Andrew D. Krystal

The Consensus Sleep Diary: Standardizing Prospective Sleep Self-Monitoring

STUDY OBJECTIVES To present an expert consensus, standardized, patient-informed sleep diary. METHODS AND RESULTS Sleep diaries from the original expert panel of 25 attendees of the Pittsburgh Assessment Conference(1) were collected and reviewed. A smaller subset of experts formed a committee and reviewed the compiled diaries. Items deemed essential were included in a Core sleep diary, and those deemed optional were retained for an expanded diary. Secondly, optional items would be available in other versions. A draft of the Core and optional versions along with a feedback questionnaire were sent to members of the Pittsburgh Assessment Conference. The feedback from the group was integrated and the diary drafts were subjected to 6 focus groups composed of good sleepers, people with insomnia, and people with sleep apnea. The data were summarized into themes and changes to the drafts were made in response to the focus groups. The resultant draft was evaluated by another focus group and subjected to lexile analyses. The lexile analyses suggested that the Core diary instructions are at a sixth-grade reading level and the Core diary was written at a third-grade reading level. CONCLUSIONS The Consensus Sleep Diary was the result of collaborations with insomnia experts and potential users. The adoption of a standard sleep diary for insomnia will facilitate comparisons across studies and advance the field. The proposed diary is intended as a living document which still needs to be tested, refined, and validated.

Eszopiclone Co-Administered With Fluoxetine in Patients With Insomnia Coexisting With Major Depressive Disorder

BACKGROUND Insomnia and major depressive disorder (MDD) can coexist. This study evaluated the effect of adding eszopiclone to fluoxetine. METHODS Patients who met DSM-IV criteria for both MDD and insomnia (n = 545) received morning fluoxetine and were randomized to nightly eszopiclone 3 mg (ESZ+FLX) or placebo (PBO+FLX) for 8 weeks. Subjective sleep and daytime function were assessed weekly. Depression was assessed with the 17-item Hamilton Rating Scale for Depression (HAM-D-17) and the Clinical Global Impression Improvement (CGI-I) and Severity items (CGI-S). RESULTS Patients in the ESZ+FLX group had significantly decreased sleep latency, wake time after sleep onset (WASO), increased total sleep time (TST), sleep quality, and depth of sleep at all double-blind time points (all p < .05). Eszopiclone co-therapy also resulted in: significantly greater changes in HAM-D-17 scores at Week 4 (p = .01) with progressive improvement at Week 8 (p = .002); significantly improved CGI-I and CGI-S scores at all time points beyond Week 1 (p < .05); and significantly more responders (59% vs. 48%; p = .009) and remitters (42% vs. 33%; p = .03) at Week 8. Treatment was well tolerated, with similar adverse event and dropout rates. CONCLUSIONS In this study, eszopiclone/fluoxetine co-therapy was relatively well tolerated and associated with rapid, substantial, and sustained sleep improvement, a faster onset of antidepressant response on the basis of CGI, and a greater magnitude of the antidepressant effect.

British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders.

Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.

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.

Seizure threshold in electroconvulsive therapy: I. Initial seizure threshold

We measured initial seizure threshold by means of a structured stimulus dosage titration procedure in a clinical sample of 111 depressed patients undergoing brief-pulse, constant-current electroconvulsive therapy (ECT). Initial seizure threshold was approximately 60 millicoumbs (mc) (10 Joules) on average, but varied widely (6-fold) across patients. Initial seizure threshold was predicted by four variables: electrode placement (higher with bilateral), gender (higher in men), age (higher with increasing age), and dynamic impedance (inverse relationship). Use of neuroleptic medication was associated with a lower seizure threshold. EEG seizure duration was inversely related to initial seizure threshold, but no other relations with seizure duration were found. These findings may have important clinical implications for stimulus dosing strategies in ECT.

Eszopiclone Coadministered With Escitalopram in Patients With Insomnia and Comorbid Generalized Anxiety Disorder

CONTEXT Insomnia and generalized anxiety disorder (GAD) are prevalent disorders that may coexist. OBJECTIVE To determine the efficacy of eszopiclone combined with escitalopram oxalate in treating insomnia comorbid with GAD. DESIGN Double-blind, randomized, placebo-controlled, parallel-group, add-on therapy 10-week study. SETTING Multicenter outpatient study from July 2005 to April 2006. PATIENTS Adults aged 18 to 64 years meeting DSM-IV-TR criteria for GAD and insomnia. INTERVENTIONS Patients received 10 mg of escitalopram oxolate for 10 weeks and were randomized to also receive either 3 mg of eszopiclone (n = 294) or placebo (n = 301) nightly for 8 weeks. For the last 2 weeks, eszopiclone was replaced with a single-blind placebo. MAIN OUTCOME MEASURES Sleep, daytime functioning, psychiatric measures, and adverse events. RESULTS Compared with treatment with placebo and escitalopram, treatment with eszopiclone and escitalopram resulted in significantly improved sleep and daytime functioning (P < .05), with no evidence of tolerance. Patients taking eszopiclone and escitalopram had greater improvements in total Hamilton Anxiety Scale (HAM-A) scores at each week (P < .05) and at weeks 4 through 10 with the insomnia item removed. Clinical Global Impressions (CGI) of Improvement scores were improved with eszopiclone and escitalopram at every point (P < .02), while CGI of Severity of Illness scores were not significantly different after week 1. The HAM-A response (63% vs 49%, respectively, P = .001) and remission (42% vs 36%, respectively, P = .09) rates at week 8 were higher in patients treated with eszopiclone and escitalopram than those treated with placebo and escitalopram, and median time to onset of anxiolytic response was significantly reduced (P < or = .05). After eszopiclone discontinuation, there was no evidence of rebound insomnia, and while treatment differences in anxiety measures were maintained, differences in sleep outcomes were not. Overall adverse event rates were 77.6% with cotherapy and 67.9% with monotherapy. The most common adverse events with cotherapy were unpleasant taste, headache, dry mouth, and somnolence. CONCLUSIONS Coadministration of eszopiclone and escitalopram was well tolerated and associated with significantly improved sleep, daytime functioning, anxiety, and mood in patients with insomnia and GAD. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00235508.

A compendium of placebo-controlled trials of the risks/benefits of pharmacological treatments for insomnia: The empirical basis for U.S. clinical practice

For many years practitioners have had limited data from double-blind, placebo-controlled studies to guide the types of decision-making needed to optimally manage patients with insomnia in clinical practice. However, in recent years there has been a great increase in insomnia research studies that address issues of clinical importance. This body of work represents an increasingly useful empirical basis for making clinical practice decisions. The purpose of this article is to compile the body of work on the pharmacological management of insomnia to make it available in as accessible form as possible for optimal application in clinical practice with the hopes that doing so will decrease the gap separating the available research and the clinical management of insomnia and, thereby, improve the care of the many individuals who suffer from this condition. The review of studies consists of the following sections: 1) basic pharmacology; 2) double-blind, placebo-controlled trials in adults with primary insomnia; 3) double-blind, placebo-controlled trials in elderly patients with primary insomnia; 4) adverse effects reported in placebo-controlled trials in elderly primary insomnia patients; 5) double-blind, placebo-controlled trials in adults and the elderly as a function of treatment duration; 6) double-blind, placebo-controlled trials of the treatment of comorbid insomnia. Issues related to the application of these data to clinical practice are discussed in the text.

Seizure threshold in electroconvulsive therapy (ECT) II. The anticonvulsant effect of ECT

To measure the anticonvulsant effects of a course of electroconvulsive therapy (ECT), we used a flexible stimulus dosage titration procedure to estimate seizure threshold at the first and sixth ECT treatments in 62 patients with depression who were undergoing a course of brief pulse, constant current ECT given at moderately suprathreshold stimulus intensity. Seizure threshold increased by approximately 47% on average, but only 35 (56%) of the 62 patients showed a rise in seizure threshold. The rise in seizure threshold was associated with increasing age, but not with gender, stimulus electrode placement, or initial seizure threshold. Dynamic impedance decreased by approximately 5% from the first to the sixth ECT treatment, but there was no correlation between the change in dynamic impedance and the rise in seizure threshold. No relation was found between the rise in seizure threshold and either therapeutic response status or speed of response to the ECT treatment course. These findings confirm the anticonvulsant effect of ECT but suggest that such effects are not tightly coupled to the therapeutic efficacy of moderately suprathreshold ECT.

Sleep disturbance in psychiatric disorders: effects on function and quality of life in mood disorders, alcoholism, and schizophrenia.

INTRODUCTION While the precise role of sleep in maintaining optimal health and function remains unknown, it is clear that disturbances of sleep have a profound impact on the lives of affected individuals. In psychiatric disorders, not only is there a relationship between sleep disturbances and impaired function, problems with sleep also appear to affect the course of the disorder. METHODS We carried out a literature review of sleep studies in mood disorders, alcoholism and schizophrenia to determine how associated alterations in sleep architecture and disturbances of sleep are related to patient function and quality of life, and the course of these disorders. RESULTS The literature speaks to the need to address sleep problems in the overall management of mood disorders, alcoholism and schizophrenia. The support for this viewpoint is best established for mood disorders. There is also relatively strong support for treatment in alcoholism. Schizophrenia, however, has received scant attention and the literature suggests a need for more studies in this area. CONCLUSIONS Further research is needed into the treatment of co-morbid insomnia and psychiatric disorders. Successful therapy is more likely to be achieved if the sleep difficulty and co-morbid disorder are simultaneously targeted for treatment.

Repetitive transcranial magnetic stimulation of the superior frontal gyrus modulates craving for cigarettes.

BACKGROUND Previous functional magnetic resonance imaging studies have shown strong correlations between cue-elicited craving for cigarettes and activation of the superior frontal gyrus (SFG). Repetitive transcranial magnetic stimulation (rTMS) offers a noninvasive means to reversibly affect brain cortical activity, which can be applied to testing hypotheses about the causal role of SFG in modulating craving. METHODS Fifteen volunteer smokers were recruited to investigate the effects of rTMS on subjective responses to smoking versus neutral cues and to controlled presentations of cigarette smoke. On different days, participants were exposed to three conditions: 1) high-frequency (10 Hz) rTMS directed at the SFG; 2) low-frequency (1 Hz) rTMS directed at the SFG; and 3) low-frequency (1 Hz) rTMS directed at the motor cortex (control condition). RESULTS Craving ratings in response to smoking versus neutral cues were differentially affected by the 10-Hz versus 1-Hz SFG condition. Craving after smoking cue presentations was elevated in the 10-Hz SFG condition, whereas craving after neutral cue presentations was reduced. Upon smoking in the 10-Hz SFG condition, ratings of immediate craving reduction as well as the intensity of interoceptive airway sensations were also attenuated. CONCLUSIONS These results support the view that the SFG plays a role in modulating craving reactivity; moreover, the results suggest that the SFG plays a role in both excitatory and inhibitory influences on craving, consistent with prior research demonstrating the role of the prefrontal cortex in the elicitation as well as inhibition of drug-seeking behaviors.