High Familial Correlation in Methylphenidate Response and Side Effect Profile

Abstract

Objective: To examine whether a familial tendency exists in clinical response to methylphenidate. Method: Nineteen pairs of siblings or parent–child stimulant-naive individuals with ADHD were prescribed methylphenidate–immediate release, and were comprehensively evaluated at baseline, Week 2, and Week 4, using the ADHD Rating Scale IV, Clinical Global Impression Scale, and the Barkley Side Effects Rating Scale. Results: We found significant intraclass correlations in family member response to methylphenidate–immediate release and side effect profile, including emotional symptoms and loss of appetite and weight. Conclusion: Family history of response to methylphenidate should be taken into account when treating ADHD.

Keywords

ADHD methylphenidate response side effects familial

Introduction

Stimulants, in particular, methylphenidate, are most commonly prescribed to treat ADHD (Van der Oord, Prins, Oosterlaan, & Emmelkamp, 2008). However, 30% of individuals with ADHD poorly respond to methylphenidate (Van der Oord et al., 2008), and many patients discontinue methylphenidate due to side effects (Dopheide, 2009; Van der Oord et al., 2008).

Currently, the effectiveness of ADHD treatment is often determined in clinical practice through trial and error with limited evidence-based predictors of treatment response. It is assumed that there is a tendency for a similar familial response to psychiatric medications, including methylphenidate, but this has been rarely studied. To date, there is only one pioneering study that reported a positive correlation among siblings in their response to methylphenidate (Meulen et al., 2005). Limitations of that study included clinical evaluation of improvement of ADHD symptoms only, without the determination of side effects.

The main aim of the present study was to examine whether there is a familial tendency in the response to methylphenidate and in the side effect profile, in family members diagnosed with ADHD. We hypothesized that there would be a positive correlation between family members in the degree of clinical improvement and the development of side effects in response to methylphenidate.

Method

Participants

Thirty-eight participants (20 males, 18 females), consisting of 19 pairs of first degree family members (6 pairs of siblings and 13 pairs of parent-child) with ADHD diagnosed according to Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV-TR; American Psychiatric Association, 2000) criteria were recruited from an ADHD clinic in Israel. All participants were naive to ADHD medications, and with at least moderate severity of ADHD symptoms (Clinical Global Impression–Severity [CGI-S] score ≥ 4). Participants with current or past medication treatment for ADHD, as well as participants with a history of psychotic disorders, autism, bipolar disorder, drug abuse, and neurological and cardiovascular diseases, were excluded from the study. The study was approved by the Institutional Review Board of Sheba Medical Center, Tel Hashomer, Israel, and the Israel Ministry of Health, and was conducted according to the Declaration of Helsinki. All adult participants signed informed consent forms. For children and adolescents, both parents signed an informed consent form, and assent to participate in the study was obtained from all children.

Diagnostic Procedure

Participants underwent a semi-structured psychiatric evaluation at baseline using the child or adult versions of the Mini International Neuropsychiatric Interview (MINI; Sheehan et al., 1998; Sheehan et al., 2010), to confirm the diagnosis of ADHD and to diagnose additional potential psychiatric comorbidities. The MINI structured clinical diagnostic interview was designed to assess the presence of current Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; APA, 1994) psychiatric disorders. In this study, we used for all participants the full ADHD module of the MINI, which is composed of the 18 ADHD signs and symptoms recorded in the DSM-IV.

Participants were treated with methylphenidate–immediate release (Ritalin-IR; Novartis Pharmaceuticals, Summit, NJ) up to 3 times a day. Methylphenidate dosages were titrated as suggested by the MTA study (Greenhill et al., 1996). The starting dose for all participants with body weight below 25 kg was 5 mg two times per day (BID) or three times per day (TID). For participants over 25 kg, the starting dose was 10 mg BID or TID. Dose escalation was conducted every three days, up to a final daily dosage target of 20 mg for those under 25 kg, 60 mg for children over 25 kg from ages 6 to 12, and then a maximal dose of 80 mg for adolescents and adults given BID or TID. In case of intolerable side effects, the dose escalation was stopped or dosage was reduced based on clinical decision. The mean daily dosage for the children (n = 25) was 31.4 ± 18.3 mg/day (0.44 ± 0.13 mg/kg/dose) and for the parents 47.3 ± 26.2 mg/day (0.36 ± 0.10 mg/kg/dose).

Clinical evaluations were conducted at baseline, Week 2, and Week 4 and included the ADHD Rating Scale IV (ADHD-RS; DuPaul, Power, Reid, & Anastopoulos, 1998), the Clinical Global Impression Scale (CGI), and the Barkley Side Effects Rating Scale (Barkley, Fischer, Newby, & Breen, 1988). Body weight, heart rate, and blood pressure were also measured at all three time points. The ADHD symptoms and side effect scales were collected systematically by an interview with the same single senior clinician (D.G.).

Statistical Analysis

Categorical variables were presented as number and percentage. Continuous variables were presented as mean ± standard deviation. Repeated-measures ANOVAs were used to compare the various scale scores in each time point against baseline values. Intraclass correlations were used to measure the association between the various scale scores in sibling or child-parent pairs. A two-tailed p value of <.05 was considered as statistical significance.

Results

Mean participant age was 10.5 ± 3.1 years for the children and adolescents, and 38.8 ± 4.5 years for the parents. The ADHD subtypes of the 38 participants were predominantly inattentive type (n = 19, 50.0%), combined type (n = 8, 21.1%), hyperactive/impulsive type (n = 3, 7.9%), and ADHD-NOS (n = 8, 21.1%). The psychiatric comorbidities included major depressive disorder (n = 4, 10.5%), generalized anxiety disorder (n = 3, 7.9%), and oppositional-defiant disorder (n = 4, 10.5%). Participants with ADHD-NOS diagnosis fulfilled at least four but less than six symptoms of inattention or hyperactivity/impulsivity.

On repeated measures ANOVAs, a significant improvement was found from baseline to Week 4 in ADHD-RS inattentive, hyperactive, and total, as well as CGI-severity scores (18.5 ± 5.3 vs. 9.5 ± 5.6, 10.3 ± 6.0 vs. 5.9 ± 4.7, 28.8 ± 8.5 vs. 15.5 ± 9.2, and 5.0 ± 0.7 vs. 2.4 ± 1.2, respectively, all p < .001). There was also a significant increase in resting heart rate from baseline to Week 4 (76.4 ± 13.0 vs. 82.7 ± 12.9 beats/minute, p = .02). Resting blood pressure did not differ significantly between baseline and Week 4 (81.2 ± 11.5 vs. 82.6 ± 10.0 mmHg, p = .34). Body weight also did not differ significantly between baseline and Week 4 (49.6 ± 18.2 vs. 49.0 ± 17.8 kg, p = .16). Side effects were reported by 94.7% of the participants and included decreased appetite (81.5%), headaches (52.6%), insomnia (39.4%), and emotional symptoms (28.9%).

The response rates were similar in the children and the adults. The mean change ±SD in the children and adults on the ADHD-RS scale was −13.9 ± 8.9 and −12.7 ± 10.3 (47.8% and 43.8% change from baseline scores) for the adults and children, respectively. Based on the Clinical Global Impression–Improvement (CGI-I) response criteria (CGI-I of 2 = much improved or 1 = very much improved) 61.5% and 72.0% of the adults and children, respectively, significantly improved.

Significant intraclass correlations were found between family members in the change in ADHD symptoms from baseline to Week 4 in ADHD-RS total (Table 1 and Figure 1A), inattentive and hyperactive/impulsive subscale scores and ΔCGI-S and CGI-I scores (Table 1). There were also significant familial correlations in weight change and in several side effects as measured by the Barkley Side Effects Rating Scale, including change in total side effect scores, loss of appetite, and emotional symptoms (Table 1 and Figure 1B-D).

Table 1.

Familial Response to Methylphenidate—Intraclass Correlations of Change (Δ) in Scores From Baseline to Week 4.

Measure	r	p
ADHD symptoms
ADHD Rating Scale
ΔAttention	.61	.03
ΔHyperactivity/Impulsivity	.86	<.001
ΔTotal	.81	<.001
ΔCGI-S	.64	.02
CGI-I	.68	.02
Physical measures
ΔWeight (kg)	.73	.01
ΔHeart rate	.37	.22
ΔMean blood pressure (mmHg)	−.17	.61
Barkley Side Effects Rating Scale
ΔSide effect total scores	.90	<.001
ΔLoss of appetite	.81	<.001
ΔEmotional symptoms^a	.85	<.001
ΔSleeping disorders^b	.00	.50
ΔActivation^c	.46	.10
ΔHeadaches^d	.47	.10
ΔTics	.08	.56

Note. CGI-S = Clinical Global Impression Scale–Severity; CGI-I = Clinical Global Impression Scale–Improvement.

Staring, talks less, disinterested in others, sadness, prone to crying, anxious, nail biting.

Insomnia, nightmares, drowsiness.

Irritable, euphoria.

Headaches, dizziness.

Figure 1.

Significant familial intraclass correlations for methylphenidate response and side effect profile: (a) change in ADHD Rating Scale total scores (r = .81, df = 17, p < .001), (b) weight change (r = .73, df = 17, p = .01), (c) loss of appetite (r = .81, df = 14, p < .001), and (d) emotional symptoms (r = .85, df = 17, p < .001).

To confirm that the significant intraclass correlations that we found for family members treated with methylphenidate are not a chance finding, we randomly paired our sample (random pairs of a participant and an unrelated participant) and repeated the analyses for the following measures that came out significant in the familial analyses: changes in ADHD-RS total, inattentive and hyperactive/impulsive scores, weight change and the Barkley Side Effects Rating Scale total, loss of appetite, and emotional symptoms. No statistical significant intraclass correlations were revealed (all ps > .2), indicating that, indeed, the correlations are valid only for pairs of first degree relatives.

Discussion

The main aim of the present study was to examine whether there is a familial tendency in the response to methylphenidate and in the side effect profile. Confirming our study hypothesis, we found significant correlations between family members in the changes in ADHD symptoms, body weight, and behavioral side effects following methylphenidate treatment.

The 61.5% to 72.0% response rate to methylphenidate treatment obtained in our study is similar to the response rate reported for methylphenidate in children and adults in other studies (Epstein, Patsopoulos, & Weiser, 2014; Pelham et al., 1999). Overall, we found relatively high rates of methylphenidate-induced side effects in our study. This observation may be related, at least partly, to the fact that the side effects’ measure used in our study, the Barkley Side Effects Rating Scale, was administered already at baseline, before the initiation of methylphenidate. This could lead to over-alertness of the participants to the side effect potential of the treatment. The rate of decreased appetite was specifically higher in our cohort (81% in our study vs. ~50% in previous studies), but the rate of emotional side effects in our study (29%) was similar to that in previous methylphenidate studies (Schachter, King, Langford, & Moher, 2001).

The common assumption that there is a familial tendency in the response to psychiatric medications has rarely been investigated. A few studies found familial response to lithium in bipolar patients (e.g., Grof et al., 2002), and there are a few case reports of favorable response of twins and siblings to specific antipsychotics (Hoyer et al., 2010; Mata, Madoz, Arranz, Sham, & Murray, 2001; Vojvoda, Grimmell, Sernyak, & Mazure, 1996). Our findings are consistent with the only published study to-date on the familial response to methylphenidate by Meulen et al. (Meulen et al., 2005). That study was conducted on a sample of 24 pairs of siblings, and it examined the efficacy of methylphenidate in siblings by asking parents to complete the SWAN Rating Scale when their children were on versus off methylphenidate. They found a positive correlation (r = .56) in the degree of improvement in ADHD symptoms following treatment (Meulen et al., 2005). Our study participants were all methylphenidate-naive individuals who were diagnosed and then prospectively followed by a pediatric psychiatrist for 4 weeks, and thus seem to be less response biased. We extended the findings of Meulen et al. (2005) also by showing that the familial response to methylphenidate existed in both sibling and parent–child dyads. Similar high intraclass correlations were observed in the parent–child and sibling cohorts both for the measures of improvement in ADHD symptoms and side effects. Thus, in our cohort, it seems that a familial predisposition of response to methylphenidate exists both in siblings and in parents.

Our study is the first to show a familial pattern of methylphenidate-induced side effects. Using objective measures (e.g., weight) and a scale, we found a strong familial tendency for two major methylphenidate side effects —loss of appetite and weight and “emotional symptoms” (e.g., “sad” and “prone to crying”). The association between methylphenidate and the relatively high rates of these side effects is a major cause of non-adherence to methylphenidate treatment (Dopheide, 2009). Our findings have clinical implications, suggesting that the response and tolerability of a family member should be considered when treating other family members. In cases with poor response or intolerability to methylphenidate, more caution (e.g., slower dosage escalation, or considering non-stimulant options) should be considered when treating a first degree relative with ADHD.

It is important to note that our study was limited by the small sample size. In addition, the rater was not blind to the familial relatedness of the participants. Only in 2 of the 19 families (10.5%) included in our study there was another family member who had been treated with a stimulant medication. It means that ~90% of our participants are not biased by previous experience of family members with stimulant medications treatment. Yet, familial attitudes and beliefs (either positive or negative) regarding the effectiveness or potential harm of stimulants are potential moderators of the familial correlation in treatment response we found.

In conclusion, in this study of 19 sibling or child–parent pairs with diagnosed ADHD, we found significant intrafamily correlations in the changes in ADHD symptoms and side effects following methylphenidate treatment. Our findings should be replicated in larger cohorts that will have enough power to include pharmacogenetic measures that may clarify, at least in part, the between-relatives pharmacological concordance observed and for which such familial studies are an excellent model.

Footnotes

Acknowledgements

This work was performed in partial fulfillment for the MSc degree of Ms. Gazer-Snitovsky at Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Ariana and Alexander Katz Internal Grant, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Author Biographies

Michal Gazer-Snitovsky graduated with an MSc degree in Medical Sciences at Tel-Aviv University Sackler Faculty of Medicine. Her master work focused on the current study at Sheba Medical Center. Her research interests include ADHD and psychopharmcology.

Ayelet Brand-Gothelf is a Child Psychiatrist. Her main research interest is pediatric psychopathology and eating disorders.

Gal Dubnov-Raz is a Pediatrician. His main clinical activities encompass general pediatrics and healthy lifestyle. His research interests also include ADHD treatment.

Abraham Weizman is a Child and Adult Psychiatrist, the Director of the Research Unit at Geha Mental Health Center, and a Professor of Psychiatry at Tel Aviv University Sackler Faculty of Medicine. His research interests include neurobiology, genetics, and psychopharmacology of pediatric mental disorders.

Doron Gothelf is a Child Psychiatrist, the Director of Child Psychiatry Department at Sheba Medical Center, and a professor at Tel Aviv University Medical School. His research interests include psychopathology and psychopharmacology in individuals with developmental disabilities and neurogenetic syndromes.

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