A Review of the Literature of Mirtazapine in Co-Occurring Depression and an Alcohol Use Disorder.

BACKGROUND: Prior medication studies involving individuals with major depression in combination with an alcohol use disorder (MDD/AUD) have mainly focused on SSRI and tricyclic antidepressants, with generally ineffective results. Consequently, effective treatments for that common comorbid condition remain elusive. Mirtazapine is an antidepressant medicine with a unique pharmacological profile, whose effectiveness for treating non-comorbid depression reportedly may exceed that of SSRIs. OBJECTIVE/METHODS: We now review the published literature regarding the tolerability and efficacy of mirtazapine for the treatment of the depression and the pathological alcohol ingestion of individuals with co-occurring MDD/AUD, including a review of four of our own small studies and two studies conducted outside the United States. RESULTS/CONCLUSIONS: The findings of these studies suggest that mirtazapine is well tolerated among persons with comorbid MDD/AUD. Results also provide some evidence of efficacy for mirtazapine for decreasing the level of depression of persons with co-occurring MDD/AUD, and suggest that decreases in depression may occur relatively quickly after starting treatment, but provide no evidence of effectiveness for decreasing the level of alcohol ingestion. Large-scale double-blind, placebo-controlled studies are warranted to further clarify the tolerability and efficacy of mirtazapine among individuals with MDD/AUD.

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.

Characterizing female bipolar alcoholic patients presenting for initial evaluation.

This study examined gender differences of age and race-matched group of bipolar disorder (BPO) patients with comorbid alcohol dependence (AD; n = 65; males = 35, females = 30) to a group of BPO patients without comorbid AD (n = 61; males = 22, females = 39). The two groups were also similar on marital status and frequency of BPO subtypes. The results revealed that female bipolar alcoholic patients were more likely to report depressive symptoms as compared to either male bipolar alcoholics or both male and female non-alcoholic bipolar patients. When compared to male bipolar alcoholics, they had higher frequency of depressed mood, slow motor behavior, low self-esteem, decreased libido, decreased appetite, and higher general anxiety symptoms. On the other hand, female bipolar alcoholics differed from female non-alcoholic bipolar patients on reports of mood lability, depressed mood, low self-esteem, suicidal indicators, decreased libido, and general anxiety symptoms. These results raise the question of whether alcohol increases the frequency of depressive symptoms among female bipolar patients.

Treating the substance-abusing suicidal patient.

Studies concerning the treatment of substance-abusing suicidal patients are scarce despite the frequent presence of suicidal behavior among this population. Indeed, suicidality (ideation or behavior) is generally an exclusion criterion for participation in treatment studies of subjects with alcohol or drug abuse. Consequently, to date, little is known about the optimal treatment of this population. The first study involving substance-abusing suicidal patients was an open-label trial conducted in the early 1990s. This study involved 12 patients, all of whom demonstrated recent suicidal ideations and had made a lifetime suicide attempt. The results of that open-label study demonstrated significant within-group improvement in both depressive symptoms (including suicidal ideations) and level of drinking. However, substantial residual depressive symptoms and drinking persisted at the end of the trial. Also, because no placebo control group was utilized, the authors of that study could not rule out the possibility that the apparent therapeutic effect from fluoxetine was the result of the placebo effect. To date, only one double-blind, placebo-controlled study of subjects with alcohol or substance abuse has included substantial numbers of suicidal patients. The study involved 51 subjects, of whom 20 (39%) had made a suicide attempt in the current depressive episode, 31 (61%) had made a suicide attempt in their lifetime, and 46 (90%) had reported suicidal ideations in the week before hospitalization. The results of that double-blind, placebo-controlled study suggest that fluoxetine was effective in decreasing but not eliminating both the depressive symptoms (including suicidal ideations) and the level of alcohol consumption among a study group of subjects with comorbid major depressive disorder and alcohol dependence, many of whom displayed suicidal ideations. A secondary data analysis from that study suggested that cigarette smoking is also significantly decreased by fluoxetine, but the magnitude of the decrease is limited and few of these patients totally quit smoking with fluoxetine treatment alone. Another secondary data analysis from that study suggested that marijuana smoking was also significantly decreased in a subgroup of subjects who demonstrated cannabis abuse and that the magnitude of this improvement was robust. A third secondary data analysis from that study suggested that cocaine abuse acts as a predictor of poor outcome for both depressive symptoms (including suicidality) and level of alcohol use in this population. The results of a 1-year naturalistic follow-up study involving the patients from that study suggest that the benefits of fluoxetine in decreasing depressive symptoms and level of drinking persist 1 year after entering the treatment program. To date, no other double-blind, placebo-controlled studies involving substantial numbers of substance-abusing suicidal patients have been reported to either confirm or refute these findings. Further studies are clearly warranted to evaluate the efficacy of various pharmacotherapeutic agents and various psychotherapies in the treatment of substance-abusing suicidal patients.

Clinical correlates of heavy tobacco use among adolescents.

The primary aim of this study was to determine the clinical factors differentiating adolescents with heavy smoking (> or = 10 cigarettes/day) from adolescents with light smoking. This study involved a study group of 812 adolescents recruited from adolescent alcoholism treatment centers and from the community. Logistic regression analyses demonstrated that adolescents with heavy smoking, compared with adolescents with light smoking, were significantly more likely to demonstrate Caucasian American ethnicity, drug-use disorders, alcohol-use disorders, and conduct disorder. Our findings suggest that the clinical correlates of heavy smoking among adolescents are generally similar to those for smoking at any level (vs. nonsmokers), except that heavy smoking is more strongly associated with Caucasian American ethnicity. Also, depressive disorders were associated with smoking at any level in our sample, but depressive disorders were not associated with heavy smoking.

Correlates of mental health service utilization and unmet need among a sample of male adolescents.

The authors sought to identify the correlates of mental health services utilization and unmet need for these services among a sample of adolescent males. We hypothesized that our findings would replicate and extend those of the recent Methods for the Epidemiology of Child and Adolescent Mental Disorders (MECA) study, which found that parental factors play a major role in their children's unmet mental health care needs. Our study involved an evaluation of mental health service utilization and unmet need during the prior 2 years, as reported by the subjects at a follow-up assessment at age 16. Four factors were found to predict increased mental health services utilization, including attention deficit hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) among the adolescent males, the father's alcohol use disorder, and the mother's amphetamine use disorder. One factor was found to predict decreased utilization, the father's cannabis use disorder. Four factors significantly predicted unmet treatment need, including conduct disorder, the mother's amphetamine use disorder, a higher number of siblings, and a parental history of having had a childhood anxiety disorder. The results of this study suggest that parental psychopathology, parental substance abuse, the presence of conduct disorder, and an increased number of siblings act as barriers to adequate mental health treatment among adolescents. These findings confirm the crucial role that parental factors play in the treatment utilization and the unmet treatment need of their children, and also suggest that an increased number of siblings can also be associated with unmet treatment need.

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.

Fluoxetine versus placebo for the marijuana use of depressed alcoholics.

The aim of this analysis was to evaluate the efficacy of the SSRI antidepressant fluoxetine versus placebo for the marijuana use of depressed alcoholics. There are no previous reports involving and SSRI antidepressant for marijuana abuse. This analysis involved a subsample of 22 depressed alcoholic marijuana users out of a total of 51 depressed alcoholics. The entire sample was involved in a 12-week double-blind, placebo-controlled study evaluating the efficacy of fluoxetine versus placebo in depressed alcoholics. During the course of the trial, the cumulative number of marijuana cigarettes used was almost 20 times as high in the placebo group as in the fluoxetine group. Also, the number of days of marijuana use during the study was five times higher in the placebo group than in the fluoxetine group. These data suggest efficacy for fluoxetine in decreasing marijuana use of depressed alcoholics.

Naltrexone utility in depressed alcoholics.

The aim of this open-label pilot study was to evaluate the utility of naltrexone (50 mg per day) in decreasing alcohol use and to examine its impact on depressive symptoms among depressed alcoholics who have failed to abstain from alcohol use despite treatment with a selective serotonin reuptake inhibitor (SSRI). Fourteen ambulatory care patients, aged 18 to 65 years, with DSM-III-R comorbid diagnoses of alcohol dependence and major depressive disorder, who failed to abstain despite treatment with an antidepressant medication were enrolled in the study. Patients were followed for 12 weeks with weekly assessment of drinking behavior, depressive symptoms, functioning, alcohol craving, and side effects. The results of this study indicated a significant decrease in alcohol use and in urges to drink alcohol in the presence of the usual triggers. There was also a trend suggesting improvement in depressive symptoms and overall functioning. Naltrexone was well tolerated, with mild side effects reported at the onset of treatment.

Fluoxetine versus placebo in depressed alcoholic cocaine abusers.

To date, few double-blind, placebo-controlled studies with any selective serotonin reuptake inhibitor (SSRI) antidepressant in pure cocaine abusers or in cocaine abusers with comorbid disorders have been reported. In this study, 17 patients with DSM-III-R diagnoses of major depressive disorder, alcohol dependence, and cocaine abuse were included along with 34 non-cocaine-abusing depressed alcoholics in a pharmacotherapy trial involving the SSRI antidepressant fluoxetine. All 51 patients participated in a double-blind, parallel group study of fluoxetine versus placebo in depressed alcoholics. The principal focus of this article is the one-third of the depressed alcoholics who also abused cocaine and how the treatment response of those 17 patients compared with that of the 34 depressed alcoholics who did not abuse cocaine. During the study, no significant difference in treatment outcome was noted between the fluoxetine group (N = 8) and the placebo group (N = 9) for cocaine use, alcohol use, or depressive symptoms. In addition, no significant within-group improvement was noted for any of these outcome variables in either of the two treatment groups. Indeed, across the combined sample of 17 depressed alcoholic cocaine abusers, the mean Beck Depression Inventory (BDI) score worsened slightly from 19 to 21 during the course of the study, and 71 percent of the patients continued to complain of suicidal ideations at the end of the study. The 17 cocaine-abusing depressed alcoholics showed a significantly worse outcome than the 34 non-cocaine abusing depressed alcoholics on the 24-item Hamilton Rating Scale for Depression (HAM-D) and BDI depression scales and on multiple measures of alcohol consumption. These findings suggest that comorbid cocaine abuse acts as a robust predictor of poor outcome for the drinking and the depressive symptoms of depressed alcoholics.

Drug use problem awareness and treatment readiness in dual-diagnosis patients.

Problem awareness and treatment readiness are factors that influence treatment-seeking behavior, and thus, morbidity and outcome. The authors elucidated patterns of problem awareness and treatment readiness among hospitalized dually diagnosed patients by administering the Problem Awareness and Readiness for Treatment subscales of the Alcohol Use Inventory to 67 psychiatric inpatients with comorbid substance-related disorders and using a multivariate model approach to data analysis. The results suggested differential and interactive effects of gender, ethnicity, voluntary admission status, and a diagnosis of major depression (MDD) on drug abuse problem awareness and treatment readiness. Female gender, voluntary admission status, and a comorbid diagnosis of MDD were associated with increased awareness and readiness for treatment.

Cocaine use associated with increased suicidal behavior in depressed alcoholics.

The aim of this study was to determine whether depressed alcoholics who used cocaine would display a higher prevalence of suicidal behavior and suicidal ideation than depressed alcoholics who did not use cocaine. Forty-one depressed alcoholics participated in this prospective study of consecutively admitted inpatients. Seventeen patients (41.5%) had made a suicide attempt during their current depressive episode, and all but 1 of these attempts occurred during the week prior to their hospitalization. Ten patients used cocaine in the week prior to hospitalization, and 7 of these 10 (70%) had made a suicide attempt during that week. In contrast, only 32% of the depressed alcoholics who did not use cocaine made a suicide attempt during that week (p < .05). Suicidal ideation was also more prevalent in alcoholics who used cocaine. These data provide evidence that cocaine use is associated with an increased prevalence of suicidal behavior and suicidal ideation in depressed alcoholics.

Regulation of pigmentation in cultured skin substitutes by cytometric sorting of melanocytes and keratinocytes.

Unpredictable pigmentation in cultured skin substitutes (CSS) is an anatomic deficiency after wound treatment and can require years to normalize. Variable numbers of human melanocytes (HM) survive in cultures of human keratinocytes (HK) as demonstrated by focal areas of pigmentation in CSS after healing. The purposes of this study were to deplete HM from HK cultures and to regulate the numbers of HM contained in CSS. A highly pigmented HM cell strain was chosen for these studies to emphasize the differences in light scattering between HK and HM by flow cytometry. Cytometric gates were set with selective cultures of HM and HK and were used to sort a mixed population of HK + 4% HM. After sorting, CSS were prepared from human fibroblasts attached to collagen-glycosaminoglycan sponges combined with cells from the HK + 4% HM (pre-treatment control), the sorted HK (experimental), or sorted HK + 3% HM (post-treatment positive control) subpopulations and grafted to athymic mice. Grafted wounds were assessed for 6 wk by planimetry for area of pigment and by a Minolta Chromameter for color density and hue in situ. Histology and staining of HLA-ABC were performed at 6 wk. Data from percent pigmented area and chromameter measurements identified quantitative and statistically significant decreases in color of healed skin after flow cytometric separation of HK and HM. Therefore, a purified HK subpopulation depleted of HM was isolated by flow cytometry that generated healed skin with reduced pigmentation. These results suggest that HM can be selectively depleted from HK cultures and then added to cultured skin substitutes at specific densities to generate predictable pigmentation for improved function and cosmesis in healed wounds.

Fluoxetine in depressed alcoholics. A double-blind, placebo-controlled trial.

BACKGROUND: The selective serotonergic medication fluoxetine has demonstrated efficacy in the treatment of major depression and has suggested efficacy in the treatment of alcoholism. However, no completed trials with any selective serotonergic medication have been reported in patients who display both major depression and alcoholism, despite previous observations that both depression and alcoholism are associated with low serotonergic functioning. METHODS: Fifty-one patients diagnosed as having comorbid major depressive disorder and alcohol dependence were randomized to receive fluoxetine (n = 25) or placebo (n = 26) in a 12-week, double-blind, parallel-group trial. Weekly ratings of depression and alcohol consumption were obtained throughout the 12-week course of the study. RESULTS: The improvement in depressive symptoms during the medication trial was significantly greater in the fluoxetine group than in the placebo group. Total alcohol consumption during the trial was significantly lower in the fluoxetine group than in the placebo group. CONCLUSIONS: Fluoxetine is effective in reducing the depressive symptoms and the alcohol consumption of patients with comorbid major depressive disorder and alcohol dependence. It is unknown whether these results generalize to the treatment of less depressed and less suicidal alcoholics.

Age effects on the clinical presentation of alcoholics at a psychiatric hospital.

Little is known about the effects of age on the clinical presentation of alcoholism in various treatment settings, despite the clinical importance of this factor. This study evaluates the effects of age on the clinical profile of 604 alcoholics who presented for initial evaluation and treatment at a psychiatric hospital. Young alcoholics displayed the most prominent substance use, antisocial behavior, depressive symptoms (including suicidality), and impulsivity. Early middle-aged alcoholics displayed the highest levels of drinking. Elderly alcoholics displayed the highest levels of cognitive dysfunction, although some level of cognitive dysfunction was present among even the youngest alcoholics. These findings confirm and clarify the effects of age on the clinical profile of alcoholics presenting for initial evaluation at a psychiatric hospital.

Double-blind fluoxetine in depressed alcoholic smokers.

Treatment trials involving smoking in alcoholics with major depression are scarce, despite the common co-occurrence of these disorders. In this study, 25 smokers with DSM-III-R diagnoses of both major depressive disorder and alcohol dependence were randomized to fluoxetine or placebo in a 12-week, double-blind, parallel group trial. Almost half (48%) of the patients had made a suicide attempt in the week before hospitalization (where recruitment was performed), and 84 percent reported suicidal ideations during that week. Those in the fluoxetine group demonstrated a significant within-group decrease in smoking during the course of the study, whereas those in the placebo group did not. Those in the fluoxetine group smoked 27 percent fewer cigarettes than those in the placebo group, although this difference was not statistically significant. Cumulative alcohol consumption during the 12 weeks of the pharmacotherapy trial was four times as high in the placebo group as in the fluoxetine group, though this difference was not statistically significant in this limited-sized sample. The change in smoking was significantly associated with a change in drinking. These preliminary findings suggest that fluoxetine has the potential for treating the smoking and drinking behaviors of depressed alcoholic smokers.

Patterns of suicidality and alcohol use in alcoholics with major depression.

The aims of this study were (1) to comprehensively characterize a population of alcoholics with major depression in a psychiatric hospital, (2) to determine the prevalence of suicidal behavior in this sample, and (3) to determine whether quantity of alcohol ingested was associated with level of suicidality. Ratings of drinking, depression, and suicidality were obtained using both self-rated and observer-rated instruments. The prevalence of suicide attempts in the week before hospitalization was remarkably high, approaching 40%, whereas 70% had made a suicide attempt at some point in their lifetime. These suicide attempts were typically impulsive in nature, involving little if any premeditation. Most subjects reported drinking more heavily than usual on the day of their suicide attempt. Recent suicidal behavior was significantly associated with recent very heavy drinking (< or = 70 drinks per week) and with number of drinks per drinking day. Quantity of drinking per drinking day was also significantly higher in those making a recent suicide attempt. However, no association was found between quantity of alcohol consumption and suicidal ideation. These findings suggest that recent heavy alcohol use primarily affects suicidality by increasing the likelihood of acting on suicidal ideation rather than by inducing suicidal ideation.

Disproportionate lethality in psychiatric patients with concurrent alcohol and cocaine abuse.

OBJECTIVE: The aim of this study was to examine the association between active, concomitant cocaine and alcohol abuse and the prevalence and severity of current suicidal and homicidal behavior among hospitalized psychiatric patients. METHOD: Three groups of patients--with cocaine and alcohol abuse (N = 38), alcohol abuse only (N = 38), and cocaine abuse only (N = 25)--consecutively admitted to a psychiatric and substance abuse dual-diagnosis unit were comparatively examined for the presence of current suicidal and homicidal behavior. RESULTS AND CONCLUSIONS: Logistic regression analysis revealed that the alcohol and cocaine abuse group had a higher likelihood of associated current homicidal behavior than the alcohol-only and the cocaine-only groups.

Racial effects on the clinical presentation of alcoholics at a psychiatric hospital.

Despite the clinical importance of race effects on comorbidity and symptom patterns in recent community studies, little is known about such effects in various treatment facilities. This study evaluated the effect of race on the clinical profile of 604 alcoholics who presented for initial evaluation and treatment at a psychiatric hospital. The factor that most strongly distinguished the racial groups was socioeconomic status (SES). After controlling for SES and other factors, no significant difference was noted between ethnic groups in the prevalence of major depressive disorder (MDD) or antisocial personality disorder. However, after controlling for SES and other factors, alcohol and drug use were more severe in African-American alcoholics, along with four symptoms associated with alcohol and drug use. In contrast, reversed neurovegetative symptoms, anxiety-related symptoms, and some personality-related symptoms were more severe in white alcoholics.