David W. Oslin

A Functional Polymorphism of the μ -Opioid Receptor Gene is Associated with Naltrexone Response in Alcohol-Dependent Patients

This study examined the association between two specific polymorphisms of the gene encoding the μ-opioid receptor and treatment outcomes in alcohol-dependent patients who were prescribed naltrexone or placebo. A total of 82 patients (71 of European descent) who were randomized to naltrexone and 59 who were randomized to placebo (all of European descent) in one of three randomized, placebo-controlled clinical trials of naltrexone were genotyped at the A+118G (Asn40Asp) and C+17T (Ala6Val) SNPs in the gene encoding the μ-opioid receptor (OPRM1). The association between genotype and drinking outcomes was measured over 12 weeks of treatment. In subjects of European descent, individuals with one or two copies of the Asp40 allele treated with naltrexone had significantly lower rates of relapse (p=0.044) and a longer time to return to heavy drinking (p=0.040) than those homozygous for the Asn40 allele. There were no differences in overall abstinence rates (p=0.611), nor were there differences in relapse rates or abstinence rates between the two genotype groups among those assigned to placebo. These preliminary results are consistent with prior literature demonstrating that the opioid system is involved in the reinforcing properties of alcohol and that allelic variation at OPRM1 is associated with differential response to a μ-receptor antagonist. If replicated, these results would help to identify alcohol-dependent individuals who may be most likely to respond to treatment with naltrexone.

Reducing Suicidal Ideation and Depression in Older Primary Care Patients: 24-Month Outcomes of the PROSPECT Study

OBJECTIVE The Prevention of Suicide in Primary Care Elderly: Collaborative Trial (PROSPECT) evaluated the impact of a care management intervention on suicidal ideation and depression in older primary care patients. This is the first report of outcomes over a 2-year period. METHOD Study participants were patients 60 years of age or older (N=599) with major or minor depression selected after screening 9,072 randomly identified patients of 20 primary care practices randomly assigned to provide either the PROSPECT intervention or usual care. The intervention consisted of services of 15 trained care managers, who offered algorithm-based recommendations to physicians and helped patients with treatment adherence over 24 months. RESULTS Compared with patients receiving usual care, those receiving the intervention had a higher likelihood of receiving antidepressants and/or psychotherapy (84.9%-89% versus 49%-62%) and had a 2.2 times greater decline in suicidal ideation over 24 months. Treatment response occurred earlier on average in the intervention group and increased from months 18 to 24, while no appreciable increase in treatment response occurred in the usual care group during the same period. Among patients with major depression, a greater number achieved remission in the intervention group than in the usual-care group at 4 months (26.6% versus 15.2%), 8 months (36% versus 22.5%), and 24 months (45.4% versus 31.5%). Patients with minor depression had favorable outcomes regardless of treatment assignment. CONCLUSIONS Sustained collaborative care maintains high utilization of depression treatment, reduces suicidal ideation, and improves the outcomes of major depression over 2 years.

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.

A "SMART" Design for Building Individualized Treatment Sequences

Interventions often involve a sequence of decisions. For example, clinicians frequently adapt the intervention to an individuals outcomes. Altering the intensity and type of intervention over time is crucial for many reasons, such as to obtain improvement if the individual is not responding or to reduce costs and burden when intensive treatment is no longer necessary. Adaptive interventions utilize individual variables (severity, preferences) to adapt the intervention and then dynamically utilize individual outcomes (response to treatment, adherence) to readapt the intervention. The Sequential Multiple Assignment Randomized Trial (SMART) provides high-quality data that can be used to construct adaptive interventions. We review the SMART and highlight its advantages in constructing and revising adaptive interventions as compared to alternative experimental designs. Selected examples of SMART studies are described and compared. A data analysis method is provided and illustrated using data from the Extending Treatment Effectiveness of Naltrexone SMART study.

Suicidal and Death Ideation in Older Primary Care Patients With Depression, Anxiety, and At-Risk Alcohol Use

The authors identified correlates of active suicidal ideation and passive death ideation in older primary care patients with depression, anxiety, and at-risk alcohol use. Participants included 2,240 older primary care patients (age 65+), who were identified in three mutually exclusive groups on the basis of responses to the Paykel suicide questions: No Ideation, Death Ideation, and Suicidal Ideation. Chi-square, ANOVA, and polytomous logistic regression analyses were used to identify characteristics associated with suicidal ideation. The highest amount of suicidal ideation was associated with co-occurring major depression and anxiety disorder (18%), and the lowest proportion occurred in at-risk alcohol use (3%). Asians have the highest (57%) and African Americans have the lowest (27%) proportion of suicidal or death ideation. Fewer social supports and more severe symptoms were associated with greater overall ideation. Death ideation was associated with the greatest medical comorbidity and highest service utilization. Contrary to previous reports, authors failed to find that active suicidal ideation was associated with increased contacts with healthcare providers. Accordingly, targeted assessment and preventive services should be emphasized for geriatric outpatients with co-occurring depression and anxiety, social isolation, younger age, and Asian or Caucasian race.

Alcohol related dementia: Proposed clinical criteria

Current diagnostic criteria for Alcohol Related Dementia (ARD) are based almost exclusively on clinical judgment. Moreover, there are no guidelines available to assist the clinician or the researcher in distinguishing Alcohol Related Dementia from other causes of dementia such as Alzheimers Disease (AD). However, this distinction may have implications for the prognosis and treatment of patients. In this article, provisional diagnostic criteria for establishing a diagnosis of Alcohol Related Dementia are proposed for further study. The criteria are based on the available literature on the relationship between alcohol consumption and dementia and were modeled after existing diagnostic criteria for AD and Vascular Dementia. Validity of these criteria for distinguishing AD from ARD will require further study.

A Double-Blind, Placebo-Controlled Trial Combining Sertraline and Naltrexone for Treating Co-Occurring Depression and Alcohol Dependence

OBJECTIVE Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence. While some studies have demonstrated that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence, most studies have not found antidepressant treatment helpful in reducing excessive drinking in these patients. The authors provide results from a double-blind, placebo-controlled trial that evaluated the efficacy of combining approved medications for depression (sertraline) and alcohol dependence (naltrexone) in treating patients with both disorders. METHOD A total of 170 depressed alcohol-dependent patients were randomly assigned to receive 14 weeks of treatment with sertraline (200 mg/day [N=40]), naltrexone (100 mg/day [N=49]), the combination of sertraline plus naltrexone (N=42), or double placebo (N=39) while receiving weekly cognitive-behavioral therapy. RESULTS The sertraline plus naltrexone combination produced a higher alcohol abstinence rate (53.7%) and demonstrated a longer delay before relapse to heavy drinking (median delay=98 days) than the naltrexone (abstinence rate: 21.3%; delay=29 days), sertraline (abstinence rate: 27.5%; delay=23 days), and placebo (abstinence rate: 23.1%; delay=26 days) groups. The number of patients in the medication combination group not depressed by the end of treatment (83.3%) approached significance when compared with patients in the other treatment groups. The serious adverse event rate was 25.9%, with fewer reported with the medication combination (11.9%) than the other treatments. CONCLUSIONS More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol, had delayed relapse to heavy drinking, reported fewer serious adverse events, and tended to not be depressed by the end of treatment.

Assessment of late life depression

This article focuses on diagnostic and nosologic challenges intrinsic to geriatric depression, including characteristics interfering with symptom and syndrome ascertainment, the impact of medical and cognitive disorders, the usefulness of screening instruments, and barriers imposed by treatment settings. The article also identifies gaps in existing knowledge and outlines a research agenda. Nosologic characterization of depressives syndromes contributed by specific medical disorders may lead to effective strategies for prevention and treatment of depression. Studies need to examine whether treatment of depression can improve the outcome of medical illnesses requiring active patient involvement in treatment. Considering disability a distinct aspect of health status may add an important dimension to the assessment of depression and result in complementary interventions aimed at depression and disability concurrently. The provisional criteria for depression of Alzheimers disease, if validated, may facilitate treatment research. Studies need to characterize cognitive dysfunctions associated with later development of dementia or poor treatment response in patients with depression. Care managers working together with primary care physicians can improve the recognition and treatment of depressed elderly patients by obtaining the training in using validated instruments and treatment algorithms.

A genetic association study of the mu opioid receptor and severe opioid dependence.

Objectives Twin, family and adoption studies have suggested that vulnerability to opioid dependence may be a partially inherited trait (Cadoret et al., 1986; Merikangas et al., 1998; Tsuang et al., 1998, 2001). Studies using animal models also support a role for genetic factors in opioid dependence, and point to a locus of major effect on mouse chromosome 10 (Berrettini et al., 1994; Alexander et al., 1996), which harbors the mu opioid receptor gene (Mor1) (Kozak et al., 1994). The gene encoding the human mu opioid receptor (OPRM1) is thus an obvious candidate gene for contributing to opioid dependence. A recent report (Hoehe et al., 2000) found a significant association between a specific combination of OPRM1 single nucleotide polymorphisms (SNPs) and substance dependence. Methods In the current study, we genotyped 213 subjects with severe opioid dependence (89 African-Americans, 124 European-Americans) and 196 carefully screened ‘supercontrol’ subjects (96 African-Americans, 100 European-Americans) at five SNPs residing in the OPRM1 gene. The polymorphisms include three in the promoter region (T–1793A, –1699T insertion and A–1320G) and two in exon 1 (C+17T [Ala6Val] and A+118G [Asp40Asn]). Results Statistical analysis of the allele frequency differences between opioid-dependent and control subjects for each of the polymorphisms studied yielded P values in the range of 0.444–1.000. Haplotype analysis failed to identify any specific combination of SNPs associated with the phenotype. Conclusions Despite reasonable statistical power we found no evidence of association between the five mu opioid receptor polymorphisms studied and severe opioid dependence in our sample. There were, however, significant allele frequency differences between African-Americans and European-Americans for all five polymorphisms, irrespective of drug-dependent status. Linkage disequilibrium analysis of the African-American genotypes indicated linkage disequilibrium (P<0.0001) across the five-polymorphism, 1911 base pair region. In addition, only four haplotypes of these five polymorphisms are predicted to exist in African-Americans.

Alcoholism Treatment Adherence: Older Age Predicts Better Adherence and Drinking Outcomes

OBJECTIVE Adherence to treatment has been demonstrated to be an important factor for remission from alcohol dependence. The authors compared therapy and medication adherence for treatment of alcohol dependence in older adults with adherence in younger adults. METHODS All subjects were participants in a randomized, double-blind, placebo-controlled efficacy trial of naltrexone for the treatment of alcohol dependence. All subjects received a medically-based psychosocial intervention focused on motivating patients to change and on adherence to treatment. The therapy is nonconfrontational and is delivered by a nurse-practitioner. RESULTS Compared with younger adults, older adults had greater attendance at therapy sessions and greater adherence to the medication. Age-group was the only pretreatment factor associated with adherence. The greater adherence in older adults translated to less relapse than in younger adults. CONCLUSION Treatment for alcohol dependence can be effective for older adults. Older adults appear to respond well to a medically-oriented program that is supportive and individualized. In fact, findings from this study suggest that older adults can be treated in mixed-age treatment settings when psychotherapeutic strategies are used that are age-appropriate and delivered on an individual basis.