Fine-scale mapping of a locus for severe bipolar mood disorder on chromosome 18p11.3 in the Costa Rican population.

We have searched for genes predisposing to bipolar disorder (BP) by studying individuals with the most extreme form of the affected phenotype, BP-I, ascertained from the genetically isolated population of the Central Valley of Costa Rica (CVCR). The results of a previous linkage analysis on two extended CVCR BP-I pedigrees, CR001 and CR004, and of linkage disequilibrium (LD) analyses of a CVCR population sample of BP-I patients implicated a candidate region on 18p11.3. We further investigated this region by creating a physical map and developing 4 new microsatellite and 26 single-nucleotide polymorphism markers for typing in the pedigree and population samples. We report the results of fine-scale association analyses in the population sample, as well as evaluation of haplotypes in pedigree CR001. Our results suggest a candidate region containing six genes but also highlight the complexities of LD mapping of common disorders.

Genome screening for linkage disequilibrium in a Costa Rican sample of patients with bipolar-I disorder: a follow-up study on chromosome 18.

Linkage disequilibrium (LD) methods offer great promise for mapping complex traits, but have thus far been applied sparingly. In this paper we describe an LD mapping study of severe bipolar disorder (BP-I) in the genetically isolated population of the Central Valley of Costa Rica. This study provides the first complete screen of a chromosome for a complex trait using LD mapping and presents the first application of a new LD mapping statistic (ancestral haplotype reconstruction (AHR)) that evaluates haplotype sharing among affected individuals. The results of this chromosome-wide analysis are instructive for genome-wide LD mapping in isolated populations. Furthermore, the analysis continues to support a possible BP-I locus on 18pter, suggested by previous analyses in this population. Evidence for a possible BP-I locus on 18q12.2 is also described.

Substance abuse and HIV infection.

This chapter reviews the associations between substance use, comorbid psychiatric disorders, and HIV risk behaviors; the prevalence of substance use disorders among HIV-positive individuals in treatment settings; the medical, psychiatric, and substance abuse treatment of individuals with substance use disorders and HIV infection; and finally, HIV risk reduction among substance abusers.

Stimulant psychosis: symptom profile and acute clinical course.

Nineteen patients seen at a psychiatric emergency service with amphetamine- or cocaine-induced psychotic disorder were assessed with structured interviews, chart review, and blood and urine testing. All had a predominance of positive symptoms from the Positive and Negative Syndrome Scale (PANSS). However, some subjects had substantial Negative Scale scores (26%), bizarre delusions (95%), and Schneiderian hallucinations (63%), mimicking a broad range of schizophrenic symptoms. Several PANSS scores were correlated with treatment intensity: Positive score with seclusion hours, General Psychopathology and Negative scores with hospitalization length, and General Psychopathology score with neuroleptic dose. Presenting symptoms may help in treatment planning.

Utility of routine drug screening in a psychiatric emergency setting.

OBJECTIVE: The study determined whether dispositions from an urban psychiatric emergency service would differ between patients who received a mandatory urine drug test and those who may or may not have had a test based on the attending psychiatrist's clinical judgment. The accuracy of clinicians' suspicion of substance use among mandatorily screened patients was also examined. METHODS: A total of 392 consenting patients presenting to an urban psychiatric emergency service were randomly assigned to a mandatory-screen group (N=198) or a usual-care group (N=194). Physicians ordered screens based on clinical judgment. Additional screens were performed without physicians' knowledge for patients in the mandatory-screen group for whom no screen was ordered. Demographic and clinical information, results of drug screens, and information about dispositions were collected from clinical charts or hospital databases. RESULTS: No difference in dispositions was found between the mandatory-screen group and the usual-care group. Survival analysis did not reveal a difference between the two groups in length of stay in inpatient psychiatric units. As for accuracy of physicians' suspicion of substance use, positive drug screens were recorded for 10.2 percent of the 198 patients in the mandatory-screen group who did not admit drug use or for whom physicians did not expect drug use. A total of 39.3 percent of the patients who were suspected of use and 88.2 percent of those who admitted use had positive drug screens. Only 20.8 percent of patients who denied substance use had positive screens. CONCLUSIONS: Routine urine drug screening in a psychiatric emergency service did not affect disposition or the subsequent length of inpatient stays. The results do not support routine use of drug screens in this setting.

Patterns of substance use among patients in an urban psychiatric emergency service.

Data from patients visiting an urban psychiatric emergency service in California were examined to document incidence and patterns of substance use and ethnic differences among users. A total of 392 patients were randomly assigned to receive a drug screen (N = 198) or to receive usual care (N = 194). Forty-four percent of the mandatorily screened patients had positive screens for any substances: 37 percent were positive for any drugs, and 7 percent were positive for alcohol only. Cocaine was present in 62 percent of the drug-positive screens. Blacks were two and a half times more likely than whites to have positive screens for drugs and five times more likely to have positive screens for cocaine.

Sulfonium salts as derivatizing agents. 3. Quantitation of the cocaine metabolite benzoylecgonine in urine using gas chromatography with ion-pair extraction/on-column alkylation.

Recent studies have demonstrated the utility of quantitative assays for benzoylecgonine in assessing the efficacy of cocaine-dependence-treatment programs to determine if the amount of cocaine consumed has been reduced. We describe a simple gas chromatographic method for determining benzoylecgonine concentrations in urine. BZE is extracted from urine as an ion pair with tri-n-propylsulfonium ion. Injection into the heated injection port of the gas chromatograph results in thermal conversion of the ion pair to the n-propyl ester of BZE. Using the structural analogue of BZE, m-toluylecgonine, as the internal standard, the analysis is carried out on a (5% phenyl)methylpolysiloxane capillary column with nitrogen-phosphorus detection. There was a good correlation between BZE concentrations determined by gas chromatography-mass spectrometry and concentrations determined by the method described in this paper. Application to cocaine-dependence-treatment programs is discussed.

Assessing the feasibility of linkage disequilibrium methods for mapping complex traits: an initial screen for bipolar disorder loci on chromosome 18.

Linkage disequilibrium (LD) analysis has been promoted as a method of mapping disease genes, particularly in isolated populations, but has not yet been used for genome-screening studies of complex disorders. We present results of a study to investigate the feasibility of LD methods for genome screening using a sample of individuals affected with severe bipolar mood disorder (BP-I), from an isolated population of the Costa Rican central valley. Forty-eight patients with BP-I were genotyped for markers spaced at approximately 6-cM intervals across chromosome 18. Chromosome 18 was chosen because a previous genome-screening linkage study of two Costa Rican families had suggested a BP-I locus on this chromosome. Results of the current study suggest that LD methods will be useful for mapping BP-I in a larger sample. The results also support previously reported possible localizations (obtained from a separate collection of patients) of BP-I-susceptibility genes at two distinct sites on this chromosome. Current limitations of LD screening for identifying loci for complex traits are discussed, and recommendations are made for future research with these methods.

Medication adherence strategies for drug abusers with HIV/AIDS.

This paper describes two clinical techniques aiming to improve adherence to medications for HIV/AIDS in methadone maintenance patients. The first technique, providing on-site dispensing of antiretroviral medications, enhanced medication adherence but did not produce enduring effects beyond the time of the intervention. To develop a more long-lasting intervention, the programme is experimenting with more individualized medication management, in which a staff member provides assessment and problem solving to help improve medication adherence. Clinical and practical issues are presented--including each technique's aims, screening and recruitment of participants, description of the technique, staff and administrative support issues, and research results. The paper aims to assist staff in drug treatment programmes to implement interventions that can increase adherence to medications for HIV/AIDS.

Buprenorphine maintenance treatment of opiate dependence: a multicenter, randomized clinical trial.

AIMS: To evaluate the safety and efficacy of an 8 mg/day sublingual dose of buprenorphine in the maintenance treatment of heroin addicts by comparison with a 1 mg/day dose over a 16-week treatment period. As a secondary objective, outcomes were determined concurrently for patients treated with two other dose levels. DESIGN: Patients were randomized to four dosage groups and treated double-blind. SETTING: Twelve outpatient opiate maintenance treatment centers throughout the United States. PARTICIPANTS: Two hundred and thirty-nine women and 497 men who met the DSM-III-R criteria for opioid dependence and were seeking treatment. INTERVENTION: Patients received either 1, 4, 8 or 16 mg/day of buprenorphine and were treated in the usual clinical context, including a 1-hour weekly clinical counseling session. MEASUREMENT: Retention in treatment, illicit opioid use as determined by urine toxicology, opioid craving and global ratings by patient and staff. Safety outcome measures were provided by clinical monitoring and by analysis of the reported adverse events. FINDINGS: Outcomes in the 8 mg group were significantly better than in the 1 mg group in all four efficacy domains. No deaths occurred in either group. The 8 mg group did not show an increase in the frequency of adverse events. Most reported adverse effects were those commonly seen in patients treated with opioids. CONCLUSIONS: The findings support the safety and efficacy of buprenorphine and suggest that an adequate dose of buprenorphine will be a useful addition to pharmacotherapy.

Buprenorphine and naloxone interactions in methadone maintenance patients.

Buprenorphine is undergoing clinical trials for the treatment of opiate addiction. Although the abuse liability of sublingual buprenorphine is low, reports of intravenous abuse have appeared. This study describes the physiologic and subjective effects of intravenously administered buprenorphine and naloxone given alone and in combination to methadone-maintained patients (40-60 mg/day). On four separate occasions at least 1 day apart, 6 subjects were administered either 0.2 mg buprenorphine, 0.1 mg naloxone, 0.2 mg buprenorphine and 0.1 mg naloxone in combination, or placebo. One male subject quit the experiment after three sessions because of excessive opiate withdrawal. Buprenorphine produced no significant physiologic or subjective effects. Naloxone produced marked opiate withdrawal symptoms. Buprenorphine in combination with naloxone produced characteristic physiologic and subjective opiate antagonist-like symptoms and signs. The parenteral abuse potential of the buprenorphine and naloxone combination is discussed.

Measurement properties of quantitative urine benzoylecgonine in clinical trials research.

Psychometric data are presented which examine the validity of using the concentration of benzoylecgonine in urine, a major metabolite of cocaine, as a measure of drug use, in studies of drug abuse treatments. In such research the standard biological indicator of drug use is usually a qualitative urine drug test, which merely indicates the presence or absence of a drug or its metabolite. A quantitative (i.e. continuous) outcome measure, such as the concentration of a drug or its metabolite in a biological fluid, has substantially more statistical power than a dichotomous measure and should, therefore, prove a more sensitive measure of drug use when viewed from a measurement perspective. Data from two placebo-controlled clinical trials of fluoxetine as an adjunct to treatment for cocaine abuse are analyzed to address this issue. Results indicate that urine benzoylecgonine level is closely related to self-reports of drug use and is independent of levels of anxiety, depression and hopelessness.

A complete genome screen for genes predisposing to severe bipolar disorder in two Costa Rican pedigrees.

Bipolar mood disorder (BP) is a debilitating syndrome characterized by episodes of mania and depression. We designed a multistage study to detect all major loci predisposing to severe BP (termed BP-I) in two pedigrees drawn from the Central Valley of Costa Rica, where the population is largely descended from a few founders in the 16th-18th centuries. We considered only individuals with BP-I as affected and screened the genome for linkage with 473 microsatellite markers. We used a model for linkage analysis that incorporated a high phenocopy rate and a conservative estimate of penetrance. Our goal in this study was not to establish definitive linkage but rather to detect all regions possibly harboring major genes for BP-I in these pedigrees. To facilitate this aim, we evaluated the degree to which markers that were informative in our data set provided coverage of each genome region; we estimate that at least 94% of the genome has been covered, at a predesignated threshold determined through prior linkage simulation analyses. We report here the results of our genome screen for BP-I loci and indicate several regions that merit further study, including segments in 18q, 18p, and 11p, in which suggestive lod scores were observed for two or more contiguous markers. Isolated lod scores that exceeded our thresholds in one or both families also occurred on chromosomes 1, 2, 3, 4, 5, 7, 13, 15, 16, and 17. Interesting regions highlighted in this genome screen will be followed up using linkage disequilibrium (LD) methods.

Psychiatric morbidity, illicit drug use and adherence to zidovudine (AZT) among injection drug users with HIV disease.

This study describes the relationship between the need for psychiatric consultation, illicit drug use, and zidovudine (AZT) adherence in HIV-infected injection drug users (IDUs) in methadone maintenance treatment (MMT). The treatment records of 57 IDUs in MMT who had been prescribed AZT between May and August of 1991 were reviewed. Those who required psychiatric consultation (P+, N = 46, 81%) were compared with those who did not require psychiatric consultation (P-, N = 11, 19%) on adherence to AZT treatment (using the mean corpuscular volume [MCV] as a biological marker), on recent illicit drug use, and on CD4 lymphocyte (T cell) count changes from the beginning to the end of AZT treatment. The P+ subjects were less likely than P- subjects to adhere to AZT treatment: fewer in the P+ group had an MCV outside of the normal range, and P+ subjects had a lower average monthly increase in MCV since the beginning of AZT treatment. Recent illicit drug use and CD4 lymphocyte count changes from the beginning to the end of AZT treatment did not show group differences. Psychiatric morbidity among HIV-infected IDUs in MMT is common, and may contribute to poor adherence to AZT treatment. Psychiatric screening and adherence-enhancing interventions should be targeted to IDUs entering drug treatment programs.

A controlled trial of fluoxetine in crack cocaine dependence.

This controlled study tested the efficacy of the selective serotonergic reuptake inhibitor fluoxetine in the out-patient treatment of primary crack cocaine dependence. Thirty-two subjects were randomly assigned, 16 in each group, to placebo or fluoxetine, 40 mg/day, in a double-blind controlled trial over a 12-week period. Outcome measures included quantitative urine benzoylecgonine concentration, self-reports of cocaine use and craving, and treatment retention. Subjects assigned to fluoxetine were retained in treatment significantly longer than those on placebo: a median of 11 weeks compared to 3 weeks (logrank test, P < 0.001). Because of the poor retention in the placebo group, between-groups comparisons of outcome were limited to the first 6 weeks of treatment. No differences in cocaine use or craving were found between the two groups over weeks 1 to 6. The significant improvement in retention associated with fluoxetine may support further study of this medication in the treatment of cocaine dependence.

An approach to investigating linkage for bipolar disorder using large Costa Rican pedigrees.

Despite the evidence that major gene effects exist for bipolar disorder (BP), efforts to map BP loci have so far been unsuccessful. A strategy for mapping BP loci is described, focused on investigation of large pedigrees from a genetically homogenous population, that of Costa Rica. This approach is based on the use of a conservative definition of the BP phenotype in preparation for whole genome screening with polymorphic markers. Linkage simulation analyses are utilized to indicate the probability of detecting evidence suggestive of linkage, using these pedigrees. These analyses are performed under a series of single locus models, ranging from recessive to nearly dominant, utilizing both lod score and affected pedigree member analyses. Additional calculations demonstrate that with any of the models employed, most of the information for linkage derives from affected rather than unaffected individuals.

Genetic mapping using haplotype, association and linkage methods suggests a locus for severe bipolar disorder (BPI) at 18q22-q23.

Manic depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome ot two Costa Rican BPI pedigrees (McInnes et al., submitted). We considered only individuals who fulfilled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.

Adherence to zidovudine (AZT) among HIV-infected methadone patients: a pilot study of supervised therapy and dispensing compared to usual care.

Twenty-seven HIV-infected methadone maintenance patients who demonstrated problems adhering to zidovudine (AZT) were randomly assigned to a group that received eight weeks of weekday supervised therapy and dispensing of AZT or a group that received usual care of the clinic. Adherence was assessed by self-report, erythrocyte mean corpuscular volume (MCV), Medication Event Monitoring Systems (MEMS), and pill counts. Subjects in the intervention group demonstrated significantly higher MCV levels during the intervention period than usual care subjects, with similar but non-significant trends for the three other adherence measures. MEMS percent indicated significant group differences on weekdays, but not weekend days. There were no differences at a one-month follow-up. Results suggest supervised therapy and dispensing may be an effective strategy for improving AZT adherence, but only while provided. Further research is needed to establish the effects of larger and longer lasting interventions.