Martina Pavlicova

Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial.

CONTEXT Daily left prefrontal repetitive transcranial magnetic stimulation (rTMS) has been studied as a potential treatment for depression, but previous work had mixed outcomes and did not adequately mask sham conditions. OBJECTIVE To test whether daily left prefrontal rTMS safely and effectively treats major depressive disorder. DESIGN Prospective, multisite, randomized, active sham-controlled (1:1 randomization), duration-adaptive design with 3 weeks of daily weekday treatment (fixed-dose phase) followed by continued blinded treatment for up to another 3 weeks in improvers. SETTING Four US university hospital clinics. PATIENTS Approximately 860 outpatients were screened, yielding 199 antidepressant drug-free patients with unipolar nonpsychotic major depressive disorder. INTERVENTION We delivered rTMS to the left prefrontal cortex at 120% motor threshold (10 Hz, 4-second train duration, and 26-second intertrain interval) for 37.5 minutes (3000 pulses per session) using a figure-eight solid-core coil. Sham rTMS used a similar coil with a metal insert blocking the magnetic field and scalp electrodes that delivered matched somatosensory sensations. MAIN OUTCOME MEASURE In the intention-to-treat sample (n = 190), remission rates were compared for the 2 treatment arms using logistic regression and controlling for site, treatment resistance, age, and duration of the current depressive episode. RESULTS Patients, treaters, and raters were effectively masked. Minimal adverse effects did not differ by treatment arm, with an 88% retention rate (90% sham and 86% active). Primary efficacy analysis revealed a significant effect of treatment on the proportion of remitters (14.1% active rTMS and 5.1% sham) (P = .02). The odds of attaining remission were 4.2 times greater with active rTMS than with sham (95% confidence interval, 1.32-13.24). The number needed to treat was 12. Most remitters had low antidepressant treatment resistance. Almost 30% of patients remitted in the open-label follow-up (30.2% originally active and 29.6% sham). CONCLUSION Daily left prefrontal rTMS as monotherapy produced statistically significant and clinically meaningful antidepressant therapeutic effects greater than sham. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00149838.

Fever after subarachnoid hemorrhage. Risk factors and impact on outcome

Objective: To identify risk factors for refractory fever after subarachnoid hemorrhage (SAH), and to determine the impact of temperature elevation on outcome. Methods: We studied a consecutive cohort of 353 patients with SAH with a maximum daily temperature (Tmax) recorded on at least 7 days between SAH days 0 and 10. Fever (>38.3 °C) was routinely treated with acetaminophen and conventional water-circulating cooling blankets. We calculated daily Tmax above 37.0 °C, and defined extreme Tmax as daily excess above 38.3 °C. Global outcome at 90 days was evaluated with the modified Rankin Scale (mRS), instrumental activities of daily living (IADLs) with the Lawton scale, and cognitive functioning with the Telephone Interview of Cognitive Status. Mixed-effects models were used to identify predictors of Tmax, and logistic regression models to evaluate the impact of Tmax on outcome. Results: Average daily Tmax was 1.15 °C (range 0.04 to 2.74 °C). The strongest predictors of fever were poor Hunt-Hess grade and intraventricular hemorrhage (IVH) (both p < 0.001). After controlling for baseline outcome predictors, daily Tmax was associated with an increased risk of death or severe disability (mRS ≥ 4, adjusted OR 3.0 per °C, 95% CI 1.6 to 5.8), loss of independence in IADLs (OR 2.6, 95% CI 1.2 to 5.6), and cognitive impairment (OR 2.5, 95% CI 1.2 to 5.1, all p ≤ 0.02). These associations were even stronger when extreme Tmax was analyzed. Conclusion: Treatment-refractory fever during the first 10 days after subarachnoid hemorrhage (SAH) is predicted by poor clinical grade and intraventricular hemorrhage, and is associated with increased mortality and more functional disability and cognitive impairment among survivors. Clinical trials are needed to evaluate the impact of prophylactic fever control on outcome after SAH.

Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial

Cannabis dependence is a substantial public health problem. Behavioral treatments have shown promise, but there are no effective medications for cannabis dependence. The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence. 156 cannabis-dependent adults were enrolled in a randomized, double-blind, placebo-controlled, 12-week trial. After a 1-week placebo lead-in phase, participants were randomized to receive dronabinol 20mg twice a day or placebo. Doses were maintained until the end of week 8 and then tapered off over 2 weeks. All participants received weekly motivational enhancement and relapse prevention therapy. Marijuana use was assessed using the timeline follow back method. There was no significant difference between treatment groups in the proportion of participants who achieved 2 weeks of abstinence at the end of the maintenance phase (dronabinol: 17.7%; placebo: 15.6%). Although both groups showed a reduction in marijuana use over time, there were no differences between the groups. Treatment retention was significantly higher at the end of the maintenance phase on dronabinol (77%), compared to placebo (61%) (P=.02), and withdrawal symptoms were significantly lower on dronabinol than placebo (P=.02). This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.

Zero-Inflated and Hurdle Models of Count Data with Extra Zeros: Examples from an HIV-Risk Reduction Intervention Trial

Background: In clinical trials of behavioral health interventions, outcome variables often take the form of counts, such as days using substances or episodes of unprotected sex. Classically, count data follow a Poisson distribution; however, in practice such data often display greater heterogeneity in the form of excess zeros (zero-inflation) or greater spread in the values (overdispersion) or both. Greater sample heterogeneity may be especially common in community-based effectiveness trials, where broad eligibility criteria are implemented to achieve a generalizable sample. Objectives: This article reviews the characteristics of Poisson model and the related models that have been developed to handle overdispersion (negative binomial (NB) model) or zero-inflation (zero-inflated Poisson (ZIP) and Poisson hurdle (PH) models) or both (zero-inflated negative binomial (ZINB) and negative binomial hurdle (NBH) models). Methods: All six models were used to model the effect of an HIV-risk reduction intervention on the count of unprotected sexual occasions (USOs), using data from a previously completed clinical trial among female patients (N = 515) participating in community-based substance abuse treatment (Tross et al. Effectiveness of HIV/AIDS sexual risk reduction groups for women in substance abuse treatment programs: Results of NIDA Clinical Trials Network Trial. J Acquir Immune Defic Syndr 2008; 48(5):581–589). Goodness of fit and the estimates of treatment effect derived from each model were compared. Results: The ZINB model provided the best fit, yielding a medium-sized effect of intervention. Conclusions and Scientific Significance: This article illustrates the consequences of applying models with different distribution assumptions on the data. If a model used does not closely fit the shape of the data distribution, the estimate of the effect of the intervention may be biased, either over- or underestimating the intervention effect.

Effectiveness of HIV/STD Sexual Risk Reduction Groups for Women in Substance Abuse Treatment Programs : Results of NIDA Clinical Trials Network Trial

Context:Because drug-involved women are among the fastest growing groups with AIDS, sexual risk reduction intervention for them is a public health imperative. Objective:To test effectiveness of HIV/STD safer sex skills building (SSB) groups for women in community drug treatment. Design:Randomized trial of SSB versus standard HIV/STD Education (HE); assessments at baseline, 3 and 6 months. Participants:Women recruited from 12 methadone or psychosocial treatment programs in Clinical Trials Network of National Institute on Drug Abuse. Five hundred fifteen women with ≥1 unprotected vaginal or anal sex occasion (USO) with a male partner in the past 6 months were randomized. Interventions:In SSB, five 90-minute groups used problem solving and skills rehearsal to increase HIV/STD risk awareness, condom use, and partner negotiation skills. In HE, one 60-minute group covered HIV/STD disease, testing, treatment, and prevention information. Main Outcome:Number of USOs at follow-up. Results:A significant difference in mean USOs was obtained between SSB and HE over time (F = 67.2, P < 0.0001). At 3 months, significant decrements were observed in both conditions. At 6 months, SSB maintained the decrease and HE returned to baseline (P < 0.0377). Women in SSB had 29% fewer USOs than those in HE. Conclusions:Skills building interventions can produce ongoing sexual risk reduction in women in community drug treatment.

Combined prolonged exposure therapy and paroxetine for PTSD related to the World Trade Center attack: a randomized controlled trial.

OBJECTIVE Selective serotonin reuptake inhibitors (SSRIs) are often recommended in combination with established cognitive-behavioral therapies (CBTs) for posttraumatic stress disorder (PTSD), but combined initial treatment of PTSD has not been studied under controlled conditions. There are also few studies of either SSRIs or CBT in treating PTSD related to terrorism. The authors compared prolonged exposure therapy (a CBT) plus paroxetine (an SSRI) with prolonged exposure plus placebo in the treatment of terrorism-related PTSD. METHOD Adult survivors of the World Trade Center attack of September 11, 2001, with PTSD were randomly assigned to 10 weeks of treatment with prolonged exposure (10 sessions) plus paroxetine (N=19) or prolonged exposure plus placebo (N=18). After week 10, patients discontinued prolonged exposure and were offered 12 additional weeks of continued randomized treatment. RESULTS Patients treated with prolonged exposure plus paroxetine experienced significantly greater improvement in PTSD symptoms (incidence rate ratio=0.50, 95% CI=0.30-0.85) and remission status (odds ratio=12.6, 95% CI=1.23-129) during 10 weeks of combined treatment than patients treated with prolonged exposure plus placebo. Response rate and quality of life were also significantly more improved with combined treatment. The subset of patients who continued randomized treatment for 12 additional weeks showed no group differences. CONCLUSIONS Initial treatment with paroxetine plus prolonged exposure was more efficacious than prolonged exposure plus placebo for PTSD related to the World Trade Center attack. Combined treatment medication and prolonged exposure therapy deserves further study in larger samples with diverse forms of PTSD and over longer follow-up periods.

Reducing heavy drinking in HIV primary care: a randomized trial of brief intervention, with and without technological enhancement

AIMS In HIV-infected individuals, heavy drinking compromises survival. In HIV primary care, the efficacy of brief motivational interviewing (MI) to reduce drinking is unknown, alcohol-dependent patients may need greater intervention and resources are limited. Using interactive voice response (IVR) technology, HealthCall was designed to enhance MI via daily patient self-monitoring calls to an automated telephone system with personalized feedback. We tested the efficacy of MI-only and MI+HealthCall for drinking reduction among HIV primary care patients. DESIGN Parallel random assignment to control (n = 88), MI-only (n = 82) or MI+HealthCall (n = 88). Counselors provided advice/education (control) or MI (MI-only or MI+HealthCall) at baseline. At 30 and 60 days (end-of-treatment), counselors briefly discussed drinking with patients, using HealthCall graphs with MI+HealthCall patients. SETTING Large urban HIV primary care clinic. PARTICIPANTS Patients consuming ≥4 drinks at least once in prior 30 days. MEASUREMENTS Using time-line follow-back, primary outcome was number of drinks per drinking day, last 30 days. FINDINGS End-of-treatment number of drinks per drinking day (NumDD) means were 4.75, 3.94 and 3.58 in control, MI-only and MI+HealthCall, respectively (overall model χ(2) , d.f. = 9.11,2, P = 0.01). For contrasts of NumDD, P = 0.01 for MI+HealthCall versus control; P = 0.07 for MI-only versus control; and P = 0.24 for MI+HealthCall versus MI-only. Secondary analysis indicated no intervention effects on NumDD among non-alcohol-dependent patients. However, for contrasts of NumDD among alcohol-dependent patients, P < 0.01 for MI+HealthCall versus control; P = 0.09 for MI-only versus control; and P = 0.03 for MI+HealthCall versus MI-only. By 12-month follow-up, although NumDD remained lower among alcohol-dependent patients in MI+HealthCall than others, effects were no longer significant. CONCLUSIONS For alcohol-dependent HIV patients, enhancing MI with HealthCall may offer additional benefit, without extensive additional staff involvement.

IMPROVING THE ANTIDEPRESSANT EFFICACY OF TRANSCRANIAL MAGNETIC STIMULATION: MAXIMIZING THE NUMBER OF STIMULATIONS AND TREATMENT LOCATION IN TREATMENT-RESISTANT DEPRESSION

Objective: To assess the efficacy of increasing the number of fast left repetitive transcranial magnetic stimulations (rTMS) (10 Hz @ 120% of motor threshold (MT) over the left dorsolateral prefrontal cortex (DLPFC)) needed to achieve remission in treatment‐resistant depression (TRD). And, to determine if patients who do not remit to fast left will remit using slow right rTMS (1 Hz @ 120% MT over the right DLPFC). Method: Patients were part of a multicenter sham‐controlled trial investigating the efficacy of fast left rTMS. Patients who failed to meet minimal response criteria in the sham‐controlled study could enroll in this open fast left rTMS study for an additional 3–6 weeks. Patients who failed to remit to fast left could switch to slow right rTMS for up to 4 additional weeks. The final outcome measure was remission, defined as a HAM‐D score of <3 or 2 consecutive HAM‐D scores less than 10. Results: Forty‐three of 141 (30.5%) patients who enrolled in the open phase study eventually met criteria for remission. Patients who remitted during fast left treatment received a mean of 26 active treatments (90,000 pulses). Twenty‐six percent of patients who failed fast left remitted during slow right treatment. Conclusion: The total number of rTMS stimulations needed to achieve remission in TRD may be higher than is used in most studies. TRD patients who do not respond to fast left rTMS may remit to slow right rTMS or additional rTMS stimulations. Depression and Anxiety, 2011.

Extended-release mixed amphetamine salts and topiramate for cocaine dependence: a randomized controlled trial.

BACKGROUND Cocaine dependence is a substantial public health problem, yet there are no clearly effective medication treatments. Amphetamine and topiramate have both shown promise for the treatment of cocaine dependence in preclinical and early-stage clinical studies. METHODS Eighty-one cocaine-dependent adults were randomized to receive a combination of extended-release mixed amphetamine salts (MAS-ER) and topiramate or placebo for 12 weeks under double-blind conditions. MAS-ER doses were titrated over 2 weeks to a maximum dose of 60 mg daily, and topiramate doses were titrated over 6 weeks to a maximum dose of 150 mg twice daily. All participants received a supportive behavioral intervention. The primary outcome was the proportion of individuals who achieved 3 consecutive weeks of abstinence as measured by urine toxicology confirmed self-report. RESULTS The overall proportion of participants who achieved 3 consecutive weeks of abstinence was larger in the extended-release mixed amphetamine salts and topiramate group (33.3%) than in placebo group (16.7%). There was a significant moderating effect of baseline total number of cocaine use days (Wald χ(2) = 3.75, df = 1, p = .05) on outcome, suggesting that the combination treatment was most effective for participants with a high baseline frequency of cocaine use. CONCLUSIONS The results of this study supported our hypothesis that the combination of MAS-ER and topiramate would be superior to placebo in achieving 3 weeks of consecutive abstinence. These findings provide evidence that the combination of MAS-ER and topiramate is efficacious in promoting abstinence in cocaine-dependent individuals.

Relationship Power and Sexual Risk among Women in Community-Based Substance Abuse Treatment

Relationship power has been highlighted as a major factor influencing women’s safer sex practices. Little research, however, has specifically examined relationship power in drug-involved women, a population with increased risk for HIV transmission. Using baseline data from a National Institute on Drug Abuse Clinical Trials Network multisite trial of a women’s HIV prevention intervention in community-based drug treatment programs, this paper examined the association between sexual relationship power and unprotected vaginal or anal sex. The Sexual Relationship Power Scale, a measure of relationship control and decision-making dominance, was used to assess the association between power and unprotected sex in relationships with primary male partners. It was hypothesized that increased relationship power would be associated with decreased unprotected sexual occasions, after controlling for relevant empirical and theoretical covariates. Findings show a more complex picture of the association between power and sexual risk in this population, with a main effect in the hypothesized direction for decision-making dominance but not for relationship control. Possible explanations for these findings are discussed, and future research directions for examining power constructs and developing interventions targeting relationship power among drug-involved women are suggested.