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Management of anxiety disorders in children with attention-deficit hyperactivity disorder: a narrative review

Golubchik, Pavela,,b; Weizman, Abrahamb,,c,,d

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International Clinical Psychopharmacology: January 2021 - Volume 36 - Issue 1 - p 1-11
doi: 10.1097/YIC.0000000000000338
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Abstract

Introduction

Prevalence of attention deficit/hyperactivity disorder and comorbid anxiety disorders

DSM-5 defines attention deficit/hyperactivity disorder (ADHD) as a persistent pattern of inattention and/or hyperactivity-impulsivity, present in two or more settings, with clear evidence that the symptoms interfere with, or reduce, the quality of social, academic, or occupational functioning and interfere with development (APA, 2013).

In populations with ADHD, the rate of various anxiety symptoms and comorbid anxiety disorders is higher than in the general population (Biederman et al., 1991; Pliszka, 1992; Sciberras et al., 2014). Approximately 1/3 of children with ADHD also have comorbid anxiety disorder (Busch et al., 2002; Kessler et al., 2006). In individuals with comorbid anxiety disorder, the ADHD tends to be diagnosed later in life than in those without anxiety disorder, possibly due to the anxiety disorder attenuating the level of impulsivity (Schatz and Rostain, 2006); and that, despite Reimherr and colleagues’ (2017) findings, showing more reported childhood ADHD symptoms and higher scores on ADHD scales in patients with ADHD and comorbid anxiety disorder. Distinguishing between primary and secondary anxiety is important. Primary anxiety develops de novo while secondary anxiety is related to the experience of performance deficits. Patients with ADHD as a primary condition and high levels of anxiety as a secondary condition demonstrated consistently more impairment on multiple ADHD functional measures. Anxiety symptoms tend to be more severe in patients with ADHD and more than two comorbid anxiety disorders and start at an earlier age. Also, additional comorbid psychiatric diagnoses occur more often in those patients than in patients with ADHD alone or with a single comorbid anxiety disorder (Sciberras et al., 2014). Moreover, comorbid anxiety tends to appear at an earlier age and often persists into adulthood in patients with ADHD compared to those without it (Mancini et al., 1999). Comorbid anxiety disorders have a severely negative impact on life, including increased risk for unemployment, disability, unstable personal relationships, and legal entanglements (Kessler et al., 2006; Moss et al., 2007). This article aims to review evidence-based data on the treatment of ADHD with comorbid anxiety disorders in children, and to suggest recommendations for clinical practice.

Diagnostic issues of anxiety disorders in the context of attention deficit/hyperactivity disorder

Diagnosis of an anxiety disorder is usually based on detailed patient history and careful interviews with the patient and close members of his or her family. Often, anxiety symptoms are not apparent during an office visit since they may appear only in specific situations, such as during separation, social interaction, or in academic/educational settings (Elkins et al., 2014; Grogan et al., 2018). In their studies on response to methylphenidate (MPH) treatment in ADHD patients with various forms of anxiety, Golubchik et al. (2014a,2014b) used established scales, such as the Child and Adolescent Separation Anxiety Scale and Screen for Child Anxiety Related Emotional Disorders for the assessment of anxiety disorders.

Tools such as structured and semistructured diagnostic interviews, neuropsychological assessments, and behavioral observations can be used to perform comprehensive assessments of both ADHD and comorbid anxiety disorder. Those tools may also help differentiate between the diagnostic entities and each one’s response to treatment. Unfortunately, such a comprehensive battery is rarely used in clinical practice (Pelham et al., 2005).

Attention deficit/hyperactivity disorder and comorbid anxiety disorders: specific combinations

Attention deficit/hyperactivity disorder with social anxiety disorder

Social anxiety disorder (SAD), also known as social phobia, is characterized by excessive fear and avoidance of social situations and often co-occurs with ADHD (Solanto et al., 2009).

In children with ADHD, the presence of social and emotional problems leads to more missed school days and higher rates of healthcare utilization (Classi et al., 2012). In patients with ADHD, SAD may develop secondary to the ADHD. It stands to reason that in such cases, the treatment should focus on the disorder that causes more distress and problems, which is usually the ADHD (Koyuncu et al., 2018).

Attention deficit/hyperactivity disorder with generalized anxiety disorder

Generalized anxiety disorder (GAD) is a very common anxiety condition, co-occurring with ADHD in childhood and adolescence, with estimates indicating its presence in up to 15% of youths with ADHD (Elia et al., 2008; Willcutt, 2012). Some ADHD and GAD symptoms overlap, for example, attention difficulties, concentration problems, and restlessness (APA, 2013). Anxious youths showed greater attentional biases toward threat-cues than inattentive impulsive youths (Weissman et al., 2012).

Attention deficit/hyperactivity disorder with separation anxiety disorder

Higher rates of separation anxiety disorder have been reported in ADHD combined type compared to ADHD inattentive type and healthy controls (Foley et al., 2004). A substantial proportion of children with ADHD may also have high levels of subsyndromal separation anxiety (SSSA), namely, a level of anxiety that does not meet the full DSM-IV-TR criteria (APA, 2000; Carter et al., 2001). This group may require a special treatment strategy. In this population, improvement in ADHD symptoms, as well as in academic, social, and family function, may be sufficient to lower tension and anxiety.

Attention deficit/hyperactivity disorder with obsessive-compulsive disorder

Although obsessive-compulsive disorder (OCD) is no longer considered to be an anxiety disorder in the DSM-5 and is currently classified as an independent disorder under its own category of obsessive-compulsive and related disorders, the presence of OCD in ADHD is associated with anxiety symptoms that require special attention.

About 2.6–8% of children with ADHD also have OCD as a comorbidity (Zohar et al., 1992; Abramovitch et al., 2015).

The OCD/ADHD combined presentation can aggravate the dysfunctions normally noted in OCD, including additional difficulties in social functioning, school performance, family functioning, and more self-reported depression (Geller et al., 2002; Sukhodolsky et al., 2005; Taormina et al., 2016). In these children, the age of OCD-symptom onset tends to be earlier, symptom severity greater, and persistence rate higher than in children without comorbid ADHD (Masi et al., 2006; Walitza et al., 2008). Differential diagnosis is complicated since symptoms of inattention and impulsive behaviors are more prominent than the OCD symptoms.

OCD and ADHD often follow a chronic course with high persistent rates (Walitza et al., 2008). Family studies showed high heritability for both ADHD and OCD; however, no genetic overlap was found in a large genome-wide association study (Ritter et al., 2017).

Neuropsychological and neuroimaging studies suggest that similar executive functions are affected in both disorders. The deficits in the corresponding brain networks may be responsible for the perseverative, compulsive symptoms in OCD but also for the disinhibited and impulsive symptoms characterizing ADHD (Brem et al., 2014). Several studies suggested that ADHD-OCD represents a distinct condition or subtype that leads to greater functional impairment and a poorer prognosis. Comorbidity of ADHD in early-onset OCD was found to be associated with a higher severity and persistence of OCD (Walitza et al., 2008; Mersin Kilic et al., 2020) and with hoarding symptoms (Sheppard et al., 2010; Fullana et al., 2013). Despite the difference in terms of their phenomenology, both ADHD and OCD may present with symptoms of inattention and distraction that could be related to primary attentional symptoms in ADHD and to attentional symptoms secondary to core OCD symptoms. In this comorbidity, it is uncertain yet whether inattention, impulsivity, and hyperactivity are secondary to OCD and related anxiety symptoms or represent a co-occurring ADHD (Geller et al., 2002).

ADHD and OCD are two psychiatric syndromes that appear to be at opposite extremities of an impulsive-compulsive continuum. ADHD is characterized by decreased fronto-striatal activity and impulsive behavior, while OCD is characterized by enhanced fronto-striatal activity, inhibited behavior, and harm- and risk-avoidance (Abramovitch et al., 2015).

Attention deficit/hyperactivity disorder with autism spectrum disorder and anxiety

Comorbid anxiety disorders are often reported in individuals with both ADHD and autism spectrum disorder (ASD) (Holtmann et al., 2007; Matson and Nebel-Schwalm, 2007; Simonoff et al., 2008; Taurines et al., 2010; Gadow et al., 2012).

ASD constitutes a group of neurodevelopmental disorders that are frequently associated with general cognitive deficits (Zamberletti et al., 2017).

Guttmann-Steinmetz et al. (2010) reported that anxiety levels in children with ASD comorbid with ADHD were higher as compared to those of children with ADHD or ASD alone. The overlap of ASD with anxiety disorders has become a rapidly emerging area of research (Matson and Williams, 2014). A meta-analysis by Reichow et al. (2013) demonstrated superiority of MPH over placebo in the treatment of ADHD symptomatology in children with ASD. MPH was also shown to be moderately successful in treating irritability and stereotypic behaviors in children with ASD (Quintana et al., 1995; Handen et al., 2000). Golubchik et al. (2017) evaluated the response of depression/anxiety symptoms to 12 weeks of MPH treatment, as expressed in a school situation of subjects with high functioning ASD with ADHD comorbidity. ADHD symptoms improved significantly and a similar beneficial effect was observed in mood/anxiety symptoms (P = 0.046). It is possible that improvement in anxiety symptoms occurred due to improvement in academic, social, and behavioral domains. A similar observation was reported previously in children with combined ADHD but no ASD (Golubchik et al., 2013).

Improvement in school-related anxiety in children with ASD may promote improvement in school functioning (Wilson et al., 2014). It is suggested that in cases with relatively mild levels of anxiety, the response of the ADHD, depression, and school-related anxiety symptomatology is similar to that reported in children with ADHD alone (Golubchik et al., 2013; Golubchik et al., 2014a,2014b).

Pharmacological treatment of attention deficit/hyperactivity disorder with comorbid anxiety

Stimulants

Methylphenidate

Methylphenidate, a dopamine-norepinephrine reuptake inhibitor (NRI), is the most common pharmacological treatment for ADHD in children. Caution is advised in preschool children, especially children with tic disorders and in adolescents with a history of drug misuse (Pozzi et al., 2018).

Methylphenidate appears safer than amphetamine, although younger patients and females may incur higher risks, especially with high-doses of immediate-release methylphenidates. Only atomoxetine holds a black-box warning, but amphetamines and methylphenidates too did not show a safe profile regarding mood and emotional symptoms (Pozzi et al., 2018).

Amphetamine

Punja et al. (2016) assessed the efficacy and safety of amphetamines in children and adolescents with ADHD and found that amphetamines seem efficacious at reducing the core symptoms of ADHD; however, they were associated with a number of adverse events. This review found no evidence to support any specific amphetamine derivative over the others. Neither did it find differences between long-acting and short-acting amphetamine preparations.

Nonstimulants

Norepinephrine reuptake inhibitors

Selective NRIs are psychotropic agents that inhibit the uptake of norepinephrine by presynaptic nerve terminals and increase its availability at the synaptic cleft by blocking the norepinephrine transporter (Zheng et al., 2016). Only atomoxetine is approved for the treatment of ADHD. Reboxetine, another NRI, has been approved only for the treatment of depression. It has been suggested, however, that it may be useful for the treatment of ADHD as well, but that still needs investigating (Ghanizadeh, 2015).

Alpha-2 agonists

Based on their ability to alter noradrenergic tone in the PFC, alpha-2 adrenergic agonists (guanfacine and clonidine) are considered alternatives to stimulants. Such modulation is related to increased noradrenergic input from the locus coeruleus and direct postsynaptic stimulation of alpha-2A receptors. The latter are located on dendritic spines of cortical pyramidal cells, thereby directly promoting functional connectivity of prefrontal cortical networks and resulting in improved regulation of attention and behavior (Moss et al., 2007). The specific and selective action of this class of drugs, namely, modulating noradrenergic tone in the PFC, is seen as an essential component of their utility in specific domains of ADHD, influencing hyperactivity, cognition, and impulsivity in a complementary manner, thus optimizing outcome, reducing impairment, and improving functionality.

General principles

It has been suggested that the presence of anxiety comorbidity in ADHD is associated with more global impairment, poorer outcomes, greater resistance to treatment, and increased costs of illness (Faraone et al., 2015).

However, two small-scale, open-label studies in children and adolescents with ADHD and comorbid separation anxiety [42 participants, age range 8–17 years (Golubchik et al., 2014a)] and ADHD and comorbid SAD [21 participants with an age range of 8–18 years (Golubchik et al., 2014b)] have demonstrated improvements in the severity of the anxiety disorders following MPH treatment. This suggests that treating first the ADHD may lead to a parallel attenuation of the anxiety disorders. It is of note, however, that the reductions in separation anxiety and social anxiety symptoms in those studies were marginal (effect size < 0.20 for both).

The reason for the decline in symptoms of anxiety in the course of the clinical trials with psychostimulants is unclear. It could be that the alleviation of ADHD symptoms leads to a parallel alleviation in anxiety accompanied by improvement in functioning (Golubchik et al., 2014a,2014b,2017; Reimherr et al., 2017). Children with ADHD and comorbid anxiety disorders may benefit from atomoxetine, serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIs), or benzodiazepine addition combined with stimulants. Comorbid anxiety does not appear to influence development of side effects or behavioral response to MPH when the dose is titrated, as is the standard clinical practice (Diamond et al., 1999).

Selective serotonin-norepinephrine reuptake inhibitors (SNRIs), which like SSRIs, are approved for anxiety disorders, may have a role in anxious ADHD patients due to their ability to stimulate the noradrenergic neurotransmission and to alleviate anxiety. This, however, is not the case with ADHD.

Additional pharmacological treatment addressing the anxiety symptoms should be considered only when ADHD treatment with the ADHD approved agents, stimulants, and atomoxetine does not bring about remission in the anxiety symptoms (Savill et al., 2015).

Effect of anxiety on response of attention deficit/hyperactivity disorder symptoms to stimulants and nonstimulants

While anxiety symptoms improved during ADHD clinical trials, the improvement did not seem to occur as a direct response to the medications that were used. There is conflicting evidence regarding the impact of anxiety on response to stimulant therapy for ADHD. Although some reports claim that anxiety does not interfere with the response of ADHD to stimulant therapy (March et al., 2000; Abikoff et al., 2005; van der Oord et al., 2008), others have found that stimulants increase anxiety in patients with ADHD and comorbid anxiety disorders (Pliszka, 1989).

Bedard and Tannock (2008) found that MPH improved auditory-verbal manipulation but only in children with ADHD and no anxiety.

Van der Meer et al. (2018) analyzed the effects of severity of ADHD and anxiety and of their interaction on-task accuracy and on neural activity associated with working memory. They found that ADHD with co-occurring anxiety is associated with lowered neural activity as reflected in brain imaging.

A meta-analysis by Coughlin et al. (2015) suggests that treatment with psychostimulants reduces significantly the risk of anxiety compared to placebo, possibly as a secondary effect of improved control of ADHD symptoms. The authors recommend considering rechallenging children with ADHD who report new-onset or worsening of anxiety with psychostimulants, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.

Abikoff et al. (2005) examined the efficacy of sequential pharmacotherapy for ADHD/anxiety in children. Children with improved ADHD who remained anxious were randomly assigned to 8 weeks of double-blind stimulant + fluvoxamine or stimulant + placebo. The response rate of children with ADHD/anxiety to ADHD stimulants is comparable to that of children with ADHD alone. The benefit of adding fluvoxamine to anxiety stimulants remains unclear.

Snircova et al. (2016) compared methylphenidate and atomoxetine’s effects on core ADHD and comorbid anxiety symptoms in children. Both reduced the symptoms of both disorders but atomoxetine was more effective in reducing anxiety symptoms starting from the fourth week of treatment and on. Savill et al. (2015) reviewed publications addressing the efficacy of atomoxetine in 6- to 18-year-olds with ADHD. They found that atomoxetine may demonstrate similar efficacy to methylphenidate on the core symptoms of ADHD.

Recently, a large (n = 176) placebo-controlled study assessed the efficacy of 12-week atomoxetine administration in pediatric ADHD with comorbid anxiety (aged 8–17 years). Atomoxetine was found to be efficacious in reducing both ADHD and anxiety symptoms in patients with these comorbidities (Geller et al., 2007). Notably, this study used a validated pediatric anxiety rating scale to measure response of the anxiety to atomoxetine as well as the effect size and both were found to be as high as is typical for SSRI (effect size = 0.5).

The use of a nonstimulant combined with an SSRI has also been explored in patients with ADHD and comorbid anxiety (Kratochvil et al., 2005). It has been suggested that in this population too, alpha-2 agonists may have anxiolytic properties (Morrow et al., 2004).

The role of combined medication treatments for ADHD and comorbid conditions is unclear and at this time there is no FDA-approved combined treatment (Spencer, 2009). Clearly, more research is required on the efficacy of alternative and combination treatment approaches for patients with ADHD and comorbid anxiety disorders, as well as on the impact of stimulants on anxiety, in those patients.

Specific agents in attention deficit/hyperactivity disorder with comorbid anxiety

Methylphenidate

Moshe et al. (2012) administered MPH – for a week in a randomized double-blind drug/placebo – drug cross-over design in order to examine the relationship between attention and anxiety and to assess the response to MPH in boys with ADHD. According to both, teachers’ and parents’ reports, at baseline, anxiety levels correlated significantly with the attention. They found that in boys with the hyperactive/impulsive and combined types and only in those, the response to MPH was inversely correlated with the reported change in anxiety levels. They furthermore found that the higher the baseline level of anxiety, the lower the level of ADHD response to MPH.

Gürkan et al. (2010) investigated the changes that occur in depression, anxiety, obsessive–compulsive symptoms, and health-related quality of life during MPH treatment in children aged 8–14 years with ADHD. The assessment was done based on self, parent, and teacher reports at baseline as well as at the end of 1 month and 3-months of an MPH treatment regime. They assessed changes in inattention, hyperactivity, impulsivity, depression, anxiety, and obsessive-compulsive symptoms. They found that after 3-months of MPH treatment, depression, trait anxiety, and checking compulsion symptoms decreased and quality of life improved as did symptoms of inattention, hyperactivity, and impulsivity. Blouin et al. (2010) examined response of ADHD symptoms to MPH treatment based on the existence of comorbid anxiety or the lack thereof. They tested two groups, one with ADHD and comorbid anxiety and one with ADHD alone. No statistically significant differences were found between the two groups in the response of ADHD symptoms to the treatment. Cognitively, however, according to the digit span sections of the Wechsler Intelligence Scale for Children, improvement in the ADHD only group was significantly more than in the group with comorbid anxiety. It seems that while anxiety does not affect behavioral response to stimulant medication in populations with ADHD, it does affect the response of more subtle symptoms of cognitive performance.

Another study by Garcia et al. (2009) assessed the possible impact of comorbid anxiety on the response of ADHD to MPH treatment. They found that after 1 month of treatment, between-group differences in the response to treatment with MPH were insignificant between children and adolescents with ADHD only and in children and adolescents with ADHD and comorbid anxiety. Following 1 month of treatment, it was demonstrated that either dimensionally or categorically (moderate response), comorbid anxiety does not interfere with the response of core ADHD symptoms to MPH.

Amphetamine

A recent study by Faraone (2018) assessed the impact of lisdexamfetamine dimesylate (LDX) on anxiety and depressive symptoms in adult outpatients with ADHD and a comorbid anxiety disorder or comorbid mild depression. Concomitant psychopharmacological treatment with SSRIs, SNRIs, benzodiazepine, beta-blockers, atypical antipsychotics, or antiepileptics was allowed, provided that the dose was stable 8 weeks prior to entry. Patients were randomly assigned to either an LDX (30–70 mg/day) group or a placebo group. Each group received its indication for 8 weeks followed by 1 week of placebo for both groups. Next, they were crossed over to the opposite treatment condition for another 8 weeks. As expected LDX reduced ADHD symptoms and did impact anxiety symptoms negatively. However, contrary to studies on response to LDX in ADHD without comorbidity, the rate of ADHD response to LDX was not significantly different from that of the placebo. The authors suggested that at least in adults ADHD with anxiety/depression comorbidity may represent a subtype of ADHD. Unfortunately, there are no similar studies in pediatric populations.

Selective norepinephrine reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors

Data on venlafaxine and duloxetine in children with ADHD are scarce. However, venlafaxine may be an alternative for patients who cannot tolerate or fail to respond to stimulants. Ratner et al. (2005), Toren et al. (2007), and Arabgol et al. (2009) evaluated the efficacy and tolerability of reboxetine – a selective norepinephrine inhibitor – in comparison to MPH in the treatment of children and adolescents with ADHD. They found that reboxetine may be beneficial in such cases; however, further studies are required to clarify the potential therapeutic effects on comorbid depression and anxiety as well as the adverse effect profile. Both atomoxetine and MPH were found to reduce the symptoms of ADHD and anxiety (Snircova et al., 2016). The safety of combinations of stimulants with atomoxetine or with SSRIs/SNRIs is unclear. Such combinations may result in over-stimulation of the noradrenergic or serotonergic systems in patients and thus adequate clinical follow-up is required.

Caution is needed when combining SSRIs, NRIs, or SNRIs with stimulants due to common interactions at the CYP2D6; this drug–drug interaction is referred to in pharmacogenetics guidelines (Wehry et al., 2018; Schoretsanitis et al., 2019).

Nonpharmacological treatment

Children’s executive attention may be improved using cognitive-behavioral interventions (Diamond, 2005). It seems that those may also help in reducing both nonclinical and clinical manifestations of psychopathology, and lead to success in the educational area (Posner and Rothbart, 2005). Sciberras et al. (2018) examined the outcomes of cognitive-behavioral therapy (CBT) intervention for children with ADHD and anxiety. According to parent and teacher reports, those interventions resulted in marked improvements in both child and family well-being as well as improving anxiety and ADHD symptoms, quality of life, and parents’ mental health. Thus, it seems that nonpharmacological interventions can improve important domains of functioning in children with ADHD and anxiety, including reduction of ADHD symptom severity.

Kendall et al. (2001) found that a cognitive-behavioral treatment program was similarly effective in children with anxiety disorder and with or without comorbid disorders, with both groups showing clinically significant improvements in pretreatment diagnoses and symptoms. In this study, presence of comorbid disorders other than anxiety disorders did not seem to moderate response to treatment.

It appears that those children who achieved a clinically significant change in anxiety symptoms are much more likely to show remission of comorbid diagnoses at posttreatment and follow-up. Furthermore, there is some evidence that the presence of an anxiety disorder moderates the response to medications used to treat ADHD (Tannock et al., 1995), although other research suggests that this effect is not present when ADHD medication is properly titrated (Diamond et al., 1999). Van der Meer et al. (2018) found that during a visuospatial working memory task, co-occurring anxiety is associated with lowered neural activity in regions that are important for information gating, and illustrates the neurobiological heterogeneity of ADHD that may be relevant to both pharmacotherapy and psychotherapy. Halldorsdottir et al. (2015) reported that anxious youths with comorbid ADHD are less likely to benefit from CBT strategies alone and raise the possibility that these youths need adjunctive pharmacotherapy or psychosocial interventions.

Additional research is needed to better understand how specific impairments associated with ADHD interact with the anxiety components of CBT, whether delivering treatment in a family or group setting results in different outcomes and whether children with anxiety and moderate to severe ADHD can benefit from CBT for anxiety (Gosch, 2018).

Pharmacotherapy for attention deficit/hyperactivity disorder with specific anxiety disorders

Attention deficit/hyperactivity disorder with social anxiety disorder

MPH has been found to normalize the neural activity and to be associated with some improvements in emotional recognition and in social adaptation (Williams et al., 2008).

In a small-scale study, Golubchik et al. (2014b) compared the scores of school-related items from the Liebowitz Social Anxiety Scale for Children and Adolescents (LSAS-CA) of children with SAD, at baseline and after 12-week MPH treatment. Significant reductions were obtained in some school-related items of LSAS.

The beneficial effect may have been related to MPH improvements in school performance, academic achievement, and self-efficacy, which may have led to improvement in self-esteem and social functioning of the individual (Abikoff et al., 2005).

Moreover, the improvements in ADHD symptoms correlated positively with the school-related SAD symptoms (Golubchik et al., 2014b).

Whalen et al. (1989) also demonstrated that efficient MPH treatment for the ADHD symptoms is associated with improvement in the peer status of hyperactive children, and increased the rate of describing hyperactive boys as ‘best friends, cooperative and fun to be with’. Conzelmann et al. (2009,2011) show that social cognition is impaired in some children with ADHD but normalized by MPH treatment. These relationships may be related to a common underlying pathogenic mechanism of ADHD and SAD (Nijmeijer et al., 2008; Uekermann et al., 2010).

The increased distractibility and impairment in executive function and attention in children with ADHD may result in insecure or anxious attachment that may lead to the development of SAD (Finzi-Dottan et al., 2006). MPH-related improvement in social cognition may alleviate some of the SAD symptoms. The relationships between SAD, ADHD, deficit in social cognition, and emotional recognition merit further investigations.

Attention deficit/hyperactivity disorder with separation anxiety disorder

Little is known about the influence of MPH treatment on comorbid separation anxiety disorder in pediatric populations with ADHD. This group may require a special treatment strategy. In this population, improvement in ADHD symptoms, as well as in academic, social, and family function, may be sufficient to lower tension and anxiety.

Golubchik et al. (2013) assessed the impact of 12 weeks of MPH monotherapy on SSSA symptoms in patients with ADHD.

MPH treatment led to significant reductions in separation anxiety symptoms, as well as corresponding improvement in ADHD symptoms. These parallel beneficial effects may be ascribed to the considerable impact that ADHD-related school difficulties have on the severity of separation anxiety in school situations (Finzi-Dottan et al., 2006).

MPH affects school performance significantly, including academic achievements, self-control, and social functioning (Wigal et al., 2011). Such beneficial effects may contribute to the MPH-related improvement in SAD symptoms in children with ADHD. Namely, the child is more attentive to school demands and assignments, has more self-confidence, and is less anxious about separation situations. It is of note that anxiety disorder unrelated to ADHD rarely responds to MPH (Ter-Stepanian et al., 2010). In contrast, it is possible that mild-to-moderate separation-anxiety levels respond to MPH treatment (Golubchik et al., 2014a).

SSSA is prevalent in ADHD patients and requires clinical attention (Liu et al., 2014a). It is possible that when SSSA symptoms are secondary to the ADHD, the MPH-related alleviation in ADHD is accompanied by a parallel relief in the separation anxiety.

MPH treatment may bring modest improvement to separation anxiety in ADHD patients, especially in the symptoms that are related to school situations. Notably, MPH treatment did not worsen symptoms of SAD in children with ADHD. It is noteworthy that the current existence of small scale, open label, short-term studies justify a large-scale, double-blind, placebo-controlled, long-term investigation.

Attention deficit/hyperactivity disorder with obsessive-compulsive disorder

The presence of OCD in children with ADHD raises issues that are different from those involved in other anxiety disorders. The use of SRIs and SSRIs in children and adolescents with depression have raised concerns and generated warnings of suicidal behavior. Still, these issues have not been well-examined in OCD. Since the treatment of OCD requires high doses of SRIs and SSRIs, some caution is therefore required. The author’s recommendation is that CBT be first-line treatment and SSRIs second-line treatment. The latter should be introduced carefully and with slow dose escalation.

Treatment options for the two disorders include stimulants or SSRIs and possibly CBT for both the ADHD and the OCD. Sometimes CBT and SSRIs with or without dopamine receptor D2 blockers are required for the OCD component. Individuals with comorbid ADHD-OCD are functionally more impaired than individuals with each disorder alone. It is critical to determine the effective treatments for this complex condition (Abramovitch et al., 2015).

While stimulants are considered to be first-line treatment for ADHD, they should be used with great caution in OCD, given their potential to exacerbate OCD symptoms (Kouris, 1998). Taormina et al. (2016) described remission of both OCD and ADHD in two children with severe OCD and comorbid ADHD following guanfacine/sertraline combined treatment. Still, further studies are needed to truly evaluate the role of stimulants or clonidine/guanfacine administration in patients with OCD/ADHD comorbidity.

Attention deficit/hyperactivity disorder with autism spectrum disorder-associated anxiety

A meta-analysis by Reichow et al. (2013) demonstrated superiority of MPH over placebo in the treatment of ADHD symptomatology in children with ASD. MPH was also shown to be moderately successful in treating irritability and stereotypic behaviors in children with ASD (Quintana et al., 1995; Handen et al., 2000). Golubchik et al. (2017) evaluated the response to 12 weeks of MPH treatment, of depression/anxiety symptoms as expressed in a high-demand social-learning context (school situation) of patients with high functioning ASD comorbid with ADHD. The achieved improvement in ADHD symptoms was accompanied by a corresponding reduction in mood/anxiety symptoms (P = 0.046). A possible explanation for this parallel improvement may be related to better general functioning, including in the academic, social, and behavioral domains. A similar correlation was shown in a previous study on children suffering from ADHD but no ASD (Golubchik et al., 2013).

Improvement in school-related anxiety in children with ASD may promote improvement in school functioning (Wilson et al., 2014). It is suggested that in cases with relatively mild levels of anxiety, the response of ADHD, depression, and school-related anxiety symptomatology is similar to that reported in children with ADHD alone (Golubchik et al., 2013,2014a,2014b).

It is of note that a study by Jahromi et al. (2009) demonstrated that MPH treatment helped to improve social communication, self-regulation, and regulated effect in children with ASD with comorbid hyperactivity. Pearson et al. (2013) examined the behavioral effects of psychostimulants and found that MPH formulations were well-tolerated in children with ASD combined with significant ADHD symptoms. No exacerbation of stereotypic behaviors was noted, and side effects were similar to those seen in children with ADHD alone. Other studies, however, reported adverse effects of MPH treatment in ASD populations (Ghuman et al., 2009; Pearson et al., 2013). Those opposing results suggest the need to closely monitor children with ASD, both with and without comorbid anxiety disorders, during MPH administration.

It thus appears that MPH treatment in patients with ASD and comorbid ADHD may be effective for both the depression and anxiety symptoms related to school. Additionally, this seems to be a safe and tolerable treatment that has the potential of alleviating school-related anxiety as well as mood symptoms in ASD/ADHD patients.

Regarding ADHD, however, stimulants seem to be less effective and poorly tolerated by a substantial portion of patients with ASD. Golubchik et al. (2013) assessed the impact of the selective NRI reboxetine on depressive/anxiety and ADHD-like symptoms in high-functioning pediatric patients with ASD. They found that reboxetine treatment may reduce depression/anxiety and ADHD symptoms in adolescents with ASD. However, they noted a high rate of adverse effects that require close monitoring.

Discussion

Early diagnosis and appropriate treatment of children with ADHD as a primary condition and comorbid anxiety disorders may prevent secondary functional difficulties due to anxiety disorders. There is some overlap between symptoms of ADHD and anxiety disorders; hence, assessment tools and treatment plans for children with anxiety disorders should be sensitive enough to discriminate ADHD symptoms from anxiety-related inattention.

ADHD pharmacotherapy seems to be as effective in reducing core ADHD symptoms in patients with comorbid anxiety disorders, as it is in patients who have no anxiety disorder comorbidity (March et al., 2000). However, the direct contribution of the drug treatment to the improvement of both ADHD and anxiety symptoms is unclear, since the improvement in one disorder may affect the other positively (Golubchik et al., 2014a,2014b; Reimherr et al., 2017). Furthermore, patients with ADHD tend to benefit less from CBT as a monotherapy and often require addition of pharmacological treatments. Their response to MPH treatment is frequently weaker and they tend to be more sensitive to the arousal side-effects. These findings, however, are inconsistent and merit large-scale studies (Faraone et al., 2015; D’Agati et al., 2019).

In treatment of ADHD with comorbid anxiety disorders of mild-moderate severity, stimulant or atomoxetine monotherapy seems to be the best choice. The same is true for comorbid subsyndromal anxiety disorders (Golubchik et al., 2014a).

It is unclear why symptoms of anxiety are attenuated in the course of psychostimulant treatment. It may be that the alleviation of ADHD symptoms leads to a corresponding decline in the level of anxiety, leading in turn to improvement in functioning.

Some authors report that the response to MPH is inversely correlated with the anxiety level (Ter-Stepanian et al., 2010; Moshe et al., 2012); however, in a laboratory situation, a single dose of MPH was shown to provoke anxiety in some children (Kritchman et al., 2019). Other studies claim that stimulants neither improve nor exacerbate anxiety symptoms in children with ADHD (Abikoff et al., 2005). Thus, it seems that stimulants can be considered as first-line medications for ADHD with comorbid anxiety disorders.

This recommendation, however, might be challenged by the impressively large effect sizes of atomoxetine (1.0 for ADHD; 0.5 for anxiety) (Geller et al., 2007), which specifically targets comorbid anxiety disorders, in addition to treating the core ADHD symptoms and should be considered in such complex cases. Geller et al. (2007) and Kratochvil et al. (2005) reported that atomoxetine treatment for pediatric patients with ADHD and comorbid anxiety disorders, including GAD, separation anxiety disorder and SAD, is efficacious in reducing both ADHD and anxiety symptoms. It thus appears that both MPH and atomoxetine treatment may be safe and effective in ADHD patients suffering from comorbid anxiety disorders. Unfortunately, there are no evidence-based guidelines for the treatment of such comorbidities.

Indeed, a substantial portion of patients with concurrent ADHD and anxiety disorders are treated with monotherapy (up to 45%) or combined pharmacotherapy (up to 30%), while most of them are treated with nonpharmacological interventions (Liu et al., 2014b). Generally, in some cases, the need for treating the ADHD outweighs the need for treating the anxiety disorders. Unfortunately, data regarding the comparative effectiveness of stimulants in children with combined ADHD and anxiety disorders are limited. Moreover, there are concerns about the possible exacerbation of anxiety or mood symptoms by stimulant administration. Such concerns lead to preferring stimulants alone or atomoxetine alone in children with ADHD and anxiety disorders.

The second- and third-line treatments include atomoxetine/alpha-2 agonists and in severe cases SSRIs or SNRIs (Liu et al., 2014b; Pan et al., 2018). It is important to realize that untreated ADHD or anxiety disorders can result in low self-esteem, poor school performance, and impaired social functioning (Harpin et al., 2016).

The combination of stimulants and SSRIs or SNRIs is a pharmacotherapeutic option for ADHD with anxiety disorders with or without depressed mood, but clinical trials evaluating this practice are very limited (Abikoff et al., 2005).

The possible risk of children and adolescents with depressed/anxious mood receiving antidepressants (SRIs, SSRIs or SNRIs and all others) to develop suicidality is also a safety concern. The black box warnings on pediatric use of antidepressants in children with depression are therefore warranted. Wider availability of psychosocial options for these children is recommended (Sparks and Duncan, 2013).

Conclusion

It appears that stimulant monotherapy may be considered as the first-line of treatment due to rapid response and high safety profile, especially in children with comorbid subsyndromal or mild anxiety disorders. There is no contraindication for stimulant monotherapy in cases with mild-moderate levels of comorbid anxiety disorders in ADHD patients. Alleviation of the ADHD symptoms achieved by stimulant therapy may lead to a corresponding decline in the level of anxiety and to improvement in functioning. Notably, a recent meta-analysis demonstrated that early treatment with stimulants has a strong protective effect on functional outcomes of youths with ADHD, including those with comorbid anxiety disorders (Biederman et al., 2019).

Adjunctive CBT for anxiety symptoms is strongly recommended. Improvement in social and educational functioning achieved by stimulant treatment combined with CBT may lead to a corresponding decrease in anxiety levels.

When symptoms of anxiety do not show remission during ADHD treatment, additional pharmacological treatments addressing specifically the anxiety symptoms should be considered. The NRI atomoxetine may be a first-or second-line treatment for ADHD comorbid with mild-moderate severity anxiety disorders. In addition, alpha-2 agonists may also be used for this population.

In moderate and severe cases of anxiety disorders, SSRIs can be added to stimulants, albeit with the usual cautions required in SSRI treatment in children. This is especially relevant to ADHD with comorbid OCD.

MPH treatment in ASD patients with ADHD and anxiety may be safe and tolerable and has the potential to improve ADHD symptoms and alleviate school-related anxiety as well as mood symptoms, in some ASD/ADHD patients. It may be, however, less effective and poorly tolerated by a substantial portion of children with ASD as compared to those with ADHD without ASD.

Safety and effectiveness studies of short-term and long-term drug combinations for the treatment of ADHD comorbid with anxiety disorders are definitely warranted in order to create evidence-based guidelines for the treatment of this clinical combination.

Acknowledgements

The authors thank Ms. Micky Gerchak for editorial assistance.

Conflicts of interest

There are no conflicts of interest.

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    Keywords:

    anxiety; anxiety disorders; ttention deficit/hyperactivity disorder; nonpharmacological treatment; pharmacological treatment

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