Update on Attention-Deficit/Hyperactivity Disorder and Tic Disorders: A Review of the Current Literature
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- Simpson, H.A., Jung, L. & Murphy, T.K. Curr Psychiatry Rep (2011) 13: 351. doi:10.1007/s11920-011-0223-1
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Tic disorders impact quality of life, but when they are co-occurring with attention-deficit/hyperactivity disorder, the combined impact takes a toll on psychosocial functioning and adds another layer of complexity to treatment approaches. A review of the current literature supports evidence of a unique relationship between comorbid attention-deficit/hyperactivity disorder and tic disorders, emphasizing the intricate phenotype and impairment associated with these co-occurring conditions. The complexity of these symptoms requires careful diagnosis and appropriate treatment as determined by the level of impairment and can include pharmacotherapy, behavioral interventions, or a combination of therapies. To achieve the greatest benefits in improving quality of life and eliminating further comorbidity, an ideal treatment plan would include a comprehensive evaluation as well as a hierarchical treatment approach involving education of the child, family, and teachers; careful medication management; and cognitive and behavioral training.
KeywordsAttention-deficit/hyperactivity disorderADHDTic disordersTourette syndromeTreatmentComorbidity
The coexistence of attention-deficit/hyperactivity disorder (ADHD) presents in about 50% of patients with a tic disorder, while 20% of ADHD patients have been found to have a comorbid tic disorder . With a prevalence of ADHD of about 2% to 12% in the general population, the frequency of co-occurring ADHD with tic disorders is markedly higher than would be expected from a chance association [2•, 3]. When ADHD and tic disorders co-occur, they often worsen social adjustment [4, 5] and academic achievement  beyond what is observed in association with ADHD or tics alone [6–10]. There is ongoing debate as to what this increased co-occurrence of ADHD with tics could signify and what the genetic and clinical implications may be.
When repetitive behaviors develop in a child with ADHD, the behaviors are often attributed to allergies, chronic cough, or habit behaviors. Tics present as sudden, rapid, recurrent, nonrhythmic, stereotyped movements or vocalizations and may be transient or chronic in nature [2•]. The mean age at onset of tics is generally 6 to 7 years, with motor tics typically preceding vocal tics [2•]. Tics may occur multiple times daily, nearly every day, or intermittently. They often have a waxing and waning course, and the frequency, complexity, type, and severity may change over time [2•]. Impulsive and self-stimulating behaviors can sometimes mimic tics (e.g., silly and impulsive animal noises to mitigate boredom), and context should help in the differentiation. Stereotypic movements, compulsions, and other medical/neurological conditions also should be considered when assessing new repetitive behaviors in a child with ADHD.
ADHD is shown to be one of the most common mental disorders—a disorder that can persist into adulthood with a complicated course due to the high rate of comorbidity . The onset of ADHD typically precedes onset of tics by 2 to 3 years. [2•, 11•]. When tics and ADHD co-occur, the risk is increased for low-frustration tolerance, outbursts, noncompliance, and aggression, as well as learning disorders and academic difficulties [12–18]. This relationship suggests great clinical importance, as each disorder can lead to impairment in several areas, and additional impairment is possible due to the co-occurring condition. Furthermore, when the disorders are co-occurring, decision making regarding treatment becomes more complex. Chronic tic disorders such as Tourette syndrome (TS) have been found to have a high rate of co-occurring psychiatric disorders, with rates as high as 60% to 80% with ADHD, 27% with obsessive-compulsive disorder (OCD), 20% with concomitant mood disorders, 18% with other anxiety disorders, and 15% with conduct disorder and/or oppositional defiant disorder [2•]. In fact, the literature suggests that only 8% to 12% of children with a diagnosis of TS have no other psychiatric diagnoses, and in general, multiple diagnoses are the rule rather than the exception .
With this high degree of disease burden, accurate diagnosis becomes essential, as does appropriate management of co-occurring conditions. When quality of life has been measured in children with tic disorders and co-occurring ADHD and/or obsessive-compulsive symptoms, determinations are related much more to the impairment secondary to comorbidities rather than the type or severity of tic disorders themselves . Children diagnosed with both ADHD and TS were noted to have even higher rates of anger control problems, sleep disturbances, specific learning disabilities, obsessive-compulsive symptoms, mood disorders, social skill deficits, sexually inappropriate behaviors, and self-injurious behaviors than those with TS alone [8, 10, 20, 21].
There are currently three models that have been developed to describe the relationship between ADHD and tics [2•]. The first, the additive model, is the current prevailing school of thought that suggests that tics and comorbid ADHD are two separate diagnostic entities. The second is the interactive model, which suggests that the combination of tics and ADHD represents a separate diagnostic entity from either individual diagnosis. Finally, the phenotype model suggests that comorbid tics with ADHD represent a phenotypic subgroup of the two main clinical diagnoses. Currently, however, the relationship between ADHD and tics continues to be studied, but at this point, the mechanisms remain unclear .
The presence of ADHD appears to be the primary determining influence for when aggressive behaviors occur in youth with tics. Studies that have compared aggression in individuals with TS only, TS and ADHD, and controls have shown that the TS only group was similar to the group of controls in terms of aggression, but when ADHD was present, rates of aggression increased . These rates of aggression in the TS and ADHD group have been compared and found to be similar to those in ADHD only groups [2•]. Results from a study measuring aggressive behavior in those with ADHD only and those with ADHD with mild tics showed no significant difference; however, higher rates of anxiety, aggression, and oppositional behaviors were noted in the ADHD with severe tics group . Aggression, or “rage attacks,” is a leading cause of morbidity in children with TS and is associated with increased levels of family distress, impaired social skills, likelihood of psychiatric hospitalization, and subsequent placements in alternative schools and residential treatment programs . It has been shown that 25% to 70% of individuals with TS have difficulties with anger control, affective lability, or recurrent behavioral dyscontrol, and that these symptoms are likely not directly related to tic type or severity, but rather to psychiatric comorbidities, particularly ADHD and OCD .
Sleep disturbances may be seen with both TS and ADHD individually—namely, children with ADHD have been noted to have increased rapid eye movement sleep, and children with TS have been noted to have a lower sleep efficiency and increased number of arousals during sleep . Children diagnosed with both ADHD and TS show an additive effect with both increased rapid eye movement sleep and decreased sleep efficiency and increased arousals, which supports the theory that ADHD and TS, although occurring together very frequently, are two separate diagnostic entities.
TS involves dysfunction of the cortico-striato-thalamo-cortical pathways, most prominently those subserving motor function. Functional imaging studies have shown decreased activity and volume and right-sided predominant asymmetry in the basal ganglia, which has been implicated as an important region for motor and behavioral expression [2•, 26]. Recent studies in patients with TS have shown a significant correlation between activation seen on functional MRI and OCD, but no significant correlations between activation patterns on functional MRI and ADHD . Other studies have described a relationship between asymmetrical globus pallidus volume and ADHD in TS patients . TS with comorbidities, including ADHD and OCD, also has been correlated with reduced volume of the anterior caudate nucleus and increased volume of the amygdala, and hippocampal volume has been correlated with severity of tics and presence of ADHD and OCD [28, 29].
Twin and family studies have provided strong support for a genetic underpinning of tic disorders and ADHD . Frame shift mutations in SLITRK1 on chromosome 13q31.1 have been studied as a genetic cause of TS, and investigations on chromosomes 4, 5, 8, 11, and 17 continue, though no specific mutations have been identified. However, the most recent literature suggests that the SLITRK1 gene is not a major risk factor for most individuals with TS [31, 32]. Recent research also has evaluated the role of copy number variants (CNVs) in families with a high prevalence of ADHD diagnoses. Among multiple genes in the ADHD CNVs studied, two chromosomal rearrangements, CNTNAP2 and IMMP2L, have been reported in patients also diagnosed with TS [33•]. As described previously, ADHD has long been thought to have a genetic correlation with TS, but more recent research has not supported this direct genetic correlation between TS and the most common form of ADHD. Mathews and Grados [34•] conducted a heritability analysis with 952 individuals from 222 TS-affected sibling pair families and described a significant genetic correlation between TS and OCD, OCD and ADHD, but not between TS and ADHD. They did describe environmental correlations between both types of comorbid presentations: ADHD and OCD, as well as ADHD and TS [34•].
Environmental risks also have been detected on a prenatal and perinatal level and shown to be associated with TS and ADHD. In a study comparing 181 children with TS and ADHD to 172 children with TS only, the TS and ADHD children had a higher likelihood of maternal smoking, premature birth, low birth weight, and breathing difficulties compared with the TS only children . Group A streptococcal infections also have been associated with sudden onset of tics, as well more difficulty paying attention and increased fidgetiness/restlessness, suggesting a possible immunologic component to this symptomatology .
There is a great deal of debate regarding the appropriate use of ADHD medications in the presence of tics. In the United States and Europe, stimulants are considered first-line treatment in ADHD cases without tic disorders . In children with ADHD and co-occurring tics, many clinicians are reluctant to use stimulants due to concerns that these medications can increase tic symptoms . However, recent reviews have found that stimulants may not worsen tics in those with both ADHD and tics and should not be disregarded in treatment planning [3, 24]. Due to the natural waxing and waning course of tics, it is often difficult to prove that a medication has caused a worsening of tics; therefore, a 3-month observation could be required by clinicians to determine appropriate symptom management .
With regard to those with ADHD and TS, some suggest that clinicians should determine which are the most impairing symptoms and target those for treatment first [2•]. To address the symptoms of inattention, impulsivity, and hyperactivity associated with ADHD, stimulants are often first-line treatment. However, stimulants are not tolerated or efficacious in 10% to 20% of cases, possibly due to exacerbation of tics [33•]. The outcomes of some case reports and studies resulted in concerns that stimulants may induce tics in children without preexisting tics [38–41]. The suggested correlation between the development or exacerbation of tics and use of stimulants has been analyzed in several clinical trials. Denckla and colleagues  reported the development of motor tics or an exacerbation of preexisting tics in approximately 1.3% of children (n = 1,520) receiving methylphenidate therapy for ADHD, suggesting that stimulant therapy does not significantly induce tics or exacerbate preexisting tics, and that this can be seen as a rare occurrence. Large-sample study data are also available that report no marked correlation among the emergence of tics, the severity and course of preexisting tics, and stimulant dosage [38, 43, 44]. Children with tic onset after beginning stimulant therapy were most commonly found to be within the age range when tics disorders had their onset spontaneously . Roessner et al.  suggest that the relationship between stimulant use and first onset of tics may be an early triggering of what would have been a later spontaneous tic onset.
A meta-analysis evaluating current treatment for comorbid tics and ADHD also found that short-term methylphenidate therapy did not seem to worsen tics significantly [11•]. In a small crossover study (n = 10) that examined the effects of stimulant dosing on a tic suppression paradigm, a one-time dose of short-acting stimulants did not increase tics in children with ADHD and TS; however, one-time administration of immediate-release dexmethylphenidate did not significantly improve tic suppression ability . In a double-blind study of prepubertal children (n = 71) receiving placebo or immediate-release methylphenidate (MPH-IR) at doses of 0.1, 0.3, and 0.5 mg/kg twice daily for 2 weeks each, there was no evidence to suggest that MPH-IR altered the overall severity of tic disorder or OCD behaviors. Teacher ratings indicated that MPH-IR therapy decreased tic frequency and severity . The presence of tics may limit the maximum dose achieved when compared with an ADHD only group. Other options are the use of atomoxetine, which has reported benefits with regard to tic symptoms as well as ADHD .
In addition to stimulants, nonstimulants such as α2 agonists, atomoxetine, and desipramine have been studied for benefit with ADHD symptoms [11•]. The current literature suggests that α2 agonists yield the best combined improvement in tics and ADHD symptoms, although ADHD improvement is not as robust as it is with stimulant therapy. Scahill et al.  conducted a double-blind, placebo-controlled trial of parallel groups with children who had ADHD and a comorbid tic disorder. Patients received guanfacine, 0.5 to 4 mg (modal dose, 1 mg three times daily). After 8 weeks, there was a 31% drop in the Yale Global Tic Severity Scale scores of youth with tic disorders, compared with a 0% improvement among those taking placebo (effect size, 0.67). Measures of ADHD showed a 37% improvement as reported by teachers (effect size, 1.23), a better response than in nonstimulant studies, but not as robust a response as stimulant medications might yield . α2 agonists also have been used to treat sleep difficulties in children with ADHD and TS [3, 22]. Clonidine has been recommended in cases in which TS is the primary disorder , with existing evidence of reduction in tic frequency and severity to go along with improvement in ADHD symptoms; an increase in tics occurred in approximately 25% of cases . Newer extended-release α2 agonists may also provide additional options in managing ADHD symptoms as well as in maintaining the benefits of tic control, but more research is needed in this area. Atomoxetine has been helpful for some children with ADHD and has mostly a neutral or beneficial impact on tics [47, 50]; however, occasional reports of tics worsening do exist [51, 52]. Desipramine has also shown benefits for ADHD without worsening tics; however, this is not a first-line treatment due to concerns about cardiac side effects [11•].
Aggressive behavior related to ADHD may respond to stimulants or α2 agonists to address conduct disorder or oppositional defiant disorder . Although there may be a widespread belief that stimulants induce aggression in ADHD patients, controlled trials show an overall decline in aggressive acts and antisocial behavior when patients are treated with stimulants [53, 54]. One might consider selective serotonin reuptake inhibitors such as fluoxetine, fluvoxamine, and sertraline, which have extensive literature supporting their benefit for aggression, especially when it occurs in the context of OCD or related symptoms .
The decision to treat tic disorders is dependent on several variables, including severity of the tics, comorbid psychiatric disorders, and functional impairment. Treatment for TS and the multiple comorbidities described previously may include pharmacologic therapy, behavioral therapy, or a combination of the two. Behavioral therapy options include habit reversal training (HRT), biofeedback and awareness training, as well as relaxation training. HRT has worked well to improve tics with long-term effects; however, the benefits of relaxation training, although short-term improvement was noted, did not last [55, 56]. In addition to HRT techniques, comprehensive behavioral intervention for tics adds relaxation training and a functional analysis of exacerbating and alleviating factors related to tic symptoms. Although many of the youth in the study were on psychotherapeutic agents, a comparable magnitude of response to comprehensive behavioral intervention for tics compared with controlled trials with antipsychotic medications for treatment of TS was noted [57•]. As noted previously, tic disorders occur frequently with some degree of oppositional or disruptive behaviors, and preliminary studies have shown that parent management training may be helpful for short-term improvement in these disruptive behavior problems . Behavior therapy for ADHD may be recommended in those with mild symptoms and minimal impairment if parents prefer to treat without medication, or if there is marked disagreement between parents and teachers . Manualized treatments in the context of behavioral parent training include key points such as psychoeducation of ADHD, attending to the child’s misbehavior, managing noncompliant behaviors in public settings, and anticipating future misconduct [53, 59].
When tics co-occur with ADHD, the diagnostic complexity increases and, correspondingly, so does the treatment complexity. Those with co-occurring ADHD and tics experience more behavioral, social, and academic difficulties than individuals with tics or ADHD alone. Most mild tics do not require additional treatment. Behavioral options and medications such as α2 agonists may benefit both presentations. Traditionally, the treatment of ADHD has relied primarily on stimulants, but this treatment option, when approached carefully, offers the potential to significantly improve academic and social function. The decision to treat the ADHD and/or the tics will depend on a careful hierarchical review of the severity of the presenting symptoms, with the primary goal of reducing impairment and improving quality of life in youth with tics and ADHD.
Dr. Murphy has received grant support from the National Institutes of Health and the Centers for Disease Control and Prevention.
Dr. Murphy has served on boards for the Tourette Syndrome Association and the International OCD Foundation; has received grant support from the Otsuka Pharmaceutical Group, Indevus Pharmaceuticals, and Shire; has received honoraria from the Arizona Psychiatric Association; and has had travel/accommodations expenses covered or reimbursed for attendance at Tourette Syndrome Association meetings/lectures and by various venues for giving talks or participating in committee meetings.
Dr. Simpson and Ms. Jung reported no potential conflicts of interest relevant to this article.