Appendix B. Individual Article Rating

Appendix B. Individual Article Rating

Core Symptoms C1: General

Core Symptoms C2: Impaired Social Interaction

Core Symptoms C3: Impaired Communication

Core Symptoms C4: Restricted, Repetitive Behavior

Maladaptive Behavior B1: General

Maladaptive Behavior B2: Hyperactivity/Inattention/Impulsivity

Maladaptive Behavior B3: Self-injury

Maladaptive Behavior B4: Aggression/Oppositionality

Regulatory Problems R1: Irritability

Regulatory Problems R2: Emotional Lability

Regulatory Problems R3: Depression/Anxiety

Regulatory Problems R4: Sensory Abnormalities/Self-stimulation

Regulatory Problems R5: Eating Problems

Regulatory Problems R6: Gastrointestinal Problems

Regulatory Problems R7: Sleeping Problems

1. Pharmacologic Treatments

1.1a. Anti-Depressant: Noradrenergic and Specific Serotonergic Antidepressants

Brief Description

Noradrenergic and Specific Serotonergic Antidepressants (NaSSA) have both noradrenergic and serotonergic properties. Because of the action of NaSSA on the serotonin system, they are postulated to have efficacy in the treatment of selected symptoms of autism including aggression, self-injury, irritability, anxiety, depression, insomnia, and interfering repetitive behavior. In addition, NaSSA are thought to be less likely to cause behavioral activation than SSRI in this population.

Potential Medications

Mirtazapine (Remeron)

Table 1.1a. Noradrenergic and Specific Serotonergic Anti-depressants

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Maladaptive Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with positive response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / U / U / U / U
Number of Articles / 1 / 1 / 1 / 1 / 0 / 0 / 0 / 0 / 1 / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 1
Articles / Mirtazapine1 / 2 / 34.6% / 7.7% / N / N / N / Y

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

Notable side effects include drowsiness, increased appetite, and weight gain. As for all antidepressants, the U.S. Food and Drug Administration recommended that there be a black box warning regarding suicidality on prescriptions for mirtazapine in pediatric and young adult patients.

Brief Review of Published Research

Only one study has examined the use of NaSSA as a treatment for individuals with ASD. This study examined the use of mirtazapine in children with ASD and was of limited scientific quality (Scientific Merit Rating Scale score=2) 1. Overall, the small number and limited study quality restrict the ability to draw conclusions about the potential benefits of NaSSA as a treatment for ASD.

Conclusions

There is not strong evidence that NaSSA are effective in children with ASD.

Recommendations and Research-to-Practice Considerations

Implications for research

Researchers may wish to conduct large studies with strong scientific designs to obtain more conclusive evidence on the degree to which NaSSA are effective.

Implications for practice

To date, treatment of children with ASD using NaSSA is unsupported by published research. Professionals should encourage families who are considering this treatment to consult with the child’s physician in order to evaluate potential benefits and side effects.

Recent Reviews – None Identified

1.1b. Anti-Depressants: Norepinephrine Reuptake Inhibitors (NRI)

Brief Description

Other depressants that have been used in the treatment of children with ASD include norepinephrine reuptake inhibitors (NRI), which target inattention and hyperactivity.

Potential Medications

Atomoxetine (Strattera)

Table 1.1b. Norepinephrine Reuptake Inhibitors.

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Associated Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with + response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / M / U / U / U / U / M / U / U
Number of Articles / 2 / 2 / 2 / 2 / 1 / 1 / 1 / 1 / 2 / 0 / 0 / 1 / 0 / 1 / 0 / 0 / 0 / 0
Articles / Atomoxe-tine2 / 4 / 56% / 6% / Y / Y / N / N / Y / N
Atomoxe-tine3 / 2 / 60% / 5% / Y / Y / Y / N

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

For atomoxetine, reported side effects include gastrointestinal disturbances, appetite suppression, irritability, mood lability, sedation, and tinnitus (ringing in the ears). As for all antidepressants, the U.S. Food and Drug Administration recommended that there be a black box warning regarding suicidality on prescriptions for atomoxetine in pediatric and young adult patients.

Brief Review of Published Research

Two studies of atomoxetine were identified, which involved few subjects.2, 3 Considered together, these studies suggest that atomoxetine may have beneficial effects on core symptoms, generally, and on hyperactivity, specifically, in children with ASD.

Conclusions

Present evidence favors psychostimulants as the first line treatment for hyperactivity and inattention in the context of autistic disorder. In the presence of tics, anxiety, or significant perseverative behavior, atomoxetine may offer an alternative to psychostimulants.

Recommendations and Research-to-Practice Considerations

Implications for research

Reductions in hyperactivity seen in the studies of atomoxetine were modest, but promising enough to warrant further investigation with randomized control trials.

Implications for practice

Owing to its pharmacological action, atomoxetine is theoretically less likely than the psychostimulants to exacerbate tics and other abnormal movements that may occur in association with autistic disorder.

Recent Reviews4, 5

1.1c. Anti-Depressants: Specific Serotonin Reuptake Enhancers

Brief Description

Specific serotonin reuptake enhancers (SSRE) are prescribed to target inattention and hyperactivity, symptoms that can occur with ASD.

Potential Medications

Tianeptine (Stablon)

Table 1.1c. Specific Serotonin Reuptake Enhancers

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Associated Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with + response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / U / U / U / U
Number of Articles / 1 / 0 / 1 / 0 / 1 / 1 / 0 / 0 / 1 / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0
Tianep-tine6 / 3 / 0% / Y / Y / Y / Y

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

For tianeptine, reported side effects include gastrointestinal disturbances, dry mouth, constipation, and drowsiness. As for all antidepressants, the U.S. Food and Drug Administration recommended that there be a black box warning regarding suicidality on prescriptions for tianeptine in pediatric and young adult patients.

Brief Review of Published Research

Because of tianeptine’s efficacy as an anxiolytic, it was hypothesized that tianeptine may reduce fear and anxiety and improve core symptomatology in children with ASD. One small placebo-controlled, double-blind crossover trial suggests that treatment with tianeptine can result in improvement of impaired social interaction and communication as well as hyperactivity and irritability in some children and adolescents with ASD.6

Conclusions

There is no strong evidence that tianeptine is effective.

Recommendations and Research-to-Practice Considerations

Implications for research

Researchers may wish to conduct large studies with strong scientific designs to obtain more conclusive evidence on the degree to which tianeptine is effective.

Implications for practice

To date, treatment of children with ASD using tianeptine is unsupported by published research. Professionals should encourage families who are considering this treatment to consult with the child’s physician in order to evaluate potential benefits and side effects.

Recent Reviews – None Identified

1.1d. Anti-Depressants: Serotonin-Norepinephrine Reuptake Inhibitors

Brief Description

Serotonin-norepinephrine reuptake inhibitors (SNRI) are prescribed to address obsessive-compulsive, hyperactivity, and social phobia problems, symptom clusters that overlap with ASD.

Potential Medications

Venlafaxine (Effexor)

Table 1.1d. Serotonin-Norepinephrine Reuptake Inhibitors

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Associated Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with + response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / U
Number of Articles / 1 / 1 / 1 / 1 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0 / 0
Articles / Venla-faxine7 / 2 / 60% / 20% / Y

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

Venlafaxine has a higher rate of treatment emergent mania than many antidepressants. Other side effects include hyperactivity, irritability, agitation, restlessness, inattention, polyuria, and nausea. As for all antidepressants, the U.S. Food and Drug Administration recommended that there be a black box warning regarding suicidality on prescriptions for venlafaxine in pediatric and young adult patients.

Brief Review of Published Research

One small open-label trial suggests that treatment with venlafaxine can result in global improvement in some children and adolescents with ASD.7

Conclusions

There is no strong evidence that venlafaxine is effective.

Recommendations and Research-to-Practice Considerations

Implications for research

Researchers may wish to conduct large studies with strong scientific designs to obtain more conclusive evidence on the degree to which venlafaxine is effective.

Implications for practice

To date, treatment of children with ASD using venlafaxine is unsupported by published research. Professionals should encourage families who are considering this treatment to consult with the child’s physician in order to evaluate potential benefits and side effects.

Recent Reviews – None Identified

1.1e. Anti-Depressants: Selective Serotonin Reuptake Inhibitors

Brief Description

There is a large set of antidepressant medications used in the treatment of autism where the prominent mechanism of action is selective serotonin reuptake inhibition (SSRI). The SSRI are used in autism for at least two reasons: (1) investigators have documented serotonin dysfunction in autism, thus medications affecting 5-HT function might alter symptoms in autism; (2) persons with autism frequently have repetitive thoughts and behaviors that are reminiscent of symptoms found in obsessive-compulsive disorder (OCD), which can be responsive to SSRI treatment.

Potential Medications

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluoxetine (Prozac)

Fluvoxamine (Luvox)

Paroxetine (Paxil)

Sertraline (Zoloft)

Table 1.1e. Selective Serotonin Reuptake Inhibitors

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Associated Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with + response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / U / U / U / M / U / U
Number of Articles / 5 / 4 / 5 / 4 / 1 / 1 / 2 / 0 / 1 / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0
Articles / Escita-lopram8 / 3 / 61% / 7% / Y / Y / Y / Y / Y / Y
Fluoxe-tine9 / 3 / 0% / N / Y
Fluvox-amine10 / 3 / 28% / 0%
Citalo-pram11 / 2 / 73% / 13% / Y
Fluoxe-tine12 / 2 / 60% / 41% / Y

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

In general, adverse side effects include irritability, hyperactivity, and decreased appetite. Children with ASD may be more sensitive to SSRI-associated side effects than children with other neuropsychiatric disorders. As for all antidepressants, the U.S. Food and Drug Administration recommended that there be a black box warning regarding suicidality on SSRI prescriptions in pediatric and young adult patients.

Brief Review of Published Research

To date, several studies have examined the use of SSRI in children with autism; these studies range in scientific quality. Evidence suggests positive effects with regard to ASD core symptoms, particularly stereotyped behavior, as well as hyperactivity and irritability.

Conclusions

Controlled studies suggest efficacy of SSRI for the treatment of repetitive and maladaptive behavior in children with autism.

Recommendations and Research-to-Practice Considerations

Implications for research

Larger studies of SSRI in children and adolescents with ASD are needed in order to make definitive statements about efficacy and tolerability in this age group. There are remaining questions about which symptoms (e.g., repetitive behavior, irritability) are most responsive to SSRI and the degree to which there are improvements in core social or language impairments. In addition, age and pubertal status have been raised as potentially important moderators of treatment response and tolerability. Larger studies that include both pre- and post-pubertal subjects with ASD could begin to address these questions.

Implications for practice

The appropriate dosing of SSRI in children with ASD is still in question. In several studies, some children treated with these medications responded to very low doses, but then became more symptomatic following small increases in dose. This apparent heightened sensitivity to side effects of SSRI may make clinical treatment challenging in this diagnostic population.

Recent Reviews13-17

1.1f. Anti-Depressants: Tricyclic Anti-Depressants

Brief Description

A tricyclic biochemical structure characterizes one of the oldest forms of antidepressant medications used in the treatment of autism. The tricyclic anti-depressants (TCA) are used in autism to address stereotypic and self-injurious behaviors, anger and aggression, impulsivity, and social relatedness.

Potential Medications

Amitriptyline (Elavil)
Clomipramine (Anafranil)
Desipramine (Norpramine)
Imipramine (Tofranil)

Table 1.1f. Tricyclic Antidepressants

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Associated Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with + response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / U / U / U / U / U / U
Number of Articles / 1 / 0 / 1 / 1 / 1 / 1 / 1 / 0 / 1 / 0 / 0 / 1 / 0 / 0 / 0 / 0 / 0 / 0
Articles / Clomipra-mine18 / 3 / 62% / N / N / N / N / N / N

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

Side effects include cardiac conduction delays, seizures, and tachycardia; for these reasons, clomipramine is not widely recommended for the treatment of autism.

Brief Review of Published Research

One relatively recent study examined the use of clomipramine in children with autism.18 The resulting evidence was mixed with no effect on ASD core symptoms but apparent benefit with general behavioral symptoms. The majority of children receiving clomipramine withdrew from the study early because of side effects (e.g., fatigue, tremors, tachycardia, insomnia).

Conclusions

Despite beneficial effects, clomipramine is not well tolerated, with side effects identified as a contributing factor in most individuals who failed to complete their treatment.

Recommendations and Research-to-Practice Considerations

Implications for research

Additional research might focus on those anti-depressants with fewer and less harmful side effects.

Implications for practice

Potentially harmful cardiovascular side effects make clinical use of TCA undesirable.

Recent Reviews – None Identified
1.2. Antiepileptic Drugs

Brief Description

There are several reasons for the use of antiepileptic drugs in autistic spectrum disorders, including the high incidence of epilepsy in these individuals, approximately 25%, with a higher frequency of epilepsy found in infants and preschoolers and in adolescents.19 In addition, one study demonstrated that 60.7% of children with ASD (with no known genetic conditions, brain malformations, prior medications, or clinical seizures) had abnormal EEG epileptiform activity in sleep.20 The treatment of seizures in autism does not differ from that of other epilepsies. However, the treatment of EEG abnormalities in children with autism without seizures is a controversial issue. In this circumstance, antiepileptics are used to address hyperactivity, impulsivity, repetitive behaviors, or aggression. Affective symptoms (e.g., irritability) often add to autistic features and anti-epileptic medications with mood-stabilizing action (e.g., valproate) may be used.

Potential Medications

Carbamazepine (Tegretol)

Lamotrigine (Lamictal)

Levetiracetam (Keppra)

Topiramate (Topamax)

Valproate (Depacon)

Table 1.2. Anti-epileptic Drugs

Treatment Effects
Benefit / Adverse Effects / ASD Core Symptoms / ASD Associated Behaviors / ASD Regulatory Problems
SMRS Score / % treated children with + response / % treated children who withdrew with adverse effects / C1 / C2 / C3 / C4 / B1 / B2 / B3 / B4 / R1 / R2 / R3 / R4 / R5 / R6 / R7
SECS Category / U / U / U / U / M / M / U / U
Number of Articles / 5 / 2 / 5 / 4 / 1 / 1 / 2 / 2 / 2 / 0 / 0 / 0 / 1 / 1 / 0 / 0 / 0 / 0
Articles / Levetir-acetam21 / 3 / 10% / Y / Y / Y
Levetir-acetam22 / 3 / 0% / N / Y
Valpro-ate23 / 2 / 71% / 14% / Y
Lamo-trigine24 / 2 / 29% / N / Y / N / N
Topira-mate25 / 2 / 53% / 20% / Y / Y / Y / N

SMRS=Scientific Merit Rating Scale. N=measured and no beneficial treatment effect; Y=measured and beneficial treatment effect.

SECS=Strength of Evidence Classification System. S=Strong evidence of benefit; M=Marginal evidence of benefit; U=Unestablished or mixed evidence; D=Discrediting evidence of no benefit; H=Evidence of harm.

Intervention Side Effects

For sodium valproate, weight gain and sedation are the most commonly reported side effects. Lamotrigine was not associated with any more side effects than placebo. The side effects most frequently leading to discontinuation of therapy with topiramate are psychomotor slowing, memory problems and confusion, as well as fatigue.

Brief Review of Published Research

There is mixed or limited evidence concerning the effectiveness of antiepileptics in reducing general core symptoms of ASD, hyperactivity, mood lability, and depression. More rigorous clinical trials are needed before recommendations can be made.

Conclusions

The efficacy of antiepileptic drugs in children with autism is limited to the treatment of seizures or to specific associated behaviors. Lack of controlled clinical trials, small numbers of subjects, and population heterogeneity limit the reliability and value of available efficacy data. Few controlled clinical trials using antiepileptic drugs in children with autism, with or without seizures, have been conducted; the evidence demonstrating effectiveness is mixed.

Recommendations and Research-to-Practice Considerations

Implications for research

Additional basic clinical research on the relations between epilepsy and autism, including the developmental effects of abnormal electrical brain activity, may increase our understanding of autism pathophysiology.

Implications for practice

The treatment of seizures in autism does not differ from that of other epilepsies. However, the treatment of EEG abnormalities in children with autism without seizures is more controversial.