi.org/10.1016/j.cld.2024.06.004
» https://doi.org/10.1016/j.cld.2024.06.004 -
17. Rashid H, Ahmed T. Muscarinic activity in hippocampus and entorhinal cortex is crucial for spatial and fear memory retrieval. Pharmacol Rep. 2019;71(3):449-56. https://doi.org/10.1016/j.pharep.2019.02.004
» https://doi.org/10.1016/j.pharep.2019.02.004 -
18. Leaderbrand K, Chen HJ, Corcoran KA, Guedea AL, Jovasevic V, Wess J, et al. Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory. Learn Mem. 2016;23(11):631-8. https://doi.org/10.1101/lm.043133.116
» https://doi.org/10.1101/lm.043133.116 -
19. Sambeth A, Riedel WJ, Klinkenberg I, Kähkönen S, Blokland A. Biperiden selectively induces memory impairment in healthy volunteers: no interaction with citalopram. Psychopharmacology (Berl). 2014;232(11):1887-97. https://doi.org/10.1007/s00213-014-3822-9
» https://doi.org/10.1007/s00213-014-3822-9 -
20. Al Rihani SB, Deodhar M, Darakjian LI, Dow P, Smith MK, Bikmetov R, et al. Quantifying anticholinergic burden and sedative load in older adults with polypharmacy: a systematic review of risk scales and models. Drugs Aging. 2021;38(11):977-94. https://doi.org/10.1007/s40266-021-00895-x
» https://doi.org/10.1007/s40266-021-00895-x -
21. Pistorio S, Scotto di Tella G, Canzanella V, Merenda R, Cuomo G, Iacotucci P, et al. Anticholinergic burden and behavioral and psychological symptoms in older patients with cognitive impairment. Front Med (Lausanne). 2025;12:1505007. https://doi.org/10.3389/fmed.2025.1505007
» https://doi.org/10.3389/fmed.2025.1505007 -
22. Ramos H, Moreno L, Pérez-Tur J, Cháfer-Pericás C, García-Lluch G, Pardo J. CRIDECO anticholinergic load scale: an updated anticholinergic burden scale. Comparison with the ACB scale in Spanish individuals with subjective memory complaints. J Pers Med. 2022;12(2):207. https://doi.org/10.3390/JPM12020207
» https://doi.org/10.3390/JPM12020207 -
23. Zheng YB, Shi L, Zhu XM, Bao Y-P, Bai L-J, Li J-Q, et al. Anticholinergic drugs and the risk of dementia: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2021;127:296-306. https://doi.org/10.1016/J.NEUBIOREV.2021.04.031
» https://doi.org/10.1016/J.NEUBIOREV.2021.04.031 -
24. Shawaqfeh B, Hughes CM, McGuinness B, Barry HE. A systematic review of interventions to reduce anticholinergic burden in older people with dementia in primary care. Int J Geriatr Psychiatry. 2022;37(6). https://doi.org/10.1002/GPS.5722
» https://doi.org/10.1002/GPS.5722 -
25. Casajús-Navasal A, Marín-Gorricho R, Gallardo-Anciano J, Nebot-Villacampa MJ, Zafra-Morales R, González-Pérez Y. Prevalence of the consumption of anticholinergic drugs in HIV patients. Farmacia Hospitalaria. 2018;42(1):1-4. https://doi.org/10.7399/FH.10842
» https://doi.org/10.7399/FH.10842 -
26. Castillo-Carniglia A, Keyes KM, Hasin DS, Cerdá M. Psychiatric comorbidities in alcohol use disorder. Lancet Psychiatry. 2019;6(12):1068-80. https://doi.org/10.1016/S2215-0366(19)30222-6
» https://doi.org/10.1016/S2215-0366(19)30222-6 -
27. Palzes VA, Parthasarathy S, Chi FW, Kline-Simon AH, Lu Y, Weisner C, et al. Associations between psychiatric disorders and alcohol consumption levels in an adult primary care population. Alcohol Clin Exp Res. 2020;44(12):2536-44. https://doi.org/10.1111/ACER.14477
» https://doi.org/10.1111/ACER.14477 -
28. Preuss UW, Gouzoulis-Mayfrank E, Havemann-Reinecke U, Schäfer I, Beutel M, Hoch E, et al. Psychiatric comorbidity in alcohol use disorders: results from the German S3 guidelines. Eur Arch Psychiatry Clin Neurosci. 2018;268(3):219-29. https://doi.org/10.1007/S00406-017-0801-2
» https://doi.org/10.1007/S00406-017-0801-2 -
29. Aranda-Michel J, Koehler A, Bejarano PA, Poulos JE, Luxon BA, Khan CM, et al. Nefazodone-induced liver failure: Report of three cases. Ann Intern Med. 1999;130(4 Part 1):285-8. https://doi.org/10.7326/0003-4819-130-4-199902160-00013
» https://doi.org/10.7326/0003-4819-130-4-199902160-00013 -
30. Stewart DE. Hepatic adverse reactions associated with nefazodone. Can J Psychiatry. 2002;47(4):375-7. https://doi.org/10.1177/070674370204700409
» https://doi.org/10.1177/070674370204700409 -
31. Friedmann PD, Rose JS, Swift R, Stout RL, Millman RP, Stein MD. Trazodone for sleep disturbance after alcohol detoxification: a double-blind, placebo-controlled trial. Alcohol Clin Exp Res. 2008;32(9):1652-60. https://doi.org/10.1111/J.1530-0277.2008.00742.X
» https://doi.org/10.1111/J.1530-0277.2008.00742.X -
32. Pan J, Rehm J, Wood E. Rethinking trazodone for insomnia in alcohol use disorder. Addict Sci Clin Pract. 2025;20(1):30. https://doi.org/10.1186/s13722-025-00552-3
» https://doi.org/10.1186/s13722-025-00552-3 -
33. Di Nicola M, Pepe M, Panaccione I, Moccia L, Janiri L, Sani G. Update on Pharmacological Treatment for Comorbid Major Depressive and Alcohol Use Disorders: The Role of Extended-release Trazodone. Curr Neuropharmacol. 2023;21(11):2195-205. https://doi.org/10.2174/1570159X21666230403080624
» https://doi.org/10.2174/1570159X21666230403080624 -
34. Gimeno C, Dorado ML, Roncero C, Szerman N, Vega P, Balanzá-Martínez V, et al. Treatment of comorbid alcohol dependence and anxiety disorder: Review of the scientific evidence and recommendations for treatment. Front Psychiatry. 2017;8:279926. https://doi.org/10.3389/FPSYT.2017.00173
» https://doi.org/10.3389/FPSYT.2017.00173 -
35. Mușat MI, Militaru F, Gheorman V, Udriștoiu I, Mitran SI, Cătălin B. Moderate alcohol consumption increases the risk of clinical relapse in male depressed patients treated with serotonin-norepinephrine reuptake inhibitors. Diagnostics. 2024;14(11):1140. https://doi.org/10.3390/DIAGNOSTICS14111140
» https://doi.org/10.3390/DIAGNOSTICS14111140 -
36. Tang VM, Yu D, Weissman CR, Jones BDM, Wang G, Sloan ME, et al. Treatment outcomes in major depressive disorder in patients with comorbid alcohol use disorder: A STAR*D analysis. J Affect Disord. 2023;339:691-7. https://doi.org/10.1016/J.JAD.2023.07.049
» https://doi.org/10.1016/J.JAD.2023.07.049 -
37. O’Malley SS, Robin RW, Levenson AL, GreyWolf I, Chance LE, Hodgkinson CA, et al. Naltrexone alone and with sertraline for the treatment of alcohol dependence in Alaska natives and non-natives residing in rural settings: a randomized controlled trial. Alcohol Clin Exp Res. 2008;32(7):1271-83. https://doi.org/10.1111/J.1530-0277.2008.00682.X
» https://doi.org/10.1111/J.1530-0277.2008.00682.X -
38. Pettinati HM, Oslin DW, Kampman KM, Dundon WD, Xie H, Gallis TL, et al. A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry. 2010;167(6):668-75. https://doi.org/10.1176/APPI.AJP.2009.08060852
» https://doi.org/10.1176/APPI.AJP.2009.08060852 -
39. Li J, Wang H, Li M, Shen Q, Li X, Rong X, et al. Efficacy of pharmacotherapeutics for patients comorbid with alcohol use disorders and depressive symptoms—A Bayesian network meta-analysis. CNS Neurosci Ther. 2020;26(11):1185-97. https://doi.org/10.1111/CNS.13437
» https://doi.org/10.1111/CNS.13437 -
40. Stella L, Addolorato G, Rinaldi B, Capuano A, Berrino L, Rossi F, et al. An open randomized study of the treatment of escitalopram alone and combined with γ-hydroxybutyric acid and naltrexone in alcoholic patients. Pharmacol Res. 2008;57(4):312-7. https://doi.org/10.1016/J.PHRS.2008.03.001
» https://doi.org/10.1016/J.PHRS.2008.03.001 -
41. Adamson SJ, Sellman JD, Foulds JA, Frampton C, Deering D, Dunn A, et al. A randomized trial of combined citalopram and naltrexone for nonabstinent outpatients with co-occurring alcohol dependence and major depression. J Clin Psychopharmacol. 2015;35(2):143-9. https://doi.org/10.1097/JCP.0000000000000287
» https://doi.org/10.1097/JCP.0000000000000287 -
42. Bach P, Franck J, Hällgren J, Widing H, Gissler M, Westman J. Antidepressants, relapse-prevention medications and both combined to reduce alcohol-related hospitalizations in individuals with severe alcohol use disorder. Eur Arch Psychiatry Clin Neurosci. 2025. https://doi.org/10.1007/s00406-025-01988-z
» https://doi.org/10.1007/s00406-025-01988-z -
43. Cornelius J, Chung T, Douaihy A, Kirisci L, Glance J, Kmiec J, et al. A review of the literature of mirtazapine in co-occurring depression and an alcohol use disorder. J Addict Behav Ther Rehabil. 2016;5(4):159. https://doi.org/10.4172/2324-9005.1000159
» https://doi.org/10.4172/2324-9005.1000159 -
44. Cornelius JR, Chung T, Douaihy AB, Kirisci L, Glance J, Kmiec J, et al. Mirtazapine in comorbid major depression and an alcohol use disorder: A double-blind placebo-controlled pilot trial. Psychiatry Res. 2016;242:326-30. https://doi.org/10.1016/J.PSYCHRES.2016.06.005
» https://doi.org/10.1016/J.PSYCHRES.2016.06.005 -
45. Walter TJ, Navarro M, Thiele TE, Pedersen C, Kampov-Polevoy A, Garbutt JC. A preliminary, open-label study of naltrexone and bupropion combination therapy for treating binge drinking in human subjects. Alcohol Alcohol. 2020;55(1):56-62. https://doi.org/10.1093/ALCALC/AGZ076
» https://doi.org/10.1093/ALCALC/AGZ076 -
46. Ray LA, Meredith LR, Kiluk BD, Walthers J, Carroll KM, Magill M. Combined pharmacotherapy and cognitive behavioral therapy for adults with alcohol or substance use disorders: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(6):e208279. https://doi.org/10.1001/JAMANETWORKOPEN.2020.8279
» https://doi.org/10.1001/JAMANETWORKOPEN.2020.8279 -
47. Yoon G, Petrakis IL. Pharmacological and psychological treatments for comorbid alcohol use disorder and depressive disorder: a review. Curr Addict Rep. 2018;5(3):312-22. https://doi.org/10.1007/S40429-018-0213-Z
» https://doi.org/10.1007/S40429-018-0213-Z -
48. Ipser JC, Wilson D, Akindipe TO, Sager C, Stein DJ. Pharmacotherapy for anxiety and comorbid alcohol use disorders. Cochrane Database Syst Rev. 2015;2017(6):CD007505. https://doi.org/10.1002/14651858.CD007505.PUB2
» https://doi.org/10.1002/14651858.CD007505.PUB2 -
49. Masood B, Lepping P, Romanov D, Poole R. Treatment of alcohol-induced psychotic disorder (alcoholic hallucinosis)—a systematic review. Alcohol Alcohol. 2018;53(3):259-67. https://doi.org/10.1093/ALCALC/AGX090
» https://doi.org/10.1093/ALCALC/AGX090 -
50. Skryabin VY, Martinotti G, Franck J, Zastrozhin MS. Acute alcoholic hallucinosis: a review. Psychopathology. 2023;56(5):383-90. https://doi.org/10.1159/000528573
» https://doi.org/10.1159/000528573 -
51. Wiesbeck GA, Weijers HG, Lesch OM, Glaser T, Toennes PJ, Boening J. Flupenthixol decanoate and relapse prevention in alcoholics: results from a placebo-controlled study. Alcohol Alcohol. 2001;36(4):329-34. https://doi.org/10.1093/ALCALC/36.4.329
» https://doi.org/10.1093/ALCALC/36.4.329 -
52. Sanders LO, Miller JJ. Cariprazine may decrease substance abuse in patients with bipolar I disorder [Internet]. 2019[Accessed May 3, 2025];36(3). Available at: https://www.psychiatrictimes.com/view/cariprazine-may-decrease-substance-abuse-patients-bipolar-i-disorder
» https://www.psychiatrictimes.com/view/cariprazine-may-decrease-substance-abuse-patients-bipolar-i-disorder -
53. Feldman M, Marmol S, Margolesky J. Updated perspectives on the management of drug-induced parkinsonism (DIP): insights from the clinic. Ther Clin Risk Manag. 2022;18:1129-42. https://doi.org/10.2147/TCRM.S360268
» https://doi.org/10.2147/TCRM.S360268 -
54. Shin HW, Chung SJ. Drug-induced parkinsonism. J Clin Neurol. 2012;8(1):15-21. https://doi.org/10.3988/JCN.2012.8.1.15
» https://doi.org/10.3988/JCN.2012.8.1.15 -
55. Teuns GBA, Tessari M. Is schedule IV suvorexant an appropriate reference drug of abuse to use in preclinical abuse liability testing in the rat? Regul Toxicol Pharmacol. 2024;148:105570. https://doi.org/10.1016/J.YRTPH.2024.105570
» https://doi.org/10.1016/J.YRTPH.2024.105570 -
56. Gahr M, Kratzer W, Fuchs M, Connemann B. Safety and tolerability of agomelatine: focus on hepatotoxicity. Curr Drug Metab. 2014;15(7):694-702. https://doi.org/10.2174/1389200215666140926155041
» https://doi.org/10.2174/1389200215666140926155041 -
57. Roehrs TA, Auciello J, Tseng J, Whiteside G. Current and potential pharmacological treatment options for insomnia in patients with alcohol use disorder in recovery. Neuropsychopharmacol Rep. 2020;40(3):211-23. https://doi.org/10.1002/NPR2.12117
» https://doi.org/10.1002/NPR2.12117 -
58. Geoffroy PA, Lejoyeux M, Rolland B. Management of insomnia in alcohol use disorder. Expert Opin Pharmacother. 2020;21(3):297-306. https://doi.org/10.1080/14656566.2019.1705279
» https://doi.org/10.1080/14656566.2019.1705279 -
59. Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, et al. Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial. Arch Intern Med. 2008;168(11):1188-99. https://doi.org/10.1001/ARCHINTE.168.11.1188
» https://doi.org/10.1001/ARCHINTE.168.11.1188 -
60. Brower KJ, Conroy DA, Kurth ME, Anderson BJ, Stein MD. Ramelteon and improved insomnia in alcohol-dependent patients: a case series. J Clin Sleep Med. 2011;7(3):274-5. https://doi.org/10.5664/JCSM.1070
» https://doi.org/10.5664/JCSM.1070
Edited by
-
Editor-in-Chief:
Sonia M. D. Brucki https://orcid.org/0000-0002-8303-6732
-
Associate Editor:
Raphael Castilhos https://orcid.org/0000-0002-1905-2084
