venlafaxine (Effexor)
Venlafaxine and generalised anxiety disorder: new preparation. Minimise recourse to drugs.

[No authors listed]

(1) Generalised anxiety disorder is defined as excessive anxiety for at least 6 months. (2) Management is based primarily on psychological measures, with the aim of limiting recourse to drugs. The reference drugs are benzodiazepines. The treatment period should be as short as possible, to avoid adverse effects such as sedation and dependence. (3) Venlafaxine is a non tricyclic, non MAOI antidepressant. A sustained-release formulation has just been granted marketing authorisation in France for generalised anxiety disorder. (4) The clinical assessment file on venlafaxine in this indication includes results from two 8-week trials and a placebo-controlled trial with 6 months follow-up. The trials showed a significant improvement with venlafaxine on standard anxiety scales, but the clinical impact (at best moderate) has been poorly assessed. We found no comparison between venlafaxine and benzodiazepines. (5) In one trial venlafaxine was no more effective than buspirone. (6) The most frequent adverse effects of venlafaxine are gastrointestinal disorders, insomnia and dizziness. Venlafaxine carries a risk of drug interactions and withdrawal symptoms. (7) In practice, venlafaxine provides nothing new in the treatment of generalised anxiety disorder. The reference drug treatment remains a benzodiazepine.

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venlafaxine (Effexor)
Effects of chronically administered venlafaxine on 5-HT receptor activity in rat hippocampus and hypothalamus.

Gur E, Dremencov E, Van De Kar LD, Lerer B, Newman ME.

Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, PO Box 12000, 91120, Jerusalem, Israel.

The effects of chronic administration of the mixed serotonin [5-hydroxytryptamine (5-HT)]/norepinephrine re-uptake inhibitor venlafaxine (5 mg/kg daily by osmotic minipump for 28 days) on the sensitivity of somatodendritic 5-HT(1A) autoreceptors on serotonergic neurons innervating the hypothalamus, and on 5-HT(1B) autoreceptors in both hypothalamus and hippocampus, were determined using in vivo microdialysis in freely moving rats. Venlafaxine induced a reduction in sensitivity of 5-HT(1B) autoreceptors in hypothalamus, but did not affect the sensitivity of 5-HT(1A) autoreceptors, or of 5-HT(1B) autoreceptors in hippocampus. The corticosterone and oxytocin responses to the 5-HT(1A) receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 0.05 or 0.2 mg/kg), a measure of postsynaptic 5-HT(1A) receptor activity in the hypothalamus, were reduced in animals administered 5 or 10 mg/kg venlafaxine daily by intraperitoneal injection for 21 days. This desensitization of post-synaptic 5- HT(1A) receptors in the hypothalamus may be a consequence of increased 5-HT levels induced by desensitization of the presynaptic 5-HT(1B) receptors. These results taken together with those of previous studies suggest that the hypothalamus might be an important site of drug action, and that venlafaxine has an overall mechanism similar to that of selective serotonin re-uptake inhibitors.

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venlafaxine (Effexor)
Distribution of venlafaxine and its O-desmethyl metabolite in human milk and their effects in breastfed infants.

Ilett KF, Kristensen JH, Hackett LP, Paech M, Kohan R, Rampono J.

Department of Pharmacology, University of Western Australia, Nedlands 6009 Western Australia. kilett receptor.pharm.uwa.edu.au

AIMS: To characterize milk/plasma (M/P) ratio and infant dose, for venlafaxine (V) and its O-desmethyl metabolite (ODV), in breastfeeding women taking venlafaxine for the treatment of depression, and to determine the plasma concentration and effects of these drugs in their infants. METHODS: Six women (mean age 34.5 years, mean weight 84.3 kg) taking venlafaxine (median dose 244 mg day(-1), range 225-300 mg day(-1)) and their seven infants (mean age 7.0 months, mean weight 7.3 kg) were studied. V and ODV in plasma and milk were measured by high-performance liquid chromatography over a 12 h dose interval at steady-state. Infant exposure was estimated as the product of estimated milk production rate (0.15 l kg(-1)day(-1)) and average drug concentration in milk, normalized to body weight and expressed as a percentage of the weight-adjusted maternal dose. RESULTS: Mean M/PAUC values of 2.5 (range 2.0-3.2) and 2.7 (range 2.3-3.2) were calculated for V and ODV, respectively. The mean maximum concentrations (95% CI) of V and ODV in milk were 1161 (95% CI, 588, 1734) microg l(-1) and 796 (362, 1230) microg l(-1). Mean infant exposure was 3.2% (1.7, 4.7%) for V and 3.2% (1.9, 4.9%) for ODV (as V equivalents). V was detected in the plasma of one out of seven infants studied (5 microg l(-1)), while ODV was detected in four of the infants, at concentrations ranging from 3 to 38 microg l(-1). All of the infants in the study were healthy, as reported by their mothers and/or by clinical examination on the study day. CONCLUSIONS: The concentrations of V and ODV in breast milk were 2.5 and 2.7 times those in maternal plasma. The mean total drug exposure (as venlafaxine equivalents) of the breastfed infants was 6.4% (5.5-7.3%), which is below the 10% notional level of concern. There were no adverse effects in any of the infants. The data support the use of V in breastfeeding. Nevertheless, since low concentrations of ODV were detected in the plasma of four out of the seven infants studied, we recommend breastfed infants should be monitored closely. Each decision to breast feed should be made as an individual risk:benefit analysis.

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venlafaxine (Effexor)
The effects of a selective noradrenaline reuptake inhibitor on the urethra: an in vitro and in vivo study.

Bae JH, Moon DG, Lee JG.

Department of Urology, Korea University College of Medicine, Seoul.

OBJECTIVE: To identify the effects of a selective noradrenaline reuptake inhibitor (venlafaxine) on urethral perfusion pressure (UPP) in rabbits and rats, and thus assess its therapeutic potential for treating stress urinary incontinence. MATERIALS AND METHODS: Strips of bladder and proximal urethra were prepared from female New Zealand White rabbits. Each strip was electrically stimulated and the contractile responses of controls strips compared with those after pretreatment with venlafaxine (100 micromol/L). In separate experiments using 80 adult female Sprague-Dawley rats (250-300 g), changes in intravesical pressure and UPP after the intra-arterial and intra-urethral administration of phenylephrine, phentolamine, fluoxetine and venlafaxine were monitored using double-lumen catheters. RESULTS: Pretreatment with venlafaxine significantly decreased the contraction of bladder strips (P=0.01) and significantly increased the contraction of urethral strips (P=0.008). In vivo, phenylephrine administered by both routes significantly increased UPP (P=0.02); phentolamine (arterial) significantly decreased UPP (P=0.001); fluoxetine (arterial) had no effect on UPP, and venlafaxine (both routes) significantly increased UPP (both P<0.001). The intravesical pressure was not changed significantly in any animal. CONCLUSIONS: Venlafaxine effectively increased UPP both in vitro and in vivo; these results imply that venlafaxine may be useful for treating stress urinary incontinence, by increasing the UPP.

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venlafaxine (Effexor)
Hyponatraemia in elderly psychiatric patients treated with Selective Serotonin Reuptake Inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit.

Kirby D, Harrigan S, Ames D.

Alfred Hospital, Victoria, Australia.

OBJECTIVE: To determine the prevalence of hyponatraemia associated with selective serotonin reuptake inhibitor (SSRI) and venlafaxine use in elderly patients compared to that in elderly patients not prescribed these drugs, while controlling for age, sex, depression status and illnesses or prescribed medications also associated with hyponatraemia. Design and setting Retrospective controlled analysis in a 36-bed inpatient unit for elderly psychiatric patients in Melbourne. PATIENTS: Inpatients (199) with a mean age of 74.2 years of whom 74 were prescribed an SSRI or venlafaxine. RESULTS: Patients on SSRIs or venlafaxine were 5.6 times as likely as patients not so treated to have hyponatraemia. Thirty-nine percent of patients on an SSRI or venlafaxine had hyponatraemia compared with 10% of controls. Ten of the 14 patients on venlafaxine were hyponatraemic. Controlling for thiazide status did not reduce the odds of these patients having hyponatraemia and taking an SSRI or venlafaxine was still strongly associated with hyponatraemia after also controlling for age, sex, and depression status, consumption of other drugs potentially causative of hyponatraemia and medical illness severity (Odds Ratio (OR) 3.5, p = 0.008). CONCLUSIONS: SSRI and venlafaxine use is strongly associated with the presence of hyponatraemia in a population of elderly psychiatric inpatients and the association is not due to confounding by age, sex, depression status, medical illness severity or consumption of other drugs. Elderly patients on SSRIs or venlfaxine should have sodium levels checked before and after commencement of antidepressant treatment. Copyright 2002 John Wiley & Sons, Ltd.

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