Venlafaxine in children and adolescents with attention deficit hyperactivity disorder
Dr Nahit Motavalli Mukaddes, Istanbul Tip Fakultesi PTT’si PK:53 34272, Capa, Istanbul, Turkey. Email: firstname.lastname@example.org
Abstract The primary purpose of this study was to describe tolerability and efficacy of venlafaxine in the treatment of children and adolescents with attention deficit hyperactivity disorder (ADHD). A 6-week open trial of venlafaxine was conducted in 13 children and adolescents (mean age 9.9 ± 2.5 years) with ADHD, and without comorbid depression. Venlafaxine was initiated at a dose of 18.75 mg/day and flexibly titrated to 56.25 mg/day. The Conners parent scale and Clinical Global Improvement (CGI) severity item were performed at baseline and at the end of the 6-week trial. All subjects completed the trial. Mean final dose of venlafaxine was 40.3 ± 7.0. Venlafaxine was significantly effective in reducing the total score of the Conners parent scale from baseline to endpoint (P < 0.002, Z =−3.113) and the CGI severity item (P < 0.05). Transient side-effects such as somnolence (n = 2), stomachache (n = 2), and headache (n = 1) disappeared after second week of treatment. Also three subjects complained of sedation after raising the dose to 56.5 mg/day, therefore the dose was reduced to the previous level. These preliminary data suggest that venlafaxine may be an effective medication in the treatment of some children and adolescents with ADHD. Future double-blind controlled trials should be undertaken.
Attention deficit/hyperactivity disorder (ADHD) is a psychiatric disorder characterized by hyperactivity, impulsivity and inattention.1 Pharmacotherapy provides one of the major treatment modalities available for ADHD. Stimulant medications are the most widely accepted treatment of ADHD in spite of controversy over their use. Stimulants have consistently been shown to potential noradrenergic brain transmission, a property also characteristic of venlafaxine. Tricyclic antidepressants which block both serotonin and norepinephrine have been recognized to ameliorate ADHD symptoms also.2 Because of these findings, venlafaxine which is dual serotonin, norepinephrine reuptake inhibitor has been of interest for the treatment of ADHD. However, the majority of studies on efficacy of venlafaxine on ADHD were conducted with adults.3–6 There is only one open-label study reporting efficacy of venlafaxine in children and adolescents.7 The present report is the second study of its kind which is aimed at investigating the efficacy and tolerability of venlafaxine in children and adolescents with ADHD.
Subjects were 13 children and adolescents (nine males, four females) aged 6–15 (mean age 9.9 ± 2.5 years), who presented to the ADHD treatment unit of the Child Psychiatry Department of Istanbul Medical Faculty, with symptoms of ADHD. A clinical interview was performed by first author. Subjects with a diagnosis of ADHD according to DSM-IV were included in the study. Twelve subjects met the criteria for combined type and one case met the criteria for inattentive type. Using the DSM-IV, two subjects met the criteria for oppositional defiant disorder (ODD), one for tic disorder and two for reading disorder.
All participants were free of medications for at least 2 weeks prior to the study. Five subjects had a prior medication history, two were taking methylphenidate, three antidepressants and one antipsychotics. No patients was taking their medication due to intolerable side-effects and lack of efficacy (Table 1).
Table 1. Characteristics of subjects and efficacy of treatment
| 1|| 7||Male||ADHD + Tic Dis.||Antidepressant||37.5||20||21||Non-responder|
| 3|| 6||Female||ADHD||Antipsychotic||37.5||22|| 7||Responder|
| 5|| 8||Female||ADHD + Dyslexia||Methylphenidate||37.5||12|| 9||Responder|
| 8|| 7||Male||ADHD + Dyslexia||0||37.5||20||13||Responder|
|10|| 9||Male||ADHD + ODD||0||37.5||26||22||Non-responder|
|13|| 9||Female||ADHD + ODD||0||37.5||21||19||Non-responder|
Parents provided written consent prior to enrolling in the study. The exclusion criteria were (i) seizure disorder; (ii) evidence of systemic disease; and (iii) comorbidity of depression.
This was a 6-week open-label trial on efficacy and tolerability of venlafaxine in children and adolescents with ADHD.
Venlafaxine was initiated at a dose of 18.75 mg/day and flexibly titrated up to 56.25 mg/day (until unwanted effects occurred). Subjects did not take other psychotropic medication during treatment.
Primary efficacy assessments were the changes from the baseline to last visit as shown on the Conners parent index8 and Clinical Global Improvement severity item (CGI-severity).9 Also the CGI global improvement item was used to assess the response of cases. Cases who were rated 1 (very much improved) or 2 (much improved) were considered as ‘responder’ (Fig. 1).
Subjects were evaluated every week. This weekly visit included an interview with the child and a review of parent and teacher reports and the completion of an adverse effects checklist.
All subjects completed the 6-week study. Wilcoxon signed ranks test were used for evaluation of efficacy.
All patients (n = 13) completed this study. The mean dose of venlafaxine at the endpoint was 40.38 ± 7.04 mg/day. There was a statistically significant improvement in mean total score of the Conner 10-item parent index from baseline to endpoint (baseline mean 20 ± 3.67; endpoint mean 14.46 ± 4.86, P < 0.002, Z =−3.113). Twelve out of 13 cases showed reduction in their symptoms based on the Conner 10-item index. One patient showed mild behavioral activation and worsening in ADHD symptoms. This patient had a comorbidity of tic disorder.
Statistically significant improvement was seen in item 4: short attention span (P < 0.01), item 6: easily distracted (P < 0.05), item 7: easily frustrated (P < 0001) and item 9: mood changes quickly (P < 0.05).
Also there was a statistically significant change from baseline to endpoint in CGI severity item (P < 0.05). Eight cases (61.5%) were considered as responder based on CGI global improvement item.
Clinical improvement in symptoms started after the second weeks of treatment, based on parents and teachers reports.
Transient side-effects such as somnolence (n = 2), stomach ache (n = 2) and headache (n = 1) disappeared after the second week of treatment. One case (case 1) showed behavioral activation and three cases (cases 2, 10 and 13) showed sedation only at higher doses (56.25 mg/day), so their doses were decreased to previous levels.
The results of this pilot study suggest that venlafaxine may be an effective treatment in children and adolescents with ADHD. Venlafaxine produced clinically and statistically significant reductions in ADHD symptoms severity as judged by parent-rated standardized rating (P < 0.002).
A comparison of the present findings with the first study7 in this field shows the rate of response in the present study to be higher than in the first study. A comparison of subjects characteristics between two studies shows that first study included 13 cases (out of 16) with high rate of comorbid conditions, while in the present study there were only five subjects with comorbid conditions. Interestingly, non-responder or non-completer cases in Olvera et al. (1996) study's had at least two or three comorbid conditions, while most of the responder cases only had diagnoses of ADHD. In our study, three out of five non-responder cases had a comorbidity of tic disorder or oppositional defiant disorder (ODD). Taken together, we suggest that the high rate of comorbidity in cases with ADHD may be complicated by treatment with venlafaxine.
The statistically significant improvement in attentional problems in the present study are consistent with Saletu et al.'s study, which states significant improvement in attention and concentration of normal volunteers after taking venlafaxine.10 The role of venlafaxine in the improvement of cognitive function may be interpreted as a result of the noradrenergic activity of this agent. However, Olvera et al. reported no improvement in cognitive function and showed that venlafaxine is more helpful for improving behavioral symptoms of ADHD.7 The difference in the results of these studies may be related to different measurement instruments. Further studies with more sophisticated psychometric instruments may clarify the effect of venlafaxine in cognitive functions.
The present findings show that although venlafaxine, in low dose is a well-tolerated agent in children and adolescents with ADHD, higher doses may cause intolerable side-effects. This finding is consistent with Olvera et al.'s study that reported that four out of 16 children and adolescents with ADHD, dropped out during the study due to intolerable side-effects and they suggest gradual titration to minimize side-effects.
In conclusion, our preliminary data show that venlafaxine may be an effective treatment for children and adolescents with ADHD. However, due to the small sample size and uncontrolled nature of the present study, we prefer to interpret these findings with caution. Double-blind, placebo-controlled studies need to be undertaken.