Efficacy and Safety of Extended-Release Venlafaxine in the Treatment of Generalized Anxiety Disorder in Children and Adolescents: Two Placebo-Controlled Trials
Rynn MA, Riddle MA, Yeung PP, Kunz NR;
Commented by , 28 Feb 2007
Aim of the study
To determine the efficacy and safety of extended-release venlafaxine for the treatment of generalised anxiety disorder (GAD) in children and adolescents.
Method
Two identical, independent studies were conducted at 29 and 37 sites, respectively, in the USA between April 2000 and September 2001 using a double blind, randomised, placebo controlled, flexible dose design.
Children (6–11 years) and adolescents (12-17 years) who met the DSM-IV criteria for generalised anxiety disorder as assessed by the Columbia Schedule for Affective Disorders and Schizophrenia in School-Age Children (Columbia K-SADS) were eligible to participate. Exclusion criteria included no concurrent psychiatric disorder or other medication use.
Five participants (3 placebo, 2 venlafaxine) continued with psychotherapy during the trial. The study protocol began with a single blind placebo lead-in for 4-10 days followed by 8 weeks venlafaxine or placebo treatment, and concluded with up to 2 weeks taper.
The primary efficacy measure was the change from baseline to end point in a 9-item composite score from the generalised anxiety disorder section of the Columbia K-SADS. Analysis was conducted on an intention to treat basis with the last observation carried forward.
Results
A combined total of 323 participantswere entered into the two studies. Extended-release venlafaxine produced greater improvements on the primary efficacy measure compared with placebo in study 1 (p<0.001) and this difference tended towards statistical significancein study 2 (p= 0.060).
A pooled analysis of both studies to allow stratification for age group found greater improvements in the extended release venlafaxine group compared to placebo in both children (p=0.045) and adolescents (p=0.004) on the primary outcome measure.
Treatment emergent adverse events during treatment included somnolence, pain, anorexia and asthenia. Dizziness appeared more commonly in the venlafaxine group compared to placebo following taper. One suicide attempt and one suicidal ideation (2/323) were reported, one each from the extended release venlafaxine and placebo groups.
The venlafaxine group also showed statistically significant increases in heart rate, systolic and diastolic blood pressure, and serum cholesterol and decreased weight. Participants in the venlafaxine group showed a smaller increase in height compared with the placebo group.
Dr Hood's and Prof Nutt's comments
This study provides some evidence that extended-release venlafaxine improves GAD in children and adolescents, although it failed to meet the FDA guidelines for efficacy (statistically significant improvement on the primary outcome variable in two independent trials).
As the authors suggested, the high placebo response rate in study two may go someway to explaining the failure to achieve a statistically significant separation between the two groups in this study. It would have been useful had the authors included more information about how placebo lead-in eligibility was determined, given the trend (p= 0.06) for statistical significance seen in the eligible study 2 cohort.
These studies suggest that extended-release venlafaxine may be a promising GAD treatment in this age group, but future research would need to consider long term outcomes, particularly in light of changes in medical parameters (BP, cholesterol, height and weight).
There was little evidence of an increase in suicide risk with venlafaxine in these studies. The selection criteria restricted participants presenting with serious suicidal ideation, major depression and recent suicide attempts from inclusion, so this cohort is not identical to routine clinical samples. Nevertheless, this result is still notable in the context of a high level of scrutiny of antidepressants in general (ref. 1) and in children and adolescents (ref. 2), as well as recent specific concerns relating to venlafaxine (ref. 3, ref. 4).
Despite the media fervour (ref. 1) over modern antidepressant risks, many clinicians continue to make considered decision to prescribe these agents – and this includes groups such as children and adolescents where the RCT evidence base is relatively sparse.
It may be especially important to actively treat anxiety disorders such as GAD in youth, as there is a growing body of evidence that anxiety in this group presages the onset of adult depressive disorder (ref. 5). The net effect of this media debate has been significant erosion in the confidence of the public in these effective medications, and it is little wonder that many are turning to even less-validated alternative therapies.
We should stop pretending that these medicines are panaceas free of side effects. Rather, clinicians should come clean and admit that these are powerful medicines with potential problems that can usually be effectively managed via candid doctor-patient communication. By building upon the therapeutic relationship it is more likely that we can continue to offer patients of all ages access to effective medication therapies in an increasingly hostile prescribing climate.
References
1. Nutt DJ. Death and dependence: current controversies over the selective serotonin reuptake inhibitors. Journal of Psychopharmacology 2003; 17 (4); 355-364
2. Hammad TA, Laughren T, Racoosin J. Suicidality in pediatric patients treated with antidepressant drugs. Archives of General Psychiatry 2006; 63 (3); 332-339
3. Rubino A, Roskell N, Tennis P, Mines D, Weich S, Andrews E. Risk of suicide during treatment with venlafaxine, citalopram, fluoxetine, and dothiepin: retrospective cohort study.BMJ 2007; 334 (7587); 242. [Epub 2006 Dec 12]. (Free full text article)
4. Cipriani A, Geddes JR, Barbui C. Venlafaxine for major depression. BMJ 2007; 334 (7587):215-216
5. Bittner A, Goodwin RD, Wittchen HU, Beesdo K, Hofler M, Lieb R. What characteristics of primary anxiety disorders predict subsequent major depressive disorder? Journal of Clinical Psychiatry 2004; 65 (5); 618-26, quiz 730