Case-control association analysis of polymorphisms in the δ-opioid receptor, OPRD1, with cocaine and opioid addicted populations.

BACKGROUND: Addiction susceptibility and treatment responsiveness are greatly influenced by genetic factors. Sequence variation in genes involved in the mechanisms of drug action have the potential to influence addiction risk and treatment outcome. The opioid receptor system is involved in mediating the rewarding effects of cocaine and opioids. The µ-opioid receptor (MOR) has traditionally been considered the primary target for opioid addiction. The MOR, however, interacts with and is regulated by many known MOR interacting proteins (MORIPs), including the δ-opioid receptor (DOR). METHODS: The present study evaluated the contribution of OPRD1, the gene encoding the DOR, to the risk of addiction to opioids and cocaine. The association of OPRD1 polymorphisms with both opioid addiction (OA) and cocaine addiction (CA) was analyzed in African American (OA n=336, CA n=503) and European American (OA n=1007, CA n=336) populations. RESULTS: The primary finding of this study is an association of rs678849 with cocaine addiction in African Americans (allelic p=0.0086). For replication purposes, this SNP was analyzed in a larger independent population of cocaine addicted African Americans and controls and the association was confirmed (allelic p=4.53 × 10(-5); n=993). By performing a meta-analysis on the expanded populations, the statistical evidence for an association was substantially increased (allelic p=8.5 × 10(-7)) (p-values non-FDR corrected). CONCLUSION: The present study suggests that polymorphisms in OPRD1 are relevant for cocaine addiction in the African American population and provides additional support for a broad role for OPRD1 variants in drug dependence.

Genetic association analyses of PDYN polymorphisms with heroin and cocaine addiction.

Genetic factors are believed to account for 30-50% of the risk for cocaine and heroin addiction. Dynorphin peptides, derived from the prodynorphin (PDYN) precursor, bind to opioid receptors, preferentially the kappa-opioid receptor, and may mediate the aversive effects of drugs of abuse. Dynorphin peptides produce place aversion in animals and produce dysphoria in humans. Cocaine and heroin have both been shown to increase expression of PDYN in brain regions relevant for drug reward and use. Polymorphisms in PDYN are therefore hypothesized to increase risk for addiction to drugs of abuse. In this study, 3 polymorphisms in PDYN (rs1022563, rs910080 and rs1997794) were genotyped in opioid-addicted [248 African Americans (AAs) and 1040 European Americans (EAs)], cocaine-addicted (1248 AAs and 336 EAs) and control individuals (674 AAs and 656 EAs). Sex-specific analyses were also performed as a previous study identified PDYN polymorphisms to be more significantly associated with female opioid addicts. We found rs1022563 to be significantly associated with opioid addiction in EAs [P = 0.03, odds ratio (OR) = 1.31; false discovery rate (FDR) corrected q-value]; however, when we performed female-specific association analyses, the OR increased from 1.31 to 1.51. Increased ORs were observed for rs910080 and rs199774 in female opioid addicts also in EAs. No statistically significant associations were observed with cocaine or opioid addiction in AAs. These data show that polymorphisms in PDYN are associated with opioid addiction in EAs and provide further evidence that these risk variants may be more relevant in females.

The therapeutic alliance in medical-based interventions impacts outcome in treating alcohol dependence.

This study examined the relationship of the therapeutic alliance and treatment outcomes for alcohol-dependent patients receiving naltrexone or placebo and one of three different types of clinical interventions, including two medical-based (non-specialty) treatments. This is a secondary analysis of a 24-week randomized, placebo-controlled, clinical trial of 100mg/day of naltrexone or placebo for patients with DSM-IV alcohol dependence. Patients were also randomized to one of three interventions: (1) medication clinic only, (2) medication clinic plus BRENDA (an intervention promoting pharmacotherapy), or (3) medication clinic plus cognitive behavioral therapy (CBT). Early in treatment, patients and clinicians completed the working alliance inventory (WAI). Regression analyses were conducted to determine the predictive validity of the WAI on percent days abstinent and percent of sessions attended over the clinical trial. In the medication clinic only condition, the clinicians' WAI total score was marginally correlated to percent of visits attended (p=.057) but not percent days abstinent. In the medication clinic plus BRENDA condition, clinicians' WAI total score was positively correlated with percent days abstinent (p=.013) but not percent visits attended. No significant relationships were found between the WAI scores and either outcome measure in the CBT condition or for any of the patient rated assessments. To our knowledge, this is the first published report providing some support for the importance of the therapeutic alliance in medical interventions for alcohol dependence but only in the context of the clinicians' ratings. The absence of other effects underscores the need for further research.

The use of selective serotonin reuptake inhibitors in treating alcoholic subtypes.

The usefulness of selective serotonin reuptake inhibitors (SSRIs) to treat alcohol dependence continues to be a subject of debate. Most recently, investigations have tried to predict whether a given patient will respond to SSRIs in terms of reducing excessive alcohol drinking. The subtyping of alcohol-dependent individuals has ranged from relatively simple classifications (e.g., presence of comorbid depression) to more complex classifications (e.g., potential to have abnormalities in serotonin [5-HT] neurotransmission). Although only a few studies have been completed, results thus far indicate that alcoholic subgroups are differentially responsive to 5-HT pharmacotherapy with respect to drinking-related outcomes. In addition, there are preliminary results encouraging the use of SSRIs in combination with other medications for treating alcohol dependence in patients with and without comorbid psychiatric disorders. Information from these studies is promising, suggesting the need for further investigation.

Predicting treatment response to naltrexone: the influence of craving and family history.

Naltrexone has repeatedly been shown to reduce drinking in alcohol-dependent patients. Previous clinical research suggests that naltrexone may be more effective at reducing drinking among patients with high levels of alcohol craving at the beginning of treatment. In addition, laboratory studies suggest that naltrexone may be more efficacious among patients with a high familial loading of alcohol problems. We explored both of these possibilities in the context of the first 12-week phase of a double blind, placebo-controlled naltrexone trial. A total of 121 patients were randomized to receive 100 mg/day naltrexone and 62 patients were randomized to receive placebo. Both naltrexone and placebo were given in conjunction with a psychosocial intervention designed to be integrated with the use of pharmacotherapy. This intervention was administered by nurse practitioners. Overall, patients randomized to naltrexone reported drinking five or more drinks on fewer days than did placebo controls (p = .04). Interactions were observed between medication group assignment and both craving level prior to randomization (p = .02) and family loading of alcohol problems (p = .05). In both cases, the interaction was in the predicted direction. These data suggest that patients with high levels of alcohol craving or a strong family history of alcoholism are more likely to benefit from naltrexone treatment.

Double-blind clinical trial of sertraline treatment for alcohol dependence.

Clinical studies that have evaluated serotonergic medications to reduce alcohol consumption have yielded conflicting results. These studies primarily treated patients with alcohol dependence, excluding those with a current depressive disorder, in an effort to differentiate any medication effects directly on drinking from those on mood. Yet despite the exclusion of current depression, a group of alcohol-dependent patients who are not depressed can be highly heterogeneous. For example, this subgroup can include those with a lifetime depressive disorder. If these patients were more sensitive to serotonergic medications than patients without a lifetime depressive disorder, medication effects in a subgroup of patients who were not depressed could be obscured. Thus, the purpose of this study was to examine the efficacy of sertraline for treating alcohol dependence in patient groups that were differentiated by the presence or absence of lifetime depression. This study examined the effectiveness of sertraline (200 mg/day) or placebo for 14 weeks in 100 alcohol-dependent subjects with (N = 53) or without (N = 47) a lifetime diagnosis of comorbid depression. Sertraline treatment seemed to provide an advantage in reducing drinking in alcohol-dependent patients without lifetime depression, illustrated best with a measure of drinking frequency during treatment. However, sertraline was no better than placebo in patients with a diagnosis of lifetime comorbid depression, and current depression did not change the results. Treatment with selective serotonin reuptake inhibitors may be useful in alcohol-dependent patients who are not depressed. Subtyping those with alcohol dependence on the basis of the absence versus the presence of a lifetime depressive disorder may help to resolve conflicting findings in the literature on the treatment of alcohol dependence with serotonergic medications.

Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: a randomized controlled trial.

CONTEXT: Electroconvulsive therapy (ECT) is highly effective for treatment of major depression, but naturalistic studies show a high rate of relapse after discontinuation of ECT. OBJECTIVE: To determine the efficacy of continuation pharmacotherapy with nortriptyline hydrochloride or combination nortriptyline and lithium carbonate in preventing post-ECT relapse. DESIGN: Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1998, stratified by medication resistance or presence of psychotic depression in the index episode. SETTING: Two university-based hospitals and 1 private psychiatric hospital. PATIENTS: Of 290 patients with unipolar major depression recruited through clinical referral who completed an open ECT treatment phase, 159 patients met remitter criteria; 84 remitting patients were eligible and agreed to participate in the continuation study. INTERVENTIONS: Patients were randomly assigned to receive continuation treatment for 24 weeks with placebo (n = 29), nortriptyline (target steady-state level, 75-125 ng/mL) (n = 27), or combination nortriptyline and lithium (target steady-state level, 0.5-0.9 mEq/L) (n = 28). MAIN OUTCOME MEASURE: Relapse of major depressive episode, compared among the 3 continuation groups. RESULTS: Nortriptyline-lithium combination therapy had a marked advantage in time to relapse, superior to both placebo and nortriptyline alone. Over the 24-week trial, the relapse rate for placebo was 84% (95% confidence interval [CI], 70%-99%); for nortriptyline, 60% (95% CI, 41%-79%); and for nortriptyline-lithium, 39% (95% CI, 19%-59%). All but 1 instance of relapse with nortriptyline-lithium occurred within 5 weeks of ECT termination, while relapse continued throughout treatment with placebo or nortriptyline alone. Medication-resistant patients, female patients, and those with more severe depressive symptoms following ECT had more rapid relapse. CONCLUSIONS: Our study indicates that without active treatment, virtually all remitted patients relapse within 6 months of stopping ECT. Monotherapy with nortriptyline has limited efficacy. The combination of nortriptyline and lithium is more effective, but the relapse rate is still high, particularly during the first month of continuation therapy.

Gender and psychiatric comorbidity: impact on clinical presentation of alcohol dependence.

We examined differences in clinical presentation for outpatient alcohol treatment in: 1) males and females, considering comorbidity; and 2) three comorbid groups, considering gender. Drinking indices and emotional, physical, and sexual abuse reports were compared in 127 male and 69 female alcohol-dependent patients who have a current (36.2%) or lifetime (20.4%) psychiatric disorder or who never had a psychiatric disorder (43.4%). Females reported more emotional and physical abuse than males. Females reported drinking smaller volumes of alcohol but on more days than males. All with current comorbidity, irrespective of gender, reported more days of heavy drinking than other groups. When evaluating drinking status, gender and comorbidity should be considered.

Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype.

BACKGROUND: Characteristic behaviors of some alcohol-dependent individuals, e.g., binge drinking, comorbid psychopathology, and some types of alcohol-related problems, have been linked to abnormalities in serotonergic neurotransmission. However, studies that have evaluated serotonergic pharmacotherapy for reducing drinking have yielded conflicting results. One explanation for these findings is a general failure to distinguish alcohol subgroups that may be differentiated on the basis of serotonergic abnormalities. However, in 1996, Kranzler and colleagues reported that Type B alcoholics, who are characterized by high levels of premorbid vulnerability, alcohol dependence severity, and comorbid psychopathology, showed less favorable drinking outcomes in response to treatment with fluoxetine, a serotonin reuptake inhibitor, than with placebo. This medication effect was not seen in Type A alcoholics, i.e., those with lower risk/severity of alcoholism and psychopathology. The aim of the present study was to explore the validity of differential responding by alcohol-dependent subtypes using the serotonin reuptake inhibitor, sertraline. METHODS: A k-means clustering procedure was applied to a sample of alcohol-dependent subjects enrolled in a 14-week, placebo-controlled trial of 200 mg/day of sertraline, classifying them into lower-risk/severity (Type A: n = 55) and higher-risk/severity (Type B: n = 45) subgroups. RESULTS: A significant interaction between alcoholic subtype and medication condition was found, confirming the findings of Kranzler and colleagues that alcoholic subtypes responded differentially to serotonergic medication. Somewhat at variance with their results, however, the present study showed that the lower risk/severity (Type A) subjects had more favorable outcomes when treated with sertraline compared to placebo. CONCLUSIONS: Alcoholic subtypes differentially responded to sertraline when used as a treatment to reduce alcohol drinking, with one subtype having more favorable outcomes. Subtyping alcoholics may help to resolve conflicting findings in the literature on serotonergic treatment of alcohol dependence.

Improving naltrexone response: an intervention for medical practitioners to enhance medication compliance in alcohol dependent patients.

The effectiveness of naltrexone, a FDA-approved medication for alcohol dependence, can be improved if we support and help patients to consistently take their medication. We illustrate how patient noncompliance with treatment negatively affects outcome, and, we describe a new intervention to enhance medication compliance. Outcome was evaluated for 196 alcohol dependent outpatients who were treated with 50 mg/day naltrexone or placebo for 12 weeks. For patients who adhered to the prescribed treatment, relapse rates were lower with naltrexone than placebo (10% vs. 38.6%, p < 0.001). For noncompliant patients, relapse rates were high and comparable between naltrexone- and placebo-treated patients (42.9% vs. 40%). In a second study of 100 alcohol dependent outpatients, we introduced an intervention that resulted in better medication compliance rates compared to a previous naltrexone study of patients who did not receive the intervention (77.0% vs. 60.8%, p < 0.01). This provided some support for the use of an intervention that targets medication compliance when prescribing naltrexone.

Role of serotonin and serotonin-selective pharmacotherapy in alcohol dependence.

The majority of studies that have examined the usefulness of pharmacotherapies selective for serotonin (5-hydroxytryptamine; 5-HT) as a treatment for alcohol dependence have been standard, double-blind clinical trials that include patients with a variety of clinical presentations. Almost all of the early studies evaluated heavy social drinkers and found only a modest advantage for 5-HT pharmacotherapies in reducing the number of drinks per day. Also, the advantage of these pharmacotherapies was observed primarily when these agents were given at higher daily dosages than suggested prescribing practices for use as an antidepressant. The few studies that evaluated treatment-seeking patients found that 5-HT pharmacotherapies were not instrumental in reducing drinking rates compared with placebo. These results led to a dampening of enthusiasm for use of these agents in treating alcohol dependence. However, more recent investigations have begun to target subgroups with potential abnormalities in 5-HT neurotransmission. The thinking is that these medications should be most useful in alcohol-dependent individuals who have more clearly delineated suggestive signs of 5-HT dysfunction, such as concomitant depression or anxiety. Although few results are available to date, there is growing evidence to suggest that alcohol-dependent subgroups are differentially responsive to 5-HT pharmacotherapies with respect to drinking-related outcomes. This may explain the modest and variable 5-HT pharmacotherapeutic effects that were reported in the earlier studies, which included large heterogeneous patient groups. Further investigations are needed to confirm these initial optimistic results.

Inpatient alcohol treatment in a private healthcare setting: which patients benefit and at what cost?

This study investigated whether selected patients have better outcomes with inpatient than outpatient treatment. There were 93 inpatients and 80 outpatients with alcohol dependence who were evaluated at treatment entry to a private healthcare setting. Patients with multiple drinking-related consequences were less likely to return to significant drinking in the first 3 months after treatment ended if they had attended inpatient compared to outpatient treatment. Thus, inpatient appeared to have some advantage over outpatient treatment in the early recovery period for patients with multiple drinking-related consequences. The gap between inpatient and outpatient costs was also reduced when computed as a cost-effectiveness ratio, although treatment costs continued to remain proportionally higher with inpatient than outpatient treatment.

Psychometric properties of the Penn Alcohol Craving Scale.

BACKGROUND: This study introduces the Penn Alcohol Craving Scale (PACS), which has been used in several clinical trials at the University of Pennsylvania's Treatment Research Center. The PACS is a five-item, self-report measure that includes questions about the frequency, intensity, and duration of craving, the ability to resist drinking, and asks for an overall rating of craving for alcohol for the previous week. Each question is scaled from 0 to 6. METHODS: To examine the questionnaire's psychometric properties, we sampled responses from 147 individuals participating in a 9-month combined natrexone (100 mg/day)/psychotherapy trial. The psychotherapy consisted of weekly sessions of nurse-administered medication compliance and supportive treatment. RESULTS: The PACS proved to have excellent internal consistency. Predictive validity was demonstrated via a logistic regression analysis of craving during the 2nd week of the study on alcohol relapse during weeks 3-12 of the trial. Construct validity of the PACS was demonstrated via its convergence with two commonly used measures for assessing craving, the Obsessive Compulsive Drinking Scale and the Alcohol Urge Questionnaire. Lack of correlation between PACS scores and several other noncraving, self-report measures indicates that the PACS also had good discriminant validity. Additional analyses revealed that there were significant differences in craving scores during the initial 3 weeks of the trial among those who did and those who did not relapse during weeks 3-12. CONCLUSION: The PACS is a reliable and valid measure of alcohol craving and can predict which individuals are at risk for subsequent relapse.

The relationship of Axis II personality disorders to other known predictors of addiction treatment outcome.

This study evaluated the prevalence of Axis II disorders in substance abuse patients and the relationship between Axis II psychopathology and two other known predictors of adverse addiction treatment outcomes, i.e., Axis I psychiatric comorbidity and illegal drug use, specifically cocaine. 232 patients with cocaine and/or alcohol dependence were admitted to either inpatient or outpatient addiction recovery programs at Carrier Foundation, a nonprofit, private-pay hospital in New Jersey. Axis II disorders were more prevalent in cocaine than alcohol dependence and in patients with Axis I psychiatric comorbidity. When all three predictors were evaluated in one prediction model, the combination of Axis I and II psychopathology was the best predictor of a return to substance use at one year post-treatment, compared to the three factors alone. These findings highlighted the importance of the interrelationship of the relative prognostic value of three known predictors of addiction treatment.

The effects of naltrexone on alcohol and cocaine use in dually addicted patients.

Concurrent dependence on cocaine and alcohol is common among patients seeking addiction treatment. This study was undertaken to explore the effectiveness of naltrexone (150 mg) as a potential treatment for patients who are alcohol and cocaine dependent. Of 15 subjects enrolled in the 12-week, open medication trial, 7 subjects did not complete the study. Relapse to clinically significant drinking occurred in 7 subjects (47%). There was a reduction in the average daily amount of alcohol consumed from pretreatment to treatment (p < .001) and the percentage of days engaged in drinking behavior (p < .001). Similarly, there was a reduction in the average weekly amount spent on cocaine from pretreatment to treatment (p = .001) and the percentage of days using cocaine (p < .001). This preliminary study suggests that naltrexone (150 mg) may be tolerable in patients dependent upon alcohol and cocaine and may be effective in reducing both cocaine and alcohol use. The results of this study provide a rationale for a double-blind placebo-controlled study of the efficacy of naltrexone in this difficult to treat but prevalent population.

Reliability and validity of the aggregate method of determining number of cigarettes smoked per day.

The authors evaluated the reliability of two pretreatment assessments (screening and intake) of cigarettes smoked per day (CPD) by the commonly used aggregate method. The validity of the aggregate method was also determined by comparison with results of the timeline followback (TLFB) method for the identical periods. The study participants were 49 outpatients undergoing nicotine patch treatment. The reliability of the two aggregate method evaluations of CPD was quite high by Pearson product-moment correlation (r) and good when based on the intraclass correlation. Correspondence between the CPD assessments based on the aggregate and TLFB methods for the two time-points ranged from fair (screening) to good (intake). Overall, the study findings indicate that the aggregate method provides reasonably consistent data.

Clinical correlations with carbohydrate-deficient transferrin levels in women with alcoholism.

Carbohydrate-deficient transferrin (CDT) has received increasing attention as a potential biological marker for heavy drinking or as an objective marker of relapse in patients who are treated for alcohol dependence. Previous studies have demonstrated the utility of CDT among men, but there are fewer and inconsistent reports on the utility of CDT among women. This study reports in a sample of 40 alcohol-dependent women, the association between CDT levels, and several different types of measures of drinking intensity including frequency of heavy drinking. Although the majority of drinking indices correlated with CDT levels in men, among women, CDT levels were significantly correlated with the percentage of days of heavy drinking when heavy drinking day was defined as drinking 6 or more drinks per drinking day. The results also support an association between current menstrual function, CDT levels, and drinking indices. These findings suggest that the pattern of drinking (combining high frequency and high intensity) may be an important determinant of CDT levels in women with alcohol dependence, compared with men.

Low use of neuroleptic drugs in the treatment of psychotic major depression.

OBJECTIVE: The adequacy of pharmacologic treatment received by patients with psychotic major depression was evaluated. METHOD: The authors systematically assessed the pharmacotherapy received by 187 depressed patients before initiation of ECT and compared the medication trials of those with psychotic (N = 53) and nonpsychotic (N = 134) depression. RESULTS: Despite a median of four medication trials and median index episode duration of 20 weeks, only two (4%) of the patients with psychotic depression received at least one adequate pharmacotherapy trial. In contrast, 70 (52%) of the patients with nonpsychotic depression received at least one adequate trial. Twenty-five (47%) of the patients with psychotic depression received either no neuroleptic treatment (N = 11) or treatment for less than 3 weeks (N = 14). Only eight (15%) received a daily neuroleptic dose higher than 200 mg of chlorpromazine equivalents. CONCLUSIONS: These findings suggest that many patients with psychotic major depression referred for ECT receive inadequate pharmacotherapy because of either the absence or the inadequate use of neuroleptic medication.

Carbohydrate-deficient transferrin: an investigative biochemical marker of heavy alcohol consumption.

Carbohydrate-deficient transferrin (CDT) has been identified as a potential biochemical marker of heavy alcohol consumption. Published studies to date primarily have focused on the ability of CDT levels to distinguish individuals with heavy alcohol drinking from nondrinking populations. In contrast, this study examines the utility of CDT levels in distinguishing alcohol-dependent patients who drink heavily from those who drink smaller amounts. This study also evaluates the potential relationship of CDT to severity of alcohol dependence and its gender differences. Serum was collected in 38 DSM-III-R alcohol-dependent outpatients at treatment entry (22 males, 16 females). CDT levels correlated with the extent of alcohol drinking in the month before treatment in males (r = 0.56, df = 20, p < .01), but not in females (r = 0.08, df = 14, NS). CDT levels also correlated with alcohol severity at pre-treatment in males (r = 0.53, df = 20, p < .05), but not in females (r = 0.27, df = 14, NS). Thus, elevated CDT levels may be mediated by alcohol severity, distinguishing CDT not only as a marker of heavy drinking, but also as an indicator of the severity of drinking-related biological and psychosocial dysfunction that may require further intervention.

Gender differences in comorbidly depressed alcohol-dependent outpatients.

UNLABELLED: Clinical profiles of alcohol-dependent male and female outpatients were evaluated at treatment entry to compare the level of clinical severity in alcoholics with a coexistent comorbid depressive disorder to alcoholics who have never been depressed. Due to a higher proportion of females than males in the depressed alcoholic population, selected patient groups were oversampled to create a study group with equivalent number of males and females with and without comorbid depression. Clinical severity was assessed by examining both the extent of alcohol problems, and depressive symptomatology at treatment entry with respect to gender differences (unrelated to depression), effects of comorbid depression (unrelated to gender), and effects from the interaction of gender and depression. There were 93 DSM-III-R alcohol-dependent outpatients (50 males, 43 females), half of whom had a current or lifetime DSM-III-R depressive disorder. The amount of drinking in the 90 days before treatment entry, the degree of alcohol severity, and the number of lifetime drinking-related consequences were collected in the first week after detoxification. Diagnoses of lifetime and current depression were determined via the Structured Clinical Interview for DSM-III-R, and depressive symptoms were evaluated with rating scales 1 week after detoxification. In most cases, a depressive disorder was diagnosed only if sometime in the patient's history depressive symptoms had either predated problem drinking or been present during a 6-month abstinent period. RESULTS: depressed males had a more severe clinical profile with respect to their alcoholism (i.e., more drinking, drinking-related problems, and alcohol severity than depressed females and never-depressed males). Surprisingly, females who had never been depressed (also no family history of depression) reported drinking the same quantities of alcohol in the 90 days before treatment and had comparable alcohol severity and number of consequences as males who had never been depressed. Depressed females, however, were more severely depressed (i.e., reported more intensive depressive symptoms than depressed male alcoholics). Thus, determining the type and extent of clinical severity at treatment entry in comorbidly depressed alcoholics depends on the gender of the patient The significant interaction between gender and the presence of comorbid depression that was found in this study may have important implications for predicting success in treatment.