Adverse drug events related to mood and emotion in paediatric patients treated for ADHD: A meta-analysis

Highlights

• Mood and emotion symptoms may arise following drug therapies for ADHD.

• We meta-analysed the occurrence of mood and emotion-related adverse events.

• Amphetamines may worsen emotional lability.

• Methylphenidates may improve irritability, anxiety and euphoria.

• Methylphenidates may worsen apathy and reduce talking.

Abstract

Background

ADHD is frequently comorbid with anxiety and mood disorders, which may increase the severity of inattention and hyperactivity symptoms. Emotional symptoms (anxiety, irritability, mood lability) also affect patients without comorbidity or emerge as adverse drug events. The influence of ADHD drugs on emotional symptoms demands investigation to improve therapies.

Methods

Systematic review of trials reporting adverse events in patients pharmacologically treated for ADHD. Meta-analysis of the occurrence of irritability, anxiety, apathy, reduced talk, sadness, crying, emotional lability, biting nails, staring, perseveration, euphoria. Meta-regression analysis.

Results

Forty-five trials were meta-analysed. The most frequently reported outcomes were irritability, anxiety, sadness, and apathy. Methylphenidates, especially immediate-release formulations, were most studied; amphetamines were half as studied and were predominantly mixed amphetamine salts. Reports on atomoxetine were scant. Meta-analysis showed that methylphenidates reduced the risk of irritability, anxiety, euphoria, whereas they worsened the risk of apathy and reduced talk; amphetamines worsened the risk of emotional lability. Factors influencing risks were study year and design, patients’ sex and age, drug dose and release formulation.

Limitations

Possible discrepancy between adverse events as indicated in clinical trials and as summarised herein. Confounding due to the aggregation of drugs into groups; uninvestigated sources of bias; incomplete lists of adverse events; lack of observations on self-injury.

Conclusions

Methylphenidates appeared safer than amphetamines, although younger patients and females may incur higher risks, especially with high-dose, immediate-release methylphenidates. Only atomoxetine holds a black-box warning, but amphetamines and methylphenidates also did not show a safe profile regarding mood and emotional symptoms.

Introduction

Attention deficit/hyperactivity disorder (ADHD) is among the commonest neurodevelopmental disorders, affecting 7.2% of children worldwide (Thomas et al., 2015) with a significant impact on familial, relational, and school functioning in more than one setting. ADHD is often associated with other comorbid mental disorders including major depressive disorder (MDD), 9–38%; bipolar disorder, 10–11%; and anxiety/social anxiety disorder (Anderson et al., 1987, Kessler et al., 2006, Kunwar et al., 2007, Tzang et al., 2009). Greater severity in the manifestation of symptoms associated with ADHD has been observed for individuals with ADHD and comorbid mental health disorders (Kuhne et al., 1997, Spencer et al., 2007). Furthermore, in ADHD patients who do not present with co-occurring mental health disorders, high levels of emotional symptoms, including anxiety, frustration intolerance, irritability, and mood lability are also observed (Shaw et al., 2014). These commonly associated features also cause considerable distress to individuals and their families.

Stimulant medications, including various drugs of the methylphenidate and amphetamine classes, are considered as first-line medications for the treatment of ADHD. Their activity is based on the strengthening of dopamine signals that are crucial to focus and to maintain attention (Arnsten and Pliszka, 2011, Arnsten and Rubia, 2012). Both methylphenidate and amphetamine are called “stimulants” since they potentiate dopamine signals. Methylphenidate acts only by increasing the intensity and duration of naturally-occurring dopaminergic signals (Volkow et al., 2002); amphetamine acts as methylphenidate and also by inducing a non-natural release of dopamine (Groves et al., 1979). This implies on one side that amphetamine can be more efficacious than methylphenidate, on another side that it can be less safe and may have a potential for abuse, which is negligible for methylphenidate in oral use (Volkow and Swanson, 2003). The commonest adverse effects of stimulants include decreased appetite, insomnia, stomach ache, and headache (Groenman et al., 2017). Stimulants are also associated with other adverse effects, including increased risk of growth retardation in weight and height of children, tics, increases in blood pressure, and possible abuse or misuse (Groenman et al., 2017). These drugs are often contraindicated in patients with comorbid disorders, including Tourette's syndrome and bipolar disorder, as well as in patients at risk for substance abuse (McIntyre, 2009, Rizzo et al., 2013). Further, some investigators advise caution in prescribing these products to patients with comorbid disorders that pose no explicit contraindication, such as tic disorders and anxiety (Blouin et al., 2010, Pringsheim and Steeves, 2011) and this is a matter of open debate. In particular, data do not seem to connect tics and stimulants (Cohen et al., 2015), and a previous meta-analysis showed beneficial effects of stimulants on anxiety (Coughlin et al., 2015). Suicidal ideation is an issue that may be present in ADHD patients with comorbid psychiatric disorders, especially depression and bipolar disorders. The presence of suicidal ideation in ADHD patients is currently a strict contraindication for the use of any methylphenidate in Europe.

Atomoxetine is the most commonly prescribed “non-stimulant” medication for the treatment of ADHD. While stimulants act on dopamine, atomoxetine potentiates naturally-occurring norepinephrine signals involved in the maintenance of attention (Arnsten and Pliszka, 2011). Atomoxetine is recommended as monotherapy for the treatment of ADHD for youths who do not respond well to stimulants (Pliszka et al., 2006; Shier et al., 2013), followed by bupropion, clonidine, or guanfacine (Wolraich et al., 2011). Atomoxetine may also be prescribed for individuals with ADHD and comorbidities including tics, mania, and suicidal ideation (Garnock-Jones and Keating, 2009, Reichart and Nolen, 2004), even though the effect of atomoxetine on mania and suicidal ideation has not yet been clarified. Atomoxetine has been associated with increased risk of suicidal behaviour in youths (Bangs et al., 2014) and the manufacturer of Strattera reported a warning on suicidal ideation. Both European and American labels for atomoxetine report a black-box warning regarding suicidal ideation in child and adolescent ADHD patients. Nevertheless, non-stimulant medication continues to be considered as a first-line treatment for individuals with comorbidities (Hah and Chang, 2005, Shier et al., 2013).

Although randomised controlled trials in children and adults with ADHD conclusively show that both groups of medications lead to clinically significant reductions in symptoms of ADHD (Storebø et al., 2015, Punja et al., 2016, Schwartz and Correll, 2014), what has not been defined is whether stimulants and atomoxetine also lead to reduced or increased severity of mood and emotional features. The action of stimulant and non-stimulant drugs on core symptoms of ADHD is thought to happen predominantly in the prefrontal cortex (Arnsten and Rubia, 2012); however, these drugs also diffuse to other regions of the brain. Dopamine has a crucial role also in the mesolimbic system, where it regulates reward-dependent behaviours. Norepinephrine is a key neurotransmitter in the limbic system and in the brainstem, which pair cognitive functions with emotional and autonomic responses. Drugs acting on dopamine and norepinephrine may thus have important effects on mood and emotion (Nestler and Carlezon, 2006, Dremencov et al., 2009). The detection of putative iatrogenic psychiatric symptoms is complicated by the fact that they may superimpose over patients’ psychiatric comorbidities.

Researchers have already studied some of these aspects: drug-induced anxiety was investigated with respect to stimulant medications (amphetamines and methylphenidates), finding that stimulants were beneficial for the reduction of anxiety (Coughlin et al., 2015). One recent meta-analysis dealt with the symptom of irritability, analysing whether treatments for ADHD increased or reduced it (Stuckelman et al., 2017). Although methylphenidate was found to reduce irritability, a sizeable worsening effect caused by amphetamines was reported. Aside from these two focused meta-analyses, no comprehensive review covered the broad spectrum of treatment-emergent mood or emotional adverse events in relationship with ADHD treatment for children and adolescents. Due to the high prevalence of ADHD, of ADHD with comorbid mood and anxiety disorders, and of ADHD with mood and/or emotional symptoms, and in view of the increasing rate of use of stimulants and atomoxetine for the treatment of ADHD, a broad systematic review of the published literature on the effect of stimulants and atomoxetine on emotional symptoms is warranted. One possibility for such investigation is to evaluate the occurrence of adverse events in clinical trials.