Cognitive-adaptive disabilities (CADs) are not frequently seen in the general pediatric setting. Yet, given the high rates of comorbidity in that population, they commonly demand a lot of time and effort on the part of clinicians. One aspect of comorbidity is the degree to which psychiatric disorders occur in children, adolescents, and young adults with CADs. This article reviews the epidemiology, associated psychopathology, and pharmacologic treatment of selected CADs.
The term “cognitive-adaptive disabilities” (CADs) denotes a group of disorders associated with significant impairments in mental abilities and in functional capabilities. Subsumed under CAD are other terms that similarly denote global or specific dysfunctions ( Box 1 ). As in other areas of medical practice, the early identification of and interventions for CADs is extremely important, the goals being prevention of mortality, reduction of morbidity, and improvement of functional status. To that end the American Academy of Neurology has developed a practice parameter for the evaluation of children with global developmental delays. The work-up should include thorough personal and family histories, complete physical, neurologic and dysmorphology examinations, and screening for visual and auditory disorders. If not already done as part of universal newborn screening, metabolic testing and evaluations for autistic and communication disorders should be considered.
Intellectual disabilities (formerly known as mental retardation)
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Implies below normal performance on standardized intellectual testing and a functional level below that expected for chronologic age or the individual requires varying levels of environmental support.
Autism spectrum disorders (pervasive developmental disorders); includes autistic disorder, Asperger disorder, Rett syndrome, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified
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Implies a variable combination of impaired socialization, communication, and interests, often accompanied by some level of intellectual disabilities.
Specific learning disorders
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Unlike intellectual disabilities and autism spectrum disorders, these are specific, not global, in their effects; more likely to affect academic performance in the areas of reading, writing, and mathematics.
Communication disorders
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May be seen in the absence of other disabilities; can affect the reception or expression of language, or the articulation of speech.
Epidemiology
The determination of prevalence of CADs has been fraught with methodologic problems, and has therefore yielded variable results. A relatively recent review on the epidemiology of mental retardation has reasonably estimated that the prevalence of severe mental retardation (intelligence quotient <35) is 1.4 per 1000, and the prevalence of mild mental retardation (IQ 50–70) is 10.6 per 1000. The US Centers for Disease Control and Prevention reported that for 8 year olds surveyed in 2006, the overall average prevalence of autism spectrum disorders (ASDs) was 9 per 1000. This means that, on average, approximately 1 child in every 110 was classified as having an ASD, an increase of 57% from the 2002 surveillance year. Epidemiologic studies have also found that intellectual disabilities (IDs) and ASDs are highly comorbid, because 50% to 70% of those with an ASD also have an ID, whereas 28% to 40% of individuals with an ID have an ASD.
Studies that have looked at the presence of psychopathology in youth with CADs have also found variable results, although they are consistent in reporting more emotional and behavioral problems in those with versus those without CADs. A survey from the United Kingdom examined 10,438 children, between the ages of 5 and 15 years, for psychiatric disorders. Compared with children with no ID, those with IDs were seven times more likely to have received any psychiatric diagnosis. In addition, rates for conduct disorders, anxiety disorders, attention-deficit/hyperactivity disorder (ADHD), and pervasive developmental disorders were statistically higher among the children with ID than among their peers without ID. The emotional and behavioral problems in children with IDs do not seem to substantially resolve as they transition into adulthood. For example, an Australian study evaluated a cohort of youth with ID (5–19.5 years of age at study entry) at four points in time, the last occurring 10 years after the end of the initial evaluation period. The prevalence of subjects meeting criteria for obvious psychopathology, or a definite psychiatric disorder, had only decreased from 41% to 31% between the first and last assessments. One possible explanation is that only 10% of those with diagnosed psychopathology received any mental health treatment during the study period. A Dutch study similarly evaluated two cohorts of youth (ages 6–18 years at study entry) with and without IDs at three points in time over 6 years. The results revealed that children with IDs continued to have a greater risk for psychopathology compared with children with no ID, although the risk for aggression was less pronounced at age 18 years than it was at age 6 years.
To better evaluate and treat child and adolescent patients with CADs, specific, relatively common developmental syndromes are discussed here in terms of epidemiology, comorbid psychiatric disorders, and psychopharmacologic treatments.
Developmental disorders
Down Syndrome
Down syndrome (DS) is the most common chromosomal disorder associated with ID. In the United States, a cross-sectional study found a DS prevalence rate of 10.3 per 10,000 children and adolescents (0–19 years old). Individuals with DS are at risk for developing certain psychiatric and behavioral problems.
Mood disorders
Depression in children and adolescents with DS seems to be uncommon; however, the vulnerability increases as those individuals age into adulthood. This has implications for the care provided by pediatricians, who are often the default clinicians for patients with DS even after they reach legal adulthood. Bipolar disorder is rare in the DS population, occurring at a lower rate than that seen in either the general population or in CAD patients without DS. Symptoms that could be interpreted as bipolar-like (eg, motor hyperactivity) are much more likely to be secondary to other psychiatric disorders (see later).
Obsessive-compulsive disorder
Adults with DS seem to have rates of obsessive-compulsive disorder (OCD) that are higher than reported in the non-DS ID and general populations. In a study comparing children with DS with typically developing children (mean age ∼5 years) there were no differences between them in terms of the number of compulsive-like behaviors they engaged in, although subjects with DS did engage in repetitive behaviors more frequently and intensely. This is consistent with reports that, in individuals with DS, the onset of OCD symptoms is typically in adolescence or young adulthood.
Attention-deficit/hyperactivity disorder
Similar to rates seen in the general population, ADHD in DS is more common in those under 20 years of age (6.1%) than in those over age 20 (2.4%).
Psychosis
Studies are mixed regarding the occurrence of delusions and hallucinations in individuals with DS. Given the limitations in communication associated with CADs, patients may not report psychotic symptoms, or clinicians may not specifically inquire about them. In a retrospective chart review of adults with IDs, there was no significant difference between the group with DS and the group without DS in terms of psychotic symptomatology. The subjects with DS were less likely to display aggressive or self-injurious behaviors, which could have lowered the index of suspicion of an underlying psychotic process.
Dementia
Contrary to popular belief, the rate of Alzheimer dementia in DS may be only slightly higher than in the general population; however, the average age of onset is much younger. Given that the presence of dementia greatly complicates the care of individuals with DS, early identification and possible treatment are very important. The recommendation has, therefore, been made that a baseline assessment of functioning should be performed by age 35 years, and that follow-up should occur yearly thereafter.
Treatments
Evidence-based treatments for the underlying pathology in DS are lacking; treatments are aimed at correcting presumed neurotransmitter abnormalities. For depression, the selective serotonin reuptake inhibitor (SSRI) antidepressants are a good choice; they have demonstrated some reversal of functional decline associated with either depression or early dementia in adults with DS. A small case series of adults with DS with OCD yielded positive responses to SSRIs, either alone or in combination with risperidone. The SSRIs can presumably be used for other anxiety disorders. Because there are no specific guidelines for the treatment of ADHD symptoms in DS, general approaches to treatment should be followed (ie, beginning with standard stimulant medications). Psychotic symptoms in young people with developmental disorders can respond to risperidone or olanzapine. Patients should be monitored for dyskinesias, especially in females, and for other side effects. Although research into treatments for Alzheimer disease in the ID population is limited, the use of donepezil for dementia in patients with DS may be a reasonable choice.
Fragile X Syndrome
Fragile X syndrome (FXS) is the most common form of inherited ID, involving excessive repeats of the CGG trinucleotide. The screening of newborn boys for full-mutation FXS, using a highly accurate assay of methylated FMR1 gene DNA, yielded an incidence of 1 in 5161.
Mood disorders
A study examined 119 males and 446 females (ages 18–50 years) selected from either the general population or from families with a history of FXS. Subjects were categorized into three groups: (1) noncarriers (≤40 CGG repeats); (2) intermediate allele carriers (41–60 repeats); and (3) premutation allele carriers (61–199 repeats). Results demonstrated a linear association between CGG repeat length and negative affect in both males and females, and with depression only in males. In a study of females (ages 4–27 years) with FXS versus those without FXS, those with FXS had higher rates of mood disorders (47% vs 6%), with one-half of those meeting criteria for major depressive disorder (MDD). In another study that compared males and females with FXS, there was no statistical difference in either “anxious-depressed” or “withdrawn” scores between the two genders.
Anxiety disorders
In the previously cited premutation study, the results did not find any association between CGG repeat length and anxiety (state or trait), social phobia, or agoraphobia. Given that cognitive and language impairments are common in children with FXS, the detection of anxiety in that population may have to be through observation rather than direct inquiry. When asked to identify anxiety symptoms by the presence of specific behaviors in a group of children with FXS, the parents rated 26% as having “clinically significant anxiety problems,” whereas the teachers rated 42% of the children as having high levels of anxiety.
Attention-deficit/hyperactivity disorder
The symptoms of ADHD are common in FXS. When compared with same-age peers, parental ratings were consistent with ADHD in 53.7% of children with FXS; similarly, teachers rated 59.2% as meeting ADHD criteria, but with higher scores for hyperactivity-impulsivity than were reported by the parents.
Aggression
Using a standardized behavioral rating form, parents of 49 boys (mean age 8.5 years) with FXS reported that 40.8% of their children scored in the borderline and clinical ranges for aggressive behaviors (compared with only 5% of the normative population that scored in those ranges).
Treatments
The SSRI antidepressants can be used to treat both depression and anxiety in patients with FXS. Alternative medications for depression include the serotonin-norepinephrine reuptake inhibitor antidepressants (eg, venlafaxine or duloxetine) or bupropion; the latter should be used with caution, given its potential for lowering the seizure threshold. Alternative medications for anxiety include buspirone or the α 2 -agonists clonidine or guanfacine. The symptoms of ADHD in FXS respond to the usual stimulant medications, such as methylphenidate or mixed amphetamine salts. If the stimulants are ineffective, intolerable, or exacerbate other symptoms (eg, irritability), the α 2 -agonists can be very useful, particularly guanfacine, the long-acting form of which is now approved for the treatment of ADHD. The treatment of aggression should start with the α 2 -agonists, especially if ADHD is also present. Other medications to consider for treating aggressive behaviors in youth with FXS are the atypical antipsychotics (AAs) risperidone and aripiprazole (low doses, because agitation occurs at higher doses).
Fetal Alcohol Syndrome
Fetal alcohol syndrome (FAS) and fetal alcohol spectrum disorders (FASD) are the most common preventable causes of ID. Prevalence estimates of FAS and FASD have varied widely, but extrapolating from school populations (where rates of FAS-FASD are higher) to the general population has yielded a prevalence of greater than or equal to 2 to 7 per 1000 for FAS and a prevalence of 2 to 5 per 100 for FASD in younger school children.
Mood disorders
One study looked at a group of children who had been exposed prenatally to high levels of alcohol, but who did not have ID. They were classified into three groups: (1) full FAS, (2) partial FAS, and (3) alcohol-related neurodevelopmental deficits (ARND). There were no cases of MDD in the full FAS and partial FAS groups; however, 33% were diagnosed with bipolar disorder. In the ARND group, 18% were diagnosed with MDD and 35% with bipolar disorder. Based on these data, children with FAS and FASD may be at more risk of developing bipolar disorder than of developing depression.
Attention-deficit/hyperactivity disorder
A chart review of 2231 children (mean age 8.7 years) referred for FASD divided the patients into four risk categories based on prenatal alcohol exposure: (1) confirmed high exposure, (2) confirmed low exposure, (3) unknown exposure, and (4) confirmed lack of exposure. Using a standardized diagnostic system, rates of ADHD varied by level of exposure risk, with 49.4% of those in the highest risk group meeting criteria for ADHD, whereas only 0.8% of the no-risk group met criteria.
Psychosis
Children with prenatal exposure to alcohol (PEA) were compared with nonexposed children on a personality inventory completed by caregivers. The PEA group (which included children with FAS) scored statistically higher on the “psychosis” subscale (which discriminates children with psychotic symptomatology from normal, behaviorally disturbed nonpsychotic, and children with ID). There was no statistical difference in psychotic symptoms between children with FAS and those with PEA without FAS.
Aggression
The connection between FAS and aggressive behavior is somewhat puzzling and counterintuitive. Children and adolescents with a history of PEA, versus those without prenatal exposure, show higher rates of delinquent behaviors, including fighting. However, in those with PEA, but without FAS, one-half met probable conduct disorder criteria, compared with none of the patients with FAS. Similarly, another study found that patients with partial FAS had significantly higher anger scores (a risk factor for aggression) than did those with full FAS.
Treatments
There are no specific guidelines available for the treatment of bipolar disorder in youth with FAS or FASD. It is reasonable to follow the recommendations for treatment of bipolar disorder proposed for children and adolescents without PEA. A recent, comprehensive literature review of the psychopharmacology of pediatric bipolar disorder found that AAs and mood stabilizers are equally effective in their treatment of manic symptoms, but that the AAs achieve mood stabilization more quickly. Risperidone and aripiprazole are both approved for the treatment of bipolar disorder I in children greater than or equal to 10 years of age. As with the other CADs, the treatment of depression in FAS should begin with the SSRIs. The symptoms of ADHD in FASD respond to psychostimulants; dextroamphetamine or mixed amphetamine salts may be preferable to methylphenidate as first-line agents. The stimulants may be more effective in ameliorating hyperactivity-impulsivity than in improving attention span. For the treatment of psychosis in FAS, either risperidone or aripiprazole can be used (both are approved for the treatment of schizophrenia in adolescents ≥13 years of age). Risperidone (and possibly other AAs) can be used to treat aggression in children with FAS that has not responded to an SSRI or a stimulant.
Autism Spectrum Disorders
As previously noted, the Centers for Disease Control and Prevention estimated the overall average prevalence of ASDs to be 9 per 1000, or 1 out of every 110 children in the general population. The etiology of ASDs is unknown, but evidence suggests an interaction between genetic vulnerability and environmental factors.
Mood disorders
Children (9–14 years old) with Asperger syndrome or high-functioning autism (higher IQs, better communication skills) were evaluated for psychiatric problems approximately 6 years after the ASD diagnoses were made. Of the children with ASDs, 16.9% scored at least two standard deviations above the population mean on a measure of depression ( P <.001). Prevalence numbers for depression in individuals with ASDs are not necessarily reliable, and may be underreported, because subjective reporting of depression can be inhibited by deficient language skills, and caretaker reporting may be inaccurate, because depressive symptoms could be attributed to the core features of the ASDs, such as social withdrawal. Bipolar disorder can also be identified in youth with ASDs. A Japanese sample of outpatients (≥12 years of age) with ASDs (excluding autistic disorder) and IQs greater than or equal to 70 were evaluated for mood disorders. Of the 44 subjects, 16 (36.4%) were diagnosed with a mood disorder, and of those 4 were diagnosed with MDD, the rest (75%) with a bipolar spectrum disorder. The authors make the statement that the “major comorbid mood disorder” in the ASDs is bipolar disorder, rather than MDD.
Anxiety disorders
In the previously cited follow-up study, the investigators also identified significant numbers of the children with ASD as having anxiety; specifically, 13.6% were “overanxious” (ie, with generalized anxiety) and 8.5% had separation anxiety. In another study, parents of 171 medication-free children (5–17 years) used a standardized symptom inventory to rate anxiety symptoms. Of the total sample, 43% met screening cut-off criteria for at least one anxiety disorder. Compared with children with IQs less than 70, those with higher IQs were significantly more likely to have generalized anxiety disorder, somatization disorder, and separation anxiety disorder.
Attention-deficit/hyperactivity disorder
Identical to the rate of depression in children with ASDs, 16.9% of a follow-up sample of children with Asperger syndrome and high-functioning autism scored high on a measure of ADHD. There is bidirectional comorbidity between ASDs and ADHD: 20% to 50% of children with ADHD meet criteria for an ASD, whereas 30% to 80% of ASD children meet criteria for ADHD. This may indicate some shared genetic factors.
Aggression
A study of 160 children with ASDs reported that 32% displayed aggressive behaviors, either toward themselves or toward others. A school-based study compared teacher and parent ratings of students (mean age 9.6 years) with identified pervasive developmental disorders. The combined moderate and severe behavioral scores from parents and teachers, respectively, were 9.6% and 14.9% for cruelty/meanness; 11.3% and 11.5% for property destruction; 5.3% (both raters) for physical fights; 9.9% and 14.8% for attacking people; and 4.5% and 7.6% for threatening people. The students with lower adaptive skills scored higher on the conduct problems and hyperactivity subscales. In another study of children and adolescents with ASDs, recruited from clinical and community settings, behavioral ratings were made by the parents or other caregivers. Aggression toward others was reported in 50% (severe in 10.2%); yelling or shouting at others in 44.3% (10.8%); property destruction in 42.6% (13.6%); throwing objects at others in 36.9% (7.4%); kicking objects in 35.8% (10.2%); and pulling others’ hair in 14.8% (4.5%).
Treatments
The treatment of depression in youth with ASDs usually begins with an SSRI, although there are no controlled studies to justify that practice. Nonetheless, if one chooses to use an antidepressant, fluoxetine is considered to be the safest first choice. Treatment studies are also lacking in the area of comorbid ASDs and bipolar disorder, although expert recommendations include the use of mood stabilizers or AAs. The approach to the pharmacotherapy of anxiety in the ASDs is the same as that proposed for the treatment of depression (ie, the use of SSRIs based on clinical indication) but without the backing of good studies. For the treatment of ADHD symptoms in children with ASDs, either methylphenidate or atomoxetine can be used, although treatment responses are lower and adverse events are greater than seen in children with ADHD without ASDs. A better choice may be an α 2 -agonist, especially the long-acting preparation of guanfacine. The most commonly prescribed agents for treating aggression in individuals with ASDs are the AAs. Two of them (risperidone and aripiprazole) have received Food and Drug Administration approval to treat the irritability (including aggressive symptoms) associated with autistic disorder. It is reasonable to extend their use to treat aggression in all of the ASDs. If the AAs are ineffective or intolerable, mood stabilizers may be tried.
Neurofibromatosis Type 1
Neurofibromatosis 1 (NF1) is an autosomal-dominant disorder with an estimated prevalence of 1 in 2000 to 1 in 5000, although it may be more common, because detection of milder forms can be missed.
Mood and anxiety disorders
Parent ratings of children with NF1 yielded significantly higher scores of anxious-depressed symptoms compared with a normative sample and with unaffected siblings. A different study did not identify any significant problems for most children with NF1 regarding anxiety-depression, with one exception: an interaction between NF1 and age (ie, older children with NF1were viewed by their mothers as having more symptoms of depression and anxiety). The authors speculate that social problems may contribute to the development of anxious and depressive symptomatology.
Attention-deficit/hyperactivity disorder
In the previously cited study, parent ratings of children with NF1 also yielded significantly higher scores on an attention problems scale. Teacher ratings were also significantly higher than the normal for attention problems. An outpatient study of 93 consecutive children with NF1 found that 46 (49.5%) met diagnostic criteria for ADHD.
Aggression
Parents of children with NF1 rated them significantly higher on aggressive behaviors compared with a normative sample, but not compared with unaffected siblings. Children with NF1 rate even higher on aggression scores when they have comorbid ADHD.
Treatments
The treatment study that used methylphenidate to treat ADHD in patients with NF1 found that not only did the medication improve attention scores, but it also significantly reduced scores on the anxiety-depression and aggression scales. What is encouraging is that the methylphenidate dose (given twice daily) averaged only 7.4 mg, thus avoiding high-dose treatment and its associated adverse effects.
Velocardiofacial Syndrome
Technically known as the 22q11.2 deletion syndrome, but traditionally called the velocardiofacial syndrome (VCFS), this CAD is fairly common, with a prevalence of 1 in 5950 total births; between 1 in 6000 and 1 in 6500 white, black, and Asian births; and 1 in 3800 Hispanic births.
Mood disorders
A study compared 84 children with VCFS (mean age 11.75 years; 55% male) with matched sibling and community controls. In the VCFS group, 10 subjects (12%) were diagnosed with MDD, which was significantly higher than in either control group. The VCFS group was also the only group in which children were diagnosed with dysthymic disorder and bipolar disorder (neither was significant). Regarding bipolar disorder in VCFS, a group of 26 patients (ages 5–34 years) with molecularly confirmed VCFS were evaluated for psychiatric disorders. Considering the diagnoses in the bipolar disorder spectrum (ie, bipolar I, bipolar II, cyclothymia, and schizoaffective-manic), 12 of 19 patients under age 18 years and 6 of 7 of those over age 18 years met diagnostic criteria for a bipolar spectrum diagnosis.
Anxiety disorders
In addition to mood disorders, the previous study found significant numbers of children with VCFS with simple phobias (22.6%) and generalized anxiety disorder (16.7%). The rate of OCD was not elevated in this study. However, in another study of 43 subjects with VCFS (mean age 18.3 years), 14 (32.6%) met diagnostic criteria for OCD. What is interesting is that, for those subjects, the onset was early for both obsessive-compulsive symptoms (mean 10.7 years of age) and for actual OCD (mean 13.1 years of age).
Attention-deficit/hyperactivity disorder
The subjects in two of the previously noted studies were diagnosed with ADHD at high rates (42.8% and 37.2%, respectively), which makes it one of the most common psychiatric comorbidities in VCFS.
Psychosis
The rate of psychosis (mostly schizophrenia) in individuals with VCFS is about 30%. Although psychotic symptoms tend to develop beyond childhood, structured interviews of adolescents with VCFS have found that 45% have positive psychotic symptoms (eg, auditory hallucinations), whereas most (85%) have negative psychotic symptoms (eg, anhedonia).
Treatment
Over the last decade, not much progress has been made in the pharmacotherapy of psychiatric disorders in VCFS. For the treatment of depression and anxiety, caution must be used if choosing SSRIs, because they could precipitate mania in these patients at high risk for bipolar disorder. However, fluoxetine has been used successfully to treat OCD without destabilizing mood. Similarly, the theoretical potential that methylphenidate has to precipitate mania in vulnerable individuals was not seen in a small, open-label trial in patients with VCFS and ADHD. Treating the psychosis associated with VCFS can proceed using any of the AAs, except perhaps clozapine, which has the greatest potential of lowering the seizure threshold (7% of children with VCFS can have unprovoked seizures ).
Tuberous Sclerosis Complex
The tuberous sclerosis complex (TSC) is a multisystem disorder with autosomal-dominant genetics. In whites it has a prevalence of 1 in 25,000.
Mood disorders
In a United Kingdom mail survey of children with TSC, parents reported that 23% of the children (all under age 18 years; over half under age 10 years) had “depressed mood.” There were no statistical differences in rates of depression whether or not ID was present, nor between males and females. A retrospective chart review of 241 patients with TSC (average age 20 years) found that 27% had a history of mood disorder symptoms, and of 43 evaluated by a psychiatrist, 11 (26%) received a formal mood disorder diagnosis.
Anxiety disorders
Parents in the United Kingdom mail survey also reported that 40% of their children with TSC had anxiety. Similar to the results related to depression, the rates of anxiety did not differ based on gender or IQ level. The chart review study also found that 27% of subjects with TSC had a history of anxiety disorder symptoms, and of 43 evaluated by a psychiatrist, 12 (28%) received a formal anxiety disorder diagnosis, over half of which were for generalized anxiety disorder.
Attention-deficit/hyperactivity disorder
The United Kingdom survey also asked the parents of children with TSC about “disruptive behaviors and attention deficit symptoms.” Overactivity, restlessness, and impulsive behavior were seen in 56%, 54%, and 52%, respectively, of the children. The chart review study identified 30% of those with TSC as having a history of ADHD symptoms; of 43 evaluated by a psychiatrist, 9 (21%) received a formal ADHD diagnosis, all but 1 of which were of the combined type. The lower rates of ADHD symptoms in this study (vs the United Kingdom study) are likely caused by the older average age of the participants.
Aggression
More than half of the children with TSC in the United Kingdom survey were reported to have aggressive outbursts (58%) and temper tantrums (57%). In the chart review study, 28% of patients with TSC had a history of aggressive-disruptive behavior disorder symptoms. Although there were no formal diagnoses made specifically related to aggression, those in the aggressive group had high degrees of overlap with other diagnostic groups: 43% in the group with mood disorders, 29% in the group with anxiety disorders, and 49% in the group with ADHD.
Treatments
The pharmacotherapy of psychiatric disorders in TSC is complicated, as in many other CADs, by the high rates of comorbid epilepsy, ID, and autism. There has also been very little research on the use of psychotropic agents to treat specific psychopathologies in individuals with TSC. Despite the limited database, pharmacotherapies can be used. The treatment of depression and anxiety should start with the SSRIs ; citalopram was shown to be effective in the treatment of both. The use of bupropion should be avoided, given its well-known ability to lower the seizure threshold. For children with ADHD and TSC, the usual ADHD medications (stimulants and atomoxetine) can be used, provided that a seizure disorder is absent or, if present, well-controlled; methylphenidate may be the safest and most efficacious agent to use in this population. If the stimulants or atomoxetine are ineffective or intolerable, the α 2 -agonists or AAs (especially risperidone) may be used to treat ADHD. Finally, the treatment of aggression in TSC should begin with identifying and treating underlying psychiatric disorders, such as ADHD, depression, or anxiety. Refractory aggression may respond to risperidone or other AAs.
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