Sheila M. Dowd

Repetitive transcranial magnetic stimulation versus electroconvulsive therapy for major depression: preliminary results of a randomized trial.

BACKGROUND Many severely depressed patients do not benefit from or tolerate existing treatments. Repetitive transcranial magnetic stimulation (rTMS) has been reported to benefit depression. We compared rTMS to electroconvulsive therapy (ECT) in severely ill, depressed patients. METHODS Twenty-five patients with a major depression (unipolar or bipolar) deemed clinically appropriate for ECT were randomly assigned to rTMS (10-20 treatments, 10 Hz, 110% motor threshold applied to the left dorsolateral prefrontal cortex for a total of 10,000-20,000 stimulations) or a course of bitemporal ECT (4-12 treatments). The primary outcome measure was the 24-item Hamilton Depression Rating Scale (HDRS). The Brief Psychiatric Rating Scale (BPRS), Young Mania Rating Scale (YMS), and Clinical Global Impression scale (CGI) were secondary measures. Minimal rescue medications were utilized. RESULTS Mean percent improvement on the baseline HDRS score did not significantly differ between the two treatments (i.e., 55% for the rTMS group vs. 64% for the ECT group [p = ns]). With response defined as a 50% reduction from baseline and a final score < or = 8 on the HDRS, there was also no significant difference between the two groups. We did not observe any differences between groups on the secondary measures. CONCLUSIONS A 2-4 week randomized, prospective trial comparing rTMS to ECT produced comparable therapeutic effects in severely depressed patients.

Neurocognitive effects of repetitive transcranial magnetic stimulation in severe major depression.

OBJECTIVE Repetitive transcranial magnetic stimulation (rTMS) is being investigated as a potential treatment for depression. Few studies have addressed the neurocognitive effects of a course of rTMS in severely depressed patients. We evaluated neurocognitive effects of a 1-4 week course (mean 3 weeks) of rTMS using an aggressive set of parameters, in 15 severely depressed subjects. METHODS A battery of neurocognitive tests relevant to attention, working memory-executive function, objective memory and motor speed were administered to 15 subjects with treatment-resistant major depression (unipolar and bipolar), before and after a course of rTMS. Mean z scores were computed for each of 4 cognitive domains and analyzed using repeated measures multivariate analysis of covariance. Significant interactions were further clarified using univariate analysis of variance. RESULTS There was no worsening of performance on any of the cognitive domains over the baseline-post rTMS period. On the contrary, evidence of modest but statistically significant improvement in performance was noted in working memory-executive function, objective memory and fine motor speed domains over the rTMS treatment period. CONCLUSIONS There was no evidence of adverse neurocognitive changes over the baseline-post rTMS period in 15 treatment-resistant depressed subjects undergoing a 3 week (mean) trial of rTMS. Significant improvements in several domains observed over the rTMS treatment period could not be explained by improved mood. Practice effects as well as other factors potentially contributing to these findings are discussed. SIGNIFICANCE rTMS is being increasingly studied as a neurophysiological probe as well as for its potential antidepressive effects. The effects on neuronal function raise appropriate questions of safety of its use at varying stimulus parameters and durations. This study contributes to the small body of evidence of the cognitive effects of rTMS in severely depressed patients.

Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study

BACKGROUND Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit. OBJECTIVE We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. METHODS Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. RESULTS Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. CONCLUSIONS These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse.

Adjunctive use of repetitive transcranial magnetic stimulation in depressed adolescents: a prospective, open pilot study.

OBJECTIVE Depression is often a serious and debilitating illness in adolescents. Unfortunately, a significant number of adolescents do not respond to antidepressant medications or psychotherapy. Repetitive transcranial magnetic stimulation (rTMS) is a novel treatment intervention shown to benefit depression in adults. This study considered rTMS as an adjunctive treatment in adolescents with major depressive disorder. METHOD This prospective, open, multicenter trial of active adjunctive rTMS was conducted with 8 adolescents with DSM-IV-TR major depressive disorder (MDD) that had not responded sufficiently to 2 adequate antidepressant medication trials. All subjects were maintained on a stable dose of a selective serotonin reuptake inhibitor during the trial. Thirty daily rTMS treatments were given 5 days per week over 6 to 8 weeks. rTMS was applied to the left dorsolateral prefrontal cortex (120% of motor threshold; 10 Hz; 4-second trains; 26-second intertrain interval; 75 trains) for a total of 3,000 stimulations per treatment session. RESULTS Seven of 8 adolescents completed all 30 treatments. rTMS was well tolerated, and no significant safety issues were identified. Suicidal ideation was present at baseline in 3 of the adolescents, and it improved during treatment. The primary outcome measure was the Childrens Depression Rating Scale-Revised (CDRS-R); results improved significantly from baseline (mean [SD]) (65.9 [6.6]) to treatment 10 (50.9 [12]), P < .02. The CDRS-R scores continued to improve through the rTMS treatment series at treatment 20 (40.1 [14]), P < .01; treatment 30 (32.6 [7.3]), P < .0001; and at 6-month follow-up (32.7 [3.8]), P < .0001. CONCLUSIONS This prospective open trial suggests that rTMS is a safe, feasible, and potentially effective adjunctive therapy for treatment-resistant MDD in adolescents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00587639.

A double-blind, randomized, prospective evaluation of the efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder

The relative efficacy and safety of risperidone versus haloperidol in the treatment of schizoaffective disorder was studied. Sixty-two patients (29 depressed type; 33 bipolar type) entered a three-site, randomized, double-blind, 6-week trial of risperidone (up to 10 mg/day) or haloperidol (up to 20 mg/day). Trained raters assessed baseline, weekly, and end-of-study levels of psychopathology with the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and the Clinician-Administered Rating Scale for Mania (CARS-M). The authors were unable to statistically distinguish between risperidone and haloperidol in the amelioration of psychotic and manic symptoms. In addition, there was no difference in worsening of mania between the two agents in either subgroup (i.e., depressed or bipolar subgroups). For the total PANSS, risperidone produced a mean decrease of 16 points from baseline compared with a 14-point decrease with haloperidol. For the total CARS-M scale, risperidone and haloperidol produced mean change scores of 5 and 8 points, respectively, and for the CARS-M Mania subscale, 3 and 7 points, respectively. Additionally, risperidone produced a mean decrease of 13 points from the baseline 24-item HAM-D, compared with an 8-point decrease with haloperidol. In those patients who had more severe depressive symptoms (i.e., HAM-D baseline score >20), risperidone produced at least a 50% mean improvement in 12 (75%) of 16 patients in comparison to 8 (38%) of 21 patients receiving haloperidol. Haloperidol produced significantly more extrapyramidal side effects and resulted in more dropouts caused by any side effect. There was no difference between risperidone and haloperidol in reducing both psychotic and manic symptoms in this group of patients with schizoaffective disorder. Risperidone did not demonstrate a propensity to precipitate mania and was better tolerated than haloperidol. In those subjects with higher baseline HAM-D scores (i.e., >20), risperidone produced a greater improvement in depressive symptoms than haloperidol.

The Behavioral and Cognitive Effects of Two Benzodiazepines Associated with Drug-Facilitated Sexual Assault

Recently, sexual assaults have included the use of benzodiazepines to impair the victim. Our aim was to examine the physiological, cognitive, and behavioral effects of flunitrazepam (FN) and clonazepam (CLO). In the first study, ten healthy volunteers received a single oral dose of 2 mg of FN. Mini Mental State Examination (MMSE), behavioral reports and staff observations were then collected. In the second study, ten healthy volunteers received a single oral dose of 3 mg of CLO. Vital signs, performance on the MMSE and Digit Symbol Substitution Test, and behavioral changes were examined. FN significantly decreased systolic and diastolic blood pressure 4 h post drug ingestion with diastolic remaining low at 6 h. CLO was associated with changes in temperature and decreased systolic pressure. FN affected memory and attention 4 h following ingestion. CLO affected memory and attention throughout the study (6 h), and psychomotor performance was decreased 2 h post ingestion. In both studies, subjects were disinhibited and did not perceive their own impairment.

Sleep quality predicts treatment outcome in CBT for social anxiety disorder.

Sleep quality may be an important, yet relatively neglected, predictor of treatment outcome in cognitive‐behavioral therapy (CBT) for anxiety disorders. Specifically, poor sleep quality may impair memory consolidation of in‐session extinction learning. We therefore examined sleep quality as a predictor of treatment outcome in CBT for social anxiety disorder and the impact of d‐cycloserine (DCS) on this relationship.

A two-phase, double-blind randomized study of three haloperidol plasma levels for acute psychosis with reassignment of initial non-responders

To clarify the plasma level/therapeutic response relationship of haloperidol (HPDL) we used a prospective double‐blind design in 95 acutely psychotic patients. After drug washout, patients were randomly assigned to a low, middle or high plasma level range for 2 weeks (phase A), and then 50% of the initial non‐responders were randomly reassigned into the putative therapeutic range for an additional 2 weeks (phase B). There were no significant differences in clinical outcome between the three plasma level ranges in phase A. However, in phase B initial non‐responders displayed greater improvement in the middle range than in the low or the high ranges. No further benefit was observed when plasma levels were raised to or maintained in the high range.

Can Medication Free, Treatment-Resistant, Depressed Patients Who Initially Respond to TMS Be Maintained Off Medications? A Prospective, 12-Month Multisite Randomized Pilot Study

BACKGROUND Repetitive transcranial magnetic stimulation (TMS) is efficacious for acute treatment of resistant major depressive disorder (MDD), but there is little information on maintenance TMS after acute response. OBJECTIVE/HYPOTHESIS This pilot feasibility study investigated 12-month outcomes comparing two maintenance TMS approaches--a scheduled, single TMS session delivered monthly (SCH) vs. observation only (OBS). METHODS Antidepressant-free patients with unipolar, non-psychotic, treatment-resistant MDD participated in a randomized, open-label, multisite trial. Patients meeting protocol-defined criteria for improvement after six weeks of acute TMS were randomized to SCH or OBS regimens. TMS reintroduction was available for symptomatic worsening; all patients remained antidepressant-free during the trial. RESULTS Sixty-seven patients enrolled in the acute phase, and 49 (73%) met randomization criteria. Groups were matched, although more patients in the SCH group had failed ≥ 2 antidepressants (p = .035). There were no significant group differences on any outcome measure. SCH patients had nonsignificantly longer time to first TMS reintroduction, 91 ± 66 days, vs. OBS, 77 ± 52 days; OBS patients were nonsignificantly more likely to need reintroduction (odds ratio = 1.21, 95% CI .38-3.89). Reintroduction lasted 14.3 ± 17.8 days (SCH) and 16.9 ± 18.9 days (OBS); 14/18 (78%) SCH and 17/27 (63%) OBS responded to reintroduction. Sixteen patients (32.7%) completed all 53 weeks of the study. CONCLUSIONS Maintaining treatment-resistant depressed patients off medications with periodic TMS appears feasible in some cases. There was no statistical advantage of SCH vs. OBS, although SCH was associated with a nonsignificantly longer time to relapse. Those who initially respond to TMS have a strong chance of re-responding if relapse occurs.

RANDOMIZED TRIAL OF D‐CYCLOSERINE ENHANCEMENT OF COGNITIVE‐BEHAVIORAL THERAPY FOR PANIC DISORDER

Initial studies have provided a mixed perspective of the efficacy of d‐cycloserine (DCS) for augmenting the efficacy of exposure‐based cognitive behavioral therapy (CBT) for panic disorder. In this multicenter trial, we examine the magnitude of DCS augmentation effects for an ultra‐brief program of CBT.