Untreated challenging behaviors are likely to interfere with the individual's development as well as educational inclusion and family life. Many individuals with ASD manifest behavioral problems that can be identified using DSM-IV-TR [2
] diagnostic symptom clusters to guide choice of comorbid diagnosis and related treatment selections. Principles of treatment selection include “First do no harm,” “Start low and go slow with any medications,” and “Individualize patient care.” For example, in terms of psychiatric treatment, a low dose of stimulant medication such as methylphenidate [61
] or dextroamphetamine [62
] may be tried initially for a person with ASD and mild to moderate symptoms of inattention, impulsivity, and/or hyperactivity, while a low dose of atomoxetine [63
] may be more suitable if the individual also has significant self-injurious behaviors, since stimulants could worsen anxiety and self-injury.
Individuals presenting with aggression, property destruction, or self-injury as main symptoms are examples that may benefit from first-line treatment with low doses of risperidone or aripiprazole prior to any treatments for hyperactivity, if needed [61
]. Once a trend towards improvement is obtained with medication, the dose may be cautiously increased to achieve significant improvement, while any side effects are closely monitored. Combination treatments may be necessary in order to minimize side effects and maximize benefits on behavior, although additional studies are needed in this population and in general [68
Comorbid diagnoses are helpful in guiding the treatment focus, while bearing in mind a likely commonality between neurobiological causes of the ASD symptoms as well as any psychiatric symptom behaviors or clusters. Common symptom clusters in ASD include the hyperactive-inattentive impulsive-distractible cluster, the compulsive-sameness-explosive symptom cluster, tics and tourette syndrome, and a mood disorder symptom cluster which may be depressive or bipolar in nature [22
]. It is not uncommon for one or more of these clusters to cooccur, emphasizing the need to prioritize treatment trials based on symptoms to target and in what order.
Hyperactivity across multiple settings, including home and school, may be the most obvious symptom suggesting the hyperactive-inattentive impulsive-distractible symptom cluster [70
]. One diagnostic difficulty is that hyperactivity in youth without disabilities is known to diminish in comparison with other symptoms of attention deficit hyperactivity disorder (ADHD) in the early teenage years, in which impulsivity and its association with ADHD treatment response may be missed [73
]. Impulsivity often presents as hitting, kicking, biting, cussing, running off, and throwing objects but responds to treatments indicated for ADHD, although combination treatments may be needed, for example, a stimulant medication such as dextroamphetamine together with low-dose atomoxetine. Inattention alone is easily missed clinically, but if identified and treated, will likely improve developmental progress. Methylphenidate may be useful, starting at 1
mg/kg/day in 3 divided doses [61
]. Dextroamphetamine is longer acting than methylphenidate, more potent and is started at 0.5
mg/kg/day, in morning and midday doses, with a possible 4pm half dose [62
While long-acting stimulant preparations of these two main stimulants are available, studies in individuals with ASD are lacking. Clinical practice suggests that the side effects of appetite decrease, anxiety, and insomnia may also show greater worsening with long-acting rather than with short-acting stimulants. Atomoxetine is started at 0.5
mg/kg/day and increased gradually as tolerated to approximately 1
mg/kg/day or up to 1.5
], although lower doses may provide meaningful help. Seizures, headaches, behavioral activation, appetite decrease, and cardiovascular side effects require close monitoring. Atomoxetine also has mood elevating properties, and thus may be a useful choice over a selective serotonin uptake inhibitor (SSRI), in the presence of depressive and attentional symptom clusters.
Another useful medication, albeit requiring caution, and close monitoring for the hyperactive-inattention symptom cluster is amitriptyline, but prospective studies are warranted [75
]. Our experience suggests that this tricyclic antidepressant, amitriptyline, is more effective in persons with ASD than is clomipramine [77
], imipramine, or desipramine, in the treatment of hyperactive, aggressive children. Amitriptyline is safe in low doses with trough blood levels at 100 to 150
mcg/dL, according to a recent chart review of 50 patients [76
]. Both clomipramine and desipramine are associated with superior response over placebo in the study reported by Gordon et al. [77
] in a 10-week randomized crossover study in seven children with ASD. Quarterly EKG monitoring is necessary to monitor for QTc prolongation, as well as documented warnings to parents to lock medications away related to overdose toxicity.
As noted above, low doses of stimulants and risperidone or aripiprazole may be used in combination treatments, necessitating close monitoring for side effects. Other treatments for this symptom cluster include the use of alpha agonist drugs, clonidine and guanfacine, and long-acting preparations thereof. Mild improvements in hyperactivity and irritability were achieved in a double-blind crossover study of clonidine and placebo in 8 children with ASD [78
], although eventual drug tolerance, sedation, and low blood pressure were problematic effects. Posey and McDougle [80
] also performed a retrospective review of 80 children with ASD treated with guanfacine, in which 19 of 80 were rated as responders. An open-label, prospective study by Scahill et al. [81
] found that 48% of 25 children with ASD and ADHD symptoms were guanfacin responders.
Individuals manifesting the compulsive-sameness-explosive symptom cluster often engage in arranging objects, hoarding, and repetitive behaviors, to an extent that interferes with their own and others' functioning [82
]. Tantrums and explosive behaviors are common if the individuals' routines are disrupted or prevented, resulting in screaming, aggression, self-injury, and property destruction if severe. Impulsivity, associated with the hyperactivity symptom cluster or a bipolar mood disorder symptom cluster may require appropriate concomitant medication treatments and may be missed if the compulsive symptoms are severe in nature. Associated bipolar mood disorder symptoms include irritable mood, laughing or crying spells, pacing, sexual preoccupation, and rapid flaring into aggression [69
]. Mood stabilizing medications such as antiseizure medications, lithium, and/or antipsychotics may be helpful in the latter cases.
While SSRIs are a mainstay of treatment for individuals with obsessive compulsive disorder in the general population, activation, and lack of response are problematic in SSRI treatments for individuals with ASD [83
]. In our experience SSRIs may be helpful mostly in mild cases without other comorbidity. A recent multisite randomized, placebo-controlled trial of citalopram showed no significant improvement over placebo for repetitive behaviors rated on the modified Yale-Brown Obsessive Compulsive scale [84
]. Two open-label studies showed benefit of sertraline and fluoxetine in individuals with ASD, although behavioral activation can be limiting [85
] and dose related. Fluvoxamine reduced aggression and compulsive behaviors by 50% in a randomized, double-blind placebo controlled study of 30 adults with ASD [87
]. In addition, drug interactions require vigilance in SSRI prescription, particularly of paroxetine, fluoxetine, and sertraline due to inhibition of the cytochrome P450 enzyme system which is responsible for breakdown of many psychotropic and nonpsychotropic medications. In addition, sexual side effects of SSRIs may be difficult to elicit in individuals who lack expressive language and may impede sexual functioning and satisfaction, also to be considered in individuals without a sexual partner.
Mood disorder cluster symptoms may be depressive or identified on the bipolar spectrum. Depressive symptoms include sadness and low mood, withdrawn behavior, insomnia or excessive sleeping, appetite increase or decrease, and suicidal thoughts or behavior. Low-dose antidepressant medications and psychotherapy are appropriate treatments. Bipolar mood disorder symptoms include irritability, euphoria, or mixed states with both laughing and crying spells. Associated externalizing behaviors include aggression, property destruction, and elopement. In individuals with ASD, bipolar disorder is more often atypical, chronic, mixed, or rapid cycling [69
]. Constant loud vocalizations, pressured speech, insomnia, and aggression together with constant pacing may occur [88
]. While atypical antipsychotics are potent mood stabilizers with rapid onset of effects, antiseizure mood stabilizing agents may also be effective and used as a first-line treatment in mild or moderate cases. These include valproic acid (VPA), gabapentin in combination with VPA [89
], and carbamazepine. Atypical antipsychotics include risperidone, which is the most studied in this population [65
], aripiprazole [90
], olanzapine [91
], quetiapine [92
], and ziprasidone [94
]. All of these medications carry a black box label (FDA warning) for weight gain, metabolic syndrome, and type II diabetes. Risperidone may further cause prolactin elevation, more pronounced in females, resulting in enlarged breasts (gynaecomastia), lactation, menstrual irregularities, and possible changes in bone and sexual development [96
]. Low doses of an antipsychotic drug in combination with antiseizure medications or lithium may also be beneficial for resistant cases, with close monitoring of metabolic indicators of weight, blood pressure, serum lipids, and HbA1c. In addition, risperidone may be effective in low doses for self-injury [65
]. Atypical antipsychotics are also prescribed as first-line treatments for irritability and aggression, although clinicians should carefully examine for missed or undertreated hyperactive-inattentive impulsive-distractible symptoms which are likely to respond more significantly to ADHD medications, as discussed above.
Several other medications have been studied so far targeting the core social relating impairments in ASD [97
]. These include memantine [98
], amantadine [100
], D-cycloserine [101
], lamotrigine [103
], secretin [104
], and naltrexone [106
]. All of these agents produced negative or mixed results. In addition, an oxytocin spray is now available, but studies are needed to clarify its effects, if any, in individuals with ASD.
In conclusion, we describe our current approach for evaluation and treatment of individuals with developmental delays and associated behavior problems in ASD. Early assessment and work-up, although laborious and requiring multidisciplinary consultation, produce the best chances for improved outcomes in children, adolescents, and adults with ASD.