1. Background
Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood disorders characterized by overactivity, impulsivity, and inattentiveness (1).
Pharmacotherapy constitutes the principal part of ADHD treatment. Psychostimulant medications, including methylphenidate and amphetamines, are the first-line therapies for ADHD (2). These agents affect the dopaminergic and noradrenergic systems (3). However, reduced appetite, insomnia, irritability, and dysphoria are among the common adverse effects associated with stimulants. In addition, a controversy exists in their use in ADHD adolescents with or at risk for substance use disorders (2, 4). Therefore, searching for alternative or more effective agents is necessary.
Antidepressant medications have been explored in the treatment of ADHD symptoms, and their benefits are mainly proposed as related to norepinephrine–dopamine agonistic activity (5, 6). Preliminary reports have been presented on the effectiveness of venlafaxine hydrochloride, a serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant, in the treatment of ADHD symptoms in children and adolescents (7, 8).
Duloxetine, an antidepressant agent with an SNRI mechanism, is currently indicated for the treatment of major depressive disorder (MDD) in adults (9, 10). In addition, it has been implicated to be a beneficial treatment for physical pain associated with depression and generalized anxiety disorder in adults (11-14). In child and adolescent psychiatry, preliminary reports have been conducted on the successful use of duloxetine in adolescents with chronic pain and comorbid MDD (15) and childhood depression with pain and dissociative symptoms (16). Moreover, duloxetine has been shown to be generally safe and well tolerated in various controlled trials (17-19). The reported side effects in adult trials include nausea, dry mouth, constipation, fatigue, decreased appetite, somnolence, and hyperhidrosis (9, 20).
2. Objectives
In this open-label clinical trial, we investigated the efficacy and safety of duloxetine in the treatment of children with ADHD.
3. Patients and Methods
3.1. Participants
The study was conducted at the Akhavan and Rofide child psychiatry clinics at the University of Social Welfare and Rehabilitation Sciences in Tehran, the capital city of Iran. Children aged 6 – 11 years with the diagnosis of ADHD were included. The sample size was calculated according to Cohen's method by power of 80%, alpha of 0.05, and effect size of 0.8. The participants were required to be off any medication at least two weeks prior to the study entry. The exclusion criteria included: (i), comorbidity of pervasive developmental disorder, bipolar disorder, conduct disorder, and psychotic disorder; (ii), a concurrent comorbidity requiring treatment prior to trial entry or during the trial; (iii), clinically significant medical illness requiring pharmacotherapy; (iv), history of hypersensitivity to duloxetine; and (v), mental retardation. The study was conducted from September 2012 until July 2014. It was fulfilled in accordance with the Declaration of Helsinki and approved by the ethics committee of the University of Social Welfare and Rehabilitation Sciences. A written informed consent was obtained from the parents.
3.2. Study Design
This study was an open-label trial for a total duration of six weeks. Duloxetine was orally titrated up starting with 15 mg/day in the first week once daily and 30 mg/day in the next five weeks once daily. The participants were not permitted to receive any other concomitant medication during the trial.
The diagnosis of ADHD based on the Diagnostic and Statistical Manual of Mental Disorder-IV (DSM-IV) criteria and the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime (K-SADS-PL) interview (for the diagnosis of ADHD and comorbidities) was fulfilled for all participants at baseline. K-SADS-PL is a semi-structured interview that enables the interviewer to make judgment during the interview (21). The reliability and the validity of the Persian translation of K-SADS-PL were established in Iranian children before (22, 23). Conners Parent Rating Scale-Revised-Short form (CPRS-R-S) and the ADHD Rating Scale were used to assess the efficacy of the therapy. The self-reported scales Revised Children’s Manifest Anxiety Scale (RCMAS) and the Children’s Depression Inventory (CDI) were used to assess anxiety and depressive symptoms, respectively. CPRS-R-S and the ADHD Rating Scales are two clinical tools for monitoring the treatment response of ADHD symptoms by parents. CPRS-R-S includes 27 questions of oppositionality, cognitive/inattentive, hyperactivity, and ADHD index subscales (24, 25). The ADHD Rating Scale includes 18 questions according to the DSM-IV-TR criteria. RCMAS is a 37-item inventory designed to assess the level and the nature of anxiety by evaluating the physiological, apprehensive, worry-oversensitivity, and social concerns– concentration areas of anxiety (26). CDI is a 27-item assessment tool evaluating the emotional, cognitive, and behavioral symptoms of depression in the preceding two weeks. The inventory consists of 14 direct and 13 indirect questions, with an overall minimum score of zero and a maximum score of 54 (27). Children with a total score between 0 and 8 are considered to not have depression. CDI and RCMAS have been translated to Persian and normalized in Iranian children, and they have been shown to have good psychometric properties (28, 29). CPRS-R-S and the ADHD Rating Scale were administered at baseline every two weeks and at the end of week six. RCMAS and CDI were assessed at baseline and at the end of week six. Safety and tolerability of the medication were monitored every two weeks using a side effect checklist (made by the researcher) and through the participants’ reported adverse effects. Children’s vital signs were monitored every two weeks, and their weight and routine laboratory tests were observed at the beginning and end of the trial. This study was registered in the Iranian Registry of Clinical Trial (Irct ID IRCT2012072210363N1).
3.3. Statistical Analysis
SPSS version 21 was used for data analysis. One-way repeated-measure ANOVA was used for the comparison of the variables that evaluate every two weeks, such as CPRS-R-S and its subscales, and the ADHD Rating Scale. Other variables such as vital signs, weight, laboratory indexes, RCMAS, CDI, CGI-I, and CGI-S were analyzed by paired-sample Student’s t-test. Statistical significance was considered as P < 0.05. Normality of the variable's distribution was tested by the Shapiro-Wilk test. If the SIG value of the Shapiro-Wilk test was greater than 0.05, the data would be normal; if the value was below 005, the data would significantly deviate from a normal distribution.
4. Results
Thirteen children complied with the study criteria and entered the study, but only 10 participants completed the study. Three participants discontinued the trial, two for noncompliance and one for developing gastrointestinal (GI) adverse drug reaction, such as nausea and abdominal pain. The characteristics of the completers and their comorbidities are shown in Table 1.
Table 1. Children’s Demographic Characteristics and Prevalence of Comorbiditiesa
| Valuesb | |
|---|---|
| Age (range) | 1.6 (7 - 11) ± 8.4 |
| Gender | |
| Male | 8 (80) |
| Female | 2 (20) |
| Combined subtype | 8 (80) |
| Inattentive subtype | 2 (20) |
| ODD | 6 (60) |
| GAD | 2 (20) |
| OCD | 2 (20) |
| LD | 1 (10) |
| Total | 10 |
aAbbreviations: GAD, Generalized Anxiety Disorder; LD, Learning Disability OCD, Obsessive Compulsive Disorder; ODD, Oppositional Defiant Disorder; SD, Standard Deviation.
bData are presented as mean ± SD or No. (%).
The severity of ADHD symptoms was evaluated using CPRS-R-S and the ADHD Rating Scale at the beginning of the trial and then every two weeks. The reduction of the scale and its subscales was then compared. Data analysis showed that the decrease in the overall Conners score and its subscales (except for the inattentiveness subscale) and also the ADHD Rating Scale was significant from the second week afterwards. The attention-deficit hyperactivity subscale showed a significant decrease compared with baseline values from the fourth week afterwards (Table 2). The overall reduction in the Conners scale compared with the baseline values in the second, fourth, and sixth weeks was 22%, 33%, and 33%, respectively. If the basis of the therapeutic effect of the drug was considered at 25% reduction at least in the overall Conners scale, this effect would start from the fourth week.
| Baseline | Week 2 | pa | Week 4 | pb | Week 6 | pc | F | P | Effect Size | 95% CI | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Lower | Upper | |||||||||||
| ADHD. Index | 22.2 ± 1.92 | 18.4 ± 3 | 0.007 | 18 ± 2.24 | 0 | 17.6 ± 2.6 | 0.002 | 20.07 | < 0.001 | 0.834 | 3.577 | 5.622 |
| O.Subscale | 10.2 ± 2.77 | 8.2 ± 2.58 | 0.034 | 7.6 ± 1.81 | 0.025 | 7.8 ± 2.68 | 0.016 | 9.59 | 0.002 | 0.706 | 1.495 | 3.304 |
| I.Subscale | 13.4 ± 3.28 | 11.2 ± 2.86 | 0.141 | 10.2 ± 1.92 | 0.051 | 9.4 ± 1.94 | 0.034 | 7.39 | 0.005 | 0.649 | 2.092 | 5.907 |
| H.Subscale | 11.4 ± 1.67 | 9.8 ± 1.30 | 0.003 | 8.8 ± 2.28 | 0.003 | 8.4 ± 1.81 | 0.001 | 33.5 | < 0.001 | 0.893 | 2.523 | 3.476 |
| ADHD R.S | 14.4 ± 0.89 | 11.4 ± 2.60 | 0.04 | 9.4 ± 2.5 | 0.012 | 8.6 ± 2.07 | 0.004 | 19.93 | < 0.001 | 0.833 | 4.337 | 7.262 |
aAbbreviations: ADHD R.S, ADHD Rating Scale; CI, Confidence Interval; CPRS-R, Conners Parent Rating Scale-Revised; H.Subscale, Subscale of Hyperactivity; I.Subscale, Subscale of Inattentiveness; O.Subscale, Subscale of Oppositionality; p
bData are presented as mean ± SD.
CGAS, CGI-I, and CGI-S were the other general scales used for the evaluation of the drug’s efficacy. They were measured at the beginning and end of the trial. These scales were compared with each other, and the changes were significant at week six. Additionally, the participants’ anxiety and depression at the beginning and end of the study were measured and compared by RCMAS and CDI tools, respectively. However, their differences were not significant (Table 3).
| Week 0 | Week6 | P Value | 95% CI | ||
|---|---|---|---|---|---|
| Lower | Upper | ||||
| CGAS | 3 ± 52 | 6 ± 65 | 0.006 | -23.823 | -3.476 |
| CGI-Ic | 0.8 ± 3.6 | 0.8 ± 2.4 | 0.004 | 1.230 | 2.269 |
| CGI-S | 0.5 ± 4.4 | 0.6 ± 2.6 | 0.009 | 0.943 | 2.256 |
| CDI | 1.1 ± 8.6 | 1.5 ± 8.0 | 0.208 | -1.922 | 2.222 |
| RCMAS | 2.5 ± 8.2 | 1.3 ± 4.8 | 0.067 | -1.974 | 1.374 |
aAbbreviations: CDI, Children’s Depression Inventory; CGAS, Children’s Global Assessment Scale; CGI-I, Clinical Global Impression-Improvement; CGI-S, Clinical Global Impression-Severity; CI, Confidence Interval; RCMAS, Revised Children’s Manifest Anxiety Scale.
bData are presented as mean ± SD.
cThis scale was assessed at weeks 2 and 6.
4.1. Drug Adverse Events
Average weight showed no significant difference at the beginning and end of the study. Changes in blood pressure, pulse, electrocardiography, and laboratory parameters including cell blood count, fasting blood sugar, thyroid function tests, blood urea nitrogen, creatinine, liver function tests, and electrolytes, were not significant.
Apart from one patient who was excluded as he did not tolerate the drug because of severe GI problems, two patients reported anorexia and one reported mild nausea during the first two weeks. These side effects were resolved though the consumption of the drug in the following weeks, and dose reduction or other interventions were not needed. Generally, this drug was well tolerated in this age group with a dose of 30 mg/day.
5. Discussion
To our knowledge, this trial is the first study investigating the efficacy of duloxetine on ADHD children aged 6 – 11 years. The results suggest that the drug is well tolerated and has a good effect on ADHD symptoms. This effect is observable from the fourth week of drug administration according to the results of CORS-R and the ADHD rating scale.
Several studies have been conducted on the effects of duloxetine in the treatment of ADHD. The first study that showed the effect of duloxetine on ADHD was a case report administering 60 mg/day duloxetine to a 53-year-old man with a recent diagnosis of ADHD. The results demonstrated a significant reduction in the Conners scale (30). Duloxetine has recently been reported to be useful in reducing ADHD symptoms in a 16-year-old girl with ADHD. Similar to our results, the treatment effect was observed after four weeks (31). In another open trial, duloxetine was given to 13 adolescents with ADHD. A significant reduction in ADHD symptoms measured by CPRS-R was observed from week four (32).
According to this study, duloxetine can reduce attention deficit, hyperactivity and oppositionality in ADHD children. Nevertheless, atomoxetine only treats the symptoms of attention deficit and hyperactivity–impulsivity but not oppositionality (33, 34).
Venlafaxine, a drug with an effect mechanism similar to that of duloxetine, may exacerbate the hyperactivity symptoms of ADHD (35). Therefore, although duloxetine and venlafaxine have similar effect mechanisms, they seem to have different effects on ADHD. As a result, more research is needed in this area.
Duloxetine is an anxiolytic and anti-depressant drug (9). This study assessed the intensity of anxiety and depression symptoms using RCMAS and CDI, respectively. The results showed that the severity of these symptoms did not change during the trial. These findings suggest that the useful effects of duloxetine in reducing ADHD symptoms are independent of its anxiolytic and anti-depressant effects.
One of the objectives of this study was to evaluate the tolerability and safety of duloxetine in the target age group. In this study, we gradually increased the dose of duloxetine to 30 mg/day, so that tolerance would be established against some minor complications developed during the first weeks. The safety profile of duloxetine in our study is consistent with the present published data mentioning GI side effects (36). Therefore, the drug can be concluded to have a tolerable side effect profile. However, studying the long-term effects of the drug in longer-term studies is necessary.
The limitations of this study include its open nature, absence of control group, small sample size, and short-term duration of the trial. Another limitation is that the Conners Teacher Rating Scale was not used in the study.
We suggest that further double-blind comparative studies should be conducted with a larger sample size, a longer trial, and the administration of higher doses of the drug.
