Sleep loss reduces diurnal rhythm amplitude of leptin in healthy men.

The aim of the current study was to investigate the effects of sleep loss on the diurnal rhythm of circulating leptin levels. An indwelling forearm catheter was used to sample blood at 90-min intervals for a total of 120 h, which included 88 h of sustained sleeplessness, in 10 healthy men. The diurnal amplitude of leptin was reduced during total sleep deprivation and returned toward normal during the period of recovery sleep. This finding provides evidence that sleep influences the nocturnal leptin profile, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome.

Does thyroid supplementation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature.

OBJECTIVE: The delayed onset of therapeutic response to antidepressants remains a major problem in the treatment of depression. Among the strategies to accelerate response to treatment, the early addition of thyroid hormone to antidepressants has been suggested as a viable method. The authors performed a meta-analysis of the literature on the use of thyroid hormone supplementation to accelerate the treatment of depression to determine whether there is sufficient evidence to support the clinical efficacy of this strategy. METHOD: Both a computer-aided search of the National Library of Medicine MEDLINE and an intensive search by hand were conducted to identify all double-blind, placebo-controlled studies assessing the concomitant administration of thyroid hormone and antidepressant to accelerate clinical response in patients with nonrefractory depression. RESULTS: Six studies were identified. All were conducted with triiodothyronine (T(3)) and a tricyclic antidepressant. Five of the six studies found T(3) to be significantly more effective than placebo in accelerating clinical response. The pooled, weighted effect size index was 0.58, and the average effect was highly significant. Further, the effects of T(3) acceleration were greater as the percentage of women participating in the study increased. CONCLUSIONS: This meta-analysis supports the efficacy of T(3) in accelerating clinical response to tricyclic antidepressants in patients with nonrefractory depression. Furthermore, women may be more likely than men to benefit from this intervention.

Caffeine eliminates psychomotor vigilance deficits from sleep inertia.

STUDY OBJECTIVES: This study sought to establish the effects of caffeine on sleep inertia, which is the ubiquitous phenomenon of cognitive performance impairment, grogginess and tendency to return to sleep immediately after awakening. DESIGN: 28 normal adult volunteers were administered sustained low-dose caffeine or placebo (randomized double-blind) during the last 66 hours of an 88-hour period of extended wakefulness that included seven 2-hour naps during which polysomnographical recordings were made. Every 2 hours of wakefulness, and immediately after abrupt awakening from the naps, psychomotor vigilance performance was tested. SETTING: N/A. PARTICIPANTS: N/A. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: In the placebo condition, sleep inertia was manifested as significantly impaired psychomotor vigilance upon awakening from the naps. This impairment was absent in the caffeine condition. Caffeine had only modest effects on nap sleep. CONCLUSIONS: Caffeine was efficacious in overcoming sleep inertia. This suggests a reason for the popularity of caffeine-containing beverages after awakening. Caffeine's main mechanism of action on the central nervous system is antagonism of adenosine receptors. Thus, increased adenosine in the brain upon awakening may be the cause of sleep inertia.

Psychosocial-immune relationships in HIV disease.

Human immunodeficiency virus (HIV) is now commonly viewed as a chronic disease, which often consists of a wide array of recurrent and sometimes severe psychosocial stressors. An individual's response to these multiple challenges over time may impact their health. In this article, we review research examining the relationship of psychologic factors (eg, depression, stressful life events, coping, social support) with immune system function and disease course. We also explore some of the potential physiologic pathways that may underlie these types of psychosocial-immune relationships, as well as the effects of psychologic interventions, particularly cognitive-behavioral stress management (CBSM), on the psychosocial, neuroendocrine, and immune functioning of people living with HIV. We conclude by suggesting some areas for future research, particularly the study of HIV-positive women.

Neuroimmunologic aspects of sleep and sleep loss.

The complex and intimate interactions between the sleep and immune systems have been the focus of study for several years. Immune factors, particularly the interleukins, regulate sleep and in turn are altered by sleep and sleep deprivation. The sleep-wake cycle likewise regulates normal functioning of the immune system. Although a large number of studies have focused on the relationship between the immune system and sleep, relatively few studies have examined the effects of sleep deprivation on immune parameters. Studies of sleep deprivation's effects are important for several reasons. First, in the 21st century, various societal pressures require humans to work longer and sleep less. Sleep deprivation is becoming an occupational hazard in many industries. Second, to garner a greater understanding of the regulatory effects of sleep on the immune system, one must understand the consequences of sleep deprivation on the immune system. Significant detrimental effects on immune functioning can be seen after a few days of total sleep deprivation or even several days of partial sleep deprivation. Interestingly, not all of the changes in immune physiology that occur as a result of sleep deprivation appear to be negative. Numerous medical disorders involving the immune system are associated with changes in the sleep-wake physiology--either being caused by sleep dysfunction or being exacerbated by sleep disruption. These disorders include infectious diseases, fibromyalgia, cancers, and major depressive disorder. In this article, we will describe the relationships between sleep physiology and the immune system, in states of health and disease. Interspersed will be proposals for future research that may illuminate the clinical relevance of the relationships between sleeping, sleep loss and immune function in humans.

Depression, sleep physiology, and antidepressant drugs.

This review summarizes current findings regarding effects of antidepressant compounds on sleep architecture and interprets their clinical relevance. Effects of the major classes of antidepressant drugs on sleep properties are presented, with the antidepressant compounds organized into categories based primarily on their putative mechanism of action. The majority of antidepressant compounds, across several different categories, exhibit robust suppression of REM sleep. Others, such as bupropion and nefazodone, lack REM suppressant effects. Such findings support the idea that critical neurochemical mechanisms involved in the regulation of discrete sleep stages can be elucidated by means of polysomnographic investigations utilizing pharmacologically targeted agents. Clinicians have appreciated the importance of antidepressant drug effects on sleep when considering therapeutic options for patients. While such decisions in the past were based on empirical observations, an increasing amount of information regarding specific effects of different antidepressant drugs on sleep continuity and sleep architecture is available. Thus, clinicians may choose to consider profiles of sleep effects for different antidepressant drugs in the initial selection of an antidepressant compound.

Potential mechanisms of the sleep therapies for depression.

Sleep deprivation for one night has been investigated as a treatment for depression since the first publications describing its antidepressant properties almost 30 years ago [Pflug and Tolle, 1971: Int Pharmacopsychiatry 6:187-196]. It remains a field of active research. It is the only intervention consistently demonstrated to produce next-day antidepressant results. This makes sleep deprivation an exciting and unique tool to study the pathophysiology of depressive disorders and to formulate targets for novel antidepressant agents. Importantly, it is also an effective, but underused, clinical treatment for unipolar and bipolar depression.

Acute mood and thyroid stimulating hormone effects of transcranial magnetic stimulation in major depression.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has recently been demonstrated to have antidepressant effects. Some work suggests that rTMS over prefrontal cortex administered to healthy individuals produces acute elevations of mood and serum thyroid-stimulating hormone (TSH). We sought to determine whether single rTMS sessions would produce acute mood and serum TSH elevations in subjects with major depressions. METHODS: Under double-blind conditions et al 14 medication-free subjects with major depression received individual sessions of either active or sham rTMS. rTMS was administered over the left prefrontal cortex at 10 Hz et al 100% of motor threshold, 20 trains over 10 min. Immediately before and after rTMS sessions, subjects' mood was rated with the Profile of Mood States (POMS) and the 6-Item Hamilton Depression Scale, and blood was drawn for later analysis of TSH. Subjects and raters were blind to treatment assignment. RESULTS: The group receiving active stimulation manifested significantly greater improvement on the POMS subscale of Depression (p < or = .0055) and a trend toward greater improvement on the modified Hamilton Rating (.05 < p < or =.1). No hypomania was induced. The change in TSH from pre- to post-rTMS was significantly different between active and sham sessions. CONCLUSIONS: This blinded, placebo-controlled trial documents that individual rTMS sessions can acutely elevate mood and stimulate TSH release in patients experiencing major depressive episodes.

Soluble TNF-alpha receptor 1 and IL-6 plasma levels in humans subjected to the sleep deprivation model of spaceflight.

BACKGROUND: The extent to which sleep loss may predispose astronauts to a state of altered immunity during extended space travel prompts evaluation with ground-based models. OBJECTIVE: We sought to measure plasma levels of selected cytokines and their receptors, including the putative sleep-regulation proteins soluble TNF-alpha receptor (sTNF-alpha R) I and IL-6, in human subjects undergoing 2 types of sleep deprivation during environmental confinement with performance demands. METHODS: Healthy adult men (n = 42) were randomized to schedules that varied in severity of sleep loss: 4 days (88 hours) of partial sleep deprivation (PSD) involving two 2-hour naps per day or 4 days of total sleep deprivation (TSD). Plasma samples were obtained every 6 hours across 5 days and analyzed by using enzyme-linked immunoassays for sTNF-alpha RI, sTNF-alpha RII, IL-6, soluble IL-2 receptor, IL-10, and TNF-alpha. RESULTS: Interactions between the effects of time and sleep deprivation level were detected for sTNF-alpha RI and IL-6 but not for sTNF-alpha RII, soluble IL-2 receptor, IL-10, and TNF-alpha. Relative to the PSD condition, subjects in the TSD condition had elevated plasma levels of sTNF-alpha RI on day 2 (P =.04), day 3 (P =.01), and across days 2 to 4 of sleep loss (P =.01) and elevated levels of IL-6 on day 4 (P =.04). CONCLUSIONS: Total sleep loss produced significant increases in plasma levels of sTNF-alpha RI and IL-6, messengers that connect the nervous, endocrine, and immune systems. These changes appeared to reflect elevations of the homeostatic drive for sleep because they occurred in TSD but not PSD, suggesting that naps may serve as the basis for a countermeasures approach to prolonged spaceflight.

Physiological effects of electroconvulsive therapy and transcranial magnetic stimulation in major depression.

Major depressive episodes are associated with dysregulation of various physiologic systems. Antidepressant medications alter regulation of the hormonal and sleep systems. A thorough understanding of these changes may elucidate the pathophysiologic basis of the disorder [Amsterdam et al., 1989: Psychoneuroendocrinology 14:43-62], and interventions targeted directly at these systems are being increasingly recognized as possible treatments for depression [Wong et al., 2000: Proc Natl Acad Sci USA 97:325-330; Szuba et al., 1996: Proc Am Coll Neuropsychopharmacol Ann Meet]. These physiologic systems are regulated by the major neurotransmitters implicated in the etiology of mood disorders--norepinephrine, serotonin, and dopamine. Many of the hormones of import for this article also act as neurotransmitters and thus alter cerebral activity themselves [Owens and Nemeroff, 1993: Ciba Found Symp 172:296-308; Weitzner, 1998: Psychother Psychosom 67:125-132]. Parenteral infusion of hydrocortisone [DeBattista, 2000: Am J Psychiatry 157:1334-1337] and thyrotropin-releasing hormone (TRH) [Prange et al., 1972: Lancet 2:999-1002; Marangell et al., 1997: Arch Gen Psychiatry 54:214-222; Szuba, 1996: Proc Am Coll Neuropsychopharmacol Ann Meet.] produce acute antidepressant effects. Antagonists to corticotropin-releasing hormone and repeated parenteral infusion of TRH may have antidepressant activity when given during several weeks [Wong, 2000: Proc Natl Acad Sci USA 97:325-330; Arborelius et al., 1999: J Endocrinol 160:1-12; Callahan et al., 1997: Biol Psychiatry 41:264-272]. Manipulations of the sleep system through sleep deprivation can ameliorate depression [Szuba et al., 1994: Psychiatry Res 51:283-295; see Wirz-Justice et al., 1999: Biol Psychiatry 46:445-453 for review]. Sleep deprivation has been shown in more than three dozen studies published in the last three decades to produce marked, acute antidepressant effects in the majority of depressed individuals [Wirz-Justice, et al., 1999: Biol Psychiatry 46:445-453]. Thus, examination of the effects the two nonpharmacologic treatments, electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS), produce in these physiologic systems may help elucidate their mechanisms of action, while enhancing understanding of the neurobiology of depressive illness. We will review these physiologic changes associated with depression, the effects that manipulations of these systems can have on depressive disorders, and then describe the effects the two techniques that can stimulate the human brain in vivo, ECT and TMS, exert on these systems.

ECT and intracranial vascular masses.

In 1990, the APA Task Force on ECT cited no "absolute" contraindications to ECT but "Substantial Risk" to be associated with ECT for patients with space occupying or other cerebral lesions with increased intracranial pressure and with bleeding or otherwise unstable vascular aneurysm or malformation. These findings indicate that patients with intracranial vascular masses are at increased risk for serious morbidity and mortality. Several authors have reported performing ECT in patients with intracranial vascular masses without adverse events by monitoring blood pressure both with and without pharmacologic intervention. Given the relatively recent change in practice of considering ECT for patients with intracranial vascular masses and the few number of cases thus far reported, we present a review of the existing literature and two additional cases of ECT performed with good result and no adverse events. With the cases we have presented, the literature now contains eight cases of ECT performed in patients with intracranial vascular masses, none of which had adverse outcomes. While such numbers do not establish unequivocal safety in this population, and the individual ECT practitioner must continue to make a risk/benefit analysis on a case-by-case basis, this report adds to the growing literature on the safety and efficacy of ECT for such patients.

Depression in the medical setting: biopsychological interactions and treatment considerations.

This article examines depression in 6 medical conditions: coronary artery disease (CAD), cancer, human immunodeficiency virus (HIV) infection, Parkinson's disease, pain, and the sex hormone changes of aging. Research is beginning to define specific biological and psychological mechanisms underlying the adverse interactions between depression and these medical conditions. Antidepressant medications, psychosocial therapies, and hormonal manipulations are effective in reducing depressive symptoms. Specific psychosocial interventions may increase longevity in CAD and cancer and may enhance quality of life in HIV infection. Newer antidepressants appear to be safer and better tolerated than older agents for medically ill patients, but do not appear to be as effective for neuropathic pain. Dopamine agonists may benefit depression associated with Parkinson's disease. Hormone replacement therapy may improve subsyndromal depressive symptoms in postmenopausal women and may enhance antidepressant response for older women with major depression.

Management of elevated intracranial pressure in patients with Cryptococcal meningitis.

BACKGROUND: The most important predictor of early mortality in patients with HIV-associated cryptococcal meningitis is mental status at presentation; patients who present with altered mental status have up to 25% mortality. Historically, cerebrospinal fluid (CSF) diversion in HIV-negative patients with cryptococcal meningitis and signs of elevated intracranial pressure (ICP) has improved survival. In an effort to affect survival and morbidity rates in patients with HIV-associated cryptococcal meningitis, we have initiated aggressive management of elevated ICP in patients with focal neurologic deficits, mental obtundation, or both. METHODS: We identified 10 patients with HIV-associated cryptococcal meningitis who presented with symptoms consistent with elevated ICP, including headache, mental obtundation, papilledema, and cranial nerve palsies. Elevated opening pressure was defined as > 20 cm CSF during lumbar puncture. In patients with elevated opening pressures who had focal neurologic deficits or mental status changes refractory to serial lumbar puncture, management consisted of immediate placement of lumbar drains for continuous drainage of CSF to maintain normal ICP (10 cm CSF). Patients with persistent elevations of spinal neuraxis pressure following lumbar drainage underwent placement of lumbar peritoneal shunts. RESULTS: All patients returned to their baseline level of consciousness following normalization of ICP. Two patients were weaned from lumbar drainage. Eight patients eventually required placement of lumbar peritoneal shunts for persistently elevated ICP despite successful antifungal therapy. Follow-up ranged from 1 to 15 months. One shunt infection occurred, one lumbar peritoneal shunt was converted to a ventriculoperitoneal shunt, and one shunt was removed. CONCLUSIONS: Elevated ICP in patients with HIV-associated cryptococcal meningitis is a significant source of morbidity and mortality. The use of lumbar drainage and selective placement of lumbar peritoneal shunts in the management of elevated ICP in patients with HIV-associated cryptococcal meningitis can ameliorate the sequelae of elevated ICP.

Rapid conversion from one monoamine oxidase inhibitor to another.

BACKGROUND: Numerous sources state that switching from one monoamine oxidase (MAO) inhibitor to another can be done only after a 14-day washout period. In hospitalized patients and severely depressed outpatients, such a wait may be impracticable. METHOD: We reviewed the case histories of eight consecutive and random patients whom we converted from one MAO inhibitor to another within less than the recommended waiting period. RESULTS: Only one patient experienced troubling adverse effects, and these effects were brief and time-limited. The patient's symptoms were indicative of either withdrawal from tranylcypromine or a mild serotonin syndrome. All other patients tolerated the conversion well with minimal or no adverse effects. Four of the eight patients eventually responded to the new MAO inhibitor. CONCLUSION: These results suggest that some patients can be cautiously but rapidly switched from one MAO inhibitor to another without prolonged drug-free periods. Unquestionably, this strategy should be used only when the clinical picture mandates a rapid conversion. Further, it should be reserved for those patients with established high compliance and should include close monitoring and the use of a low-tyramine diet. Extreme caution must still be undertaken in utilizing this approach until larger studies more accurately determine the frequency of serious adverse effects.

Electroconvulsive therapy increases circadian amplitude and lowers core body temperature in depressed subjects.

BACKGROUND: Reduced amplitude of the circadian temperature rhythm and elevated nocturnal body temperature normalize after successful pharmacotherapy of major depression. METHODS: Core body temperature was continually monitored in three groups: a) 6 depressed patients before an electroconvulsive therapy (ECT) course and b) after an ECT course; and c) 6 healthy, sex-matched controls of similar age. RESULTS: The 24-hour profile of temperature was significantly different in patients pre-ECT than in patients post-ECT or in controls. Post-ECT subjects and controls manifested 24-hour profiles similar to one another. Circadian temperature rhythm amplitude increased after ECT. The mean asleep and mean 24-hour temperatures were significantly higher in patients pre-ECT than post-ECT and controls. CONCLUSIONS: We find that ECT restores a disrupted circadian temperature rhythm in depressed patients.

Pharmacologic management of psychiatric illness during pregnancy: dilemmas and guidelines.

OBJECTIVE: Given concerns about use of psychotropic medication during pregnancy, the authors reviewed the literature regarding the effects of prenatal exposure to psychotropic medications on fetal outcome. METHOD: A MEDLINE search of all articles written in English from 1966 to 1995 was performed to review information on the effects of psychotropic drug use during pregnancy on fetal outcome. Where sufficient data were available and when methodologically appropriate, meta-analyses were performed to assess risk of fetal exposure by psychotropic medication class. RESULTS: Three primary effects are associated with medication use during pregnancy: 1) teratogenicity, 2) perinatal syndromes (neonatal toxicity), and 3) postnatal behavioral sequelae. For many drug classes there are substantial data regarding risk for teratogenicity. Tricyclic antidepressants do not seem to confer increased risk for organ dysgenesis. The available data indicate that first-trimester exposure to low-potency phenothiazines, lithium, certain anticonvulsants, and benzodiazepines may increase the relative risk for congenital anomalies. However, the absolute risk of congenital malformations following prenatal exposure to most psychotropics is low. CONCLUSION: Exposure to certain psychotropic drugs in utero may increase the risk for some specific congenital anomalies, but the rate of occurrence of these anomalies even with the increased risk remains low. Use of psychotropic medications during pregnancy is appropriate in many clinical situations and should include thoughtful weighing of risk of prenatal exposure versus risk of relapse following drug discontinuation. The authors present disorder-based guidelines for psychotropic drug use during pregnancy and for psychiatrically ill women who wish to conceive.

The relationship between antimanic agent for treatment of classic or dysphoric mania and length of hospital stay.

BACKGROUND: This retrospective study was conducted to evaluate the relationship between the mood-stabilizing agents lithium, carbamazepine, and divalproex sodium and time course of drug response as measured by length of hospital stay. METHOD: Seventy-eight patients were evaluated. Discharge date and length of hospitalization were obtained by review of the dictated discharge summary by investigators who were blind to medication status. Drug choice, including blood levels, was then identified as well as any adjunctive treatment. Statistical evaluation (SAS software) of time to improvement was conducted using nonparametric survival models. Possible confounding variables were assessed by parametric survival regression models and proportional hazards models. RESULTS: The individual survival curves of four major antimanic treatment groups revealed a significant difference by the second week of hospitalization in the divalproex sodium and the lithium/carbamazepine combination groups as compared with the lithium or carbamazepine groups (chi 2 = 13.83, df = 3, p = .003). The mean +/- SD length of stay was approximately 40% shorter for the divalproex sodium (10.2 +/- 2.0 days) and the lithium/carbamazepine combination (11.7 +/- 2.1 days) groups compared with the lithium alone (17.6 +/- 1.0 days) and the carbamazepine alone (18.1 +/- 3.0 days) groups. Regression analysis of possible confounding variables including adjunctive treatment (benzodiazepines and neuroleptics), severity of illness (number of years ill and previous hospitalizations), and discharge date revealed no statistically significant effect. CONCLUSION: Shortcomings of our study include those inherent in the design of a non-randomized, small naturalistic study and retrospective chart review. Our study does, however, suggest different drug response rates for the treatment of classic and dysphoric mania and warrants further controlled investigation.

Adrenal insufficiency, recurrent bacteremia, and disseminated abscesses caused by Nocardia asteroides in a patient with acquired immunodeficiency syndrome.

Nocardia asteroides is an opportunistic pathogen of increasing incidence in human immunodeficiency virus (HIV)-infected persons. The lungs are the most common site of infection, followed by the brain; involvement of other extrapulmonary sites is less common. We describe a patient with acquired immunodeficiency syndrome who presented with a number of unique manifestations of nocardial infection: the first reported case of bilateral adrenal abscesses with adrenal insufficiency, the first case of a renal abscess due to N. asteroides alone, and the first case of recurrent, symptomatic bacteremia. A review of the literature on nocardial infections in HIV-positive individuals is presented.