Search This Blog

468x60.

728x90

 


Mohandas E, Rajmohan V. Lithium use in special population. Indian J Psychiatry. 2007;49:211–218.

Kleiner J et al. Lithium-induced subclinical hypothyroidism: review of the literature and guidelines for treatment.

J Clin Psychiatry. 1999;60:249.

Zhang ZJ et al. Differences in hypothyroidism between lithium-free and lithium-treated patients with bipolar

disorders. Life Sci. 2006;78:771.

Livingstone C, Rampes H. Lithium: a review of its metabolic adverse effects. J Psychopharmacol. 2006;20:347.

Ernst CL, Goldberg JF. The reproductive safety profile of mood stabilizers, atypical antipsychotics, and

broadspectrum psychotropics. J Clin Psychiatry. 2002;63(Suppl 4):42.

Jain AE, Lacy T. Psychotropic drugs in pregnancy and lactation. J Psychiatr Pract. 2005;11:177.

Cohen LS et al. A reevaluation of risk of in utero exposure to lithium. JAMA. 1994;271:146.

Troyer WA et al. Association of maternal lithium exposure and premature delivery. J Perinatol. 1993;13:123.

Ward S, Wisner KL. Collaborative management of women with bipolar disorder during pregnancy and

postpartum: pharmacologic considerations. J Midwifery Womens Health. 2007;52:3.

Cunnington MC et al. Final results from 18 years of the international lamotrigine pregnancy registry. Neurology.

2011;76(21):1817–1823.

Newport DJ et al. Atypical antipsychotic administration during late pregnancy: placental passage and obstetrical

outcomes. Am J Psychiatry. 2007;164:1214.

Perlis RH et al. Atypical antipsychotics in the treatment of mania: a meta-analysis of randomized, placebocontrolled trials. J Clin Psychiatry. 2006;67:509.

Scherk H et al. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and

metaanalysis of randomized controlled trials. Arch Gen Psychiatry. 2007;64:442.

Smith LA et al. Acute bipolar mania:systematic review and meta-analysis of co-therapy vs. monotherapy. Acta

Psychiatr Scand. 2007;115:12.

Cipriani A et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments

meta-analysis. Lancet. 2011;378:1306–1315.

Correll CU et al. Antipsychotic and mood stabilizer efficacy and tolerability in pediatric and adult patients with

bipolar I mania: a comparative analysis of acute, randomized, placebo-controlled trials. Bipolar Disord.

2010;12:116–141.

American Diabetes Association et al. Consensus development conference on antipsychotic drugs and obesity

and diabetes. Diabetes Care. 2004;27:596.

Banov MD et al. Clozapine therapy in refractory affective disorders: polarity predicts response in long-term

follow-up. J Clin Psychiatry. 1994;55:295.

Calabrese JR et al. Clozapine for treatment—refractory mania. Am J Psychiatry. 1996;153:759.

Suppes T et al. Clinical outcome in a randomized 1-year trial of clozapine versus treatment as usual for patients

with treatment-resistant illness and a history of mania. Am J Psychiatry. 1999;156:1164.

Mclntyre RS, Konarski JZ. Tolerability profiles of atypical antipsychotics in the treatment of bipolar disorder. J

Clin Psychiatry. 2005;66(Suppl 3):28.

Sachs G et al. Aripiprazole in the treatment of acute manic or mixed episodes inpatients with bipolar I disorder: a

.

.

.

.

.

.

.

.

.

.

.

.

143.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

3-week placebo-controlled study. J Psychopharmacol. 2006;20:536.

Keck PE, Jr et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole inpatients

with acute bipolar mania. Am J Psychiatry. 2003;160:1651.

Sachs GS et al. Cariprazine in the treatment of acute mania in bipolar I disorder: a double-blind, placebocontrolled, phase III trial. J Affect Disord. 2015;174:296–302.

Saphris (asenapine) [package insert]. Whitehouse Station, NJ: Merck & Company; December 2014.

Stahl SM, Shayegan DK. The psychopharmacology of ziprasidone: receptor-binding properties and real-world

psychiatric practice. J Clin Psychiatry. 2003;64(Suppl 19):6.

Lieberman JA et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia [published

correction appears in N EnglJ Med. 2010;363:1092]. N EnglJ Med. 2005;353:1209.

Post RM et al. Thirty years of clinical experience with carbamazepine in the treatment of bipolar illness:

principles and practice. CNS Drugs. 2007;21:47.

Ceron-Litvoc D et al. Comparison of carbamazepine and lithium in treatment of bipolar disorder: a systematic

review of randomized controlled trials. Hum Psychopharmcol. 2009;24:19–28.

Pratoomsri W et al. Oxcarbazepine in the treatment of bipolar disorder: a review. Can J Psychiatry.

2006;51:540.

Vasudev A et al. Oxcarbazepine for acute affective episodes in bipolar disorder. Cochrane Database Syst Rev.

2011;12:CD004857.

Vasudev A et al. Oxcarbazepine in the maintenance treatment of bipolar disorder. Cochran Database Sys Rev.

2008;23(1):CD005171.

Rosa AR et al. Is anticonvulsant treatment of mania a class effect? Data from randomized clinical trials? CNS

Neurosci Ther. 2011;17:167–177.

Young TL et al. Gabapentin as an adjunctive treatment in bipolar disorder. J Affect Disord. 1999;55:73.

Schaffer CB, Schaffer LC. Gabapentin in the treatment of bipolar disorder. Am J Psychiatry. 1997;154:291.

Ghaemi SN et al. Gabapentin treatment of mood disorders: a preliminary study. J Clin Psychiatry. 1998;59:426.

Pande AC et al. Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disord.

2000;2(3, pt 2):249.

Chengappa KN et al. The evolving role of topiramate among other mood stabilizers in the management of bipolar

disorder. Bipolar Disord. 2001;3:215.

Kushner SF et al. Topiramate monotherapy in the management of acute mania: results of four double-blind

placebo-controlled trials. Bipolar Disord. 2006;8:15.

Wolfsperger M et al. Pharmacological treatment of acute mania in psychiatric in-patients between 1994 and

2004. J Affect Disord. 2007;99:9.

Allen MH et al. What do consumers say they want and need during a psychiatric emergency? J Psychiatr Pract.

2003;9:39.

Currier GW, Medori R. Orally versus intramuscular administered antipsychotic drugs in psychiatric emergencies.

J Psychiatr Pract. 2006;12:30.

Lesem MD et al. Intramuscular ziprasidone, 2 mg versus 10 mg, in the short-term management of agitated

psychotic patients [published correction appears in J Clin Psychiatry. 2001;62:209]. J Clin Psychiatry.

2001;62:12.

Daniel DG et al. Intramuscular (IM) ziprasidone 20 mg is effective in reducing acute agitation associated with

psychosis: a double-blind, randomized trial. Psychopharmacology (Berl). 2001;155:128.

Zimbroff DL et al. Management of acute agitation in patients with bipolar disorder: efficacy and safety of

intramuscular aripiprazole. J Clin Psychopharmacol. 2007;27:171.

Meehan K et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of

olanzapine, lorazepam, or placebo in treatment of acutely agitated patients diagnosed with bipolar mania. J Clin

Psychopharmacol. 2001;21:389.

Battaglia J et al. Haloperidol, lorazepam, or both for psychotic agitation? A multicenter, prospective, double-blind,

emergency department study. Am J Emerg Med. 1997;15:335.

Zyprexa [package insert]. Indianapolis, IN: Eli Lilly & Co; 2014.

Allen MH et al. The expert consensus guideline series. Treatment of behavioral emergencies 2005. J Psychiatr

Pract. 2005;11(Suppl 1):5.

Baldessarini RJ et al. Bipolar depression: overview and commentary. Harv Rev Psychiatry. 2010;18:143.

Tondo L et al. Suicidal risks among 2826 Sardinian major affective disorder patients. Acta Psychiatr Scand.

2007;116:419.

.

.

.

.

.

.

.

.

.

.

170.

171.

.

.

.

.

.

177.

.

.

.

.

.

.

.

.

.

Malhi GS et al. Medicating mood with maintenance in mind: bipolar depression pharmacotherapy. Bipolar

Disord. 2009;11(Suppl 2):55.

Yatham LN et al. Bipolar depression: criteria for treatment selection, definition of refractoriness, and treatment

options. Bipolar Disord. 2003;5:85.

Tondo L et al. Long-term clinical effectiveness of lithium maintenance treatment in types I and II bipolar

disorders. Br J Psychiatry Suppl. 2001;41:s184.

Geddes JR et al. Long-term lithium therapy for bipolar disorder: systematic review and meta-analysis of

randomized controlled trials. Am J Psychiatry. 2004;161:217.

Cipriani A et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood

disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805.

Calabrese JR et al. Lamotrigine in the acute treatment of bipolar depression: results of five double-blind,

placebo-controlled clinical trials. Bipolar Disord. 2008;10:323.

Geddes JR et al. Lamotrigine for treatment of bipolar depression: independent meta-analysis and metaregression of individual patient data from five randomised trials. Br J Psychiatry. 2009;194:4.

Goodwin GM et al. A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium

maintenance in bipolar I disorder. J Clin Psychiatry. 2004;65:432.

van der Loos ML et al. Efficacy and safety of lamotrigine as add-on treatment to lithium in bipolar depression: a

multicenter, double-blind, placebo-controlled trial. J Clin Psychiatry. 2009;70:223.

Calabrese JR et al. A randomized, double-blind, placebo controlled trial of quetiapine in the treatment of bipolar I

or II depression. Am J Psychiatry. 2005;162:1351.

Thase ME et al. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebocontrolled study (the BOLDER II study) [published correction appears in J Clin Psychopharmacol. 2007;27:51].

J Clin Psychopharmacol. 2006;26:600.

McElroy SL et al. A double-blind, placebo-controlled study of quetiapine and paroxetine as monotherapy in

adults with bipolar depression (EMBOLDEN II). J Clin Psychiatry. 2010;71:163.

Young AH et al. A double-blind, placebo-controlled study of quetiapine and lithium monotherapy in adults in the

acute phase of bipolar depression (EMBOLDEN I). J Clin Psychiatry. 2010;71:150.

Tohen M et al. Efficacy of olanzapine and olanzapine-fluoxetine combination in the treatment of bipolar I

depression [published correction appears in Arch Gen Psychiatry. 2004;61:176]. Arch Gen Psychiatry.

2003;60:1079.

Brown EB et al. A 7-week, randomized, double-blind trial of olanzapine/fluoxetine combination versus

lamotrigine in the treatment of bipolar I depression. J Clin Psychiatry. 2006;67:1025.

Brown E et al. Olanzapine/fluoxetine combination vs. lamotrigine in the 6-month treatment of bipolar I

depression. Int J Neuropsychopharmacol. 2009;12:773.

Loebel A et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind,

placebo-controlled study. Am J Psychiatry. 2014;171:170–168.

Loebel A et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I

depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2):169–177.

Findlay LJ et al. Management of bipolar I depression: clinical utility of lurasidone. Ther Clin Risk Manag.

2015;11:75–81.

Thase ME et al. Aripiprazole monotherapy in nonpsychotic bipolar I depression: results of 2 randomized,

placebo-controlled studies [published correction appears in J Clin Psychopharmacol. 2009;29:38]. J Clin

Psychopharmacol. 2008;28:13.

Sachs GS et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med.

2007;356:1711.

Lamictal (lamotrigine) [package insert]. Research Triangle Park, NC. GlaxoSmithKline; October 2010.

Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review

and meta-analysis. J Clin Psychiatry. 2011;72:156.

Gelenberg AJ et al. Comparison of standard and low serum levels of lithium for maintenance treatment of

bipolar disorder. N EnglJ Med. 1989;321:1489.

Bowden CL et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in treatment of

outpatients withbipolar I disorder. Divalproex Maintenance Study Group. Arch Gen Psychiatry. 2000;57:481.

Vieta E et al. Effectiveness of psychotropic medications in the maintenance phase of bipolar disorder: a metaanalysis of randomized controlled trials. Int J Neuropsychopharmacol. 2011;14:1029–1049.

Miklowitz DJ et al. Intensive psychosocial intervention enhances functioning in patients with bipolar depression:

.

.

.

.

.

.

.

.

.

.

197.

.

results from a 9-month randomized controlled trial. Am J Psychiatry. 2007;164:1340.

Kilbourne AM et al. Nutrition and exercise behavior among patients with bipolar disorder. Bipolar Disord.

2007;9:443.

Freeman MP et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry

[published correction appears in J Clin Psychiatry. 2007;68:338]. J Clin Psychiatry. 2006;67:1954.

Nierenberg AA et al. Treatment-resistant bipolar depression: a STEP-BD equipoise randomized effectiveness

trial of antidepressant augmentation with lamotrigine, inositol, or risperidone. Am J Psychiatry. 2006;163:210.

Bailine S et al. Electroconvulsive therapy is equally effective in unipolar and bipolar depression. Acta Psychiatr

Scand. 2010;121:431.

Mukherjee S et al. Electroconvulsive therapy of acute manic episodes: a review of 50 years’ experience. Am J

Psychiatry. 1994;151:169.

Meeter M et al. Retrograde amnesia after electroconvulsive therapy: a temporary effect? J Affect Disord.

2011;132:216.

Virupaksha HS et al. Comparison of electroconvulsive therapy (ECT) with or without anti-epileptic drugs in

bipolar disorder. J Affect Disord. 2010;127:66.

Sienaert P et al. Concurrent use of lamotrigine and electroconvulsive therapy. J ECT. 2011;27:148.

Small JG, Milstein V. Lithium interactions: lithium and electroconvulsive therapy. J Clin Psychopharmacol.

1990;10:346.

Thirthalli J et al. Aprospective comparative study of interaction between lithium and modified electroconvulsive

therapy. World J Biol Psychiatry. 2011;12:149.

Masdrakis VG et al. Safety of the electroconvulsive therapyziprasidone combination. J ECT. 2010;26:139.

Masdrakis VG et al. The safety of the electroconvulsive therapy-aripiprazole combination: four case reports. J

ECT. 2008;24:236.

p. 1850

Developmental disorders are a group of conditions in which early brain

development is impaired. This very large group of disorders includes

diagnoses such as intellectual disability (ID) and autism spectrum

disorder (ASD). The core diagnostic features of ASD include

impairment in reciprocalsocial communication and social interaction,

and restricted, repetitive patterns of behavior, interests, or activities.

These symptoms must be present from early childhood and impair

everyday functioning. ASD is diagnosed clinically, though standardized

behavioral diagnostic instruments can assist this process. ASD is more

common in boys than girls, and the core diagnostic features can be

addressed through multiple different types of nonpharmacologic

interventions, including specialized education, physical therapy,

occupational therapy, speech and language therapy, and behavioral

therapy, such as applied behavior analysis (ABA).

Case 88-1 (Question 1),

Table 88-1

Individuals with ID/ASD have high rates of comorbid ADHD.

Treatment of ADHD, especially hyperactivity, in individuals with

ID/ASD is similar to the treatment of ADHD in neurotypical individuals,

and includes stimulants, α2

agonists, and atomoxetine. Compared to

their neurotypical peers though, individuals with ID/ASD and comorbid

ADHD experience lower effect sizes with ADHD treatment, lower

tolerated doses of ADHD medication, and more risk of adverse effects,

including increased rates of decreased appetite, insomnia, depressive

symptoms, irritability, and social withdrawal.

Case 88-1 (Question 2)

Some individuals with developmental disorders demonstrate symptoms of

irritability and aggression, which can sometimes be helped with a

pharmacologic intervention if nonpharmacologic interventions are

ineffective. The strongest evidence for the pharmacologic treatment of

irritability/aggression in individuals with developmental disorders exists

for the use of risperidone and aripiprazole to treat irritability in children

with ASD. Doses for this purpose are likely lower than those used to

treat schizophrenia or bipolar disorder, and adverse events are relatively

common and may include sedation, weight gain, and extrapyramidal

symptoms.

Case 88-2 (Question 1)

Individuals with developmental disorders are at high risk of having

comorbid anxiety and depression. Although no large prospective,

randomized, controlled trials (RCTs) exist to support the use of selective

Case 88-3 (Questions 1, 2)

serotonin reuptake inhibitors (SSRI) for this purpose, case studies and

open-labelstudies have shown possible benefits. RCTs of SSRIs for the

treatment of repetitive behavior in children with developmental disorders

have shown mixed results, although they have demonstrated that

individuals with developmental disorders may be at increased risk of

emotional and behavioral adverse events from SSRIs, and therefore,

target dosing should be lower than in individuals with typical

development.

Individuals with developmental disorders have high rates of comorbid

medical and psychiatric disorders, and therefore may often be

prescribed multiple different concurrent medications. Precaution should

be taken to avoid any pharmacodynamic or pharmacokinetic drug–drug

interactions, and such interactions should always be considered to

describe any adverse events.

Case 88-3 (Questions 1, 2)

Sleep disturbances are common in individuals with developmental

disorders. Melatonin has the strongest body of evidence for being a safe

and effective treatment of sleep disturbances in this population.

Case 88-4 (Question 1)

p. 1851

p. 1852

Developmental disorders are a group of conditions characterized by impaired early

brain development, resulting in deficits of cognitive, communicative, behavioral,

sensory, or motor functioning. This broad group of disorders includes diagnoses such

as intellectual disability, and autism spectrum disorder (ASD), which will be the

focus of this chapter, attention-deficit/hyperactivity disorder (ADHD) and tic

disorder, which are covered in another chapter, and communication disorders,

learning disorders, cerebral palsy, congenital hearing loss, and congenital blindness.

Intellectual disability (ID), previously labeled mental retardation, is a disorder with

deficits in intellectual and adaptive functioning. Although ID is typically reserved for

older children, for whom intellectual testing is more valid and reliable, global

developmental delay (GDD) is the diagnosis given to younger children in which

delays exist in two or more developmental domains. ASD, which includes prior

diagnoses of autistic disorder, Asperger disorder, and pervasive developmental

disorder (PDD) not otherwise specified, is a condition involving deficits in social

communication, as well as the presence of restricted and repetitive patterns of

behavior, interests, or activities.

1

EPIDEMIOLOGY, NATURAL COURSE OF THE

DISEASE, AND PROGNOSIS

Developmental disorders are common in the community, affecting as many as 15% of

children in the U.S., based on parent report.

2 Collectively, developmental disorders

are nearly twice as likely in boys and children insured by Medicaid, relative to girls

and those insured by private insurance, respectively.

2 Additionally, a higher

prevalence of developmental disorders is reported by families with incomes below

the federal poverty level and with lower maternal education (any educational

attainment less than a college degree).

2

For ID and GDD, the overall prevalence is estimated to be between 1% and 3% of

the population, though with considerable variability depending on how the diagnosis

is defined and reported in the literature.

3,4

Intellectual disability is more prevalent in

males versus females, and in low- and middle-income countries relative to highincome countries.

3

ASD is increasing in prevalence, with the Centers for Disease Control and

Prevention reporting about 1 in 68 children (1.47%) being identified with the

disorder.

5 Although around one-third of children with ASD may also qualify for

intellectual disability, the proportion of children with average or above average

intelligence being diagnosed with ASD has been steadily increasing over the years

and may explain some of the increase in overall ASD prevalence.

5 The proportion of

children with ASD who are boys has consistently been 4 to 5 times that of girls.

5

In

the United States, around 30% of children with ASD have some level of ID.

5

The course and prognosis of both ID and ASD vary considerably depending on the

severity of the deficits, the impact of comorbid medical and psychiatric conditions,

and the access to services and treatments. Many individuals will go on to live rich

and fulfilling lives, with minimal required assistance in daily life functioning, though

some will require constant supervision in supportive group housing, and assistance

for basic tasks of daily living.

PATHOPHYSIOLOGY: DISEASE ETIOLOGY,

ANATOMY, AND PHYSIOLOGY

Many different known and unknown genetic and environmental factors can lead to the

impairment in early brain development associated with developmental disorders.

For both ID and ASD, risk factors include preterm birth, low birth weight, small

for gestational age, and low Apgar scores, though all of these are associated more

strongly with ID.

6 For ID specifically, risk factors may differ depending on the

severity of ID. Studies have shown risk factors for mild ID to include mothers under

the age of 20 years or older than 30 years, paternal age greater than 40 years,

increasing birth order, increasing social disadvantage, maternal education less than

high school, being part of a multiple birth, and being second or later in the birth

order.

7,8 The risk of severe ID was consistently increased with increasing maternal

age and decreasing level of maternal education.

7 For ASD without ID, additional risk

factors include mothers aged 35 years or older, first-born infants, male infants, and

increasing socioeconomic advantage.

8

In only about half of all cases of ID can a specific etiology be identified and may

include genetic anomalies, intrapartum asphyxia, cerebral dysgenesis, and

environmental causes.

9

In only about 30% of children with ASD can an identifiable

genetic etiology be determined.

10 Although inherited genetic forms of ID likely

represent a minority of identified cases, ASD on the other hand is widely considered

to be one of the most heritable neuropsychiatric conditions with heritability estimates

of 60% to 90%.

11 For parents with one child with ASD, the recurrence rate in future

siblings is thought to be 5% to 20%, with higher rates if the original child with ASD

is female.

12 This recurrence rate increases to about 33% if a family already has two

children with ASD.

12

For inherited genetic anomalies, X-linked gene defects account for 10% to 12% of

all ID cases in males, with fragile X syndrome being the most common.

13 Fragile X

syndrome, marked by a CGG triplet repeat expansion in the FMR1 gene on the X

chromosome, is also the most common single-gene cause of ID, accounting for about

0.5% to 3% of individuals with ID,

14 and ASD, accounting for around 1% to 3% of

cases.

10,15 Single-gene disorders, some heritable like fragile X syndrome, account for

about 5% to 7% of ASD cases and include PTEN macrocephaly syndrome (~1%),

tuberous sclerosis complex (~1%), and Rett syndrome (~1%).

10,15 Other inherited

causes of ID and ASD include inherited metabolic disorders, such as

phenylketonuria, adenylosuccinate lyase deficiency, and Smith–Lemli–Opitz

syndrome.

15 Although inherited metabolic disorders are relatively rare, accounting

for only 1% to 5% of cases of ID, the potential for positive prognosis with treatment

is high.

4

Other genetic anomalies that can lead to ID and ASD include noninherited, or de

novo, single-gene mutations, chromosomal aberrations, and imprinting/epigenetic

disorders.

14 Chromosomal aberrations may account for up to 25% of individuals with

ID, about 8% or 9% of which is due to trisomy 21, or Down syndrome, the most

common known cause of ID.

14,16 Prader–Willi and Angelman syndromes, both

associated with developmental delays, are two examples of disorders involving

imprinted genes.

Environmental causes of ID range in the literature from 2% to 13% and include

antenatal toxin exposure (e.g., fetal alcohol spectrum disorders), antenatal infection

(e.g., TORCH infections), and early severe psychosocial deprivation.

17,18

Environmental causes of ASD include first trimester intrauterine exposure to

valproic acid, thalidomide, misoprostol, the organophosphate insecticide

chlorpyrifos, and phthalates, in addition to first trimester rubella infection.

19 While

receiving much scrutiny, multiple studies have shown no support linking vaccines to

autism.

20

CLINICAL PRESENTATION

Developmental disorders are typically recognized clinically once it becomes clear

that a child is delayed in meeting one or more developmental milestones. Primary

care providers have been

p. 1852

p. 1853

tasked by the American Academy of Pediatrics (AAP) to assess development at

every routine preventative visit throughout childhood.

21 Additionally, the AAP

encourages pediatricians to use standardized developmental screening tools (e.g.,

Ages and Stages Questionnaires—ASQ and Parents’ Evaluation of Developmental

Status—PEDS) at the 9-, 18-, and 24- or 30-month visit, and an autism-specific

screening tool at the 18- and 24-month visits (e.g., Modified Checklist for Autism in

Toddlers—MCHAT).

21,22 Once concerns are raised by routine surveillance or

screening measures, children should be referred to early intervention and early

childhood programs, as well as to developmental specialists, when indicated.

21

Early recognition of developmental disorders depends on children having access

to preventative medical care, and almost 25% of children with special health care

needs might not have that access.

23 The nature and severity of the developmental

deficits also contribute to the age at recognition. The sensitivity of developmental

and autism screening measures rarely reaches 0.9,

21 and so relatively mild

developmental deficits may go undetected. For children with ASD, the mean age of

diagnosis has been around 53 months,

5

though children with intellectual disability

and those diagnosed with autistic disorder are typically diagnosed earlier; children

with higher IQ scores and those eventually diagnosed with Asperger disorder, whose

limitations do not include communication delays, are typically diagnosed later.

5

Some individuals with particularly subtle deficits may not be diagnosed until

adulthood. Individual symptoms that may lead to an earlier diagnosis of ASD may

include severe language deficits, hand flapping, toe walking, and sustained odd

play.

24

DIAGNOSIS

ID is defined by both the American Psychiatric Association and the American

Association on Intellectual and Developmental Disability (AAIDD) as a disorder

with deficits in intellectual and adaptive functioning in conceptual, social, and

practical domains.

1,25 The Diagnostic and Statistical Manual of Mental Disorders,

Fifth Edition (DSM-V) requires that the disability has onset “during the

A.

1.

2.

3.

B.

1.

developmental period,” whereas the AAIDD requires the disability to start before

age 18 years. Intellectual functioning is assessed clinically and by standardized tests

of intelligence, like IQ testing (e.g., Wechsler Intelligence Scale for Children and the

Stanford–Binet Intelligence Scale), with a cutoff being two standard deviations

below the mean for the general population, or a score of around 65 to 75, for

disability.

1 Older references focused diagnosis primarily around IQ scores, and

subcategories of intellectual disability (then called mental retardation) were set to

specific IQ scores.

1 Current methods of diagnosis focus more on measures of

adaptive functioning, because this is more relevant to planning treatment and

supports. Adaptive functioning is also assessed clinically or with standardized tests

of adaptive functioning (e.g., Vineland Adaptive Behavior Scales). Subcategories for

intellectual disability in the DSM-V are now based on levels of adaptive functioning,

mild, moderate, severe, and profound. As standardized testing for intellectual and

adaptive functioning is typically valid for children above the age of 5 years, for

children younger than 5 years, the diagnosis of GDD is used and describes significant

delays in two or more developmental domains, including gross/fine motor,

speech/language, cognition, social/personal, and activities of daily living.

26

ASD is defined by the DSM-V as the presence of persistent impairment in

reciprocal social communication and social interaction, and restricted, repetitive

patterns of behavior, interests, or activities, present from early childhood, and

impairing everyday functioning (Table 88-1).

1 The diagnosis is made clinically,

though standardized behavioral diagnostic instruments, including caregiver

interviews, questionnaires, and clinician observation measures (e.g., Autism

Diagnostic Interview and Autism Diagnostic Observation Schedule), are available to

potentially assist in diagnosis.

Table 88-1

DSM-V Criteria for ASD1

Persistent deficits in social communication and social interaction across multiple contexts, as manifested

by all of the following, currently or by history (examples below):

Deficits in social–emotional reciprocity, ranging, for example, from abnormalsocial approach and failure

of normal back-and-forth conversation; to reduced sharing of interests, emotions, or affect; to failure to

initiate or respond to social interactions.

Deficits in nonverbal communicative behaviors used for social interaction, ranging, for example, from

poorly integrated verbal and nonverbal communication; to abnormalities in eye contact and body

language or deficits in understanding and use of gestures; to a total lack of facial expressions and

nonverbal communication.

Deficits in developing, maintaining, and understanding relationships, ranging, for example, from difficulties

adjusting behavior to suit various social contexts; to difficulties in sharing imaginative play or in making

friends; to absence of interest in peers.

Restricted, repetitive patterns of behavior, interests, or activities, as manifested by at least two of the

following, currently or by history (examples below):

Stereotyped or repetitive motor movements, use of objects, or speech (e.g., simple motor stereotypies,

lining up toys or flipping objects, echolalia, idiosyncratic phrases).

2.

3.

4.

C.

D.

E.

Insistence on sameness, inflexible adherence to routines, or ritualized patterns or verbal nonverbal

behavior (e.g., extreme distress at small changes, difficulties with transitions, rigid thinking patterns,

greeting rituals, need to take same route or eat food every day).

Highly restricted, fixated interests that are abnormal in intensity or focus (e.g., strong attachment to or

preoccupation with unusual objects, excessively circumscribed or perseverative interest).

Hyper- or hyporeactivity to sensory input or unusual interests in sensory aspects of the environment (e.g.,

apparent indifference to pain/temperature, adverse response to specific sounds or textures, excessive

smelling or touching of objects, visual fascination with lights or movement).

Severity is based on social communication impairments and restricted, repetitive patterns of

behavior [Level 1 (requiring support), Level 2 (requiring substantialsupport), Level 3 (requiring very

substantialsupport)]

Symptoms must be present in the early developmental period (but may not become fully manifest until

social demands exceed limited capacities, or may be masked by learned strategies in later life).

Symptoms cause clinically significant impairment in social, occupational, or other important areas of

current functioning.

These disturbances are not better explained by intellectual disability (intellectual developmental disorder)

or global developmental delay. Intellectual disability and autism spectrum disorder frequently co-occur;

to make comorbid diagnoses of autism spectrum disorder and intellectual disability, social communication

should be below that expected for general developmental level.

p. 1853

p. 1854

After a child is identified to have a developmental disorder, further diagnostic

workup is warranted to identify an etiologic cause, because some causes may be

treatable (e.g., metabolic disorder), some may inform of other potential comorbid

medical problems (e.g., cardiac conditions in Down syndrome and fragile X

syndrome), and some may help inform parents of risks for future children. This

further etiologic workup should include a thorough medical history (including

prenatal and birth history), a family history going back three or more generations, and

a physical and neurologic examination focused on findings consistent with

recognizable syndromes.

4

If children with ID or GDD still do not have a known etiologic cause after this

workup, they should be referred for chromosomal microarray and possibly screening

for inborn errors of metabolism given the treatable nature of some metabolic

disorders.

4 The American College of Medical Genetics and Genomics proposes that

in the event of a diagnosis of ASD without a known cause despite the above workup,

all children should undergo chromosomal microarray, those children with clinical

indicators should undergo metabolic or mitochondrial testing, fragile X testing should

be performed for all boys, MECP2 (Rett syndrome) testing should be performed in

all girls, PTEN testing in children with macrocephaly, and neuroimaging only if

specific clinical indicators (e.g., seizures, regression, history of stupor/coma,

microcephaly).

27

CASE 88-1

QUESTION 1: L.B. is a 3-year-old boy who is brought to his pediatrician for a well-child visit. During the

behavioral health screening, his mother notes that L.B. speaks very few words, does not express many different

emotions on his face, does not seem to share enjoyment in activities, and remains fairly unmotivated to interact

with other children in daycare. He has more recently been making repetitive loud “woop”-ing sounds that are

nonprompted and occur multiple times per day. He also becomes quite aggressive during any transitions. During

the visit, the pediatrician completes the Childhood Autism Rating Scale, Second Edition (CARS-2). The result is

a score of 32, suggesting a diagnosis of autism spectrum disorder (ASD). The pediatrician refers L.B. and his

mother to a developmental pediatrician, who specializes in ASD, for further evaluation. After a thorough

evaluation, and review of the differential diagnosis, L.B. is given a diagnosis of ASD and is referred for applied

behavior analysis (ABA) services.

What signs and symptoms of autism spectrum disorder does L.B. demonstrate?

Based on the DSM-5 criteria for ASD, L.B. is showing persistent deficits in social

communication and social interaction in multiple settings, as demonstrated by his

deficits in nonverbal communication (poor facial expressions), lack of relationship

building with children, and poor social–emotional reciprocity (lack of shared

enjoyment). L.B. also demonstrates restricted, repetitive patterns of behavior with his

stereotyped “woop”-ing noises and his inflexible insistence on sameness, with

aggression associated with transitions.

OVERVIEW OF TREATMENT

Therapy and Psychosocial Interventions

Individuals with ID or ASD can benefit from many different services to help with

issues of communication, social skills, sensory integration, behavior modification,

gross and fine motor, executive functioning, and adaptive functioning. Most of these

services are provided to children through the public education system, at no cost to

the families, as ensured by the Individuals with Disabilities Education Act (IDEA).

The IDEA provides all states with grants to provide early intervention services for

children with developmental delays under the age of 3. Services vary between states,

though each child and family are evaluated and given an Individualized Family

Service Plan (IFSP), which spells out the services to be provided, which may

include, but are not limited to, physical therapy, occupational therapy, speech and

language therapy, and behavioral therapy. For children reaching the age of 3 years,

and still eligible for specialized education, an Individualized Education Plan (IEP) is

drafted, which outlines the services to be provided in the school setting, starting in

preschool. IEP services could include all of the same types of services as above, as

well academic support, social skills groups, social pragmatics counseling,

vocational training, and emotional counseling. IEPs are required to be reevaluated

every 3 years, with updated testing and evaluation. Families must consent to both

IFSPs and IEPs, and if they disagree with the supports proposed, there is a process

by which they can appeal to have changes made.

Despite the services assured by the IDEA, children and families with

developmental disabilities also often receive psychosocial services in their

communities. In fact, in the 2011 Survey of Pathways to Diagnosis and Services,

almost two-thirds of children with ASD and/or ID were receiving a communitybased service.

28 The odds of using any school- or community-based service were

almost 8 times more likely for children with ASD, and over 9 times more likely for

children with ID, compared to children without those respective diagnoses.

28

To address the core symptoms of ASD, which include social communication

deficits and repetitive, restricted behaviors and interest, the most prevalent treatment

modality has been applied behavior analysis (ABA). ABA is a behavioral therapy

rooted in the concepts of operant conditioning, in which an antecedent leads to a

behavior, which results in a consequence. In ABA, preferred behavior, such as an

appropriate social response, is reinforced with an incentive. Classic ABA employs

the use of discrete trial training (DTT), in which specific skills are broken down into

discrete components and systematically taught in highly structured settings, often

using incentives like food and stickers. Critics of this form of ABA worry that

children with ASD are unlikely to apply the learned skills outside of the trial setting.

As a result, multiple different therapy approaches have been created, such as Pivotal

Response Therapy and the Early Start Denver Model, both derivations of ABA, and

the Developmental, Individual-differences, Relationship-based (DIR) Floortime

approach, which all operate in more naturalistic settings, focus more on building

child initiation and motivation, and employ natural incentives like positive affect and

affection. The research evidence to support such interventions for children and young

adults with ASD varies widely, as is explored in Wong et al.’s

29 comprehensive

recent review. Operant conditioning though, and the principles of manipulating

antecedents, behavior, and reinforcements, remains the mainstay for the treatment of

aggressive behaviors in individuals with developmental disabilities.

30

Individuals with ID often require the same types of interventions as individuals

with ASD, though perhaps with a stronger emphasis on adaptive functioning training,

and building skills of independent living. Likewise, for individuals with ID, the

evidence base for psychological interventions is varied. One recent review and

meta-analysis of psychological therapies for individuals with ID showed that in the

literature, individual therapy seems to be superior to group interventions, and

moderate to large effect

p. 1854

p. 1855

sizes exist for therapy for depression and anger, though there is no evidence that

therapy has an effect on interpersonal functioning.

31

Pharmacologic Interventions

The evidence supporting psychopharmacologic interventions in individuals with

ID/ASD is relatively limited. There are only a few large double-blind, randomized,

placebo-controlled trials (RCTs), many of which were funded by, or affiliated with,

the manufacturers of the particular study medications. Most of the existing RCTs are

for individuals with ASD and are of children and adolescents, likely, in part, because

of the complications involved in consenting adults with ID/ASD to participate in

research. Additionally, the targets for medication intervention with the strongest

research evidence are behaviors, which relay little about any possible underlying

emotional etiology for the individual.

Despite the limitations of the evidence, clinicians working with individuals with

ID/ASD know that medications can often serve a very important role as part of a

comprehensive treatment plan. Although much of the literature is of studies of

children with ASD, it should be noted that a large percentage of these studies

contained many individuals with comorbid ID (76%,

32 71%,

33 53%,

34 mean IQ,

63

35,36

). However, the literature confirms that individuals with ID/ASD are more

sensitive to adverse events from medications compared to their neurotypical peers,

and therefore, pharmacologic interventions should be performed with caution.

At the time of this writing, there are no medications approved by the U.S. Food

and Drug Administration (FDA) to treat any of the core diagnostic elements of

ID/ASD. The target symptom behaviors with the most research evidence include

hyperactivity, irritability, repetitive behaviors, and self-injurious behavior. As

anxiety disorders are the most common comorbid psychiatric conditions in

individuals with ID/ASD, anxiety/depression is another frequent target for

psychopharmacologic intervention, though with considerably less research support.

Sleep disturbances are also remarkably common in individuals with developmental

disabilities and often are a target for medication intervention.

Hyperactivity

Individuals with ID/ASD have high rates of comorbid ADHD, with literature in

children with ASD showing prevalence rates of about 30% for children derived from

community, nonclinical, populations (28%37 and 31%38

), and 41% to 78% for

children evaluated in the clinical setting.

39 The mainstay of treatment for symptoms of

ADHD in individuals with ID/ASD, like their neurotypical peers, includes

stimulants, α2 agonists, and atomoxetine.

Stimulants

Stimulants are a group of medications derived either from methylphenidate or

amphetamine that act by increasing the amount of dopamine and norepinephrine in the

neuronal synaptic cleft. This increase in dopamine and norepinephrine is the result of

blocking the reuptake of dopamine and norepinephrine (methylphenidate and

amphetamine) and increasing the release of dopamine and norepinephrine

(amphetamine).

Reichow et al.,

40

in their recent meta-analysis of pharmacologic treatments of

symptoms of ADHD in children with PDD, found four RCTs of stimulant

medications. All four RCTs studied methylphenidate and found it to be superior to

placebo for the treatment of global ADHD symptomatology and specifically

hyperactivity. In the largest of the four RCTs (n = 66),

41 effect sizes for hyperactivity

and impulsivity symptoms were greater than for inattention symptoms (0.77 vs. 0.60

for parent rating; 0.48 vs. 0.35 for teacher rating).

35

The effect size for the treatment of ADHD symptoms in children with PDD (0.67

for methylphenidate),

40 however, was lower than estimates in a meta-analysis of

stimulant treatment of typically developing children with ADHD (0.77 for

methylphenidate and 1.03 for amphetamine).

42

In the study conducted by the Research

Unit on Pediatric Psychopharmacology (RUPP) group,

41 49% of children experienced

a therapeutic response, compared to 69% in the Multimodal Treatment Study of

Children with ADHD (MTA), which studied mostly neurotypical children (ID was an

exclusion criteria, and ASD was not mentioned as a comorbid diagnosis in any

participants).

43

Adverse events were more common in children with PDD treated with

methylphenidate versus placebo, with increased rates of decreased appetite,

insomnia, depressive symptoms, irritability, and social withdrawal.

40 Rates of

adverse events with methylphenidate were also larger in children with PDD

compared to typically developing children, as evidenced by 18% of RUPP study

participants

41 discontinuing the medication due to adverse events (primarily

irritability), compared to 1.4% in the MTA study.

43

Mean dosage in the four RCTs ranged from 0.29 to 0.45 mg/kg/dose.

40 Secondary

analysis of the RUPP study data showed that methylphenidate doses of 0.25 and 0.5

mg/kg/dose were more consistently effective for treating ADHD symptoms than the

lower 0.125 mg/kg/dose.

35 The highest dose used in the RUPP study was 0.625

mg/kg/dose, compared to the MTA study, in which the highest dose used was 0.8

mg/kg/dose.

41

Daily methylphenidate doses may be titrated weekly, until an optimal dose is

obtained. Improvement in symptoms should be noted within the first week.

44

Overall, the research literature shows that methylphenidate can be used to improve

ADHD symptoms, especially hyperactivity, in children with PDD, though with lower

effect sizes, lower tolerated doses, and more risk of adverse effects than children

without developmental disabilities.

Although no RCTs have been conducted studying the effects of amphetaminederived stimulants for the treatment of ADHD in children with ASD, consensus

guidelines suggest that amphetamine salts can be an option for children demonstrating

insufficient benefit or dose-limiting adverse events from methylphenidate.

45

α2 Agonists

Although the exact mechanism in ADHD is unknown, α2 agonists are thought to work

by stimulating the α2 adrenoceptors on norepinephrine-containing neuron cell bodies

in the locus coeruleus which modulates the tonic and phasic firing to the prefrontal

cortex. This allows the person to have increased attention on the desired task.

46

α2 Agonists include clonidine, a nonselective α2 adrenergic receptor agonist, and

guanfacine, a selective α2A adrenergic receptor agonist. α2 Agonists were initially

marketed for the treatment of hypertension, though have been shown to also improve

symptoms of ADHD.

For clonidine, one small study (n = 8)

47 was identified by Reichow et al.

40

looking

at clonidine versus placebo for the treatment of ADHD in children with PDD.

Although the original study found no statistically significant results, the effect size

calculated by Reichow et al.

40

for improvement in ADHD symptoms and irritability

was in the medium range (γ = 0.51 and 0.64, respectively) and smaller for

improvements in hyperactivity (γ = 0.30) and stereotypic behavior (0.24). The

authors of the original study

47

report increased rates of hypotension and drowsiness

in some children who took clonidine. Mean dosage ranged from 0.15 to 0.20 mg/day.

One small pilot RCT (n = 11) looking at guanfacine treatment in children with

developmental disabilities showed statistically

p. 1855

p. 1856

significant reductions in hyperactivity subscales and global rating of improvement,

with 5 of the 11 participants deemed to be responders.

48

No comments:

Post a Comment

اكتب تعليق حول الموضوع

mcq general

 

Search This Blog