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J Neural Transm. 1999;106(2):197-211.
Pharmacological effects of venlafaxine, a new antidepressant, given repeatedly, on the alpha 1-adrenergic, dopamine and serotonin systems.

Maj J, Rogoz Z.

Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.

Venlafaxine (VEN) is a representative of a new class of antidepressants (SNRIs) which inhibit selectively the uptake of serotonin and noradrenaline, but--in contrast to tricyclics--show no affinity for neurotransmitter receptors. The present study was aimed at determining whether repeated VEN (given twice daily for 14 days) induced adaptive changes in the alpha 1-adrenergic, dopamine and serotonin systems, similar to those reported by us earlier for tricyclic antidepressants. The results indicate that VEN potentiates the clonidine-induced aggressiveness and the methoxamine-induced exploratory hyperactivity, both these effects being mediated by alpha 1-adrenoceptors. VEN increased the hyperlocomotion induced by D-amphetamine and (+/-)-7-OH-DPAT. Neither the apomorphine and quinpirole hyperlocomotion, nor the apomorphine and D-amphetamine stereotypies were changed. VEN did not affect the behavioural syndrome induced by 8-OH-DPAT (a 5-HT1A effect), and decreased both the head twitch reaction induced by L-5-HTP or (+/-)DOI and the hyperthermia induced by trifluoromethylphenylpiperazine, all those effects being mediated by 5-HT2 receptors. Repeated VEN did not change the hypothermia evoked by oxotremorine (a central cholinergic agonist). The above results indicate that repeated VEN increases--as do tricyclics--the responsiveness of alpha 1-adrenergic and dopaminergic (mainly D3) systems and decreases the responsiveness of the 5-HT2 system. It may be concluded that the lack of affinity for neurotransmitter receptors is of no importance to the development of adaptive changes in the studied systems, observed after repeated treatment.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10226939&dopt=Abstract

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Br J Clin Pharmacol. 1999 Apr;47(4):450-3.
Effect of the CYP2D6*10 genotype on venlafaxine pharmacokinetics in healthy adult volunteers.

Fukuda T, Yamamoto I, Nishida Y, Zhou Q, Ohno M, Takada K, Azuma J.

Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan.

AIMS: Interindividual differences in the pharmacokinetics of venlafaxine, a new antidepressant, were shown during early clinical trials in Japan. Venlafaxine is metabolized mainly by CYP2D6 to an active metabolite, O-desmethylvenlafaxine (ODV). Therefore, the influence of the CYP2D6 genotypes on venlafaxine pharmacokinetics was examined in a Japanese population. METHODS: Twelve adult Japanese men in good health participated in this study. Genomic DNA was isolated from peripheral lymphocytes, and the CYP2D6 genotypes were determined by codon 188C/T, 1934G/A, 2938G/A and 4268G/C mutations using endonuclease tests based on PCR and by Xba I-RFLP analysis. Subjects were categorized into the following 3 groups (n=4 in each group); Group1: CYP2D6*10/*10, *5/*10, Group2: CYP2D6*1/*10, *2/*10 and Group3: CYP2D6*1/*1, CYP2D6*1/*2. Venlafaxine (25 mg, n=6; 37.5 mg, n=6) was administered orally at 09.00 h following an overnight fast. Plasma concentrations of venlafaxine and ODV were monitored by h.p.l.c. for 48 h. RESULTS: The Cmax and AUC of venlafaxine were 184% and 484% higher in the group 1 subjects than in the group 3 subjects, and 101% and 203% higher in the group 1 than in the group 2, respectively. CONCLUSIONS: These results suggest that CYP2D6*10 influences the pharmacokinetics of venlafaxine in a Japanese population.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10233212&dopt=Abstract

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J Clin Psychiatry. 1999;60 Suppl 6:15-9.
Redefining antidepressant efficacy toward long-term recovery.

Thase ME.

Department of Psychiatry, Western Psychiatric Institute, University of Pittsburgh, PA 15213, USA.

Most studies of antidepressant therapy assess short-term or acute phase efficacy and tolerability. However, 30% to 50% of patients with major depression will experience a relapse during the 4 to 6 months following treatment of a depressive episode. Patients who do not remit fully during the acute phase of therapy are at particularly high risk for relapse. In addition, 75% to 80% of patients will experience recurrent depression during their lifetime. Thus, full remission and long-term recovery, rather than short-term response, are the desired outcomes from antidepressant treatment. There is a need for prospective, long-term studies to investigate the response and recovery to antidepressant therapy. Research conducted by our group at the University of Pittsburgh has demonstrated that the rate of recurrence can be significantly reduced across 3 to 5 years of continuous treatment with imipramine. Although relatively little research on longer term, preventative pharmacotherapy has been conducted, studies with newer agents including selective serotonin reuptake inhibitors (SSRIs), nefazodone, and mirtazapine also indicate a lower relapse rate with active drug compared with placebo. The long-term efficacy of venlafaxine has been demonstrated in both an extension study and a recent prospective, double-blind discontinuation study. There is increasing evidence that antidepressants, including the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine, are well tolerated and effective options for longer term therapy.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10235120&dopt=Abstract

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