Clinical indicators for the use of antidepressants in the treatment of bipolar I depression.

OBJECTIVES: Current guidelines provide little practical information on the clinical characteristics of bipolar I patients who are likely to benefit from the combination of a mood stabilizer and an antidepressant. Rather, guidelines simply state that an adjunctive antidepressant is recommended in cases of 'severe' depression. Our objective was to evaluate the clinical and demographic differences between patients who remitted on a mood stabilizer alone and patients who subsequently required an adjunctive antidepressant to achieve stabilization. METHODS: We retrospectively compared the pharmacological treatment strategies of 39 patients with bipolar I disorder who were in a current depressive episode. Patients who did not respond to mood stabilizer monotherapy were prescribed an adjunctive antidepressant. We evaluated the clinical differences at baseline and week 1, 2 and 3 of treatment between patients stabilizing on a mood stabilizer alone and patients that did not remit until they subsequently received an adjunctive antidepressant. RESULTS: Patients who required an adjunctive antidepressant had significantly higher total Hamilton Depression Rating (HRS-D) scores at week 1, 2 and 3 of treatment, but not at baseline. Patients who remitted on mood stabilizer monotherapy were more likely to be married, achieved stabilization in less time, presented with higher Young Mania Rating Scale (YMRS) scores, and experienced the previous episode of depression more recently than patients who required an antidepressant. CONCLUSIONS: Our findings suggest that rapid improvement after achieving a therapeutic dose of a mood stabilizer is clinically significant and represents a surrogate endpoint in the treatment of bipolar I depression. Larger, prospective, and controlled studies are needed to verify our results and to identify additional indicators for a mood stabilizer and antidepressant combination treatment strategy.

Methadone medical maintenance (MMM): treating chronic opioid dependence in private medical practice--a summary report (1983-1998).

BACKGROUND: Methadone Medical Maintenance (MMM) was implemented in 1983 to enable socially rehabilitated methadone patients to be treated in the offices of private physicians rather than in the traditional clinic system. Over a period of 15 years, 158 methadone patients who fulfilled specific criteria within the clinic system entered this program in New York City. Participating patients reported to their physician once a month and received a one-month supply of methadone tablets rather than a one-day liquid dose in a bottle. METHOD: Of the 158 patients who entered this program, 132 (83.5%) were compliant with the regulations and proved to be treatable within the hospital-based private practices of internists participating in the program. Compliant MMM patients found it easier to improve their employment status and business situations, finish their educations, and normalize their lives in MMM as opposed to the traditional clinic system because they had simplified reporting schedules and fewer clinical restrictions. Twelve (8%) compliant patients were able to successfully withdraw from methadone after an average of 17.7 years of treatment in both the traditional clinics and MMM. Twenty compliant patients (13%) died from a variety of causes, 40% of which were related to cigarette smoking. None of the deaths were attributable to long-term methadone treatment. Other causes of death included hepatitis C, AIDS, cancer, homicide, complications of morbid obesity and meningitis. RESULTS: The 26 noncompliant patients (16.5%) were referred back to their clinics for continued treatment or were discharged for failure to report as directed. A major cause of failure in MMM was abuse of crack/cocaine. CONCLUSIONS: Stigma concerning enrollment in methadone treatment was a major social issue that patients faced. Many refused to inform employers, members of their families, friends, and other physicians who treated them for a various of conditions that they were methadone patients. The methadone medical maintenance physician, therefore, functions as a medical ombudsman for the patient, educating other physicians who treat the patient about methadone maintenance and its applicability to the patient. Our results can serve as a model for the expansion of office-based MMM treatment.

The impact of hepatitis C virus infection on methadone maintenance treatment.

Hepatitis C virus infection is now recognized as a common and serious complication of injection drug use and will be encountered frequently in methadone maintenance patients. Approximately 1.8% of the United States population, or 3.9 million persons, are infected with hepatitis C virus. A majority of acute hepatitis C virus infections are associated with injection drug use, and 64-88% of injection drug users in seroprevalence studies have antibodies to hepatitis C. Hepatitis C virus infection is almost always chronic, and alcohol use increases the clinical severity. Therapy with interferon and ribavirin will induce long-term remission in up to 43% of patients with hepatitis C virus infection. Proper diagnosis and treatment of hepatitis C virus infection will be indicated for many patients in methadone programs and will require considerable resources.

Hepatitis C virus serology in parenteral drug users with chronic liver disease.

Chronic liver disease is a common complication of parenteral drug use, and liver cirrhosis is frequently seen in users of both parenteral drugs and alcohol. In 1978-83, we studied 88 parenteral drug users with sufficient evidence of chronic liver disease to warrant liver biopsy. Current alcohol abuse was noted in 63 (72%), and six (7%) were former alcohol abusers. Cirrhosis was found in 33 (38%). Hepatitis C antibody (anti-HCV) was detected in 86 (98%). Also, 40 of the anti-HCV positive sera were tested with recombinant immunoblot assay and all of these were reactive. All but one of the 31 patients with anti-HCV and cirrhosis were alcohol abusers. We conclude that parenteral drug users with chronic liver disease almost always have evidence of HCV infection.

Richard Lane: a tireless fighter for treatment of drug addiction.

After a long and courageous battle with cancer, Richard Lane died in 1994. He had been a long-term heroin addict and spent 12 years in prisons. After commencing treatment with methadone, he began to work with other addicts and helped to start Man Alive, the first methadone program in Baltimore. He later became Executive Director of Man Alive and a national leader in the effort to improve and expand methadone maintenance treatment. Among the innovations he promoted within the methadone program were on-site alcoholism treatment, protocols for poly-drug abuse, services for patients with acquired immune deficiency syndrome, improved pain management for methadone patients, and fewer restrictions for socially rehabilitated patients on methadone. He fought tirelessly for acceptance of methadone maintenance treatment by those in medicine, law enforcement, and politics. His accomplishments can inspire all in the addiction field to continue their efforts to improve the care of the addict.

Effects of the opioid antagonist naloxone on human natural killer cell activity in vitro.

Studies from several groups have shown that exogenous opiates as well as endogenous opioids may have direct or indirect effects on natural killer cell (NK) activity. Both enhanced and reduced NK activity have been reported in different in vivo and in vitro studies. The present study was performed to determine the effects of the opioid antagonist, naloxone, on human NK activity in vitro. Human peripheral blood mononuclear cells (PBMC) from 10 healthy normal subjects, as well as from 7 otherwise healthy methadone-maintained former heroin addicts, were used. These PBMC were incubated with a wide-concentration range (1 x 10(-12) to 1 x 10(-3) M) of (-)naloxone, the active enantiomer, and in parallel assays with (+)naloxone, the inactive enantiomer, prior to and during the NK activity assay. A significant reduction of NK activity by each enantiomer of naloxone was found only at very high concentrations, 1 x 10(-3) M (P < 0.01) and above. These concentrations are much higher than plasma levels of naloxone reached in humans during any therapeutic or research use of this opioid antagonist. This effect is probably due to an action at some site other than on classical opioid receptors. No effect was found at concentrations of naloxone below 1 x 10(-3) M. Thus, the data showed no naloxone-induced effects at concentrations of (-)naloxone which are sufficient to displace endogenous opioids from all types of classical opioid receptors, suggesting that the endogenous opioids that remained intact and bound to PBMC in vitro do not have any measurable modulatory effect on NK cell cytotoxicity activity.

Outcomes of treatment of socially rehabilitated methadone maintenance patients in physicians' offices (medical maintenance): follow-up at three and a half to nine and a fourth years.

OBJECTIVE: To determine whether selected socially rehabilitated former heroin addicts maintained on methadone can continue successful rehabilitation while maintained on methadone by primary care physicians rather than licensed clinics. This procedure has been termed "medical maintenance." DESIGN: Cohort study with 42-111 months of follow-up. SETTING: Offices of hospital staff physicians (internists or family practitioners). PATIENTS: The 100 patients met extensive entry criteria, including five or more years in conventional methadone maintenance treatment; stable employment or other productive activity; verifiable financial support; and no criminal involvement, use of illegal drugs, or excessive alcohol use within three or more years. MEASUREMENTS AND MAIN RESULTS: Outcome measures used were retention in treatment, discharge for one of several reasons, lost medication incidents, and substance abuse. At one, two, and three years of treatment, 98, 95, and 85 patients, respectively, remained in medical maintenance. Cumulative proportional survival in treatment was 0.735 +/- 0.048 at five years and 0.562 +/- 0.084 at nine years. After 42-111 months, 72 patients remained in good standing; 15 patients had unfavorable discharges (11 for cocaine use, three for misuse of medication, and one for administrative violations); seven voluntarily withdrew from methadone in good standing (after receiving it for 9.1-24.4 years); four died; one transferred to a chronic care facility; and one voluntarily left the program. CONCLUSIONS: Carefully selected methadone maintenance patients in medical maintenance have a high retention rate and a low incidence of substance abuse and lost medication. Voluntary withdrawal from methadone maintenance after one or two decades is possible. The authors believe that medical maintenance should be made available to appropriate patients in other localities.

The medical status of methadone maintenance patients in treatment for 11-18 years.

To assess the safety and potential health consequences of long-term methadone maintenance treatment, we identified 111 male patients admitted to methadone maintenance treatment between 1965 and 1968, still enrolled in 1980 and in continuous treatment for at least 10 years. We were able, between 1980 and 1985, to examine patients or review records of 110 patients (99%). Most medical diagnoses, symptomatic complaints, physical examination findings and laboratory test results occurred with similar frequency in the long-term methadone maintenance patients and in a group of 56 long-term heroin addicts. These data suggest that prolonged methadone maintenance treatment is safe and is not associated with unexpected adverse effects.

Epidemiology of infection with HIV-1 in Sardinia: a multicentre prospective study.

To study the spread of human immunodeficiency virus type 1 (HIV-1) in Sardinia, we conducted a multicentre prospective study of the prevalence of antibody to HIV-1 (anti-HIV-1) in various populations during 1985-1989. The highest anti-HIV-1 prevalence (61.4%) was found in intravenous drug users. Anti-HIV-1 was found in 32% of haemophiliacs, 4.2% of thalassemics and less than 1% in the other groups. We conclude that control of HIV infection in Sardinia will require a major expansion of prevention and treatment programs for drug addiction.

Medical maintenance: the treatment of chronic opiate dependence in general medical practice.

Medical maintenance was created to treat rehabilitated methadone maintenance patients within the context of general medical practice. One hundred methadone patients who met screening criteria were transferred for continuing care from traditional methadone clinics either to the practices of hospital-based physicians or to a health maintenance organization. Patients see their physicians about once per month, submit urine samples at the time of the office visits, drink a dose of methadone in the presence of their doctor or nurse, and receive a 28-day supply of methadone in pill or tablet form. The methadone prescriptions are filled by the hospital pharmacies. Physicians are responsible for the patients' annual physicals and can treat patients for other conditions. In our initial analysis of medical maintenance, 82.5% of the patients remained in good standing and 5% left the program voluntarily in good standing; the remaining 12.5% who were unable to respond favorably were returned to clinic programs. For rehabilitated patients requiring long-term or life-long care, medical maintenance is a viable alternative to traditional clinic programs. With proper policies and procedures, medical maintenance can be implemented in many hospitals.

Liver function tests in non-parenteral cocaine users.

To investigate the effect of cocaine on standard liver function tests (LFT), we studied 46 cocaine users with no history of parenteral drug use or homosexuality. LFT were similar in 21 users of cocaine only (Group A) and 25 users of cocaine and alcohol (Group B). Only three patients, two of whom were hepatitis B carriers, had an alanine aminotransferase level more than five units above normal limits. Group B patients were significantly more likely to complain of headaches, irritability, and loss of memory. We conclude that (1) non-parenteral cocaine use is rarely associated with significant LFT abnormalities and (2) alcohol may potentiate some adverse effects of cocaine.

Contrasting prevalence of delta hepatitis markers in parenteral drug abusers with and without AIDS.

Parenteral drug abusers are the second largest group at risk for developing AIDS (25% of US cases) and a major risk group for infection with both hepatitis B virus (HBV) and the HBV-dependent RNA hepatitis delta virus (HDV). This study was conducted to determine the prevalence in 1984-1985 and relationships of HDV and HBV infections in 372 unselected parenteral drug abusers without AIDS or symptoms related to human immunodeficiency virus type 1 (HIV-1) infection (but 49% of whom were positive for HIV-1 antibodies) and in 53 drug abusers hospitalized with AIDS. The prevalence of HDV markers in the combined study groups was 20%; 81% of study subjects with hepatitis B surface antigenemia (HBsAg) had one marker for HDV infection. Significant differences were found between patients with and without AIDS with respect to the prevalence of hepatitis delta antigen (5.7% vs. 0.8%, P less than .05) and antibody (0 vs. 21.4%, P less than .01) and HBsAg (15.1% vs. 5.1%, P less than .05). The significantly higher prevalence of hepatitis delta antigen and HBsAg in subjects with AIDS suggests that persistence or reactivation of these viruses is significantly greater among parenteral drug abusers with AIDS than among those without AIDS. These findings, along with the absence of hepatitis delta antibodies in the drug abusers with AIDS, are probably related to the profound general immunosuppression that occurs in AIDS.

In vitro studies of the effect of methadone on natural killer cell activity.

Heroin addicts are reported to have numerous immunological abnormalities. The purpose of this study was to determine whether methadone, a long-acting synthetic opioid agonist used in the maintenance treatment of heroin addiction as well as in the treatment of chronic pain, alters natural killer (NK) cell cytotoxicity activity. We incubated human peripheral mononuclear cells with a wide concentration range (1 x 10(-13) to 1 x 10(-3) M) of (-) methadone, the active enantiomer of methadone, or with (+) methadone, the inactive enantiomer, prior to and during an assay of NK activity. We found no effect of methadone at concentrations of 1 x 10(-13) to 1 x 10(-5) M, but higher concentrations (1 x 10(-4) to 1 x 10(-3) M) of either enantiomer of methadone caused a significant reduction in NK activity. We conclude that methadone concentrations that are normally achieved in the plasma during methadone maintenance treatment or during chronic pain management, and much higher concentrations, have no effect on NK activity in vitro.

Absence of antibody to human immunodeficiency virus in long-term, socially rehabilitated methadone maintenance patients.

Human immunodeficiency virus (HIV) infection has become widespread among parenteral drug abusers. We measured antibody to HIV and hepatitis B virus markers in 58 long-term, socially rehabilitated methadone-maintained former heroin addicts. None of the 58 had antibody to HIV, but one or more markers of hepatitis B virus infection were seen in 53 (91%). The duration of methadone maintenance was 16.9 +/- 0.5 years, and the median dose of methadone was 60 mg (range, 5 to 100 mg). Before methadone treatment, the patients had abused heroin parenterally for 10.3 +/- 1.7 years, and they had engaged in additional high-risk practices for HIV infection. We conclude that successful outcomes during methadone maintenance treatment are associated with sparing of parenteral drug abusers from HIV infection.