Helen M. Pettinati, PhD

After reading this article, you will be familiar with:


• Identifying the typical daily doses of FDA-approved medications for the treatment of alcohol dependence.
• Describing the significance of medication adherence on treatment outcomes in patients with alcohol dependence.
• Detailng strategies for recognizing, probing and improving medication nonadherence in patients who are prescribed a medication for a chronic illness like alcohol dependence.
• Describing novel options that might enhance medication adherence.

Alcoholism is a chronic and serious disorder with often devastating consequences. One out of three families in the United States is negatively impacted by a family member's excessive drinking and painful drinking-related problems.

 Sadly, alcohol disorders are largely undertreated. The National Institute of Alcohol Abuse and Alcoholism (NIAAA) estimates that of the approximately 7.9 million people in the United States who suffer from alcohol dependence, only approximately 2.2 million people seek treatment.

For decades, the standard in the United States for treating alcohol dependence, following detoxification, has been addiction-specialty counseling and regular attendance at mutual support groups like Alcoholics Anonymous. 

(Only a percentage of patients with alcohol dependence seek medical treatment for their disorder.

 This is highlighted by the fact that pharmacologic agents for the treatment of alcohol dependence have been available for over 10 years. However, historically, only a small fraction of patients are ever prescribed a pharmacologic agent-Ed.)

 Successful treatment recovery rates, while notable, still leave a large proportion of people who continue to drink heavily even in treatment or who rapidly relapse following treatment. Analysis of data from the NIAAA 2001-2002 U.S. National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) found that among alcohol-dependent patients who have received treatment, 54.5% relapsed soon after completing treatment. 

 Initiating pharmacotherapy with counseling, in a number of cases, has been shown to be a valuable tool toward reducing relapse rates and increasing abstinence in alcohol-dependent patients. The NIAAA advises clinicians to consider initiating medications that have been approved by the U.S. Food and Drug Administration in patients who are still drinking or are abstinent but continue to experience slips or intense cravings for alcohol.

In addition, however, it is recognized that the success of pharmacotherapy is largely dependent on an individual's adherence to taking the medication as prescribed. Daily pill-taking over an extended period of time can often be problematic, not just for patients with addictions, but for anyone suffering from a chronic disorder. Higher levels of medication nonadherence have been associated with patients suffering from psychiatric disorders, including addictive disorders.

 This article briefly describes the FDA-approved medications for the treatment of alcohol dependence and discusses strategies to address treatment challenges like medication nonadherence.


In the last decade, as more knowledge has been discovered about the neurobiology of addiction and the effects of alcohol on the brain, clinical studies have been completed on initiating medications with counseling (types of counseling have ranged from medical management and advice to addiction-specialty therapies). These studies have been systematically conducted for the purpose of evaluating the advantage of pharmacotherapy in improving early and long-term outcomes. Essentially, medications are evaluated as to whether or not they provide an incremental advantage to counseling, or whether or not they can be paired with a relatively modest type of medical management counseling as an alternative to more intensive and specialized addiction therapy. To date, the FDA has approved four medications for the treatment of alcohol dependence; they are listed in the 

Disulfiram's (Antabuse) mechanism of action is different from the other subsequent medications that have been approved by the FDA for alcoholism. Disulfiram blocks aldehyde dehydrogenase, an enzyme needed to convert acetaldehyde to acetate for the body to fully metabolize alcohol.

 When someone taking disulfiram consumes alcohol, its enzyme-blocking action creates disagreeable physical symptoms, primarily nausea and vomiting. The usual daily dose of disulfiram prescribed today is 250 mg/day, but the unpleasant symptoms are dose dependent. That is, the aversive reaction escalates with a higher daily dose of disulfiram and/or with greater quantities of alcohol. Severe ethanol-disulfiram reactions, even death, have been reported, but were almost always associated with much higher daily doses (eg, 1000 mg/day to 3000 mg/day).

While usually the unpleasant feelings will cause most people to stop drinking, disulfiram prescribers primarily believe that it is the psychological threat of discomfort that deters a disulfiramtreated patient from drinking any alcohol, which, in turn, removes the patient's chances of actually experiencing aversive symptoms.

 When patients are highly motivated or are supervised in their taking of disulfiram, it has been reported that drinking is avoided and thus aversive symptoms are not experienced. Treatment regimens including incentive-driven interventions or disulfiram supervision by physicians have shown beneficial treatment outcomes, such as decreases in drinking and increases in the rate of abstinence.

 However, in many primarily unsupervised situations, patients essentially have not accepted this medication, and, rather than discontinuing their alcohol intake, they stop taking disulfiram. Fuller and colleagues

 reported an astoundingly high nonadherence rate of 80% in a large multisite study of alcohol-dependent patients who were asked to take 250 mg/day of disulfiram or placebo. See Suh et al

Naltrexone (ReVia), an opioid receptor antagonist that originally had been approved for the treatment of opiate addiction in 1984, was the second medication to be approved by the FDA for the treatment of alcohol dependence in 1994. It utilizes a novel mechanism of action to reduce alcohol use. That is, naltrexone is thought to decrease drinking in alcohol-dependent individuals by blocking the release of alcohol-inducing endorphins via neural reward pathways. This action is thought to reduce the high or reinforcement that alcohol-dependent people report feeling when they drink alcohol. Naltrexone has also been shown to reduce craving for alcohol, which for motivated patients can promote long-term abstinence. Finally, naltrexone has proven to be a relatively safe medication for people suffering from alcoholism, with the most frequent side effect reported being nausea, which generally dissipates by the end of the second or third week of treatment. Also, when naltrexone-adherent patients with initial elevated liver enzyme levels reduce their alcohol intake over the treatment course, they show significant reductions in pre-treatment liver enzyme levels.

 The reduction in liver enzymes widely reported in alcohol-treatment populations is in direct contrast to naltrexone's black box warning of potential hepatoxicity, which actually was derived from a few very early studies using a 300 mg/day dose of naltrexone to treat obesity (not an alcohol-disordered population).

The usual daily dose of naltrexone prescribed today for alcohol treatment ranges from 50 mg/day to 100 mg/day. Naltrexone's efficacy in reducing heavy drinking (heavy = ≥5 drinks a day for men; ≥4 for women) and promoting abstinence has been demonstrated in numerous randomized, placebocontrolled clinical trials worldwide.

 Nonetheless, naltrexone has not been embraced by the clinical community since its original approval in 1994, due in part to problems with getting many patients to regularly take their daily pills for any length of time. Relapse rates are high in patients who are nonadherent to taking naltrexone as prescribed-a situation that usually appears to clinicians as patients unresponsive to naltrexone.

Acamprosate (Campral), like naltrexone, affects neural reward pathways to reduce craving for alcohol and alcohol use, although this medication works through a different neurobiological remediation, i.e., acamprosate targets glutamatergic pathways. Acamprosate is thought to promote abstinence by first reducing physical and psychological discomfort often experienced during alcohol withdrawal, such as sweating, anxiety and sleep disturbances. Secondly, it is thought that acamprosate may have abstinent-sustaining properties. A number of randomized, controlled clinical trials conducted in Europe provide support for acamprosate's efficacy in maintaining abstinence.

However, in a recently published U.S. randomized, placebo-controlled clinical trial of 1998 mg/day acamprosate for alcohol dependence in 601 patients, acamprosate was associated with higher rates of abstinence only in patients whose initial goal was to stop drinking completely.

 This study suggested that acamprosate might best target alcohol-dependent patients with greater motivation for abstinence. The usual daily dose of acamprosate prescribed today for alcohol treatment is 1998 mg/day (essentially two capsules of 333 mg tid).

Related to both naltrexone and acamprosate, the most recently published NIAAA-supported study, the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) study, is the largest investigation of the efficacy of pharmacotherapy in treating alcohol dependence that has been published to date.

 This study investigated the combination of naltrexone and acamprosate, and each alone, in treating 1,383 alcohol-dependent patients at 11 sites across the country. The findings of this large, well-controlled trial revealed that although all patients enrolled in this treatment study showed a considerable decrease in drinking, those who received naltrexone with a very basic type of medical counseling (called medical management [MM]

) reported the highest number of abstinent days while in treatment (approximately 80.6%).

Naltrexone with MM is a pharmacopsychosocial treatment combination that can be easily administered by primary health care providers, potentially reaching more patients than can be serviced in specialty care settings. Contrary to the original hypothesis, the results from the COMBINE study did not support better efficacy of a naltrexone and acamprosate combination, although this combination was safe and relatively well tolerated.

With all three of these medications, there are a formidable number of patients in both clinical trials and private practices who skip medication doses and generally have difficulties taking pills on a daily basis for any length of time. These patients traditionally have poor outcomes and appear as medication nonresponders, when, in fact, they may not have been adequately exposed to the active medication that would allow clinicians to accurately assess treatment response. Most physicians feel their patients are good about taking prescribed medication(s), but these same clinicians also say that they cannot readily prove this assumption. All attempts to gather adherence data in research trials have documented that the prevalence of medication nonadherence in alcoholdependent patients is less than optimal and typically higher than anticipated.

If a patient's possibilities for being medication nonadherent can be minimized or bypassed, then patient nonadherence as a barrier to treatment response would be eliminated. This was the rationale for developing the fourth FDA-approved medication: a long-acting extendedrelease formulation (once-monthly) injection of naltrexone (Vivitrol). Each injection delivers 380 mg of naltrexone that remains in the body at therapeutic plasma concentrations for approximately a month's duration. This delivery system removes the patient burden of daily decision making. In addition, this type of delivery system for treating an alcohol disorder allows clinicians to be certain that their patients are taking and, hopefully, benefiting from treatment every day for 30 days.

Data have been reported that treatment response to injectable naltrexone is observable after only one injection, i.e., in the first month of treatment, according to a recent study.

 Thus, given that medication adherence is a non-issue in the month following a naltrexone injection, this type of innovative delivery system provides a simple and direct way for the clinician to evaluate whether or not the patient is responding to treatment.

Evidence for the efficacy of injectable naltrexone in reducing heavy drinking in the majority of patients, and in also maintaining abstinence in a number of patients, comes from a large, national, multisite study of two doses (380 mg or 190 mg) or placebo in 627 alcoholdependent participants who were given six injections over a six-month treatment period.

 Patients treated with the 380- mg dose monthly (the FDA-approved dose) demonstrated a greater reduction in heavy drinking than placebo-treated patients who had received counseling and a dummy injection.


As we acquire promising pharmacotherapies that can be initiated with counseling for treating alcohol dependence, there are many challenges and barriers to fully introducing medication into mainstream clinical practice in the medical community. As mentioned above, the foremost challenge is a patient's nonadherence to prescribed treatment. All physicians understand that their patient's adherence to their medication(s) and attendance at their counseling sessions are critical for achieving successful outcomes. However, in practice, it has been demonstrated time after time how difficult it can be to ensure patient adherence to treatment, especially in chronic illnesses. For example, studies of insulin adherence in diabetes treatment report poor medication adherence in nearly 40% of patients, and the rate of medication nonadherence is as high as 50% in patients with hypertension.

Adherence to treatment in alcoholdependent patients is no different from the rates reported above. Nonadherence rates, which vary by the type of medication and by the adherence definition, have ranged from 20% to 60% for daily naltrexone and as high as 80% for disulfiram.

 A recent meta-analysis found an average medication nonadherence rate of approximately 47% in acamprosate studies, which ranged from three to 24 months in duration.


Interaction of Naltrexone and Treatment Compliance on the Rate of Relapse in the Combined Study Group of the VAMC and the TRC Studies (N = 196)

provides an illustration of relapse rates in a study group from the University of Pennsylvania that combined two double-blind, placebocontrolled clinical trials of 50 mg/day of naltrexone for 12 weeks to treat alcoholdependent outpatients.

 In the Figure, a patient who relapsed was defined as one who drank ≥5 drinks on one occasion. A patient who was medication adherent was defined as one who attended at least 80% of counseling sessions and took medications as prescribed. The data in the Figure illustrate the critical mediating role of medication adherence in evaluating treatment outcomes in daily pill-takers receiving medication with counseling for their alcohol dependence. That is, the proportion of patients who relapsed was relatively high and comparable among naltrexone-treated (42.9% relapsed) and placebo-treated (40% relapsed) patient groups in the medication nonadherent patients, as well as in placebo-treated patients who were medication adherent (38.6% relapsed). However, the naltrexonetreated, medication-adherent patient group had a dramatically smaller relapse rate of only 10%.

Thus, while the problem of medication nonadherence in alcohol-dependent patients is comparable to other disorders, it remains a formidable one for this patient population. This problem could cause the incorrect interpretation that a medication does not work, when in fact it was not taken as prescribed. The challenge is then how do we best identify, monitor and change medication nonadherence?

Clinicians need to inquire at each patient visit about patient pilltaking: Are there any problems or not? However, even when clinicians inquire at each visit about pill-taking problems, patients' responses may not be uniformly accurate. Identification of medication nonadherence may be the most difficult task the clinician faces, as most physicians want to trust that their patients are taking their medications as prescribed; and most patients want to tell their physicians that they are taking their medications according to their doctor's prescription. However, all published research data on this issue suggest that, overall, a number of patients with chronic disorders fail to take their medication as prescribed, with the most common occurrence being that patients just stop taking their medication(s).

Nonadherence in a patient is probably best identified by the clinician who proactively discusses nonadherence with the patient as a collaborator in trying to achieve 100% medication adherence. In addition, before nonadherence has a chance to happen, pitfalls associated with nonadherence and helpful strategies that produce good adherence can be discussed with the patient. Importantly, it is wise to establish a system for routinely monitoring medication adherence at each visit. This can be done using simple techniques such as asking patients to bring their pill bottles or blister cards to each visit, and/or asking them to keep a monthly calendar, indicating on each day the time that they took their medicine(s). Prevention and improvement of medication nonadherence can occur for some patients simply by the clinician routinely expressing interest and instructing patients on ways to selfmonitor their pill-taking as part of their treatment.

A selection of tools has been created to help monitor and validate patient pilltaking. 

 Of course, all of these tools vary in their cost, dependability and clinical function. The more frequently used tools include medication blister cards, where each dose per day is clearly marked and there is a clear plastic encasing per dose that indicates at a glance whether or not the dose was taken out of the card; Medication Event Monitoring System (MEMS) Caps, where each bottle cap encases a computer chip that records the day and time of each bottle cap opening, a sort of proxy for a patient taking their pills; B-vitamin riboflavin markers; and medication blood plasma level monitoring. These tools can be used in conjunction with routine clinician-patient discussions that target establishing true adherence rates. In addition, the clinician talking to the patient can resolve discrepancies between patient reports and any monitoring device. While none of these tools should be considered a gold standard, they all have their unique assets and liabilities and many of these can be helpful toward improving patient adherence. Medication blister cards possibly have the most number of desirable features and also have clinical utility as they are relatively inexpensive, easy for patients to use and transport, and appear to assist both the patient who wants to take the pills as prescribed and the practitioner who wants to monitor adherence.

At the start of pharmacotherapy, clinicians should proactively probe patients for typical medicationnonadherence risk factors. Once a pattern of medication nonadherence is identified, establishing more exact reasons for an individual patient's medication nonadherence should be probed so that strategies to improve medication adherence can be tailored to the individual patient and incorporated at each patient visit. As a word of caution, it is especially important to probe for reasons beyond the most socially acceptable and frequently stated reason of "I forgot." For example, if the patient truly forgot to take the pills because, say, they are not used to taking pills regularly, then strategies could be suggested like placing sticky notes on a bathroom mirror, patient's toothbrush or orange juice carton. However, if the problem is not simply forgetting, a clinician's attempt to organize the patient with systematic reminders, as just described, may not be useful.

There are many reasons for medication nonadherence, and most reasons are not easy for patients to admit. Some patients also may have difficulties identifying and/or articulating the actual reason(s) for not following the prescribed medication regimen. However, a more in depth discussion can be revealing. For example, it has been reported that patients who have better social support or believe that the medication will be effective tend to show better adherence.

 Worse adherence is predicted in patients who report side effects from treatment (particularly nausea or fatigue) or who abuse other drugs. In addition, adherence may be adversely affected by the treatment setting (eg, a long wait time for appointments or staff or others at the facility who create an uncomfortable atmosphere or pessimistic outlook for recovery).

In summary, most patients' problems with medication adherence, if identified and probed, may be correctable with clinician diligence and advice. Clinician strategies for correcting medication nonadherence in a patient may be as simple as talking with the patient about things to do to overcome individual challenges. On the other hand, structured psychosocial interventions may aid in alleviating medication nonadherence beyond what can be achieved via a continued monitored basis or clinicianpatient dialogue.

 minimally intensive intervention that can be employed by private, office-based medical practitioners. The goal of MM is to support the use of pharmacotherapy while providing individualized advice to patients to help them stop drinking. In addition, the MM clinician creates a dialogue with the patient meant to specifically increase medication adherence across treatment. All of this is done in a supportive atmosphere that conveys optimism for recovery.

The initial MM visit requires almost an hour to complete and involves reviewing results of the initial evaluation with emphasis on drinking-related problems and need for treatment. It includes patient education on alcohol dependence and the rationale for treating this disorder with medication. The clinician also gives the patient instructions on dosing and side-effect management, constructs a medication adherence plan for the patient to follow, and provides referral to local support groups. The plan for follow-up MM visits is also reviewed at the initial visit. Follow-up visits (lasting 15 to 30 minutes) involve a brief check of the patient's medical status, as well as the patient status regarding drinking and pill-taking. Advice given at followups is tailored to the current status of the patient.


Alcohol dependence is a treatable disease, but the proportion of affected individuals who come to treatment is less than 30%. The low proportion of patients seeking treatment may be due in part to the fact that successful treatment recovery rates, while notable, still leave a large number of treated people who rapidly relapse. In the last decade, advanced knowledge of the neurobiology of addiction plus the FDA approval of new medications for treating alcohol dependence provide some optimism that pharmacotherapy may be a valuable part of treatment for decreasing heavy drinking and maintaining abstinence and sobriety in many cases. Nonetheless, there are still challenges, with the primary barrier to successful treatment response being that a formidable number of patients tend to skip doses or stop their medication altogether for a variety of reasons. This, of course, ultimately compromises chances for a good treatment response. The most recent FDA-approved pharmacotherapy, however, is a long-acting, once-a-month injection that relieves patients of the daily decision to take their medication, as well as for the need for clinician monitoring of patients' pill adherence. This type of delivery system also aids the physician in evaluating the patient's response to treatment, i.e., in the initial clinical trial, positive changes in reducing alcohol use and craving were seen as early as the first injection in most patients.

An accumulation of clinical trial results have now indicated that following detoxification for alcohol dependence, initiating pharmacotherapy (FDAapproved for alcohol dependence) with counseling in the rehabilitation/recovery phase to treat alcohol dependence is very important to consider if we wish to provide recovery to more of our patients and, hopefully, attract more alcoholdependent patients to seek treatment. As new advances that change standard treatment unfold, it is essential to be attuned and prepared for the challenges that pharmacotherapy brings to our patients as we move forward with innovative addiction treatment in the 21st century.

[Editor's Note: This article is an update of a CME activity originally published in 

). The exam period has expired. However, the authors have approved the material for publishing in 2012.]

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Articles

Advances and Challenges in Treating Alcohol Dependence With Pharmacotherapy

Patients who are seen in clinical practice commonly have multiple problems, yet efficacy data often reflect treatment of a single illness. Thus, it is useful to know how standard treatment approaches need to be modified for comorbid disorders. This article briefly describes prevalence, assessment, clinical features, and treatment of comorbid major depression and alcohol dependence.

Evidence from clinical treatment trials and changes made in the delivery of treatment from inpatient to outpatient settings bring into question the long-held view that patients with co-occurring depression and alcohol dependence must achieve abstinence from alcohol before treatment of depression can begin. Historically, there were good reasons for adhering to this view.

There are real concerns about medication interactions with alcohol in patients who were still drinking. Also, depressive symptoms can be brought on by excessive alcohol use, which makes it difficult to separate a substance-induced depression from an independent disorder of clinical depression. Traditionally, placing patients in 28-day inpatient settings, which helped patients abstain from alcohol, easily permitted an independent depressive disorder to be identified and treated. This practice is much less of an option in today’s US health care environment, and this has challenged us to rethink our clinical management of these patients.

Both major depression and alcohol dependence carry a significant risk for the development of the other. Severity in one disorder is associated with severity in the other.

 Moreover, alcohol dependence prolongs the course of depression, and persistent depression during abstinence from alcohol is a risk factor for relapse to heavy drinking.

 Thus, logic dictates that both disorders be identified and managed concurrently and aggressively. Integrated psychosocial outpatient treatment programs and the ability to treat alcohol and depression simultaneously have reinforced the need to revisit the traditional management of comorbid major depression and alcohol dependence more formally.

Recent estimates of the co-occurrence of these disorders in the general population are derived from the 

National Epidemiologic Survey on Alcohol and Related Conditions

, a large-scale, nationally representative survey using DSM-IV diagnostic criteria.

 Data were collected on a sample of 43,093 adults (18 years and older) who were interviewed between 2001 and 2002 to determine lifetime and current (past 12 months) DSM-IV diagnoses. For those with a diagnosis of current alcohol dependence, the prevalence rate for an independent major depressive disorder was 20.5%. These alcohol-dependent individuals were 3.7 times more likely to have major depression than those without alcohol dependence. For those individuals with a current alcohol use disorder (abuse or dependence) who were seeking treatment, 40.7% had at least 1 current independent mood disorder.

What is already known about treating alcohol dependence and comorbid depression?


Prevalence rates of co-occurring psychiatric and substance dependence disorders are formidable, and numerous reports describe individuals with both major depression and alcohol dependence as clinically more severely ill and more difficult to keep well than those who either are depressed or are alcohol-dependent. Over the past quarter of a century, results from well-controlled trials have demonstrated that antidepressant medications can reduce depressive symptoms in some persons who suffer from both major depression and alcohol dependence. However, the majority of these trials demonstrated that these medications had virtually no effect on reducing excessive drinking.

What new information does this article add?


This article reports on a recently published controlled trial that indicated that the combination of a medication to treat alcohol dependence (eg, naltrexone) and an antidepressant (eg, sertraline) might be the optimal course of treatment for patients with co-occurring depression and alcohol dependence.

What are the implications for psychiatric practice?


Combining a medication to treat alcohol dependence (eg, naltrexone) with an antidepressant (eg, sertraline) with some basic psychosocial support and advice for both disorders can provide an aggressive approach to treating patients with co-occurring depression and alcohol dependence. 

Identifying the cause of the depression in individuals with alcohol dependence has been thought to be important for determining the course of the disorder and the optimal treatment approach. For example, if the depressive symptoms are clearly related to 

, then an antidepressant may not have any therapeutic impact beyond what abstinence would achieve. In some cases, depressive symptoms will spontaneously remit with abstinence from alcohol. In such cases, antidepressant pharmacotherapy may be an unnecessary cost and may be burdensome to the patient. However, it is often difficult to distinguish a substance-induced depression from major depression in the presence of alcohol dependence because the clinical symptoms of a substance-induced depression can appear identical to those seen in major depression.

Prolonged abstinence from alcohol can be of great value in making a distinction. Indeed, Brown and Schuckit

 demonstrated a significant drop in depressive symptoms for those with primary alcohol dependence who completed a 4-week inpatient program. Nonetheless, many patients have difficulty in abstaining from alcohol during outpatient treatment and eventually may drop out of treatment because of continued drinking and/or deepening depression. To this point, Greenfield and colleagues

 demonstrated that untreated depression-whether primary or secondary-predicted worse drinking outcomes. Finally, while depression may precede or be precipitated by alcohol dependence, implying causation, there may be common risk factors for depression and for alcohol dependence. These include stressful events, psychological trauma, and genetic vulnerability that lead to co-occurring expression, without one disorder causing the other.

DSM-IV-TR distinguishes between major and substance-induced depressive episodes and related disorders. For a depressive episode to be considered substance-induced, the depressed mood and/or diminished interest and pleasure must occur during (or within 1 month of) periods of intoxication or withdrawal and symptoms cannot be better explained by an independent mood disorder. A careful history can help make the differential diagnosis.

The following scenarios strongly suggest an independent mood disorder (eg, major depression):

• The mood disturbance persists following prolonged abstinence (at least 1 month)

• Depressive symptoms occur in excess of those typically seen considering the quantity and frequency of alcohol consumption

 that carefully assessed DSM-IV criteria have shown that the prevalence of primary, independent depressive disorders (eg, major depression) are more common than substance-induced disorders in individuals with alcohol use disorders.

 Furthermore, women who are alcohol-dependent and depressed are more likely to have an independent mood disorder than a substance-induced disorder.

Today in the United States, alcohol dependence is almost always treated in an outpatient setting, where continued drinking and poor treatment attendance can be major obstacles to observing periods of abstinence. Clinicians are typically expected to decide how to treat depression in patients who are actively drinking, without benefit of observing that patient during an extended period of abstinence. Interview techniques that have been developed to help clinicians determine the origin of a patient’s depression have demonstrated reliability and validity in academic settings.

 However, little is known of the utility of these techniques in general practice.

Further studies are needed to elucidate a way to make accurate diagnoses of major depressive disorder and substance-induced depression in the presence of current alcohol dependence. It would be beneficial to know precisely under what conditions antidepressant therapy would yield optimal outcomes for treating comorbid depression and alcohol dependence.

Psychosocial treatment for major depression and alcohol dependence

• Sequential: treating the primary disorder initially, followed by treating the other disorder

• Parallel: treating both disorders at the same time but in different settings

• Integrated: simultaneously treating both disorders

Although research and experience have been limited, integrated approaches have been shown to be superior to other approaches.

 identified only 5 randomized clinical trials that focused on the treatment of comorbid substance abuse and depressive disorders: those trials showed that integrated treatment programs had statistically superior alcohol and drug outcomes compared with addiction treatment only. Measures of depression outcomes and treatment retention also appeared to favor integrated treatment programs, although these results did not reach statistical significance.?

Research has been sparse on integrated psychosocial approaches and even less information is available on how to use pharmacotherapy for co-occurring major depression and alcohol dependence. Moreover, no evidence-based guide exists on how to integrate psychosocial and pharmacotherapy approaches in depressed alcohol-dependent patients. Major depression is generally responsive to pharmacological treatment, and antidepressants can be lifesaving for individuals at risk for suicide. However, studies that supported FDA approvals for these antidepressants typically excluded patients with comorbid alcohol dependence. Thus, the depression literature does not adequately address questions such as: Are antidepressants actually effective for reducing depressive symptoms in this patient population? Will antidepressants help reduce alcohol drinking, either directly or indirectly, by reducing depression? Would an antialcohol medication, singly or in combination with an antidepressant, reduce clinical symptoms for either or both disorders?

Historically, long-term drinkers were denied medications (except for detoxification) because of long-standing stigmas about alcohol-dependent patients taking any medications (“treating a drug with a drug”). Fortunately, this attitude is fading as scientists impart knowledge to professionals and the public about the possibilities of correcting the neurobiology of addiction by treating the addicted brain with certain medications. In addition, there are legitimate safety concerns about the potential interaction of medications with alcohol, or the potential for antidepressant overdose in depressed intoxicated patients.

The advent of SSRIs, many of which are FDA-approved, mitigated many of the safety concerns about depressed alcohol-dependent patients taking antidepressants. If a patient drinks alcohol or feels suicidal, SSRIs are better tolerated and are generally thought to be safer than, for example, tricyclic antidepressants (TCAs). In addition, the frequency of adverse effects is relatively low and the severity of most ad-verse effects is mild or moderate. Investigators have been more willing to examine the efficacy of SSRIs in alcohol-dependent patients, and clinicians have been more likely to prescribe SSRI medications than drugs in other classes for depression in alcohol-dependent patients because of the safety profile of these agents.

 summarizes the results of recent, well-controlled, double-blind, placebo-controlled studies of pharmacotherapies for comorbid depression and alcohol dependence. Typically, these trials have provided antidepressant medication and some form of weekly psychosocial treatment or counseling. (See also earlier reviews by Nunes and Levin

Six of the 9 studies (67%) that compared an antidepressant medication with placebo found a relationship between the medication and reductions in depressive symptoms, irrespective of type of antidepressant (eg, TCAs, SSRIs). Only 3 of the 9 studies (33%) found an advantage for the medication over placebo in reducing drinking in depressed alcohol-dependent patients. In the largest (N = 345) multicenter trial of sertraline (50 to 150 mg/d for 10 weeks), the drug provided no advantage over placebo in reducing depressive symptoms, nor did it reduce drinking, compared with placebo.

 Because of this trial’s size, the results challenged those of all the other trials, indicating that antidepressants alleviate depression in depressed patients with alcohol dependence.

 of a double-blind, placebo-controlled, 14-week trial of 170 alcohol-dependent patients with major depressive disorder. Two FDA-approved medications were evaluated, one for depression (sertraline) and one for alcohol dependence (naltrexone).

 An important aim of the study was to compare mood and drinking outcomes with the combined medications with those with placebo and with single-medication treatment. Patients received either 200 mg/d of sertraline, 100 mg/d of naltrexone, a combination of the two, or a double placebo for 14 weeks while receiving weekly cognitive-behavioral therapy.

The sertraline-naltrexone combination produced a higher alcohol abstinence rate (53.7%; P = .001; odds ratio [OR] = 3.7) and a longer delay before relapse to heavy drinking (median delay, 98 days; P = .003; Cohen d = .54) than the other treatments: naltrexone (21.3% abstinent; delay, 29 days), sertraline (27.5% abstinent; delay, 23 days), or placebo (23.1% abstinent; delay, 26 days). A trend was also seen in the relief of depression symptoms in the medication combination group by the end of treatment (83.3% not depressed; P = .014; OR = 3.6) compared with the single-medication or placebo group.

The patients treated with an SSRI and an opiate antagonist achieved greater abstinence from alcohol, delayed relapse to heavy drinking, and relief of depression symptoms by the end of treatment than did patients who received naltrexone or sertraline alone or placebo. As with other initial findings from clinical trials, the results await replication in other settings with different patient populations and with other antidepressants.

Empirical data that support effective treatments for co-occurring depression and alcohol dependence are long overdue. Comorbid prevalence rates are formidable, and numerous reports describe patients with comorbid depression and alcohol dependence as clinically more severely ill and more difficult to keep well than patients who are either depressed or alcohol-dependent. Positive outcomes may depend on both the type and timing of the medication and psychosocial interventions needed to treat both disorders to symptom remission, as well as a solid doctor-patient relationship, attention to treatment compliance, and a commitment to treat both the alcohol dependence and the mood disorder.

While it seems logical to prescribe antidepressants for patients who are depressed, some alcohol-dependent patients-as well as some clinicians who treat them-are unwilling to use a medication. Fortunately, bias is fading as scientists learn more about treating the addicted brain with certain medications and correcting the neurobiology of addiction. Over the past 20 years, results from the majority of well-controlled trials have showed that antidepressants reduced depressive symptoms in patients with depression and alcohol dependence. However, in most of the trials, these medications had virtually no effect on reducing excessive drinking.

Recently published results of a controlled trial indicate that combining a medication to treat alcohol (naltrexone) with the antidepressant sertraline might be the optimal course of treatment for co-occurring depression and alcohol dependence.

 While these findings require replication, they provide a practical recommendation to integrate or combine 2 medications-1 for treating alcohol dependence and 1 for treating depression. This combined pharmacotherapy, with some platform counseling that integrates support and advice for both disorders, can provide an aggressive approach to treating co-occurring depression and alcohol dependence.

Acknowledgment-We thank Amy Leshner for technical assistance.

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 Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study. 

 Gilman SE, Abraham HD. A longitudinal study of the order of onset of alcohol dependence and major depression. 

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 Greenfield SF, Weiss RD, Muenz LR, et al. The effect of depression on return to drinking: a prospective study. 

 Hasin DS, Grant BF. Major depression in 6050 former drinkers: association with past alcohol dependence. 

 Kranzler HR, Del Boca FK, Rounsaville BJ. Comorbid psychiatric diagnosis predicts three-year outcomes in alcoholics: a posttreatment natural history study. 

 Grant BF, Stinson FS, Hasin DS, et al. Immigration and lifetime prevalence of DSM-IV psychiatric disorders among Mexican Americans and non-Hispanic whites in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. 

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Niciu MJ, Chan G, Gelernter J, et al. Subtypes of major depression in substance dependence. 

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 Reis RK, Yuodelis-Flores C, Comtois KA, et al. Substance-induced suicidal admissions to an acute psychiatric service: characteristics and outcomes. 

Nunes EV, Liu X, Samet S, et al. Independent versus substance-induced major depressive disorder in substance-dependent patients: observational study of course during follow-up. 

17. Lydecker KP, Tate SR, Cummins KM, et al. Clinical outcomes of an integrated treatment for depression and substance use disorders. 

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Depression and alcoholism treatment requires the proper use of medication and psychosocial interventions, as well as a solid doctor-patient relationship and a commitment to treat both disorders.

Comorbid Depression and Alcohol Dependence

This article was originally presented as an independent educational activity under the direction of CME LLC. The ability to receive CME credits has expired. The article is now presented here for your reference.

-Identifying the typical daily doses of FDA-approved medications for the treatment of alcohol dependence.

-Describing the significance of medication adherence on treatment outcomes in patients with alcohol dependence.

Detailng strategies for recognizing, probing and improving medication nonadherence in patients who are prescribed a medication for a chronic illness like alcohol dependence.

Describing novel options that might enhance medication adherence.

Who will benefit from reading this article?

This activity was designed to meet the continuing education needs of psychiatrists and other physicians, physician assistants, registered nurses and advanced practice psychiatric nurses. Other mental health care professionals may find this activity informative.


 In the last decade, as more knowledge has been discovered about the neurobiology of addiction and the effects of alcohol on the brain, clinical studies have been completed on initiating medications with counseling (types of counseling have ranged from medical management and advice to addiction-specialty therapies). These studies have been systematically conducted for the purpose of evaluating the advantage of pharmacotherapy in improving early and long-term outcomes. Essentially, medications are evaluated as to whether or not they provide an incremental advantage to counseling, or whether or not they can be paired with a relatively modest type of medical management counseling as an alternative to more intensive and specialized addiction therapy. To date, the FDA has approved four medications for the treatment of alcohol dependence; they are listed in the 

 When someone taking disulfiram consumes alcohol, its enzyme-blocking action creates disagreeable physical symptoms, primarily nausea and vomiting. The usual daily dose of disulfiram prescribed today is 250 mg/day, but the unpleasant symptoms are dose dependent. That is, the aversive reaction escalates with a higher daily dose of disulfiram and/or with greater quantities of alcohol. Severe ethanol-disulfiram reactions, even death, have been reported, but were almost always associated with much higher daily doses (e.g., 1000 mg/day to 3000 mg/day).

 When patients are highly motivated or are supervised in their taking of disulfiram, it has been reported that drinking is avoided and thus aversive symptoms are not experienced. Treatment regimens including incentivedriven interventions or disulfiram supervision by physicians have shown beneficial treatment outcomes, such as decreases in drinking and increases in the rate of abstinence.

 reported an astoundingly high nonadherence rate of 80% in a large multisite study of alcohol-dependent patients who were asked to take 250 mg/day of disulfiram or placebo. See Suh et al.

If a patient's possibilities for being medication nonadherent can be minimized or bypassed, then patient nonadherence as a barrier to treatment response would be eliminated. This was the rationale for  developing the fourth FDA-approved medication: a long-acting extendedrelease formulation (once-monthly) injection of naltrexone (Vivitrol). Each injection delivers 380 mg of naltrexone that remains in the body at therapeutic plasma concentrations for approximately a month's duration. This delivery system removes the patient burden of daily decision making. In addition, this type of delivery system for treating an alcohol disorder allows clinicians to be certain that their patients are taking and, hopefully, benefiting from treatment every day for 30 days.


 As we acquire promising pharmacotherapies that can be initiated with counseling for treating alcohol dependence, there are many challenges and barriers to fully introducing medication into mainstream clinical practice in the medical community. As mentioned above, the foremost challenge is a patient's nonadherence to prescribed treatment. All physicians understand that their patient's adherence to their medication(s) and attendance at their counseling sessions are critical for achieving successful outcomes. However, in practice, it has been demonstrated time after time how difficult it can be to ensure patient adherence to treatment, especially in chronic illnesses. For example, studies of insulin adherence in diabetes treatment report poor medication adherence in nearly 40% of patients, and the rate of medication nonadherence is as high as 50% in patients with hypertension.

 provides an illustration of relapse rates in a study group from the University of Pennsylvania that combined two double-blind, placebocontrolled clinical trials of 50 mg/day of naltrexone for 12 weeks to treat alcoholdependent outpatients.

Nonadherence in a patient is probably best identified by the clinician who proactively discusses nonadherence with the patient as a collaborator in trying to achieve 100% medication adherence. In addition, before nonadherence has a chance to happen, pitfalls associated with nonadherence and helpful strategies that produce good adherence can be discussed with the patient. Importantly, it is wise to establish a system for routinely monitoring medication adherence at each visit. This can be done using simple techniques such as asking patients to bring their pill bottles or blister cards to each visit, and/or asking them to keep a monthly calendar, indicating on each day the time that they took their medicine(s). Prevention and improvement  of medication nonadherence can occur for some patients simply by the clinician routinely expressing interest and instructing patients on ways to selfmonitor their pill-taking as part of their treatment.

 Worse adherence is predicted in patients who report side effects from treatment (particularly nausea or fatigue) or who abuse other drugs. In addition, adherence may be adversely affected by the treatment setting (e.g., a long wait time for appointments or staff or others at the facility who create an uncomfortable atmosphere or pessimistic outlook for recovery).


 Alcohol dependence is a treatable disease, but the proportion of affected individuals who come to treatment is less than 30%. The low proportion of patients seeking treatment may be due in part to the fact that successful treatment recovery rates, while notable, still leave a large number of treated people who rapidly relapse. In the last decade, advanced knowledge of the neurobiology of addiction plus the FDA approval of new medications for treating alcohol dependence provide some optimism that pharmacotherapy may be a valuable part of treatment for decreasing heavy drinking and maintaining abstinence and sobriety in many cases. Nonetheless, there are still challenges, with the primary barrier to successful treatment response being that a formidable number of patients tend to skip doses or stop their medication altogether for a variety of reasons. This, of course, ultimately compromises chances for a good treatment response. The most recent FDA-approved pharmacotherapy, however, is a long-acting, once-a-month injection that relieves patients of the daily decision to take their medication, as well as for the need for clinician monitoring of patients' pill adherence. This type of delivery system also aids the physician in evaluating the patient's response to treatment, i.e., in the initial clinical trial, positive changes in reducing alcohol use and craving were seen as early as the first injection in most patients.

The author, Dr. Pettinati, is professor of psychiatry and director of the division of treatment research in the Center for the Studies of Addiction at the University of Pennsylvania School of Medicine. Dr. Pettinati's co-author, Ms. Gallis, is a research assistant and the regulatory and monitoring coordinator at the Center for the Studies of Addiction at the University of Pennsylvania School of Medicine.

Dr. Pettinati receives grants/research support from Alkermes, Inc.,  AstraZeneca, Bristol-Myers Squibb Company, Cephalon, Inc., Forest  Laboratories, and Ortho-McNeil Pharmaceutical, Inc. She is also on the  Advisory Board and Speakers’ Bureau and a consultant for Alkermes, Inc.,  AstraZeneca, Cephalon, Inc., and Forest Laboratories.

Ms. Gallis has indicated that she has nothing to disclose.

This article briefly describes pharmacotherapy for the treatment of alcoholism and discusses strategies to address treatment challenges like medication nonadherence.

Mental disorders and substance use disorders (SUDs) represent a major public health problem, and when these disorders are left untreated, they have devastating consequences for affected individuals, their families and society. While not widely known, a number of important advances have been made in the past decade toward understanding and treating SUDs and SUD-related disorders. For example, one of the more recent innovations in treating specific SUDs has been the addition of pharmacotherapy to improve treatment response, beyond what patients obtain from psychotherapy or counseling. The benefit of pharmacotherapy has now been well documented in the treatment of nicotine, alcohol, opiate and, just recently, cocaine dependence disorders.

Historically, addictive behaviors were considered a "deficiency in self-control" or the "result of ineffective thinking" (Steigerwald and Stone, 1999). While such perspectives are not widely held today, they have generated a number of useful and important remedial interventions that focused on spirituality, motivation and cognitive skill learning. The 12-step philosophy, typified by Alcoholics Anonymous, remains the most prevalent approach for changing alcoholic behaviors in the United States (Owen et al., 2003). Nonetheless, relapse rates in some settings remain high, and further investigation of alternative or adjunctive treatment options, such as pharmacotherapy, is of paramount importance.

In the past decade, the scientific community has come to better understand the neurobiological actions of excessive alcohol and drug use in the brain and the potential neurochemical disruptions associated with chronic, uncontrollable and excessive drug use. The scientific comprehension that an SUD is a chronic, biological disease (McLellan et al., 2000) has led to a conceptual mapping of drug-related constructs like 

 onto neurological substrates. This, in turn, has driven the investigation of the usefulness of pharmacological agents to reduce these constructs (Anton, 1999; Pickering and Liljequist, 2003; Swift, 1999; Volpicelli et al., 1995). In addition, we have learned that the etiology and course of SUDs are influenced by genetic heritability, biology, personal choice and environmental factors. Currently, further areas in the study of addictive behaviors have been identified that may be directly or indirectly related to substance dependence. These areas of study are summarized in this issue of 

Kyle M. Kampman, M.D., begins this Special Report with both data and optimism in identifying investigative pharmacotherapies for treating cocaine dependence. For the first time in over two decades of clinical trial research, there are several published controlled trials of various types of medications that have proven to be an advantage over counseling. Interestingly, the action of these medications varies widely. Among the brief list of proven medications is disulfiram (Antabuse), which is approved by the U. S. Food and Drug Administration for treating alcohol dependence. The author also describes an exciting and novel direction in treating cocaine dependence: a vaccine under development that is capable of stimulating the production of cocaine-specific antibodies that prevent the typical high or reinforcement from cocaine use.

Judith A. Richman, Ph.D., and Kathleen M. Rospenda, Ph.D., bring further into focus hidden alcohol or drug use as a coping response to the trauma experienced as a victim of sexual harassment. In this article, the authors describe the consequential substance abuse and dependency that can result from being a victim of sexual harassment.

Jeffrey N. Wilkins, M.D., provides us with a comprehensive summary of the pharmacotherapies that have been used to treat withdrawal and intoxication, as well as the rehabilitative stages of a wide spectrum of substance dependencies. He is quick to identify the medications that have been approved by the FDA for treatment of selected alcohol and drug dependencies. Wilkins then goes on to describe medications that, while approved for other uses, have been shown to be useful in treating selected substances in a particular stage of treatment (e.g., withdrawal as opposed to rehabilitation). Overall, this summary serves as a gentle reminder of the many pharmacotherapy options that are available to our patients. Wilkins provides us with practical knowledge that is useful to any physician who may have occasion to treat substance abuse in their practice.

The advances in this field that have been outlined in this Special Report will undoubtedly have an important impact on the way that problematic addiction-related behaviors and disorders are identified, treated and understood in the future.

acknowledges Dr. Pettinati for her assistance in planning and reviewing this Special Report.

Dr. Pettinati is professor in the department of psychiatry Treatment Research Center at the University of Pennsylvania in Philadelphia.

Anton RF (1999), What is craving? Models and implications for treatment. Alcohol Res Health 23(3):165-173.

McLellan AT, Lewis DC, O'Brien CP, Kleber HD (2000), Drug dependence, a chronic medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA 284(13):1689-1695 [see comment].

Owen PL, Slaymaker V, Tonigan JS et al. (2003), Participation in alcoholics anonymous: intended and unintended change mechanisms. Alcohol Clin Exp Res 27(3):524-532.

Pickering C, Liljequist S (2003), Cue-induced behavioural activation: a novel model of alcohol craving? Psychopharmacology (Berl) 168(3):307-313.

Steigerwald F, Stone D (1999), Cognitive restructuring and the 12-step program of alcoholics anonymous. J Subst Abuse Treat 16(4):321-327.

Swift RM (1999), Medications and alcohol craving. Alcohol Res Health 23(3):207-213.

Volpicelli JR, Watson NT, King AC et al. (1995), Effect of naltrexone on alcohol "high" in alcoholics. Am J Psychiatry 152(4):613-615.

In the past decade, important advances have been made in detecting and treating substance abuse disorders. In addition, research has revealed influences on the etiology and course of SUDs. Dr Pettinati introduces this Addictive Disorders Special Report, noting that the articles add to this knowledge base.

Helen M. Pettinati, PhD

Articles

Advances and Challenges in Treating Alcohol Dependence With Pharmacotherapy

Comorbid Depression and Alcohol Dependence

Advances and Challenges in Treating Alcohol Dependence With Pharmacotherapy

Recent Advances in Treatment