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GME Research Review

GME Research Review is a monthly newsletter where internationally recognized experts select, summarize, and provide a clinical commentary on the latest published research in psychiatry.  Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by our expert.


ISSUE 16, JULY 2013 — Guest Commentator: Peter Selby, MBBS, CCFP, University of Toronto, Canada


Pharmacological Interventions for Smoking Cessation: An Overview and Network Meta-Analysis

Cahill K, Steven S, Perera R, Lancaster T.
Cochrane Database Syst Rev. 2013 May 31;5:CD009329.

Objectives: There were 4 objectives of this overview and comparative effectiveness of various firs- line pharmacotherapies for smoking cessation.

  • Is nicotine replacement therapy (NRT) bupropion and varenicline better than placebo and are there differences between these medications in helping smokers achieve long-term abstinence (6 months or longer)?
  • How do other treatments, such as clonidine and nortriptyline, compare with placebo in achieving long-term abstinence?
  • Are some options safer than others?
  • When do the risks of harm outweigh the benefits of smoking cessation medications?


  • This overview was restricted to Cochrane reviews, all of which include randomized trials.
  • Inclusion: These studies were restricted to adult smokers. Medications included in the review included NRT, antidepressants (bupropion and nortriptyline), nicotine receptor partial agonists (varenicline and cytisine), anxiolytics, selective type 1 cannabinoid receptor antagonists (rimonabant), clonidine, lobeline, dianicline, mecamylamine, Nicobrevin, opioid antagonists, nicotine vaccines, and silver acetate.
  • Exclusions: Studies exclusively done on pregnant women, particular disease groups, or specific settings.
  • Outcome measures: for benefit -continuous or prolonged abstinence at least 6 months from the start of treatment compared to placebo or each other.
  • For harms – the incidence of serious adverse events.
  • Search strategy: Cochrane Database of Systematic Reviews (CDSR) in The Cochrane Library, for any reviews with “smoking” in the title, abstract, or keyword fields. The last search was conducted in November 2012.
  • Methodological quality was assessed using a revised version of the AMSTAR scale, which is a validated tool to rate the quality of systematic reviews.
  • The authors conducted a network meta-analyses to compare between active treatment and to compare the risks of serious adverse events between varenicline and bupropion. This is a method utilized when multiple interventions have been used and compared for the same disease and outcomes, and allows for the interpretation of the overall evidence and to understand the relative merits of these multiple interventions.


  • Twelve treatment-specific reviews were identified, including a total of 267 studies, representing 101,804 smokers most of whom smoked 10 or more cigarettes per day.
  • For every 10 smokers who quit with placebo, 18 quit with NRT or bupropion (odds ratios [OR] 1.84; 95% credible interval [CredI] 1.71 to 1.99, and 1.82; 95% CredI 1.60 to 2.06 respectively).
  • Bupropion and NRT were equally efficacious (OR 0.99; 95% CredI 0.86 to 1.13).
  • For every 10 smokers who quit with placebo, 28 quit with varenicline (OR 2.88; 95% CredI 2.40 to 3.47).
  • Varenicline was more efficacious than monotherapy NRT (OR 1.57; 95% CredI 1.29 to 1.91), and bupropion (OR 1.59; 95% CredI 1.29 to 1.96).
  • Varenicline was superior to the nicotine patch (OR 1.51; 95% CredI 1.22 to 1.87), nicotine gum (OR 1.72; 95% CredI 1.38 to 2.13), and “other” NRT (inhaler, spray, tablets, lozenges; OR 1.42; 95% CredI 1.12 to 1.79), but was not more effective than combination NRT (OR 1.06; 95% CredI 0.75 to 1.48). Combination NRT was better than single formulations.
  • The four categories of NRT performed similarly against each other, apart from “other” NRT, which was marginally more effective than NRT gum (OR 1.21; 95% CredI 1.01 to 1.46).
  • For every 10 quitters with placebo, 39 quit with cytisine, a nicotine receptor partial agonist, (risk ratio [RR] 3.98; 95% CI 2.01 to 7.87), without significant adverse events or SAEs. Cytisine is not available in North America.
  • Across the 82 included and excluded bupropion trials, the risk of seizures was lower than that expected, at about 1:1500.
  • There were no excess of neuropsychiatric (RR 0.88; 95% CI 0.31 to 2.50) or cardiovascular events (RR 0.77; 95% CI 0.37 to 1.59) in the studies of bupropion.
  • In the 14 varenicline trials, there were no differences in adverse events between varenicline and placebo (RR 1.06; 95% CI 0.72 to 1.55).  Subgroup analyses detected no significant excess of neuropsychiatric events (RR 0.53; 95% CI 0.17 to 1.67), or of cardiac events (RR 1.26; 95% CI 0.62 to 2.56).
  • Nortriptyline increased the chances of quitting (RR 2.03; 95% CI 1.48 to 2.78).
  • Adding nortriptyline or bupropion to NRT did not improve outcomes.
  • Clonidine increased the chances of quitting (RR 1.63; 95% CI 1.22 to 2.18). However, the side effects negated any positive outcomes.
  • The results for other treatments were either inconclusive or failed to show any advantage over placebo.
  • Nicotine vaccines are not yet licensed for use as an aid to smoking cessation or relapse prevention.


  • NRT, bupropion, varenicline, nortriptyline, and cytisine improve the chances of quitting over placebo.
  • Combination NRT and varenicline are equally effective.
  • All treatments are generally safe, but further monitoring of varenicline is required.
  • No further study is required to establish the safety and efficacy of NRT.

Clinical Commentary
Tobacco use kills almost half a million Americans annually, making it the most deadly addictive disorder. However, it is very treatable as demonstrated in the review of reviews. For every two smokers a psychiatrist helps quit, one life will be saved from premature mortality. Medications roughly double the chances of success for every quit attempt. Of note, the findings are so robust for nicotine replacement therapy (NRT), additional studies to establish efficacy are not needed. What is needed is for clinicians to use these evidence-based therapies, and this review confirms the evidence that prescribers have safe and effective options for all patients. Tobacco use disorders are highly prevalent in patients with other addictions and mental illness. Although relapse is common, repeated or even extended treatment may be necessary. In patients with psychiatric comorbidity, the choice of medication might pose a concern. However, at least two medications have indications for other psychiatric conditions, namely bupropion and nortriptyline, that are also effective options in patients who smoke. Varenicline might be associated with idiosyncratic neuropsychiatric side effects so education and monitoring is required for emergent depression and suicidal or homicidal ideation. From a safety perspective, NRT does not provide the 4000-7000 chemicals present in smoke that are associated with harm. Combination NRT maybe more effective because a greater percent of baseline nicotine is replaced. The reviews included in this study also establish that concurrent smoking with NRT is safe and more effective than quitting abruptly. Although not specifically included in this review, there is evidence of safety for the use of varenicline in patients with stable schizophrenia. This review also did not address the role of nicotine to manage acute nicotine withdrawal in psychiatric patients admitted to hospitals where they are not allowed to smoke. In conclusion, psychiatrists can be reassured that they can treat patients who smoke with a combination of pharmacotherapy and counseling to reduce the premature mortality that frequently befalls these patients.


A Randomized, Double-Blind, Placebo-Controlled Trial of Venlafaxine Extended Release for Co-occurring Cannabis Dependence and Depressive Disorders

Levin FR, Mariani J, Brooks DJ, et al
Addiction. 2013;108(6):1084-1094.

 Is venlafaxine-extended release (VEN-XR) an effective treatment for cannabis dependence with concurrent depressive disorders?


  • 12-week randomized, double-blind, placebo-controlled trial of outpatients (n=103).
  • Adults between the ages of 18-60 years with DSM-IV-TR cannabis dependence with marijuana as their primary drug of abuse, and major depressive disorder or dysthymia.  
  • Hamilton Depression Rating Scale (HDRS) score at least 12 with depression for at least 3 months.
  • Excluded were individuals with psychotic disorders, bipolar disorders, and those who failed to respond to venlafaxine in the past or were allergic to it. Women who were pregnant or lactating were excluded as well.
  • Patients received up to 375 mg venlafaxine extended release (XR) on a fixed-flexible schedule or placebo and weekly individual cognitive-behavioral psychotherapy that primarily targeted marijuana use.
  • The trial included a 1-week placebo lead-in phase, a 3-week medication titration phase, and an 8-week medication maintenance phase.
  • Placebo responders were not randomized and excluded from the analyses.

The primary outcome measures were: (1) abstinence from marijuana defined as at least two consecutive urine-confirmed abstinent weeks and; (2) improvement in depressive symptoms based on the HRDS. Missing data was interpreted as being positive for use of marijuana.


  • 63% of venlafaxine- and 69% of placebo-treated patients had clinically significant mood improvement (50% decrease in HDRS score from baseline) (χ12 = 0.48, P=0.49).
  • Abstinence rates were significantly worse on VEN-XR (11.8%) compared to placebo (36.5%) (χ12 = 7.46, P<.01; odds ratio=4.51, 95% confidence interval: 1.53, 13.3).
  • For every 10 ng/ml increase in the THC urine level at baseline, there was a 1.5% decrease in the odds of abstinence (inter-rater reliability [IRR]=0.985, 95% CI: 0.974, 0.996).
  • Mood improvement was associated with reduction in marijuana use in the placebo group (F1,179 = 30.49, P<.01), but not the VEN-XR group (F1,186=0.02, P=.89).

Conclusions: Contrary to what the authors expected, for depressed, cannabis-dependent patients, venlafaxine XR does not appear to be effective at reducing depression and may lead to an increase in cannabis use. Also heavily dependent users had a worse prognosis in this study.

Clinical Commentary
Cannabis is the most widely used illicit substance worldwide, with significant consequences including an increased risk of psychosis in vulnerable individuals. Cannabis dependence doubles the odds of a depressive disorder in the general population and depression is very common in cannabis dependence treatment-seeking patients. The investigators chose to study venlafaxine because of its dual action on serotonin and noradrenergic systems. This was justified on the basis of previous RCTs where tricyclic antidepressants appeared to be  superior to selective serotonin reuptake inhibitors in reducing substance use in depressed patients. The patients recruited were a mix of clinical treatment seekers and those recruited via advertisement. They used the SCID to define the population and excluded those whose mood  symptoms could be attributed to cannabis withdrawal. Of the subjects, 62% completed all 12 weeks of the trial. This negative trial demonstrates a significant difference between placebo and venlafaxine in this population and it could be argued that the medication increases cannabis use. The lack of effect of the active medication could be due to the ceiling effect of response produced by cognitive-behavioral therapy (CBT). Most subjects had mild to moderate depression, which is very responsive to CBT without any additional benefit from medication. The increase in use of cannabis could be explained by the adrenergic effects of venlafaxine worsening cannabis withdrawal. However, this is speculative at best. For every one patient who would achieve abstinence with CBT and placebo, four would be harmed by the addition of venlafaxine XR. In conclusion, in depressed outpatients using cannabis, it might be prudent to engage the patient in CBT to stop or reduce marijuana use before initiating treatment for depression, and venlafaxine is best avoided. However, practical considerations such as patients perceptions of the antidepressant and anxiolytic effects of marijuana will require psychoeducation and motivational interviewing to engage in CBT.


Anxiety Disorders and Drug Dependence: Evidence on Sequence and Specificity Among Adults

Goodwin RD, Stein DJ.
Psychiatry Clin Neurosci. 2013;67(3):167-173.


  • To describe the association between specific anxiety disorders and substance dependence.
  • Control for demographic confounders, such as age and sex, and comorbidities such as alcohol dependence and depression.


  • Secondary data analysis of an old cross sectional survey (1990-1992; use of DSM-III-R diagnostic criteria) but still valid for the purposes of the stated objectives of this study.
  • The database analyzed was the National Comorbidity Survey (NCS), a nationally representative population sample of the US adult population 15-54 years of age.
  • There was an 82.4% response rate.
  • The following DSM-III-R diagnoses were included: major depression, generalized anxiety disorder (GAD), simple phobia, social phobia, panic attacks, panic disorder, post-traumatic stress disorder (PTSD), alcohol dependence, and substance (illicit drug) dependence.
  • The temporal sequence of onset of anxiety and substance dependence disorders was examined.
  • Logistic regression was used to measure the association between anxiety disorders and substance dependence (past year and lifetime) while controlling for other variables.


  • All anxiety disorders were associated with substance dependence even after controlling for alcohol dependence and depression.
  • The onset of substance dependence occurred prior to the onset of anxiety disorder in a majority of cases especially in those with panic attacks, agoraphobia, GAD, and PTSD
  • The anxiety disorder preceded substance dependence in more than 50% of social phobia cases, nearly 40% of PTSD cases, and in nearly 30% of GAD cases.
  • After adjusting for depression and demographic variables, only the link between a history of agoraphobia and substance dependence remained statistically significant.
  • A lifetime history (excluding a current history) of drug dependence was associated with a significantly increased likelihood of current panic attacks, agoraphobia, panic disorder, and social phobia even after adjusting for alcohol dependence and depression. The highest association was with panic disorder (OR 2.62; 95% CI 1.29 to 5.32)

Conclusions: The strongest association was between panic disorder and past substance dependence. The authors suggest this might be due to the effects of substances on the neurocircuitry involved in panic, such as the extended amygdala. Moreover, there was an association between anxiety disorders and substance dependence not accounted for by depression or alcohol dependence. The limitations include the cross sectional nature of the study; thus, no inferences can be drawn on causality. The specificity as to which substance caused the problem was not possible due to limited sample sizes in the cells.

Clinical Commentary
In this study, substance dependence predated the onset of anxiety disorders, suggesting that self-medication might not always be the reason patients use drugs. This study points to the possibility of a substance-induced anxiety disorder or some shared vulnerability to both. Substance use is a stigmatized behavior and may be underreported in traditional psychiatric and primary care settings whilst treating anxiety disorders. Anxiety disorders are common reasons to seek care, and the use of benzodiazepines to manage these symptoms in the short term might cause vulnerable individuals to develop or worsen substance dependence. Regardless, clinicians need to be able to prevent harm and yet offer treatment to those who present with impairing levels of anxiety. Therefore, it is imperative to screen for lifetime and current substance use prior to the initiation of benzodiazepines. Moreover, stimulant use disorders and marijuana use might also be the cause of anxiety and these substance-induced anxiety disorders need to be ruled out or treated with appropriate addiction counseling before the initiation of benzodiazepines. Screening tests can include obtaining a detailed history with third-party corroboration where feasible, and a urine toxicology screen. Moreover, newer screening tools such as the Global Assessment of Individual Need-Short Screener (GAIN-SS) are highly valid and reliable whilst being easy to administer in busy ambulatory settings. There is little evidence published on the management of co-occurring anxiety disorders in patients with substance use disorders. Therefore, to balance the need for symptom control and to prevent or worsen the course of a substance use disorder, it is important to use non-addictive alternatives such as SSRIs combined with CBT to treat the anxiety disorder. Concurrent treatment of the addiction is also warranted. If benzodiazepines are prescribed, those with lower abuse liability such as clonazepam should be used. Short duration of prescriptions with pill counts and monitoring of urine toxicology might optimize management and reduce the risk of iatrogenic addiction. A pragmatic goal of treatment in patients with concurrent addiction and anxiety disorders might be improvement in quality of life and fulfillment of role responsibilities rather than complete abstinence from benzodiazepines. Further research is required to determine the optimal management of these patients.


Randomized Trial of Long-Acting Sustained-Release Naltrexone Implant vs Oral Naltrexone or Placebo for Preventing Relapse to Opioid Dependence

Krupitsky E, Zvartau E, Blokhina E, et al
Arch Gen Psychiatry. 2012;69(9):973-981.



  • To compare outcomes of naltrexone implants, oral naltrexone hydrochloride, and non-medication treatment for opioid dependence.
  • Six-month, double-blind, double-dummy, randomized trial in St. Petersburg, Russia.
  • Three hundred and six recently detoxified opioid-dependent patients between the ages  of 18 to 40 years who met DSM-IV criteria for opioid dependence.
  • Subjects had to be opioid dependent with physiological features for at least 1 year, diagnosed clinically and using the Composite International Diagnostic Interview (CIDI). 
  • To be included in the study subjects were confirmed to: be abstinent from heroin and other substances for the past week or more; have negative results of urine toxicology and alcohol breath tests; not be taking any psychotropic medication; and be able to provide informed consent.
  • They also needed to have stable housing and a family member willing to supervise therapy at home. Subjects with psychotic illness and bipolar disorder were excluded.
  • All enrolled subjects received biweekly counseling and were randomized to one of the following 3 treatments for 24 weeks after a naloxone challenge test to ensure adequate detoxification:

    (1) Naltrexone implant 1000 mg and oral placebo (NI+OP group; 102 patients)

    (2) Placebo implant and 50-mg oral naltrexone HCL  (PI+ON group; 102  patients)

    (3) Placebo implant and oral placebo (PI+OP group; 102 patients).

  • The primary outcome measure was the percentage of patients retained in treatment without relapse confirmed by urine toxicology.
  • The implants were aseptically inserted subcutaneously by a surgeon using a syringe and a small incision requiring one or two sutures and replaced every 60 to 90 days during the trial.


  • Most subjects were male and were about 28 years of age.
  • They had an average of 8 years of opioid dependence and between 3 to 6 previous treatment attempts. 
  • 47% were HIV positive ; 95% were HCV positive,
  • 26% were using marijuana and 11% were using amphetamines at baseline.  
  • NI+OP group (52.9%) remained in treatment without relapse compared with PI+ON group (15.7%) (survival analysis, log-rank test, P<.001) and PI+OP group (10.8%) (P<.001).
  • The PI+ON vs PI+OP comparison showed a non-significant trend favoring the PI+ON group (P=.07).
  • Counting missing test results as positive, the proportion of urine screening tests yielding negative results for opiates was 63.6% (95% CI, 60%-66%) for the NI+OP group; 42.7% (40%-45%) for the PI+ON group; and 34.1% (32%-37%) for the PI+OP group (P<.001, Fisher’s exact test, compared with the NI+OP group).
  • Wound infection rate was 4.9% in the NI+OP group, 1.1% in the PI+ON group, 0.7% in the PI+OP group (P=.02). All events were in the first 2 weeks after implantation and resolved with antibiotic therapy.
  • Four local-site reactions (redness and swelling) occurred in the second month after implantation in the NI+OP group (P=.12), and all resolved with anti-allergy medication treatment. There was no increase in overdose deaths once naltrexone was discontinued.

In regions where there is no access to opioid agonist therapy, injectable naltrexone was found to be superior to oral naltrexone in retaining patients in treatment for up to 6 months. About half the patients responded to treatment and half of these relapsed after treatment ends, indicating the need for chronic treatment.

Clinical Commentary
The standard of care for opioid dependence in North America is agonist therapy with methadone or buprenorphine. However, there are patients for whom these medications are not an option either due to personal choice or availability of treatment. Injectable naltrexone, which is available in the US, might be an alternative for these patients and negates the need for daily observed ingestion of the oral formulation. Although the oral formulation performed better than placebo, these subjects had engaged family members who supervised their medication compliance. There were no reports of depression, anxiety, or anhedonia, suggesting the implant was well tolerated. The limitations of the implant are the invasive nature of the procedure and failure in 13% of subjects. Cravings were also reduced in those who remained abstinent. Given the high prevalence of HIV in this population, any treatment that can reduce injection potentially reduces the spread of the disease to others. Therefore, this option deserves serious consideration for the appropriate opioid-dependent patient who does not or cannot tolerate an opioid agonist. Weighing the risks and benefits, including the lack of efficacy of opioid agonists for acute pain should the patient require pain management, will help the patient and provider decide if this approach is a viable option. It should be noted that the implant is not available in the US but a sustained-release injectable formulation is available and is administered every 30 days. Moreover, naltrexone injection is also approved for alcohol dependence and might be well suited for those with dual opioid and alcohol dependence. In summary, naltrexone can be effective if the problem of non-adherence can be overcome by injecting or implanting a sustained-release formulation of the medication.



Predictors of the 2‐Year Recurrence and Persistence of Alcohol Dependence 

Boschloo L, Vogelzangs N, van den Brink W, et al
Addiction. 2012;107(9):1639-1640.


To identify independent risk factors of the recurrence of alcohol dependence (AD) in people with a remitted disorder at baseline and persistence of AD in people with a current disorder at baseline.


  • Secondary analysis of data from a prospective cohort study with assessments at baseline and 2-year follow-up.
  • Data were derived from the Netherlands Study of Depression and Anxiety (NESDA), an ongoing cohort study examining the long-term course and consequences of depressive and anxiety disorders in adults (18-65 years).
  • Patients with bipolar disorder and psychosis were excluded. 
  • All participants were seen in person and assessed using the Composite International Diagnostic Interview (CIDI) to arrive at DSM-IV diagnoses.
  • Over 80% returned for a follow-up and were re -interviewed at 2 years.
  • Subjects were recruited from primary care, specialty care, and the community, representing a mix of treatment and non-treatment seeking individuals.
  • The sample consisted of 253 patients with remitted AD (n=253) and 135 patients with current AD.
  • Recurrence and persistence of AD during 2-year follow-up were established using the CIDI interview based on DSM-IV.
  • The authors described the recurrence of AD in people with remitted AD at baseline (i.e. not meeting any AD criteria in the year before baseline; median time since remission: 4 years) based on the presence of a CIDI diagnosis of AD at any time during the 2-year follow-up. 
  • Persistence of AD in people with current (i.e. past-year) AD at baseline was defined as the presence of a past-year CIDI-diagnosis of AD at the 2-year follow-up.
  • Both outcomes indicate the naturalistic course of AD, as only 4.8% of people with life-time AD participated in alcohol treatment (i.e. at an addiction treatment center or Alcoholics Anonymous) in the 6 months before baseline.
  • Logistic regression analyses were performed to explore the role of potential risk factors (i.e. baseline severity of alcohol problems, measures for depression and anxiety, socio-demographics, vulnerability factors, and addiction-related factors) as independent predictors of a negative course.


  • Overall recurrence and persistence rates of AD were 14.6 and 40.7%, respectively, and were highly conditional on the severity of alcohol problems (adjusted odds ratio [OR] per standard deviation [SD] increase: OR=3.64, 95% confidence interval [CI]: 2.21-6.01 and OR=2.12, 95% CI: 1.32-3.40, respectively).
  • Regardless of setting from where these subjects were recruited, there was a dose-response relationship between the severity of alcohol problems and recurrence. Less than 5% of the subjects had attended formal or informal addiction treatment.
  • Severity of depressive/anxiety symptoms but not disorders was an additional independent predictor of the recurrence of AD (recurrence rate: 17.4% versus 7.2%; OR=2.69, 95% CI: 1.00-7.23), whereas male gender and high education were significant independent risk factors of the persistence of AD.

Conclusions: Both recurrence and persistence of alcohol dependence are highly dependent on severity of baseline alcohol problems, whereas severity of depressive/anxiety symptoms predicts only the recurrence of alcohol dependence. Both measures may be useful in identifying people at an increased risk of a negative course and who could be targeted by prevention strategies. 

Clinical Commentary
Only 2 to 6% of treated patients with alcohol dependence remit annually. The strength of this cohort study is that participants were heterogeneous and selected from community settings, primary care settings, and mental health settings with follow-up rates of  >80%. The findings suggest that therapeutic nihilism is not warranted because the majority of subjects remit within 2 years and it is not always a chronic and relapsing disorder. The severity of alcohol problems and depressive/anxiety symptoms may be useful in identifying people at an increased risk of developing a new episode of AD. Assessment instruments such as the AUDIT , IDS, and BAI may be used to screen for alcohol problems, depressive symptoms, or anxiety symptoms, respectively. Given that the recurrence rate was only 2% in the quintile of people with the mildest alcohol problems versus 43% in the quintile of people with the most severe alcohol problems, these findings might be useful to personalize advice regarding additional treatment. The observation might be explained by either a shared diathesis for both depression/anxiety symptoms and alcohol dependence or “self-medication,” where the person is trying to mitigate negative mood states by drinking alcohol. Alcohol use disorders present a particular challenge for psychiatrists. Although alcohol use is associated with all psychiatric disorders, the causal link between the two is less well established. Often the clinician is not sure if the patient is self-medicating symptoms of anxiety or depression or if the depression or anxiety is due to alcohol intake. Although the temporal association between use and affective symptoms might provide a clue, the ideal intervention would be to examine the effects of alcohol withdrawal treatment on affective symptoms and treat residual symptoms of depression or anxiety with SSRIs and CBT.  Most alcohol-induced mood disorders improve dramatically within 1-2 weeks of abstinence. In addition, it is important to assess the immediacy of risk to the patient since most completed suicides occur during intoxication. Such patients need admission, detoxification, relapse-prevention medication such as naltrexone or acamprosate, the appropriate SSRI, and CBT and addiction counseling. Ideally, this should be provided concurrently wherever possible or at least collaboratively by mental health and addiction treatment providers. Therapy should initially focus on maintaining sobriety and resolving the effects of past trauma where appropriate, and management of depression and or anxiety with medications with low abuse potential. Monitoring the effects of SSRIs on drinking is also warranted given that some studies have found increased rates of drinking. Long-term benzodiazepine prescriptions should be avoided given the greater risk of dependence in patients with AD. 

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