Thomas Owley, MD Rush Medical Center

Transcription

1 Thomas Owley, MD Rush Medical Center

2 Disclosure No conflicts of interest or disclosures I will be discussing the following medications which are all off label: --risperidone, olanzapine, aripiprazole, ziprasidone, loxapine, methylphenidate, amphetamine salts, fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, escitalopram, melatonin, topiramate, clonidine, trazadone, secretin

3 Why study comorbidity? Parsing out comorbid disorders will help us to identify targets for interventions and improve quality of life for these children and their families Funding sources are endorsing this approach: Example: UIC ACE is studying a Insistence on sameness symptom:

4 Challenges to Studying Comorbidity in ASD As in MR/ID, children with ASD often have their symptoms attributed to their intellectual disabilities Symptom overlap or complicated symptom attribution may lead to viewing problems in multiple contexts (one person s oppositionality is another s rigidity or insistence on sameness)

5 Is there comorbidity in ASD? (Simonoff et al, JAACP; August 2008) Assessed 112 British children years old with ASD for comorbidity using the Child and Adolescent Psychiatric Assessment (CAPA) CAPA requires behavioral description of symptoms, which decreases the chance that symptoms of ASD would be double coded as symptoms of another disorder [ie repetitive language (ASD) being coded as excessive need for reassurance (Anxiety]

6 Is there comorbidity in ASD? (Simonoff et al, JAACP; August 2008) 112 children: 62 classic autistic disorder, 50 children with other PDDs All confirmed by ADI/ADOS 95% White British Mean IQ = 72.7 (19-124)

7 Is there comorbidity in ASD? (Simonoff et al, JAACP; August 2008) Yes, there is comorbidity: Overall, 79.8% had at least one additional diagnosis (Leyfer et al, JADD, 2006 =72%) 57% had more than one additional diagnosis (Leyfer = 50%)

8 Comorbid Anxiety Disorders (Simonoff, 2008) Overall w/any Anxiety d/o: 41.9% Social Anxiety Disorder: 29.2 Generalized Anxiety Disorder: 13.4% Panic Disorder: 10.1% Obsessive Compulsive Disorder: 8.2% * * = lower than others have found (Leyfer, 2006 = 37.2%); CAPA requires purposeful quality to obsess/compuls

9 Other Comorbid Disorders (Simonoff, 2008) ADHD: 28.2% (did not subtype) Oppositional Defiant Disorder: 28.1% Conduct Disorder: 3.2% Any Depressive D/O (MDD or Dysthymic D/O): 1.4% (Leyfer = 12%)

10 Other findings of interest (Simonoff, 2008) Consistent with other studies of ASD, no sex difference in rates of comorbid ADHD Lower rates of MDD rates in this study may reflect younger age Overall: there is lots of comorbidity

11 Whaddaya Mean By Off Label, Doc? Comorbid symptoms/disorders are the primary targets of most pharmacological interventions in ASD Only one medication with an indication for ASD, and that is for a very specific symptom, NOT a treatment for a core diagnostic criteria

12 Two Types of Treatment Type I: Treatment of Core Symptom --This is a treatment that is aimed at treating the primary (core) social and language problems in autism Examples: secretin, Alzheimer s medications --Rare, and usually done in the context of a study --No med has been shown to be useful for this indication thus far in controlled trials

13 Two Types of Treatments Type II: Treatment of Problem or Target Symptom Examples: amphetamine salts for hyperactivity, escitalopram for anxiety 95+% of what we do everyday; lots of evidence for usefulness

14 So how do we medicate? Two Concepts 1. Target Symptoms and 2. Risk/Benefit Ratio

15 First Concept: Target Symptoms Almost always, we don t treat autism Instead, we find target symptoms Target symptoms are: --symptoms that are causing significant difficulties --symptoms that we can expect to respond to medication

16 Target Symptoms Typical target symptoms that respond to medication --Irritability/Anxiety --Obsessions/Compulsions --Hyperactivity --Attention/Concentration --Aggression --Sleep difficulties

17 Target Symptoms Not great medication target symptoms (in addition to social/communication problems): Stereotypies and most stimming Narrow food interests Running away (unless hyperactivity-based) Self injurious behavior (SIB; although occasionally we do succeed)

18 Are kids with ASD taking medication? Yes: Martin (1999): 55% Lam (2002): 50.2% Aman (2003): 51.6% Oswald (2007): 57%

19 Pharmacology of Developmental Disorders Humbling work Little to guide us in the clinic --Paucity of controlled studies/open trials --Specifically relevant to this discussion, most comorbid disorders are considered trumped by autism --Incidence high enough to interest pharmaceutical industry? --Enough etiological information to develop a medication pipeline?

20 Complexity of Drug Trials in ASD Patients Extreme heterogeneity in presentation in terms of combinations of medical and psychiatric difficulties Communication problems may limit ability of patient to articulate presenting problems/side effects May be especially vulnerable to drug side effects

21 Before Considering Medication Optimize educational, behavioral, psychotherapeutic, vocational, and recreational programming (psychopharmacology is an adjunct to these primary interventions)

22 Are the ADHD symptoms ADHD symptoms or ASD symptoms? Inattention in ASD could also be: 1. Poor joint attention (social difficulty) 2. Restrictive attention or trouble shifting 3. Severe anxiety Hyperactivity in ASD could also be: 1. Severe anxiety 2. Frenetic stereotypies 3. Mania 4. Akathisia

23 Workup on Inattention in Kids with Autism Inattention Sub-Subtype I: Señor Decreased Social Valence Defining Characteristics: --doesn t listen when spoken to directly --not making eye contact with the teacher (but still performing) --changes subject to preferred interest --shows sustained attention and attention to detail in other tasks --doesn t follow through on instructions

24 Workup on Inattention in Kids with Autism Inattentive Sub-Subtype II: Señor Classic ADHD Defining characteristics: --Difficulty organizing tasks --Often loses things --Distracted by extraneous stimuli --Is often forgetful in daily activities

25 Workup on Inattention in Kids with Autism Inattentive Sub-Subtype III: Señor Nervioso Defining characteristics: --No sustained attention --Forgetful, scattered thinking --Socially Anxious, Obsessive, Rigid, Insistence on Sameness, Needs Reassurance, Phobic --Take his pulse

26 Treatment of Inattentive ASD Sub-Subtypes: Mapping on Substrate Senor Decreased Social Valence: Etiological information insufficient; unknown substrate Senor Classic ADHD: Best knowledge suggests substrate is dopamine and/or norepinephrine Senor Nervioso: Best knowledge of substrate is serotonin

27 Treatment of Inattentive ASD Sub-Subtypes Rx: Senor Decreased Social Valence: Rote social learning and social groups Rx: Senor Classic ADHD: Stimu/Atomox Rx: Senor Nervioso: Complicated. 1. I usually try an SSRI first. 2. Sometimes only need SSRI, sometimes need SSRI plus stimulant.

28 Treatment Myth: Stimulants worsen stereotypies and agitation in children with ASD to the extent that stimulant treatment is contraindicated

29 Rupp Multidose Crossover (2005)

30 Comparing MTH response in ASD (RUPP) and nonasd kids (MTA) Kids with ASD have a lower response rate (49%) vs. kids without ASD (69%) Kids with ASD do not tolerate MTH as well (18% with Adverse Events; mostly irritability) as kids without ASD (1.4%) But the take home is still: half the kids respond, which is substantial

31 Anecdotal Pearl Comorbid ADHD and Anxiety/OCD? Try an amphetamine product over methylphenidate: anecdotal experience and case studies suggest the possibility of decreases in anxiety in addition to decreases in ADHD symptoms (Insel et al 1983) (Owley et al 2002)

32 The Great Impersonator: Comorbidity and Anxiety in ASD Anxiety, in some form, often disguised, is common common common common common common common common common common common common common common common common common common common common common common common common common common common common in these kids

33 Serotonin and Autistic Disorder: Evidence for Involvement Hyperserotonemia: --Schain and colleagues [Freedman] (1961); replicated multiple times --Platelet-poor ultrafiltrates are not elevated in autism, suggesting increased serotonergic uptake or decreased serotonergic release (Cook, 1988; Cook and Leventhal, 1996)

34 Platelets and Serotonin

35 Serotonin and Autistic Disorder: Evidence for Involvement Tryptophan Depletion studies (McDougle, 1996) led to increase in stereotypical behaviors (rocking, whirling, anxiety) --(tryptophan 5-OH tryptophan serotonin) Finally, we have many positive open label and controlled trials of selective serotonin reuptake inhibitors in ASD

36 The Great Impersonator: Anxiety in ASD No matter what the parent presents as the primary symptom, see if it makes sense in the context of anxiety. This means: 1. Social difficulties (Core symptom or social phobia?) 2. Hyperactivity (ADHD or disorganizing anxiety?) 3. Aggression! (Without precipitant or mediated by rigidity and insistence on sameness?)

37 Problems with SSRI Treatment in Autistic Disorder Problem #1: Clinically, we see WIDE variablility in the final dose needed (and we are not aided by weight, gender, or age); in a related problem, some kids have dramatic side effects to even tiny doses Problem #2: Subsequently, many children are dosed too high in the community, do not benefit, and go on to try agents from other classes of medications with less palatable side effect profiles

38 How do we know when the dose is too high? Primary symptoms seen can include: --Irritability --Decreased need for sleep (consistently going to bed later and/or early morning awakening) --Aggressiveness --Excessive silliness or disinhibition --Mixed state

39 The Effect of Weight on Final Dose (Owley, 2005) Weight vs. Final Lexapro Dose Final Dose (Milligrams) Weight (Lbs)

40 The Effect of Age on Final Dose (Owley, 2005) Age vs. Final Lexapro Dose Final Dose (Milligrams) Age (Months)

41 Final Dose: Frequency and Cumulative % (Owley, 2005) Final Dose Frequency Cumulative %

42 Which SSRI in ASD? Fluoxetine Paroxetine Fluvoxamine Sertraline Citalopram Escitalopram

43 Cormorbid Medical Problems Important because they: Are common Ultimate behavioral manifestations may imitate/create psychiatric symptoms Are not always obvious in a population of children in which kids do not communicate well Are not always obvious in a population of kids with high pain thresholds

44 Cormorbid Medical Problems Otitis media GERD Dental Problems

45 Constipation Murch et al (2003): Studied 103 children with autism referred for GI assessment Rate of constipation was 36% Rate in unaffecteds going to the ER with GI pain was 10% Rate of mod/severe rectosigmoid loading or acquired megarectum was 54.5% vs. 24.1% of control subjects

46 Cormorbid Medical Problems Otitis media GERD Dental Problems

47 Sleep Difficulties in ASD Sleep-Wake cycle difficulties are well-established in autism including: --latency to sleep --early awakening --decreased overall sleep (the exceptions to these findings were studies that excluded meds or used young children)

48 Sleep Difficulties in ASD: Pharmacological Choices Three separate groups have shown reduced melatonin levels in children with autism (around 65% of kids with ASD) Melatonin is produced by the conversion of N- acetylserotonin to melatonin by acetylserotonin methyltransferase (ASMT) Are mutations and variants of ASMT the problem?

49 Melatonin

50 Melatonin (Garstang, et al 1997)

51 While we are on the topic, meds I wouldn t use in noncommunicative kids Trazadone Topiramate

52 Obesity A big problem

53 DD/MR and Weight Gain: Rimmer and Yamaki, 2006

54 Antipsychotic Family: Side Effect of Weight Gain The weight gain is especially troublesome in that it come from increase appetite; this leads to: 1. The usual long-term associated problems of obesity, including Type II diabetes, heart problems 2. Compounds other social problems 3. Issues over food may become the issues that are most problematic

55 Antipsychotic Family: Side Effect of Weight Gain Manufacturer s recommendations: For snacking, offer low-calorie/high-fiber foods such as rice cakes, carrots, celery, and popcorn Help your family member avoid fast foods-when your family must eat at a fast food restaurant, suggest a salad instead of a hamburger Provide positive reinforcement for sticking to a healthy diet Exercise All of which leads to

56 Antipsychotic Family: Side Effect of Weight Gain More weight gain since: Neither diet or exercise have any real chance of working Neither does giving other drugs that decrease appetite Real solution: start thinking about another medication

57 The Now What Problem risperidone/olanzapine (does very well but weight way up) Switch to aripiprazole (works but no change in weight). ziprasidone (doesn t work for this kid) Now what?

58 Now what? Just like visiting an old friend: Loxapine Why, you ask? --Loxapine is a mid-potency typical that acts like an atypical at low doses due to its affinity for not just D2 but also 5HT2 --low propensity to cause EPS (see Reinblatt et al 2006 for more info)

59 Even if you didn t ask for it, here it is: Permission On this day, _(date here), I give you permission to not have to do every single treatment that comes along. I give you permission to use your judgment regarding your choices for your child without suffering guilt from any person or group or nagging regrets from yourself for not instituting every single thing that is proposed on the Internet. Sincerely, Tom