December 2007

High Doses of Venlafaxine
Higher doses of venlafaxine (Effexor and others) likely increase the chance of antidepressant response, but also increase the risk of side effects.

SSRIs and Bleeding Risk in Patients with Hepatitis C
The risk of selective serotonin reuptake inhibitors causing bleeding in patients with hepatitis C is modest.

Bupropion versus SSRIs for Anxiety in MDD
According to Papakostas and colleagues, bupropion (Wellbutrin and others) appears to work as well as selective serotonin reuptake inhibitors to treat anxiety in patients with major depressive disorder.

Torsades de Pointes with Haloperidol
Intravenous administration of haloperidol (Haldol and others), especially at high doses, can cause QT prolongation and torsades de pointes.

In Brief
Ziprasidone for borderline personality disorder: A negative trial; Adjunctive medications for weight loss in patients with schizophrenia or bipolar disorder

High-Dose Ziprasidone
Patients with treatment-resistant psychosis may benefit from higher-than-recommended doses of ziprasidone (Geodon).

Baby Steps
Our clinical knowledge in psychiatry has increased over the past year, but scientific understanding and intervention technology still leaves much to be desired.

Index, Volume 30, 2007

High Doses of Venlafaxine

December 2007

Venlafaxine (Effexor and others), which inhibits the reuptake of both serotonin and norepinephrine, appears to have a positive dose-effect relationship. In other words, higher doses produce greater probability of antidepressant efficacy, albeit at the cost of more side effects. The immediate-release form of venlafaxine carried a maximum recommended dose of 375 mg/day. However, when the extended-release formulation, which was better tolerated, became available, the manufacturer chose a recommended maximum of only 225 mg/day. Recently, Thase and colleagues studied standard versus higher doses of extended-release venlafaxine in depressed outpatients who either had not responded to or could not tolerate a trial of a selective serotonin reuptake inhibitor (SSRI).1

Two hundred thirty-two patients were randomized in this trial: 161 had failed a trial of at least 6 weeks with a minimum adequate dose of an SSRI, and 77 had discontinued an SSRI because of an adverse event. (Six patients did not respond to one SSRI and were intolerant of another.) Previous antidepressants were stopped, and subjects were randomly assigned to open-label treatment with either standard doses of venlafaxine ER, which began at 37.5 mg/day and could be increased up to 150 mg/day, or higher-dose therapy, up to 375 mg. After 8 weeks, nonresponders in the standard-dose group could receive doses up to 375 mg daily.

The higher-dose group showed a greater rate of treatment response at week 8 on the Clinical Global Impressions-Improvement (CGI-I) scale—68% versus 52% (P < .001). Not all comparisons between groups were statistically significant, however, including remission rates. Higher doses were associated with more side effects—particularly constipation, sweating, hypertension, agitation, and urinary frequency. Slower titration appeared to improve tolerability.

Another group of investigators performed a chart review of patients with major depression who were receiving venlafaxine treatment.2 In this retrospective survey, patients were divided between those taking standard doses, defined as 75 to 300 mg/day, versus those on high doses, defined as 375 to 600 mg daily.

The most frequently reported side effects were concentration difficulties (48%), increased fatigue (48%), sleepiness/sedation (37%), and failing memory (44.4%)—all statistically significantly greater in the high-dose group than in the low-dose group. Almost 30% of patients gained weight, with no statistical difference between the two groups. Patients on higher doses were less likely to report the absence of side effects and more likely to report side effects of greater severity. Nonetheless, high doses were not associated with increased rates of medication discontinuation. Nausea as a side effect usually decreased after the first week of treatment. Elevations in blood pressure occurred but were not statistically different between the two groups. The authors suggest, however, that it would be prudent to monitor blood pressure, particularly when venlafaxine doses are above 300 mg/day.

So, what may we conclude? Most likely, higher doses of venlafaxine will increase the chance of antidepressant response. Slower titration is apt to be better tolerated, but higher doses increase the probability of more side effects and side effects of greater severity. Blood pressure should be monitored in patients taking venlafaxine—especially in those at risk for hypertension or taking doses of 300 mg/day or higher.

1Thase ME, Shelton RC, Khan A: Treatment with venlafaxine extended release after SSRI nonresponse or intolerance: A randomized comparison of standard- and higher-dosing strategies. J Clin Psychopharmacol 2006;26:250–258.

2Harrison CL, Ferrier N, Young AH: Tolerability of high-dose venlafaxine in depressed patients. J Psychopharmacol 2004;18:200–204.