Dr. Grodberg is clinical instructor in the Department of Psychiatry at the Seaver and New York Autism Center of Excellence and Dr. Kolevzon is assistant professor of psychiatry and pediatrics in the Department of Psychiatry, both at Mount Sinai School of Medicine in New York City.

Disclosures: Dr. Grodberg receives research support from the National Institutes of Health. 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: David M. Grodberg, MD, Clinical Instructor, Department of Psychiatry, Seaver and N.Y. Autism Center of Excellence, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029-6574; Tel: 212-241-3276; Fax: 212-241-5670; E-mail: david.grodberg@mssm.edu.


 

Autism is a severe neuropsychiatric disorder characterized by delays or deviation in the development of social and communication skills and the presence of restricted patterns of interests and/or stereotypic motor mannerisms. Autistic disorder is categorized under the pervasive developmental disorders (PDD) in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition–Text Revision.1 The other PDDs include Asperger’s disorder, Rett’s disorder, childhood disintegrative disorder, and pervasive developmental disorder not otherwise specified (PDD-NOS).1 The term “autism spectrum disorder” (ASD) has recently taken hold in medical practice and research and is considered to be synonymous with PDD, though not a formal DSM-IV-TR diagnosis.

Symptoms of inattention, hyperactivity, and impulsivity are common in individuals with ASD, and may be the primary reason for referral among less impaired patients with Asperger’s disorder and PDD-NOS. In fact, the earliest published accounts of autism2 extensively describe attention deficits, and these symptoms continue to be an important area of clinical focus and ongoing research. This is despite the fact that the DSM-IV-TR currently prohibits the diagnosis of attention-deficit/hyperactivity disorder (ADHD) when an underlying PDD is present.

In a recent survey3 of 487 children and adolescents with ASD, >50% had moderate to severe symptoms of inattention and hyperactivity. In another sample of 101 children with ASD,4 95% exhibited attention deficit, 50% demonstrated impulsive behavior, and 75% were found to manifest symptoms consistent with ADHD. The presence of ADHD symptoms in children with ASD is particularly important to clarify because comorbidity may predict greater impairment in activities of daily life4 and higher rates of hospitalization than otherwise exist for children with ASD alone.5

It may be possible in several ways to distinguish symptoms of ADHD in ASD from ADHD in typically developing children. For example, individuals with ASD may exhibit selective inattention to social stimuli while sustaining focus on idiosyncratic interests or inanimate objects. This type of inattention may be differentiated from the more pervasive inattention and distractibility seen in uncomplicated ADHD. Similarly, hyperactivity seen in ASD can often be manifestations of motor stereotypy, social anxiety, or agitation. In ADHD, however, typically developing children are often impulsive and motorically hyperactive as a result of inhibitory deficits.

The complex neurodevelopmental syndrome of ASD appears to contain a subgroup of affected individuals who display significant inattention, hyperactivity, and impulsivity. Yet, the precise mechanisms and treatment for these symptoms in individuals with ASD remain to be elucidated.

In this issue, Ellen J. Hoffman, MD, offers an important comprehensive review of the clinical features of ASD and of the diagnostic challenges in identifying comorbid conditions such as ADHD. Latha V. Soorya, PhD, and Danielle Halpern, PsyD, review behavioral interventions for this complicated group of patients. Alexander Kolevzon, MD, reviews the pharmacologic treatment of ADHD symptoms in patients with ASD. PP

References

1.    Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
2.    Kanner L. Autistic disturbances of affective contact. Nerv Child. 1943;2:217-250.
3.    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.
4.    Goldstein S, Schwebach AJ. The comorbidity of pervasive developmental disorder and attention deficit hyperactivity disorder: results of a retrospective chart review. J Autism Dev Disord. 2004;34(3):329-339.
5.    Frazier JA, Biederman J, Bellordre CA, et al. Should the diagnosis of attention-deficit/hyperactivity disorder be considered in children with pervasive devlopmental disorder? J Atten Disord. 2001;4(4):203-211.

 

An expert review of clinical challenges in primary care and psychiatry

 

This supplement is supported by Pamlab.

 

Dr. Farah is chief of Psychiatry at High Point Regional Health Systems, High Point NC, and is clinical faculty at Wake Forest University, Winston-Salem NC.

Disclosures: Dr. Farah serves as consultant to and receives honoraria from Pamlab.

 

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.

 

Introduction

Major depressive disorder (MDD) is a debilitating illness affecting 7% to 12% of men and 20% to 25% of women.1,2 It is usually a recurrent illness, with up to 30% of patients experiencing a depressive episode lasting over 2 years.3 Depression may also increase the morbidity and mortality of numerous medical conditions, such as cardiac disease, myocardial infarction, chronic pain, diabetes, cerebrovascular events, and respiratory illnesses.4-11 The goal of antidepressant therapy is to achieve full remission and functional recovery, and continuing treatment beyond the acute phase is usually necessary to maintain remission. In contrast with full remission, individuals who experience residual symptoms, however mild, have a higher chance of experiencing one or more additional episodes.

An initial antidepressant trial is effective at achieving remission for ~30% of patients when prescribed as monotherapy, with the majority of patients returning as either partial or non-responders.12 Switching antidepressants or adding augmentation agents are standard therapeutic options used to achieve and maintain remission. Adequate levels of central nervous system (CNS) folate are likely essential for a patient to fully recover from a depressive episode. Suboptimal serum and red blood cell (RBC) 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.13-20 Lower systemic levels of folate  can result from poor dietary intake, diabetes, various gastrointestinal disorders, hypothyroidism, renal failure, nicotine dependence, alcoholism, and a particular genetic polymorphism prevalent in 50% of the United States population,21,22 and up to 70% of depressed patients.23-26 Folate may also be depleted by numerous medications including oral contraceptives, metformin, as well as first generation anticonvulsants and lamotrigine, which are commonly used in psychiatry.

This article reviews the evidence for L-methylfolate as an augmentation agent in depression and discusses its clinical use elaborated by three clinical presentations. L-methylfolate offers a safe and tolerable alternative to traditional agents, particularly for patients at risk for lower systemic folate levels.

The Need for Improved Treatment Strategies

Depression has been traditionally considered one of the most “treatable” of all illnesses, with authors commonly citing study response rates of 50% to 70%. However, “response” as measured and defined by clinical trials has traditionally meant a reduction in score (usually 50%) on a Hamilton Rating Scale for Depression (HAM-D) or a Montgomery-Åsberg Depression Rating Scale (MADRS). A reduction in score may reflect symptomatic improvement but not full remission. In a long-term study following MDD patients, 76% of subjects who did not attain full remission (HAM-D>7) had relapsed by month 15, while a HAM-D of ≤7 was associated with a far lower likelihood of relapse (25%), by month 15.27 Thus, if recovery is only partial, patients remain at high risk for a relapse, possibly as severe as their initial episode.

Upon follow-up, patients generally fall into three categories: full remission, some response but not full remission (thus “partially responding” to antidepressants), and non-responders (Slide 1). Recent attention to the reality of low remission rates in studies and clinical practice, as well as drop-out rates, highlight the fact that a significant number of patients fail to benefit from advances in depression treatment. It is well documented that many patients discontinue antidepressant therapy due to side effects, the most common being sexual dysfunction and weight gain. Further, a perceived lack of efficacy may often lead to antidepressant discontinuation [unpublished data]. Long-term investigations of MDD patients (>10 years) indicate that depressive symptoms will often persist beyond the initial treatment phase, up to 60% of the time during long-term follow-up. The resultant disability is pervasive and chronic, and even a few depressive symptoms, though below the diagnostic threshold for MDD or even dysthymia, are associated with a significant increase in psychosocial disability compared to months in which the same patients are asymptomatic.28,29

 

 
Achieving and maintaining remission, rather than a reduction in symptom severity, should be the goal of therapy. Clinicians are faced daily with the question of what steps to take in order to achieve a full response for patients on antidepressant therapy. When no response is reported after an adequate time (generally accepted to be at least 4 weeks), and side effects are minimal, increasing the dose is a common strategy. However, if no response is reported but side effects are significant, switching agents would be preferred over dose escalation because most side effects are dose-dependent. For partial and non-responders, augmentation of antidepressants may have several advantages over dose escalation or switching.

Augmentation of Antidepressants

Practitioners currently have many effective options for depressed patients including several Food and Drug Administration approved antidepressants and several effective psychotherapies, the most common being cognitive-behavioral. Because no one treatment is universally effective, and many depressed patients do not experience a satisfactory clinical benefit from the initial treatment they receive, a series of therapies or a combination may be required.  Augmentation/combination has been generally defined as the addition of one or more agents to existing antidepressant therapy to enhance recovery and speed response. Traditional agents have included lithium, thyroid hormone (T3), buspirone, bupropion, stimulants, pindolol, and in recent years, atypical antipsychotics, and modafinil. Currently, aripiprozole is the only drug FDA-approved for adjuvant therapy in depression.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was a longitudinal, multi-center, 5-year study of common strategies for treating depression. To date, it is the United States’ largest National Institute of Mental Health funded study including over 4,000 patients. This four level trial compared traditional augmentation strategies with switching agents (Slide 2).30-34 Unlike most depression studies, in STAR*D the outcome measure was full remission. 

 

 

 
In Level 1, the initial monotherapy phase, citalopram (mean dose of 41.8 mg) was effective at achieving remission for only ~30% of subjects. This finding has been accepted as an accurate reflection of clinical experience with any initial monotherapy. The remaining 70% were randomized to either receive bupropion or buspirone augmentation, or switched to one of three antidepressants as monotherapy—bupropion, venlafaxine, or sertraline. Augmentation resulted in a 30% response, while switching antidepressants resulted in ~20% of patients achieving remission. Level 3 included those non-remitters from Level 2 who were then randomized to either T3 or lithium augmentation, resulting in remission rates of 25% and 16% respectively. A Level 3 switch to nortriptyline (NTP) or mirtazapine (MTZ) was in general less successful than Level 3 augmentation, with 20% of NTP patients and 12% of MTZ patients remitting. Level 4 treatment options (monoamine oxidase inhibitors [MAOIs] or venlafaxine–mirtazapine-combination therapy) were provided to patients who had not responded satisfactorily to previous levels of the treatment protocol, and very few experienced full remission (14% and 7% respectively).12,35

An overall analysis of STAR*D results indicates that the chances of achieving and maintaining remission in patients with difficult-to-treat depression diminishes with every additional strategy needed.  Those who fully remit early in the course of treatment have a better chance of remaining well than those who experience only symptomatic improvement. STAR*D does not tell us which treatment works better as a first or second adjunct, simply that the greatest chance of recovery appears to lie with the first two sequential treatments.

While there are advantages to switching antidepressants in some cases, augmentation has several advantages over switching antidepressants as well. It eliminates the need to taper some medications that pose a risk of withdrawal, and augmentation may allow the patient to build on the partial response already achieved rather than risk losing that response, which can occur when switching the primary agent to a newer choice. Further, some augmentation agents can often ameliorate the side effects of primary agents (such as sexual side effects) or have other benefits (eg, lower anxiety or help with insomnia). Clinicians must also be aware that potential benefits of augmentation may be countered by issues arising from polypharmacy, such as higher costs to patients and a greater potential for side effects and possible drug interactions. 

Association of Low Folate with Depression

Since the early 1960s, reports have shown a correlation between low folate levels and MDD. Since these initial findings, community studies have strengthened the association between low folate and depressive illnesses.36 Whether measuring serum, plasma, or RBC folate, patients diagnosed with MDD have been shown to have significantly lower folate levels when compared to non-depressed controls. RBC folate levels will generally reflect CNS folate levels,37 and have been demonstrated to be low in as many as 56% of depressed patients.19,38 Folate deficiency has also been linked to courses of depressions that are more severe, longer in duration, and treatment resistant.20,39-47 Suboptimal folate may also predict non-responders and partial responders, as patients with low RBC folate are 6 times more likely not to respond to antidepressant therapy and are less likely to achieve and maintain remission.15,48 The connection between folate and MDD is believed to be L-methylfolate, a necessary cofactor in the synthesis of monoamine neurotransmitters. Thus, a deficiency may result in inadequate CNS synthesis of serotonin, norepinephrine, and dopamine.49

Folate and L-methylfolate

Folate is a water soluble B vitamin (B9), considered one of the 13 essential vitamins. The primary function of folate is the transfer of methyl and formyl groups, thus, it is essential for cell growth and reproduction, the breakdown and utilization of proteins, the formation of nucleic acids, red blood cell maturation, and a variety of CNS reactions. Dihydrofolate is the dietary form found in orange juice, spinach, asparagus, beans, liver, yeast, whole grain cereals, and eggs. Folic acid is the synthetic form of folate in over-the-counter vitamins and used to fortify the food supply (to help prevent neural tube defects, the FDA mandated folic acid fortification of flour in 1998). Folic acid is also the predominant form used in prescription strength prenatal vitamins. Both folic acid and dihydrofolate are not biologically active forms of folate, but are essentially pro-drugs, and must undergo enzymatic transformation to L-methylfolate in order to be used by cells, and unlike other forms of folate, L-methylfolate readily crosses the blood-brain barrier for use in the CNS.

Almost 85% of dietary folate and nearly all supplemental folic acid is absorbed into the venous system in the proximal small intestine. The enzymatic conversion begins in the intestinal wall—it is a three step process for dihydrofolate, and a four step process for folic acid (Slide 3). Folic acid is converted to dihydrofolate (DHF) by dihydrofolate reductase enzyme (DHFR), and DHF is then converted to tetrahydrofolate (THF). The conversion of THF to 5,10-methyleneTHF follows. Finally, the conversion of 5,10-methyleneTHF to L-methylfolate is achieved by the methyltetrahydrofolate reductase enzyme (MTHFR). This last step completes the four step transformation process by which the bioactive cofactor, L-methylfolate, is made available to the brain to be used in the synthesis of monoamine neurotransmitters associated with mood regulation (serotonin, norepinephrine, and dopamine).50

 

 

 
For many, dietary folate will result in adequate delivery of L-methylfolate to the brain, however, inhibition of any of the above enzymes, or having defective, less functional forms of enzymes could result in inadequate CNS L-methylfolate levels. There are over 40 identified mutations of the MTHFR gene that codes for the enzyme responsible for the last step in the conversion of folate to L-methylfolate,51 but the three main genotypes are of particular interest. The most common genotype is the C/C which codes for a normally functioning enzyme. The C/T and T/T polymorphisms are less functional forms that result in suboptimal amounts of L-methylfolate. This variant is known as C677T polymorphism.

C677T polymorphism is characterized by a mutation at position 677 of the MTHFR gene resulting in a single amino acid substitution, rendering the MTHFR enzyme thermolabile, thus significantly reducing its activity (Slide 4).52 Numerous studies indicate an association between the C677T polymorphism and depression.52-60 In one study, 70% of depressed individuals were positive for either the heterozygous or homozygous from of the C677T polymorphism (14% T/T, 56% C/T). The C/T, or heterozygous polymorphism reduces the MTHFR activity by 35%, while for the homozygous, T/T form, enzyme activity is decreased by more than 70%. Thus depressed patients may be at significant risk for inadequate levels of CNS L-methylfolate, and thus, lower synthesis of serotonin, norepinephrine, and dopamine.26,52-58

 

 

The Evidence for L-methylfolate in Depression

There are five trials that examine folate therapy in depressive disorders. In a study59 with patients who had low or borderline low RBC folate, depressed patients on tricyclic antidepressants or MAOIs were augmented with methylfolate 15 mg (L-methylfolate 7.5 mg) experienced significantly greater clinical improvement and social improvement at 3 months (P<.02) and 6 months (P<.01) compared to patients treated with antidepressants alone. The methylfolate-augmented patients continued to improve for 6 months compared to patients augmented with placebo, and none experienced relapse. In a separate double-blind, controlled trial60 comparing methylfolate 50 mg/day  to trazodone 100 mg/day, depressed patients experienced a significant decrease in HAM-D scores at 4 and 8 weeks in both groups, with response rates in the methylfolate group at 45%, and in the trazodone group (not statistically significant) at 29%.

An open label trial61 of methylfolate as monotherapy in elderly depressed subjects demonstrated an 81% response rate (>50% reduction in HAM-D) by 6 weeks of therapy. A second monotherapy study examined a depressed population of 36 chronic alcoholics. After a week of placebo wash-out, subjects received 4 weeks of 90 mg methylfolate therapy. This dosing (30 mg TID) significantly improved depressive symptoms based on the HAM-D scale with the majority reporting improved mood and less fatigue (P<.01).62 Alpert and colleagues63 conducted an open label trial augmenting selective serotonin reuptake inhibitor (SSRIs) with folinic acid in patients who had failed at least 4 weeks of SSRI therapy. The response to folinic acid was not robust (P<.01, n=22), but it was well tolerated overall.

Clinical Presentations

Clinical Presentation # 1

EF is a 62-year-old female with Parkinson’s disease who was taking ropinirole when she presented with significant depressive symptoms. She had failed to respond to citalopram 20 mg/day at 5 weeks, and due to past weight gain and excessive anxiety while taking serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitors she requested no dose escalations. Symptoms included dysphoria, poor concentration, short term memory deficits, fatigue, hypersomnia, and irritability. Mindful of her request to maintain the current SRI dose, L-methylfolate was started at 7.5 mg/day. By week 4 she reported a resolution in most of her symptoms, but still had residual fatigue and felt her concentration was not baseline. L-methylfolate was doubled to 7.5 mg BID, and within 2 weeks she was in remission. L-methylfolate augmentation was well tolerated and EF remains well after 9 months of therapy.

Clinical Presentation #2

JL is a 28-year-old female who presented with severe depression of rapid postpartum onset. Symptoms included crying spells, guilty ruminations, poor memory and concentration, insomnia, fatigue, and intrusive thoughts of harming her infant. She had failed to fully respond to sertraline 150 mg/day for 4 weeks, and L-methylfolate was added, as well as lorazepam PRN. After 3 weeks of combination therapy, she had achieved remission (HAM-D of 5), and reported no further intrusive thoughts. She remains stable and euthymic at 7 months of sertraline 150 mg/day and L-methylfolate 7.5 mg/day therapy. She continues breast feeding while on these agents.

Clinical Presentation # 3

BR is a 54-year-old male who met the Diagnostic and Statistical Manual, Fourth Edition, criteria for MDD, severe without psychosis, and was suffering from fatigue, insomnia, excessive anxiety and ruminations, and suicidal thoughts. He reported stress at work and recently had placed his mother in a nursing home due to rapidly progressing dementia. He was already on escitalopram 10 mg/day without benefit. After 5 weeks, his dose was escalated to 20 mg/day, and clonazepam 1 mg TID PRN was added. He was on this new regimen for three weeks when he presented to our clinic with only modest improvement in symptoms. He reported sedation when he took clonazepam. The dose of his benzodiazepine was cut in half, and L-methylfolate was added at 7.5 mg/day. At day 10 he phoned to report he was nearly baseline, and by day 14 was euthymic. He remains stable at 10 weeks of therapy reporting no additional side effects with L-methylfolate augmentation.

Specific Populations that May Benefit

Depressed patients are known to be at risk for C677T polymorphism, which translates into lower serum levels of L-methylfolate64 and possibly lower CNS folate, and thus lower monoamine levels. Specific ethnic groups are at higher risk for the less functional forms of MTHFR. The T/T genotype is present in as many as 10% of whites, and up to 22% of samples of Hispanic or Mediterranean populations.26,54 Several other groups are also at risk for lower L-methylfolate levels, including substance abusers, smokers, and those with gastrointestinal disorders (Slide 5).   

 

Medications that are known to reduce folate levels include all first-generation anticonvulsants (phenytoin, valproic acid products, carbamazepine, primidone, and phenobarbital) and the second-generation anticonvulsant lamotrigine, which is a specific inhibitor of dihydrofolate reductase (DHFR) (Slide 6). DHFR activity is the first step necessary for the conversion of dietary folate or supplemental folic acid to L-methylfolate. Other second-generation anticonvulsants are not known to be folate depleting (though information is limited, and this cannot be ruled out). This may explain why traditional mood stabilizers have had less success at preventing or treating depression and perhaps why the antidepressant effects of lamotrigine can be lost with continued therapy over a period of weeks to months and dose escalation is not usually helpful. Other medications associated with folate depletion include oral contraceptives, acne medicine, metformin, lithium, dopaminergic medications for Parkinson’s disease and methotrexate, which, like lamotrigine, is a specific inhibitor of DHFR.

 

 

 

Mechanism of Action and Clinical Use of L-methylfolate

There are numerous CNS roles for L-methylfolate, and those affecting neurotransmitter production are believed to be critical to its antidepressant properties. L-methylfolate is thought to exert its action by enhancing synthesis of monoamine neurotransmitters, and has been categorized as a “trimonoamine modulator” because it is necessary for serotonin, dopamine, and norepinephrine synthesis.50 

Depression is well known to involve dysregulation of one or more monoamines—­serotonin (5-HT), norepinephrine (NE), and dopamine (DA). L-methylfolate  acts as an important regulator of a critical cofactor needed for neurotransmitter synthesis. The cofactor is known as tetrahydrobiopterin (BH4). L-methyloflate combines with BH2 utilizing MTHFR to synthesize BH4. The trimonoamine synthetic enzymes that require BH4 as a cofactor are tryptophanhydroxylase, the rate-limiting enzyme for 5-HT synthesis, and tyrosine hydroxylase, the rate-limiting enzyme for DA and NE synthesis (Slide 7).49,50

 

 
Another mechanism of antidepressant activity of L-methylfolate is its role in the homocysteine cycle. High CNS homocysteine levels are associated with depression, dementia, and stroke,65 as well as negative symptoms of schizophrenia.66 Homocysteine is transformed to methionine utilizing B12 and L-methylfolate, both necessary cofactors for this transformation. Methionine is then converted to s-adenyl-methionine, which serves as the methyl donor for all three monoamines—serotonin, norepinephrine, and dopamine. Thus, patients with low CNS L-methylfolate are less able to convert homocysteine to methionine, the first necessary step of the homocysteine cycle.65

Unlike antidepressants, which block the re-uptake of neurotransmitters in short supply, L-methylfolate allows necessary methyl donation for adequate formation of trimonoamines.  Results are often seen within 2 weeks, sometimes even remission. As is common with other traditional augmentation strategies, some form of early response is encouraging. Drop-out rates due to side effects are consistently similar to placebo.59-62

Safety of L-Methylfolate

The standard dose of L-methylfolate for the augmentation of antidepressants is one 7.5 mg tablet/day. No titration is necessary, and it is not associated with withdrawal symptoms at discontinuation. The maximum amount of L-methylfolate that can be absorbed in one dose is ~15 mg.67 If more than one 7.5 mg tablet/day is needed, it may be prudent to give in divided doses. All reported adverse events occur at placebo rates or lower, and overall it is an extremely well tolerated agent, allowing patients to continue L-methylfolate therapy as long as necessary to maintain remission.  There are no known contraindications and no known drug interactions. 

L-methylfolate is available by prescription and is regulated by the FDA as a prescription medical food for the specific nutritional requirements of depressed individuals with suboptimal serum, RBC, or CNS folate. It is specifically intended as adjunctive therapy for depressed patients who have only partially responded to antidepressant therapy. However, L-methylfolate may provide benefit to patients with or without serum or RBC folate deficiency, particularly if they are at risk for low neurotransmitter production. 

Placement Among Augmentation Agents

Adding an additional therapy to augment an antidepressant effect usually carries the concern of adding additional side effects or potential drug interactions.  Although buproprion and buspirone are considered well tolerated, discontinuation due to side effects in the STAR*D trial ranged from 13% to 21%. Response rates to these therapies in STAR*D approximated 30% when added to existing antidepressant therapy, and discontinuation rates were ~15%.12 The recent trend of adding antipsychotics as augmenters is worrisome as it assumes that all newer agents (those launched after clozapine) qualify as “atypical,” and this assumption has recently been challenged in the literature.68 The importance of this debate is underscored by the fact that patients with affective disorders are at higher risk for tardive dyskinesia (TD). Thus, when giving antipsychotic medications to non-psychotic individuals, one must not only consider weight and metabolic concerns, but also risks of extrapyramidal symptoms, akathisia, and TD.

There have been recent concerns about the safety of very high levels of circulating unmetabolized synthetic folic acid.69 In one study, high amounts of unmetabolized folate did lower the effectiveness of natural killer cells in postmenopausal women, yet other forms of folate, such as L-methylfolate have not been associated with such risks. High dose folic acid has been associated with toxic effects in healthy subjects70 and an increase in depressive symptoms in some studies.71

There have been eight folate studies (including all forms of folate) published thus far that evaluate the use of folate in depression,44,45,48,59-62,72 and though various forms have been used, L-methylfolate appears to be the optimal compound for augmentation, as it is the active form utilized by the CNS, and readily crosses the blood-brain barrier. It is a necessary cofactor for the synthesis of monoamine neurotransmitters. Many depressed patients are at risk for low levels of CNS folate due to lifestyle, medications, and genetics, but even those with normal CNS folate may benefit from L-methylfolate augmentation. There are no known drug interactions and no case reports to date of mania induction. L-methylfolate is a well tolerated agent which stands out as one of the safest of available augmentation options. 

References

1.  Depression Guideline Panel. Clinical Practice Guideline Number 5: Depression in Primary Care Volume 1: Detection and Diagnosis. Rockville, Md: HHS; 1993. AHCR publication 93-0550.
2.  Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
3.  Keller MB, Boland RJ. Implications of failing to achieve successful long-term maintenance treatment of recurrent unipolar major depression. Biol Psychiatry. 1998;44(5):348-360.
4.  Carney RM, Saunders RD, Freedland KE, et al. Association of depression with reduced heart rate variability in coronary artery disease. Am J Cardiol. 1995;76(8):562-564
5.  Stein PK, Carney RM, Freedland KE, et al. Severe depression is associated with markedly reduced heart rate variability in patients with stable coronary heart disease. J Psychosom Res. 2000;48(4-5):493-500.
6.  Penninx BW, Beekman AT, Honig A, et al. Depression and cardiac mortality: results from a community-based longitudinal study. Arch Gen Psychiatry. 2001;58(3):221-227.
7.  Frasure-Smith N, Lésperance F, Talajic M. Depression following myocardial infarction: impact on 6-month survival. JAMA. 1993;270(15):1819-1825.
8.  Bush DE, Ziegelstein RC, Tayback M, et al. Even minimal symptoms of depression increase mortality risk after acute myocardial infarction. Am J Cardiol. 2001;88(4):337-341.
9.  Lésperance F, Frasure-Smith N, Talajic M, Bourassa MG. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation. 2002;105(9):1049-1053.
10. Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of pain? a review. Clin J Pain. 1997;13(2)116-137.
11. Egede LE, Zheng D, Simpson K. Comorbid depression is associated with increased health care use and expenditures in individuals with diabetes. Diabetes Care. 2002;25(3):464-470.
12. Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the Sequenced treatment alternatives to relieve depression (STAR*D) study. Psych Clin North Amer. 2003;26(2):457-494.
13. Alpert M, Silva RR, Pouget ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J Clin Psychopharmacol. 2003;23(3):309-313.
14. Bottigleri T. Homocysteine and folate metabolism in depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29(7):1103-1112
15. Papakostas GI, Iosifescu DV, Renshaw PF, et al. Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part II). Psychiatry Res. 2005;140(3):301-307.   
16. Levitt AJ, Joffe RT. Folate, B12, and life course of depressive illness. Biol Psychiatry. 1989;25(7):867-872.
17. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145-149.   
18. Wesson VA, Levitt AJ, Joffe RT. Change in folate status with antidepressant treatment. Psychiatry Res. 1994;53(3):313-122.
19. Coppen A, Bolander-Gouaille C. Treatment of depression: time to consider folic acid and vitamin B12. J Psychopharmacol. 2005;19(1):59-65.   
20. Abou-Saleh MT, Coppen A. Serum and red blood cell folate in depression. Acta Psychiatr Scand. 1989;80(1):78-82.
21. Botto LD, Yang Q. 5,10-methylenetetrahydofolate reductase gene variants and congenital anomalies: a HuGE review. Am J Epidemiol. 2000;151(9):862-877.
22. Bailey LB, Gregory JF 3rd. Polymorphisms of MTHFR and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr. 1999;129(5):919-922.
23. Bjelland I, Tell GS, Vollset SE, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
24. Arinami T, Yamada N, Yamakawa-Kobayashi K, et al. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;74(5):526-528.
25. Procopciuc LM, Jebeleanu GH, Fodoreanu L, Crisan C, et al. C677T MTHFR Polymorphism and Psychiatric Diseases Schizophrenia-like Psychosis and Depression in Romanian Patients.  In: 60th Annual Meeting of the Society of Biological Psychiatry. May 19-21, 2005, Atlanta, Georgia. Poster P86.
26. Kelly CB, McDonnell AP, Johnston TG, et al. The MTHFR C677T polymorphism is associated with depressive episodes in patients from Northern Ireland. J Psychopharmacol. 2004;18(4):567-571.
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31. 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(11):1905-1917.
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33. Trivedi MH, Fava M, Marangell LB, et al. Use of treatment algorithms for depression. J Clin Psychiatry. 2006;67(9):1458-1465.
34. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243-1252.
35. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28-40.
36. Morris MS, Fava M, Jacques PF, et al. Depression and folate status in the US Population. Psychother Psychosom. 2003;72(2):80-87.
37. Obeid R, Kostopoulos P, Knapp JP, et al. Biomarkers of folate and vitamin B12 are related in blood and cerebrospinal fluid. Clin Chem. 2007;53(2):326-333.
38. Alpert JE, Fava M. Nutrition and depression: the role of folate. Nutr Rev. 1997;55(5):145-149.   
39. Coppen A, Swade C, Jones SA, et al. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989;16(2-3):103-107
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41. Papakostas, GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psych. 2004;65:1090-1095.
42. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy. J Clin Psych. 2004;65:1096-1098.
43. Gilbody S, Lewis S, Lightfoot T. Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphism and psychiatric disorders: a HuGE review. Am J Epidemiology. 2007;165:1-13.
44. Coppen A, Bailey J. Enhancement of the antidepressant action of fluoxetine by folic acid: a ramdomised placebo controlled trial. J Affect Disord. 2000;60:121-130.
45. Coppen A, Chaudhry C, Swade C. Folic acid enhances lithium prophylaxis. J Affect Disord. 1986;10:9-13.
46. Carney NW, Chary TK, Laundy M, et al. Red cell folate concentrations in psychiatric patients. J Affect Disord. 1990;19:207-213
47. Reynolds EH, Preece JM, Bailey J, Coppen A. Folate deficiency in depressive illness. Br J Psychiatry. 1970;117:287-292.
48. Alpert M, Silva RR, Pouget ER. Prediction of treatment response in geriatric depression from baseline folate level: interaction with an SSRI or a tricyclic antidepressant. J Clin Psychopharmacology. 2003;23(3):309-13.
49. Stahl SM. Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. 3rd ed. New York: Cambridge University Press; 2008:625-632
50. Stahl SM. Novel therapies for depression: l-methylfolate as a trimonoamine modulator and antidepressant agent. CNS Spectr. 2007;12;739-744.
51. Bolander-Gouaille C, Bottiglieri T. Clinical impact of enzyme defects. Homocysteine Related Vitamins and Neuropsychiatric Disorders. New York, NY; Springer: 2004;151-162.
52. Tan EC, Chong SA, Lim LC, et al. Genetic analysis of thermolabile methylenetertrahydrofoalte  reductase variant in schizophrenia and mood disorders. Psychiatr Genet. 2004;14:227-231.
53. Bjelland I, Tell GS, Vollset SE, et al. Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry. 2003;60(6):618-626.
54. Arinami T, Yamada N, Yamakawa-Kobayashi K, et al. Methylenetetrahydrofolate reductase variant and schizophrenia/depression. Am J Med Genet. 1997;74:526-528.
55. Hickie I, Scott E, Naismith S, et al. Late-onset depression: genetic vascular and clinical contributions. Psychol Med. 2001:31;1403-1412.
56. Kunugi H, Fukuda R, Hattori M, et al. C677T polymorphism in methylenetetrahydrofolate reductase gene and psychosis variant. Mol Psychiatry. 1998;3:435-437.
57. Reif A, Pfuhlmann B, Lesch KP.  Homocysteine as well as methylenetertrahydrofoalte reductase polymorphism are associated with affective psychosis. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:1162-1168.
58. Zintzaras E. C677T and A1298C methylenetertrahydrofoalte reductase gene  polymorphism in schizophrenia, bipolar disorder and depression: a meta-anylsis of genetic association studies. Psych Genet. 20067;16:105-115.
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60. 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(1):63-71.
61. 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.
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63. Alpert JE, Mischoulon D, Rubenstein GE, et al. Folinic acid as an adjunctive treatment for SSRI-refractory depression. Ann Clin Psych 2002:14:33-38.
64. Yang QH, Botto LD, Gallagher M, et al. Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the US: findings from the third national health and nutrition examination survey DNA bank. Am J Clin Nutr. 2008;88(1):232-246.
65. Folstein M, Liu T, Peter I, et al. The homocysteine hypothesis of depression. Am J Psychiatry. 2007;164(6):861-867.
66. Roffman JL, Weiss AP, Purcell S, et al. Contribution of methylenetertrahydrofoalte reductase (MTHFR) polymorphism to negative symptoms in schizophrenia. Biol Psychiatry. 2008;63:42-48.
67. Deplin [package insert]. Covington, LA: Pamlab; 2008.
68. Farah A. Atypicality of atypical antipsychotics. Prim Care Companion J Clin Psychiatry. 2005;7:268-274.
69. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006;136:189-194.
70. Hunter  R, Barnes J. Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet. 1(7637):61-63.
71. Aisen PS, Schneider LS, Sano M, et al. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008;300(15):1774-1783.
72. Resler G, Lavie R, Campos J, et al.  Effect of folic acid combined with fluoxetine in patients with major depression on plasma homocysteine and vitamin B12, and serotonin levels in lymphocytes. Neuroimmunomodulation. 2008;15(3):145-152.

 

 

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

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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

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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.
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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.
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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

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