Roger F. Haskett

Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects.

CONTEXTnMedication resistance is the leading indication for use of electroconvulsive therapy (ECT) in major depression. The practice of stopping antidepressant medications prior to ECT derived from studies in the 1960s and 1970s in nonresistant samples. There is also continuing controversy regarding the relative efficacy and adverse effects of right unilateral and bilateral ECT.nnnOBJECTIVEnTo test the hypotheses that, compared with placebo, concomitant treatment with nortriptline or venlafaxine during the ECT course enhances short-term efficacy without a meaningful effect on adverse effects and reduces the rate of post-ECT relapse, and to test the hypotheses that high-dose, right-sided, unilateral ECT is equivalent in efficacy to moderate-dosage bilateral ECT and retains advantages with respect to cognitive adverse effects.nnnDESIGNnProspective, randomized, triple-masked, placebo-controlled study conducted from 2001 through 2005.nnnSETTINGnThree university-based hospitals.nnnPATIENTSnOf approximately 750 consecutive patients referred for ECT, 319 with a major depressive episode consented, were randomized to pharmacological or ECT treatment conditions, and received at least 1 ECT treatment.nnnMAIN OUTCOME MEASURESnScores on the Hamilton Rating Scale for Depression, remission rate following completion of ECT, and selective measures of cognitive adverse effects.nnnRESULTSnTreatment with nortriptyline enhanced the efficacy and reduced the cognitive adverse effects of ECT relative to placebo. Venlafaxine resulted in a weaker degree of improvement and tended to worsen cognitive adverse effects. High-dosage right unilateral ECT did not differ or was superior to bilateral ECT in efficacy and resulted in less severe amnesia.nnnCONCLUSIONSnThe efficacy of ECT is substantially increased by the addition of an antidepressant medication, but such medications may differ in whether they reduce or increase cognitive adverse effects. High-dose, right-sided, unilateral ECT is at least equivalent to moderate-dosage bilateral ECT in efficacy, but retains advantages with respect to cognitive adverse effects.

Screening for Depression in the Postpartum Period: A Comparison of Three Instruments

OBJECTIVESnPostpartum depression, the most prevalent complication of childbirth, is often unrecognized. Our objective was to compare the effectiveness of three screening instruments--Edinburgh Postnatal Depression Scale (EPDS), Patient Health Questionnaire (PHQ-9), and the 7-item screen of the Postpartum Depression Screening Scale (PDSS)--for identifying women with postpartum depression in the first 6 months after delivery.nnnMETHODSnWe administered the three instruments via telephone to women who were > or =18 years and had delivered infants 6-8 weeks earlier. We arranged home interviews to confirm DSM-IV criteria current major depressive disorder (MDD) in women who had an above-threshold score on any of the instruments. For women who screened negative on the 6-8 week call, we repeated the screening at 3 months and 6 months to identify emergent symptoms. The primary outcome measures were the screening scores and DSM-IV diagnoses.nnnRESULTSnOf 135 women reached, 123 (91%) were screened, 29 (24%) had home visits, and 13 (11%) had an MDD within 6 months of delivery. Analyses of the scores at 6-8 weeks postpartum and the DSM-IV diagnoses indicated the EPDS at a cutoff point of > or =10 identified 8 (62%) of cases, the PHQ-9 at a cutoff point of > or =10 identified 4 (31%), and the PDSS 7-item Short Form (PDSS_SF) at a cutoff point of > or =14 identified 12 (92%). However, 15 of 16 (94%) women without current MDD screened positive on the PDSS_SF. The EPDS was significantly more accurate (p = 0.01) than the PDSS_SF and PHQ-9 with the cutoff points used. After correcting for verification bias, we found the EPDS and the PDSS_SF were significantly more accurate than the PHQ-9 (p < 0.03).nnnCONCLUSIONSnAdministering the EPDS by phone at 6-8 weeks postpartum is an efficient and accurate way to identify women at high risk for postpartum depression within the first 6 months after delivery.

Determinants of seizure threshold in ECT: Benzodiazepine use, anesthetic dosage, and other factors

The electrical dosage of the ECT stimulus impacts on efficacy and cognitive side effects, yet seizure threshold (ST) may vary as much as 50-fold across patients. It would be desirable to predict ST on the basis of patient and treatment characteristics. In particular, concerns have been raised that benzodiazepine use and higher dosage of barbiturate anesthetics elevate ST. In a three-site study, ST was quantified at the first ECT session using an identical empirical titration procedure in 294 patients who met RDC and DSM-IIIR criteria for a major depressive episode. ST varied over a 35-fold range across patients treated with right unilateral (RUL) (n = 267) and bilateral (BL) (n = 27) ECT. Higher ST was associated with BL electrode placement (p = 0.001). Among patients treated with RUL ECT, univariate analyses indicated that higher ST was associated with advanced age (p < 0.001), male gender (p < 0.001), greater burden of medical illness (p < 0.001), weight (p < 0.01), duration of mood disorder (p < 0.01), and history of previous ECT (p < 0.05). Average lorazepam dose in the 48 hours prior to ECT was not associated with ST, but was associated with decreased seizure duration (p < 0.01). Absolute, but not weight-adjusted, methohexital dose was associated with ST (p < 0.01). Multivariate analyses in patients treated with unilateral ECT showed that only 27.6% of the variance in ST (p < 0.0001) could be predicted. In the multivariate analyses, only age (p = 0.0001), gender (p = 0.01), and methohexital dose (p = 0.0001) were independently related to ST. Low dosage of lorazepam and methohexital dosage below 1 mg/kg are unlikely to impact on ST. Given the limited capacity to predict ST, empirical titration remains the only accurate method to determine electrical dosage in RUL ECT.

Addressing depression in obstetrics/gynecology practice ☆

Efforts to improve the care of depression in primary care patients have largely ignored the potential of obstetrics/gynecology (OB/GYN) practices. We describe feasibility studies of a depression screening and care management intervention in three diverse OB/GYN practices. Patients were screened using the Patient Health Questionnaire. A depression care manager offered education and referral assistance to women who screened positive for depression. The prevalence of depression was higher in the hospital clinic (20.2%, 47/233) than the suburban clinic (10.7%, 8/75) or the office practice (8.2%, 48/583). Seventy-two women participated in the care management intervention. Patient satisfaction with the intervention was high and at 1-month follow-up, 31.9% of patients had kept or scheduled a new mental health appointment. Depression interventions developed in primary care can be successfully adapted for use with patients in OB/GYN practices. Additional modifications, particularly efforts to improve coordination of care with both general medical and mental health providers, are needed.

Fluoxetine versus placebo for the marijuana use of depressed alcoholics

The aim of this analysis was to evaluate the efficacy of the SSRI antidepressant fluoxetine versus placebo for the marijuana use of depressed alcoholics. There are no previous reports involving and SSRI antidepressant for marijuana abuse. This analysis involved a subsample of 22 depressed alcoholic marijuana users out of a total of 51 depressed alcoholics. The entire sample was involved in a 12-week double-blind, placebo-controlled study evaluating the efficacy of fluoxetine versus placebo in depressed alcoholics. During the course of the trial, the cumulative number of marijuana cigarettes used was almost 20 times as high in the placebo group as in the fluoxetine group. Also, the number of days of marijuana use during the study was five times higher in the placebo group than in the fluoxetine group. These data suggest efficacy for fluoxetine in decreasing marijuana use of depressed alcoholics.

Fluoxetine versus placebo in depressed alcoholics: A 1-YEAR follow-up study

The authors conducted a first study to evaluate the long-term efficacy of fluoxetine for decreasing the depressive symptoms and the drinking of patients with comorbid major depressive disorder and alcohol dependence. This study consisted of a 1-year naturalistic follow-up of 31 patients who previously had completed a 3-month double-blind, placebo-controlled study of fluoxetine in depressed alcoholics. The fluoxetine group continued to demonstrate less depressive symptoms and less drinking than the placebo group at the 1-year follow-up evaluation. The results of the 1-year follow-up evaluation suggest persistent efficacy for fluoxetine for treating the depressive symptoms and the drinking of depressed alcoholics.

Citalopram Intervention for Hostility: Results of a Randomized Clinical Trial

Hostility is associated with an increased risk for cardiovascular disease (CVD). Because central serotonin may modulate aggression, we might expect selective serotonin reuptake inhibitors (SSRIs) to be effective in reducing hostility. Such effects have never been examined in individuals scoring high on hostility who are otherwise free from major Axis I psychopathology according to criteria in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., Text Revision; American Psychiatric Association, 2000). A total of 159 participants (ages 30?50 years, 50% female) scoring high on 2 measures of hostility and with no current major Axis I diagnosis were randomly assigned to 2 months of citalopram (40 mg, fixed-flexible dose) or placebo. Adherence was assessed by electronic measurement and by drug exposure assessment. Treated participants showed larger reductions in state anger (Condition x Time; p = .01), hostile affect (p = 02), and, among women only, physical and verbal aggression (p = .005) relative to placebo controls. Treatment was also associated with relative increases in perceived social support (p = .04). The findings have implications for understanding the central nervous system correlates of hostility, its associations with other psychosocial risk factors for CVD, and, potentially, the design of effective interventions.

Pharmacological strategies in the prevention of relapse after electroconvulsive therapy.

Objective To determine whether starting antidepressant medication at the start of electroconvulsive therapy (ECT) reduces post-ECT relapse and to determine whether continuation pharmacotherapy with nortriptyline (NT) and lithium (Li) differs in efficacy or adverse effects from continuation pharmacotherapy with venlafaxine (VEN) and Li. Methods During an acute ECT phase, 319 patients were randomized to treatment with moderate dosage bilateral ECT or high-dosage right unilateral ECT. They were also randomized to concurrent treatment with placebo, NT, or VEN. Of 181 patients to meet post-ECT remission criteria, 122 (67.4%) participated in a second continuation pharmacotherapy phase. Patients earlier randomized to NT or VEN continued on the antidepressant, whereas patients earlier randomized to placebo were now randomized to NT or VEN. Lithium was added for all patients who were followed until relapse or 6 months. Results Starting an antidepressant medication at the beginning of the ECT course did not affect the rate or timing of relapse relative to starting pharmacotherapy after ECT completion. The combination of NT and Li did not differ from VEN and Li in any relapse or adverse effect measure. Older age was strongly associated with lower relapse risk, whereas the type of ECT administered in the acute phase and medication resistance were not predictive. Across sites, 50% of the patients relapsed, 33.6% continued in remission 6 months after ECT, and 16.4% dropped out. Conclusions Starting an antidepressant medication during ECT does not affect relapse, and there are concerns about administering Li during an acute ECT course. Nortriptyline and VEN were equally effective in prolonging remission, although relapse rates after ECT are substantial despite intensive pharmacology. As opposed to the usual abrupt cessation of ECT, the impact of an ECT taper should be evaluated.

Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.

OBJECTIVESnAttenuation of protein kinase C (PKC) is a mechanism common to both established (lithium, valproate) and some novel (tamoxifen) antimanic agents. Verapamil, although primarily known as a calcium channel blocker, also has PKC inhibitory activity. Verapamil has shown antimanic activity in some but not all studies. Therefore, we investigated verapamil, used alone or as an adjunctive treatment, in manic patients who did not respond to an initial adequate trial of lithium.nnnMETHODSnEach study phase lasted three weeks. Subjects were treated openly with lithium in Phase 1 (n = 45). Those who failed to respond were randomly assigned to double-blind treatment in Phase 2 with either verapamil (n = 10) or continued-lithium (n = 8). Phase 2 nonresponders (n = 10) were assigned to combined verapamil/lithium in Phase 3.nnnRESULTSnResponse in Phase 2 did not differ significantly between verapamil and continued-lithium. During Phase 3, response to combined treatment was significantly better than overall response to monotherapy in Phase 2 (Fishers Exact test, p = 0.043). Mania ratings improved during combined treatment in Phase 3 by 88.2% (linear mixed model analysis, F = 4.34, p = 0.013), compared with 10.5% improvement during Phase 2.nnnCONCLUSIONSnIn this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.

Health-related quality of life in a clinical trial of ECT followed by continuation pharmacotherapy: effects immediately after ECT and at 24 weeks.

Objective: To examine the determinants of health-related quality of life (HRQOL) immediately after a clinical trial of electroconvulsive therapy (ECT) for major depression and then again after 24 weeks of a continuation pharmacotherapy in a clinical trial comparing nortriptyline (NT) plus lithium (Li) versus venlafaxine (VEN) plus Li. Method: During acute ECT, 184 patients randomized to treatment with moderate-dosage bilateral (BL) ECT or high-dosage right unilateral (RUL) ECT completed the Medical Outcomes Study Short Form-36 (SF-36) as a measure of HRQOL before and immediately after ECT. They were also randomized to concurrent treatment with placebo, NT, or VEN. Seventy-four of these met remission criteria and agreed to be further randomized to 24 more weeks of VEN + Li versus NT + Li for relapse prevention and completed a final SF-36. Cognitive testing was also completed. Results: Scores from SF-36 were low before ECT, and the SF-36 subscales reflecting mental health were particularly low. Right unilateral electrode placement was associated with better SF-36 scores immediately after ECT, even after controlling for improvement in depression. Medication assignment during ECT (VEN, NT, or placebo) was not related to immediate HRQOL outcome, and cognitive performance was not related to immediate HRQOL. Remission immediately after ECT was associated with robust improvement in SF-36 scores compared with those who did not remit. Remission status remained a strong predictor of HRQOL 24 weeks after ECT, and sustained remitters showed additional gains in HRQOL 24 weeks after ECT. Electrode placement and medication assignment were not predictors at 24 weeks. Conclusions: Using state-of-the-art delivery of acute ECT and continuation antidepressant medication, HRQOL improves remarkably after ECT, and this improvement shows further gains with those persons who sustain remission. Health-related QOL is superior with RUL versus BL ECT in the immediate post-ECT period, but at 24-weeks HRQOL has absent or inconsistent relationship with mode of ECT delivery or type of continuation antidepressant pharmacotherapy.