Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MDMA (3,4-methylenedioxymethamphetamine) or 'Ecstasy' was scheduled as an illegal drug in 1986, but since then its recreational use has increased dramatically. This review covers 15 years of research into patterns of use, its acute psychological and physiological effects, and the long-term consequences of repeated use. MDMA is an indirect monoaminergic agonist, stimulating the release and inhibiting the reuptake of serotonin (5-HT) and, to a lesser extent, other neurotransmitters. Single doses of MDMA have been administered to human volunteers in double-blind placebo-controlled trials, although most findings are based upon recreational MDMA users. The 'massive' boost in neurotransmitter activity can generate intense feelings of elation and pleasure, also hyperactivity and hyperthermia. This psychophysiological arousal may be exacerbated by high ambient temperatures, overcrowding, prolonged dancing and other stimulant drugs. Occasionally the 'serotonin syndrome' reactions may prove fatal. In the days after Ecstasy use, around 80% of users report rebound depression and lethargy, due probably to monoaminergic depletion. Dosage escalation and chronic pharmacodynamic tolerance typically occur in regular users. Repeated doses of MDMA cause serotonergic neurotoxicity in laboratory animals, and there is extensive evidence for long-term neuropsychopharmacological damage in humans. Abstinent regular Ecstasy users often display reduced levels of 5-HT, 5-HIAA, tryptophan hydroxylase and serotonin transporter density; functional deficits in learning/memory, higher cognitive processing, sleep, appetite and psychiatric well-being, and, most paradoxically, 'loss of sexual interest/pleasure'. These psychobiological deficits are greatest in heavy Ecstasy users and may reflect serotonergic axonal loss in the higher brain regions, especially the frontal lobes, temporal lobes and hippocampus. These problems seem to remain long after the recreational use of Ecstasy has ceased, suggesting that the neuropharmacological damage may be permament. Copyright 2001 John Wiley & Sons, Ltd.
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PMID:Human psychopharmacology of Ecstasy (MDMA): a review of 15 years of empirical research. 1240 36

Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. The wake-promoting action of histamine H(3) receptor antagonists has been evidenced in numerous animal studies. They may therefore be a viable strategy for use as an antidepressant therapy in conjunction with selective serotonin reuptake inhibitors. JNJ-28583867 (2-Methyl-4-(4-methylsulfanyl-phenyl)-7-(3-morpholin-4-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline) is a selective and potent histamine H(3) receptor antagonist (K(i)=10.6 nM) and inhibitor of the serotonin transporter (SERT) (K(i)=3.7 nM), with 30-fold selectivity for SERT over the dopamine and norepinephrine transporters. After subcutaneous administration, JNJ-28583867 occupied both the histamine H(3) receptor and the SERT in rat brain at low doses (<1 mg/kg). JNJ-28583867 blocked imetit-induced drinking (3-10 mg/kg i.p.), confirming in vivo functional activity at the histamine H(3) receptor and also significantly increased cortical extracellular levels of serotonin at doses of 0.3 mg/kg (s.c.) and higher. Smaller increases in cortical extracellular levels of norepinephrine and dopamine were also observed. JNJ-28583867 (3-30 mg/kg p.o.) showed antidepressant-like activity in the mouse tail suspension test. JNJ-28583867 (1-3 mg/kg s.c.) caused a dose-dependent increase in the time spent awake mirrored by a decrease in NREM. Concomitantly, JNJ-28583867 produced a potent suppression of REM sleep from the dose of 1 mg/kg onwards. JNJ-28583867 has good oral bioavailability in the rat (32%), a half-life of 6.9 h and a C(max) of 260 ng/ml after 10 mg/kg p.o. In summary, JNJ-28583867 is a combined histamine H(3) receptor antagonist-SERT inhibitor with in vivo efficacy in biochemical and behavioral models of depression and wakefulness.
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PMID:Pharmacological characterization of JNJ-28583867, a histamine H(3) receptor antagonist and serotonin reuptake inhibitor. 1776 21

The prevalence of attention-deficit hyperactivity disorder (ADHD) in the USA is estimated at approximately 4-9% in children and 4% in adults. It is estimated that prescriptions for ADHD medications are written for more than 2.7 million children per year. In 2010, US poison centers reported 17,000 human exposures to ADHD medications, with 80% occurring in children <19 years old and 20% in adults. The drugs used for the treatment of ADHD are diverse but can be roughly separated into two groups: the stimulants such as amphetamine, methylphenidate, and modafinil; and the non-stimulants such as atomoxetine, guanfacine, and clonidine. This review focuses on mechanisms of toxicity after overdose with ADHD medications, clinical effects from overdose, and management. Amphetamine, dextroamphetamine, and methylphenidate act as substrates for the cellular monoamine transporter, especially the dopamine transporter (DAT) and less so the norepinephrine (NET) and serotonin transporter. The mechanism of toxicity is primarily related to excessive extracellular dopamine, norepinephrine, and serotonin. The primary clinical syndrome involves prominent neurological and cardiovascular effects, but secondary complications can involve renal, muscle, pulmonary, and gastrointestinal (GI) effects. In overdose, the patient may present with mydriasis, tremor, agitation, hyperreflexia, combative behavior, confusion, hallucinations, delirium, anxiety, paranoia, movement disorders, and seizures. The management of amphetamine, dextroamphetamine, and methylphenidate overdose is largely supportive, with a focus on interruption of the sympathomimetic syndrome with judicious use of benzodiazepines. In cases where agitation, delirium, and movement disorders are unresponsive to benzodiazepines, second-line therapies include antipsychotics such as ziprasidone or haloperidol, central alpha-adrenoreceptor agonists such as dexmedetomidine, or propofol. Modafinil is not US FDA approved for treatment of ADHD; however, it has been shown to improve ADHD signs and symptoms and has been used as an off-label pharmaceutical for this diagnosis in both adults and children. The mechanism of action of modafinil is complex and not fully understood. It is known to cause an increase in extracellular concentrations of dopamine, norepinephrine, and serotonin in the neocortex. Overdose with modafinil is generally of moderate severity, with reported ingestions of doses up to 8 g. The most common neurological effects include increased anxiety, agitation, headache, dizziness, insomnia, tremors, and dystonia. The management of modafinil overdose is largely supportive, with a focus on sedation, and control of dyskinesias and blood pressure. Atomoxetine is a selective presynaptic norepinephrine transporter inhibitor. The clinical presentation after overdose with atomoxetine has generally been mild. The primary effects have been drowsiness, agitation, hyperactivity, GI upset, tremor, hyperreflexia, tachycardia hypertension, and seizure. The management of atomoxetine overdose is largely supportive, with a focus on sedation, and control of dyskinesias and seizures. Clonidine is a synthetic imidazole derivative with both central and peripheral alpha-adrenergic agonist actions. The primary clinical syndrome involves prominent neurological and cardiovascular effects, with the most commonly reported features of depressed sensorium, bradycardia, and hypotension. While clonidine is an anti-hypertensive medication, a paradoxical hypertension may occur early with overdose. The clinical syndrome after overdose of guanfacine may be mixed depending on central or peripheral alpha-adrenoreceptor effects. Initial clinical effects may be drowsiness, lethargy, dry mouth, and diaphoresis. Cardiovascular effects may depend on time post-ingestion and may present as hypotension or hypertension. The management of guanfacine overdose is largely supportive, with a focus on support of blood pressure. Overdose with ADHD medications can produce major morbidity, with many cases requiring intensive care medicine and prolonged hospital stays. However, fatalities are rare with appropriate care.
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PMID:Overdose of drugs for attention-deficit hyperactivity disorder: clinical presentation, mechanisms of toxicity, and management. 2375 86

A variety of agents are currently used to treat the different anxiety disorders. Benzodiazepines, such as diazepam, are still preferred by some for the treatment of acute anxiety, with the advantage of a rapid onset of action, but they are less suitable for long-term treatment due to their potential for memory disturbances, sleepiness, lethargy, physical dependence and withdrawal. Compounds acting on monoamine neurotransmission are more suitable in the treatment of long-term or chronic anxiety disorders. Tricyclic antidepressants, such as imipramine, and monoamine oxidase inhibitors have been shown to be effective anxiolytics, but their side effects and safety concerns have limited their use. The probable role of disturbed serotonergic neurotransmission in anxiety is widely accepted and is the theoretical basis for the use of serotonergic agents such as the 5-HT1A receptor partial agonist, buspirone, and the selective serotonin reuptake inhibitors (SSRI), such as sertraline and paroxetine, which have largely replaced the earlier antidepressants. There is clear evidence for decreased serotonergic function in anxiety as well as in depression. Studies of patients with anxiety disorders show reduced levels of serotonin in cerebrospinal fluid (CSF) as well as reduced serotonin transporter binding. The role of noradrenaline in the control of anxiety is less well understood, although there is considerable evidence to suggest that a disturbance of noradrenergic neurotransmission may also contribute to the symptoms of anxiety. Noradrenaline modulates the activity of brain regions such as the amygdala which are associated with anxiety. In addition, anxiety states are associated with increases in the metabolite of noradrenaline, 3-methoxy-4-hydrophenylglycol (MHPG), and hypersecretion of noradrenaline in plasma and CSF. It appears likely that modulation of both serotonin and noradrenaline systems by dual-reuptake inhibitors may prove to be an advantage in the treatment of anxiety disorders. The serotonin-noradrenaline reuptake inhibitors (SNRI), venlafaxine, milnacipran and duloxetine are efficacious in relieving anxiety symptoms within depression, and some have proven efficacy in certain anxiety disorders. Initial studies suggest that dual acting agents may have an advantage over selective reuptake inhibitors in certain anxiety disorders, such as post-traumatic stress disorder (PTSD), and in patients with comorbid anxiety and depression.
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PMID:Serotonin noradrenaline reuptake inhibitors: A new generation of treatment for anxiety disorders. 2492 77