One of my first mentors in psychiatry said early in my career: “when a disorder impacts an organ in the body, other problems and challenges often follow suit within that same organ.” This is apparent in many areas of medicine: a leg deformity related to a prior growth problem may lead to joint erosion and pain of that same leg or the first heart attack weakens the heart in a manner such that the second is often more severe. This rule applies to the brain. Certain types of brain infections or tumors increase risk for seizures which can further damage neurons and interrupt their function. Accordingly, it is intuitive that the neuronal differences that are in place for individuals with Autism Spectrum Disorders (ASDs) may also elevate risk for the development of other psychiatric disorders. Conversely, disorders that may damage the brain, such as certain infections, environmental exposures, or seizures, also impart added risk for development of ASD. Finally, though no causal relationship between the conditions may be evident, ASDs can share common risk factors and neurobiology with other psychiatric disorders. Given these factors, co-occurring illness (comorbidity) with ASD is frequent; treatment of distressing and impairing symptoms related to comorbidity is often necessary. This article will review the most common disorders associated with ASDs, rare but severe disorders, and their treatments.
Depending upon the population, the rate of identifiable genetic disorders in ASD can vary but is typically in the range of 10-20% (Shishido, 2014). These rates have and will continue to increase as technology advances to permit rapid and cost-effective pathways to identify new alleles that play a role in ASD. Indeed, the rate of identifiable genetic contributions to ASD pathophysiology has prompted several organizations, including the American Academy of Child and Adolescent Psychiatry, to recommend genetics evaluation for all children diagnosed with an ASD (Volkmar, 2014). More commonly associated genetic disorders associated with ASDs include tuberous sclerosis, fragile X, neurofibromatosis, Angelman’s, Prader Willi, Williams syndrome, Down’s Syndrome, and 22q11 syndromes, including Velocardiofacial and DiGeorge Syndrome. Currently, biological interventions directed at some of these identified genetic mutations are underway. The other advantage of genetic testing in ASD includes evaluating risk for other medical conditions associated with that same genetic disorder as well as guidance for family members considering having children. While it is beyond the scope of this article to review associated medical conditions for each of these disorders, and others not listed, it is clear that early identification of these disorders permits rapid evaluation and treatment of potentially serious conditions that may be associated with these alleles, including seizures, cardiovascular defects, and ophthalmologic disease, amongst others.
Given the broad inter-individual differences with respect to the numerous domains in the diagnosis of Autism Spectrum Disorder, it continues to be challenging in drawing a clear boundary between symptoms that exist as the direct result of ASD and those stemming from other neuropsychiatric disorders. This is not at all surprising as most of these conditions are syndromes with some overlapping symptoms – not at all atypical for medical conditions. This is reflected in the new DSM-5 criteria which now permit for the diagnosing of other psychiatric disorders, along with ASD. That brings a clear advantage in planning treatment of impairing symptoms associated with common ASD comorbidities. However, it also brings with it the possibility for polypharmacy. Generally I apply four rules of thumb when approaching medication treatment of co-occurring illness in ASD:
- Individuals with ASD are more likely to respond to pharmacological and other interventions when co-occurring symptoms form a constellation that closely approximates the standard diagnostic criteria for a disorder for which the medications are indicated.
- Individuals with ASD may have more challenges in managing medication side effects. This may be related to difficulty in communicating those side effects as well as individual differences in medication metabolism
- Individuals with ASD may respond to low doses of medicine quite nicely
- Individuals with ASD who respond to low doses of medicine do not necessarily respond to higher doses and may even do worse
Attention-Deficit/Hyperactivity Disorder (ADHD) is commonly comorbid with ASD. Attentional symptoms and hyperactivity were also amongst the first symptoms described (Kanner, 1943). Interestingly, until recently, the DSM did permit individuals with ASD to receive a diagnosis of Attention-Deficit/Hyperactivity Disorder (ADHD) (APA, 2000; APA, 2013). This was largely related to a still ongoing debate about whether ADHD and ASD are truly separate conditions or a part of a separate subgroup of disorders that share both features. Despite this debate, rates of ADHD symptoms in individuals with ASD are high; it is estimated that 20-50% of individuals with ASD can independently meet ADHD diagnostic criteria (depending upon which specific ASD population is being studied) (Hanson 2013).
While joint attention (one’s ability to engage in a shared area of focus with another individual) is best managed with behavioral and educational intervention, treatment of “classic” ADHD symptoms such as sustained attention in the context of ASD with stimulant medications may be as effective as treatment in individuals without ASD (Kylkylo, 2012). However, rates of medication discontinuation due to side effects are higher relative to treatment of ADHD in individuals without ASD (RUPP, 2005). Other medication interventions such as atomoxetine have also been shown to be helpful in treatment of ADHD symptoms in the context of ASD (Harferterkamp, 2012).
Rates of Obsessive-Compulsive Disorder (OCD) have been reported to be as high as 37% in ASD (Leyfer, 2006). Given that restricted and repetitive patterns of behavior (such as inflexible adherence to routine or fixated interests) are one of the two major symptom domains in DSM-5 ASD diagnostic criteria, clarifying a diagnosis of OCD in this context can be challenging. This is particularly challenging if language limitations impair the ability of an individual to outline intrusive and irrational thoughts that are common in OCD. Symptoms of OCD (such as intrusive thoughts of contamination leading to repetitive hand-washing routines) can occur within the context of ASD and may be responsive to medication intervention. However, repetitive and restrictive behaviors are significantly more common in ASD and the effectiveness of medications in their treatment is less clear. Prior studies of selective serotonin reuptake inhibitors targeting these repetitive and restrictive behaviors have demonstrated mixed results in symptom improvement (Hollander, 2012; King, 2009).
Other Common Co-occurring Disorders
Treatment of other common co-occurring disorders has been less studied rigorously in treatment trials. Major Depressive Disorder and subclinical depressive symptoms in ASD are estimated to occur in approximately 10% and 24%, respectively. Rates of specific phobia vary between 30-45%. Individuals with ASDs may have other anxiety disorders such as generalized anxiety disorder and separation anxiety, at rates in the range of 3 to 12% (Leyfer, 2006). Given the paucity of research on pharmacologic treatment of these disorders within the context of ASD, careful consideration of risks and benefits of medication use should be considered along with clear plans for measuring treatment progress and side effects.
Psychotic illnesses, such as schizophrenia, are characterized by some level of a loss of reality testing. Symptoms may also include, “hearing voices that others don’t hear” (hallucinations) or strongly believing things to be true that are not (delusions). Clinicians who are unaccustomed to working with individuals with ASD and are unfamiliar with developmental contributions to their symptoms, particularly for those individuals who also have intellectual disability, may falsely characterize a developmentally typical experience such as an imaginary friend or “self-talk” as symptoms of psychotic illness. Therefore caution is required when considering a diagnosis of psychosis in the context of ASD. However, though epidemiologic data are mixed and limited by the lower prevalence of psychotic illness, individuals with ASD can experience psychotic illness; further, several genetic loci associated with ASD (such as 22q11) have also been associated with schizophrenia (Shishido, 2014). But, for now, the clinical significance of these findings remains unclear. Nonetheless, irrespective of diagnosis, principle pharmacologic treatment of psychotic symptoms includes the neuroleptic class of medications. This medication class also includes the only two medications approved by the Food and Drug Administration for any use in ASD (albeit for the specific indication of treatment of irritability and aggression associated with ASD).
In summary, ASD represents a broad phenotype that can vary along numerous dimensions (functional, cognitive, social, etc.). There are also broad inter-individual differences in the types of co-occurring symptoms and disorders. While as many as 70% of individuals may have comorbidity with their ASD (Lefyer, 2006), the ways in which these co-occurring disorders are diagnosed and the populations of individuals with ASD in which they are studied vary. Therefore, at the moment, it may be best for clinicians to apply the standard DSM-5 criteria to symptoms when they appear and to then consider appropriate, evidence-based treatments for disorders when the diagnostic criteria are met. If a co-occurring disorder is identified, individuals with ASD are often more sensitive to medication side effects, may respond to lower doses of medication, and may do no better or even worse at higher doses. Clear pathways for measurement of treatment response and side effects should be outlined prior to medication initiation and adhered to during treatment in order to assist in the ongoing assessment of benefit versus risk while minimizing the probability of escalating doses and polypharmacy.
Russell Tobe, MD, is a board-certified child and adolescent psychiatrist and a board-certified adult psychiatrist. He is Director of Outpatient Research at the Nathan Kline Institute for Psychiatric Research, Director of Psychiatric Services at ARC of Rockland, President of the West Hudson Psychiatric Society, and a faculty member at Columbia University and New York University. Correspondence may be addressed to Dr. Tobe at email@example.com.
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed.). Arlington, VA: American Psychiatric Publishing.
American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Arlington, VA: American Psychiatric Publishing.
Hanson, E., Cerban, B., Slater, C., Caccamo, L., Bacic, J., and Chan, E. (2013). Brief Report: Prevalence of Attention Deficit/Hyperactivity Disorder Among Individuals with an Autism Spectrum Disorder. J Autism Dev Disord (2013) 43: 1459-1464.
Harferterkamp, M., Van De Loo-Neus, G., Minderaa, R.B., Van Der Gaag, R., Escobar, R., Schacht, A., Pamulapati, S., Buitelaar, J., and Hoekstra, P.J. (2012). A randomized double-blind study of atomoxetine versus placebo for ADHD symptoms in children with Autism Spectrum Disorders. JAACAP 51(7) 733-741
Hollander, E., Soorya, L., Chaplin, W., Anagnostou, E., Taylor, B., Ferretti, C., Wasserman, S., Swanson, E., and Settipani, B. (2012). A Double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. Am J Psychiatry 169: 292-299.
Kanner, L. (1943). Autistic disturbances of affective contact. Nervous Child, 2, 217–250.
King, B.H., Hollander, E., Sikich, L., McCracken, J.T., Scahill, L., Bregman, J.D., Donnelly, C.L., Anagnostou, E., Dukes, K., Sullivan, L., Hirtz, D., Wagner, A., Ritz, L., STAART Psychopharmacology Network: Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behaviors. Arch Gen Psychiatry 2009; 66:583–590
Klykylo W.M. and Kay. J. (2012) Clinical Child Psychiatry. West Sussex, UK: John Wiley and Sons, Ltd. pp.353-376.
Leyfer, O.T., Folstein, S.E., Bacalman, S., Davis, N.O., Dinh, E., Morgan, J., Tager-Flusberg, H., and Lainhart, J. 2006. Comorbid Psychiatric Disorders in Children with Autism: Interview Development and Rates of Disorders. J Autism Dev Disord 36: 849-891.
RUPP. (2005). Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry 62: 1266-1274.
Shishido, E., Aleksic, B., and Ozaki N. (2014). Copy-number variation in the pathogenesis of autism spectrum disorder. Psychiatry and Clinical Neurosciences, 68: 85-95.
Volkmar, F., Siegel, M., Woodbury-Smith, M., King, B., McCracken, J., State, M., and the American Academy of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI) (2014). Practice Parameter for the Assessment and Treatment of Children and Adolescents with Autism Spectrum Disorder. JAACAP, 53(2): 237-257.