Penetration of amitriptyline, but not of fluoxetine, into brain is enhanced in mice with blood-brain barrier deficiency due to mdr1a P-glycoprotein gene disruption.
(25/684)
Mice with a genetic disruption (knockout) of the multiple drug resistance (Mdr1a) gene were used to examine the effect of the absence of the drug-transporting P-glycoprotein at the blood-brain barrier on the uptake of amitriptyline (AMI) and fluoxetine (FLU) and their metabolites into the brain. One hour after intraperitoneal injection of AMI or FLU, knockout (-/-) and wild-type (+/+) mice were sacrificed and drug concentrations of brain, kidney, liver, testis, and plasma were measured. The plasma concentrations of the AMI metabolites and the brain:spleen ratios of AMI, nortriptyline (NOR), 10-OH-AMI and 10-OH-NOR were significantly higher in the -/- mice, demonstrating that AMI and its metabolites are substrates of the P-glycoprotein and that mdr1a activity at the level of the blood-brain barrier reduces the penetration of these substances into the brain. In contrast, tissue distributions of FLU and its metabolites among the various tissues tested were indistinguishable between groups. The herein reported differences in brain penetration of antidepressant drugs depending on the presence of the mdr1a gene may offer an explanation for differences in the treatment response at a given plasma concentration. Moreover, individual differences in mdr1 gene activity may account for variable response patterns at different episodes and development of therapy resistance. (+info)
Drug coverage decisions: the role of dollars and values.
(26/684)
Given the increasing costs of pharmaceuticals today, it is important to understand how pharmacy benefits decisions are made and the role of cost and values in these decisions. This study examines what coverage decisions insurers make and the information and processes used in making these decisions. Fifty-three organizations, differing in size, tax status, and region, were asked about their policies for four new and controversial drugs: Viagra, Enbrel, Zyban, and Celebrex. Enbrel and Celebrex were much more likely to be covered than Viagra and Zyban. In addition, coverage of Enbrel and Celebrex was limited through strategies such as prior authorization, to encourage medically appropriate use of these agents, whereas coverage of Viagra and Zyban was limited predominantly through generalized exclusion or through restrictions on quantity or duration of use. Value judgments, rather than cost, seem to play a central, though largely unspoken, role in these coverage decisions. (+info)
Venlafaxine-induced serotonin syndrome with relapse following amitriptyline.
(27/684)
A case of venlafaxine-induced serotonin syndrome is described with relapse following the introduction of amitriptyline, despite a 2-week period between the discontinuation of one drug and the commencement of the other. Electroencephalography may play an important part in diagnosis. With the increasing use of selective serotonin re-uptake inhibitors, greater awareness of the serotonin syndrome is necessary. Furthermore, the potential for drug interactions which may lead to the syndrome needs to be recognised. (+info)
Naltrexone vs. nefazodone for treatment of alcohol dependence. A placebo-controlled trial.
(28/684)
This study compared the effects of nefazodone, a serotonergic antidepressant, with the opioid antagonist naltrexone, and an inactive placebo in 183 alcohol-dependent subjects receiving weekly relapse prevention psychotherapy. Following a single-blind, placebo lead-in period, subjects were randomly assigned to receive study medication, which they took under double-blind conditions for 11 weeks. Naltrexone treatment was associated with significantly more adverse neuropsychiatric and gastrointestinal effects, poorer compliance, and a greater rate of treatment attrition. There were no reliable between-group differences in drinking behavior. These results indicate that nefazodone is not efficacious for treatment of alcohol dependence. Furthermore, the clinical utility of naltrexone seems to be limited by its adverse effects, a finding that has important implications for efforts to develop medications to treat alcohol dependence. (+info)
Phaeochromocytoma unearthed by fluoxetine.
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Non-specific noradrenaline reuptake inhibition by high dose selective serotonin reuptake inhibitors, along with catecholamine release from phaeochromocytoma, may lead to a hypertensive paroxysm. This may unmask a clinically silent phaeochromocytoma. Hypertensive paroxysm induced by paroxetine leading to detection of phaeochromocytoma has been reported. The first patient in whom fluoxetine unmasked a phaeochromocytoma is reported. (+info)
A comparison of nefazodone, the cognitive behavioral-analysis system of psychotherapy, and their combination for the treatment of chronic depression.
(30/684)
BACKGROUND: Patients with chronic forms of major depression are difficult to treat, and the relative efficacy of medications and psychotherapy is uncertain. METHODS: We randomly assigned 681 adults with a chronic nonpsychotic major depressive disorder to 12 weeks of outpatient treatment with nefazodone (maximal dose, 600 mg per day), the cognitive behavioral-analysis system of psychotherapy (16 to 20 sessions), or both. At base line, all patients had scores of at least 20 on the 24-item Hamilton Rating Scale for Depression (indicating clinically significant depression). Remission was defined as a score of 8 or less at weeks 10 and 12. For patients who did not have remission, a satisfactory response was defined as a reduction in the score by at least 50 percent from base line and a score of 15 or less. Raters were unaware of the patients' treatment assignments. RESULTS: Of the 681 patients, 662 attended at least one treatment session and were included in the analysis of response. The overall rate of response (both remission and satisfactory response) was 48 percent in both the nefazodone group and in the psychotherapy group, as compared with 73 percent in the combined-treatment group. (P<0.001 for both comparisons). Among the 519 subjects who completed the study, the rates of response were 55 percent in the nefazodone group and 52 percent in the psychotherapy group, as compared with 85 percent in the combined-treatment group (P<0.001 for both comparisons). The rates of withdrawal were similar in the three groups. Adverse events in the nefazodone group were consistent with the known side effects of the drug (e.g., headache, somnolence, dry mouth, nausea, and dizziness). CONCLUSIONS: Although about half of patients with chronic forms of major depression have a response to short-term treatment with either nefazodone or a cognitive behavioral-analysis system of psychotherapy, the combination of the two is significantly more efficacious than either treatment alone. (+info)
cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment.
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Regulation of gene transcription via the cAMP-mediated second messenger pathway has been implicated in the actions of antidepressant drugs, but studies to date have not demonstrated such an effect in vivo. To directly study the regulation of cAMP response element (CRE)-mediated gene transcription by antidepressants, transgenic mice with a CRE-LacZ reporter gene construct were administered one of three different classes of antidepressants: a norepinephrine selective reuptake inhibitor (desipramine), a serotonin selective reuptake inhibitor (fluoxetine), or a monoamine oxidase inhibitor (tranylcypromine). Chronic, but not acute, administration of these antidepressants significantly increased CRE-mediated gene transcription, as well as the phosphorylation of CRE binding protein (CREB), in several limbic brain regions thought to mediate the action of antidepressants, including the cerebral cortex, hippocampus, amygdala, and hypothalamus. These results demonstrate that chronic antidepressant treatment induces CRE-mediated gene expression in a neuroanatomically differentiated pattern and further elucidate the molecular mechanisms underlying the actions of these widely used therapeutic agents. (+info)
Antidepressants and the serotonin syndrome in general practice.
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BACKGROUND: As a consequence of the greater use of agents affecting the serotonergic system, a syndrome of serotonin hyperstimulation has been recognized more frequently. The serotonin syndrome is characterized by a constellation of symptoms that include mental status changes, agitation, myoclonus, hyperreflexia, sweating, shivering, tremor, diarrhoea, lack of coordination, and fever. Deaths have been reported. AIM: To identify cases of the serotonin syndrome among patients prescribed a new antidepressant in general practice, and to determine doctors' awareness of the syndrome. METHOD: Patients who were dispensed nefazodone in England between 1996 and 1997 were identified using dispensed prescription data. Prescribing doctors were sent questionnaires as part of a post-marketing surveillance study. Patients reported to have experienced two or more features of the serotonin syndrome were identified, and specific questionnaires were sent to their general practitioners. RESULTS: There was a 96.2% return rate of serotonin syndrome questionnaires. Nineteen cases met criteria for the syndrome (incidence = 0.4 cases per 1000 patient-months of treatment with nefazodone). Eight patients developed symptoms while taking nefazodone alone. Serotonergic symptoms were reported to a similar degree with five other antidepressants studied by the same method. In total, 85.4% of responding general practitioners were unaware of the serotonin syndrome. CONCLUSION: Improved awareness of the syndrome is needed within general practice. There is a need to distinguish the relatively minor serotonergic symptoms from those of a severe, life-threatening serotonin syndrome. (+info)