Treating Autism With Drugs

Pharmacological Treatments for Behavioral Symptoms Associated with Autism Spectrum Disorders (ASD)

This is a summary of a 2012 review paper by Doyle and McDougle. Of course, the pharmacological treatments should only follow AFTER behavioral interventions have been tried consistently and repeatedly without sufficient success and if the problem at hand is actually getting in the way of the patient’s daily functioning.

I am now always through with this review and will finish this post over the next days. This will include the information from newer reviews published after 2012. 

While I am a psychiatrist, this is not intended to replace a psychiatric consultation or discussion of medication with your psychiatrist. 

I have been supervising NP students while on call at NYP-Brooklyn Methodist Hospital and instead of repeating myself, I will post important professional information on my blog for my students to review.

With that said:

Tl;dr: 

• Behavioral Symptoms in ASD are repetitive and stereotyped behaviors, irritability & aggression, hyperactivity & inattention, and social impairment.
• Antispychotic drugs (APD) are the most efficacious drugs for the treatment of irritability & aggression in ASD, and maybe useful for the tx of other sxs as well.
• Psychostimulants demonstrate some benefit for the tx of hyperactivity & inattention in patients with ASD BUT are less officiations and associated with more adverse effects compared with patients receiving them for ADHD.
• SSRIs are less efficacious and 
• D-cycloserine and memantine appear helpful in the tx of social impairment, HOWEVER, the evidence for this is still limited.

In-depth:

Autism Spectrum Disorders (ASDs) is a widely used term, most commonly referring to disorders such as Autism, Asperger’s (disorder) and Pervasive Developmental
Disorder (PDD). 

A few definitions are in place:

1. Autism:
1. Characterized by 
1. Impaired reciprocal social interaction
2. Aberrant language development
3. Repetitive, stereotyped behaviors, interests or activities.
4. Delay/dysfunction of social interaction, language or symbolic/imaginative play must be present before age 3.
2. Asperger’s disorder requires impairment in social interaction and a pattern of restricted & stereotyped behavior but differs in that language and cognitive development are preserved (“weird but smart”, think Sheldon Cooper).
3. PDD-NOS (Pervasive Developmental Disorder Not Otherwise Specified) is diagnosed when there is a
1. Severe and pervasive social impairment
2. Abnormal communication or stereotyped behavior 
3. But the criteria for Autism or Asperger’s disorder are NOT met.
4. Other rare pervasive developmental disorders include
1. Rett’s disorder
2. Childhood Disintegrative Disorder

Side note here: You might notice that the diagnostic criteria for Autism and PDD sound quite similar. In fact, do not assume that people use the terms above as defined above. Many doctors use PDD as a way to not diagnose autism and to avoid the word. This might be done to avoid stigma. However, by narrowing autism to only the most severe cases, the definition is narrowed without scientific evidence and diagnosis terms lose their value. In my clinical practice, I try to use the term Autism Spectrum Disorder and explain to my patients and parents that Autism exists on a spectrum of symptoms and severity. I find this clearer and less stigmatizing because most people can conceptualize that human traits and behaviors are seldom qualitative (“yes/no” or “on/off”) but rather quantitative.

Children and adults “on the spectrum” often have behavioral symptoms associated with their condition:

• Repetitive and stereotyped behaviors
• Stereotyped motor mannerisms such as hand-flapping, clapping, rocking, spinning, inflexible adherence to nonfunctional routines or rituals (the latter might look like OCD sxs).
• Irritability and aggression
• Severe tamper outbursts and/or impulsive aggression towards self and others (occurs in 30% of children and adolescents with ASDs)
• Hyperactivity and inattention
• 40-60% of children dx with ASDs also meet criteria for ADHD.
• Common in ASDs but ASD dx excludes concurrent ADHD dx.
• Social Impairment
• Lack of social or emotional reciprocity
• Impaired gestures used to regulate social interaction

Doyle and McDougle reviewed the literature about pharmacological interventions to treat these disorders. The most common meds used in behavioral sxs associated with ASDs are 

• SRIs (Serotonin Reuptake Inhibitors)
• Antipsychotics (APDs)
• ADHD meds

Overall: 

1. SRIs are LESS efficacious  and more poorly tolerated in children with ASDs compared with adults.
2. APDs are the most efficacious drugs for the treatment of irritability but useful for the tx of other sxs, too.
3. Psychostimulants demonstrate some benefit for the tx of hyperactivity and inattention. They are less efficacious and have MORE adverse affect when given to patients with ASDs compared to their use in patients with ADHD.
4. Other meds that MAY be helpful for various sxs include
1. Mirtazipine
2. Atomoxetine
3. Alpha-2 agonists
4. D-cycloserine
5. Memantine

SRIS and other meds affecting serotonin neurotransmission

Serotonin abnormalities have been implicated in ASD for >50yrs. Therefore, studies have looked into the effectiveness of SRIs in ASDs. Results have been MIXED, SRIs appear to work better in adults than children with ASDs and have less side effects when used in adults as well.

1. Clomipramine has been shown to be efficacious for the tx of repetitive behaviors and stereotypes in some individuals with ASDs, and may be helpful with aggression and hyperactivity. HOWEVER, many children and adolescents have adverse effects. 
1. The dose range across various studies ranged from 75 to 250mg/day, sometimes in divided doses.
2. Adverse effects from minor to significant included
1. Sleep disturbance
2. Dry mouth
3. Constipation
4. Fatigue/lethargy
5. Dystonia
6. Depression
7. Behavioral problems
2. Fluvoxamine is minimally effective and poorly tolerated in children and adolescents with ASDs ALTHOUGH it has been found to be officiations in the management of repetitive and maladaptive behaviors and aggression in some adults with autism.
3. Fluoxetine has not been found to be effective in the treatment of repetitive behaviors in children. Again it has been proven to be more effective in adolescents and adults with autism with adolescents having more side effects from it. The dose range for fluoxetine in adult studies was 20-80mg/day.
4. Sertraline is moderately effective and relatively well-tolerated in the management of repetitive behavior and aggression in adults with ASD. There is only minimal data in children. Adults tolerated 25-200mg/day. Discontinuation occurred 2/2 increased anxiety or agitation, worsening of self-picking or non-complicance. The most common adverse effects were weight gain and anxiety or agitation.
5. Citalopram limited efficacy for children and adolescents and higher associations with side effects. Not sufficient data base for adults with ASDs.
6. Esicalopram does not have enough data to draw conclusions.
7. Venlafaxine is a combined serotonin and norepinephrine reuptake inhibitor (SNRI). Studies are limited and small and found that it is somewhat effective in children, adolescents and adults.
8. Trazodone, a heterocyclic AD, has not been sufficiently studied.
9. Mirtazapine, a tetracyclic AD, which antagonizes both alpha-2 adrenergic and serotonergic receptors, is somewhat effective in managing some symptoms associated with autism, including inappropriate sexual behaviors.

Antipsychotics

1. Haloperidol has been demonstrated to be efficacious in the short- and longterm tx of sxs associated with autism. 
1. In adults, haloperidol is superior to clomipramine in the management of irritability.
2. Studies in children have shown that haloperidol is superior to placebo in reducing stereotypes and social withdrawal and maladaptive behavior.
3. Higher IQ is more predictive of a greater symptom reduction and there was a greater reduction of sxs when the severity of illness was greater.
4. Adverse effects include
1. Dose-related sedation
2. Rarely dyskinesias
3. Long-term dyskinesias are not found to be a problem during short-term tx.
4. Found efficacious in long-term tx (>6mt) with greatest response for irritability, labile and angry affect and uncooperativeness. 
5. HOWEVER, 34% of subjects developed dyskinesias in one long-term study.
6. Risk factors for dyskinesia are
1. Female sex
2. Treatment length
3. Higher doses
7. Haloperidol appears to be more effective compared to fluphenzine.
8. HOWEVER, haloperidol has been less effective than risperidone in the short- and longterm tx of behavioral sxs, impulsivity, and impaired language skills and social relations. 
9. Haldol is COMPARABLE to olanzapine in sxs reduction in children.
5. The effective dose range in studies was between 0.5 and 4mg/day.
2. Clozapine carries an INCREASED risk of agranulocytosis and lowers the seizure threshold. That said, the few studies do suggest good tolerability and effective management of severe aggression & irritability. The dose range in the few studies that exist were between 200-475mg/day.
3. Risperidone is efficacious in the tx of irritability in children, adolescents and adults with ASD, as demonstrated in a number of studies. A combination of risperidone and parent management training was found to reduce irritability, stereotypic behavior, hyperactivity even better than mono therapy with risperidone alone. 
1. Dose ranges for risperidone ranged from 0.5 to 3.5mg/day in studies. 
2. Adverse effects included:
1. Increased appetite
2. Weight gain
3. Fatigue
4. Somnolence
5. Drowsiness
6. Dizziness
7. Anxiety
8. Hypersalivation
9. URIs
10. Rhinitis
11. Transient dyskinesia occurred in 15% of one study
4. Olanzapine is moderately efficacious in children with ASD and has demonstrated some effectiveness in adults.
1. Adverse effects included:
1. Increased appetite
2. Weight gain
3. Sedation
2. Doses ranged from 2.5-20mg/day
5. Quetiapine has been minimally effective in individuals with ASDs.
1. Adverse effects included weight gain, sedation, behavioral activation, akathisia, probably seizures
2. Dosages ranged from 25-800mg/day.
6. Ziprsidone is moderately effective in individuals with ASDs
1. Doses ranged from 10-160mg per day.
2. Most common adverse event being transient sedation.
7. Aripiprazole appears to be effective in children, adolescents and adults with ASDs but studies are limited.
1. Dosages ranged from 2.5-15mg/day. 
2. Adverse events included:
1. Sedation
2. Hypersalivation
3. Aggression
4. Weight increase
5. EPS-like tremor, hyperactivity, akathisia, dyskinesia
8. Paliperidone appears to be effective for children, adolescents and adults with ASDs, although studies are limited.
1. Dosages ranged from 5-12mg/day. 
2. The only noted adverse effect in the few studies was increased appetite

Treatment of hyperactivity and inattention

1. Methylphenidate (MPH) is a psychostimulant and moderately efficacious in the tx of hyperactivity in children with ASD. Its use is usually limited by side effects in children and adolescents with ASD.
1. Dosages ranged from 7.5mg-50mg/day in studies, sometimes divided and often dosed by weight (0.3-0.6mg/kg/day). Dosages for preschool children were between 5-20mg/day.
2. Atomoxetine is a selective norepinephrine reuptake inhibitor