Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Stress and shortage of sleep may cause daytime somnolence and impaired vigilance at the wheel, especially among those suffering from sleep disturbances. According to the international consensus meeting in Stockholm in May of 2000 on "The sleepy driver and pilot--causes, risks and countermeasures", drowsy driving is an underestimated risk factor in official statistics, and as many as 15-30 percent of today's traffic accidents are related to drowsiness; thus it is an even greater risk factor than alcohol. Drowsy drivers suffer from inattention, impaired concentration and may even fall asleep at the wheel. Accidents during dozing result in three times as many fatalities as other accidents. There are a number of reasons for habitual drowsiness at the wheel aside from sleep deprivation, including rhonchopathy, shift work and jet lag, mental depression, insomnia, narcolepsy, endocrinological diseases, periodic limb movement disorder, medication, pain-disordered sleep, and heart disease. Among the most active drivers, i.e. middle aged men, obstructive sleep apnea syndrome (OSAS) has been found to be the most common reason for habitually drowsy driving. OSAS causes a 2-3 fold increased risk of traffic accidents, and it impairs simulated driving. Palatoplasty as well as nasal CPAP have been shown to improve vigilance and driving performance to an extent that the increase in risk is eliminated. Drivers suffering from habitual drowsiness and micro-sleep attacks forcing them to take repeated rests are at special risk. Even if they are as dangerous as drivers with unlawful blood alcohol levels they cannot be caught in a police checkpoint. However they often seek medial advice, and properly treated they may often return safely to traffic. If not, there could be a need to report them to the authorities so as to limit or prohibit their driving.
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PMID:[Drowsiness--greater traffic hazard than alcohol. Causes, risks and treatment]. 1146 75

Methylphenidate (Ritalin) is a commonly used central nervous stimulant. It has been used in various neurological conditions, including attention deficit disorder, depression, and narcolepsy. Methylphenidate has been advocated in patients with traumatic brain injury and stroke for a variety of cognitive, attention, and behavioral problems. It also has been shown to speed recovery from poststroke depression so that patients can participate more fully in rehabilitation programs. Research suggests that it also may have a role in augmenting activity of injured neuronal tissue in the comatose patient, thus facilitating a return to consciousness. The neuroscience nurse plays an important role in monitoring response to Ritalin, including identifying its side effects. A review of the limited studies on the use of Ritalin, its mechanisms of action, dosing, and weaning provide a current understanding of this adjunctive agent's role in treatment for the neurological population.
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PMID:Ritalin revisited: does it really help in neurological injury? 1250 13

The process of falling asleep can best be measured by considering a convergence of behavioural, EEG, physiological and subjective information. Doing so allows one to see sleep processes as they unfold, but relying on any single sleep index can bias the description of this complex process. The studies reviewed do not support the idea that sleep begins "in a moment", but rather that entry into sleep is a continuous, interwoven series of changes which begin in relaxed drowsiness and continue through stage 1, often into the first minutes of stage 2. The transition from waking brain to sleeping brain is traced accurately by Hori's nine-stage EEG system. Event-related potential (ERP) studies map complex changes in information processing as sleep begins, while quantitative EEG investigations have identified important spatiotemporal re-organisations of primary EEG frequencies which take place as one moves from waking to sleeping mode. To consider evidence from multiple levels of analysis, a three step electrophysiological model of central nervous system (CNS) regulation during sleep onset is proposed: initial processes appear to be alpha-related; intermediate processes, poorly studied to date, parallel the development of theta and vertex sharp wave activity, while the processes which terminate wakefulness are sigma sleep spindle-related. Clinical investigations of the sleep onset period in people with narcolepsy, insomnia, depression or sleep apnoea appear to indicate the presence of relatively unique electrophysiological signatures which may be of clinical significance. 2001 Harcourt Publishers Ltd
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PMID:The process of falling asleep. 1253 Sep 90

Modafinil is a novel stimulant approved by the FDA for use in the management of excessive sleepiness associated with narcolepsy. Utility for other indications includes attention deficit-hyperactivity disorder (ADHD), depression, and management of cocaine dependence. To investigate the pharmacokinetics of modafinil in these patients, the authors improved and validated an HPLC method to separate and quantitate the separate enantiomers of modafinil in human serum. d- and l-Modafinil and the internal standard 3,3-diphenylpropylamine were extracted from serum, separated by gradient elution on a beta-cyclodextrin column, and then detected by UV absorbance at 225 nm. The elution gradient was developed to eliminate interferences by other drugs used to manage narcolepsy, ADHD, and stimulants of abuse, and endogenous substances in human serum. Validation studies included determination of stability, selectivity, precision, accuracy, and recovery. The method was used to investigate the pharmacokinetics of d- and l-modafinil in a volunteer after receiving 400 mg twice daily of racemic modafinil for 5 days. Interday and intraday assay variability (CV) typically ranged from 3% to 4%. The limits of detection (0.01 microg/mL) and quantitation (0.5 microg/mL) were well below the concentration expected in serum from patients receiving therapeutic doses of modafinil. The method was free from interference by methylphenidate, cocaine, commonly used antidepressants, and amphetamines. An example of apparent stereoselective disposition is presented as d-modafinil was eliminated more rapidly than l-modafinil from human serum. The validation data support the use of this method for human pharmacokinetic studies of modafinil in patients with known or suspected use of common antidepressants, psychostimulants, and drugs of abuse.
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PMID:Chiral analysis of d- and l-modafinil in human serum: application to human pharmacokinetic studies. 1265 14

Episodic brain disorders (EBD) form an intriguing group of neurological diseases in which at least some of the symptoms occur in attacks. The hypothalamus integrates many brain functions, including endocrine and autonomic control, and governs various body rhythms. It seems a likely site in which the initiation of attacks of EBD can be modulated. Indeed, the hypothalamus has a crucial role in EBD such as narcolepsy and cluster headache. The same may be true for migraine and depression. Here we summarise the evidence supporting an important role for the hypothalamus in the initiation of disease episodes in various EBD. Study of the various pathophysiological concepts of EBD within the context of the hypothalamus may prove a fruitful example of cross-fertilisation between various research areas.
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PMID:The hypothalamus in episodic brain disorders. 1284 66

Recent studies have led to the discovery of a neuropeptide system that regulates arousal states. The hypocretins (hcrt1 and hcrt2, also called the orexins) are neuropeptides of related sequence derived from the same precursor whose expression is restricted to a few thousand neurons of the lateral hypothalamus. Two G-protein-coupled receptors for the hypocretins have been identified, and these have different distributions within the central nervous system and differential affinities for the two hypocretins. Hypocretin fibers project throughout the brain, including several areas implicated in cardiovascular function and regulation of the sleep-wake cycle. Central administration of synthetic hypocretin-1 affects blood pressure, hormone secretion and locomotor activity, and increases wakefulness while suppressing rapid eye movement sleep. Most human patients with narcolepsy have greatly reduced levels of hypocretin peptides in their cerebral spinal fluid and no or barely detectable hypocretin neurons in their hypothalami, suggestive of autoimmune attack. Development of nonpeptidergic hypocretin antagonists may prove useful in sleep disorders, whereas hypocretin agonists may be used to treat narcolepsy and excessive daytime sleepiness. The hypocretins are also an excellent target for the pharmacological treatment of the deregulated arousal state that characterizes depression or addictive behavior.
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PMID:The role of the hypocretinergic system in the integration of networks that dictate the states of arousal. 1466 48

Modafinil is a wake-promoting agent approved by the Federal Drug Administration for the treatment of narcolepsy. Preliminary evidence indicates that modafinil may improve fatigue and excessive sleepiness associated with a variety of conditions. The purpose of this study was to investigate the utility of modafinil as an adjunctive treatment of depressed patients. Subjects with a history of major depression with partial response on a stable therapeutic dose of an antidepressant were eligible to participate. All subjects endorsed complaints of significant fatigue and/or excessive sleepiness on clinical assessment. Modafinil was added to their existing regimen at a dose of 100 to 400 mg/d for 4 weeks. Subjects were assessed at 2-week intervals for improvement using the standard depression scales (HDRS, BDI, CGI), fatigue scales (VASF, FSI), and a neuropsychologic battery. Thirty-five subjects were entered and 31 subjects completed the 4-week trial. Significant improvements were seen across all 3 measures of depression (HDRS, BDI, CGIS) and both measures of fatigue (VASF, FSI). On the neurocognitive battery, significant gains in the Stroop Interference Test were seen at 4 weeks, whereas the other cognitive tests showed no change. Modafinil may be a useful and a well-tolerated adjunctive agent to standard antidepressants in the treatment of major depression.
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PMID:A prospective trial of modafinil as an adjunctive treatment of major depression. 1470 53

We compared the effects of laughter and several respiratory movements on spinal motor excitability to unravel their respective influences. We measured H-reflexes in 13 healthy volunteers during 10 different tasks (including laughter, simulated laughter, and various respiratory movements). We compared the percentage that remained of the initial H-reflex during each task with that during a neutral task. H-reflex percentage differed between the neutral task (79.4 +/- 16.1%), true laughter (43.7 +/- 17.9%), and simulated laughter (66.6 +/- 24.3%), and between the two latter tasks. Coughing also resulted in H-reflex suppression, but not as deeply as true laughter. During the other respiratory maneuvers, the H-reflex increased compared to the neutral task. Our finding that true laughter evoked more H-reflex depression than simulated laughter suggests that mirth on its own depresses the H-reflex. This mechanism may also be involved in the pathophysiology of cataplexy, the main symptom of narcolepsy.
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PMID:Is motor inhibition during laughter due to emotional or respiratory influences? 1503 90

gamma-Hydroxybutyrate (sodium oxybate, GHB) is an approved therapeutic agent for cataplexy with narcolepsy. GHB is widely abused as an anabolic agent, euphoriant, and date rape drug. Recreational abuse or overdose of GHB (or its precursors gamma-butyrolactone or 1,4-butanediol) results in dose-dependent central nervous system (CNS) effects (respiratory depression, unconsciousness, coma, and death) as well as tolerance and withdrawal. An understanding of the CNS transport mechanisms of GHB may provide insight into overdose treatment approaches. The hypothesis that GHB undergoes carrier-mediated transport across the BBB was tested using a rat in situ brain perfusion technique. Various pharmacological agents were used to probe the pharmacological characteristics of the transporter. GHB exhibited carrier-mediated transport across the BBB consistent with a high-capacity, low-affinity transporter; averaged brain region parameters were V(max) = 709 +/- 214 nmol/min/g, K(m) = 11.0 +/- 3.56 mM, and CL(ns) = 0.019 +/- 0.003 cm(3)/min/g. Short-chain monocarboxylic acids (pyruvic, lactic, and beta-hydroxybutyric), medium-chain fatty acids (hexanoic and valproic), and organic anions (probenecid, benzoic, salicylic, and alpha-cyano-4-hydroxycinnamic acid) significantly inhibited GHB influx by 35 to 90%. Dicarboxylic acids (succinic and glutaric) and gamma-aminobutyric acid did not inhibit GHB BBB transport. Mutual inhibition was observed between GHB and benzoic acid, a well known substrate of the monocarboxylate transporter MCT1. These results are suggestive of GHB crossing the BBB via an MCT isoform. These novel findings of GHB BBB transport suggest potential therapeutic approaches in the treatment of GHB overdoses. We are currently conducting "proof-of-concept" studies involving the use of GHB brain transport inhibitors during GHB toxicity.
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PMID:GHB (gamma-hydroxybutyrate) carrier-mediated transport across the blood-brain barrier. 1517 14

Affective disorders often occur in combination with disrupted sleep-wake cycles and abnormal fluctuations in hypothalamic neurotransmitters. Hypocretin (orexin) is a hypothalamic neuropeptide linked to narcolepsy, a sleep-related disorder characterized by profound disturbances in the normal sleeping pattern and variable degrees of depression. Wistar-Kyoto (WKY) rats exhibit depressive characteristics and patterns of sleep disruption similar to that observed in depressed human patients. In this study we sought to determine whether the total number or the size of hypothalamic hypocretin neurons in WKY rats differ from their control, Wistar (WIS) rats. Immunocytochemical and stereological methods were applied to quantify hypocretin-1 containing neurons in the hypothalamus. The study revealed 18% fewer hypocretin-1 positive neurons as well as a 15% decrease in average neuronal soma size of hypocretin-1 producing cells in the hypothalamus of WKY rats compared to WIS rats. These findings support the view that reduced number or size of hypothalamic hypocretinergic neurons may underlie the disrupted sleep pattern associated with depressive characteristics in WKY rats.
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PMID:Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. 1546 97


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