Peter B. Rosenquist

Bright light therapy : Improved sensitivity to its effects on rest-activity rhythms in alzheimer patients by application of nonparametric methods

Sleep-wake rhythm disturbances in patients with Alzheimers disease (AD) make a strong demand on caregivers and are among the most important reasons for institutionalization. Several previous studies reported that the disturbances improve with increased environmental light, which, through the retinohypothalamic tract, activates the suprachiasmatic nucleus (SCN), the biological clock of the brain. The data of recently published positive and negative reports on the effect of bright light on actigraphically assessed rest-activity rhythms in demented elderly were reanalyzed using several statistical procedures. It was demonstrated that the light-induced improvement in coupling of the rest-activity rhythm to the environmental zeitgeber of bright light is better detected using nonparametric procedures. Cosinor, complex demodulation, and Lomb-Scargle periodogram-derived variables are much less sensitive to this effect because of the highly nonsinusoidal waveform of the rest-activity rhythm. Guidelines for analyses of actigraphic data are given to improve the sensitivity to treatment effects in future studies.

Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: Clinical predictors of outcome in a multisite, randomized controlled clinical trial

Randomized controlled trials support the antidepressant efficacy of transcranial magnetic stimulation (TMS); however, there is individual variability in the magnitude of response. Examination of response predictors has been hampered by methodological limitations such as small sample sizes and single-site study designs. Data from a multisite sham-controlled trial of the antidepressant efficacy of TMS provided an opportunity to examine predictors of acute outcome. An open-label extension for patients who failed to improve provided the opportunity for confirmatory analysis. Treatment was administered to the left dorsolateral prefrontal cortex at 10 pulses per second, 120% of motor threshold, for a total of 3000 pulses per day. Change on the Montgomery–Asberg Depression Rating Scale after 4 weeks was the primary efficacy outcome. A total of 301 patients with nonpsychotic unipolar major depression at 23 centers were randomized to active or sham TMS. Univariate predictor analyses showed that the degree of prior treatment resistance in the current episode was a predictor of positive treatment outcome in both the controlled study and the open-label extension trial. In the randomized trial, shorter duration of current episode was also associated with a better outcome. In the open-label extension study, absence of anxiety disorder comorbidity was associated with an improved outcome, but duration of current episode was not. The number of prior treatment failures was the strongest predictor for positive response to acute treatment with TMS. Shorter duration of current illness and lack of anxiety comorbidity may also confer an increased likelihood of good antidepressant response to TMS.

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

CONTEXT Medication 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. OBJECTIVE To 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. DESIGN Prospective, randomized, triple-masked, placebo-controlled study conducted from 2001 through 2005. SETTING Three university-based hospitals. PATIENTS Of 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. MAIN OUTCOME MEASURES Scores on the Hamilton Rating Scale for Depression, remission rate following completion of ECT, and selective measures of cognitive adverse effects. RESULTS Treatment 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. CONCLUSIONS The 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.

Insomnia Severity is an Indicator of Suicidal Ideation During a Depression Clinical Trial

OBJECTIVE Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and longitudinal population-based studies. A link between insomnia and suicide has not been previously examined in the setting of a clinical trial. Herein we describe the relationship between insomnia and suicidal thinking during the course of a clinical trial for depression with insomnia. METHODS Sixty patients aged 41.5±12.5 years (2/3 women) with major depressive episode and symptoms of insomnia received open-label fluoxetine for 9 weeks and also received blinded, randomized eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI), and suicidal ideation was assessed with The Scale for Suicide Ideation (SSI). Depression symptoms were assessed with the depressed mood item and the anhedonia item from the Hamilton Rating Scale for Depression-24 (HRSD24), as well as a sum score for all non-sleep and non-suicide items from the HRSD (HRSD20). Measurements were taken at baseline and weeks 1, 2, 4, 6, and 8. SSI was examined by generalized linear mixed models for repeated measures as the outcome of interest for all 60 participants with ISI and various mood symptoms as independent variables, with adjustment for age, gender, treatment assignment, and baseline SSI. RESULTS Higher levels of insomnia corresponded to significantly greater intensity of suicidal thinking (p<0.01). The depressed mood item of the HRSD, and the sum of the HRSD20, both corresponded to greater suicidal thinking (p<0.001). The anhedonia item did not correspond with suicidal thinking. When both ISI and the depressed mood item, or ISI and the anhedonia item, were included together in the same model, the ISI remained an independent predictor of suicidal thinking. CONCLUSIONS The results support the concept that insomnia may be a useful indicator for suicidal ideation and now extend this idea into clinical trials. Insomnia remains an independent indicator of suicidal ideation, even taking into account the core symptoms of depression such as depressed mood and anhedonia. The complaint of insomnia during a depression clinical trial might indicate that more direct questioning about suicide is warranted.

Exome Sequencing Followed by Large-Scale Genotyping Suggests a Limited Role for Moderately Rare Risk Factors of Strong Effect in Schizophrenia

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous. However, it remains unclear whether the underlying genetic variants are mostly moderately rare and can be identified by the genotyping of variants observed in sequenced cases in large follow-up cohorts or whether they will typically be much rarer and therefore more effectively identified by gene-based methods that seek to combine candidate variants. Here, we consider 166 persons who have schizophrenia or schizoaffective disorder and who have had either their genomes or their exomes sequenced to high coverage. From these data, we selected 5,155 variants that were further evaluated in an independent cohort of 2,617 cases and 1,800 controls. No single variant showed a study-wide significant association in the initial or follow-up cohorts. However, we identified a number of case-specific variants, some of which might be real risk factors for schizophrenia, and these can be readily interrogated in other data sets. Our results indicate that schizophrenia risk is unlikely to be predominantly influenced by variants just outside the range detectable by GWASs. Rather, multiple rarer genetic variants must contribute substantially to the predisposition to schizophrenia, suggesting that both very large sample sizes and gene-based association tests will be required for securely identifying genetic risk factors.

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.

Markedly suprathreshold right unilateral ECT versus minimally suprathreshold bilateral ECT: antidepressant and memory effects.

Right unilateral (RUL) ECT is reported to have fewer memory side effects than bilateral (BL) ECT. We compared RUL ECT at eight times the seizure threshold (ST) against BL ECT at 1.5 times the ST. Adults with major depression were randomly assigned to RUL ECT at eight times ST or BL ECT at 1.5 times the ST. Blinded ratings of mood and memory were made before ECT, 1 to 3 days after the final ECT, and at 2 and 4 weeks after ECT. Forty patients received RUL and 37 received BL ECT. The antidepressant response rate was not significantly different for the RUL and BL groups (60% vs. 73%). Sustained antidepressant response, accompanied by recovery from anterograde memory side effects, was seen through the first month with both treatments. Measures of mood and memory were not significantly different for the two groups at any time point. The modest sample sizes of this study do not rule out a type II error in the detection of small but meaningful differences between assigned treatments. Also, the period of post-ECT observation consisted of 1 month of naturalistic treatment. Both RUL ECT at eight times the ST and BL ECT at 1.5 times the ST produce similar mood and memory effects. Both forms of ECT produced acceptable antidepressant response rates and only transient anterograde amnesia. No clear advantage emerged for either form of ECT, and both are justifiable as first-line techniques of ECT.

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.

Successful ECT treatment for medically refractory nonconvulsive status epilepticus in pediatric patient

Status epilepticus is a life threatening condition with a high mortality rate in spite of aggressive treatment. There is little consensus on third and fourth line approaches in refractory cases. While electroconvulsive therapy (ECT) has been employed successfully as a treatment for refractory epilepsy and status epilepticus (SE) after exhausting conventional therapy, its use for pediatric patients is limited. We describe a 7-year-old pediatric case in which ECT was used successfully to treat medically refractory nonconvulsive status epilepticus (NCSE) without complete withdrawal of antiepileptic drugs (AED).

Seizure length and clinical outcome in electroconvulsive therapy using methohexital or thiopental.

Seizure duration is an extensively studied and controversial indicator of treatment quality in electroconvulsive therapy. Previous research comparing the effect of the barbiturate anesthetics methohexital and thiopental on seizure duration has yielded conflicting results. A recent period of unavailability of methohexital in the United States allowed for retrospective comparison of seizure length as well as clinical improvement in treatment using each agent. Retrospective review was made of 837 treatments administered to 97 patients between January 2, 2002, and May 31, 2003, examining anesthetic, seizure duration, and Global Assessment of Functioning (GAF) scores of inpatients at hospital admission and discharge. Analysis of variance of treatments 2-5 showed no significant effect for anesthetic on seizure duration. Analysis on a treatment-by-treatment basis revealed a marginally significant trend toward shorter EEG seizures in the thiopental group at the second treatment (50.5 ± 23.6 s vs. 61.1 ± 27.9 s; P = 0.07) and fifth treatment (41.7 ± 16.9 s vs. 51.8 ± 24.0 s; P = 0.07). A difference approaching statistical significance revealed shorter convulsion length in the thiopental group at treatment 5 (29.0 ± 12.3 s vs. 34.8 ± 12.3 s; P = 0.07). Comparison of GAF score improvement at hospital discharge revealed no significant difference (GAF increase 26.4 ± 9.4 for methohexital-treated patients vs. 24.8 ± 12.0 for thiopental-treated patients; t = 1.00, df = 82, P > 0.1). Trends approaching significance in treatments 2 and 5 revealed shorter seizures in the thiopental group. However, data on clinical recovery reveals no greater improvement in the methohexital group. Thus, this study calls further into question the premise that choice of barbiturate anesthetic may affect clinical efficacy.