Extended release naltrexone injection is performed in the majority of opioid dependent patients receiving outpatient induction: a very low dose naltrexone and buprenorphine open label trial.

BACKGROUND: The approval of extended release injectable naltrexone (XR-NTX; Vivitrol(®)) has introduced a new option for treating opioid addiction, but studies are needed to identify its place within the spectrum of available therapies. The absence of physiological opioid dependence is a necessary and challenging first step for starting XR-NTX. Outpatient detoxification gives poor results and inpatient detoxification is either unavailable or too brief for the physiological effects of opioids to resolve. Here we present findings from an open label study that tested whether the transition from opioid addiction to XR-NTX can be safely and effectively performed in an outpatient setting using very low dose naltrexone and buprenorphine. METHODS: Twenty treatment seeking opioid addicted individuals were given increasing doses of naltrexone starting at 0.25mg with decreasing doses of buprenorphine starting at 4 mg during a 7-day outpatient XR-NTX induction procedure. Withdrawal discomfort, craving, drug use, and adverse events were assessed daily until the XR-NTX injection, then weekly over the next month. RESULTS: Fourteen of the 20 participants received XR-NTX and 13 completed weekly assessments. Withdrawal, craving, and opioid or other drug use were significantly lower during induction and after XR-NTX administration compared with baseline, and no serious adverse events were recorded. CONCLUSIONS: Outpatient transition to XR-NTX combining upward titration of very low dose naltrexone with downward titration of low dose buprenorphine was safe, well tolerated, and completed by most participants. Further studies with larger numbers of subjects are needed to see if this approach is useful for naltrexone induction.

Smoking and opioid detoxification: behavioral changes and response to treatment.

INTRODUCTION: The relevance of tobacco use in opioid addiction (OA) has generated a demand for available and more effective interventions. Thus, further analysis of less explored nicotine-opioid clinical interactions is warranted. METHODS: A post-hoc analysis of OA participants in a double-blind, randomized very low dose naltrexone (VLNTX) inpatient detoxification trial evaluated measures of opioid withdrawal and tobacco use. Intreatment smokers were compared with nonsmokers, or smokers who were not allowed to smoke. RESULTS: A total of 141 (81%) of 174 OA participants were smokers, all nicotine-dependent. Inpatient smoking was a predictor of opioid withdrawal discomfort. Intreatment smokers (n = 96) showed significantly higher opioid craving (F = 3.7, p < .001) and lower detoxification completion rate (χ(2) = 7.9, p < .02) compared with smokers who were not allowed to smoke (n = 45) or nonsmokers (n = 33). Smoking during treatment was associated with more elevated cigarette craving during detoxification (F = 4.1, p < .001) and a higher number of cigarettes smoked at follow-up (F = 3.6, p < .02). Among intreatment smokers, VLNTX addition to methadone taper was effective in easing opioid withdrawal and craving more than other treatments, whereas the combination VLNTX-clonidine was associated with significantly reduced cigarette craving and smoking during detoxification. CONCLUSIONS: Failure to address tobacco use may negatively affect pharmacologically managed opioid discontinuation. Opioid detoxification may offer a window of opportunity to expand smoking cessation treatment, hence improving OA outcomes. The observed effects support testing of VLNTX-clonidine in smoking cessation trials among individuals with or without substance abuse.

Buprenorphine-mediated transition from opioid agonist to antagonist treatment: state of the art and new perspectives.

Constant refinement of opioid dependence (OD) therapies is a condition to promote treatment access and delivery. Among other applications, the partial opioid agonist buprenorphine has been studied to improve evidence-based interventions for the transfer of patients from opioid agonist to antagonist medications. This paper summarizes PubMed-searched clinical investigations and conference papers on the transition from methadone maintenance to buprenorphine and from buprenorphine to naltrexone, discussing challenges and advances. The majority of the 26 studies we examined were uncontrolled investigations. Many small clinical trials have demonstrated the feasibility of in- or outpatient transfer to buprenorphine from low to moderate methadone doses (up to 60-70 mg). Results on the conversion from higher methadone doses, on the other hand, indicate significant withdrawal discomfort, and need for ancillary medications and inpatient treatment. Tapering high methadone doses before the transfer to buprenorphine is not without discomfort and the risk of relapse. The transition buprenorphine-naltrexone has been explored in several pilot studies, and a number of treatment methods to reduce withdrawal intensity warrant further investigation, including the co-administration of buprenorphine and naltrexone. Outpatient transfer protocols using buprenorphine, and direct comparisons with other modalities of transitioning from opioid agonist to antagonist medications are limited. Given its potential salience, the information gathered should be used in larger clinical trials on short and long-term outcomes of opioid agonist-antagonist transition treatments. Future studies should also test new pharmacological mechanisms to help reduce physical dependence, and identify individualized approaches, including the use of pharmacogenetics and long-acting opioid agonist and antagonist formulations.

Pharmacological enhancement of naltrexone treatment for opioid dependence: a review.

PURPOSE: Opioid dependence (OD) is a serious and growing clinical condition with increasing social costs that requires expanding treatment beyond opioid agonist substitution. The opioid antagonist naltrexone has displayed a remarkable association of theoretical effectiveness and poor clinical utility in treating OD due to noncompliant behavior and low acceptability among patients, only partly modified by psychosocial interventions. We reviewed pharmacological studies, including naltrexone depot formulations and combination treatments. METHOD: We searched PubMed for clinical studies on the use of naltrexone implants and slow-release injections in OD, and investigations using adjunct medications to improve naltrexone maintenance therapy of OD. We discussed the results in view of their application to the clinical practice. RESULTS: Significant reduction in opioid use and improved retention in treatment have been found in several studies using depot naltrexone formulations, some of which are controlled clinical trials. Pilot investigations have gathered initial positive results on the use of naltrexone in combination with serotonin reuptake inhibitors, α-2 adrenergic, opioid, and γ-aminobutyric acid agonist medications. CONCLUSION: Current evidence suggests that more research on effectiveness and safety is needed in support of depot naltrexone treatment for OD. Further research comparing slow-release with oral naltrexone and opioid agonist medications will help characterize the role of opioid antagonist-mediated treatment of OD. Preliminary investigations on naltrexone combination treatments suggest the opportunity to continue study of new mixed receptor activities for the treatment of OD and other drug addictions.

Polypharmacy in pregnant women with major psychiatric illness: a pilot study.

OBJECTIVE: There is increasing concern about the use of multiple medications in populations with psychiatric illnesses. One large study reported that 99% of pregnant women had received a prescription for at least one medication during pregnancy, with a mean of 13.6 medications per woman. The present descriptive study examined patterns of medication use across pregnancy in a low socioeconomic status population of women who had a psychiatric illness as a primary diagnosis. METHOD: Data on 115 pregnant women were extracted from a Medicaid Database of 5,000 women who received prenatal and other medical care over a 2-year period (2002-2004). Subjects included women with bipolar disorder, schizoaffective disorder, and schizophrenia. Information on age, diagnoses, dates prescriptions were filled, and type, dose, and quantity of medications was recorded in the database. RESULTS: Data were collected on 115 pregnancies; complete data throughout pregnancy were available for 75 women, while data on certain gestational months were available for the other 40 women. A majority of the 115 women were diagnosed with bipolar or schizoaffective disorder. Their mean age was 26 years. The mean number of medications taken during pregnancy was three (range 0-10; mode = 3); 26.8% of the pregnant women filled prescriptions for 6-10 medications during their pregnancy. No dose changes were made for the prescribed medications to accommodate changing metabolism across pregnancy. The most frequently prescribed medications for these psychiatrically ill women were from the opiate family. CONCLUSIONS: Multiple medications are frequently prescribed to pregnant women with psychiatric disorders because of comorbid diagnoses. However, the effects of taking multiple psychotropic or other medications during pregnancy on pregnancy outcome and fetal development are unknown. Therefore, more research is needed concerning the effects on the developing fetus of taking multiple medications with central nervous system effects during pregnancy.

Trends in nonheroin opioid abuse admissions: 1992-2004.

AIMS: This study examines trends for treatment admissions for nonheroin opioid abuse from 1992 to 2004. METHODS: Databases from the Substance Abuse Mental Health Services Administration (SAMHSA, U.S.A.): Treatment Episode Data Set (TEDS) were used to examine the changing characteristics of admissions to treatment for nonheroin opioid abuse. Data are collected annually from each state on characteristics of admissions to treatment for all substances abused in the United States. Using the Mann-Kendall test for examining annual trends, we determined any significant trend changes by modeling data for every 2years of TEDS information from 1992 to 2004. RESULTS: We found significant changes for admissions to substance abuse treatment from 1992 to 2004. Overall, nonheroin opioid admissions to treatment have increased, specifically among adolescents. Other significant trends included an increase in the never-married group admitted, a higher rate of psychiatric problems for nonberoin opioid abuse admissions, changes in the treatment services and significant associations between age of first use of marijuana and methamphetamine, and subsequent nonheroin opioid abuse admissions. CONCLUSION: Characteristics of admissions to treatment are changing over time and identify an admitted treatment group that is historically different from heroin abusers. These findings will give providers information about who is seeking treatment for nonheroin opiate abuse. Altered treatment strategies that target the changing population who seek treatment for nonheroin opioid abuse need to be universally available.

Postpartum depression: a randomized trial of sertraline versus nortriptyline.

Symptom reduction and improvement in functioning in women with postpartum major depression treated with a tricyclic antidepressant versus a serotonin reuptake inhibitor were compared. The design was a double-blind, 8-week comparative trial of nortriptyline (NTP) versus sertraline (SERT) with a 16-week continuation phase. Women aged 18 to 45 years with postpartum major depression and a 17-item Hamilton Rating Scale for Depression score of 18 or more were eligible. Subjects were randomized to NTP or SERT and treated with a fixed-dosing strategy. Of 420 women interviewed, 109 eligible women received medication, and 95 provided follow-up data. The proportion of women who responded and remitted did not differ between drugs at 4, 8, or 24 weeks. Times to response and remission also did not differ. Psychosocial functioning improved similarly in both drug-treated groups of mothers. The total side effect burden of each drug was similar, although side effect profiles differed between agents. No clinical or demographic variables differentiated responders by drug. Women who were responders and remitters at week 8 could be identified earlier if they were treated with SERT than with NTP. Breast-fed infant serum levels were near or below the level of quantifiability for both agents.

Weight changes in postpartum women with remitted depression.

OBJECTIVE: To compare weight loss after birth in women who took the antidepressants nortriptyline or sertraline or placebo in 2 clinical studies designed to prevent recurrent postpartum major depression. METHOD: Data were collected from 1995 to 2001. All subjects had at least 1 prior episode of Research Diagnostic Criteria- or DSM-IV-defined major depressive disorder. Data on weight were available for 467 weeks from 60 women who were weighed 8 times from 2 to 17 weeks postpartum. The dependent measures were weight at weeks 11 and 17 and weight change from weeks 2 to 17 postpartum. RESULTS: At week 17, the women's weights ranged from 109 to 268 lb. Their weight change ranged from +14 to -19 lb over the 15-week postpartum period (mean = -1.8, SD = 5.1 lb). After controlling for week 2 weights, the mean weights at week 17 for the women treated with nortriptyline, sertraline, or placebo were not significantly different. Of 60 women with 3 or more weight assessments, those who were randomly assigned to nortriptyline lost weight more rapidly than the other 2 groups; however, the mean weight change across all groups was only -1.8 lb (SD = 5.1 lb). CONCLUSIONS: Weight loss was not compromised by antidepressant pharmacotherapy. Postpartum weight retention occurred in this group of nondepressed women with previous histories of major depression independent of drug treatment.

Prevention of postpartum episodes in women with bipolar disorder.

BACKGROUND: The aim of this study was to evaluate the efficacy of divalproex (VLP) to prevent episode recurrence in postpartum women with bipolar disorder. METHODS: The design was a single-blind, nonrandomized clinical trial. Subjects were enrolled during pregnancy and chose either VLP plus symptom monitoring or monitoring without medication for immediate postpartum management. Mania and depression symptoms were assessed weekly for 20 weeks by an independent evaluator. RESULTS: Data were available for 26 women. There were no significant differences between groups in the proportions of women who developed postpartum hypomania/mania, depression, or mixed states. The time to development of episodes also did not vary between groups. Women who were treated with VLP tended to have lower levels of hypomanic/manic symptoms. CONCLUSIONS: Divalproex was not significantly more effective than monitoring without drug for the prevention of postpartum episodes of bipolar disorder. The most prudent pharmacologic plan is to use the drug(s) to which the individual woman has responded and prepare a plan for rapid augmentation if a breakthrough episode occurs.

Prevention of postpartum depression: a pilot randomized clinical trial.

OBJECTIVE: The authors attempted to reduce the rate of postpartum depression in high-risk women and to increase the time to recurrence. METHOD: Nondepressed pregnant women with at least one past episode of postpartum major depression were recruited into a randomized clinical trial. Mothers were assigned randomly to a 17-week trial of sertraline or placebo immediately after birth and assessed for 20 sequential weeks with the Hamilton Rating Scale for Depression. RESULTS: Of 14 subjects who took sertraline, one (7%) suffered a recurrence. Of eight subjects who were assigned to placebo, four (50%) suffered recurrences. This difference was significant. The time to recurrence was significantly longer in the sertraline-treated women than in the placebo-treated women. CONCLUSIONS: Sertraline conferred preventive efficacy for postpartum-onset major depression beyond that of placebo.

Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings.

BACKGROUND: Bright light therapy was shown to be a promising treatment for depression during pregnancy in a recent open-label study. In an extension of this work, we report findings from a double-blind placebo-controlled pilot study. METHOD: Ten pregnant women with DSM-IV major depressive disorder were randomly assigned from April 2000 to January 2002 to a 5-week clinical trial with either a 7000 lux (active) or 500 lux (placebo) light box. At the end of the randomized controlled trial, subjects had the option of continuing in a 5-week extension phase. The Structured Interview Guide for the Hamilton Depression Scale-Seasonal Affective Disorder Version was administered to assess changes in clinical status. Salivary melatonin was used to index circadian rhythm phase for comparison with antidepressant results. RESULTS: Although there was a small mean group advantage of active treatment throughout the randomized controlled trial, it was not statistically significant. However, in the longer 10-week trial, the presence of active versus placebo light produced a clear treatment effect (p =.001) with an effect size (0.43) similar to that seen in antidepressant drug trials. Successful treatment with bright light was associated with phase advances of the melatonin rhythm. CONCLUSION: These findings provide additional evidence for an active effect of bright light therapy for antepartum depression and underscore the need for an expanded randomized clinical trial.

Identifying depression in the first postpartum year: guidelines for office-based screening and referral.

BACKGROUND: Some 10-15% of women experience postpartum-onset major depression (PPMD). The objective of this study was to determine if the Edinburgh Postnatal Depression Scale (EPDS) is an effective screen for major depression (MD) prospectively. The outcome of the study was identification of a recurrence of major depression in the first year postpartum by a clinical interview and the EPDS. We had the unique opportunity to examine the relationship between EPDS scores and PPMD. METHODS: Participants were pregnant women who had experienced an episode of previous PPMD but were well during their index pregnancy. This study was part of a double-blind, randomized clinical trial in which new mothers received nortriptyline or placebo within 24 h following delivery for prevention of PPMD. Recurrence of depression was established according to Research Diagnostic Criteria. Participants completed the EPDS weekly through 20 weeks postpartum and into a 1-year follow-up phase. RESULTS: Out of 50 women, 13 experienced recurrence of MD in the first 20 weeks postpartum with a total of 20 out of 50 recurring in the first year. The EPDS score of >9 at week 4 postpartum identified 60% of women who nurtured in the first 20 weeks and 80% who recurred in the first postpartum year. LIMITATIONS: The study population included only women who had a previous episode of postpartum depression. The generalizability to all women is limited. CONCLUSIONS: The EPDS is an effective depression screen for women who had a previous episode of PPMD. Clinical guidelines are provided for use of the EPDS to identify MD in the first postpartum year in primary care settings.

Timing of depression recurrence in the first year after birth.

BACKGROUND: Women who have suffered from one episode of postpartum-onset major depression (PPMD) experience increased risk for recurrence in the year following another birth. METHODS: Non-depressed women (N=51) who had at least one past episode of PPMD were recruited during pregnancy. After birth, subjects were assessed prospectively each week for 20 weeks with the Hamilton Rating Scale for Depression and Research Diagnostic Criteria for recurrence of major depression. Evaluations were carried out at 24, 36, and 52 weeks to assess for episodes beyond 20 weeks postpartum. RESULTS: The data revealed a clustering of cases, with five of the 21 recurrences (24%) occurring in the first 2 weeks. Thirteen of the 21 recurrences (67%) and 19/21 recurrences (90%) occurred in the first 20 and 28 weeks following birth, respectively. LIMITATIONS: Although it is unusual for studies of this type to be prospective, the sample size is relatively small. CONCLUSIONS: The 1-year recurrence rate was 21/51 or 41%, with a clustering of cases near delivery. All recurrences except two occurred by 28 weeks postpartum.

Successful recruitment strategies for women in postpartum mental health trials.

Recruiting women into research protocols allows investigators to examine the efficacies of treatments and to study other outcomes among women with mental illnesses. However, achieving recruitment goals has been difficult for researchers. The objective of this study was to examine the success rates of different strategies for recruiting women into clinical trials for the prevention and treatment of postpartum major depression. This is a descriptive study designed to examine which recruitment efforts, over a 4-year period, yielded women who participated in the studies. It was conducted in an outpatient clinic affiliated with a major urban teaching hospital where women of childbearing age sought treatment for affective disorders. All women (n=589) who called about our research studies were systematically screened. The women were either pregnant or in the postpartum period. Our results show that in both studies, obstetricians and other healthcare professionals referred a large number of women. These referrals yielded relatively high rates of participation. However, other methods were differentially successful for the two studies: media appearances and advertising resulted in almost 50% of the screening calls for the prevention study, whereas mass mailings and other promotional materials were more effective for the treatment study. Those materials contributed 44% of screening calls for the treatment study. Our conclusions were that women were most likely to enter the research studies when referred by an obstetrician or other professional.

Bridging the gap: recruitment of African-American women into mental health research studies.

OBJECTIVE: To develop a strategy for recruiting African-American women into a research study for pregnant women. METHODS: With few exceptions, NIH-funded investigators must include women and minorities in clinical research. The authors used the recommendations provided in the Outreach Notebook for the NIH Guidelines on Inclusion of Women and Minorities as Subjects in Clinical Research as a guide to help them reach out to African-American women in the community. RESULTS AND CONCLUSIONS: The outreach experience led to a conference for African-American women about mental health. On the basis of this experience, the authors formulated a five-pronged approach for recruitment of African-American women into their study. The NIH guidelines were useful for this purpose.

Serum bupropion levels in 2 breastfeeding mother-infant pairs.

BACKGROUND: These are the first reported data on bupropion and hydroxybupropion levels in infants whose treated mothers were breastfeeding. The information will assist physicians and parents in the risk-benefit decision-making process for bupropion treatment during breastfeeding. METHOD: Serum samples were obtained by venipuncture from 2 mother-infant pairs. The serum was assayed for levels of bupropion and its most active metabolite, hydroxybupropion. RESULTS: Neither infant had quantifiable serum levels of bupropion or its metabolite at steady state. Neither infant had medical problems during the time of maternal therapy. CONCLUSION: We recommend obtaining and publishing additional serum level findings for breastfeeding mother-infant pairs since data for bupropion are favorable but limited.

Verapamil treatment for women with bipolar disorder.

BACKGROUND: Additional pharmacological treatments are needed for patients with bipolar disorder. We describe our experience with verapamil in an inclusive, sequential series of outpatient women (some pregnant) with bipolar disorder. METHODS: All women who were prescribed verapamil for bipolar disorder (n = 37) were included. We used the criterion of 50% reduction in scores on the Mania Rating Scale or the Hamilton Rating Scale for Depression to define response for women who were treated for an acute episode of bipolar hypomania/mania or depression, respectively. For euthymic women who chose verapamil maintenance treatment, we evaluated whether they met criteria for a recurrent episode during therapy. RESULTS: Treatment for acute episodes was initiated in 28 women. Of women with depression and mania, 39% and 100% responded, respectively. Seven of the nine patients (77%) with mixed states responded: all seven improved to response criterion on the mania scale, and two responded on the depression scales as well. Six of eight patients who received continuation therapy remained well. CONCLUSIONS: These data provide evidence that verapamil is effective for mania. The response rate for mania compares favorably to that for other mood stabilizers. After decades of case reports and underpowered clinical trials, we must definitively study verapamil for efficacy and gender specificity in bipolar disorder.

An open trial of morning light therapy for treatment of antepartum depression.

OBJECTIVE: About 5% of pregnant women meet criteria for major depression. No pharmacotherapy is specifically approved for antepartum depression; novel treatment approaches may be welcome. The authors explored the use of morning bright light therapy for antepartum depression. METHOD: An open trial of bright light therapy in an A-B-A design was conducted for 3-5 weeks in 16 pregnant patients with major depression. The Hamilton Depression Rating Scale, Seasonal Affective Disorders Version, was administered to assess changes in mood. A follow-up questionnaire was used to assess outcome after delivery. RESULTS: After 3 weeks of treatment, mean depression ratings improved by 49%. Benefits were seen through 5 weeks of treatment. There was no evidence of adverse effects of light therapy on pregnancy. CONCLUSIONS: These data provide evidence that morning light therapy has an antidepressant effect during pregnancy. A randomized controlled trial is warranted to test this alternative to medication.