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Letter to the Editor
Somatic symptoms are the foremost reason that individuals seek medical care, and most patients present with these symptoms in the primary care setting. Thus, clinicians must be able to recognize the manifestations of chronic pain as well as devise and implement an individualized treatment strategy that will relieve pain, manage any psychiatric comorbidities, and improve functioning and quality of life. This video includes 3 example patient cases and expert recommendations on accurately identifying, diagnosing, and treating the illnesses related to chronic pain, including comorbid depression and anxiety.
Background:Excessive sleepiness often goes unrecognized in the primary care setting despite its high prevalence and deleterious effects on both individual and public safety. Patients with neurologic and psychiatric illnesses, as well as those with acute and chronic medical conditions, plus those with sleep disorders, often have symptoms of excessive sleepiness, tiredness, and fatigue. Recognition and prompt treatment of these symptoms are important, even though their etiology may not be immediately understood. This review focuses on the underlying causes, consequences, identification, and treatment of excessive sleepiness.
Data Sources: A search of the literature to 2007 was performed using the PubMed search engine. English-language articles were identified using the following search terms: excessive sleepiness, fatigue, circadian rhythm, obstructive sleep apnea, shift work disorder, narcolepsy, drowsy driving, and wakefulness. Additional references were identified through bibliography reviews of relevant articles.
Data Synthesis:Current assessments of the prevalence, consequences, and etiologies of excessive sleepiness, with leading treatment strategies, were extracted, reviewed, and summarized to meet the objectives of this article.
Conclusions: Excessive sleepiness is associated with a wide range of medical, neurologic, and psychiatric disorders frequently seen in primary care practice. Excessive sleepiness is a serious, debilitating, potentially life-threatening condition, yet also treatable, and it is important to initiate appropriate intervention as early as possible. Physicians should place increasing emphasis on the substantial benefits that accompany improvements in wakefulness.
Objective: To investigate the efficacy of duloxetine in the treatment of pain and improvement in functional impairment and quality of life in patients with fibromyalgia from a pooled analysis of 4 placebo-controlled, double-blind, randomized trials.
Method: Patients were eligible for inclusion in the studies if they were at least 18 years of age, met criteria for fibromyalgia as defined by the American College of Rheumatology, and had specified minimum pain severity scores. Across all studies, 797 patients received duloxetine 60-120 mg/d and 535 patients received placebo. Pain was assessed by the Brief Pain Inventory (BPI) 24-hour average pain severity score; other efficacy measures included the Clinical Global Impressions-Severity of Illness scale (CGI-S), Patient Global Impressions-Improvement scale (PGI-I), 17-item Hamilton Depression Rating Scale (HDRS-17), Fibromyalgia Impact Questionnaire (FIQ) total score, BPI pain interference items, Sheehan Disability Scale (SDS), and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) mental and physical components. Changes from baseline to endpoint (last observation carried forward) for most of the above efficacy measures were analyzed using an analysis-of-covariance model.
Results: After 12 weeks of treatment, pain was significantly reduced in patients treated with duloxetine (P < .001) compared with placebo. In addition, duloxetine was superior to placebo in improving CGI-S (P < .001); PGI-I (P < .001); FIQ total (P < .001); HDRS-17 total (P = .003); SDS global functioning (P < .001), work/school (P = .018), and family life (P < .001); SF-36 mental (P < .001) and physical (P = .026) component; and BPI pain interference (P < .001) scores. Treatment-by-subgroup interactions were not significant for sex (P = .320), age (P = .362), or race (P = .180).
Conclusions: This pooled analysis provides evidence that 12 weeks of treatment with duloxetine 60-120 mg/d effectively improves fibromyalgia symptoms and may offer benefits beyond pain relief.
Objective: To examine whether sleep impairment is associated with attention-deficit/hyperactivity disorder (ADHD) in adults.
Method: In a study conducted from 1998 to 2003, we identified sleep characteristics in a community sample of 182 cases of DSM-IV ADHD or ADHD not otherwise specified and 117 non-ADHD controls aged 18 to 55 years. Attention-deficit/hyperactivity disorder status, current and lifetime psychiatric comorbidity, and pharmacologic treatment of ADHD were identified with the Structured Clinical Interview for DSM-IV and with modules from the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Epidemiologic Version. Sleep problems were characterized by self-report. We separately accounted for the contribution of age at ADHD onset, ADHD pharmacotherapy, lifetime bipolar disorder, and the following lifetime and current comorbidities: depression, generalized anxiety, substance abuse, and multiple anxiety disorders.
Results: Adults with ADHD went to bed later than control subjects and had a wider range of bedtimes (mean ± SD = 18 ± 92 min vs 54 ± 69 min before midnight; P < .001), were more likely to take over an hour to fall asleep (OR = 5.22, P = .001), and were more likely (P < .003) to experience difficulty going to bed, going to sleep, sleeping restfully, or waking in the morning. Adults with ADHD experienced daytime sleepiness more often (OR = 2.23, P = .003) and reported more sleep problems (mean ± SD = 6.7 ± 2.5 vs 4.3 ± 2.2; P < .001) than controls. All sleep impairments were significantly associated with ADHD independent of contributions to sleep disruption from ADHD pharmacotherapy, comorbidities likely to contribute to sleep disturbance, and age at ADHD onset.
Conclusion: Sleep disturbances that are not attributable to comorbid mental health conditions or ADHD pharmacotherapy are associated with ADHD in adulthood. Clinicians and researchers should consider the potential contribution of sleep disruption to the clinical presentation of adults with ADHD.
Submitted: June 13, 2008; accepted November 4, 2008.
Online ahead of print: July 28, 2009.
Corresponding author: Craig B. H. Surman, MD, Clinical and Research Program in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Suite 2000, 185 Alewife Brook Parkway, Cambridge, MA 02138 ([email protected]).
Objective: To examine cognitive effects of pharmacologically induced somnolence in cognitively normal carriers and noncarriers of the apolipoprotein E (APOE)-e4 allele, a common Alzheimer's disease susceptibility gene.
Method: Between December 2005 and July 2007, healthy and cognitively normal carriers of the APOE-e4 allele (heterozygotes; n = 18) and noncarriers (n = 18), 50 to 65 years old, participated in a double-blind crossover study of cognitive function before, 2.5 hours after, and 5 hours after administration of 2 mg oral lorazepam or placebo. Main outcome measures included the Groton Maze Learning Test (GMLT) for executive functioning and visuospatial working memory, the Rey Auditory-Verbal Learning Test (AVLT) for verbal memory, and the one-back test for attention and simple working memory.
Results: At 2.5 hours after lorazepam administration, GMLT total errors score (P = .04), AVLT long-term memory (P = .01), and AVLT percent recall (P = .005) reflected worse performance in heterozygotes. By multivariate analysis, the combined set of all 6 measures for heterozygotes versus noncarriers yielded P = .003 for 2.5 hours and P = .58 for 5 hours. No differences were observed for somnolence, speed, attention, or simple working memory at any time points.
Conclusions: Despite comparable levels of associated somnolence, lorazepam appears to diminish verbal and visuospatial memory more in healthy late-middle-aged heterozygotes than in noncarriers, whereas attention and reaction time are similarly affected in both. Additional studies are needed to determine whether substantial lorazepam-induced memory detriments predict subsequent onset of cognitive decline and conversion to mild cognitive impairment or Alzheimer's disease. Clinicians should be aware of the potential for cognitive decline with lorazepam in healthy late-middle-aged individuals, especially those at a higher risk for Alzheimer's disease.
Trial Registration: clinicaltrials.gov Identifier: NCT00586430
Submitted: July 25, 2008; accepted October 9, 2008.
Online ahead of print: June 30, 2009.
Corresponding author: Cynthia M. Stonnington, MD, Division of Adult Psychiatry, Mayo Clinic, 13400 East Shea Blvd, Scottsdale, AZ 85259 ([email protected]).
Two articles and a commentary in this issue underscore the need to clarify the roles of antidepressants and mood stabilizers in the treatment of Alzheimer's disease (AD). Siddique and colleagues investigate the effects of the selective serotonin reuptake inhibitor (SSRI) citalopram on the treatment of irritability and apathy in AD. Hampel and colleagues use a biomarker strategy to investigate the potential of lithium to modify tau phosphorylation, a cardinal feature of AD pathology.
Background: Mild cognitive impairment (MCI) is a transitional state between normal aging and dementia, at least for some patients. Behavioral symptoms in MCI are associated with a higher risk of dementia, but their association with dementia risk in patients without MCI is unknown. Mild behavioral impairment (MBI) refers to a late-life syndrome with prominent psychiatric and related behavioral symptoms in the absence of prominent cognitive symptoms that may also be a dementia prodrome. This study sought to compare MCI and MBI patients and to estimate the risk of dementia development in these 2 groups.
Method: Between January 2001 and January 2006, a consecutive series of 358 elderly (≥ 65 years old) patients (239 with MCI and 119 with MBI) presenting to an outpatient general hospital specialty clinic were followed for up to 5 years until conversion to dementia or censoring.
Results: Thirty-four percent of MCI patients and over 70% of patients with MBI developed dementia (log-rank p =.011). MBI patients without cognitive symptoms were more likely to develop dementia (log-rank p
Conclusion: MBI appears to be a transitional state between normal aging and dementia. MBI (specifically in those without cognitive symptoms) may confer a higher risk for dementia than MCI, and it is very likely an FTD prodrome in many cases. These findings have implications for the early detection, prevention, and treatment of patients with dementia in late life, by focusing the attention of researchers on the emergence of new behavioral symptoms.
Objective: To evaluate the long-term safety and subjective sleep effects of ramelteon in adults with chronic insomnia.
Method: Subjects with primary insomnia (DSM-IV-TR criteria) for ≥ 3 months received ramelteon nightly for 1 year; a 3-day placebo run out followed. Subjects aged ≥ 65 years received open-label ramelteon 8 mg (N = 248); those aged 18 to 64 years received ramelteon 16 mg (N = 965). Subjects completed sleep diaries and returned to the clinic at week 1 and at months 1, 2, 3, 4, 6, 8, 10, and 12 for safety assessments and investigator-performed Clinical Global Impressions. The study was conducted from February 2003 through September 2004.
Results: There were no noteworthy changes in vital signs, physical examinations, clinical chemistry, hematology, or urinalysis values and no electrocardiogram changes to suggest adverse cardiac effects. Endocrine values remained within normal range throughout treatment. Consistent statistically significant (p ≥.05) decreases in free thyroxine (in adults) and free testosterone (in older men) were detected. Duration of menses increased by approximately 1 day. A total of 40.8% of subjects reported at least 1 adverse event possibly associated with ramelteon use. The adverse events reported varied considerably, the incidence of individual adverse events was low, and the frequencies of adverse events were similar at months 6 and 12. In both groups, subjective sleep latency and total sleep time improved by month 1 and was sustained during the 1-year period. At 6 months and 1 year, Clinical Global Impressions indices were improved. During placebo run out, subjective sleep latency did increase but did not return to baseline.
Conclusion: Year-long administration of ramelteon was well tolerated. Ramelteon was associated with sustained improvements in subjective sleep latency, subjective total sleep time, and Clinical Global Impressions.
Trial Registration: clinicaltrials.gov Identifier: NCT00671086
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