Sertraline and cognitive behavioral therapy for depressed alcoholics: results of a placebo-controlled trial

Alcoholism and depression are common disorders that frequently co-occur in the same individual. Selective serotonin reuptake inhibitors (SSRIs) are effective in the treatment of depression and also had decreased drinking in some studies of heavy drinkers and alcoholics. The reported effect of serotonergic medications on alcohol intake in depressed alcoholics has not been consistent. Most previous studies have not investigated the use of an SSRI in the context of cognitive behavioral therapy (CBT), a known efficacious treatment of both alcoholism and depression. The study presented here was a randomized placebo-controlled 12-week trial of sertraline combined with individual CBT focused on both alcoholism relapse prevention and depressive symptoms. Subjects were 82 currently depressed, actively drinking alcohol-dependent individuals. Subjects had either primary (independent) major depression (70 subjects) or substance-induced mood disorder and at least 1 first-degree relative (parent, sibling, or child) with an affective disorder (12 subjects). Depression and alcohol consumption outcomes were measured weekly over 12 weeks. Sertraline was well tolerated and all subjects had decreases in both depression and alcohol use during the study compared with baseline. Subjects who received sertraline had fewer drinks per drinking day than subjects who received placebo, but other drinking outcomes were not different between the 2 treatment groups. Treatment with sertraline was associated with less depression at the end of treatment in female subjects compared with female subjects who received placebo. Less drinking during the study was associated with improved depression outcome. The findings in this study suggest that sertraline, compared with placebo, may provide some modest benefit in terms of drinking outcome and also may lead to improved depression in female alcohol-dependent subjects. Additionally, alcohol relapse prevention CBT, delivered according to manual guidelines with modifications that provide specific attention to depression, appeared to be of benefit to subjects, although this interpretation is limited by the design of the study.     

Nefazodone treatment of major depression in alcohol-dependent patients: a double-blind, placebo-controlled trial

Depression is the most common comorbid psychiatric illness in patients with alcohol dependence. This double-blind study tested the efficacy of nefazodone versus placebo for the treatment of depression in actively drinking alcohol-dependent patients who were also participating in weekly group treatment for alcoholism. Sixty-four subjects with major depression disorder and alcohol dependence with a history of at least one prior episode of depression when not drinking were randomly assigned to receive 12 weeks of either nefazodone or placebo and participated in a weekly psychoeducational group on alcoholism. Subjects were assessed every 2 weeks for depression, anxiety, side effects, and drinking frequency. Subjects taking nefazodone were significantly more likely to complete the study (62%) than those taking placebo (34%). Analyses of covariance using drinks per week as a time-dependent covariate showed lower Hamilton Rating Scale for Depression scores at week 8 for end-point analysis and at weeks 8 and 12 for completers. The endpoint analysis demonstrated a significantly greater response in the nefazodone group (48%) than in the placebo group (16%). Both groups showed a similarly significant decrease in the average number of alcoholic drinks consumed per day over the course of the study. Although the number of adverse effects was significantly greater for the nefazodone group, there were no severe adverse events, and nefazodone was well tolerated. Nefazodone is a safe and effective antidepressant to use in a population of alcohol-dependent patients with depression who have a high degree of comorbidity. Nefazodone treatment was superior to placebo in alleviating depression in these patients but did not add any advantage over the psychoeducational group in terms of drinking outcomes.     

An overview of the development of medications including novel anticonvulsants for the treatment of alcohol dependence

The development of treatments for alcohol dependence has been significantly complicated by the multiple actions of ethanol at the neurotransmitter level, heterogeneity among patients with alcohol dependence, the complexity of defining and measuring the phenomenon of craving, and the challenge of quantifying alcohol intake in patients. Increasingly, anticonvulsant medications are showing promise for the safe and effective amelioration of alcohol withdrawal symptoms. Furthermore, there is evidence that anticonvulsant medications are promising treatments for reducing drinking and preventing relapse among alcohol-dependent individuals. In recent years, many medications have been evaluated for the treatment of alcohol dependence, including those that interact with dopaminergic, serotonergic, opioid or glutamate and/or GABA systems. So far, naltrexone, acamprosate and, more recently, the anticonvulsant, topiramate, have shown some efficacy for the treatment of heterogeneous populations of individuals with alcohol dependence. Both ondansetron and sertraline appear to have some efficacy in treating different subgroups of alcoholic.     

An overview of the development of medications including novel anticonvulsants for the treatment of alcohol dependence

The development of treatments for alcohol dependence has been significantly complicated by the multiple actions of ethanol at the neurotransmitter level, heterogeneity among patients with alcohol dependence, the complexity of defining and measuring the phenomenon of craving, and the challenge of quantifying alcohol intake in patients. Increasingly, anticonvulsant medications are showing promise for the safe and effective amelioration of alcohol withdrawal symptoms. Furthermore, there is evidence that anticonvulsant medications are promising treatments for reducing drinking and preventing relapse among alcohol-dependent individuals. In recent years, many medications have been evaluated for the treatment of alcohol dependence, including those that interact with dopaminergic, serotonergic, opioid or glutamate and/or GABA systems. So far, naltrexone, acamprosate and, more recently, the anticonvulsant, topiramate, have shown some efficacy for the treatment of heterogeneous populations of individuals with alcohol dependence. Both ondansetron and sertraline appear to have some efficacy in treating different subgroups of alcoholic.     

Sertraline treatment of co-occurring alcohol dependence and major depression

BACKGROUND: Major depressive disorder occurs commonly in association with alcohol dependence, both in clinical samples and in the community. Efforts to treat major depressive disorder in alcoholics with antidepressants have yielded mixed results. This multicenter, double-blind, placebo-controlled trial of sertraline was designed to address many of the potential methodological shortcomings of studies of co-occurring disorders. METHOD: Following a 1-week, single-blind, placebo lead-in period, 328 patients with co-occurring major depressive disorder and alcohol dependence were randomly assigned to receive 10 weeks of treatment with sertraline (at a maximum dose of 200 mg/d) or matching placebo. Randomization was stratified, based on whether initially elevated scores on the 17-item Hamilton Depression Rating Scale declined with cessation of heavy drinking, resulting in a sample of 189 patients with Hamilton Depression Rating Scale scores > or =17 (group A) and 139 patients with Hamilton Depression Rating Scale scores < or =16 (group B). RESULTS: Both depressive symptoms and alcohol consumption decreased substantially over time in both groups. There were no reliable medication group differences on depressive symptoms or drinking behavior in either group A or B patients. CONCLUSION: Despite careful attention to methodological considerations, this study does not provide consistent support for the use of sertraline to treat co-occurring major depressive disorder and alcohol dependence. The high rate of response among placebo-treated patients may help to explain these findings. Further research is needed to identify efficacious treatments for patients with these commonly co-occurring disorders.     

Fluoxetine versus placebo in depressed alcoholics: a 1-year follow-up study

The authors conducted a first study to evaluate the long-term efficacy of fluoxetine for decreasing the depressive symptoms and the drinking of patients with comorbid major depressive disorder and alcohol dependence. This study consisted of a 1-year naturalistic follow-up of 31 patients who previously had completed a 3-month double-blind, placebo-controlled study of fluoxetine in depressed alcoholics. The fluoxetine group continued to demonstrate less depressive symptoms and less drinking than the placebo group at the 1-year follow-up evaluation. The results of the 1-year follow-up evaluation suggest persistent efficacy for fluoxetine for treating the depressive symptoms and the drinking of depressed alcoholics.     

CSF monoamine metabolites and lethality of suicide attempts in depressed patients with alcohol dependence.

BACKGROUND: Alcohol dependence (alcoholism) and major depressive disorder are frequently comorbid and are risk factors for suicidal behavior. Monoaminergic abnormalities have been implicated in the pathophysiology of depression, alcohol dependence, and suicidal behavior. Lower cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-HIAA) levels are associated with higher lethality of suicide attempts in major depression and predict a higher rate of future suicide. We sought to study the relationship of CSF monoamine metabolites to lethality of suicidal acts in depressed subjects with comorbid alcoholism. METHODS: We compared 16 high- and 16 low-lethality drug-free depressed suicide attempters with comorbid alcoholism. Subjects were free from any substance use disorder for at least two months. Demographic and clinical parameters, and CSF 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were examined. RESULTS: The two groups did not differ with regard to the demographic characteristics. CSF 5-HIAA levels were lower in high-lethality attempters compared to low-lethality attempters. There were no group difference in CSF HVA or MHPG levels. CONCLUSION: Higher lethality of suicidal behavior in depressed patients with alcoholism is related to lower serotonergic activity.     

Bupropion and sertraline combination treatment in refractory depression

A sizeable minority of depressed patients, estimated at 15-20%, suffer chronic symptoms which often persist despite appropriate treatment. The search for new, more efficacious pharmacotherapies has included testing existing medications for additional therapeutic effects, such as in combination treatment. Four treatment- refractory patients who presented to the authors for clinical care are described, in which the combination of bupropion and sertraline was effective for a major depressive episode. None of the patients experienced adverse effects. Two carried the diagnosis of unipolar depression, and two, bipolar disorder. All had prior adequate, but ineffective, separate trials of buproprion and a selective serotonin re-uptake inhibitor (SSRI), including sertraline. All had chronic depression with multiple failed medication treatments, arguing against the alternative explanation that their improvement represented a placebo response or spontaneous remission. The efficacious combination of sertraline and bupropion may be due to synergism of its two distinct antidepressant mechanisms involving serotonergic, dopaminergic and noradrenergic systems.     

Positron emission tomography study of regional brain metabolic responses to a serotonergic challenge in major depressive disorder with and without comorbid lifetime alcohol dependence.

This is the first study contrasting regional glucose metabolic rate (rCMRglu) responses to a serotonergic challenge in major depressive disorder (MDD) with and without comorbid alcohol dependence. In a university hospital, patients with MDD without a history of alcohol dependence (MDD only) and patients with MDD and comorbid alcohol dependence (MDD/ALC) were enrolled in this study. Subjects with comorbid borderline personality disorder were excluded. A bolus injection of approximately 5 mCi of (18)fluorodeoxyglucose was administered 3 h after the administration of placebo or fenfluramine. We found an anterior medial prefrontal cortical area where MDD/ALC subjects had more severe hypofrontality than MDD only patients. This area encompassed the left medial frontal and left and right anterior cingulate gyri. This group difference disappeared after fenfluramine administration. The fact that the observed group difference disappeared after the fenfluramine challenge suggests that serotonergic mechanisms play a role in the observed differences between the groups.     

Psychotropic drug safety issues: continuing vigilance is needed

Alcoholism is a progressive neurological disorder that represents one of the leading preventable causes of morbidity and mortality in the USA. Individuals with alcohol dependence may exhibit differences in their sensitivity to intoxication, the age at which they begin heavy drinking or the presentation of comorbid psychiatric illness. The heterogeneous nature of the disorder has complicated efforts to predict treatment outcomes, indicating a need for improved diagnostic and therapeutic approaches. Pharmaceutical development has focused on treating the symptoms of alcohol withdrawal, reducing consumption of and craving for alcohol, preventing relapse and treating associated psychiatric problems. Current therapies may be optimized by combining psychosocial and pharmacologic approaches to treat alcoholic patients with the most appropriate regimen to achieve the desired therapeutic outcome. This article will describe the neurobiological mechanisms of dependence on alcohol in brief and review major medications approved for the treatment of alcoholism with regard to recent clinical evidence for the therapeutic efficacy of each agent. Investigations on the use of drugs with other indications (e.g., antidepressants and anticonvulsants) to target alcohol-dependent subtypes will also be discussed.     

Is long-term heavy alcohol consumption toxic for brain serotonergic neurons? Relationship between years of excessive alcohol consumption and serotonergic neurotransmission.

The relationship between years of excessive alcohol consumption and central serotonergic neurotransmission, as assessed by the prolactin (PRL) response to D-fenfluramine, was investigated in 22 male alcohol-dependent subjects. A negative correlation was obtained, that is, the longer duration of excessive alcohol consumption the lower PRL response to D-fenfluramine. It is therefore suggested that long duration of excessive alcohol consumption in alcohol-dependent subjects causes a reduction in central serotonergic neurotransmission, possibly by a toxic effect of alcohol on serotonin neurons. The relationship between depressive and anxiety symptoms during on-going drinking and the PRL response to D-fenfluramine was also investigated. No such correlations were obtained, suggesting that reduction in central serotonergic neurotransmission does not pre-dispose to the development of depressive and anxiety symptoms, at least in relation to on-going drinking in alcohol-dependent subjects.     

Current progress in pharmacologic treatment strategies for alcohol dependence

Alcoholism is a progressive neurological disorder that represents one of the leading preventable causes of morbidity and mortality in the USA. Individuals with alcohol dependence may exhibit differences in their sensitivity to intoxication, the age at which they begin heavy drinking or the presentation of comorbid psychiatric illness. The heterogeneous nature of the disorder has complicated efforts to predict treatment outcomes, indicating a need for improved diagnostic and therapeutic approaches. Pharmaceutical development has focused on treating the symptoms of alcohol withdrawal, reducing consumption of and craving for alcohol, preventing relapse and treating associated psychiatric problems. Current therapies may be optimized by combining psychosocial and pharmacologic approaches to treat alcoholic patients with the most appropriate regimen to achieve the desired therapeutic outcome. This article will describe the neurobiological mechanisms of dependence on alcohol in brief and review major medications approved for the treatment of alcoholism with regard to recent clinical evidence for the therapeutic efficacy of each agent. Investigations on the use of drugs with other indications (e.g., antidepressants and anticonvulsants) to target alcohol-dependent subtypes will also be discussed.     

Higher cerebrospinal fluid homovanillic acid levels in depressed patients with comorbid posttraumatic stress disorder.

Major depression and posttraumatic stress disorder (PTSD) are often comorbid, resulting in more impairment compared than with either diagnosis alone. Both major depression and PTSD are thought to be associated with monoamine transmitter abnormalities. This study compared clinical features and cerebrospinal fluid (CSF) monoamine metabolites in drug-free depressed subjects with a current major depressive episode (MDE) without comorbid PTSD, subjects with a current MDE and comorbid PTSD, and healthy volunteers. Depressed subjects with comorbid PTSD had higher CSF homovanillic acid (HVA) levels compared with depressed subjects without comorbid PTSD or healthy volunteers. Higher HVA was present after adjustment for sex, lifetime aggression severity and depression scores, alcoholism, tobacco smoking, comorbid cluster B personality disorder, reported childhood abuse, and psychosis. We found no group difference in CSF 5-hydroxyindolacetic acid (5-HIAA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels. Higher dopaminergic activity may contribute to alterations in memory and other cognitive functions, anhedonia, and hypervigilance observed in PTSD.     

Serum levels of brain‐derived neurotrophic factor in comorbidity of depression and alcohol dependence

Alcohol dependence is often comorbid with depression. The purpose of the present study was to compare serum brain‐derived neurotrophic factor (BDNF) levels between depressive patients with and without alcohol dependence. Our subjects were 16 inpatients (M/F: 13/3, age: 48 ± 8 years) at our university hospital who met the DSM‐IV‐TR criteria for both major depressive disorder and alcohol dependence and whose Hamilton Rating Scale for Depression (HAM‐D) scores were at least 15. Twenty sex‐ and age‐matched depressive patients and 20 healthy subjects were also examined. Serum BDNF levels in the depressive patients with (9.0 ± 4.3 ng/ml) and without (9.8 ± 5.2 ng/ml) alcohol dependence were significantly lower than those in the healthy subjects (21.1 ± 7.0 ng/ml); however, no significant difference was found in the serum BDNF levels of depressive patients with and without alcohol dependence. Eight of the 16 (50%) depressive patients suffering from both depression and alcohol dependence responded to 8 weeks of treatment with antidepressant drugs which significantly increased their serum BDNF levels. These results suggest that the serum BDNF level is a useful biological marker for depression in patients with alcohol dependence. Copyright © 2009 John Wiley & Sons, Ltd.     

Comorbid psychiatric diagnoses among individuals presenting to an addiction treatment program for alcohol dependence

A retrospective patient record review was conducted to examine comorbid psychiatric diagnoses, and comorbid substance use, among 465 patients below 45 years of age, presenting to a national alcohol addiction treatment unit in Dublin, between 1995 and 2006. Rates were high for depressive disorder (25.3%) particularly among females (35.4%). Lifetime reported use of substances other than alcohol was 39.2%, and further analysis showed significantly higher rates of deliberate self-harm among this group. Lifetime reported use of ecstasy was also significantly associated with depression in this alcohol-dependent population using logistic regression analysis. Implications and limitations of the findings are discussed.     

Fluoxetine in adolescents with major depression and an alcohol use disorder: an open-label trial.

Recently, a first placebo-controlled study of an selective serotonin reuptake inhibitor (SSRI) medication was conducted among a sample of adolescents with major depression by Emslie et al. [Arch. Gen. Psychiatry 54 (1997) 1031.]. That study demonstrated efficacy for fluoxetine vs. placebo for treating adolescents with major depression. However, to date, no studies have been conducted to assess the efficacy of fluoxetine or any other SSRI medication in adolescents with major depression in combination with an alcohol use disorder (AUD). In this study, the authors investigated whether fluoxetine decreases the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD. The authors conducted a 12-week open-label study of fluoxetine (20 mg) in 13 adolescents with current comorbid major depression and an AUD. A significant within-group decrease (improvement) was found for both depressive symptoms and drinking during the course of the study. The fluoxetine was well tolerated during the study. These data suggest promise for fluoxetine for decreasing both the depressive symptoms and the drinking of adolescents with comorbid major depression and an AUD.     

Naltrexone and disulfiram in patients with alcohol dependence and current depression

OBJECTIVE: Although disulfiram and naltrexone have been approved by the Food and Drug Administration for the treatment of alcoholism, no medications have been approved for individuals with alcohol dependence and comorbid psychiatric disorders. In particular, the effect of these medications on alcohol use outcomes and on specific psychiatric symptoms is still unknown in patients with the most common co-occurring disorder, major depression. METHOD: Two hundred fifty-four patients with a major Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at 3 Veterans Administration outpatient clinics. Randomization included (1) open randomization to disulfiram or no disulfiram, and (2) double-blind randomization to naltrexone or placebo. This resulted in 4 groups: (1) naltrexone alone, (2) placebo alone, (3) disulfiram and naltrexone, and (4) disulfiram and placebo. Primary outcomes were measures of alcohol use. Secondary outcomes included psychiatric symptoms assessed by the Hamilton Depression Rating Scale, alcohol craving, gamma-glutamyltransferase levels, and adverse events. RESULTS: One hundred thirty-nine subjects (54.7%) met the current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for major depression. There was no relationship between the diagnosis of depression and medication treatment on alcohol use outcomes, psychiatric symptoms, or the reporting of side effects for these medications. There was a significant interaction between diagnosis, medication group, and craving, where subjects with depression on disulfram reported lower craving over time than subjects with depression on naltrexone. CONCLUSIONS: The results suggest that disulfiram and naltrexone are safe pharmacotherapeutic agents for dually diagnosed individuals with depression for the treatment of alcohol use disorders.     

Comorbid Psychiatric Diagnoses Among Individuals Presenting to an Addiction Treatment Program for Alcohol Dependence

A retrospective patient record review was conducted to examine comorbid psychiatric diagnoses, and comorbid substance use, among 465 patients below 45 years of age, presenting to a national alcohol addiction treatment unit in Dublin, between 1995 and 2006. Rates were high for depressive disorder (25.3%) particularly among females (35.4%). Lifetime reported use of substances other than alcohol was 39.2%, and further analysis showed significantly higher rates of deliberate self-harm among this group. Lifetime reported use of ecstasy was also significantly associated with depression in this alcohol-dependent population using logistic regression analysis. Implications and limitations of the findings are discussed.     

Polydrug dependence and psychiatric comorbidity among heroin injectors

The prevalence of diagnoses of substance dependence, anxiety disorders and depressive disorders were estimated in a sample of 222 heroin injectors, using the Composite International Diagnostic Interview. Subjects had a median of three lifetime substance diagnoses and two current diagnoses. A total of 60% met the criteria for a lifetime anxiety disorder, and 51% had a current anxiety disorder. A depressive disorder was diagnosed in 41% of subjects, with 30% having a current diagnosis. There were significant positive correlations between the number of lifetime drug dependence diagnoses and the number of lifetime anxiety and affective disorders (r = 0.41), and the number of current drug dependence diagnoses and the number of current comorbid diagnoses (r = 0.32). After controlling for other variables, the only significant independent predictor of the number of lifetime and current dependence diagnoses was the number of comorbid diagnoses.     

The relationship of aggression to suicidal behavior in depressed patients with a history of alcoholism

BACKGROUND: Alcoholism and depression are often comorbid. Studies suggest that depressed subjects with alcoholism have more chronic impairment and suicidal behavior than individuals with either diagnosis alone. The reason for higher rate of suicide and suicide attempts in comorbid subjects is uncertain. We explored clinical characteristics that may be associated with this increased suicidality. METHODS: In all, 219 depressed subjects (n=62 males and n=157 females) without a history of any alcohol or substance use disorder and 129 (n=49 males and n=80 females) depressed individuals with a prior history of alcohol use disorder participated in the study. Demographic and clinical parameters were assessed and recorded. RESULTS: Depressed subjects with a history of alcoholism had higher lifetime aggression and impulsivity, and were more likely to report a history of childhood abuse, suicide attempts, and tobacco smoking. Depressed suicide ideators with a history of alcoholism had higher suicide ideation scores than depressed suicide ideators without a history of alcoholism. Subjects with a history of alcoholism were younger at the time of the first depressive episode and first hospitalization than those without a history of alcoholism. Logistic regression analysis indicated that alcoholism was significantly associated with smoking and aggression. Suicidal behavior and higher suicidal ideation in depressed subjects with a history of alcoholism might be attributed to higher aggression scores in this group. CONCLUSION: The greater frequency of suicidal behavior and severity of suicidal ideation in major depression with comorbid alcoholism appears related to associated aggressive traits. Alcoholism, aggression, smoking, and suicide may have a common biological causal substrate.