Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.

Reversal of overdose on fentanyl being illicitly sold as heroin with naloxone nasal spray: A case report.

BACKGROUND: This is a case report describing a reversal of fentanyl overdose with naloxone nasal spray. The patient was not aware that he overdosed on fentanyl being sold as heroin. METHODS: The Veterans Health Administration (VHA) has implemented an initiative to provide education for veterans, their families, friends and significant others about opioid overdose and use of naloxone reversal kits. The Atlanta VA Medical Center adopted this program to reduce the risk of opioid overdose in high risk patients. RESULTS: Over the past year, we provided educational sessions for 63 veterans and their families. We also prescribed 41 naloxone kits. We have received three reports of opioid overdose reversal with use of naloxone kits prescribed by the Atlanta VA Medical Center. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: The authors recommend that public health administrators and policy makers advocate for the implementation of these programs to reduce the rising number of overdose death in the United States and worldwide.

Risk behavior in opioid-dependent individuals after the administration of a therapeutic dose of methadone.

BACKGROUND AND OBJECTIVES: Evidence suggests that methadone may play a protective role in the faulty decision-making in heroin-addicted individuals. This may reduce craving for opioids and the risky decisions associated with active opioid use. METHODS: We tested the effect of a daily therapeutic dose of methadone on faulty decision-making in eighty (n = 80) individuals with a history of opioid addiction. We used the Iowa Gambling Task (IGT) and compared the score and response time before and after the daily methadone dosing. RESULTS: The mean net IGT score before methadone dose was 10 (±22) and 22 (±23) after methadone dose (t = 4.23, p = .00006). These results reflect statistically significant improvement in faulty decisions after the administration of the daily methadone dose. The mean response time for the reward cards before methadone dose were 1,856 ms (±871) and 1,465 ms (±851) after methadone dose (t = 2.55, p = .012). The mean response time for the punishment cards before methadone dose were 1,688 ms (±911) and 1,399 ms (±827) after methadone dose (t = 1.86, p = .065). These results reflect statistically significant improvement in response time to a rewarding healthy decisions after the administration of the daily methadone dose. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This is the first study to report the effect of a therapeutic dose of methadone on improving faulty decisions for individuals with a long history of opioids addiction. This study demonstrated that the time to making a healthy decision was significantly shorter as a result of administration of methadone.

Predictors of diabetes mellitus and abnormal blood glucose in patients receiving opioid maintenance treatment.

BACKGROUND: Buprenorphine is a partial opioid agonist and may have less impact on the risk of developing diabetes mellitus (DM) compared to full opioid agonists like methadone. METHODS: We conducted an observational retrospective study to investigate the predictable factors for impaired glucose tolerance and predisposition to DM in two groups of opiate addicts receiving long-term methadone maintenance treatment (MMT) [n = 58] or buprenorphine maintenance treatment (BMT) [n = 61]. RESULTS: In our cohort, being African American, hepatitis C positive status, elevated AST, and ALT, and being on methadone were significantly correlated to being diagnosed with DM. Among all those factors, being on methadone was most significantly related to being diagnosed with DM (χ² = 3.9888, p-value = .0458). The BMI was the only factor that was significantly correlated to having abnormal A1c level (χ² = 6.4229, p-value = .0113). CONCLUSIONS: Buprenorphine may be less likely to contribute to the development of DM than methadone. More research is needed to understand the link between opioids and DM.

Predictors of substance abuse treatment outcome in hospitalized veterans.

BACKGROUND AND OBJECTIVES: Historically patients consulted for the substance abuse treatment from the medical surgical floors have a very low show rate for the substance abuse treatment. The authors performed retrospective chart review to find predictors of substance abuse treatment outcome in hospitalized veterans at Atlanta VA Medical Center. METHODS: The medical records from all the patients who were admitted to the medical/surgical floor with substance abuse consults from January-December 2009 were reviewed. A total of 235 consults were received. Those records were examined to find the predictors for substance abuse treatment. RESULTS: Multiple variables were tested for significance - patient demographics, housing status, employment, reason for hospitalization, toxicology screens, co-morbid psychiatric and medical conditions, physician visits, and patients on waiting list. All variables were given cut-off point for the p-value of .10. These variables were then included in the logistic regression model. It was found that homelessness (χ2 = 16.14 and p < .0001) was the only individual variable that showed a statistically significant correlation with starting the program. It was found that homelessness (χ2 = 19.21 and p < .0001) was the only individual variable that showed statistically significant correlation with completing the program. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Our study supports that for veterans with substance abuse, housing was the only consistent predictor to enter intensive outpatient program (IOP), complete IOP, and start aftercare. Our study demonstrates the need for and potential benefit of providing stable housing for the homeless veterans.

QTc interval prolongation for patients in methadone maintenance treatment: a five years follow-up study.

BACKGROUND: QTc prolongation for patients in methadone maintenance treatment (MMT) has been reported. In this study we wanted to identify the predictor factors for QTc prolongation >500 ms and other medical risk factors for mortality in this population. METHODS: A retrospective chart review study with 55 patients who had previously been included in our performance improvement project and who were eligible to be reviewed. A linear regression model with one-sided p value was used for data analysis. RESULTS: Over 5 years, 41% to 56% of patients had QTc > 450 and <500 ms and 4% to 10% of patients had at least one reading of QTc > 500 ms. This QTc prolongation from baseline showed statistical significance (p < 0.0001). Being diagnosed with congestive heart failure (CHF), elevated HgA1c level and recent cocaine use were significantly associated with QTc prolongation >500 ms. The model as a whole showed statistical significance (F = 3.50, p = 0.02). Being diagnosed with CHF and elevated HgA1c level was significantly associated with mortality. The model as a whole also showed statistical significance (F = 4.63, p = 0.01). CONCLUSIONS: This study confirms that methadone may be associated with QTc prolongation. It identified three risk factors for significant QTc prolongation for patients on MMT which are recent cocaine use, uncontrolled blood glucose and CHF. Two of these three risk facts (uncontrolled blood glucose and CHF) were associated with mortality in this cohort. Patients with these medical co-morbidities may benefit from EKG screening and aggressive treatment of the medical risk factors while taking MMT.

Treatment outcome for flexible dosing buprenorphine maintenance treatment.

BACKGROUND AND OBJECTIVES: Achieving the best treatment outcome with the least cost should be the goal for buprenorphine office-based treatment. METHODS: We conducted an observational retrospective chart review to compare the treatment outcome for patients (n = 56) receiving high dose of buprenorphine (above 16 mg daily) and patients (n = 21) receiving moderate doses (8-16 mg daily). RESULTS: The percentages of the first four urine drug screens (UDS) positive for opiates were significantly higher for the high-dose group than for the moderate-dose group (F = 7.93, df = 7, p < .0001). However, the percentages of the most recent four UDS positive for opiates were not statistically significant (F = .62, df = 7, p = .74). The difference in the percentages of the first and last UDS for the high-dose group showed significant reduction from admission to most recently but there was no significant difference for the moderate-dose group (t = 3.1, df = 105, p = .002 for the high-dose group and t = 1.1, df = 40, p = .27 for the moderate-dose group). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Using flexible buprenorphine dosing schedule with the option of titrating the dose up to 32 mg daily may offer better treatment outcome for patients who would not respond to the lower dose range.

Mitigation of Covid-19 infection in substance use disorder residential settings.

Managing infection control of the Corona virus disease (Covid-19) could be very challenging for substance use disorder (SUD) residential treatment programs. The Centers for Disease Control (CDC) is providing guidelines for the public on how to reduce the risk of contracting Covid-19. The American Society of Addiction Medicine (ASAM) provided specific guidelines to assist clinicians in the mitigation of Covid-19 infection in residential SUD facilities. Controlling an infection in a SUD residential setting is challenging because these facilities are not locked, and they are considered a subacute level of care. In this commentary the details of the infection mitigation plan in a SUD residential setting will be explained along with the outcome measure of this plan.

Heroin anticraving medications: a systematic review.

BACKGROUND: Heroin craving is a trigger for relapse and dropping out of treatment. Methadone has been the standard medication for the management of heroin craving. OBJECTIVES: We explored the medication options other than methadone which may have heroin anticraving properties. METHODS: To be selected for the review, articles had to include outcome measures of the effect of the studied medication on subjective and/or objective opiate craving and be of the following two types: (1) randomized, controlled, and/or double-blind clinical trials (RCTs) examining the relationship between the studied medication and heroin craving; (2) nonrandomized and observational studies (NRSs) examining the relationship between the studied medication and heroin craving. Thirty-three articles were initially included in the review. Twenty-one were excluded because they did not meet the inclusion criteria. We present the results of 12 articles that met all the inclusion criteria. RESULTS: Some new medications have been under investigation and seem promising for the treatment of opiate craving. Buprenorphine is the second most studied medication after methadone for its effect on opiate craving. At doses above 8 mg daily, it seems very promising and practical for managing opiate craving in patients receiving long-term opioid maintenance treatment. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: In doses higher than 8 mg daily, buprenorphine is an appropriate treatment for opiate craving. More research with rigorous methodology is needed to study the effect of buprenorphine on heroin craving. Also more studies are needed to directly compare buprenorphine and methadone with regard to their effects on heroin craving.

Evolution of opioid addiction as a brain disease from stigma to modern neurosciences.

The concept of addiction as a brain disease has been challenged by the public for a long time. Addiction has been considered a moral defect for centuries. Recently, neurobiological studies have shown that addiction can change certain brain circuits, which impairs its functions in a way that makes the addicted individual vulnerable for relapse. This commentary will discuss the evolution of opioid addiction and how it progressed into what it is now. It will provide the scientific evidence that supports the concept of opioid addiction as a brain disease.

Effect of heroin use on changes of brain functions as measured by functional magnetic resonance imaging, a systematic review.

In this study the authors focus on reviewing imaging studies that used resting state functional magnetic resonance imaging for individuals with a history of heroin use. This review study compiled existing research addressing the effect of heroin use on decision making by reviewing available functional neuroimaging data. Systematic review of the literatures using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Eligible articles were retrieved through a computer-based MEDLINE and PsycINFO search from 1960 to December 2015 using the major medical subject headings "heroin, fMRI" (all fields). Only English language was included. Thirty-seven articles were initially included in the review. Sixteen were excluded because they did not meet the inclusion criteria. The results of 21 articles that met all the inclusion criteria were presented. Based on the 21 studies included in the current review, there is evidence that heroin use may have a direct and damaging effect on certain brain functions and that these changes may be associated with impulsive and unhealthy decision making. From the review of these studies, the authors understand that a longer duration of heroin use may be associated with more damaging effects on brain functions. The authors also understand that these brain changes could last long after abstinence, which may increase the risk of relapse to heroin use. More research is needed to create a biomarker map for patients with heroin use disorder that can be used to guide and assess response to treatment.

Improvement of saccadic functions after dosing with methadone in opioid addicted individuals.

In the current experiment, we used the saccadometric test to study the effect of a single therapeutic dose of methadone on the integrity of cortico-subcortical brain functioning. In this prospective study, we used the Saccadometer System (Advanced Clinical Instrumentation, Cambridge, UK). The saccadometric test was performed before and 1.5 hours after methadone dosing. We analyzed the following saccadic parameters: latency, duration, amplitude, average and peak velocity, and processing performance (promptness) as well as a number of different types of saccades (like correct/incorrect, under/overshoot, and left-sided/right-sided). The sample consists of 40 subjects with an average 18 years of opioid addiction. The mean age is 35.3 ± 7 (80% males and 20% females). The mean period of heroin dependence is 15.3 ± 6.3 years. The mean daily dose of methadone in substitution therapy is 90 ± 26.5 mg. After administration of a single therapeutic dose of methadone, there were statistically significant differences in the values of saccade duration and latency when compared to the values before the drug administration. Average duration of saccade was significantly longer [51.40 ± 8.75 ms versus 48.93 ± 6.91 ms, z = 2.53, p = .01] and average latency was significantly longer [198.85 ± 52.57 ms versus 183.05 ± 30.95 ms, z = 2.09 p < .03]. This is the first study to test the therapeutic effect of daily methadone dosing on the integrity of the cortico-subcortical brain functions as measured by the saccadometry. More research is needed to explore the effect of illicit opioid use on the integrity of brain structures and functions, and the protective effect of opioid agonist therapy on reversing the damaging effects of illicit opioid use.

Factors affecting noncompliance with buprenorphine maintenance treatment.

BACKGROUND: The current study aimed to identify risk factors for treatment noncompliance in a sample of veterans receiving buprenorphine/naloxone for an opioid use disorder. METHODS: Records from all patients who are currently or had previously been maintained on buprenorphine in the buprenorphine maintenance treatment program at the Atlanta VA Medical Center during the years 2006 to 2013 were evaluated. Of the 209 patients treated in the clinic between 2006 and 2013, 140 were excluded from the study because they did not have a call-back done at the time of data collection. Thus, 69 patient charts were selected for review. RESULTS: The multiple linear regression analysis of the predictable variables for noncompliance with the buprenorphine pill count showed that positive urine drug screen (UDS) for marijuana, benzodiazepines, and being a smoker (F = 3.08; P = 0.03) are significantly associated with noncompliance with buprenorphine pill count.Also, the multiple linear regression analysis of the predictable variables for noncompliance with the buprenorphine pill count showed that the psychiatric comorbidity independently (F = 4.88; P = 0.03) is significantly associated with noncompliance with buprenorphine pill count. CONCLUSIONS: Patients found to be noncompliant were more likely to suffer from comorbid psychiatric illness. Patients who tested positive for benzodiazepines or cannabis were more likely to be noncompliant with treatment. Although the rate of noncompliance (inaccurate pill count) was high, patients were still found to be taking their prescribed buprenorphine as evidenced by positive UDS for buprenorphine/norbuprenorphine. In addition, our sample had a high rate of negative UDS screens for opioids and cocaine.

Comparison of QTc interval prolongation for patients in methadone versus buprenorphine maintenance treatment: a 5-year follow-up.

The authors investigated whether patients receiving buprenorphine maintenance treatment (BMT) will have corrected QT (QTc) prolongation after taking buprenorphine for an extended period of time. They also compared QTc prolongation for patients in methadone maintenance treatment (MMT) versus BMT to determine which medication is the better option for patients with heart disease. A retrospective chart review study of 73 patients in BMT and 55 patients in MMT was performed. A linear regression model with a one-sided P value was used for data analysis. The MMT group had statistically significant prolongation of QTc compared with the BMT group (F = 3.94, P = .0001). Being diagnosed with congestive heart failure and taking methadone were the only individual variables that showed a statistically significant association with a QTc prolongation > 500 ms. The model as a whole showed statistical significance (F = 5.203, P = .007). Being diagnosed with congestive heart failure was the only individual variable that showed a statistically significant association with mortality. The model as a whole also showed statistical significance (F = 17.15, P = .000). This study supports previous findings that methadone may be associated with QTc prolongation, whereas buprenorphine may not. This study has the advantage of confirming that QTc prolongation persists in patients in MMT but not in those in BMT over an extended period of time (i.e., 5 years). Buprenorphine might a better first-line opioid maintenance treatment for patients with heart disease because buprenorphine was not associated with QTc prolongation. Patients in BMT may not need to be screened routinely for QTc prolongation.

Comorbid posttraumatic stress disorder and opiate addiction: a literature review.

Treatment of comorbid posttraumatic stress disorder (PTSD) and opioid dependence has been a challenge for many clinicians. There are limited evidence-based guidelines for treatment of this comorbidity. Symptoms of PTSD and opiate dependence may converge, and it is sometimes difficult to differentiate between both conditions. For example, opioid withdrawal symptoms may mimic the hypervigilance and exacerbated startle response of patients with PTSD. A common neurobiologic circuit is suggested for the pathophysiologic mechanism of this comorbidity. There is evidence that opioid substitution therapy may improve treatment outcomes for opioid addiction in patients with comorbid PTSD and opioid dependence. Evidence-based psychotherapeutic intervention is recommended for this population to improve the psychological outcome as well. Combining opioid substitution therapy with evidence-based cognitive behavioral therapy designed for individuals with comorbid PTSD and substance abuse (e.g., Seeking Safety) may improve treatment outcomes in this population. More research is needed to understand the underlying mechanisms for this comorbidity and to improve treatment response.

Effect of buprenorphine dose on treatment outcome.

The goal of this meta-analysis is to provide evidence based information about proper dosing for buprenorphine maintenance treatment to improve treatment outcome. To be selected for the review and inclusion in the meta-analysis, articles had to be randomized, controlled, or double-blind clinical trials, with buprenorphine as the study drug; the length of buprenorphine maintenance treatment had to be 3 weeks or longer; doses of buprenorphine had to be clearly stated; outcome measures had to include retention rates in buprenorphine treatment; outcome measures had to include illicit opioid use based on analytical determination of drugs of abuse in urine samples as outcome variables; and outcome measures had to include illicit cocaine use based on analytical determination of drugs of abuse in urine samples as outcome variables. Twenty-nine articles were excluded because they did not meet the inclusion criteria. The authors present the results of 21 articles that met inclusion criteria. The higher buprenorphine dose (16-32 mg per day) predicted better retention in treatment compared with the lower dose (less than 16 mg per day) (P = .009, R(2) adjusted = 0.40), and the positive urine drug screens for opiates predicted dropping out of treatment (P = .019, R(2) Adjusted = 0.40). Retention in treatment predicted less illicit opioid use (P = .033, R(2) Adjusted = 0.36), and the positive urine drug screens for cocaine predicted more illicit opioid use (P = .021, R(2) Adjusted = 0.36). Strong evidence exists based on 21 randomized clinical trials that the higher buprenorphine dose may improve retention in buprenorphine maintenance treatment.

Effect of methadone maintenance treatment on heroin craving, a literature review.

Despite agreement that methadone maintenance treatment (MMT) is an effective and safe option for treatment of heroin dependence, there have been controversies about its effect on heroin craving. A systematic literature review of the PubMed database was used to find studies eligible for inclusion in the study. The authors present the results of 16 articles that met all inclusion criteria. Overall, 7 studies reported that methadone could reduce heroin craving, 4 studies reported that patients in MMT are still at risk of having heroin craving, 1 study reported that methadone could increase heroin craving, and 4 studies reported that methadone has a neutral effect on heroin craving. One may speculate from these data that methadone may help with heroin craving, but patients in MMT may still be at risk of cue-induced heroin cravings. Methadone provides a helpful tool for reducing some components of craving and risk of relapse for patient receiving MMT.