Dr. Kolevzon is assistant professor of psychiatry and pediatrics in the Department of Psychiatry at Mount Sinai School of Medicine in New York City.

Disclosure: Dr. Kolevzon receives grant support from the Beatrice and Samuel A. Seaver Foundation, Bristol-Myers Squibb, Johnson and Johnson, the National Institutes of Health, and Neuropharm.

Please direct all correspondence to:  Alexander Kolevzon, MD, Assistant Professor of Psychiatry and Pediatrics, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029; Tel: 212-659-9134; Fax: 212-659-8710; E-mail: alexander.kolevzon@mssm.edu.


 

Focus Points

• Methylphenidate and atomoxetine can be useful in the treatment of attention-deficit/hyperactivity disorder (ADHD) symptoms in autism spectrum disorders (ASD).
• Response rates and tolerability may be lower than in typically developing individuals with ADHD.
• Patients with ASD and symptoms of ADHD, aggression, and/or self-injury may benefit from risperidone if cautiously administered and monitored.

 

Abstract

Autism is a pervasive developmental disorder defined by social impairment, language impairment, and repetitive patterns of behavior. Symptoms of attention deficit and hyperactivity frequently occur in autism and autism spectrum disorders (ASD), yet current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria prohibit the diagnosis of attention-deficit/hyperactivity disorder (ADHD) in the presence of an underlying pervasive developmental disorder. Autism is characterized by broad heterogeneity in symptoms and associated features and may be a challenge to diagnose clinically. Yet, the accurate identification of ADHD symptoms in ASD has important implications for treatment. There is a significant body of evidence to support the use of medications to treat ADHD in typically developing populations, but a relative dearth of research to explore the effect of pharmacotherapy in populations with ASD and symptoms of ADHD. This article focuses on the medication management of ADHD symptoms in ASD to evaluate the current state of evidence and help guide providers in their clinical judgment.

Introduction

Autism is a severe neurodevelopmental disorder characterized by social impairment, language impairment, and repetitive patterns of behavior. The autism spectrum, also called pervasive developmental disorders, includes Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified.1 Symptoms of attention deficit, impulsivity, and hyperactivity are extremely common in autism spectrum disorders (ASD), with some surveys reporting estimates of 50%2 to 75%.3 However, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision1 precludes the diagnosis of attention-deficit/hyperactivity disorder (ADHD) if symptoms occur in the context of an underlying pervasive developmental disorder (ie, ASD). Nevertheless, some clinical symptoms of ASD and ADHD clearly overlap and the boundaries between the disorders are sometimes unclear.4

In the absence of biologic markers, clinicians must rely on behavioral characteristics using a variety of diagnostic tools in addition to a comprehensive developmental history to evaluate individuals with ASD. The use of validated diagnostic instruments, cognitive testing, and assessment of adaptive behavior functioning are crucial in developing individualized treatment plans in ASD. Symptoms of ADHD should be specifically explored and rating scales, such as the Conners’ Rating Scale5 can be distributed to parents and teachers both for diagnostic purposes and also as a means to measure improvement from baseline.

The first line of treatment in ASD is behavioral and educational interventions, though their consideration is beyond the scope of this article. Pharmacotherapy in ASD is used to target symptom domains and is not curative. While much evidence supports the use of medications to treat symptoms of ADHD in typically developing children, questions remain as to their utility in patients with developmental delays. There is a paucity of research to examine the effect of pharmacotherapy in populations with co-occurring ASD and symptoms of ADHD, with minimal data to guide providers in their clinical judgment. The following article focuses on the medication management of ADHD-related symptoms in ASD with the goal of providing clinicians with a systematic evaluation of the evidence to date.

Methods

Relevant studies were identified by searching the PubMed database for English-language articles on clinical trials of medication in the treatment of autism and autism spectrum disorders, and screening reference lists of original studies. PubMed is a National Library of Medicine service that includes citations from Medline and additional life science journals that date back to the 1950s. For inclusion in this article, identified studies used randomized controlled designs of agent versus placebo or active agent; a well-defined sample of subjects that included children, adolescents, or adults with autism or autism spectrum disorders; and at least one outcome measure with an assessment of inattention, hyperactivity, or impulsivity. Retrospective and open-label studies were also reviewed when relevant to controlled trials.

Results

Methylphenidate

Methylphenidate is a psychostimulant that binds to the presynaptic dopamine transporter decreasing reuptake and increasing synaptic dopamine in the striatum and other brain regions. Several randomized, placebo-controlled trials have explored the use of methylphenidate in ASD. Quintana and colleagues6 used 20–40 mg/day doses in 10 children with ASD and found that methylphenidate produced significant improvement in hyperactivity as compared to placebo. No significant differences in the occurrence of side effects were noted between groups, although higher doses appeared to produce a greater likelihood of insomnia and irritability. Another placebo-controlled trial by Handen and colleagues7 of 13 children with ASD and symptoms of ADHD compared doses of 0.3 and 0.6 mg/kg given 2–3 times/day. Hyperactivity improved significantly as compared to placebo and eight of the 13 children (62%) were considered responders. Five of the 13 (38%) children experienced significant side effects as compared to placebo, including social withdrawal, dullness, sadness, and irritability.

The largest controlled trial8 with methylphenidate to date was done by the Research Units of Pediatric Psychopharmacology (RUPP) Autism Network using a double-blind, placebo-controlled, crossover design in 72 children and adolescents with ASD. Methylphenidate was administered in low (.125 mg/kg), medium (.250 mg/kg), and high (.5 mg/kg) doses TID. Methylphenidate was superior to placebo on measures of inattention and hyperactivity and 49% of subjects were classified as responders. Side effects were significantly more likely to occur in patients on methylphenidate, including decreased appetite, difficulty falling asleep, irritability, and emotional outbursts. A total of 13 out of 72 subjects (18%) withdrew from the study due to adverse events and the most common reason for discontinuation was irritability (six subjects). A follow-up of the RUPP methylphenidate study by Posey and colleagues9 confirmed results from the original study using secondary outcomes to measure core symptoms of ADHD but found that hyperactivity and impulsivity were more likely to improve than inattention. Higher doses (.25–.50 mg/kg) were also more consistently effective than low doses (.125 mg/kg).

Atomoxetine

Atomoxetine is a non-stimulant, norepinephrine reuptake inhibitor which also enhances prefrontal dopaminergic transmission because the norepinephrine transporter is sensitive to dopamine in the frontal cortex. Retrospective10 and open-label studies11 of atomoxetine found significant effects on measures of hyperactivity and inattention in children and adolescents with ASD. One double-blind, placebo-controlled, crossover study12 examined the safety and efficacy for symptoms of ADHD in 16 children and adolescents with ASD. Atomoxetine was started at doses of .25 mg/kg/day and increased to a maximum dose of 1.4 mg/kg/day given in divided doses. Atomoxetine significantly improved symptoms of hyperactivity and impulsivity as compared to placebo, but results only approached significance on measures of inattention. Patients who received atomoxetine exhibited significantly more side effects, including gastrointestinal distress, fatigue, and tachycardia. Other side effects such as decreased appetite and irritability were reported but rates did not differ significantly from placebo.

Haloperidol

Haloperidol is a first-generation antipsychotic that acts by blocking postsynaptic dopamine receptors. Antipsychotics have been used extensively in developmentally disabled populations and typically developing children with ADHD. Aman and Langworthy13 identified 11 clinical trials that evaluated antipsychotics for hyperactivity in children with ASD. Four of these were controlled trials that examined the use of haloperidol.14-17 Haloperidol appears to improve hyperactivity in ASD, although results were not always consistent, depending on the outcome measure utilized.

Risperidone

Risperidone is a second-generation antipsychotic that acts by blocking postsynaptic dopamine and serotonin receptors. The remaining seven studies identified in the article by Aman and Langworthy13 used open-label designs; six were with risperidone18-23 and one examined the use of olanzapine.24 Results of these open-label trials were mostly positive and found that risperidone significantly reduces hyperactivity in ASD.

The RUPP Autism Network later conducted a large placebo-controlled trial25 of risperidone in 101 children and adolescents (5–17 years of age) to examine impact on tantrums, aggression, and self-injury. The Aberrant Behavior Checklist Irritability subscale was the primary outcome measure but the Hyperactivity subscale was also used. Risperidone was initiated at 0.5 mg/day and titrated to a maximum of 2.5 mg/day in divided doses (mean=1.8 mg/day). Risperidone significantly improved hyperactivity as compared to placebo (effect size=1). Irritability also improved significantly (effect size=1.2). Sixty nine percent of patients receiving risperidone were considered responders according to global ratings as compared to 12% of patients who received placebo. Risperidone was significantly more likely to produce side effects, including mild (49%) to moderate (24%) increases in appetite, fatigue (59%), drowsiness (49%), drooling (27%), dizziness (16%), and weight gain (2.7±2.9 kg). There was no evidence of extrapyramidal symptoms and no child required discontinuation due to side effects.

Overall, there have been at least five additional controlled trials26-30 of risperidone with positive results in patients with ASD, though not all systematically assessed symptoms of ADHD.

Clonidine

Clonidine is an alpha-2 adrenergic agonist that reduces sympathetic discharge and lowers levels of catecholamine production. Several studies31-33 have found clonidine effective in improving inattention, hyperactivity, and impulsivity in children with ADHD. In patients with ASD, clonidine has been examined in two controlled studies34,35 with a total of 15 males. The first study34 did not show improvement on measures of hyperactivity but did find improvement on global ratings of change according to both parents and clinicians. The second study35 found improvement on parent and teacher ratings of hyperactivity, irritability, and oppositional behavior, but not on the clinician ratings. Side effects included sedation and hypotension. Hyperactivity may improve due to initial sedation, and benefit appears to diminish in some cases after 6–8 weeks.35

Guanfacine

The efficacy of guanfacine, another alpha-2 agonist, was examined in two open-label studies.36,37 The first study36 was a large retrospective review of 80 children and adolescents with ASD and symptoms of ADHD. Doses ranged from 0.25–9.0 mg/day administered in divided doses (mean=2.6 mg/day) and treatment duration ranged 7–1,776 days. Twenty-seven percent of patients showed improvement in hyperactivity and 21% showed improvement in symptoms of inattention. Twenty-four percent of patients were considered responders based on global improvement scores and there was a small but statistically significant improvement on global severity ratings. Later, Scahill and colleagues37 conducted a prospective open-label trial of guanfacine in 25 children with ASD and hyperactivity with a history of non-response to methylphenidate. Doses ranged from 1–3 mg/day in divided doses. Forty-eight percent of children were considered responders and results from parent and teacher ratings of inattention and hyperactivity showed significant improvement for both symptoms across two different measures, although parent ratings demonstrated a larger effect. Both studies36,37 suggest that guanfacine was well tolerated and no serious adverse events occurred. Side effects included sedation, irritability, increased aggression and self-injury, decreased appetite, sleep disturbance, constipation, headache, and nocturnal enuresis. Heart rate, blood pressure, and electrocardiogram changes were not deemed clinically significant and did not require discontinuation for any cases in either of the studies of guanfacine.

Amantadine

Amantadine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist indicated for the treatment of Parkinson’s disease. A placebo-controlled study of amantadine by King and colleagues38 in 43 children and adolescents with ASD assessed the impact on behavioral symptoms. Amantadine was started at doses of 2.5 mg/kg/day and increased to 5 mg/kg/day BID. Significant improvement was found on clinician-rated measures of hyperactivity but not on parent-rated measures. Fifty-three percent of patients demonstrated response on measures of global improvement as compared to 25% of patients receiving placebo; however, this difference was not statistically significant. There were no significant differences in side effects between groups but the most common side effects in patients taking amantadine were insomnia and somnolence. There were no reports of hallucinations, which have been associated with higher doses of amantadine.38

Naltrexone

Naltrexone is an opiate antagonist studied in children and adolescents with ASD using open-label designs39-41 and is found to effectively reduce autistic symptoms, including hyperactivity and inattention. At least six randomized, placebo-controlled studies have also examined its efficacy,42-47 although results from these trials are mixed. Campbell and colleagues42 found that hyperactivity was significantly improved according to parent and teacher ratings on the Conners Rating Scale, whereas Willemsen-Swinkels and colleagues43 reported no significant improvement according to parent ratings, but teacher ratings did find improvement in hyperactivity. In contrast, Kolmen and colleagues44 found significant improvement on parent ratings, but not on teacher ratings. Both the Willemsen-Swinkels and colleagues45 and Kolmen and colleagues44 also measured activity level using an actometer and no difference was found between the naltrexone and placebo groups. Bouvard and colleagues46 examined the use of naltrexone in 10 children with ASD using a placebo-controlled design and again no significant differences were found. None of the controlled trials with naltrexone reported significant differences in side effect profiles as compared to placebo.

Other Medications

Many other medications have been studied in ASD, but few specifically measured symptoms of ADHD, and a list of these trials is beyond the scope of this article. Some studies have shown promise for several selective serotonin reuptake inhibitors, tianeptine, divalproex sodium, lamotrigine, and omega-3 fatty acids, among others. However, to date, no additional randomized controlled trials have found evidence to support their use for symptoms of ADHD in ASD.

Conclusion

Methylphenidate and atomoxetine are both typically used to treat ADHD and are also effective in ASD. Recently, Santosh and colleagues48 conducted a retrospective and an open-label prospective trial to compare response to stimulants (methylphenidate or dextroamphetamine) between children with ASD and ADHD and children with ADHD alone, and found no significant differences in treatment response or side-effect profiles between groups. However, other studies suggest that response rates of methylphenidate may differ in ASD as compared to what is reported in typically developing children with ADHD alone. The National Institute of Mental Health Collaborative Multisite Multimodal Treatment Study of Children with ADHD (MTA) reported response rates of 70% to 80% as compared to the 49% reported in the RUPP Autism Network trial of methylphenidate.8 In terms of tolerability, 18% of subjects in the RUPP trial withdrew, yet discontinuation rates were quite low in the MTA study (1.4%). While methylphenidate may improve irritability in ADHD without ASD, it appears to worsen irritability in some patients with ASD. In the only controlled study of atomoxetine,12 results were significantly better than placebo, but the sample size was small and only seven of 16 children (43%) were considered responders. Overall, both methylphenidate and atomoxetine appear to effectively treat ADHD-related symptoms in ASD. However, response rates may be lower in ASD plus ADHD than in ADHD alone, and symptoms of inattention may be less likely to respond than symptoms of hyperactivity and impulsivity. Finally, treatment success may be limited by tolerability.

Many studies have demonstrated efficacy for antipsychotics, and since the RUPP trial with risperidone25 this medication in particular has consistently shown benefit for hyperactivity in ASD.26,27,49,50 In 2006, The United States Food and Drug Administration approved risperidone for the treatment of irritability in ASD in children and adolescents 5–16 years of age. Symptoms of aggression and self-injury are especially distressing for patients with ASD and their families, and risperidone is an effective pharmacotherapeutic option for this symptom constellation. However, significant concerns about tolerability remain and suggest that benefits of this medication must be carefully weighed against the risks. Metabolic monitoring, nutritional counseling, and a physical activity regimen should be included for all children treated with risperidone.

Evidence from controlled studies of alpha-2 agonists for ADHD-related symptoms in ASD is inconsistent and response rates are relatively low. Open-label studies of guanfacine appear promising but additional controlled studies are needed. alpha-2 agonists may, nevertheless, be a reasonable alternative or augmentation strategy and have the advantage of being relatively benign. Amantadine and other NMDA antagonists are interesting compounds to consider in the treatment of ASD but their use for ADHD-related symptoms is limited by a relative dearth of evidence and only one controlled trial to date. Despite multiple controlled trials, naltrexone appears to exert minimal benefit and inconsistent results indicate that isolated findings should be interpreted with caution.

Regardless of medication choice, treatment of children and adolescents with ASD should be initiated at very low starting dosages using very slow titration schedules. Benefits must be carefully weighed against risks, and future research would benefit from systematic assessment of side effects to clarify safety profiles and identify patients who are most vulnerable. Future studies to specifically examine treatment of ADHD symptoms in ASD should utilize specific outcome measures that clearly assess medication impact on symptoms of inattention, hyperactivity, and impulsivity.

Several weaknesses of this article are important to note. First, its focus is primarily on studies of children and adolescents because inattention and hyperactivity occur more commonly in this population. Second, mental retardation has not been adequately addressed. The presence of mental retardation may play a role in predicting treatment response and some studies suggest a trend for lower response rates for patients with mental retardation. Despite this, many studies have demonstrated the efficacy of stimulant medications, for example, in patients with mental retardation,51-56 though some investigators have suggested that an IQ of ≥45 is required in order to see favorable effects.53,54 However, among the studies reviewed above which specifically examined IQ as a moderator of methylphenidate response, none showed a significant effect.7,8,57 Third, there is limited discussion of methodologic weaknesses of the studies reviewed because the focus has been primarily on randomized controlled trials. This selection bias does not imply that controlled trials are beyond criticism, and is not intended to dismiss the value of case reports, case series, and open-label trials. Finally, and despite best efforts, some relevant studies may not have been included in this article. PP

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
2.    Lecavalier L. Behavioral and emotional problems in young people with pervasive developmental disorders: relative prevalence, effects of subject characteristics, and empirical classification. J Autism Dev Disord. 2006;36(8):1101-1114.
3.    Sturm H, Fernell E, Gillberg C. Autism spectrum disorders in children with normal intellectual levels: associated impairments and subgroups. Dev Med Child Neurol. 2004;46(7):444-447.
4.    Hattori J, Ogino T, Abiru K, Nakano K, Oka M, Ohtsuka Y. Are pervasive developmental disorders and attention-deficit/hyperactivity disorder distinct disorders? Brain Dev. 2006;28(6):371-374.
5.    Conners CK. Conners’ Rating Scales: Revised Technical Manual. North Tonawanda, NY: Multi-Health Systems Inc; 1997.
6.    Quintana H, Birmaher B, Stedge D, et al. Use of methylphenidate in the treatment of children with autistic disorder. J Autism Dev Disord. 1995;25(3):283-294.
7.    Handen BL, Johnson CR, Lubetsky M. Efficacy of methylphenidate among children with autism and symptoms of attention-deficit hyperactivity disorder. J Autism Dev Disord. 2000;30(3):245-255.
8.    Research Units on Pediatric Psychopharmacology Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch Gen Psychiatry. 2005;62(11):1266-1274.
9.    Posey DJ, Aman MG, McCracken JT, et al. Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: an analysis of secondary measures. Biol Psychiatry. 2007;61(4):538-544.
10.    Jou RJ, Handen BL, Hardan AY. Retrospective assessment of atomoxetine in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2005;15(2):325-330.
11.    Posey DJ, Wiegand RE, Wilkerson J, Maynard M, Stigler KA, McDougle CJ. Open-label atomoxetine for attention-deficit/hyperactivity disorder symptoms associated with high-functioning pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006;16(5):599-610.
12.    Arnold LE, Aman MG, Cook AM, et al. Atomoxetine for hyperactivity in autism spectrum disorders: placebo-controlled crossover pilot trial. J Am Acad Child Adolesc Psychiatry. 2006;45(10):1196-1205.
13.    Aman MG, Langworthy KS. Pharmacotherapy for hyperactivity in children with autism and other pervasive developmental disorders. J Autism Dev Disord. 2000;30(5):451-459.
14.    Campbell M, Anderson LT, Meier M, et al. A comparison of haloperidol and behavior therapy and their interaction in autistic children. J Am Acad Child Psychiatry. 1978;17(4):640-655.
15.    Campbell M, Anderson LT, Deutsch SI, Green WH. Psychopharmacological treatment of children with the syndrome of autism. Pediatr Ann. 1984;13(4):309-313,316.
16.    Anderson LT, Campbell M, Adams P, Small AM, Perry R, Shell J. The effects of haloperidol on discrimination learning and behavioral symptoms in autistic children. J Autism Dev Disord. 1989;19(2):227-239.
17.    Locascio JJ, Malone RP, Small AM, et al. Factors related to haloperidol response and dyskinesias in autistic children. Psychopharmacol Bull. 1991;27(2):119-126.
18.    Fisman S, Steele M. Use of risperidone in pervasive developmental disorders: a case series. J Child Adolesc Psychopharmacol. 1996;6(3):177-190.
19.    Horrigan JP, Barnhill LJ. Risperidone and explosive aggressive autism. J Autism Dev Disord. 1997;27(3):313-323.
20.    McDougle CJ, Holmes JP, Bronson MR, et al. Risperidone treatment of children and adolescents with pervasive developmental disorders: a prospective open-label study. J Am Acad Child Adolesc Psychiatry. 1997;36(5):685-693.
21.    Perry R, Pataki C, Munoz-Silva DM, Armenteros J, Silva RR. Risperidone in children and adolescents with pervasive developmental disorder: pilot trial and follow-up. J Child Adolesc Psychopharmacol. 1997;7(3):167-179.
22.    Malek-Ahmadi P, Simonds JF. Olanzapine for autistic disorder with hyperactivity. J Am Acad Child Adolesc Psychiatry. 1998;37(9):902.
23.    Nicolson R, Awad G, Sloman L. An open trial of risperidone in young autistic children. J Am Acad Child Adolesc Psychiatry. 1998;37(4):372-376.
24.    Potenza MN, Holmes JP, Kanes SJ, McDougle CJ. Olanzapine treatment of children, adolescents, and adults with pervasive developmental disorders: an open-label pilot study. J Clin Psychopharmacol. 1999;19(1):37-44.
25.    McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347(5):314-321.
26.    Troost PW, Lahuis BE, Steenhuis MP, et al. Long-term effects of risperidone in children with autism spectrum disorders: a placebo discontinuation study. J Am Acad Child Adolesc Psychiatry. 2005;44(11):1137-1144.
27.    Shea S, Turgay A, Carroll A, et al. Risperidone in the treatment of disruptive behavioral symptoms in children with autistic and other pervasive developmental disorders. Pediatrics. 2004;114(5):e634-e641.
28.    McDougle CJ, Holmes JP, Carlson DC, Pelton GH, Cohen DJ, Price LH. A double-blind, placebo-controlled study of risperidone in adults with autistic disorder and other pervasive developmental disorders. Arch Gen Psychiatry. 1998;55(7):633-641.
29.    Nagaraj R, Singhi P, Malhi P. Risperidone in children with autism: randomized, placebo-controlled, double-blind study. J Child Neurol. 2006;21(6):450-455.
30.    Hellings JA, Zarcone JR, Reese RM, et al. A crossover study of risperidone in children, adolescents and adults with mental retardation. J Autism Dev Disord. 2006;36(3):401-411.
31.    Steingard R, Biederman J, Spencer T, Wilens T, Gonzalez A. Comparison of clonidine response in the treatment of attention-deficit hyperactivity disorder with and without comorbid tic disorders. J Am Acad Child Adolesc Psychiatry. 1993;32(2):350-353.
32.    Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1999;38(12):1551-1559.
33.    Hazell PL, Stuart JE. A randomized controlled trial of clonidine added to psychostimulant medication for hyperactive and aggressive children. J Am Acad Child Adolesc Psychiatry. 2003;42(8):886-894.
34.    Fankhauser MP, Karumanchi VC, German ML, Yates A, Karumanchi SD. A double-blind, placebo-controlled study of the efficacy of transdermal clonidine in autism. J Clin Psychiatry. 1992;53(3):77-82.
35.    Jaselskis CA, Cook EH Jr, Fletcher KE, Leventhal BL. Clonidine treatment of hyperactive and impulsive children with autistic disorder. J Clin Psychopharmacol. 1992;12(5):322-327.
36.    Posey DJ, Puntney JI, Sasher TM, Kem DL, McDougle CJ. Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective analysis of 80 cases. J Child Adolesc Psychopharmacol. 2004;14(2):233-241.
37.    Scahill L, Aman MG, McDougle CJ, et al. A prospective open trial of guanfacine in children with pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006;16(5):589-598.
38.    King BH, Wright DM, Handen BL, et al. Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry. 2001;40(6):658-665.
39.    Leboyer M, Philippe A, Bouvard M, et al. Whole blood serotonin and plasma beta-endorphin in autistic probands and their first-deree relatives. Biol Psychiatry. 1999;45(2):158-163.
40.    Campbell M, Adams P, Small AM, Tesch LM, Curren EL. Naltrexone in infantile autism. Psychopharmacol Bull. 1988;24(1):135-139.
41.    Herman BH, Hammock MK, Arthur-Smith A, Kuehl K, Appelgate K. Effects of acute administration of naltrexone on cardiovascular function, body temperature, body weight and serum concentrations of liver enzymes in autistic children. Dev Pharmacol Ther. 1989;12(3):118-127.
42.    Campbell M, Anderson LT, Small AM, Adams P, Gonzalez NM, Ernst M. Naltrexone in autistic children: Behavioral symptoms and attentional learning. J Am Acad Child Adolesc Psychiatry. 1993;32(6):1283-1291.
43.    Willemsen-Swinkels SH, Buitelaar JK, Weijnen FG, van Engeland H. Placebo-controlled acute dosage naltrexone study in young autistic children. Psychiatry Res. 1995;58(3):203-215.
44.    Kolmen BK, Feldman HM, Handen BL, Janosky JE. Naltrexone in young autistic children: a double-blind, placebo-controlled crossover study. J Am Acad Child Adolesc Psychiatry. 1995;34(2):223-231.
45.    Willemsen-Swinkels SH, Buitelaar JK, van Engeland H. The effects of chronic naltrexone treatment in young autistic children: a double-blind placebo-controlled crossover study. Biol Psychiatry. 1996;39(12):1023-1031.
46.    Bouvard MP, Leboyer M, Launay JM, et al. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res. 1995;58(3):191-201.
47.    Kolmen BK, Feldman HM, Handen BL, Janosky JE. Naltrexone in young autistic children: replication study and learning measures. J Am Acad Child Adolesc Psychiatry. 1997;36(11):1570-1578.
48.    Santosh PJ, Baird G, Pityaratstian N, Tavare E, Gringras P. Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study. Child Care Health Dev. 2006;32(5):575-583.
49.    Gagliano A, Germanò E, Pustorino G, et al. Risperidone treatment of children with autistic disorder: effectiveness, tolerability, and pharmacokinetic implications. J Child Adolesc Psychopharmacol. 2004;14(1):39-47.
50.    Malone RP, Maislin G, Choudhury MS, Gifford C, Delaney MA. Risperidone treatment in children and adolescents with autism: short- and long-term safety and effectiveness. J Am Acad Child Adolesc Psychiatry. 2002;41(2):140-147.
51.    Aman MG. Stimulant drug effects in developmental disorders and hyperactivity–toward a resolution of disparate findings. J Autism Dev Disord. 1982;12(4):385-398.
52.    Gadow KD. Prevalence and efficacy of stimulant drug use with mentally retarded children and youth. Psychopharmacol Bull. 1985;21(2):291-303.
53.    Aman MG, Marks RE, Turbott SH, Wilsher CP, Merry SN. Methylphenidate and thioridazine in the treatment of intellectually subaverage children: effects on cognitive-motor performance. J Am Acad Child Adolesc Psychiatry. 1991;30(5):816-824.
54.    Aman MG, Kern RA, McGhee DE, Arnold LE. Fenfluramine and methylphenidate in children with mental retardation and ADHD: clinical and side effects. J Am Acad Child Adolesc Psychiatry. 1993;32(4):851-859.
55.    Handen BL, Feldman HM, Lurier A, Murray PJ. Efficacy of methylphenidate among preschool children with developmental disabilities and ADHD. J Am Acad Child Adolesc Psychiatry. 1999;38(7):805-812.
56.    Johnson CR, Handen BL, Lubetsky MJ, Sacco KA. Affective disorders in hospitalized children and adolescents with mental retardation: a retrospective study. Res Dev Disabil. 1995;16(3):221-231.
57.    Stigler KA, Desmond LA, Posey DJ, Wiegand RE, McDougle CJ. A naturalistic retrospective analysis of psychostimulants in pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2004;14(1):49-56.

e-mail: ns@mblcommunications.com

 

Dr. Sussman is editor of Primary Psychiatry as well as professor of psychiatry and interim chairman in the Department of Psychiatry at the New York University School of Medicine in New York City.

Dr. Sussman reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


 

The function of any medical journal is to provide readers with information that can be translated into better understanding their patients, their illnesses, and the most effective ways to prevent or treat those conditions. As editor of Primary Psychiatry, I endeavor each month to ensure that the content of the publication is accurate and balanced. Topics for issues and individual articles are selected based on their merits. Despite the efforts of myself and the editorial staff, there is much more that clinicians need to know than we can print or put on our Website. Thus, like our readers, I am constantly looking for sources of easily accessed information that may be relevant to clinical decision making, teaching, and writing. 

One problem that I encounter with many psychiatry Websites is a content bias. Most contain information that is unduly weighted toward therapeutic areas or disease states that are associated with medications that are still on patent. I have been searching for a Website that I can log onto every morning, or whenever I want to scope out what is new in the field. For the most part, I have set up Google alerts to notify me about reports involving topics I follow.

However, just last week I was pleasantly surprised when my colleague at the New York University School of Medicine, David L. Ginsberg, MD, alerted me to a Website I had never visited called MedlinePlus.1 There is no advertising on this Website. The home page has a feature on current health news, which provides access to late-breaking articles of interest. A person can search for specific topics as well. For example, I was interested in anticonvulsants and birth defects, mainly because these drugs are frequently used to treat bipolar disorder. My search directed me to a very helpful article2 from a neurology journal that I would not otherwise run across. I read the following:

“The finding of worse anatomic and neurodevelopmental outcomes following fetal valproate exposure in multiple studies suggests that it poses a special risk. Thus, it seems prudent not to use valproate as a first choice antiepileptic drug in women of childbearing age. When valproate is employed in women of childbearing potential, dosage should be kept as low as possible since its effect appears to be dose dependent…. Lamotrigine and carbamazepine may have a specific risk for cleft lip/palate but with an overall modest risk for major malformations.”

MedlinePlus gathers information from National Library of Medicine, the National Institutes of Health, and other government agencies and health-related organizations. Preformulated MEDLINE searches are included and link to medical journal articles. There are numerous links to other sites that are very useful. To test the Website, I clicked on the topic “Panic Disorder” on the link to ClinicalTrials.gov. It provided specific information about 36 clinical trials that are currently recruiting subjects. This Website will prove very helpful for clinicians who want to refer patients to research protocols.

While I hope that readers continue to consider Primary Psychiatry and its Website3 as a regular source of information, the fact is that in the Internet age, no single Website can provide comprehensive access to emerging clinical and research publications. I would appreciate readers letting me know of Websites that they find helpful, and in a future issue we can publish a list of these sites.

I want call attention to a review article in this issue by Jagoda Pasic, MD, and colleagues, discussing factitious disorders, a puzzling, curious, but nevertheless serious illness. Patients with factitious disorder perplex caregivers in terms of accounting for the patient’s motivation in feigning illness, making the diagnosis, and determining how to treat the disorder once it is recognized. As the authors note, these cases are especially challenging in the initial, emergency department setting, where clinicians have no access to historic data. Even if factitious illness is suspected, genuine illness needs to ruled out. The authors present two patients who sought emergency psychiatric care and discuss diagnostic and treatment issues. They offer psychological explanations for staff and clinicians’ reactions and suggest interventions that may prove useful in the emergency setting.

I also want to welcome David N. Neubauer, MD, who, starting with this issue, will contribute a regular column entitled “Clinical Updates in Sleep Medicine.” Dr. Neubauer is associate director of the Johns Hopkins Sleep Disorders Center and assistant professor in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

Finally, I would like to thank the excellent and hard work of our peer reviewers, without whom we could not maintain the high standards of the journal. PP

References

1.    MedLinePlus. Available at: http://medlineplus.gov. Accessed December 10, 2008.
2.    Meador KJ, Pennell PB, Harden CL, et al. Pregnancy registries in epilepsy: a consensus statement on health outcomes. Neurology. 2008;71(14):1109-1117.
3.    Primary Psychiatry. Available at: www.primarypsychiatry.com. Accessed December 16, 2008.

 

Dr. Soorya is assistant professor of psychiatry and Dr. Halpern is clinical instructor in the Department of Psychiatry at the Mount Sinai School of Medicine in New York City.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Latha V. Soorya, PhD, Department of Psychiatry, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1230, New York, NY 10029; Tel: 212-241-7250; E-mail: latha.soorya@mssm.edu.


 

Focus Points

• Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share several similar cognitive and behavioral impairments including motor functions, executive functions/behavioral regulation, and socialization.
• Behavioral interventions for shared deficits across ASD and ADHD include socialization skills therapies and behavior management strategies.
 

Abstract

Autism spectrum disorders (ASDs) and attention-deficit/hyperactivity disorder (ADHD) are among the most commonly diagnosed psychiatric syndromes in childhood. While the syndromes have unambiguous distinctions, ADHD and ASD share several common cognitive and behavioral disturbances including deficits in behavior regulation, deficits associated with executive functions impairments (planning, inattention, behavioral regulation), motor coordination problems, and impairments in peer relationships/socialization. This article provides an overview of the available clinical research data on the shared cognitive and behavioral symptoms in ASD and ADHD, with a focus on implications for psychosocial treatments. Evaluating the overlap between these common developmental disorders, as well as the subset of individuals exhibiting comorbid ADHD and ASD, has potential to advance conceptualizations of each disorder including factors influencing treatment response.

Introduction

This article provides an overview of the emerging scientific literature on the shared and disassociated symptoms across autism spectrum disorders (ASDs) and attention-deficit/hyperactivity disorder (ADHD). Both neurodevelopmental disorders share several characteristics, including strong genetic liabilities and heterogeneous presentations. Findings from genetics, neurobiology, and neuropsychological studies have found intriguing overlaps between the disorders. Molecular genetics studies suggest that some genes may influence both ADHD and ASDs, with some studies finding an overlap in linkage peaks in ASD and ADHD in genome-wide scans.1 Genetic syndromes such as Fragile X also have strong associations with both ASDs and ADHD.2 Findings also support commonalities in brain abnormalities associated with both conditions, including structural and functional abnormalities of the front-striatal systems.3,4 Brieber and colleagues5 reported findings of structural abnormalities in gray matter in both ADHD and autism compared to typically developing controls, with reduced gray matter in left medial temporal lobe and higher gray matter volumes in left inferior parietal cortex. The study also reported dissociation between ASD and ADHD in volumetric gray matter development; ASD (but not ADHD) individuals exhibited increased gray matter volume in the right temporo-parietal junction, a region which may be associated with perspective-taking abilities. Such research has potential to inform conceptualizations of endophenotypes that span diagnostic categories and provide insight into variability observed in treatment response in both disorders.

This article focuses on the substantial overlap between cognitive and behavioral symptoms in ASD and ADHD, with an emphasis on psychosocial interventions which target these symptom domains across disorders. The article inherently adopts a dimensional perspective since available psychological and psychiatric interventions, particularly in ASDs, have been most successful when aimed at treating specific symptom domains (eg, impulsivity, repetitive behaviors) rather than the broad syndrome. A review of shared phenotypic features in ASD and ADHD is complicated, and tempered, by the heterogeneity within ASDs and ADHD as well as the high rates of comorbidity between the disorders.6 Leyfer and colleagues,6 in a study piloting their Autism Comorbidity Interview-Present and Lifetime Version, found that ADHD was diagnosed with autism in 31% of their sample. This rate was increased to ~55% when subsyndromal cases were included. Within their sample, 65% of the children diagnosed with ADHD had the inattentive sub-type. Furthermore, empirical literature providing joint evaluations of ASD and ADHD is in its early stages. Thus, this article draws from the available empirical and clinical literature within and across disorders, with the aim of identifying areas of potential overlap and future directions for conceptualizations of ASDs and psychosocial intervention research.

Cognitive and Behavioral Phenotypes and Interventions in ASD and ADHD

Several cognitive and behavioral domains have been evaluated in both ASDs and ADHD, including motor coordination, executive functions/behavioral regulation, and social cognition/social skills. Research questions have addressed shared versus disassociated symptoms across disorders as well as the specificity of symptom domains to either ASD or ADHD (Table).7-32

 

 

Motor Coordination

Motor coordination deficits are a well-known neurologic soft sign associated with ADHD and have been associated with various childhood disorders including ASDs.33 In ADHD, motor coordination deficits include but are not limited to manual dexterity, fine-motor speed, and hand-eye coordination, and may be more prominent in the ADHD-inattentive subtype and combined subtype.7 Neurocognitive research in ASDs have found impairments in tasks of motor speed and dexterity,8,9 gross motor development,10 posture,11 and skilled motor actions.12,13

A few studies with negative findings suggest deficits in basic motor skills may not be specific to autism, but rather are associated with delayed development.14,15 Studies with negative findings to date utilized developmental disability control groups (vs. typically developing controls). The failure to find ASD-specific deficits in studies utilizing controls for delay or disability may provide support to the intriguing, yet controversial concept of DAMP (deficits in attention, motor control, and perception),16 which proposes a syndrome characterized by deficits in motor coordination, inattentive symptoms, and deficits in visual-perceptual abililities, and which has a high co-occurance with ASDs. Such dimensional concepts may imply common treatment approaches across disorders.

Targeted Treatments for Motor Coordination

To date, targeted psychosocial treatments addressing motor coordination problems in ADHD and ASD, including physical therapy and sensory integration therapies (SIT), have received limited attention in the empirical literature. Physical therapy involves the treatment of injuries, disorders, or delays, using physical methods such as exercising specific parts of the body, in an effort to strengthen these parts or improve their range of motion. Watemberg and colleagues18 conducted a randomized trial comparing outcomes of physical therapy (vs. no treatment) in a group of 28 children with ADHD and developmental coordination disorder with findings suggesting improvements on standardized motor testing for the treatment group. Similar controlled trials of physical therapy are not available to date for individuals with ASD, nor are controlled studies of the widely used SIT. SIT involves gradually exposing a child to various sensory stimuli so as to encourage the nervous system to process, integrate, and organize sensory input. The available data on SIT is not promising; the only meta-analytic study17 of SIT suggests children receiving the therapy improved no more than children who received no treatment at all. When SIT has been compared to alternative treatments such as perceptual motor therapy and academic tutoring, there has been no difference in effect.

Executive Functions

Executive functions are among the most well-studied neurocognitive deficit in the ASD and ADHD literature. Across disorders, executive function is a broad construct consisting of several higher-order cognitive abilities (eg, working memory, response inhibition, set-shifting, planning, and monitoring skills), which govern one’s ability to perform adaptive responses to complex or novel situations. Executive function deficits are at the core of the neurocognitive profile in ADHD with findings supporting deficits in inattention, inhibition, and working memory. Less conclusive evidence is available for deficits in other executive function domains such as fluency, perseveration, and self-regulation/monitoring. The neurocognitive deficits in ADHD are present across the lifespan, familial, and specific (not associated with comorbid symptoms).19

While the presence of executive function deficits in ASD has been the subject of several investigations, the nature of the executive function problems in ASD are less established. For example, several questions remain; the profile of executive function deficits,20,22 specificity of executive function deficits to ASD, and presence across the lifespan remain to be established. Ozonoff and colleagues21 provide a comprehensive review of executive function research in ASD and suggest that when evaluating components of executive function in ASD, a consistent pattern of abilities and disabilities appear. Generally, the literature suggests that sustained attention and response inhibition are two components of executive function that are relatively preserved in ASD. In contrast, set-shifting/flexibility and planning are commonly found deficits. Deficits in other executive functions are more mixed, particularly in the area of working memory. Certain studies have found no deficits in working memory,34 with others suggesting verbal35 or spatial36 working memory deficits.

Happé and colleagues22 investigated executive function in males ages 8–16 years with ASD or ADHD and in typically developing children. The study utilized multiple measures of skills in three executive function domains, namely, response selection, flexibility, and planning/working memory. Results indicated the clinical groups performed below typically developing children on all but one variable measuring response selection. Additionally, the ADHD patients exhibited greater impairments than the ASD patients and typically developing children groups on measures of response inhibition (eg, go–no go) and planning/working memory. Specific impairments in cognitive flexibility in children with ASD were not found, in contrast to previous research. The results also found age-related improvements in executive function in children with ASD, but not ADHD. These findings suggest that observed problems in executive function in ASD may relate to delayed brain maturation, in which the frontal cortices are the last to achieve full functionality, rather than an autism-specific executive function deficit.

Targeted Treatments for Executive Functions

Psychosocial treatments of executive function deficits are emerging in the ADHD literature and are not available to date in the ASD literature. Functional impairments associated with the executive function domains of attention and inhibition are cardinal features of ADHD and common associated symptoms of ASD. Of the available psychosocial treatments for executive functions in both disorders, interventions targeting behavioral regulation are among the most well established and widely used. Studies24,25 overwhelmingly support the use of behavior therapies based on operant conditioning paradigms, focused on contingency management and identification of common predictors of problem behaviors.

In ADHD, a large pool of studies support the efficacy of behavioral parent training and behavioral classroom management in managing the core symptoms of inattention and behavioral regulation,37 although the additive value of behavioral interventions to the standard of care (ie, medication treatment) remains a contentious debate in the field.19 The behavioral interventions involve parent or teacher training in the use of effective reinforcement (eg, token systems) and punishment procedures (eg, time-out) for target behaviors (eg, following directions, completing homework). The rationale for these behavioral interventions is to provide compensatory systems for the executive function deficits found in ADHD (eg, behavioral regulation, working memory, internalized/self-directed speech).

Behavioral interventions for inattention and impulsivity in ASD generally utilize similar contingency management approaches, in combination with antecedent-based (or preventative) interventions. For example, children may appear impulsive or inattentive but the function of such outward behaviors may be related to accessing/engaging in a preoccupation. Interventions which create scheduled access to a child’s intense interests (eg, through picture activity schedules) may be helpful.

Research in ADHD includes cognitive remediation programs targeting a broad range of functional deficits associated with executive function26,37 and computerized attention training programs.23 Stevenson and colleagues23 conducted the only randomized controlled trial of targeted executive function interventions in ASD utilizing an 8–12-week psychosocial program targeting time management, organization, and planning skills in adults. Findings suggest clinically significant improvements in ADHD symptomology and organization skills, with maintenance seen 12 months post-intervention. Studies of computerized attention training have shown promise in clinic settings and untrained tasks, but have failed to show generalization outside of the lab (eg, academic settings, teacher/parent ratings of ADHD symptoms).23 Interventions directly targeting organization and planning skills in ASD have not been published to date.

Socialization Deficits and Interventions in ASD and ADHD

Social dysfunction is the central, unifying feature of ASDs and may be among the most debilitating functional impairments in both ASD and ADHD. A few recent studies38 evaluating the overlap in socialization impairments in ADHD and ASD suggest that individuals with clinically significant symptoms in both ASD and ADHD may be at greater risk for peer rejection and significant social dysfunction than individuals with ASD or ADHD alone. Furthermore, social impairment and peer rejection have been found to be predictors of long-term outcomes (eg, academic achievement and mental health).39

While similar functional outcomes are associated with the social skills deficits across ASD and ADHD, it is important to note the considerable differences in socialization problems found between disorders. In particular, children and adolescents with ADHD do not demonstrate social avoidance or deficits in social motivation; in fact, they often initiate social exchanges and often direct attention to peers during play activities. However, these individuals are frequently excitable and the intensity of their overtures is often not consistent with social situation. Research has found various deficits including difficulties with social-cognitive skills (eg, inattention to and misinterpretation of social cues), inappropriate behaviors (eg, impulsivity), and poor interpersonal skills (eg, less social involvement during conversations).40

In ADHD, social dysfunction appears in early childhood and adolescence, resulting in fewer friendships and high levels of peer rejection,27 with social dysfunction clearly exacerbated by comorbidity with aggression and conduct problems.28 Further, research has demonstrated behavioral and social differences between children and adolescents with different subtypes of ADHD as well as differences in treatment response. In particular, children with combined type ADHD, especially those who are impulsive and hyperactive, tend to be rejected and disliked, whereas children with only inattention tend to be ignored.41

In ASD, social impairments are evident from infancy and include difficulty with eye gaze, emotion recognition, play skills, social motivation, and understanding communicative intent.29 High-functioning individuals with ASD also have substantial socialization deficits, particularly in discerning subtleties of complex social interactions. For example, individuals with high functioning autism (HFA) and Asperger’s syndrome can often identify basic emotions, but research on visual scanning patterns in social situations suggest these individuals may use alternative strategies that may not be sufficient when social requirements are more complex and dynamic.42,43 Similarly, while high-functioning children with ASD may pass basic theory of mind (ie, understanding the perspectives/intentions of others), they continue to have difficulty understanding the intent behind nonliteral speech.44,45

It has been hypothesized that the basis of social problems in children with ADHD is associated with performance rather than knowledge or skills deficits. Thus, interventions in ADHD would emphasize determining when and where such skills would be useful rather than skills training, as is seen in social skills interventions in ASD.19 Further, as social impairment and peer acceptance are predictors of long-term outcome, including later peer acceptance, academic achievement, and mental health,39 these skills are also critical treatment targets for intervention in both disorders. However, at present, empirical support for existing interventions for socialization skills are limited in ASD and ADHD, although some studies suggest improvements in third-party ratings of socialization skills in children with ADHD treated with stimulants.30

Targeted Treatments: Social Skills Interventions in ASD

Treatment targets for children and adolescents with ASDs are broad and reflect the diversity of problems seen across the autism spectrum. Many of these treatments focus on the variety of socialization deficits present in individuals in this population. In lower functioning individuals deficits and treatment targets include: initiation of speech, use of appropriate speech intonation, use of appropriate facial affect and initiation and modulation of eye contact. Many of these difficulties persist into adulthood and without intervention, may increase rather than diminish with age.46

For higher functioning individuals, deficits and treatment targets include initiation of social interactions, interpretation of social cues (both verbal and nonverbal),47 and theory of mind (a skill essential to the development of friendships).48 Children with Asperger’s syndrome or HFA often do not outgrow these deficits; rather, these social difficulties may persist into adulthood, where they continue to negatively impact social, emotional, and occupational functioning. Adults with Asperger’s syndrome/HFA are far more likely than the general population to be unemployed or have jobs that are not commensurate with their cognitive skills and level of education. In addition, these adults are far less likely to have satisfying social relationships.49,50

Although social skills therapy groups are widely used in the community for individuals with Asperger’s syndrome/HFA, empirical support for these programs is limited and do not include randomized controlled trials. Preliminary studies suggest promise for social skills group therapies in Asperger’s syndrome/HFA, particularly for structured approaches such as cognitive-behavioral therapy.31 A recent article reported ~70% of studies yielded positive treatment effects for targeted social skills.32 Specific group therapies targeting social cognitive skills (eg, emotion recognition, theory of mind) are also showing promise in small-scale pilot studies (eg, social cognition training).51,52

Aside from social skills training, other commonly utilized psychosocial interventions for individuals with HFA and Asperger’s syndrome are inclusion with typically developing peers and peer-mediated social skills interventions. Research on inclusion strategies suggests that although inclusion may improve the frequency of interactions, this approach may not develop the quality of these social exchanges. Further, without concurrent targeted skills training, inclusion may not be sufficient in treating the core deficits of autism.53 As a result, a combination of target-child (addressing specific social skills) and peer-mediated approaches (teaching typical children to engage their peers with ASDs) are recommended and have some support from preliminary studies.54

While preliminary studies in both group and peer-mediated interventions suggest promise, the efficacy of these psychosocial interventions remains to be tested in controlled treatment trials. Both group therapies and peer-mediated interventions need to address the central questions of generalizability of treatment effects across settings and maintenance of treatment gains across time.

Targeted Treatments: Socialization Interventions in ADHD

Research on social skills training for children and adolescents with ADHD has produced mixed results.19 Certain studies yield positive outcomes; for example, Frankel and colleagues55 compared two groups of children with ADHD treated with stimulant medication, one group receiving concurrent social skills treatment and the other group a wait-list control. Results indicated significant benefits on both parent and teacher ratings.56 However, results of other studies are less encouraging. Sheridan and colleagues56 found no evidence that social skills training generalized to improved peer interaction in an educational setting.57 In addition, others studies yielded mixed results. Pfiffner and McBurnett57 found that short-term social skills training combined with parent training was superior to a wait-list control but only on parent ratings.

The Multimodal Treatment Study of Children with ADHD,58 the most comprehensive ADHD treatment study to date, suggests a limited role for social skills interventions in children with ADHD. Findings from this study indicated that “in young children with ADHD, there is no support for clinic-based social skills training as part of a long-term psychosocial intervention to improve social behavior.” Although children treated with stimulant medication (methylphenidate) did evidence certain social improvements when social skills intervention was integrated with methylphenidate treatment, these children demonstrated no gains in social functioning beyond those associated with stimulant treatment alone, except for the finding of greater positive responses to positive behaviors by peers and teachers in the second year of the study.

Social problems in children with ADHD are heterogeneous; as a result, research outcomes may vary with subtype. Certain research demonstrates that behaviorally based psychosocial treatment, when specifically adapted for ADHD-Inattentive subtype (ADHD-I), may be effective in reducing symptoms and impairment associated with ADHD-I, especially when parents, teachers, and children are involved. For example, Pfiffner and colleagues57 designed a social skills treatment (the Child Life and Attention Skills program) that led to statistically and clinically significant reductions in attention problems and improvement in organizational and social skills at posttreatment relative to the control group. These improvements were maintained at follow-up. The inclusion of teachers in the treatment protocol and the more intensive parent intervention likely enhanced generalization.

Although certain studies may yield promising outcomes, empirical research is limited and results are inconsistent. In particular, there are a limited number of studies using randomized assignment to treatment groups, the majority of studies involve parent and teacher awareness of treatment conditions, and studies involve an absence of alternative treatment groups and limited evidence of generalization to the school setting.

Conclusion

The study of the overlap in symptom domains of motor coordination, executive functions, and socialization skills in ASD and ADHD is relatively recent, and few conclusions can be drawn. Data on motor coordination difficulties suggests the presence of motor dysfunction across many developmental disorders, including ADHD and autism. These findings may relate to the relative vulnerability of the motor system to developmental insult. Additional research on this symptom domain may have implications for motor skills as a shared endophenotype across disorders. Research on executive functions deficits is well established with regards to its central role in the neurocognitive profiles of individuals with ADHD. In contrast, research continues to evaluate the presence and specificity of executive functions deficits in ASDs. Available data suggest the nature of executive function impairments may be qualitatively different in ADHD and ASD. Psychosocial treatments for behavioral dysregulation related to executive function in both disorders have strong empirical support and primarily include behavioral interventions based in operant conditioning theory. Promising psychosocial treatments for other executive function domains such as attention and organizational/planning skills are emerging in ADHD and may provide interesting avenues for applications in ASD.

 In the domain of socialization impairments, while both ASD and ADHD are associated with deficits in social perception and poor peer relationships, the cause and nature of these deficits appear fundamentally different. In ASD, social perceptual deficits are apparent from infancy in fundamental social skills (eg, joint attention, eye gaze), are pervasive through development, and are a defining feature of the disorder. In ADHD, social perceptual deficits are highly specific (overly negative interpretation of social cues) and appear largely related to problems with performance, rather than knowledge, of appropriate social skills. Subsequently, psychosocial interventions showing promise in ASD tend to be structured, skills-based interventions, while similar approaches have not been successful in the ADHD literature.

The present article highlights the need for ongoing research on these symptom domains, including iterative studies advancing the knowledge of efficacy of commonly used psychosocial interventions as well as investigations evaluating adapted therapies across these similar disorders. Furthermore, increased focus on the subset of individuals exhibiting clinically significant or comorbid ADHD and ASD symptoms may prove useful in understanding the variability in treatment response associated with psychosocial interventions in both disorders. PP

References

1.    Smalley SL, Loo SK, Yang MH, Cantor RM. Toward localizing genes underlying cerebral asymmetry and mental health. Am J Med Genet B Neuropsychiatr Genet. 2005;135B(1):79-84.
2.    Farzin F, Perry H, Hessl D, et al. Autism spectrum disorders and attention deficit/hyperactivity disorder in boys with fragile X permutation. J Dev Behav Pediatr. 2006;27(2):S137-S144.
3.    Bachevalier J, Loveland KA. The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism. Neurosci Biobehav Rev. 2006;30(1):97-117.
4.    Dickstein SG, Bannon K, Castellanos FX, Milham MP. The neural correlates of attention deficit hyperactivity disorder: An ALE metaanalysis. J Child Psychol Psychiatry. 2006;47(10):1051-1062.
5.    Brieber S, Neufang S, Bruning N, et al. Structural brain abnormalities in adolescents with autism spectrum disorder and patients with attention deficit/hyperactivity disorder. J Child Psychol Psychiatry. 2007;48(12):1051-1062.
6.    Leyfer OT, Folstein SE, Bacalman S, et al. Comorbid psychiatric disorders in children with autism: Interview development and rates of disorders. J Autism Dev Disord. 2006;36(7):849-861.
7.    Pitcher T, Piek J, Hay D. Fine and gross motor ability in males with ADHD. Dev Med Chil Neurol. 2003;45(8):525-538.
8.    Ghaziuddin M, Butler E, Tasi L. Is clumsiness a marker for Asperger syndrome. J Intellect Disabil Res. 1994;38(4):519-527.
9.    Szatmari P, Tuff L, Finlayson AJ, et al. Asperger’s syndrome and autism: neurocognitive aspects. J Am Acad Child Adolesc Psychiatry. 1990;29(1):130-136.
10.    Berkeley S, Zittel L, Pitney L, et al. Locomotor and object control skills of children diagnosed with autism. Adapt Phys Activ Q. 2001;18:405-416.
11.    Kohen-Raz R, Volkmar F, Cohen D. Postural control in children with autism. J Autism Dev Disord. 1992;22(3):419-432.
12.    Smith I, Bryson S. Gesture imitation in autism I: nonsymbolic postures & sequences. Cogn Neuropsychol. 1998;15(6/7/8):747-770.
13.    Rinehart N, Bradshaw J, Brereton A, Tonge BJ. Movement preparation in high-functioning autism and asperger disorder: a serial choice reaction time task involving motor reprogramming. J Autism Dev Disord. 2002;31(1):79-88.
14.    Green D, Baird G, Barnett AL, Henderson L, Huber J, Henderson SE. The severity and nature of motor impairment in Asperger’s syndrome: a comparison with specific developmental disorder of motor function. J Child Psychol Psychiatry. 2002;43(5):655-668.
15.    Noterdaeme M, Mildenberger K, Minow F, Amorosa H. Evaluation of neuromotor deficits in children with autism and children with specific speech and language disorder. Eur Child Adolesc Psychiatry. 2002;11(5):219-225.
16.    Gillberg C. Deficits in attention, motor control, and perception: a brief review. Arch Dis Child. 2003;88(10):904-910.
17.    Vargas S, Camilli G. A meta-analysis of research on sensory integration treatment. Am J Occup Ther. 1999;53(2):189-198.
18.    Watemberg N, Waiserberg N, Zuk L, et al. Developmental coordination disorder win children with attention deficit hyperactivity disorder and physical therapy intervention. Dev Med Child Neurology. 2007;49(12):920-925.
19.    Smith B, Barkley R, Shapiro C. Attention deficit hyperactivity disorder. In: Mash E, Barkley RA, eds. Treatment of Childhood Disorders. 3rd ed. New York, NY: Guilford Press; 2006:65-136.
20.    Ozonoff S, Cook I, Coon H, et al. Performance on Cambridge Neuropsychological Test Automated Battery subtests sensitive to frontal lobe function in people with autistic disorder: evidence from the Collaborative Programs of Excellence in Autism network. J Autism Dev Disord. 2004;34(2):139-150.
21.    Ozonoff S, South M, Provecal S. Executive functions. In: Volkmar F, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:606-627.
22.    Happé F, Booth R, Charlton R, Hughes C. Executive function deficits in autism spectrum disorders and attention deficit/hyperactivity disorder: examining profiles across domains and ages. Brain Cogn. 2006;61(1):25-39.
23.    Stevenson C, Whitmont S, Bornholt L, Livesey D, Stevenson RJ. A cognitive remediation programme for adults with attention deficit hyperactivity disorder. Aust N Z J Psychiatry. 2002;36(5):610-616.
24.    Kerns KA, Eso K, Thomson J. Investigation of a direct intervention for improving attention in young children with ADHD. Dev Neuropsychology. 1999;16:273-295.
25.    Solanto MV, Marks DJ, Mitchell KJ, Wasserstein J, Kofman MD. Development of a new psychosocial treatment for adult ADHD. J Atten Disord. 2008;11(6):728-736.
26.    O’Neill R, Horner R, Albin R, et al. Functional Assessment and Program Development for Problem Behavior: A Practical Handbook. 2nd ed. Pacific Grove, CA: Brooks/Cole Publishing Co; 1997.
27.    Bagwell CL, Molina BS, Pelham WE Jr, Hoza B. Attention deficit hyperactivity disorder and problems in peer relations: Predictions from childhood to adolescence. J Am Acad Child Adolesc Psychiatry. 2001;40(11):1285-1292.
28.    Hinshaw SP. Interventions for social competence and social skill. Child Adolesc Psychiatr Clin N Am. 1992;1(2):539-552.
29.    Sigman M, Spence S-J, Wang AT. Autism from developmental and neuropsychological perspectives. Annu Rev Clin Psychol. 2006;2:327-355.
30.    A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56(12):1073-1086.
31.    Williams-White S, Koenig K, Scahill L. Toward the development of effective social skills intervention in children with autism spectrum disorders. J Autism Dev Disord. 2008;37:1858-1868.
32.    Myles BS, Simpson RL, Ormsbee CK, Erickson C. Integrating preschool children with autism with their normally developing peers: research findings and best practices recommendations. Focus on Autistic Behavior. 1993;8(5):1-18.
33.    Reiersen A, Constantino JN, Todd RD. Co-occurance of motor problems and autistic symptoms in attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2008;47(6):662-672.
34.    Edgin J, Pennington B. Spatial cognition in autism spectrum disorders: superior, impaired, or just intact?  J Autism Dev Disord. 2005;35(6):729-745.
35.    Bennetto L, Pennington B, Rogers S. Intact and impaired memory functions in autism. Child Dev. 1996;67(4):1816-1835.
36.    Luna B, Doll S, Hagedus S, et al. Maturation of executive function in autism. Biol Psychiatry. 2007;61(4):474-481.
37.    Pelham W, Fabiano G. Evidence based psychological treatments for attention-deficit/hyperactivity disorder. J Clin Child Adol Psychol. 2008;37(1):184-214.
38.    Greene RW, Biederman J, Faraone SV, Ouellette CA, Penn C, Griffin SM. Toward a psychometric definition of social disability in children with attention deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1996;35(5):571-578.
39.    Hartup W. Social relationships and their developmental significance. Am Psychol. 1999;44:120-126.
40.    Stroes A, Alberts E, Van Der Meere JJ. Boys with ADHD in social interaction with a nonfamiliar adult: an observational study. J Am Acad Child Adolesc Psychiatry. 2003;42(3):295-302.
41.    Montas G, Halterman J. Bullying among children with autism and the influence of comorbidity with ADHD: A population based study. Ambul Pediatr. 2007;7(3):253-257.
42.    Klin A, Jones W, Schultz R, Volkmar F, Cohen D. Visual fixation patterns during viewing of naturalistic social situations as predictors of social competence in individuals with autism. Arch Gen Psychiatry. 2002;59(9):809-816.
43.    Pelphrey KA, Sasson NJ, Reznick JS, Paul G, Goldman BD, Piven J. Visual scanning of faces in autism. J Autism Dev Disord. 2002;32(4):249-261.
44.    Happé FG. An advanced test of theory of mind: understanding of story characters’ thoughts and feelings by able autistic, mentally handicapped, and normal children and adults. J Autism Dev Disord. 1994;24(2):129-154.
45.    Martin I, McDonald S. An exploration of causes of non-literal language problems in individuals with asperger syndrome. J Autism Dev Disord. 2004;34(3):311-328.
46.    Howlin P, Mawhood L, Rutter M. Autism and developmental receptive language disorder–a follow-up comparison in early adult life. II: social, behavioural, and psychiatric outcomes. J Child Psychol Psychiatry. 2000;41(5):561-578.
47.    Weiss MJ, Harris SL. Teaching social skills to people with autism. Behav Modif. 2001;25(5):785-802.
48.    Gutstein SE, Whitney T. Asperger syndrome and the development of social competence. Focus Autism Other Dev Disabl. 2002;17:161-171.
49.    Szatmari P, Bartolucci G, Bremmer R. Asperger’s syndrome and autism: comparisons on early history and outcome. Dev Med Child Neurol. 1989;31:287-299.
50.    Venter A, Lord C, Schopler E. A follow-up study of high-functioning autistic children. J Child Psychol Psychiatry. 1992;33(3):489-507.
51.    Rao PA, Beidel DC, Murray MJ. Social skills interventions for children with Asperger’s Syndrome or high-functioning autism: a review and recommendations. J Autism Dev Disord. 2008;38(2):353-361.
52.    Gevers C, Clifford P, Mager M, Boer F. Brief report: a theory-of-mind-based social-cognition training program for school-aged children with pervasive developmental disorders: an open study of its effectiveness. J Autism Dev Disord. 2006;36(4):567-571.
53.    Turner-Brown L, Perry T, Dichter G, Bodfish J, Penn D. Brief report: feasibility of social cognition and interaction training for adults with high functioning autism. J Autism Dev Disord. In press.
54.    Carpenter L, Soorya L, Halpern D. High functioning autism and Asperger’s disorder. Pediatr Ann. In press.
55.    Frankel F, Myatt R, Cantwell DP, Feinberg DT. Parent-assisted transfer of children’s social skills training: effects on children with or without attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1997;36(8):1056-1064.
56.    Sheridan S, Dee C, Morgan J, et al. A multi-method introduction for social skills deficits in children with ADHD and their parents. School Psych Rev. 1996;25:401-416.
57.    Pfiffner LJ, McBurnett K. Social skills training with parent generalization: Treatment effects for children with attention deficit disorder. J Consult Clin Psychol. 1999;65(5):749-757.
58.    A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiatry. 1999;56(12):1073-1086.

 

Researchers Determine Rates of Self-Medication in Mood Disorders Patient

Self-medication, defined as using alcohol and/or drugs to alleviate emotional distress, is a dangerous habit for patients suffering from mood disorders. Although rates of self-medication have previously been found to be fairly high in mood disorders patients, research on this topic has been at a minimum.

James Bolton, MD, and colleagues from the University of Manitoba in Canada, studied 43,093 patients >18 years of age enrolled in the National Epidemiologic Survey on Alcohol and Related Conditions. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria was used to determine the self-medication prevalence rates for patients suffering from bipolar I disorder, bipolar II disorder, dysthymia, and major depressive disorder (MDD).

Bolton and colleagues found 2,184 patients had dysthymia, 7,822 had MDD, 1,546 had bipolar I disorder, 538 bipolar II disorder, and 8,420 had any mood disorder. Of these patients, ~24% of patients with mood disorders were self-medicated with drugs and/or alcohol. Self-medication prevalence rates by disease state were as follows: 41% of bipolar I disorder patients; ~35% of bipolar II disorders patients; ~23% of dysthymic patients; and ~23% of MDD patients.  Regarding comorbidities, the researchers found significant amounts of panic disorder and dependent personality disorder in men and high rates of generalized anxiety disorder and dependent personality disorder in women.

Due to the high rates of self-medication found in bipolar I disorder, the researchers further reviewed this subset of the overall patient population. They found that self-medication was at its highest rates during depressive episodes (~41% for bipolar I patients and ~32% for bipolar II patients). They also found patients self-medicating ~29% of the time during manic episodes and ~8% of the time during hypomanic symptoms.

 Bolton and colleagues believe that it is up to the clinician to monitor each patient’s medication misuse as well as drug and alcohol intake during treatment. They also recommend that the clinician inquire as to each patient’s reason for using drugs and alcohol during treatment.  (J Affect Disorder. 2008; epub ahead of print) –CDN

Smoking Cessation More Difficult for Patients with ADHD

For patients with attention-deficit/hyperactivity disorder (ADHD), rates of tobacco use are higher than in the general population, and smoking cessation is less likely for ADHD patients than for those without the disorder. Prior studies have shown that use of tobacco and nicotine is not only related to the presence of ADHD but may also differ in presentation depending on the increased presence of inattentive or hyperactive/impulsive symptoms, which comprise the core symptomology of ADHD. Additional studies into ADHD symptoms and smoking cessation have not been conducted. An improved understanding of the associations between ADHD subtypes, tobacco use, and smoking cessation could lead to improved smoking cessation and decreased tobacco-related mortality for patents with ADHD.

Lirio Covey, PhD, and colleagues at the Columbia University Medical Center and New York State Psychiatric Institute in New York City evaluated smoking cessation patterns of 583 adult smokers, who were treated with bupropion and nicotine patch during the 8-week study period. They sought to determine if the separate domains of ADHD—inattention or hyperactivity—affected rates of smoking cessation differently. 

All patients were evaluated for ADHD using the ADHD Current Symptom Scale. Two subtypes of ADHD were identified among all patients with the disorder: ADHD with predominate inattentive symptoms (ADHD-inattention) and ADHD with predominate hyperactive/impulsive symptoms with or without inattention (ADHD-hyperactivity/impulsivity with or without inattention). To aid smoking cessation, patients were treated with bupropion, nicotine patch, and cessation counseling. Study outcome was rate of smoking abstinence, which was measured by amount of expired carbon monoxide.

Covey and colleagues found that among all patients, 540 showed no symptoms of ADHD, 20 patients met criteria for ADHD-inattention, and 23 patients met criteria for ADHD-hyperactivity/impulsivity with or without inattention. When compared to patients without ADHD, patients with both subtypes of the disorder showed lower rates of smoking cessation. The authors also found that patients with ADHD-hyperactivity/impulsivity with or without inattention had the lowest rates of smoking cessation when compared to patients without ADHD or with ADHD-inattention. The proportion of patients without ADHD or with ADHD-inattention who abstained from smoking were also similar (55% compared to 54%).

In addition, the treatment approach of bupropion and nicotine patch was more helpful for patients with ADHD-inattention than those with ADHD-hyperactivity/impulsivity with or without inattention. Study data also found that the frequency of past major depressive disorder was highest in patients with ADHD-inattention, and the frequency of past alcohol dependence was highest in patients with ADHD-hyperactivity/impulsivity with or without inattention.

They concluded that more research is necessary for an improved understanding of ADHD, particularly the ADHD-hyperactivity/impulsivity with or without inattention subtype, and tobacco use, which could lead to early prevention of one or both of these conditions. Prior studies have shown that nicotine improves attentiveness and other performance deficits for patients with ADHD and may be used as a form of self-medication for patients, although more data in needed to understand the mechanism behind ADHD and tobacco use.  

Funding for this research was provided by the National Institute on Drug Abuse. (Nicotine Tob Res. 2008;10(12):1717-1725.) –CP

Psychiatric Diagnoses and Treatment Seeking in College Students: Findings from the NESARC

Psychiatric disorders are not uncommon among young, college-aged adults. Those attending college, however, are less likely to seek psychiatric treatment than their non-college-attending peers. This finding was reported in a recent study that assessed the differences in 1-year prevalence of psychiatric disorders, sociodemograhic correlates, and rates of treatment in United States college students, compared to peers not attending college for at least the previous year. Carlos Blanco, MD, PhD, at Columbia University Medical Center in New York City, and colleagues used data from the large (N=43,093) National Epidemiologic Survey on Alcohol and Related Conditions to conduct their subsample analyses.

The subsample comprised 2,188 college attending, and 2,904 non-college-attending adults 19–25 years of age. Approximately 50% of the subsample had at least one Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychiatric disorder in the previous year. The unadjusted risk for alcohol use disorders was significantly greater for college students (odds ratio=1.25; 95% CI, 1.04–1.50) than non-college-attending peers, but not after adjusting for sociodemographic characteristics (adjusted odds ratio=1.19; 95% CI, 0.98–1.44).

Diagnosis of a drug use disorder, nicotine dependence, or tobacco use were all significantly less likely to occur in those attending college, although non-college-attending subjects were more likely to receive relevant psychiatric treatment—especially regarding alcohol-use disorders.

The authors note that, overall, <25% of those with a psychiatric disorder sought treatment within the year preceding the survey. This statistic suggests that a more centralized mental healthcare structure may be helpful for college and university campuses.

This study is supported by grants from the American Foundation for Suicide  Prevention, the National Institutes of Health, and the New York State Psychiatric Institute. (Arch Gen Psychiatry. 2008;65(12):1429-1437). –LS

Association Between MDD and Adverse Cardiovascular Events May Be Due to Changes in Patient Behavior

Despite lacking data on causality, researchers have long established that major depressive disorder (MDD) and other depressive disorders increase the risk of cardiovascular disease for physically healthy patients as well as increase the likelihood of recurring adverse cardiac events for patients with existing cardiovascular disease. Understanding the causality of the relationship between MDD and adverse cardiovascular symptoms would allow for primary care physicians (PCPs), psychiatrists, and other healthcare professionals to develop treatments that would slow or stop the progression of cardiovascular disease in patients with MDD.

Mary A. Whooley, MD, of the Veteran’s Affairs Medical Center in San Francisco, California, and colleagues, evaluated 1,017 patients with stable coronary heart disease to determine why depressive symptoms are associated with an increased risk of cardiovascular events in patients with cardiovascular disease. All patients were gathered from area hospitals and followed by researchers for an average of 4.8 years after study beginning.

Depressive symptoms were assessed using the Patient Health Questionnaire (PHQ), and presence of depressive symptoms was defined as a PHQ score of ≥10. Various analyses were used to determine the rate of cardiovascular events in patients with MDD symptoms as compared to patients without MDD. Recorded cardiovascular events included heart failure, heart attack, stroke, transient ischemic attack—a temporary reduction of blood supply to the brain—or death.

Whooley and colleagues found that 341 cardiovascular events occurred during the study period. Patients with MDD symptoms had an ~50% increased risk of cardiovascular events than patients without MDD. The annual rate of cardiovascular events was 10% for the 199 patients with MDD when adjusted for age. For the 818 patients without MDD, the annual rate of cardiovascular events was 6.7% during the study period. When adjusted for the severity of cardiac disease and other factors, the authors found that patients with MDD symptoms were at a 31% increased risk of experiencing adverse cardiac events as compared to patients with depression.

In addition, after adjusting findings for particular health behaviors, including lack of physical activity, Whooley and colleagues found that there was no significant difference between patients with or without MDD and subsequent development of adverse cardiac events. However, lack of physical exercise was associated with a 44% increase in cardiovascular events for all patients. The authors concluded that although depressive symptoms are associated with cardiovascular events, this association may be due to changes in behavior—particularly lack of exercise—due to MDD symptoms.

Whooley and colleagues said that the relationship between MDD and cardiovascular events may be caused when patients with MDD symptoms do not adhere to exercise, dietary, and other recommendations by PCPs and other medical professionals, which leads to cardiovascular events. Medication adherence for this group may also be reduced when compared to patients without MDD. The authors added that these findings are useful for PCPs as they illustrate that adverse cardiovascular events could potentially be prevented if depressed patients modify certain health behaviors, such as increasing amount of exercise. (JAMA. 2008;300(20):2379-2388.) –CP


Psychiatric dispatches is written by Christopher Naccari, Carlos Perkins, Jr, and Lonnie Stoltzfoos.

 

Dr. Pasic is associate professor of psychiatry in the Department of Psychiatry and Behavioral Sciences at the University of Washington School of Medicine and medical director of the Psychiatric Emergency Services at Harborview Medical Center in Seattle, Washington. Dr. Combs is clinical assistant professor and Dr. Romm is clinical associate professor in the Department of Psychiatry at Harborview Medical Center at the University of Washington.

Disclosure: The authors report no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Jagoda Pasic, MD, PhD, Associate Professor of Psychiatry, Department of Psychiatry and Behavioral Sciences, Harborview Medical Center, 325 Ninth Ave, Box 359896, Seattle, WA 98104-2499; Tel: 206-744-2377; Fax: 206-744-8615; E-mail: jpasic@u.washington.edu.


 

Focus Points

• The hallmark of factitious disorder is motivation to assume a sick role.
• Deception is an integral part of factitious disorder.
• Care providers must be attentive to their own responses to patients who might have the diagnosis of factitious disorder.

 

Abstract

Factitious disorders can represent diagnostic and treatment dilemmas for all clinicians who come in contact with these perplexing patients. Presentations are unusual; symptoms may be incongruent with known diagnoses or match textbook descriptions. As demanding as it may be to care for such patients in the long term, it is equally challenging to assess a case in the initial emergency department where patients can present without historic data, demonstrate the ability to deceive, have unclear motivation, and exhibit puzzling symptoms. Missing a serious condition can be disastrous but there can also be sequelae of inadvertently ordered expensive and potentially harmful treatment. This article presents two patients who sought care in the psychiatric emergency services of a large, county hospital and discusses diagnostic and treatment issues. The authors propose psychological explanations for staff and clinicians’ reactions and suggest interventions useful in the emergency setting. The article emphasizes the necessity of caring for the patient in an ethical and appropriate manner and raises issues of risk management.

Introduction

Factitious disorders, classified as major mental illnesses by the American Psychiatric Association (APA),1 can represent diagnostic and treatment dilemmas for all who come in contact with these perplexing patients. Psychiatrists and medical practitioners are confronted with individuals whose presentations are unusual, with symptoms either incongruent with known diagnostic categories or that match textbook descriptions with surprising precision. As demanding as it may be to care for such patients in the long term, it is equally challenging to assess a case in the initial, emergency treatment setting.

Identifying factitious disorder is difficult in the emergency department where patients may present without available historic data, unclear motivation, and puzzling symptoms. The literature is a less helpful diagnostic aid than with other conditions. Because deception is integral, accurate epidemiologic data is unavailable2 and causes are equally puzzling.3 Missing a serious condition can be disastrous but there can also be sequelae of inadvertently ordered expensive and potentially harmful treatment.4

This article presents two patients, one with chiefly psychological symptoms and the second whose symptoms were predominantly physical, who sought care in the psychiatric emergency services of a large, county hospital. The authors discuss diagnostic and treatment issues, propose psychological explanations for staff and clinicians’ emotional reactions,5-7 and suggest interventions useful in the emergency setting.8 The authors also emphasize the necessity of caring for the patient in an ethical and appropriate manner and raise issues of risk management.9,10

Clinical Case Reports

Case Report 1

Mr. X is a 28-year-old male who presented multiple times to the psychiatric emergency services of Seattle, Washington’s Harborview Medical Center; he had also sought care at local emergency rooms. He presented with bizarre behavior and confusion, though he showed no signs of internal preoccupation or responding to internal stimuli which would have be indicative of a true psychotic state. He was noted to be uncooperative during prior visits. Disorganized, he had been brought by ambulance at the request of the police. Medical and psychiatric history was unknown except for indication that in the past he had “lived in an institution.” Mr. X remained mute on questioning so, for considerations of safety, he was referred to the County Designated Mental Health Professionals for involuntary psychiatric admission; however, he was not detained due to insufficient evidence as required by Washington State Mental Health Law.

Although discharged, the patient declined to leave the area. He also refused to walk although he had been previously observed to ambulate. When he left the hospital, he did so with the assistance of security officers. He yelled and spat throughout the discharge process, insisting there was “something seriously wrong.” A similar scenario had occurred in previous visits; on reluctant discharge from emergency services, he publicly disrobed, walked in front of a moving car, and jumped into a construction site, dangerous and bizarre behaviors that caused the police to return him to the emergency room.

Case Report 2

Mr. Y is a 38-year-old male with an esophageal stricture previously dilated on several occasions. He presented to the emergency department because he was experiencing difficulty swallowing. His history included ingestion of objects such as tacks and safety pins, behaviors which lacked obvious external incentives. On the current occasion, a computed axial tomography scan showed the presence of a coin in his esophagus which was subsequently removed by endoscopy. His post-operative course was complicated by intentional ingestion of a pulse oximeter which had lodged in his cervical esophagus and caused respiratory difficulty. Surgeons removed this with a rigid endoscope. After evaluation by psychiatry, he was deemed neither suicidal nor homicidal and was discharged. Within 24 hours, he presented to an affiliated hospital with a razor blade in his esophagus. Psychiatric evaluation was repeated and this time he was detained by the County Designated Mental Professionals as a danger to himself.

Discussion

Factitious disorder is classified as a major mental illness by the APA.1 The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, offers three diagnostic criteria for this condition (Table 1), including the intentional production of physical or psychological symptoms; the motivation to assume the sick role; and the absence of external incentives for this behavior. The condition can present with either physical or psychological symptoms by themselves or by a combination of the two. Variants exist and are classified as factitious disorder not otherwise specified. Munchausen’s syndrome, a chronic variant, most often presents with numerous physical symptoms. It was first described by Asher2 in 1951, who identified patients traveling from hospital to hospital to dramatically offer their complaints. Munchausen’s syndrome by proxy3 is another version of the disease in which a person, typically a parent, intentionally creates symptoms in their child so enabling the adult to identify with the sick role.

 

Prevalence and Etiology

Because of difficulty in diagnosing the disorder and deception is a prominent componant, accurate epidemiologic data is absent and long-term follow-up is almost impossible to obtain.4 Estimated prevalence rates vary from 0.1% in an Italian community study5 of 2,363 people to 9.3% of referrals of fever of unknown origin to the National Institute for Allergy and Infectious Disease. Causes are equally puzzling. One theory is that the condition develops as a result of stressful life events such as early loss and abandonment. The resulting use of the medical arena to enact life’s dramas allows them to gain control over situations where previously there was none.6

Demographics

The majority presenting with what ultimately proves to be factitious disorder are women 20–40 years of age, often employed in the medical field as nurses, medical technicians, or other health-related jobs. Common presenting conditions are self-induced wounds or infections and simulated disease states.7,8

Making the Correct Diagnosis

Accurate diagnosis is difficult. There are no specific tests to aid in assessment. Clinical acumen is vital. The patient may tell a story that seems almost unbelievable; laboratory finding may be inconsistent; and there may be inexplicable gaps in the record or the patient may refuse to allow gathering of historic data. In spite of the impulse to collect as much information as possible, regulations regarding privacy and confidentiality must be respected.9

Differential diagnosis can be perplexing. Diagnostic boundaries blur between factitious disorder, the somatoform disorders where symptoms are unconsciously generated, and malingering with its accompanying external incentives. Foremost, a genuine organic etiology of the condition must be eliminated.10

Unlike the outpatient setting where patients, after exhaustive medical work-up, are referred to a psychiatrist who diagnoses factitious disorder, several visits to an emergency department may take place before this occurs. According to one study11 of psychiatrists providing emergency services at an urban general hospital, 13% of patients were suspected of feigning symptoms.

Emergency room providers are familiar with homeless or substance-abusing patients who produce symptoms to obtain food and shelter. These individuals evoke frustration and negative reactions from the staff. However, malingerers, unlike those with factitious disorder, intentionally produce or feign symptoms by which to benefit such as economic gain in the form of disability payment or the avoidance of legal responsibility.1 Assumption of the sick role is benefit enough for those with factitious disorder. Because factitious disorders are often diagnoses of exclusion, an individual presenting in the emergency setting with physical complaints is entitled to medical screening for acute illness and stabilization. Similarly, a thorough psychiatric evaluation is warranted for a patient with psychological symptoms.

Psychodynamics Associated with Diagnosis and Treatment

Countertransference, or feelings evoked in the treator, poses problems for both patient and provider. Patients who feign illness to gain privileges afforded those in the sick role stir up strong negative reactions. Clinicians and staff respond with despair, anger, and frustration. Patients are pejoratively labeled “chronic complainers,” “difficult,” and “frequent flyers,” because they repeatedly seek healthcare services. Staff reaction may be so strong that they lose ability to respond with empathy.12

Countertransference complicates treatment. Clinicians may harbor a conviction that all patients with factitious disorder are untreatable, causing the patient to feel not only incurable but worthless. Anger, fear, aversion or disgust undermines a therapeutic alliance. The inherent drama of factitious behaviors can create inappropriate levity, titillation, or gossip, reflecting the provider’s underlying rage caused by the patient’s manipulation of his peers and practitioners. Providers, in turn, may treat the patient or referring physician with undue harshness.13 If feelings go unrecognized, there is the potential danger of missing a diagnosis of an accompanying condition or that the care provider’s anger or resignation will mobilize the patient’s resistance.13,14 Furthermore, clinicians may over-identify with the patients, who often are healthcare providers themselves, which can interfere with diagnosis and appropriate treatment.

Groves12 identified four subtypes of difficult patients. (Table 2) These descriptions can promote insight into patient behavior and clinician response. Case Report 1 may, at first, be seen as a malingerer, but on closer scrutiny can be identified as a “manipulative help-rejecter.” Case Report 2 is identified as “self-destructive denier” in combination with “dependant clinger.”

 

 

Providing Necessary Medical or Surgical Care

Surgeons are used to operating on patients for truly emergent reasons, sometimes even without obtaining consent as an urgent intervention. However, with patients who deliberately create pathology, surgeons may feel less inclined to intervene. In such cases, psychiatry consultation can be a great resource. Helpful techniques include assessment of danger to self and/or decisional capacity, validation of the surgical team’s concerns, setting limits for the patient, and maintaining a safe setting which can include assigning a constant observer or placing the patient in a room monitored by camera.

The challenge comes with a surgical team reluctant to operate because of concern that self-injurious behavior will continue. This did not occur when Case Report 2 required urgent surgical intervention because of risk of airway obstruction.

In Case Report 2, the patient exhibited disturbing behavior necessitating the involvement of more than one discipline, ie, emergency medicine, psychiatry, and otorhinolaryngology. The initial assessment was conducted by the emergency medical physician who deemed necessary the consultation for dysphagia. Because a history of self-injury and swallowing objects was noted, referral to psychiatry was also made. The psychiatrist found the patient not suicidal so recommended neither hospitalization nor involuntary detention.

Treatment: Emergency Room Interventions Beyond Medical Interventions

The literature on reports on emergency room treatment of factitious disorder patients is limited. Outside of clear-cut emergent medical procedures or medication administration, interventions with factitious disorder patients are problematic at best and carry the risk for iatrogenic harm at worst.

The authors of this article have found recommendations in the literature for office treatment and suggest that they may be adapted for use in the emergency room. Either a confrontational or non-confrontational approach has been tried by the primary physician or in conjunction with a psychiatrist.15 Reich and Gottfried9 studied 12 patients with factitious disorder confronted with their behaviors. Although it has been reported that psychosis can occur,16 none became suicidal or psychotic using this approach yet only one patient acknowledged his conduct.9 If the patient feels humiliated and exposed by confrontation, no matter how sensitively handled, proceeding with any therapy is difficult.

Hollender and Hersh15 advocate the non-confrontational approach. They recommend that the consulting psychiatrist avoid the role of prosecutor and try to help the patient understand behaviors identified by the primary physician.

Another technique that can be employed to allow narcissistically vulnerable patients to relinquish symptoms without threat of exposure and humiliation was developed by Eisendrath.17 He originated a “double-bind” approach. The patient is informed that his failure to respond to the next offered treatment will prove the illness is faked. The patient can simultaneously make his recovery and save face. This approach is based on the hypothesis that confrontation fails because symptoms of factitious disorder serve as an important psychological defense and can be relinquished only in an atmosphere of safety.18

There is an absence of robust research supporting the effectiveness of any management technique for factitious disorder. Eastwood and Bisson5 reviewed treatment outcomes in 32 case reports and 13 case series. They found no significant difference between confrontational and non-confrontational approaches, between treatment with psychotherapy compared to treatment with none, and with the addition or avoidance of medications. They concluded that long-term management plans which include consistent care and a holistic approach are beneficial, a model difficult to achieve in an acute hospital setting. The authors5 suggest that various strategies may be helpful but there is no definitive way to help select a particular management plan. Of note is a report of two cases ending in suicide, a reminder of the necessity of vigilance.5 One management goal is to modify patient’s often unrealistic expectations of the medical profession. The clinician should offer encouragement to cope with symptoms rather than expect a cure19 and acknowledge that the patient is manifesting physical symptoms for psychic distress. It is this distress that must be identified and treated.

It is not unreasonable to refer the patient to psychotherapy, a treatment that may be interpersonal or psychoanalytically oriented.20-23 Realistically, a referral to therapy by an emergency room provider may be immediately rejected by the patient for emotional or financial reasons.

System Interventions

While there are no evidence-based studies to suggest interventions in the emergency department, in the case of suspected or presumed factitious disorder, the authors of this article recommend the creation of a care plan, the consideration of psychiatric consultation, and, if possible, the assignment of the same provider on repeated emergency room visits (Table 3).

 

Risk Assessment

Patients with factitious disorder engage in behaviors endangering themselves. Researchers24,25 propose three types of self-harm, including direct self-harm such as self-inflicted burns; self-created disease, including symptoms produced by the application of noxious agents, such as self-inflicted hypoglycemia (Case Report 1 best fits this category); and indirect or delegated harm, which includes damage or health risks created by medical interventions provoked by the patient. In such cases, the medical staff is “delegated” to carry out a procedure due to feigned symptoms or manipulated findings as exemplified by Case Report 2.

In Case Report 1, the patient engaged in behavior that put himself at risk of serious harm (eg, jumping from a high place; inviting being hit by a car) and created his own disease. In Case Report 2, the otolaryngology team initially hesitated to operate on this patient using a procedure that by itself has potential for an adverse outcome. Controversy may exist around the question of whether patients with feigned symptoms or illness should have the same kind of treatment administered to patients with “legitimate” symptoms or diseases. However, it is the physician’s ethical duty to provide adequate care if a patient’s symptoms pose a risk of serious harm if left without intervention. The two patients received care that met community standards. In Case Report 1, an evaluation for involuntary psychiatric treatment was indicated due to self-harm behaviors, and in Case Report 2 surgery was required for foreign body removal to prevent bleeding, infection, and perforation. While hospitalization would rarely be appropriate for cases of malingering, it may be indicated for patients with factitious disorders when there is an acute medical issue or a psychiatric issue that poses imminent risk of harm to self, or the patient’s symptoms are causing grave disability. Factitious disorders are rarely associated with risk of harm to others except in cases of Munchausen’s by proxy; hence, hospitalization on this ground is not indicated.

Risk Management

Tempting as it may be to dismiss patients in the emergency department who are suspected of factitious disorder, stabilization must be provided according to the Emergency Medical Treatment and Active Labor Act (Social Security Act: Sections 1866 and 1867). An individual suspected of factitious disorder has the same rights as any patient, ie, the right to reasonable care, respect, privacy, safety, and confidentiality.26 The clinician must adequately document physical and psychological findings and include positive and negative laboratory results. If confusion is an issue, decisional capacity must be established. If the standard of care is ignored, clinicians are vulnerable for risk management review and possible litigation.

Patients with factitious disorder may refuse treatment because of anger and humiliation; they may leave against medical advice or consider themselves wronged, feelings that can motivate them to sue. While no physician is immune to a lawsuit, abiding by federally mandated regulations, adhering to the standard of care, and keeping accurate documentation are the best protective measures.

Conclusion

From personal experiences combined with a literature review, the authors of this article conclude the following. First, in spite of provider reaction, a thorough medical and psychiatric assessment should be performed on patients whether or not they are suspected of having a factitious disorder. Serious acute problems must not be overlooked. Second, every effort must be made to engage the patient in care in the acute setting to help with immediate assessment and to encourage appropriate follow-up. Third, although there is absence of robust support for any treatment, there is some evidence for trying either a confrontational or non-confrontational approach or Eisendrath’s “double-bind” technique.5,8,15,18 Fourth, hospitalization or consideration for involuntary detainment is strongly recommended when there is potential for the patient harming him or herself or when the patient lacks decisional capacity. Fifth, creation of a care plan, easily accessible in the medical record, gives the opportunity for consistent, informed assessment and treatment. Last, all involved with patient care must accurately and neutrally provide thorough documentation to minimize legal risk for the provider and accomplish good patient care. PP

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994:471-472.
2.    Asher R. Munchausen’s syndrome. Lancet. 1951;1(6650):339-341.
3.    Meadow R. Munchausen syndrome by proxy. The hinterland of child abuse. Lancet. 1977;2(8033):343-345.
4.    Fehnel CR, Brewer EJ. Munchausen’s syndrome with 20-year follow-up. Am J Psychiatry. 2006;163(3):547.
5.    Eastwood S, Bisson JI. Management of factitious disorders: a systematic review. Psychother Psychosom. 2008;77(4):209-218.
6.    Jones RM. Factitious disorders. In: Kaplan HI, Sadock BJ, eds. Comprehensive Textbook of Psychiatry. 6th ed. Baltimore, MD: Williams & Wilkins; 1995:1271-1279.
7.    Lipsitt DR. Factitious disorder and Munchausen syndrome. In: UpToDate. Schwenk TL, ed. UpToDate. Waltham, MA: 2008. Available at: www.uptodate.com. Accessed December 3, 2008.
8.    Eisendrath S. Current overview of factitious physical disorders. In: Feldman MD, Eisendrath SJ, eds. The Spectrum of Factitious Disorders. Washington, DC: American Psychiatric Association Press; 1996:195-213.
9.    Reich P, Gottfried LA. Factitious disorders in a teaching hospital. Ann Intern Med. 1983;99(2):240-247.
10.    Wise MG, Ford CV. Factitious disorders. Prim Care. 1999;26(2):315-326.
11.    Yates BD, Nordquist CR, Schultz-Ross RA. Feigned psychiatric symptoms in the emergency room. Psychiatr Serv. 1996;47(9):998-1000.
12.    Groves JE. Taking care of the hateful patient. N Engl J Med. 1978;298(16):883-887.
13.    Willenberg H. Countertransference in factitious disorder. Psychother Psychosom. 1994;62(1-2):129-134.
14.    Nadelson T. Victim, victimizer: interaction in the psychotherapy of borderline patients. Int J Psychoanal Psychother. 1976;5:115-129.
15.    Hollender MH, Hersh SP. Impossible consultation made possible. Arch Gen Psychiatry. 1970;23(4):343-345.
16.    Fras I, Coughlin BE. The treatment of factitial disease. Psychosomatics. 1971;12(2):117-122.
17.    Eisendrath SJ. Factitious physical disorders: treatment without confrontation. Psychosomatics. 1989;30(4):383-387.
18.    Weiss J. The integration of defences. Int J Psychoanal. 1967;48(4):520-524.
19.    Bass C, May S. Chronic multiple functional somatic symptoms. BMJ. 2002;325(7359):323-326.
20.    Schoenfeld H, Margolin J, Baum S. Munchausen syndrome as a suicide equivalent: abolition of syndrome by psychotherapy. Am J Psychother. 1987;41(4):604-612.
21.    Tucker LE, Hayes JR, Viteri AL, Liebermann TR. Factitial bleeding: successful management with psychotherapy. Dig Dis Sci. 1979;24(7):570-572.
22.    Mayo JP Jr, Haggerty JJ Jr. Long-term psychotherapy of Munchausen syndrome. Am J Psychother. 1984;38(4):571-578.
23.    Spivak H, Rodin G, Sutherland A. The psychology of factitious disorders. A reconsideration. Psychosomatics. 1994;35(1):25-34.
24.    Willenberg H, Eckhardt A, Freyberger H, Sachsse, U, Gast U. Self-destructive behavior: classification, and basic documentation. Psychotherapeut. 1997;42:211-217.
25.    Fliege H, Scholler G, Rose M, Willenberg H, Klapp BF. Factitious disorder and pathological self-harm in a hospital population: an interdisciplinary challenge. Gen Hosp Psychiatry. 2002;24(3):164-171.
26.    Medical-Legal Survival: A Risk Management Guide for Physicians. Oak Brook, IL: University Health System Consortium; 2007.

 

An expert review of clinical challenges in primary care and psychiatry

 

This supplement is supported by Pamlab.

 

Dr. Shelton is the James G. Blakemore Research Professor and Vice Chair for Research in the Department of Psychiatry at the Vanderbilt University School of Medicine.

Disclosures: Dr. Shelton serves as consultant to Eli Lilly, Pamlab, Pfizer, and Sierra; serves on the speakers bureau of Abbott, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, Sierra, and Wyeth; and receives research support from Abbott, Eli Lilly, GlaxoSmithKline, Janssen, Pamlab, Pfizer, and Wyeth.

 

Abstract

Major depressive disorder (MDD) is a debilitating and often recurrent illness. An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as partial or non-responders. Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Suboptimal serum and red blood cell folate levels have been associated with a poorer response to antidepressant therapy, a greater severity of symptoms, later onset of clinical improvement, and overall treatment resistance. This Expert Review Supplement reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations.

 

Recent research, particularly the data coming out of the National Institute of Mental Health Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,1 have highlighted the reality that depression is a difficult condition to treat to remission and even more troublesome to maintain in a remitted state. Several problems with currently available modalities emerged from that landmark study. The STAR*D program provided high quality, multi-level treatment using the best evidence-based treatments, including both medications and cognitive behavioral psychotherapy.2 Only a small proportion of patients remitted with any of the treatments at any level. A very low proportion of patients responded to treatment after Level 3 (ie, three treatment trials). At all levels, relapse rates were high even after achieving remission.

These data suggest several conclusions. Despite notions to the contrary, depression is a very difficult condition to treat to sustained remission. In addition, there appear to be significant problems with current treatment modalities; although most produce a degree of improvement, there appear to be countervailing influences that either prevent remission in the first place or that “defeat” wellness in the long run. This may be explainable by a fundamental biological substrate that resists correction to a normal baseline mood.

The accompanying article by Farah reviews the evidence for the possible effectiveness of L-methylfolate as a novel alternative to achieve remission in treatment resistant depression. Folic acid is a normal dietary constituent; unlike the past, deficiency is uncommon in the United States because of the fact that grain products are fortified with folic acid. However, simple addition of folic acid does not solve the “true folate deficiency” problem; the conversion of folic acid to its active metabolite, L-methylfolate is of low efficiency in humans, requiring four metabolic steps. Moreover, as noted by Farah, a common single nucleotide polymorphism of one of the metabolic enzymes, methyltetrahydrofolate reductase, reduces the conversion of folic acid to L-methylfolate. L-methylfolate, in turn, is involved in the synthesis of tetrahydrobiopterin, a cofactor in the synthesis of the three key neurotransmitters involved in the regulation of mood: serotonin, norepinephrine, and dopamine.

This is significant because of the fact that all of the currently available treatments require sufficient quantities of one or more of these transmitters. A synthetic deficiency of the key monoamines involved in mood regulation may, in fact, explain several of the findings noted earlier. For example, take Level 1 treatment in STAR*D: citalopram was dosed as high as 50 mg/day, which would achieve saturation levels of the serotonin transporter in most people. Clearly, sustained serotonin signaling is required to achieve and maintain the antidepressant response of serotonin selective reuptake inhibitors (SSRIs). This has been demonstrated by research that has shown that acute depletion of tryptophan, the amino acid precursor of serotonin, leads to rapid relapse in people who have achieved sustained response to an SSRI.3 Under normal conditions, serotonin is taken up presynaptically following release by the serotonin transporter, and repackaged in synaptic vesicles. However, since SSRIs block the reuptake mechanism, ongoing synthesis of serotonin is required to provide adequate levels of the transmitter to response to depolarization-dependent release. A deficiency of synthesis of serotonin, then, could be expected to either prevent remission in the first place, or increase risk of relapse.

Although there is a clear therapeutic rationale for L-methylfolate, the clinical trials data supporting its effectiveness are very limited. Five studies have evaluated the effectiveness of L-methylfolate treatment in major depression, most of which are of questionable relevance to L-methylfolate in typical treatment-resistant depression. One early report4 showed open treatment with methylfolate of patients with depression or schizophrenia with low red blood cell folate levels. Another study5 evaluated the effectiveness of 15 mg of racemic methylfolate in persons with “organic mental disorders with depression,” who also had low red blood cell folate levels. The third6 involved a monotherapy trial of 50 mg of methylfolate (roughly 25 mg of L-methylfolate) compared against an inadequate dose of trazodone (100 mg/day) in elderly depressed patients. The fourth7 was, again, a open monotherapy trial of 90 mg of methylfolate (45 mg of L-methylfolate) in depressed alcoholic patients. The closest to a real augmentation trial is the study by Alpert and colleagues8 using folinic acid, a 5-formyl derivative of folic acid that is metabolized to racemic methylfolate without the action of methyltetrahydrofolate reductase. In this project, persons who were non-responders to SSRIs were given 15-30 mg/day of folinic acid. The Hamilton Rating Scale for Depression score reduced, on average, from 19.1 to 12.8 points, a significant but modest effect. This is reflected by only 27% achieving response status—a 50% reduction in depression scores. Although suggestive of benefit, larger scale controlled clinical trials are needed before L-methylfolate can be recommended as a first-line treatment. 

References

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905-1917.
2. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the sequenced treatment alternatives to relieve depression (STAR*D) study. Psychiatr Clin North Am. 2003;26:457-494.
3. Delgado PL, Miller HL, Salomon RM, et al. Tryptophan-depletion challenge in depressed patients treated with desipramine or fluoxetine: implications for the role of serotonin in the mechanism of antidepressant action. Biol Psychiatry. 1999;46:212-220.
4. Godfrey PS, Toone BK, Carney MW, et al. Enhancement of recovery from psychiatric illness by methylfolate. Lancet. 1990;336:392-395.
5. Passeri M, Cucinotta D, Abate G, et al. Oral 5’-methyltetrahydrofolic acid in senile organic mental disorders with depression: results of a double-blind multicenter study. Aging (Milano ). 1993;5:63-71.
6. Guaraldi GP, Fava M, Mazzi F, La Greca P. An open trial of methyltetrahydrofolate in elderly depressed patients. Ann Clin Psychiatry. 1993;5:101-105.
7. Di Palma C, Urani R, Agricola R, Giorgetti V, Della Verde G. Is methylfolate effective in relieving major depression in chronic alcoholics? A hypothesis of treatment. Curr Ther Res. 1994;55:559-568.
8. Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid (Leucovorin) as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psychiatry. 2002;14:33-38.

 

 

This interview took place on September 23, 2008, and was conducted by Norman Sussman, MD.

 

This interview is also available as an audio PsychCastTM at http://psychcast.mblcommunications.com.

Disclosure: Dr. Siegel reports no affiliation with or financial interest in any organization that may pose a conflict of interest.


 

Jerome M. Siegel, PhD, is professor of psychiatry at the University of California, Los Angeles, former president of the Sleep Research Society, and the recipient of Merit and Javits awards from the National Institutes of Health and the Distinguished Scientist award from the Sleep Research Society. His laboratory has made discoveries concerning the role of hypocretin in human narcolepsy and Parkinson’s disease. He has studied the phylogeny of sleep as a clue to sleep function, discovering that the primitive mammal platypus has rapid eye movement sleep and that marine mammals can go without extended periods of sleep for long periods without ill effects.

 

What is narcolepsy?

Narcolepsy is a disorder characterized by excessive sleepiness. The four classic symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. For diagnostic purposes, excessive daytime sleepiness is usually followed up with a multiple sleep latency test. That is, the patient is given repeated opportunities to go to sleep. Narcoleptics have very short latency to the onset of rapid eye movement (REM) sleep. In clinical practice, persistent sleepiness combined with short latency to the onset of REM sleep is sufficient to diagnose narcolepsy.

What is cataplexy?

Cataplexy is a sudden loss of muscle tone triggered by the sudden onset of strong emotion. The most common trigger for cataplexy is laughter, but in some patients sudden anger and other rapid-onset emotions will trigger it as well. There is a spectrum of intensity of cataplexy. A person might fall to the floor for seconds or even minutes. More typically, there is weakness, such as the jaw or head dropping, which may be transient.

Most cases of narcolepsy with cataplexy are caused by a deficit in the peptide hypocretin (ie, orexin). In autopsy material, patients with narcolepsy with cataplexy showed a 90% loss of hypocretin cells on average. However, most patients with narcolepsy without cataplexy do not have a complete loss of hypocretin in the cerebrospinal fluid. This has lead to the question of whether these two groups, in fact, have the same disease.

Is narcolepsy adequately diagnosed?

Narcolepsy occurs in ~1 in 2,000 people in the United States. It is underdiagnosed. It used to be that >15 years would pass between the onset of symptoms and a correct diagnosis. Though that lag has been reduced, I think many patients with excessive sleepiness are not correctly diagnosed and may just be told that they need to sleep more or that they should get more exercise. Thus, they are not adequately treated. The age of onset is typically in the teens or twenties. In many cases children will not be able to stay awake in school and may be ridiculed for these symptoms. It is very important that they get correctly diagnosed and treated so that their educational and social development are not impaired.

Once narcolepsy manifests, do the intensity and frequency of symptoms change over time?

There is a progression during the year or two after the onset. Typically, the sleepiness presents first and cataplexy comes later. The onset of cataplexy can be delayed by up to 2 years or, in a few cases, more than that. Many patients with narcolepsy with cataplexy report that they have learned to reduce the cataplexy, mostly by avoiding situations that trigger it, such as anything which causes one to laugh. That in itself is quite sad.

However, I am not certain that this cognitive explanation is adequate, because in narcoleptic dogs we see the same progression. That is, the symptoms appear and then as the animal ages, the cataplexy in particular gets more and more infrequent. There is no reason to think that the dogs have any incentive to avoid cataplexy. They are not embarrassed, and the condition does not cause injury or “social” problems. Thus, it appears that with aging there may be some brain reorganization or some normal maturational change that may counter the effect of hypocretin loss on cataplexy. All in all, the general picture is that once the symptoms are established they do not continue to worsen.

Certainly, there is no generalized degeneration leading to other symptoms such as Parkinson’s disease or Alzheimer’s disease. However, a recent article1 showed that Parkinson’s disease patients do have a depletion of hypocretin cells. Though this depletion is not quite as extensive as in narcolepsy, it is still quite severe. This may account for the sleepiness that characterizes Parkinson’s disease, which is quite similar to narcolepsy in many ways. However, it is clear from examining the brains of Parkinson’s disease patients that the cause of the cell loss is not the same as in narcolepsy.

Is narcolepsy related to abnormalities in REM sleep?

In normal REM sleep, several groups of monoaminergic cells become silent. Norepinephrine-, serotonin-, and histamine-containing neurons are inhibited. This is partially responsible for the phenomena of REM sleep. In narcolepsy, these cells are no longer so well coordinated. That is, they do not all stop being active at the same time. Norepinephrine cells become inactive during waking, which never happens in the normal animal. This loss of norepinephrine activity is responsible for the loss of muscle tone in cataplexy. This presumably occurs because of the loss of hypocretin. Normally, hypocretin, an excitatory peptide, keeps the norepinephrine cells active in waking. In the absence of hypocretin, which is the case in narcolepsy, these cell groups can fall silent in waking when strong emotions are triggered. That, then, causes cataplexy.

Have you been able to identify any genetic markers for narcolepsy?

Genetic mutations can cause narcolepsy but that is extremely rare. There are only one or two human cases identified in which there is a mutation in genes synthesizing hypocretin or its receptors. Most narcoleptics do not have such mutations and do not have first-order relatives with narcolepsy. In addition, 87% of identical twins are discordant for narcolepsy, even many years after onset. One identical twin may have narcolepsy but 30 years later the other twin will still be symptom free. However, in the case of some animal models, it is entirely genetic. Two narcoleptic dogs with a mutation that inactivates a hypocretin receptor produce only narcoleptic offspring.

However, there is a genetic risk factor in human narcolepsy, namely, a particular human leukocyte antigen (HLA) subtype called DQB-10602. The HLA system is related to the immune system and mediates tissue compatibility. Most HLA-linked disorders are autoimmune in nature. Ninety-five percent of Caucasian narcoleptics have this particular HLA subtype, whereas in the general population only 20% to 30% have it. Certainly, the HLA subtype by itself is not sufficient to produce the disease. The HLA correlation suggests that narcolepsy may be an autoimmune disease. There is some direct evidence in the postmortem brains of narcoleptics of gliosis in the region of cell loss, which is an indication of prior inflammation. This suggests that something happened at symptom onset that caused these particular cells to be destroyed. In fact, adjacent cells are left untouched. This points to an immune mechanism that would recognize particular cell types, rather than just the destruction of a particular area of the brain as the cause of most human narcolepsy.

Are there any characteristic psychiatric symptoms associated with narcolepsy?

There appears to be a greater incidence of depression in narcolepsy. Although this has not been very well documented or quantified, it has been reported in an anecdotal manner. However, now that we understand that the hypocretin system is the key to this disorder, and we can work with narcoleptic animals, we notice behavioral signs that seem to be similar to depression. For example, it has long been known that narcoleptics tend not to get addicted to various drugs. They very seldom abuse drugs of treatment, such as amphetamines and g-hydroxybutyrate. It has also been documented that mice without hypocretin do not get addicted to agents that produce addiction in normal mice. We know that the hypocretin system connects very strongly to the dopamine system, which has been implicated in addictive behavior and in pleasure. Therefore, the loss of hypocretin may cause depression. This may also be the case of Parkinson’s disease, which has a similar loss of hypocretin cells and similar symptoms of depression.

Should a practitioner who suspects someone might have narcolepsy start treating it or first send the patient to a sleep lab?

I think it is always desirable to go to a sleep lab. The drugs that are prescribed are potential drugs of abuse so it is certainly highly desirable to get objective evidence that the patient has the symptoms that are diagnostic for narcolepsy before prescribing these drugs. Typically, patients will take these drugs for the rest of their lives. In the sleep center, narcolepsy with cataplexy is easily diagnosed. For narcolepsy without cataplexy it is certainly desirable to have the full electroencephalographic workup that can document that the patient has sleep-onset REM periods. Of course, excessive daytime sleepiness is quite common, and other potential causes, particularly sleep apnea, must be ruled out. Another disease category which can look like narcolepsy is idiopathic hypersomnia, where people are just sleepy all the time but do not have cataplexy or REM sleep near sleep onset.

What are the treatments for narcolepsy?

Sleepiness in narcolepsy has traditionally been treated by dextroamphetamine and methamphetamine. Methylphenidate and modafinil are also used. Tricyclic antidepressants are used if cataplexy is a major complaint. More recently, selective serotonin reuptake inhibitors such as fluoxetine have been used. Antidepressants, such as venlafaxine, protriptyline, and imipramine are also commonly used to treat cataplexy. Typically, a narcoleptic will be treated with both anticataplectic drugs and stimulants.

A relatively new drug being used is sodium oxybate (ie, g-hydroxybutyrate). Its mode of action is not well understood but it seems to help both the sleepiness and the cataplexy. It is taken in liquid form, in very large doses of up to approximately 8 grams per night. The patient has to wake up in the middle of the night to take the second half of the dose. It is inconvenient to use but it can be uniquely effective on both symptoms.

The hope is that hypocretin itself or hypocretin agonists will be used as a treatment since that is the underlying deficit. We have shown that hypocretin given to narcoleptic dogs can reverse symptoms. Deadwyler and colleagues2 showed that hypocretin can be administered by nasal inhalation to monkeys that were sleepy. It reversed the sleep deficits very effectively. Potentially, that would be a very useful treatment, but to my knowledge it has not been tested in human narcoleptics. PP

References

1.    Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in Parkinson’s disease. Brain. 2007;130(Pt 6):1586-1595.
2.    Deadwyler SA, Porrino L, Siegel JM, Hampson RE. Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci. 2007;27(52):14239-14247.

 

Dr. Hoffman is a child psychiatrist and research fellow in the Albert J. Solnit Integrated Training Program at the Yale Child Study Center at Yale University School of Medicine in New Haven, Connecticut.

Disclosure: Dr. Hoffman previously received the American Academy of Child and Adolescent Psychiatry Pilot Research Award, sponsored by Eli Lilly.

Please direct all correspondence to: Ellen J. Hoffman, MD, Yale Child Study Center, 230 S Frontage Rd, PO Box 207900, New Haven, CT 06520-7900; Tel: 203-785-4659; Fax: 203-785-7560; E-mail: ellen.hoffman@yale.edu.


 

Focus Points

• Pervasive developmental disorders (PDDs) affect social interaction and communication and are associated with repetitive, stereotyped behaviors.
• Autistic disorder is the most characteristic PDD which involves deficits in these three developmental domains.
• Early identification of PDDs is essential as early intervention improves prognosis.

 

Abstract

Pervasive developmental disorders (PDDs), or autism spectrum disorders, are neurodevelopmental disorders resulting in impaired social interaction, verbal and nonverbal communication deficits, and repetitive, stereotyped behaviors and restricted interests. This article reviews the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria for the PDDs, which include autistic disorder, Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and PDD not otherwise specified, with a focus on autistic disorder, which is most characteristic of the PDDs. In addition, associated clinical and epidemiologic features of the PDDs and comorbidities are discussed. Principal components of the diagnostic evaluation are presented with an emphasis on early identification of these disorders.

Introduction

Pervasive developmental disorders (PDDs), as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision,1 are characterized by dysfunction in three core areas of early childhood development, namely, social interaction; communication and language skills; and behavior, specifically by the presence of stereotyped, repetitive behaviors and restricted activities and interests. Autistic disorder, or autism, which is the most representative type of PDD2 and the most researched to date,3 was first described by Leo Kanner in 1943, who reported many of the principal diagnostic features of children with the disorder.4 These include an “inability to relate” socially or “to convey meaning to others” through language and an “insistence on sameness” in daily routines.4 Kanner posited that these symptoms were “innate,”4 and in fact, our current conceptualization of autism and other PDDs is that these are “complex neurodevelopmental disorders”5 which are highly heritable6 and most likely involve early dysfunction in central nervous system development.3

PDD was introduced as a diagnostic category in the DSM-III7 and has come to be synonymous with autism spectrum disorder (ASD), as both terms refer to disorders affecting a child’s social, communicative, emotional, and cognitive development.2 The terms PDD and ASD are used interchangeably in this article depending on which term was utilized by the referenced study (eg, the DSM-IV-TR utilizes “PDD” while some current research studies prefer “ASD”). In addition to autism, there are four other disorders that are currently classified as PDDs by both the DSM-IV-TR and the International Statistical Classification of Diseases and Health Related Problems, Tenth Revision,8 namely, Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder (CDD), and PDD-not otherwise specified (NOS).1,3 While each involves deficits in the same core developmental domains as autism, they are distinguished by the ways in which these domains are affected, along with differences in age of onset, gender distribution, course, and prognosis (Table).1,3,5,6,9-14

 

 
This article reviews the diagnostic criteria and associated clinical features of PDDs, with an emphasis on autism itself, as it is the most characteristic of the PDDs2 and the focus of increased research efforts in recent years; this research has led to a greater understanding of the genetics and neurobiology of these disorders.15,16 Both greater public awareness of autism and PDDs and reports of their increasing prevalence (the most recent estimate is one in 166 for all PDDs)9 have contributed to the growing interest in these disorders. While the increased prevalence is likely due in large part to new diagnostic categories and broadening of the diagnostic criteria over the past 50 years,9 these developmental disorders are not uncommon and the importance of early diagnosis and referral for educational and behavioral interventions cannot be overemphasized.3,17 That is, understanding the clinical features, associated medical and genetic aspects, and comorbidities of PDDs, reviewed here, is critical for early identification and intervention, which improve long-term prognosis.5,17

Autistic Disorder

The DSM-IV-TR1 criteria for the diagnosis of autistic disorder include manifestations of dysfunction in social interaction and communication as well as the presence of repetitive, stereotyped behavior. Specifically, there must be a total of at least six impairments in these three areas, and at least two of the six must be deficits in social interaction (Criterion A).1 In addition, delays or dysfunction in either social interaction, language (used in social communication), or symbolic play had to begin before 3 years of age (Criterion B).1 Also, Rett’s disorder or CDD must not be more appropriate diagnoses (Criterion C).1 The Table summarizes the principal clinical features of autism as well as the other PDDs, which are discussed below.

Impairments in social interaction (Criterion A1) may include pronounced deficits in non-verbal social behaviors (eg, lack of eye contact, facial expressions, body posturing, and gesturing), lack of age-appropriate peer relationships, absence of spontaneous attempts to share interests or pleasure with others (eg, not pointing or showing things to others), or “lack of social or emotional reciprocity.”1 That is, children with autism primarily lack joint attention in that they fail to share actively in others’ activities or interests.5 They may behave as if they are unaware of the presence of others, select solitary over social activities, and possibly only interact with parts of people (eg, someone else’s hand, using them “as tools or ‘mechanical’ aids,”1 or as Kanner4 observed, “as if they are objects.” For these reasons, children with autism are sometimes described as being in their “own little world.”5

Deficits in communication (Criterion A2) encompass both verbal and nonverbal disabilities, and thus are closely aligned with social impairments.1 More specifically, these deficits may include delay or absence in spoken language (which is not compensated for by attempts to communicate through gestures or other means); inability to converse appropriately with others, despite the presence of speech; odd, stereotyped, or repetitive uses of language; or the absence of imaginative or pretend play.1 There may be a great deal of variability in the area of communication, ranging from no expressive or receptive language to fluent speech but with semantic or inappropriate social uses of language.5 For example, speech may be monotonous in its tone or involve abnormal pitch, rate, rhythm, or emphasis.1 Language may involve meaningless, stereotyped repetitions of phrases or peculiar uses of words,1 and children may refer to themselves in the second or third person, instead of as “I.”3,4 Echolalia, which can be immediate (repetition of a phrase one has just heard) or delayed (repetition of a phrase heard in the past),18 occurs in up to 75% of individuals with an ASD who are verbal,19 and is a cardinal feature of autism.5 However, not all children with autism demonstrate echolalia. In addition, echolalia can be present in other disorders,18,19 such as dementia, other childhood language disorders, and blindness in children as well as in normal development.18 Additionally, receptive language is marked by difficulties in understanding abstractions (eg, irony, sarcasm), which further impairs social communication.1,5 The hallmark of these deficits in speech and language in autism is that neither is used to perform a social function; that is, as Kanner4 described, in children with autism, “speech is rarely communicative.” Not only communication in the form of receptive and expressive language, but communication via gesturing (eg, pointing, showing) or imitating is also substantially impaired,1,5 underscoring the primacy of social dysfunction in this disorder.

Restricted and stereotyped behavioral patterns (Criterion A3) may include restricted interests that are abnormally intense, rigid adherence to routines or rituals, repetitive motor mannerisms, or preoccupation with the parts of objects.1 Restricted interests are often variable, ranging from cars and trains to numbers and letters, for example, but they are by definition inappropriately intense or odd in their content.5 Children with autism may engage in compulsive behaviors, such as repeatedly lining up objects in a specific way.1,5 They may become overly interested in the moving parts of objects, or engage in repetitive acts such as opening and closing doors.1,5 In addition, slight changes in daily routines can lead to behavioral outbursts.1 Kanner4 described this obsessive rigidity affecting both interests and behavior as an “insistence on sameness.” Motor stereotypes may include hand or finger-flapping, rocking, and spinning,1,5 or there may be nonspecific motor abnormalities such as toe-walking or unusual hand movements or body postures.1 The course of autism is “continuous,”1 though school-age children may show some improvement in social, play, and communicative functioning, which may improve with appropriate intervention.19 Positive prognostic factors include greater language and cognitive abilities.1,20

Although cognitive abnormalities are not part of the DSM-IV-TR criteria for autistic disorder, most children with autism have mental retardation, which can range from mild to profound.1,3 Typically, nonverbal skills are superior to verbal skills, and there tends to be an irregular distribution of cognitive abilities.1,3 Some children with autism, however, may have above-average cognitive skills, such as being able to calculate calendar dates.1,3 At the same time, autism may be associated with conditions that cause mental retardation, such as fragile X syndrome and tuberous sclerosis.3,21 While autism is ~4 times more common in boys than in girls, this varies based on level of cognitive functioning; the male:female ratio is greatest in children with normal cognitive functioning and lowest for children with profound mental retardation.22,23 That is, females with autism are more likely to have more severe mental retardation.1,22,23 Epilepsy and electroencephalograph (EEG) abnormalities without seizures are common in autism and PDDs,1,5,24 and will be discussed further in the “Diagnostic Evaluation and Comorbidities” section of this article. With respect to neurologic abnormalities, macrocephaly, poor motor coordination, and mild hypotonia are more likely in children with ASDs.5 There is evidence that head circumferences are normal at birth, but increase abnormally from 6–12 months, resulting in macrocephaly.5,25 Children with autism may display abnormal responses to sensory stimuli, ranging from hypersensitivity to noise to decreased sensitivity to pain.1,5 In addition, the heritability of autism is >90%, with greater concordance rates in monozygotic versus dizygotic twins, though autism is likely polygenic and involves complex genetics.6

While the DSM-IV-TR specifies that dysfunction must be present prior to 3 years of age for autism to be diagnosed,1 questions have been raised as to how early the diagnosis can be made accurately and to what extent the current diagnostic criteria are applicable to very young children.25 ASDs can be diagnosed at 14 months, but the diagnoses are less stable at early ages.25 In particular, one study of 48 children diagnosed with autism or an ASD by 2 years of age found that diagnostic stability was 68% for autism and 63% for ASDs.26 Diagnosis prior to 30 months of age, lower symptom severity (notably in the area of social functioning), and better cognitive skills predicted less diagnostic stability by 4 years of age.26 Many parents (~80%) observe abnormalities in their child’s development by 2 years of age, most often due to speech and language delays,25 and some parents become aware of problems in the child’s social relatedness from around the time of birth.1 Signs of dysfunction in children 6–12 months of age may include poor eye contact, lack of facial expression, delayed babbling, poor coordination, and hypotonia.25 From 9–14 months of age, children with ASDs may demonstrate delayed receptive and expressive language. They may not point or gesture often or respond to their names being called. They may have repetitive behaviors.25 However, motor mannerisms typically emerge in the preschool years5 and some young children may meet criteria for autism but not the full criteria for repetitive behaviors until around 3 years of age.3 During 20–24 months, children with ASDs may not show interest in other children; they have limited facial expressions, “abnormal prosody” in their speech, and restricted interests in addition to repetitive behaviors.25 Early identification of ASDs is critical, as studies have shown that early interventions led to improvement in social functioning, language, and cognitive abilities.25 (Landa25 provides a comprehensive list of early signs of ASDs from 6–24 months of age.)

While there are early signs of dysfunction within the first year of life in most children with autism, there is evidence of developmental regression in ~20% to 25%,3 with even greater percentages reported.27 That is, following a period of normal or mildly delayed development during the first 1–2 years, these children lose social and communication skills.1,27 Initially, this phenomenon was questioned, as it was based on parental reports,3 though retrospective studies have demonstrated that a subgroup of children with autism experience regression in social and language development.27 In a recent prospective, longitudinal study, Landa and colleagues27 assessed 125 infants between 14 and 36 months of age, most of whom were at high risk for developing autism, as they had siblings with the disorder. The developmental trajectories of toddlers who received an early diagnosis of an ASD (at 14 months of age) were clearly distinct from those of toddlers who were diagnosed later, with respect to sharing positive affect, joint attention, and gesturing (though almost all of the toddlers who were not given an ASD diagnosis at 14 months of age did have signs of “developmental disruption” at that time). Specifically, this study found that the “later-diagnosis” group regressed from being almost indistinguishable from the non-ASD group at 14 months (except that children in the later diagnosis group shifted gaze less frequently from an object to another’s eyes and to the object again [or vice versa] compared to a non-“broader autism phenotype” group), to displaying similar social and communication deficits as the “early-diagnosis” group by 24 months of age (following a period in the later-diagnosis group of slowed language growth, lack of gains in joint attention, and losses in shared positive affect and gesturing).27 Other investigations of early signs of autism, including prospective studies of the high-risk infant siblings of children with ASDs,28,29 indicated that infants and toddlers who are later diagnosed with ASDs demonstrate delays in communication, affect sharing, joint attention, and repetitive behaviors early on, but that signs of autism may not be clinically identifiable or present from birth.16,30

Recent research has focused on characterizing and understanding the mechanisms underlying the social dysfunction in ASDs.31 For example, Klin and colleagues31 utilized eye-tracking technology to compare how individuals with autism view movie scenes involving social situations. These studies showed that adolescents and young adults with autism spent more time looking at others’ mouths and bodies or objects and less time looking at eyes compared to control subjects, and thus they miss social cues.31 Similar findings of a preference for focusing on mouth over eye regions were observed in 2-year-old children with autism compared to children who were either typically developing or developmentally delayed but did not have autism.32 In this study,32 less time spent looking at eyes was associated with greater social impairment. There is also evidence that individuals with ASDs have difficulties in facial recognition and have been found to show decreased activation of the fusiform region and amygdala when perceiving faces.33 In addition, one theory proposed by Baron-Cohen34 is that ASDs may represent a “hyper-systemising” approach to the environment, which may account for resistance to change and poor social functioning in these disorders.16

Asperger’s Disorder

Asperger’s disorder is defined in the DSM-IV-TR as involving the same deficits in social interaction (Criterion A) and stereotyped behavior and restricted interests (Criterion B) as in autistic disorder, but without any language or cognitive delays (Criteria D and E).1 These deficits, particularly in social relatedness, significantly impair the individual’s daily functioning (Criterion C).1 In addition, the DSM-IV-TR specifies that criteria cannot be met for another PDD or schizophrenia (Criterion F).1 Although Asperger’s disorder and autism share diagnostic criteria, there are qualitative differences in the nature of the social dysfunction and repetitive behaviors in the two disorders.11 Unlike autism, individuals with Asperger’s disorder are not necessarily socially withdrawn and are usually interested in interacting with others, but their socially inappropriate or odd style of relating to others (eg, speaking in a formal way as if giving a “monologue”) and difficulty reading social cues cause them to become isolated.10,11 In Asperger’s disorder, restricted interests and rigidity in adhering to rituals are more common than motor mannerisms.10 Individuals with Asperger’s disorder will become experts in a particular circumscribed area of interest, learning a great deal of factual information on this topic often to the exclusion of other types of experience, eg, social activities.10,11 This furthers their social isolation, as they attempt to talk to others about these singular interests as if they are giving a lecture, and for this reason, individuals with Asperger’s disorder are sometimes described as “little professors.”10,11

In contrast to autism, there are no delays in language or cognition early in life in Asperger’s disorder.11 However, speech in individuals with the disorder may be characterized by abnormal prosody, tone, or rate, and may be tangential, circumstantial, or overly verbose, consistent with a lack of attunement to the social uses of language and a focus on the individual’s own interests.10,11 While mental retardation is not common in Asperger’s disorder, there have been cases of mild mental retardation.1 Usually, verbal skills (eg, vocabulary, verbal memory) are superior to non-verbal (eg, fine and gross motor, visual-spatial, visual-motor abilities), as individuals with Asperger’s disorder frequently have motor difficulties such as poor coordination, odd gait, and “clumsiness.”1,11 Asperger’s disorder is often not recognized until a child reaches school age and begins to experience social difficulties with peers, particularly as there is no language delay, the child’s vocabulary can be precocious, and social problems do not emerge at home where their interactions are primarily mediated by adults.1,11

Asperger’s disorder is much more common in males (with male:female ratios estimated at 5:1 to at least 9:1).1,10 While there are few genetic studies of Asperger’s disorder specifically, there is evidence for a family history of the disorder in first-degree relatives.10 In his original description of the disorder, pediatrician Hans Asperger noted that family members of those affected demonstrated similar features.11 Other traits that Asperger reported included decreased facial expressions and gestures, peculiarities in communication, lack of empathy and intellectualization of feelings, and school behavioral problems such as aggression stemming from their social deficits.11 The question of distinguishing Asperger’s disorder and autism diagnostically continues to be a challenge, yet it is clear that social dysfunction in this disorder leads to significant functional impairment.1,11

Rett’s Disorder

Rett’s disorder is characterized by a defined pattern of regression, with respect to social, language, motor, and cognitive development, beginning at ~5–18 months of age.1,12 The DSM-IV-TR diagnostic criteria specify that from birth to 5 months of age, children with Rett’s disorder appear to demonstrate typical development (Criterion A), in that prenatal, perinatal, and psychomotor development seems to be unremarkable and head circumference is normal at birth.1 Retrospectively, however, subtle abnormalities, such as mild hypotonia and atypical or excessive hand movements, have been described during this period.12 A period of developmental regression follows (Criterion B), characterized by deceleration of head growth (between 5–48 months of age); loss of hand skills (between 5–30 months of age) and development of stereotypical hand movements; early loss of social skills, though this improves later; poor coordination of gait or truncal movements; and severe impairment in expressive and receptive language with marked psychomotor retardation.1 Severe or profound mental retardation is often also found in Rett’s disorder.1 Deceleration in head growth may not occur in all children with Rett’s disorder, and regression may not begin until ~18 months of age in some cases.12 Classically defined Rett’s disorder is found only in females, as the disorder has been linked to a gene on the X chromosome that encodes methyl-CpG binding protein-2 (MECP2), which is involved in regulating the expression of other genes during development.12 Mutations in MECP2, which have been reported in 87% of females with classical Rett’s disorder, and 50% of girls with a variant form of the disorder, occur more often on the paternal X chromosome and are thought to be lethal in males, accounting for the predominantly female distribution of the disorder.12 As autistic symptoms occur less often in very young females than in males, Rett’s disorder should be considered diagnostically in females with these symptoms.12 In addition, Rett’s disorder is second to Down’s syndrome as a cause of mental retardation in females.12 Molecular genetic analysis for mutations in MECP2 should be included in the diagnostic evaluation.12

It is important to underscore how the progression of motor and social abnormalities in Rett’s disorder, initially described by physician Andreas Rett in 1966, distinguishes it from other PDDs. Specifically, following the initial period of generally unremarkable development up to ~6 months of age, motor development seems to plateau. Significant developmental delays and neurologic symptoms are present by 15 months of age in ~50% of girls. Ages 1–4 are characterized by rapid loss of social and cognitive abilities, along with speech and hand use. Stereotyped hand movements, consisting of hand-wringing, washing or clasping, and hand-to-mouth movements, are characteristic of Rett’s disorder, and occur almost continuously during the day, interfering with purposeful use of the hands. Ataxia and loss of motor function affect ambulation, such that girls may lose or not develop the ability to walk. Social skills, including interest in others, are also lost during this stage, though in contrast to autism, eye contact is not affected. However, social interaction improves from 2–10 years of age. For this reason, many girls with Rett’s disorder may not demonstrate signs of autism at particular stages of the disorder, notably when they are <6 months of age or >3–5 years of age. Motor symptoms progress to involve spasticity, scoliosis, and rigidity at older ages. Additional features of Rett’s disorder include seizures, which are common, and EEG abnormalities, which are present in almost all cases beginning during the period of regression. Respiratory and sleep problems and bruxism have also been described. There is limited research on the long-term course of Rett’s disorder, and many cases are undiagnosed due to lack of familiarity with this disorder.12

Childhood Disintegrative Disorder

CDD is characterized in the DSM-IV-TR by developmental regression that begins after at least 2 years of what appears to be normal development in the areas of social interaction, communication, play, and adaptive behavior (Criterion A). This is followed by loss of skills prior to 10 years of age in the following areas: receptive and expressive language, social abilities, bowel and bladder control, play, and motor skills (Criterion B). In addition, there is similar dysfunction as that described in autistic disorder in social interaction, communication, or restrictive, repetitive behaviors (at least two of these areas are affected; Criterion C). Another PDD and schizophrenia must not be more appropriate diagnoses (Criterion D). Severe mental retardation is often found in CDD.1

CDD, which is also known as Heller’s syndrome, as it was first described by educator Theodore Heller in 1908, is rare and research on the disorder is limited.1,13 Onset of regression is typically at ~3–5 years of age, and may be rapid (within days to weeks) or gradual (within weeks to months), and occasionally is associated with behavioral changes (eg, agitation, anxiety, irritability).1,13 While CDD may be associated with medical conditions in some cases, such as tuberous sclerosis, metachromatic leukodystrophy, neurolipidoses, and others, this has not been found in most, though a thorough medical and neurologic work-up is recommended.1,13 CDD is characterized by a marked loss of language, social, and even self-help skills, such as toileting, and appears similar to autism following the regression.13 In addition, occurrence of seizures and EEG abnormalities are similar to autism.13 The course is continuous, and in most cases, deterioration reaches a plateau with minimal gains and “a limited recovery”; in a minority of cases, deterioration is progressive.13 CDD appears to be “sporadic,” as cases of the disorder occurring in families have not been identified, though genetic studies are limited and there may be genetic or gene-environment etiologies that have yet to be identified.13

Pervasive Developmental Disorder-Not Otherwise Specified

The DSM-IV-TR describes PDD-NOS as “a severe and pervasive impairment in the development of reciprocal social interaction” that is associated with nonverbal or verbal communication deficits or stereotyped behaviors and interests, but the specific criteria for another PDD are not met.1 The disorder cannot be due to schizophrenia or schizotypal or avoidant personality disorders.1 In addition, the DSM-IV-TR includes “atypical autism” in this category, which refers to cases that do not meet full diagnostic criteria for autistic disorder, as symptoms are “atypical” or “subthreshold,” or age of onset may be delayed.1,14 That is, PDD-NOS refers to cases primarily involving social deficits1,5,14 where symptoms are fewer or less severe than in autistic or Asperger’s disorders and do not meet criteria for Rett’s disorder or CDD,14 though the criteria for PDD-NOS are vaguely defined.5,14 As Towbin14 states, it “is likely that PDD-NOS is not just one condition.” Genetics and family studies indicate that there is an association between PDD-NOS and autism, as siblings of individuals with autism are equally likely to be diagnosed with either PDD-NOS or autism.14 At the same time, ~33% of the first-degree relatives of individuals with an ASD may be part of what has been called the “broader autism phenotype,” which describes individuals who may have similar features to ASDs but are not impaired functionally and do not meet the criteria for an ASD.35 The concept of functional impairment distinguishes PDD-NOS from the broader phenotype, yet further research is required to make the diagnostic criteria more specific and to characterize further “endophenotypes” such as differences in cognitive abilities, face recognition, or eye tracking, within this category.14

Diagnostic Evaluation and Comorbidities

Early identification of ASD symptoms and signs (eg, lack of social smile; poor eye contact; no babbling, pointing, or gesturing by 12 months of age; no spoken words by 16–18 months of age or two-word phrases by 2 years of age; atypical play behavior; loss of language or social skills) by primary care physicians (PCPs) and early referral to a multidisciplinary team (including a child psychiatrist and psychologist, pediatric neurologist, neuropsychologist, and developmental pediatrician) are critical in the diagnosis of ASDs, as recent evidence has shown that early intervention improves prognosis.5,17 For this reason, in 2007, the American Academy of Pediatrics published a “Surveillance and Screening Algorithm” for ASDs that recommends universal surveillance (ie, obtaining a developmental history, addressing parental concerns, assessing risk factors) and screening at preventive visits.17 While there is no conclusive test or biologic marker for ASDs, there are numerous screening and diagnostic tools that may be utilized to assist in the evaluation of children who may have an ASD.5,17 Among the available screening tools are the “level 1” tests, which can be administered at primary care visits, including the Checklist for Autism in Toddlers (CHAT; parent report/clinician observation; 18–24+ months of age),36-38 which is characterized by low sensitivity but high specificity, and the modified CHAT (parent report; 16–48 months of age),39 which is more sensitive.5,17,22 “Level 2” screening tools, which aid in distinguishing between ASDs and other developmental disabilities, include the Autism Behavior Checklist (interviewer completes; ≥18 months of age)40 and the Childhood Autism Rating Scale (trained interviewer completes; >2 years of age).17,41 The “gold standard” diagnostic tests for ASDs are the Autism Diagnostic Interview-Revised,42 which is a semi-structured, standardized interview for parents, and the Autism Diagnostic Observation Schedule,43 which is a “structured observation” of the patient, both of which require formal training to administer.5 PCPs are advised to refer children for a comprehensive evaluation as early as possible when there are concerns regarding the child’s development or if there is a positive result on a screening test, and to be particularly “vigilant” in monitoring at-risk siblings of children with ASDs,17 as the risk of a younger sibling of a child with autism having the disorder has been reported as >15%.44

The initial evaluation of any child who may have an ASD should include vision and hearing exams, as disabilities in these areas may mimic characteristics of ASDs.5,17 That is, while lack of eye contact or response to one’s name being called may occur in autism, these signs may instead be indicative of impairments in vision or hearing, respectively.17 In addition, lead testing is recommended due to pica.17 It is also important to be aware that autism is associated with numerous genetic syndromes, which occur in individuals with autism at various rates, including fragile X syndrome (~2%), tuberous sclerosis (0% to 4%; 8% to 14% of patients with autism and epilepsy), Down syndrome (0% to ~17%), and Angelman syndrome (~1%), among others.21 For this reason, high-resolution karyotype and fragile X testing is recommended in children with an ASD and mental retardation; dysmophic features; or a family history of fragile X, mental retardation, or dysmorphic features.5,17 Testing for MECP2 mutations (Rett’s disorder) and fluorescence in situ hybridization for chromosome 15q (Angelman and Prader-Willi syndromes) should also be considered.5 In addition, epilepsy is common in ASDs, with prevalence ranging from 5% to 40%,5,24 and all seizure types have been described, though seizures are more likely to occur in individuals with ASDs and mental retardation.24 EEGs are clearly indicated in children with clinical signs of seizures and in children who have language regression (as Landau-Kleffner syndrome is characterized by language regression between 4–7 years of age and EEG abnormalities),5,17,24 though some clinicians recommend performing EEGs in all children with autism.5 Metabolic and imaging studies are recommended when there is a specific clinical indication.5,17 Other medical problems that have been reported to occur often in or to be associated with autism include disturbances in sleep, gastrointestinal symptoms, dietary restrictions, and allergies and immunologic abnormalities.5,45

Behavioral and affective symptoms that may also occur in patients with ASDs include attentional difficulties, hyperactivity, obsessive-compulsive symptoms, tics, mood lability, anxiety, and depression.3 For this reason, it is important to consider other psychiatric conditions that may co-occur with ASDs. Although the DSM-IV-TR states that attention-deficit/hyperactivity disorder (ADHD) and autistic disorder cannot be co-diagnosed, Reiersen and Todd46 reported that there is evidence that some patients with autism may meet criteria for ADHD, which is associated with greater behavioral and social impairment, and that in less severe ASD cases the ADHD symptoms may be the chief complaint that leads to the clinical presentation. Forty-one percent to 78% of children with an ASD have ADHD symptoms in clinic studies.46 At the same time, attentional difficulties may be due to the developmental and cognitive deficits in autism, and may not indicate the presence of ADHD as a distinct disorder.3 Nonetheless, Reiersen and Todd46 argued that there are instances where the two disorders co-occur, and that evaluation should include assessment of both ASD and ADHD symptomatology when present. In addition, a recent study47 found that 70% of 11–14-year-old children with an ASD in a population-derived sample, most of whom were boys, met criteria for at least one other psychiatric disorder, based on parent interviews, including anxiety disorders (~42%, which included a high rate of “social anxiety disorder”; the authors note that this may be due to the social deficits of ASDs, or may represent social anxiety in these individuals), ADHD (~28%), and oppositional-defiant disorder (~28%). These studies underscore the importance of evaluating the full range of psychiatric symptoms that may occur in patients with ASDs.

Conclusion

The PDDs, as described in the DSM-IV-TR, are disorders that affect the core developmental domains of social interaction and verbal and nonverbal communication, and involve repetitive, stereotyped behaviors and restricted interests. These disorders, which are also referred to as the ASDs, include autistic disorder (which is the most paradigmatic of the PDDs), Asperger’s disorder, Rett’s disorder, CDD, and PDD-NOS. In addition, cognitive development is often affected in these disorders, although there is a range across disorders, and there may be associated neurologic signs (eg, motor symptoms, EEG abnormalities). Some of the disorders (Rett’s disorder, CDD, the regressive type of autistic disorder) are characterized by developmental regression, that is, loss of acquired skills. While the etiology of these disorders is unknown, there is evidence of heritability in most of these disorders. Given that the PDDs as a group are not uncommon, early identification and referral of patients with these disorders cannot be overemphasized, as early intervention improves long-term prognosis. PP

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
2.    Volkmar FR, Paul R, Klin A, Cohen D. Section 1: diagnosis and classification. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:1-3.
3.    Volkmar FR, Klin A. Chapter 1: issues in the classification of autism and related conditions. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:5-41.
4.    Kanner L. Autistic disturbances of affective contact. Nervous Child. 1943;2:217-250.
5.    Spence SJ, Sharifi P, Wiznitzer M. Autism spectrum disorder: screening, diagnosis, and medical evaluation. Semin Pediatr Neurol. 2004;11(3):186-195.
6.    Gupta AR, State M. Recent advances in the genetics of autism. Biol Psychiatry. 2007;61(4):429-437.
7.    Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Washington, DC: American Psychiatric Association; 1980.
8.    International Statistical Classification of Diseases and Health Related Problems. 10th rev. 2nd ed. Geneva, Switzerland: World Health Organization; 2004.
9.    Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66(suppl 10):3-8.
10. Woodbury-Smith MR, Volkmar FR. Asperger syndrome. Eur Child Adolesc Psychiatry. 2008 Jun 18. [Epub ahead of print].
11.    Klin A, McPartland J, Volkmar FR. Chapter 4: Asperger syndrome. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:88-125.
12.    Van Acker R, Loncola JA, Van Acker EY. Chapter 5: Rett syndrome: a pervasive developmental disorder. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:126-164.
13.    Volkmar FR, Koenig K, State M. Chapter 3: childhood disintegrative disorder. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:70-87.
14.    Towbin KE. Chapter 6: pervasive developmental disorder not otherwise specified. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:165-200.
15.    Abrahams BS, Geshwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9(5):341-355.
16.    Caronna EB, Milunsky JM, Tager-Flusberg H. Autism spectrum disorders: clinical and research frontiers. Arch Dis Child. 2008;93(6):518-523.
17.    Johnson CP, Myers SM, Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics. 2007;120(5):1183-1213.
18.    Tager-Flusberg H, Paul R, Lord C. Chapter 12: language and communication in autism. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:335-364.
19.    Loveland KA, Tunali-Kotoski B. Chapter 9: the school-age child with an autism spectrum disorder. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:247-287.
20. Howlin P. Chapter 7: outcomes in autism spectrum disorders. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:201-220.
21.    Zafeiriou DI, Ververi A, Vargiami E. Childhood autism and associated comorbidities. Brain Dev. 2007;29(5):257-272.
22.    Volkmar FR, Lord C, Bailey A, et al. Autism and pervasive developmental disorders. J Child Psychol Psychiatry. 2004;45(1):135-170.
23.    Lord C, Schopler E, Revicki D. Sex differences in autism. J Autism Dev Disord. 1982;12(4):317-330.
24.    Canitano R. Epilepsy in autism spectrum disorders. Eur Child Adolesc Psychiatry. 2007;16(1):61-64.
25. Landa RJ. Diagnosis of autism spectrum disorders in the first 3 years of life. Nat Clin Pract Neurol. 2008;4(3):138-147.
26.    Turner LM, Stone WL. Variability in outcome for children with an ASD diagnosis at age 2. J Child Psychol Psychiatry. 2007;48(8):793-802.
27.    Landa RJ, Holman KC, Garrett-Mayer E. Social and communication development in toddlers with early and later diagnosis of autism spectrum disorders. Arch Gen Psychiatry. 2007;64(7):853-864.
28.    Yirmiya N, Gamliel I, Pilowsky T, Feldman R, Baron-Cohen S, Sigman M. The development of siblings of children with autism at 4 and 14 months: social engagement, communication, and cognition. J Child Psychol Psychiatry. 2006;47(5):511-523.
29.    Bryson SE, Zwaigenbaum L, Brian J, et al. A prospective case series of high-risk infants who developed autism. J Autism Dev Disord. 2007;37(1):12-24.
30. Yirmiya N, Ozonoff S. The very early autism phenotype. J Autism Dev Disord. 2007;37:1-11.
31.    Klin A, Jones W, Schultz R, et al. Defining and quantifying the social phenotype in autism. Am J Psychiatry. 2002;159(6):895-908.
32.    Jones W, Carr K, Klin A. Absence of preferential looking to the eyes of approaching adults predicts level of social disability in 2-year-old toddlers with autism spectrum disorder. Arch Gen Psychiatry. 2008;65(8):946-954.
33. Schultz RT. Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area. Int J Dev Neurosci. 2005;23(2-3):125-141.
34. Baron-Cohen S. Two new theories of autism: hyper-systemising and assortative mating. Arch Dis Child. 2006;91(1):2-5.
35.    Steyaert JG, De La Marche W. What’s new in autism? Eur J Pediatr. 2008;167(10):1091-1101.
36.    Baron-Cohen S, Allen J, Gillberg C. Can autism be detected at 18 months? The needle, the haystack, and the CHAT. Br J Psychiatry. 1992;161:839-843.
37.    Baron-Cohen S, Cox A, Baird G, et al. Psychological markers in the detection of autism in infancy in a large population. Br J Psychiatry. 1996;168(2):158-163.
38.    Baird G, Charman T, Baron-Cohen S, et al. A screening instrument for autism at 18 months of age: a 6-year follow-up study. J Am Acad Child Adolesc Psychiatry. 2000;39(6):694-702.
39.    Robins DL, Fein D, Barton ML, Green JA. The modified checklist for autism in toddlers: an initial study investigating the early detection of autism and pervasive developmental disorders. J Autism Dev Disord. 2001;31(2):131-144.
40.    Krug DA, Arick J, Almond P. Behavior checklist for identifying severely handicapped individuals with high levels of autistic behavior. J Child Psychol Psychiatry. 1980;21(3):221-229.
41.    Schopler E, Reichler RJ, DeVellis RF, Daly K. Toward objective classification of childhood autism: childhood autism rating scale (CARS). J Autism Dev Disord. 1980;10(1):91-103.
42.    Lord C, Rutter ML, Le Couteur A. The autism diagnostic interview-revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord. 1994;24(5):659-685.
43.    Lord C, Risi S, Lembrecht L, et al. The autism diagnostic observation schedule–generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord. 2000;30(3):205-223.
44.    Sutclilffe JS. Insights into the pathogenesis of autism. Science. 2008;321(5886):208-209.
45. Filipek PA. Chapter 20: medical aspects of autism. In: Volkmar FR, Paul R, Klin A, Cohen D, eds. Handbook of Autism and Pervasive Developmental Disorders. Vol. 1. Hoboken, NJ: John Wiley & Sons, Inc.; 2005:534-578.
46. Reiersen A, Todd RD. Co-occurrence of ADHD and autism spectrum disorders: phenomenology and treatment. Expert Rev Neurotherapeutics. 2008;8(4):657-669.
47.    Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry. 2008;47(8):921-929.

 

Dr. Neubauer is associate director of the Johns Hopkins Sleep Disorders Center and assistant professor in the Department of Psychiatry at the Johns Hopkins University School of Medicine in Baltimore, Maryland. He is also medical director of the Psychiatry Mobile Treatment Program at the Johns Hopkins Bayview Medical Center.

Disclosure: Dr. Neubauer is consultant to sanofi-aventis and Takeda.

Please direct all correspondence to: David N. Neubauer, MD, Johns Hopkins Bayview Medical Center, 4940 Eastern Ave, Box 151, Baltimore, MD 21224.


 

“Health consists of having the same diseases as one’s neighbors.” —Quentin Crisp

 

I am delighted to have the opportunity to write about sleep and sleep disorders in Primary Psychiatry. I aim to bridge the emerging neuroscience of sleep with the clinical realities of sleep disorders and, along the way, share with readers the stories of some of the patients I see at the Sleep Disorders Center at Johns Hopkins in Baltimore, Maryland. I am fortunate to be able to evaluate and treat such a diverse group of patients that have trouble sleeping at night or staying awake during the daytime. Even after nearly 25 years, I continue to learn from our patients every week in the sleep clinic and from our review of challenging cases in the staff conferences. Although there are dozens of defined sleep disorders, each patient seeking help for these problems is unique.1 I am fascinated by how people view their sleep problems and the assorted methods they use in trying to improve them. Their solutions sometimes help, but other times cause new problems.

People have many different motivations for consulting doctors and other healthcare professionals about their difficulties with sleep or wakefulness. Usually, the bottom line is some degree of suffering—a sense of daytime impairment, perhaps poor concentration or excessive sleepiness, or a feeling that nighttime sleep somehow is abnormal. Patients may come in complaining of difficulty getting to sleep or staying asleep, or that their sleep simply is not refreshing. They may also describe unusual experiences or behaviors that occur during their sleep, such as kicking, walking, screaming, or eating. Sometimes, concerned spouses or other family members bring in reluctant patients, and sometimes patients are referred by doctors concerned that their symptoms might be explained by a sleep disorder. Occasionally, employers or school administrators insist on evaluations when the patient obviously is functioning poorly due to excessive sleepiness.

One key issue that must be considered in evaluating people presenting with concerns about bothersome daytime sleepiness or poor concentration is the degree to which the cause is chronic sleep insufficiency. One of my patients had seen a television program on sleep apnea and was worried that it could be the reason that he was nodding off during afternoon meetings. However, most nights he was not getting to bed until nearly midnight and he had his alarm set for 5 AM so that he could exercise before going to his office. He was surprised when his revised schedule of getting to bed earlier and sleeping a little later in the morning had a big impact on his daytime alertness. Getting enough sleep seems obvious, but often it is overlooked.

We do tend to be a sleep-deprived society. The majority of working Americans are not getting an optimum amount of sleep most nights. That is true for students as well. Our culture in general does not value sleep and there are endless distractions that lure us from the time we should be devoting to sleep. Television and the Internet are chief offenders these days. For many, work schedules and commuting time significantly undermine the ability to get adequate sleep.

Evidence regarding the negative consequences of insufficient sleep has been growing rapidly. Certainly, the sleepiness and cognitive impairment resulting from acute or chronic sleep deprivation increase the risk for mistakes and accidents, which sometimes are catastrophic. However, numerous recent reports have emphasized other adverse health effects, such as impaired glucose utilization, diabetes, obesity, hypertension, cardiovascular disease, depression, and exacerbation of pain. These may be compounded further by the presence of sleep disorders that undermine sleep quality.

A 2006 Institute of Medicine (IOM) report2 highlighted the fact that 50–70 million Americans chronically suffer from a disorder of sleep and wakefulness, and that the cumulative effects of these conditions represent a major unrecognized public health problem. Recommendations in the report included strategies to increase the awareness of these sleep-related problems both in the general public and among healthcare professionals.

In December 2008, the IOM issued a new and highly relevant report3 in response to a request by the United States Congress. Medical training traditionally has required extended periods of work with no sleep or schedules that produce chronic sleep deprivation. The resulting fatigue and sleepiness during work hours are not conducive for safety or learning. Excellent lectures and other educational programs are worthless to the residents that are nodding off. The increase in medical errors with sleep deprivation is well documented.4 While patient safety is a critical issue, so is the health and safety of the trainees. I, for one, was one of very many residents involved in an automobile accident while driving home after a night on call.5 Fortunately, the 2003 Accreditation Council on Graduate Medical Education rules for resident working hours have offered some relief for the problem. The new IOM report, however, argues that further revisions are necessary. For example, the current guidelines limit the longest consecutive period of work at 30 hours, but the IOM report suggests that this still may be associated with significant fatigue and should be revised to include protected sleep time.3

While chronic sleep deprivation is a public health problem, there are many people who do have the opportunity to get enough sleep, but nevertheless are unable achieve adequate sleep or feel too sleepy during their waking hours. Lifestyle choices still may be part of the problem, as with the excessive use of caffeine or other stimulants, or use of sedating substances that cause daytime sleepiness. Various medications also may cause these problems. However, sleep-related symptoms often result directly from primary sleep disorders.

The Quentin Crisp quote wonderfully highlights the relativity in peoples’ perception of illnesses, and it captures an important aspect of many sleep disorders. That is, people need to conclude that their experience, or symptom, is different from most other people and, therefore, is abnormal and possibly treatable. Insomnia and excessive sleepiness are perfect examples. Insomnia fundamentally is the complaint when people feel that something is wrong with their ability to fall asleep, remain asleep, or achieve refreshing good quality sleep. Typically, the insomnia complaint incorporates presumed daytime consequences that would improve if the nighttime sleep would improve. However, there are no specific criteria of how long it takes to fall asleep, the number of awakening, the total amount of sleep, or the quality of sleep that define abnormality or clinical significance. The root of insomnia is the subjective complaint. From that point, history can be elucidated and a multitude of possible influences can be explored.

Similarly, the complaint of excessive daytime sleepiness begins with a subjective experience. Fortunately, one’s ability to remain awake during the daytime can be approached objectively in a sleep laboratory with the multiple sleep latency test or the maintenance of wakefulness test. Primary sleep disorders that may result in clinically significant daytime sleepiness include obstructive sleep apnea and narcolepsy, although there are several less well-defined syndromes that may incorporate chronic or episodic excessive sleepiness. Often overlapping complaints of fatigue and the presence of medical or psychiatric comorbidities, or even other sleep disorders, complicate the evaluation of patients reporting bothersome daytime sleepiness.

It is terrific that sleep medicine has evolved and that we now have a greater appreciation of the epidemiology and pathophysiology of sleep disorders. However, we still have the problem of the under-recognition and undertreatment of sleep disorders, whether it is a form of insomnia, circadian rhythm disorder, parasomnia, restless legs syndrome, sleep-disordered breathing, or disorder of excessive sleepiness. People may be unaware of their sleep disorder, as with obstructive sleep apnea, because it is occurring during their sleep, or they may not have been educated about disorders of sleep and wakefulness.

Healthcare professionals should screen patients routinely for sleep disorders and sleep deprivation. A few quick questions about nighttime sleep and daytime alertness will find those patients that should be evaluated further. Incorporating sleep-related questions into a review of systems form is a great idea. More detailed inquiries are appropriate for patients at higher risk for sleep disorders. For example, overweight and obese patients should be asked about symptoms of obstructive sleep apnea and patients with mood or and anxiety disorders should be asked about insomnia symptoms.

In future issues, I will cover sleep disorders in greater detail and highlight new and interesting research findings related to sleep. At times I will also take broad cultural and historic perspectives regarding sleep and discuss issues related to sleep in society. I will continue to argue that a sufficient amount of good quality sleep is essential for the health of our patients and for the population at large as well. It is important that enough time be devoted to sleeping and that problems with sleep and wakefulness be evaluated and treated. Exploring the causes of sleep problems may reveal other comorbid health conditions and treating sleep disorders may represent an opportunity to decrease other health risks. PP

References

1. American Academy of Sleep Medicine. The International Classification of Sleep Disorders: Diagnostic & Coding Manual, ICSD-2. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005.
2. Colten HR, Altevogt BM, eds. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington, DC: The National Academic Press; 2006.
3. Ulmer C, Wolman DM, Johns, Michael M. E., eds. Resident Duty Hours: Enhancing Sleep, Supervision, and Safety. Washington, DC: The National Academic Press; 2008.
4. Barger LK, Ayas NT, Cade BE, et al. Impact of extended-duration shifts on medical errors, adverse events, and attentional failures. PLoS Med. 2006;3(12):e487.
5. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med. 2005;352(2):125-134.

 

Dr. Kennedy is professor in the Department of Psychiatry and Behavioral Sciences at Albert Einstein College of Medicine, and director of the Division of Geriatric Psychiatry at Montefiore Medical Center in the Bronx, New York. Dr. Olson is professor in the Department of Anatomy and Structural Biology at Albert Einstein College of Medicine.

Disclosure: Dr. Kennedy is a consultant to Myriad; is on the speaker’s bureaus of Forest and Pfizer; and has received grant support from Forest, Myriad, Novartis, Pfizer, and Takeda. Dr. Olson reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

Please direct all correspondence to: Gary J. Kennedy, MD, Director, Department of Geriatric Psychiatry, MMC, 111 East 210th St, Klau One, Bronx, NY 10467; Tel: 718-920-4236; Fax: 718-920-6538; E-mail: gjkennedy@msn.com.


 

Numerous medical schools in the United States and abroad have determined that anatomy taught through cadaver dissection is untenable. Concerns for cost effectiveness, educational efficacy, the shortage of trained anatomist teachers, the increasing demand for cadavers, and pressure to convert dissection rooms to research laboratories, all argue for minimizing or eliminating cadaver dissection. However, arguments against dissection tend to ignore the emotional growth students experience in the process. Cadaver dissection prepares them for one of the core dilemmas of patient care, namely, the need to be personally engaged yet clinically detached. This dilemma, traditionally encountered with the first incision in the dissection lab, will persist throughout professional life, and it must be addressed in order to provide humanistic care with scientific objectivity. What follows is one perspective on how to shape students’ self-awareness in the first weeks of dissection. The premise is simply that examination of the cadaver provides the student a unique opportunity to examine the self.

Background

From its origins, human dissection has been an emotionally charged topic.1 Although the morality of dissection for the advancement of medical science is widely accepted,2 the emotional impact on medical students is often ignored.3-5 Failure to provide an avenue for students to discuss their feelings misses a unique opportunity to explore the emotional relationship they will experience with subsequent patients. In addition, it misses a rare educational moment when a confluence of events provokes an openness and vulnerability in which students can reflect and grow. The Albert Einstein College of Medicine in New York City has developed several approaches within the Clinical and Developmental Anatomy Course to facilitate discussions of first-year student reactions to the dissection of a human cadaver. The stated goals for the course focus on a patient-centered approach to learning the basic human anatomy needed to prepare the student for preclinical course work as well clinical experience. Within the course are several opportunities to enhance the students’ capacity for empathy with subsequent patients by addressing empathically their reactions to their cadaver.

For the students’ initial encounter, “Introduction to the Cadaver,” they are asked to perform a physical examination of the body focused on surface anatomy under the supervision of non-anatomist clinical faculty. Students work in teams with one cadaver assigned to a table of four students. For this exercise, the nude cadaver is presented to the students face up, covered by a single shroud. Bed sores and entry wounds for tubes, infusions, and other evidence of invasive procedures are all clearly visible. After the introductory session, the team is required to write an essay describing their findings and speculating on the cause of death and quality of care at the end of life. Next, faculty facilitators not responsible for grading the students meet for 90 minutes with eight students during the second week of dissection for the “Cadaver Conference.” By the time of the conference the student teams will have dissected the back, and begun to work on the chest and most of the chest and thoracic viscera. During the conference, students are encouraged to speak freely of thoughts and feelings that have emerged during dissection. Finally, a memorial service acknowledging the gratitude students owe those who have donated their bodies for dissection is held at the end of the course. Memorial events such as the one held at the Albert Einstein College of Medicine are almost universal practice at medical schools across the US. The other course activities are not. The following describes how the Cadaver Conference facilitates student discussion of their sensory impressions as a prelude to the disclosure of deeper feelings.

Introduction

The volume of information as well as the pace at which it must be acquired leave the first-year student little time for reflection. As a result, asking students directly to reflect upon their reactions may evoke superficially protective responses. The session begins with brief introductions all around as an ice breaker followed by a purposefully vague description of the goal for the next 90 minutes. Students are reminded that the cadaver is their first patient6 and that the vivid initial impressions can be useful for subsequent encounters provided they have the opportunity for discussion. In some groups a student will seize the leadership with a deeply felt reaction which will propel all the students into the desired openness. More often the students are not prepared for the intensity of their reactions much less the invitation to share them with peers. It is then generally more productive to start with the least intimate perceptions before proceeding to more threatening fears and feelings. At critical junctures the clinical relevance of their reactions is highlighted.

First Sight

The first perception the students will have of the cadaver is visual. As a result, the facilitator begins by asking, “Who among you have seen or touched a dead body before the anatomy course?” Most students have done neither. However, they have performed a physical examination of the cadaver so that the next question focuses on their first glimpse of the body which the facilitator will call “the person” thereafter. The students are asked to describe what they saw, more specifically, “What was the gender, age, race, and condition of the body?” Students are asked if they have seen the hands, face, or genitals, each a more intimate part of the anatomy. These questions give permission for the students to voice their natural curiosity despite initial reservations. Some describe the appearance as “unreal or not human” or note that surgical scars, entry wounds for embalming fluids, bed sores, or compression of soft tissues due to positioning have distorted the anatomy. They are also asked again to speculate on the cause of death and state of the person’s care at the end of life. They are asked to determine whether the nails are manicured, the scalp hair is recently cut or dyed, or the appearance of the hands offers clues to the person’s work or self-care. In one instance, the person’s finger nails had been manicured shortly before death but the toenails “were in terrible shape.” In another, the boundary between dyed and natural hair color was nearly an inch. The hands of one of the bodies were heavily calloused prompting one student to say, “He must have worked hard right up to the end.” These observations allowed students to project themselves into the person’s immediate history to promote identification and lessen the interpersonal distance. Students are also asked how they left the body at the end of the initial dissection. In the initial stages of dissection with the body relatively intact, students are more meticulous in repositioning the cadaver’s anatomy prior to covering it with a shroud. When asked why, students generally respond it is simply matter of respect. This provides the clinically relevant observation that no matter what condition of the patient, living or dead, likable or not, admirable or not, the physician’s stance must always be one of respect. Starting with these more passive observations sets the stage for their responses to actual dissection.

Touch

The facilitator’s next line of inquiry starts with, “At your table, who made the first incision? Why were you chosen to be the first?” Students who have already identified themselves as future surgeons often initiate the dissection. However, on occasion a student will take the scalpel to overcome self doubt or embarrassment, saying that is easier to do it than to watch. The student who made the first cut is asked to describe the experience. “Was the flesh tough or difficult to incise? Was the force needed to retract the skin from the back greater or lesser than expected? Was a finger-sized stab wound opened to provide a better grip on the skin for retraction to reveal the anatomy below the surface?” Most students find the dissection of the back physically arduous. One mentioned, “When I first started it was really slow and I did not want to mess it up, but the instructor said I had to move along and not be so cautious. Then I got really into it; it was like I was just hacking away to get down to the spine. It was a little creepy.” Another student mentioned, “I was [dissecting] okay until I reached the scalp. It actually gave me a chill when I cut into the hair line.” Here the student is touching on the dread of inflicting harm, but also the latent sadism that doing so may be a source of delight. Yet, physicians are expected to enjoy their work and be proficient even if it means causing pain or disfigurement in order to prevent agony or death. Students are warned that no patient wants a surgeon who lacks confidence, is tentative, or is squeamish about making an incision.

Students are then reminded that this same push and pull, take action but do no harm, will recur throughout their professional lives. Sharing a dreaded diagnosis such as cancer, dementia, or terminal illness invariably distresses the patient and is unpleasant for the physician. But doing so in a skillful manner provides the patient and family a platform both to grieve and to act. To be an ongoing source of stability for patient and family unsettled by their realization of mortality is one of the more satisfying moments in medicine. Further, a seasoned, empathic physician can provide the leadership needed by the other members of the healthcare team as well. Confronting death in the person of a cadaver is the student’s first professional encounter with death and dying.7-9 The goal of the discussion, then, is to help students become aware of their own fears of death as well as fears of the inevitable errors in technique or judgment which they will commit.

Olfactory and Gustatory Dimensions of Dissection

The facilitator should ensure that no one in the group remains silent. Smell is a particularly effective sensation with which to elicit participation. Invariably, the students become animated when discussing smell. Most often the smell of the preservative receives the most discussion. When asked, “How did you manage to work on the person despite the smell?” most students, especially those who were first to make an incision, describe becoming habituated as concentration to the task at hand absorbs their attention. Others express an abiding revulsion which is present at the start of every class. However, asking how the odor is managed after class brings a wider range of responses. Some students retreat to their apartments, which are across the street from the anatomy room, to bathe and shampoo immediately after the dissection. For others, discarding their apron and washing their hands is sufficient. Some will admit to remembering the smell even when they know their clothing as well as their person has been thoroughly cleansed. Some will wear the same apparel to every dissection to contain fears of contamination. Asking questions about smell inevitably leads to a discussion of how dissection has affected appetite. Some leave class ravenous after the manual effort and prolonged standing at the dissection table. Others experience a temporary loss of appetite or forgo the consumption of meat.

Hearing

Added to the sight, smell, and feel of the cadaver is the sound associated with the procedures to free up bony parts of the anatomy using a Striker saw. A laminectomy performed during the early dissection assignments to view the spinal cord can provoke a noticeable reaction. One student was surprised by the amount of effort required to cut through the lamina. But the snap heard as the lamina was successfully sectioned was startling. The event made the student pause. “That was the first time it really got to me,” reflected the student. Thus, inquiring about the sound of the procedure also provides an opportunity to uncover complex feelings. The pause of self awareness is something to nurture rather than avoid.

Disavowals and Emotional Blunting

When shared among table mates, the sensory perception and emotional experiences promote openness and acceptance. However, equally important are expressions to the contrary by students who disavow strong feelings. There will be some who legitimately question the value of dissection to their individual careers. Even for them, hearing fellow students discuss the intense reactions can be enlightening. On rare occasions, students will deny strong reactions or even any reaction despite the facilitator’s questions. At times, students will form protective pairs to keep the discussion superficial by rationalizing emotional reactions as limited to the group setting and thereby artificial. This may well keep threatening feelings out of awareness, but is precisely what the conference is meant to prevent. Rather than allowing blunting to be a group norm, it may be helpful for the facilitator to express disappointment or surprise that what is usually an intense experience has eluded them. This normalizes the expression of feelings and allows the remaining students to continue the discussion uninhibited.

Shame and Authority

In contrast, some groups will dwell on difficult emotions as though they were mourning the loss of innocence rather than exploring a professionally important phenomenon. One student found herself in tears in her apartment after the first dissection, saying, “How could we do this? This could have been someone’s mom. I know we need to learn but it just does not feel right.” Indeed, the legitimacy of dissection has been questioned both before and after the 1832 Anatomy Act which allowed English hospitals to receive unclaimed dead bodies for dissection.1 At the Albert Einstein College of Medicine, many of the cadavers are provided by donors who have bequeathed their bodies for medical education. However, an equal and often greater number are donated annually by the decedent’s family members or estate executor. Thus, most cadavers used at the college of medicine are obtained without the informed consent of the living individual. This is most often the case for cadaveric organ donation as well. Nonetheless, this lack of prior permission is distressing for students already unsure of their “right” to dissect.

As a result, some students will continue to minimize contact with the body. The question, “Has everyone had a chance to make an incision?” helps students, such as the one mentioned above, to disclose their reasons. A more provocative question is, “How do you justify the mutilation of this person?” Here, the clinically relevant point is that dissection is a privilege performed so that others, not just the students, may benefit. It is a reminder that the moral authority of their profession is based on beneficence.

Alternatively, for groups stuck in their own mourning, it may be helpful to reflect, “Yes, these are inconvenient feelings, but was there nothing about the dissection that you enjoyed? Did not anybody have fun?” This often serves to uncover the students’ pride in newly acquired skills or an appreciation for the feel of anatomy that was absent from texts or Websites. Students will also mention the fascination of discovery. It also reminds students that cadaver dissection is only one among many of the challenges they will embrace to become effective, mature physicians. Mastering the work of dissection will facilitate mastery of the emotional work involved in patient care—both the successes and failures.

Other Considerations

Humor can create a protective distance from threatening reality but risks loss of sensitivity. One student admitted that for a moment he found himself too detached. As the heart was being excised from the chest cavity he humorously imagined passing it like a football. His ability to share this with the team added to rather than detracted from his moral stature. His insight had brought him closer, not farther, from the person, and closer to his classmates as well. He had, in effect, apologized to the cadaver and his classmates. The facilitator used the opportunity to reflect that when an error occurs, an apology delivered directly and without excuses more often sustains than ruptures the doctor-patient relationship. Patients can be remarkably forgiving, but not of sarcasm, indifference, or abandonment. Given the power, complexity, and cost of modern medicine, knowing how to apologize is a critical skill.

One student recalled being asked by a friend who was not a medical student what the dissection experience was like. The student welcomed the opportunity to discuss his feelings away from his instructors and classmates. However, as he began to describe his feelings, he became aware that his friend seemed distant, unable to relate to the experience. Similarly, patients will ask for personal information or express genuine concern when the physician cannot conceal the effects of personal illness or loss. Yet, the physician is responsible for maintaining a working distance that keeps the patient close without crossing the boundary of using the patient to meet the physician’s personal needs. Personal questions most often indicate a need to know what doctors think of their patients rather than what doctors think of themselves. Without the student’s example of the friend who could not relate, the boundary concept would have seemed little more than an ethical abstraction.

Finally, when asked, most students do not consider donating their bodies for dissection. Though for some this is the result of religious precepts, it is more often not the case. Throughout the session, the facilitator has sought to examine the boundary between the cadaver and the student in an effort to pave the way for a more empathically effective stance toward their patients. Yet, no matter how much they may identify with the cadaver, rarely do they identify themselves as future donors.

Conclusion

This column has focused on only one pedagogic technique and does not offer experimental evidence of beneficial outcomes associated with the experience. However, student evaluations of the experience are positive. One student commented at the end of the conference, “I never knew there was so much to this.” Another had a morbid fear of how she would respond to dissection, which seized her from the first moment she read her acceptance letter from the college of medicine. Two years later, during her clerkship, she told the facilitator how much she appreciated the opportunity to confront her fears in an open, non-judgmental arena. Admittedly, the sensitivities evoked by this technique may easily be blunted by overwork, cynical attendings, or clinical rotations that do not promote an empathic environment. In addition, there is no shortage of events during the clerkships that bring to light the dilemma of sustaining clinical detachment while remaining emotionally engaged. Yet, the intensity of the experience occurring as it does in the first year of medical education uniquely captures the duality and boundaries of patient care. For the patient’s sake, the physician cannot afford to be emotionally overwhelmed or unable to act. A physician paralyzed by fear or doubt has effectively abandoned the patient. Yet, unfeeling detachment is impersonal and unlikely to inspire trust. However anatomy is to be taught in the evolving medical school curriculum,10-13 student dissection provides a rare avenue to promote clinician self awareness and improve patient care. Dissection of the cadaver provokes an examination of the self. PP

References

1. Richardson R. The Making of Mr. Gray’s Anatomy: Bodies, Books, Fortune, Fame. London, UK: Oxford University Press; 2008.
2. Korf HW, Wicht H, Snipes RL, et al. The dissection course–necessary and indispensable for teaching anatomy to medical students. Ann Anat. 2008;190(1):16-22.
3. Finkelstein P, Mathers LH. Post-traumatic stress among medical students in the anatomy dissection laboratory. Clin Anat. 1990;3(3):219-226.
4. Lempp HK. Perceptions of dissection by students in one medical school: beyond learning about anatomy. A qualitative study. Med Educ. 2005;39(3):318-325.
5. Snelling J, Sahai A, Ellis H. Attitudes of medical and dental students to dissection. Clin Anat. 2003;16(2):165-172.
6. Coulehan JL, Williams PC, Landis D, Naser C. The first patient: reflections and stories about the anatomy cadaver. Teach Learn Med. 1995;7(1):61-66.
7. Druce M, Johnson MH. Human dissection and attitudes of pre-clinical students to death and bereavement. Clin Anat. 1994;7:42-49.
8. Nnodim JO. Preclinical student reactions to dissection, death, and dying. Clin Anat. 1996;9(3):175-182.
9. Marks SC, Bertman SL, Penney JC. Human anatomy: a foundation for education about death and dying in medicine. Clin Anat. 1997;10(2):118-122.
10. Aziz MA, McKenzie JC. The dead can still teach the living. The status of cadaver-based anatomy in the age of electronic media. Perspec Biol Med. 1999;42:402-421.
11. Dinsmore CE, Daugherty S, Zeitz HJ. Teaching and learning gross anatomy: dissection, prosection, or “both of the above?” Clin Anat. 1999;12(2):110-114.
12. Olson TR. A.D.A.M. Student Atlas of Anatomy. 2nd ed. Cambridge, MA: Lippincott, Williams & Wilkins; 2008.
13. McLachlan JC, Patten D. Anatomy teaching: ghosts of the past, present and future. Med Educ. 2006;40(3):243-253.