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.

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.

Alcohol use in late life: disability and comorbidity.

Alcohol use by older adults is common, yet the risks and/or benefits of drinking, especially moderate drinking, are not well understood. Heavy drinking is a well-established factor in causing disability and excessive mortality among all age groups, including the elderly. However, literature is emerging that suggests that among elders with chronic medical and emotional health disorders, even modest alcohol consumption can lead to excessive disability and poorer perceived health. This article reviews the current literature on alcohol use and the relationship to common health problems in late life and suggests a model for examining the interaction of alcohol use and disability. Implications for intervention development are also discussed.

Effects of alcohol consumption on the treatment of depression among elderly patients.

The authors examined the effects of alcohol use on the short-term and 3-4-month treatment outcomes of patients with late-life depression. Patients (N=2,666) were assessed for symptoms of depression, alcohol use, and disability during an initial inpatient hospitalization and then 3-4 months postdischarge. Contrary to our hypothesis that alcohol consumption imparted a significant additive detriment to treatment outcome in patients already suffering from major depression, the results suggest that treatment was effective even in those with concomitant use of alcohol. Moreover, there appeared to be an added benefit when even modest alcohol consumption was decreased among elderly patients suffering from depression.

Change in disability follows inpatient treatment for late life depression.

OBJECTIVES: The objective of this study was to examine the relationship between functional disability and improvement in late life depression after acute inpatient treatment. DESIGN: The study was a longitudinal assessment of depression and disability. Patients were assessed during an initial inpatient hospitalization and then 3 months postdischarge. SETTING: All patients were evaluated initially after admission to one of 71 inpatient psychiatric treatment facilities. PARTICIPANTS: The study comprised of 2572 patients older than age 60 who were relatively cognitively intact and experiencing significant depressive symptoms. MEASUREMENTS: Depressive symptoms were measured using the Geriatric Depression Scale. Disability was measured using the Instrumental Activities of Daily Living Scale and the Medical Outcomes SF-36. RESULTS: Depressive symptoms improved in the majority of patients. Moreover, improvement in depressive symptomatology was significantly related to improvement in instrumental activities of daily living (IADLs) and to health-related quality of life as measured by the SF-36. This relationship was strongest among those who initially presented with some disability in IADLs. CONCLUSIONS: This work underscores further the disabling nature of depression. Moreover, findings from this study suggest that treatment focused on depression can lead to significant improvements in both depressive symptoms and functional abilities. However, the results also suggest that the relationship between depression and disability is complex and that the effect of treating depression is not the only factor in the reversal of disability.

Heuristic comparison of sertraline with nortriptyline for the treatment of depression in frail elderly patients.

Studies have demonstrated that the selective serotonin reuptake inhibitor antidepressants have similar efficacy to other agents, such as tricyclic antidepressants. However, data are limited for direct comparisons with other antidepressants. The authors conducted a contemporaneous comparison of nursing home residents treated with open-label sertraline in doses up to 100 mg/day with nursing home residents treated in a double-blind randomized study of low vs. regular doses of nortriptyline. There were 97 patients enrolled in the study (28 treated with sertraline), with an average treatment duration of 55 days. There were no differences in the tolerability of sertraline vs. nortriptyline. However, in this group of frail older adults, sertraline was not as effective as nortriptyline for the treatment of depression.

Drug treatment of depression in frail elderly nursing home residents.

The authors conducted a randomized, double-blind, 10-week clinical trial of two doses of nortriptyline in eight nursing homes. Sixty-nine patients, average age 79.5 years, were randomized to receive regular doses (60 mg-80 mg/day) vs. low doses (10 mg-13 mg/day) of nortriptyline. Among the more cognitively intact patients, there was a significant quadratic relationship defining a "therapeutic window" for nortriptyline plasma levels and clinical improvement. There were also significant differences in plasma level-response relationships between depressed patients who were cognitively impaired and those who were more cognitively intact. Depression remains a syndrome that responds to specific treatment, even in frail nursing home patients, and those depressions that occur in patients with significant dementia may represent a treatment-relevant condition with a different plasma level-response relationship than in depression alone.

The BRENDA model: a psychosocial addiction model to identify and treat alcohol disorders in elders.

Studies have shown that up to 10% of the elderly drink daily and as much as 4% have alcoholism. Although many elders visit a primary care provider, the problem frequently is overlooked or misdiagnosed. We have found that primary care-based nursing is an effective treatment for older adults with alcoholism. In this article, we introduce the BRENDA model and show its effectiveness in retaining older adults in treatment. BRENDA involves biopsychosocial assessment, reporting the assessment to the patient, an empathetic approach, identified and stated patient needs, direct advice to stop or decrease alcohol consumption, and assessment of the compliance with or outcome of the direct advice. We also describe the utility of the BRENDA model for the pharmacotherapeutic treatment of addiction in late life.

The disabling nature of comorbid depression among older DUI recipients.

Alcoholism and depression are two of the most common and disabling mental illnesses in late life. This study is a descriptive report of a sample of 49 adults who had recently been convicted of Driving Under the Influence of alcohol (DUI). A lifetime history of alcohol abuse or dependence was present in 48 subjects (98%), while a depressive disorder occurred in 24 (49%) of the subjects. Concurrent alcoholism and depression, present in 12 subjects (24.5%), produced greater self-reported disability compared to those subjects with alcoholism alone. One-year longitudinal follow-up was available on 31 subjects (63.3%). Over the course of one year, there were no changes in drinking behavior, depressive symptoms, or self-reported quality of life. These data support previous studies that suggest greater disability in patients with concurrent mental illnesses.

Examination of the cognitive effects of cimetidine in normal elderly volunteers.

The authors evaluated the cognitive effects of acute challenges with the H2 receptor-antagonist cimetidine in normal older volunteers. The study was a double-blind, placebo-controlled, crossover study of 12 volunteers, average age 71.25 years. Baseline assessment was followed by randomized administration of a placebo or ascending doses of cimetidine (400 mg, 800 mg, or 1,600 mg) in test sessions separated by 1 week. Cognitive performance was evaluated with a 1-hour battery of tests beginning 90 minutes after administration of a single dose of drug (or placebo). There were no significant cognitive decrements associated with cimetidine. Despite numerous case reports of cognitive toxicity, this study found no observable decrements in cognitive performance in a group of healthy elderly subjects; therefore, case reports in the literature may be reporting effects for patients with specific impairments or sensitivities.

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.

Exploring the affective toxicity of commonly prescribed medications in the elderly.

Adverse effects of medications that occur at low frequency or low severity are often not detected in the current framework of drug approval and monitoring. Of particular concern are potential behavioral consequences such as depression or cognitive dysfunction that may occur from commonly prescribed medications. This study explores the use of measuring daily affect, both positive and negative, as a method for detecting clinically relevant affective toxicity from medications commonly prescribed to older adults. Findings from this study suggest that metoclopramide may have the potential for causing significant changes in affect among healthy elderly adults. This may suggest that more vulnerable or disabled adults may be at even greater risk for affective changes related to this medication.

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.

Alcohol abuse: a source of reversible functional disability among residents of a VA nursing home.

The prevalence of psychiatric disorders was determined in a sample of 196 VA nursing home residents who were interviewed using the modified Schedule for Affective Disorders and Schizophrenia (mSADS). Of the 160 subjects for whom data were available, 86% had a diagnosis of at least one psychiatric disorder. The prevalence of clinically significant cognitive impairment was 60.6% and of major depression 13.8%. Of 110 residents for whom alcohol histories were obtained, 32 (29%) had a lifetime diagnosis of alcohol abuse. The degree of impairment in activities of daily living improved significantly from the time of admission to the time of the evaluation (average 1.4 years) among those who were recently abusing alcohol compared to those who formerly abused alcohol and those who never abused alcohol. The effect is clinically as well as statistically significant and has the potential benefit of reducing caregiver burden and health care costs for the elderly.

Early versus late onset of alcoholism in the elderly.

The age of onset of alcohol-related problems is a typology that is gaining prominence among clinicians. Findings from epidemiological studies suggest that there are a significant number of older alcoholics who first begin to drink alcohol "abusively" in their later years. While few demographic differences appear between late onset and early onset alcoholics, a number of studies have reported clinical differences between these groups that may affect the natural course and treatment outcome of the illness.

Alcoholism in older persons: a review of the literature.

Alcohol abuse and dependence in elderly persons is of growing social concern. The most consistent findings of cross-sectional and longitudinal studies are that the quantity and frequency of alcohol consumption is higher in elderly men than in elderly women, as is the prevalence of alcohol-related problems. Most studies show a decrease with age in consumption and alcohol-related problems among heavy drinkers. Longitudinal studies show no changes in consumption among light drinkers. Elderly persons with lower incomes consume less alcohol than those with higher incomes. Hospitalized and outpatient populations have more problem drinkers, and the elderly alcoholic is at greater risk for medical and psychiatric comorbidity. About one-third to one-half of elderly alcoholics experience the onset of problem drinking in middle or late life. Outcomes seem to be better for those who have late-onset drinking and may be improved for those treated in same-age rather than mixed-age groups.