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)

Depressed patients consult with their primary care physician before engaging the services of a mental health care provider. Primary care physicians initiate more antidepressant pharmacotherapy than psychiatrists. Major depression has been estimated to have a 5% to 10% prevalence, with up to three times that percentage having significant subsyndromal depression symptoms. Patients frequently deny their depression, often neglecting to recognize their own somatic and cognitive/behavioral subjective symptoms, underestimating symptom severity, and possessing a reluctance to validate their existence because of social stigmata. There remains an underrecognition of the diagnosis of depression by primary care physicians. Often, depressed primary care patients present with somatic symptoms, which include gastrointestinal, skeletal muscle, and cardiovascular complaints, as opposed to describing nonsomatic criteria for depression. Elderly patients presenting with depression have an estimated prevalence of 5% to 50%, and the rate of suicide increases with age. In this patient group, depression may exist independently or secondary to insults or events. Major depressive disorders occur throughout the life cycle; however, the rate of major depression has increased, and the age of onset has become younger. Not uncommonly, complicating psychosocial factors coupled with multiple chronic disease states and physical pathology may mask the diagnosis of depression. Furthermore, up to 25% of extended care facility patients may satisfy the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for depression. Comorbid diseases and pharmacotherapy have been associated with secondary depression. Antidepressant pharmacotherapy combined with cognitive and behavioral therapy appears to offer the most benefit to the patient. Antidepressants independently act as catalysts to facilitate or correct the dysregulation of neurotransmission in depressed patients. The elderly present pharmacotherapeutic challenges based on a changing internal milieu in the absorption, distribution, metabolism, and elimination of most of the antidepressants. Polypharmacy may act to induce or inhibit the metabolism of substrate medication that the patient is currently using. A comprehensive list of cytochrome P450 interactions is provided. Generally the antidepressants display similarity in efficacy; however, effectiveness may be substantially different among and within antidepressant pharmacotherapeutic classes. The pharmacotherapeutic selection of antidepressants is a multifactorial cognitive process, including consideration of medication side effects and adverse effects and patient-specific factors. Other factors in this selection process include drug interaction potential, patient's prior drug response, and both the patient's concomitant pathology and pathophysiology and pharmacotherapy-mediated events. In conjunction with age-related, gender-related, and genetic factors, a full description of current serotonin pharmacotherapy-mediated events is provided. Included in this article are a review of traditional and newer antidepressants, their pharmacokinetics, their pharmacodynamics, and an elaborate interaction focus. Special emphasis is focused on individual antidepressants and class of antidepressants. This article provides comprehensive insights in perception, recognition, treatment, and the selection process involving antidepressants.
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PMID:Recognition and management of depression in primary care: a focus on the elderly. A pharmacotherapeutic overview of the selection process among the traditional and new antidepressants. 1131 69

Sertraline (Zoloft, Pfizer) has been shown in numerous controlled studies to have similar efficacy to other selective serotonin (5-HT) re-uptake inhibitors (SSRIs) in the treatment of depression and anxiety disorders. Further research is indicating that the efficacy of sertraline extends even beyond the treatment of depression and anxiety to include utility in eating disorders, premenstrual dysphoric disorder (PMDD) and possibly substance abuse treatment. Along with other SSRIs, sertraline offers several advantages over older antidepressants, including improved patient tolerability, low risk of lethality in overdose and no dependence potential. In head-to-head comparisons, sertraline appears to be at least as well-tolerated as other SSRIs and may even have a more favourable side effect profile. Low potential for pharmacokinetic drug interactions is another advantage of sertraline. Unlike fluoxetine, fluvoxamine and paroxetine, sertraline is not a potent inhibitor of any of the cytochrome P450 isoenzyme systems. As a result of its proven efficacy, good tolerability and lack of pharmacokinetic interactions, sertraline should be considered first-line in the treatment of anxiety and depressive disorders.
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PMID:Review of sertraline and its clinical applications in psychiatric disorders. 1133 29

There are no aetiologically-based treatments available to cure autism. Though psychotropics have a role in the management of some symptoms of autism, clinical trial evidence for the use of psychotropics is in its infancy and needs close monitoring. About half of the subjects with high functioning pervasive developmental disorders (PDDs) are currently reported to be on psychotropics (anti-depressants, stimulants and antipsychotics), with many of them being on anti-epileptic medication simultaneously. Despite this high level of psychotropic use, few studies exist investigating the pharmacokinetics, pharmacodynamics or side-effect profiles in this population. Multiprofessional and parent partnership is essential in managing autism and psychopharmacology should be used in conjunction with environmental manipulation, educational modification and/or behavioral management strategies. A symptomatic approach to managing the difficult behaviours associated with autism is recommended. Some symptoms of autism may be medication responsive (hyperactivity, obsessions, rituals, inattention, tics, etc), while other symptoms may be responsive to behavioural interventions, but may require medication (aggression, anxiety, depression, impulsivity, sleep difficulties, etc), and symptoms which need specific skill remediation are usually non-responsive to medication (deficits in academic, social or sport domains). The new atypical antipsychotics (such as risperidone, olanzapine, amisulpiride, quetiapine) and SSRIs are increasingly being used in autism, with encouraging results, but a risk-benefit ratio of pharmacotherapy is essential with due weight being given to the side-effects of medication. Despite symptomatic improvement with medication, one should remain cautious about long-term use of psychotropics. It is also important to recognize that psychotropics can sometimes worsen behaviour, and can produce iatrogenic symptoms. Certain anti-epileptic medication and psychotropic drugs are metabolized by the same cytochrome P450 isoenzymes in the liver. In such circumstances, the addition of a psychotropic agent may drastically alter the levels of the anti-epileptic medication and vice versa. It is suggested that specialist clinics should be involved when one is considering complex medication regimes, experimental drugs, polypharmacy, or if patients show unusual side-effects or is drug resistant.
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PMID:Pharmacotherapy of target symptoms in autistic spectrum disorders. 1140 59

The naphthylamine derivative sertraline is a potent and selective inhibitor of serotonin reuptake into presynaptic terminals. Sertraline has a linear pharmacokinetic profile and a half-life of about 26 h. Its major metabolite, desmethylsertraline does not appear to inhibit serotonin reuptake. Sertraline mildly inhibits the CYP2D6 isoform of the cytochrome P450 system but has little effect on CYP1A2, CYP3A3/4, CYP2C9, or CYP2C19. It is, however, highly protein bound and may alter blood levels of other highly protein bound agents. Sertraline is a widely used serotonin reuptake inhibitor that has been shown to have both antidepressant and antianxiety effects. Many clinical trials have demonstrated its efficacy in depression compared with both placebo and other antidepressant drugs. Its efficacy has also been demonstrated in randomized, controlled trials of patients with obsessive-compulsive disorder, panic disorder, social phobia, and premenstrual dysphoric disorder. In short-term, open-label studies it has appeared efficacious and tolerable in children and adolescents and in the elderly, and data are positive for its use in pregnant or lactating women. Typical side effects include gastrointestinal and central nervous system effects as well as treatment-emergent sexual dysfunction; withdrawal reactions may be associated with abrupt discontinuation of the agent. The safety profile of sertraline in overdose is very favorable. Sertraline's efficacy for both mood and anxiety disorders, relatively weak effect on the cytochrome P450 system, and tolerability profile and safety in overdose are factors that contribute to make it a first-line agent for treatment in both primary and tertiary care settings.
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PMID:The selective serotonin reuptake inhibitor sertraline: its profile and use in psychiatric disorders. 1142 May 70

A turpentine-induced inflammatory reaction (TIIR) down-regulates multiple isoforms of hepatic cytochrome P450 (P450) and increases microsomal lipid peroxidation. Since the synthesis of nitric oxide (NO*) is stimulated by inflammatory reactions, and NO* can depress the P450, it was of interest to investigate in vivo whether L-NAME and theophylline, by its anti-inflammatory properties, could prevent the depression of P450 caused by a TIIR. Control and rabbits with a TIIR received L-NAME for 72 h, and the activity of P450 was assessed in vivo and in vitro. In vivo, TIIR reduced theophylline systemic clearance by 50% (p<0.05), P450 total content by 67%, and the amount of CYP1A1/2 proteins by around 60% (p<0.05). L-NAME partially prevented the decrease in theophylline systemic clearance and in P450 total content, as well as the increase in lipid peroxidation; however, L-NAME did not hinder CYP1A1/2 proteins down-regulation. L-NAME did not modify the in vitro ability of the serum of rabbits with TIIR to decrease P450 activity, suggesting that the effect of L-NAME is not associated to a decrease in serum mediators. As assessed by the concentration in seromucoids, theophylline did not modify the severity of the inflammatory reaction, nor did it prevent the decrease in P450 activity. In conclusion, a TIIR down-regulates and reduces P450 activity, decrease that is at least in part mediated by NO*; theophylline does not prevent TIIR-induced P450 decrease in activity.
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PMID:L-NAME prevents in vivo the inactivation but not the down-regulation of hepatic cytochrome P450 caused by an acute inflammatory reaction. 1155 17

St. John's wort (Hypericum perforatum) is the most widely used herbal medicine for the treatment of depression. However, concerns have arisen about the potential of its interaction with other drugs due to the induction of cytochrome P450 isozymes 1A2 and 3A4 by the components hypericin and hyperforin, respectively. Structurally similar natural products are often employed as antitumor agents due to their action as inhibitors of DNA topoisomerases, nuclear enzymes that modify DNA during cellular proliferation. Preliminary findings that hypericin inhibited the DNA relaxation activity of topoisomerase IIalpha (topo II; EC 5.99.1.3) led us to investigate the mechanism of enzyme inhibition. Rather than stabilizing the enzyme in covalent complexes with DNA (cleavage complexes), hypericin inhibited the enzyme prior to DNA cleavage. In vitro assays indicate that hypericin is a potent antagonist of cleavage complex stabilization by the chemotherapeutics etoposide and amsacrine. This antagonism appears to be due to the ability of hypericin to intercalate or distort DNA structure, thereby precluding topo II binding and/or DNA cleavage. Supporting its non-DNA damaging, catalytic inhibition of topo II, hypericin was shown to be equitoxic to both wild-type and amsacrine-resistant HL-60 leukemia cell lines. Moreover, hypericin was incapable of stimulating DNA damage-responsive gene promoters that are activated by etoposide. As with the in vitro topo II assay, antagonism of DNA damage stimulated by 30 microM etoposide was evident in leukemia cells pretreated with 5 microM hypericin. Since many cancer patients experience clinical depression and concomitantly self-medicate with herbal remedies, extracts of St. John's wort should be investigated further for their potential to antagonize topo II-directed chemotherapy regimens.
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PMID:Catalytic inhibition of human DNA topoisomerase IIalpha by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum). 1159 74

1,1-Dichloroethane (DCE) is a solvent that is often found as a contaminant of drinking water and a pollutant at hazardous waste sites. Information on its short- and long-term toxicity is so limited that the U.S. EPA and ATSDR have not established oral reference doses or minimal risk levels for the volatile organic chemical (VOC). The acute oral LD(50) in male Sprague-Dawley (S-D) rats was estimated in the present study to be 8.2 g/kg of body weight (bw). Deaths appeared to be due to CNS depression and respiratory failure. In an acute/subacute experiment, male S-D rats were given 0, 1, 2, 4, or 8 g DCE/kg in corn oil by gavage for 1, 5, or 10 consecutive days. The animals were housed in metabolism cages for collection of urine and sacrificed for blood and tissue sampling 24 h after their last dose. There were decreases in body weight gain and relative liver weight at all dosage levels, as well as increased renal nonprotein sulfhydryl levels at 2 and 4 g/kg after 5 and 10 days. Elevated serum enzyme levels, histopathological changes, and abnormal urinalyses were not manifest. For the subchronic study, adult male S-D rats were gavaged with 0.5, 1, 2, or 4 g DCE/kg 5 times weekly for up to 13 weeks. Animals receiving 4 g/kg exhibited pronounced CNS depression, with more than one-half dying by week 11. The 2-g/kg rats exhibited moderate CNS depression. One 2-g/kg rat died during week 6. There were very few manifestations of organ damage in animals that succumbed or in survivors at any dosage level. Decreases in bw gain and transient increases in enzymuria were noted at 2 and 4 g/kg. Serum enzyme levels and blood urea nitrogen were not elevated, nor were glycosuria or proteinuria present. Chemically induced histological changes were not seen in the liver, kidney, lung, brain, adrenal, spleen, stomach, epididymis, or testis. Hepatic microsomal cytochrome P450 experiments revealed that single, high oral doses of DCE did not alter total P450 levels, but did induce CYP2E1 levels and activity and inhibit CYP1A1 activity. These effects were reversible and regressed with repeated DCE exposure. There was no apparent progression of organ damage during the 13-week subchronic study, nor appearance of adverse effects not seen in the short-term exposures. One g/kg orally (po) was found to be the acute, subacute, and subchronic LOAEL for DCE, under the conditions of this investigation. In each instance, 0.5 g/kg was the NOAEL.
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PMID:Acute, subacute, and subchronic oral toxicity studies of 1,1-dichloroethane in rats: application to risk evaluation. 1160 9

This review summarizes the current knowledge of the biosynthesis of neurosteroids in the human brain, the enzymes mediating these reactions, their localization and the putative effects of neurosteroids. Molecular biological and biochemical studies have now firmly established the presence of the steroidogenic enzymes cytochrome P450 cholesterol side-chain cleavage (P450SCC), aromatase, 5alpha-reductase, 3alpha-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase in human brain. The functions attributed to specific neurosteroids include modulation of gamma-aminobutyric acid A (GABAA), N-methyl-d-aspartate (NMDA), nicotinic, muscarinic, serotonin (5-HT3), kainate, glycine and sigma receptors, neuroprotection and induction of neurite outgrowth, dendritic spines and synaptogenesis. The first clinical investigations in humans produced evidence for an involvement of neuroactive steroids in conditions such as fatigue during pregnancy, premenstrual syndrome, post partum depression, catamenial epilepsy, depressive disorders and dementia disorders. Better knowledge of the biochemical pathways of neurosteroidogenesis and their actions on the brain seems to open new perspectives in the understanding of the physiology of the human brain as well as in the pharmacological treatment of its disturbances.
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PMID:Neurosteroid metabolism in the human brain. 1172 Aug 89

The interaction and modulation of hepatic cytochrome P450 enzymes by infection and inflammation has been well described both in clinical settings and in animal models. Recent evidence found that inflammation in the central nervous system (CNS) leads to alterations in cytochrome P450 activity in both brain and liver. The bacterial endotoxin lipopolysaccharide (LPS) was used to induce an inflammatory response in cultured astrocytes as a model of CNS inflammation. This inflammatory response involves a range of immune mediators, such as acute phase cytokines, nitric oxide, prostanoid products, and reactive oxygen species. It is hypothesized that cytokines, released during inflammation, act to modulate the expression of specific isoforms of cytochrome P450 resulting in altered activity levels. High levels of the cytokines tumor necrosis factor-alpha and interleukin-1beta were released into culture medium after the addition of LPS to astrocyte cultures. When these same cytokines were added directly to the cultures, they also were able to modulate levels of CYP1A activity. The concurrent addition of dexamethasone to astrocytes blocked both the cytokine release and the alteration of CYP1A activity, thus supporting a role for these cytokines in this response. These results provide evidence suggesting an involvement of acute phase cytokines in mediating the LPS-induced depression of CYP1A activity in cultured astrocytes.
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PMID:The role of cytokines in the depression of CYP1A activity using cultured astrocytes as an in vitro model of inflammation in the central nervous system. 1174 10

A role for cytokines as mediators of the depression in cytochrome P450 activity in brain and liver during CNS inflammation is proposed. Lipopolysaccharide (LPS) was given directly into the lateral ventricle of the brain to mimic a localized CNS infection. CYP1A activity and protein in both brain and liver were depressed in response to this treatment. The administration of the pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interferon-gamma (IFN-gamma) directly into the lateral ventricle emulated the effects of LPS on CYP1A activity only in the brain. In contrast, these centrally administered cytokines did not produce a concomitant loss of CYP1A activity in the liver. Significant levels of several cytokines (TNF-alpha, IL-1beta, and IFN-gamma) were produced in the serum of animals following intracerebroventricular (i.c.v.) administration of LPS. This production of peripheral cytokines by LPS could not be mimicked by the i.c.v. injection of IL-1beta or TNF-alpha. These results suggest that induction of cytokines in the brain may play a direct role in the depression of CYP1A activity in the CNS following the administration of LPS into the lateral ventricle. The production of cytokines within the brain does not appear to participate in the signaling process in the brain that leads to the concomitant loss of CYP1A activity in the liver. The subsequent production of cytokines in peripheral tissues, however, does appear to play a role in the loss of cytochrome P450 in the liver.
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PMID:Role of cytokines in the lipopolysaccharide-evoked depression of cytochrome P450 in the brain and liver. 1175 25


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