venlafaxine (Effexor)
Melperone is an inhibitor of the CYP2D6 catalyzed O-demethylation of venlafaxine.

Grozinger M, Dragicevic A, Hiemke C, Shams M, Muller MJ, Hartter S.

Department of Psychiatry, University of Mainz, Mainz, Germany.

INTRODUCTION: Melperone, a butyrophenone neuroleptic, is frequently used for its sleep-inducing properties. Despite its common use for more than 30 years, it is not yet characterized regarding its effects on cytochrome P450 s (CYPs). In an open pilot study, effects of melperone on the steady-state blood levels of venlafaxine, a recently introduced serotonin- and noradrenaline reuptake inhibiting antidepressant, were assessed. METHODS: The dose-corrected serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed retrospectively in a therapeutic drug-monitoring (TDM) database comprising 94 patients. In addition, three patients received venlafaxine and melperone concomitantly and the serum concentrations of venlafaxine and O-desmethylvenlafaxine were analyzed before, during, and after melperone co-medication. The effect of melperone on CYP2D6 was further assessed in seven patients by means of the dextromethorphan O-demethylation, which serves as a CYP2D6 probe reaction. RESULTS: Patients treated concomitantly with venlafaxine and melperone had significantly higher (mean +/- SD) venlafaxine (3.27 +/- 2.9 vs. 0.97 +/- 0.99 ng/ml per mg/d; p < 0.05) and lower O-desmethylvenlafaxine serum concentrations (0.69 +/- 0.35 vs. 1.51 +/- 0.9 ng/ml per mg/d; p < 0.01) compared to patients without melperone comedication. In the three patients, venlafaxine serum concentrations increased, on average by 52 % during melperone co-medication, whereas O-desmethylvenlafaxine was decreased, on average by 29 %. Administration of melperone over three days elevated the ratio of dextromethorphan to dextrorphan from 0.044 +/- 0.04 to 0.09 +/- 0.083 (p < 0.05). DISCUSSION: This study pointed to an inhibitory effect of melperone on the O-demethylation of venlafaxine. Because the O-demethylation of venlafaxine is almost exclusively catalyzed by CYP2D6 it is concluded that melperone is an inhibitor of CYP2D6. The hypothesis was further corroborated by the inhibitory effect of melperone on the dextromethorphan O-demethylation.

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Effexor, Effexor XR

venlafaxine (Effexor)
Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants.

Whyte IM, Dawson AH, Buckley NA.

School of Population Health Sciences, Faculty of Medicine and Health Sciences, University of Newcastle, and Department of Clinical Toxicology & Pharmacology, Newcastle Mater Misericordiae Hospital, NSW, Australia. mdimw cc.newcastle.edu.au

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) and venlafaxine have been regarded as less toxic in overdose than tricyclic antidepressants (TCAs). Within the TCAs, dothiepin has greater toxicity. Venlafaxine may be more toxic than SSRIs. AIM: To assess the toxicity in overdose of venlafaxine and SSRIs compared to TCAs, and of dothiepin compared to other TCAs. DESIGN: Cohort study of prospectively collected data from the Hunter area, NSW, Australia. METHODS: First admissions with antidepressant deliberate self-poisoning (DSP) (November 1994 to April 2000) were identified; the presence of seizures, life-threatening arrhythmias, coma, serotonin toxicity or ICU admission, and QRS duration were noted. RESULTS: There were 538 admissions, with no deaths. The odds ratio (OR) for seizures with dothiepin vs. other TCAs was 3.4 (95%CI 1.2-9.9). Seizures occurred in 7/51 (14%) venlafaxine overdoses; all patients with seizures consumed > or =900 mg. The OR for seizures vs. TCAs was 4.4 (95%CI 1.4-13.8). Coma was less likely with venlafaxine and SSRIs. SSRIs, but not venlafaxine, were less likely to prolong the QRS to > or =100 ms. ICU admission was less likely for SSRIs. Serotonin toxicity was much more common with venlafaxine and SSRIs. DISCUSSION: Venlafaxine and dothiepin are pro-convulsant in overdose. Venlafaxine is more likely to cause serotonin toxicity, but less likely to cause coma than TCAs. SSRIs are less likely to cause coma, require ICU admission, or prolong the QRS, but are more likely to cause serotonin toxicity. Antidepressants other than TCAs or venlafaxine should be considered in patients at risk of seizure or suicide.

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Effexor, Effexor XR

venlafaxine (Effexor)
Stability indicating LC method for the estimation of venlafaxine in pharmaceutical formulations.

Makhija SN, Vavia PR.

Pharmaceutical Division, University Department of Chemical Technology (Autonomous), University of Mumbai, Nathalal Parikh Marg, Matunga, Mumbai, India.

A rapid, selective and stability indicating high performance liquid chromatographic method was developed and validated for the estimation of venlafaxine in pharmaceutical dosage forms. The analysis was done on a Spherisorb C8 (4.6 x 250 mm, 5 microm) column. The mobile phase consisted of acetonitrile:sodium dihydrogen orthophosphate [0.04 M], pH 6.8 (75:25) at a flow rate of 1.5 ml/min. Detection was carried out at a wavelength of 224 nm. The developed method was found to give good separation between the pure drug and the degraded product. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 1-10 microg/ml with r=0.9999. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable and minimum quantifiable amounts were found to be 150 and 600 ng/ml, respectively. The drug was stable under basic and oxidative conditions. However, the sample treated with acid showed an additional peak at a retention time of 4.32 min other than the main peak at a retention time of 5.32 min. Statistical analysis proves that the method is reproducible and selective for the estimation of venlafaxine. As the method could effectively separate the drug from the degradation product, it can be employed as a stability indicating one.

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Effexor, Effexor XR

venlafaxine (Effexor)
The effects of venlafaxine on the subjective, reinforcing, and cardiovascular effects of cocaine in opioid-dependent and non-opioid-dependent humans.

Foltin RW, Ward AS, Collins ED, Haney M, Hart CL, Fischman MW.

Division on Substance Abuse, New York State Psychiatric Institute and College of Physicians and Surgeons of Columbia University, New York 10032, USA. rwf2 columbia.edu

The effects of maintenance on venlafaxine, which blocks both norepinephrine and serotonin reuptake, on the response to smoked cocaine (0, 12, 25, or 50 mg) in 7 opioid-free and 7 methadone-maintained cocaine abusers was examined during a 42-day study. Participants received venlafaxine (225 mg daily) and placebo as part of a double-blind crossover design. Cocaine significantly increased heart rate, blood pressure, cocaine choice, cocaine ratings, and ratings of positive subjective effects (e.g., "I feel high") in both groups. Venlafaxine significantly decreased the subjective effects of cocaine by 10-20% without affecting cocaine choice or cardiovascular response in both groups. Although the reduction in cocaine's effects was small, further studies using a longer venlafaxine maintenance period or a larger venlafaxine dose are warranted.

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Effexor, Effexor XR

venlafaxine (Effexor)
Global Benefit-risk Evaluation of Antidepressant Action: Comparison of Pooled Data for Venlafaxine, SSRIs, and Placebo.

Entsuah R, Gao B.

Department of Global Clinical Biostatistics, Wyeth Research, Collegeville, Pennsylvania, USA.

Do antidepressants have an equivalent risk-benefit ratio? Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is an effective antidepressant for treating major depression. The results of some clinical studies have suggested that venlafaxine may have more potent efficacy in sustaining remission in patients with major depression. Comparative clinical studies, however, lack suitable power to discern treatment differences in safety and also lack a quantitative basis for comparing risk and benefit. A global benefit-risk analysis of pooled data from eight randomized, double-blind, clinical trials of the safety and efficacy of venlafaxine and selective serotonin reuptake inhibitors (SSRIs) was performed. By using the ratio measure of risk-benefit, patients treated with venlafaxine (n=851) for 6-8 weeks experienced a relative gain of 1.57 compared with SSRI-treated patients (n=743) and a relative gain of 2.27 compared with placebo-treated patients (n=439). Subgroup analyses showed a relative gain of 1.35 for venlafaxine-treated patients (n=538) compared with fluoxetine-treated patients (n=549) and a relative gain of 2.53 compared with placebo-treated patients (n=357). A dose-response relationship was apparent between low (<75 mg/day), medium (75-150 mg/day), and high (>150 mg/day) dosages of venlafaxine; r values were 0.758, 0.822, and 1.181, respectively (P=.023, high dosage versus placebo; P=.030, medium dosage versus placebo). Important differences in risk and benefit exist between venlafaxine and SSRIs as a group compared with fluoxetine alone. A significant gain in benefit-risk in the treatment of major depression was observed with an increase in venlafaxine dosage from 75->150 mg/day.

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Effexor, Effexor XR