Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0085631 (agitation)
12,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The first choice group of psychotropic agents in schizophrenia is neuroleptics. However, this treatment is not effective in all patients and with every symptom. We summarize papers published on the role of antiepileptic drugs in treatment-resistant schizophrenia. We have searched the computer database system MEDLINE for relevant articles including reviews, reports of drug studies and case histories. Antiepileptic drugs can change symptoms of schizophrenia by their action on GABA-ergic neurotransmission or via anti-glutamatergic mechanisms. High doses of adjunctive benzodiazepines reduce positive symptoms, anxiety, and agitation. Carbamazepine is effective in affective symptoms of schizophrenia and influences violent behavior in psychotic patients. Its anti-kindling action may represent a promising treatment strategy for some patients with chronic course of schizophrenia. Valproate treatment leads to a decrease in positive symptoms as well as hostility. Lamotrigine is expected to influence the positive, negative, affective, and cognitive symptoms of schizophrenia. New antiepileptics (e.g., gabapentin, oxcarbazepine, topiramate, vigabatrin) present a promise as potential adjuncts to neuroleptic treatment in resistant symptoms of schizophrenia.
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PMID:Antiepileptic drugs in schizophrenia: a review. 1254 2

Intrathecal baclofen is used as a muscle relaxant and antispasmodic in cases of spasticity resulting from central nervous system trauma. The baclofen withdrawal syndrome may include hyperthermia, tachycardia, hypertension, seizures, altered mental status, and psychomotor agitation. We report a case in which the removal of a baclofen pump lead tothe development of severe withdrawal symptoms despite oral baclofen replacement therapy. In order to avoid the development of withdrawal, adequate doses of GABA agonist agents should be administered immediately prior to, and following, baclofen pump removal.
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PMID:Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. 1470 58

We report two adult patients with succinic semialdehyde dehydrogenase deficiency, manifesting as gamma-hydroxybutyric aciduria. For both, the clinical presentation included significant behavioral disturbances and psychosis (hallucinations, disabling anxiety, aggressive behavior, and sleep disorder), leading to multiple therapeutic attempts. Intervention with benzodiazepines appeared most efficacious, resulting in decreased aggression and agitation and improvement in anxiety. A review of 56 published and unpublished studies of SSADH-deficient patients revealed that 42% manifested behavioral disturbances, whereas 13% (predominantly adults) displayed psychotic symptomatology. To explore the potential biochemical basis of these behavioral abnormalities, we studied cerebrospinal fluid derived from 13 patients, which revealed significantly elevated GHB (65- to 230-fold), high free and total GABA (up to threefold), and low glutamine. Although within the control range, homovanillic and 5-hydroxyindoleacetic acids (end products of dopamine and serotonin metabolism, respectively) showed a significant linear correlation with increasing GHB concentration, suggesting enhanced dopamine and serotonin turnover. We conclude that elevated GABA combined with low glutamine suggest disruption of the glial-neuronal glutamine/GABA/glutamate shuttle necessary for replenishment of neuronal neurotransmitters, whereas altered dopamine and serotonin metabolism may be causally linked to the hyperkinetic movement disorders and behavioral disturbances seen in SSADH-deficient patients.
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PMID:Significant behavioral disturbances in succinic semialdehyde dehydrogenase (SSADH) deficiency (gamma-hydroxybutyric aciduria). 1451 18

Antipsychotic-induced akathisia is characterized by subjective and objective motor restlessness, which is observed as a common extrapyramidal side-effect of antipsychotic agents. A patient is described who had antipsychotic-induced akathisia unresponsive to conventional therapy, and who began gabapentin therapy for insomnia. Significant improvement in his akathisia occurred when the gabapentin dose was increased, and his other treatment for akathisia was decreased and discontinued. Gabapentin may be effective by mechanisms similar to its action in restless legs syndrome and Parkinsonism, and/or via the GABA neurotransmitter system.
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PMID:Gabapentin in the treatment of antipsychotic-induced akathisia in schizophrenia. 1581 71

Insomnia is the most frequently encountered sleep complaint worldwide. While many prescription drugs are used to treat insomnia, extracts of valerian (Valeriana officinalis L., Valerianaceae) are also used for the treatment of insomnia and restlessness. To determine novel mechanisms of action, radioligand binding studies were performed with valerian extracts (100% methanol, 50% methanol, dichloromethane [DCM], and petroleum ether [PE]) at the melatonin, glutamate, and GABA(A) receptors, and 8 serotonin receptor subtypes. Both DCM and PE extracts had strong binding affinity to the 5-HT(5a) receptor, but only weak binding affinity to the 5-HT(2b) and the serotonin transporter. Subsequent binding studies focused on the 5-HT(5a) receptor due to the distribution of this receptor in the suprachiasmatic nucleus of the brain, which is implicated in the sleep-wake cycle. The PE extract inhibited [(3)H]lysergic acid diethylamide (LSD) binding to the human 5-HT(5a) receptor (86% at 50 microg/ml) and the DCM extract inhibited LSD binding by 51%. Generation of an IC(50) curve for the PE extract produced a biphasic curve, thus GTP shift experiments were also performed. In the absence of GTP, the competition curve was biphasic (two affinity sites) with an IC(50) of 15.7 ng/ml for the high-affinity state and 27.7 microg/ml for the low-affinity state. The addition of GTP (100 microM) resulted in a right-hand shift of the binding curve with an IC(50) of 11.4 microg/ml. Valerenic acid, the active constituent of both extracts, had an IC(50) of 17.2 microM. These results indicate that valerian and valerenic acid are new partial agonists of the 5-HT(5a) receptor.
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PMID:Valerian extract and valerenic acid are partial agonists of the 5-HT5a receptor in vitro. 1592 20

Patients with neurologic disorders commonly experience sleep dysfunction and psychiatric disorders. The most common sleep dysfunction is insomnia, which is a primary symptom in 30% to 90% of psychiatric disorders. Insomnia and fatigue are prominent symptoms of anxiety disorders and major depression, including patients who are treated but have residual symptoms. Anxiety and depressive disorders account for 40% to 50% of all cases of chronic insomnia. It is also recognized that primary insomnia and other primary sleep disorders produce symptoms that are similar to those reported by patients with psychiatric disorders. A clinician must judge whether sleep deprivation causes mood disturbance or whether depressive or anxiety disorder represents the primary reason for sleep dysfunction. When insomnia is comorbid with mild to moderate depression, therapy should begin with bedtime dosing of sedating antidepressants such as mirtazapine, nefazodone, or tricyclic antidepressants, which are preferred because of their sedative effects, although side effects may limit their usefulness. Intervention for chronic insomnia is similar in nonpsychiatric and psychiatric patients. Behavioral therapies, particularly cognitive behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia. Sedative hypnotic agents are the most studied agents to treat insomnia, particularly those that are active through the benzodiazepine receptor-GABA complex, such as benzodiazepines, eszopiclone, zaleplon, and zolpidem. The new melatonin-receptor agonist ramelteon has not yet been studied in psychiatric patients. Prescription of adjunctive trazodone 50 to 150 mg is a common clinical practice to treat comorbid insomnia during antidepressant therapy, but published data are surprisingly limited when considered against the frequent usage of trazodone. Although there has been insufficient research on the use of atypical antipsychotic agents in severe insomnia, psychiatrists use quetiapine, olanzapine, or other agents to lessen agitation that disrupts sleep onset or maintenance. When insomnia or hypersomnia continues even as mood, anxiety, or thought disorders improve with standard therapy, the physician should consider the potential presence of underlying sleep disorders.
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PMID:Treatment of sleep dysfunction and psychiatric disorders. 1690 76

Topiramate is an antiepileptic drug, recently also used in the treatment of psychiatric diseases. Inasmuch as topiramate and valproate, which are currently used for aggressive behavior, share several pharmacological mechanisms (positive modulatory effect on the GABA activity and negative modulatory effect on glutamatergic neurotransmission), the objective of the present study was to compare the pharmacological effects of topiramate with those of valproate and their combination in patients with psychiatric disorders showing marked aggression and agitation. A retrospective, case-controlled, mirror-image study was carried out in a sample of 45 inpatients affected by schizophrenia, schizoaffective and bipolar disorder, and hospitalized in a maximum-security Canadian psychiatry hospital. Overt Aggression Scale, Agitation-Calmness Evaluation Scale, number and intensity of psychotic episodes, number of episodes of withdrawal from group activities per week, and number of therapeutic isolation per week and of strict surveillance intervention per week were evaluated before and after the treatments. Results indicate that patients treated with topiramate show a decrease in the average score of the Overt Aggression Scale, a decrease of episodes of agitation and of strict surveillance interventions. This effect was similar to the group treated with valproate or with the combination of valproate-topiramate. However, valproate therapy, but not topiramate therapy, decreased the intensity of agitation episodes measured by the Agitation-Calmness Evaluation Scale; valproate and the combination topiramate-valproate decreased the number of psychotic disorganization episodes as well. These results suggest that topiramate could be a valid medicine in the control of aggression in psychosis. Double-blind, randomized, placebo-controlled studies need to further assess this pharmacological indication.
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PMID:Efficacy of topiramate, valproate, and their combination on aggression/agitation behavior in patients with psychosis. 1697 86

RLS cases may carry a genetic vulnerability called EEG alpha activity gate dyscontrols which appear during changes in vigilance and generally during sleep. It is triggered by forced EEG shifts either from alpha activity to delta or high alpha. Expressions of alpha activity gate dyscontrols may have a gate effect that trigger a second vulnerability-dopamine receptor specific individual sensitivity (DRSIS) and this leads to a deficiency in dopamine transmissions at diencephalospinal dopamine system (DSDS). Due to altered gene expressions in states of dopamine receptor function, DRSIS EEGs and RLS symptoms may be interpreted as follows: A. Disinhibition state is alpha activity gate dyscontrols induced inhibition of DSDS inhibitory dopamine modulations. Dopaminergic disinhibitions inhibit inhibitory interneurons of sensory and motor nuclei neurons that are involved in RLS. These sleep sensitive inhibitory interneurons possibly have GABA-ergic functions in sleep. (I) DSDS thalamic neurons' disinhibitory effects in thalamus on GABA-ergic interneurons of: (a) Intralaminar nuclei non-discriminative sensation neurons at thalamocortical premotor network leading to symptom of "a sense of urgency to move" generally referenced to legs.(b) Reticular thalamic nucleus (RTN) neurons. At polysomnography,during NREM sleep, disinhibited RTN neurons show alpha activity gate dyscontrol 1. These are recurrent subtypes of CAP in alpha band (7-12 Hz) pointing a difficulty in shifting to subtypes of CAP in low delta bands (0.25-2.5 Hz) and sleep fragmentations.(II) Supraspinal disinhibitory projections from DSDS thalamic neurons on GABA-ergic interneurons of: (a) Sensory neurons at posterior horns of spinal cord leading to dysesthesias, generally referenced to legs.(b) Medullary-reticulospinal neurons and by way of independent spinal rhythm generators on motoneurons leading to periodic limb movements in sleep.B. Activation state is an increase in symptoms. Sensory intralaminar and motor pontin nuclei neurons are in fact excitatory but are disinhibited in RLS. Due to altered gene expression, these neurons begin to perceive 'disinhibition' as reduced inhibition. Their glutamate receptors may activate deficient dopamine transmissions on RTN leading to alpha activity gate dyscontrol 2. This implies a failure in preventing shifts to frequent subtypes of CAP in high alpha and low beta bands (12-13 Hz) resulting in an increase of sensorimotor symptoms and appearance of motor restlessness, behavioral arousals and insomnia. C. Inhibition state is spontaneous relief from sensorimotor symptoms. Short or long-term synaptic plasticities of dopamine receptors towards activations initiate negative feedbacks from inhibitory interneurons. They are supported by inhibitory dopamine modulations- alertness and some awareness generally with regular high alpha EEGs, supraspinal inhibitions and a reverse movement pattern of PLMS during standing up and continuing to walk.
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PMID:In restless legs syndrome, during changes in vigilance, the forced EEG shifts from alpha activity to delta or high alpha may lead to the altered states of dopamine receptor function and the symptoms. 1732 Mar 7

Valerian extracts have been used for centuries to alleviate restlessness and anxiety albeit with unknown mechanism of action in vivo. We now describe a specific binding site on GABA(A) receptors with nM affinity for valerenic acid and valerenol, common constituents of valerian. Both agents enhanced the response to GABA at multiple types of recombinant GABA(A) receptors. A point mutation in the beta2 or beta3 subunit (N265M) of recombinant receptors strongly reduced the drug response. In vivo, valerenic acid and valerenol exerted anxiolytic activity with high potencies in the elevated plus maze and the light/dark choice test in wild type mice. In beta3 (N265M) point-mutated mice the anxiolytic activity of valerenic acid was absent. Thus, neurons expressing beta3 containing GABA(A) receptors are a major cellular substrate for the anxiolytic action of valerian extracts.
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PMID:GABA A receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root extracts. 1860 6

Patients with neurologic disorders commonly experience sleep dysfunction and psychiatric disorders. The most common sleep dysfunction is insomnia, which is a primary symptom in 30% to 90% of psychiatric disorders. Insomnia and fatigue are prominent symptoms of anxiety disorders and major depression that may occur in patients who are treated but have residual sleep dysfunction. Anxiety and depressive disorders account for 40% to 50% of all cases of chronic insomnia. It is also recognized that primary insomnia and other primary sleep disorders produce symptoms that are similar to those reported by patients with psychiatric disorders. A clinician must judge whether sleep deprivation causes mood disturbance or whether depressive or anxiety disorder represents the primary reason for sleep dysfunction. When insomnia is comorbid with mild to moderate depression, therapy should begin with bedtime dosing of sedating antidepressants such as mirtazapine, nefazodone, or tricyclic antidepressants, which are preferred because of their sedative effects. Often side effects limit their usefulness. Intervention for chronic insomnia is similar in nonpsychiatric and psychiatric patients. Behavioral therapies, particularly multicomponent cognitive-behavioral therapy, and lifestyle changes show significant long-term efficacy as treatments for chronic insomnia. The most studied pharmacologic agents to treat insomnia are sedative hypnotic agents, particularly those that are active through the benzodiazepine receptor-GABA (gamma-aminobutyric acid) complex, such as benzodiazepines, eszopiclone, zaleplon, and zolpidem. Melatonin and the melatonin-receptor agonist ramelteon have not had adequate study in psychiatric patients to define their use, but small studies suggest benefit. Prescription of adjunctive trazodone (50-150 mg) is a common clinical practice to treat comorbid insomnia during antidepressant therapy, but published data are surprisingly limited, considering its frequent use. Although there has been insufficient research on the use of atypical antipsychotic agents in severe insomnia, psychiatrists use quetiapine, olanzapine, or others to lessen agitation that disrupts sleep. When insomnia or hypersomnia continue even as mood, anxiety, or thought disorders improve with standard therapy, the physician should consider the potential presence of underlying sleep disorders.
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PMID:Treatment of sleep dysfunction and psychiatric disorders. 1974 1


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