venlafaxine (Effexor)
Long-term treatment strategies in affective disorders.

Keller MB.

Department of Psychiatry and Human Behavior, Brown University, Providence, RI, USA. sheri_harrison brown.edu

Unipolar major depression is a disorder with a high incidence of relapse and recurrence. Some patients with major depression fail to recover from an episode and develop chronic depression. Both episodic and chronic depression are associated with considerable morbidity and mortality. An improved long-term outcome for patients may be achieved by the use of longer courses of treatment in the management of depression, which may ultimately enable recovery from depressive symptoms. The data reviewed in this article indicate that both selective serotonin reuptake inhibitors (SSRIs) and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine are effective in reducing the incidence of relapse during 6 months of continuation therapy for major depression. In addition, longer-term treatment using imipramine or venlafaxine has shown maintenance therapy to be effective in reducing the risk of recurrence of major depression. Pharmacotherapy using sertraline or imipramine for extended periods of time has also been shown to be effective in attaining remission from, and preventing, recurrence of symptoms in patients with chronic depression. The data reviewed suggest that long-term therapy is beneficial in achieving a sustained return to complete functioning for patients with depression. The significantly higher remission rates attained with venlafaxine treatment as compared with some SSRIs warrant further studies of SNRIs for the long-term treatment of depression.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12490822&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Long-term treatment strategies in anxiety disorders.

Allgulander C, Hirschfeld RM, Nutt DJ.

Karolinska Institute, Neurotec Department, Huddinge University Hospital, Stockholm, Sweden. Allgulander neurotec.ki.se

Anxiety disorders are prevalent and associated with increased morbidity and mortality. Some chronic anxiety disorders, including generalized anxiety disorder (GAD), may be characterized by an underlying high level of anxiety on which exacerbations of symptoms are superimposed. Effective treatment of anxiety disorders should therefore strive to attain both an acute reduction in the symptoms of anxiety (a response) and sustained resolution of the symptoms of any underlying chronic anxiety (remission). This strategy may necessitate long-term treatment of these disorders by pharmacotherapy and/or psychotherapy. Studies using the serotonin and norepinephrine reuptake inhibitor (SNRI), venlafaxine extended release (XR), suggest that these aims may be achieved using this newer class of drugs. Studies with venlafaxine XR in patients with GAD have demonstrated robust anxiolytic efficacy over placebo, particularly regarding worry, cognitive dysfunction, and muscular tension, which are specific to GAD. Administration of venlafaxine XR over both short- (8-week) and long-term (6-month) periods resulted in a significantly greater number of patients achieving response and remission than obtained with placebo. Long-term treatment with venlafaxine XR in patients with GAD showed greater efficacy than that observed in short-term studies. This was achieved without any loss of short-term efficacy and patients' social functioning was also restored. While available data indicate that venlafaxine XR is an appropriate choice of agent in the long-term treatment of GAD, more studies are needed to determine how to further increase remission rates and to maintain remission beyond 6 months.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12490824&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Venlafaxine oxidation in vitro is catalysed by CYP2D6.

Otton SV, Ball SE, Cheung SW, Inaba T, Rudolph RL, Sellers EM.

Clinical Research and Treatment Institute, Addiction Research Foundation, Toronto, Ontario, Canada.

1. Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes. 2. Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent Ki values determined using CYP2D6-dependent dextromethorphan O-demethylation were: 33, 52 and 22 microM for rac-venlafaxine, R(+)-venlafaxine and S(-)-venlafaxine, respectively, vs 0.065 to 1.8 microM for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline. 3. Microsomes from human livers (n = 3) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed the O-demethylation of venlafaxine, which is the major metabolic pathway in vivo. Intrinsic metabolic clearance values (Vmax/Km) indicated that S(-)-venlafaxine was cleared preferentially via this pathway. 4. In microsomes from CYP2D6-deficient livers (n = 2), Vmax/Km of O-demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate of N-demethylation. 5. Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxine N-demethylation. 6. These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as O-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8838442&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Dose-related effects of chronic antidepressants on neuroprotective proteins BDNF, Bcl-2 and Cu/Zn-SOD in rat hippocampus.

Xu H, Steven Richardson J, Li XM.

Neuropsychiatric Research Institute, Department of Psychiatry, College of Medicine, University of Saskatchewan, Saskatooon, Canada.

It has been proposed that antidepressants have neuroprotective effects on hippocampal neurons. To further test this hypothesis, brain-derived neurotrophic factor (BDNF), B cell lymphoma protein-2 (Bcl-2), and copper-zinc superoxide dismutase (Cu/Zn-SOD) were examined immunohistochemically in hippocampal neurons of Sprague-Dawley rats following daily treatment with 5 or 10 mg/kg of amitriptyline or venlafaxine for 21 days. At 5 mg/kg, both amitriptyline and venlafaxine increased the intensity of BDNF immunostaining in hippocampal pyramidal neurons, and the intensity of Bcl-2 immunostaining in hippocampal mossy fibers, but did not alter the Cu/Zn-SOD immunoreactivity. The high dose of venlafaxine, however, decreased the intensity of BDNF immunostaining in all subareas of the hippocampus and increased the intensity of Cu/Zn-SOD immunostaining in the dentate granular cell layer. The high dose of amitriptyline increased the intensity of Cu/Zn-SOD immunostaining, but did not affect the immunoreactivity of Bcl-2 or BDNF. These findings suggest that the chronic administration of amitriptyline or venlafaxine at 5 mg/kg, but not 10 mg/kg, may be neuroprotective to hippocampal neurons. These dose-related effects of antidepressant drugs on hippocampal neurons may have relevance to disparate findings in the field.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12496940&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR

venlafaxine (Effexor)
Comparison of analytical methods in the determination of two venlafaxine fatalities.

Long C, Crifasi J, Maginn D, Graham M, Teas S.

Saint Louis University School of Medicine, Department of Pathology, Berkeley, Missouri 63134, USA.

Two venlafaxine (Effexor)-related deaths are reported with comparison of results from the analysis of specimens using capillary gas chromatography with a nitrogen-phosphorous detector (GC-NPD) and high-performance liquid chromatography (HPLC) using a UV-vis detector. Blood concentrations in Case 1 were 7.27 micrograms/mL venlafaxine and 5.03 micrograms/mL O-desmethylvenlafaxine, and Case 2 had 89.67 micrograms/mL venlafaxine with 3.44 micrograms/mL of the desmethyl metabolite. A comparison of analytical methods and specimen concentration is presented.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9083836&dopt=Abstract venlafaxine Effexor refs
Effexor, Effexor XR