Amitriptyline for Autism

Overseen By Zamani Ishrath

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Missouri, Kansas City

Must not be taking: Psychotropics, others

Disqualifiers: Psychosis, Bipolar, Seizures, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 10 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of amitriptyline, an antidepressant, in reducing problematic repetitive behaviors in children and teens with autism. Participants will receive either amitriptyline or a placebo for 10 weeks to observe any noticeable behavior changes. The trial seeks children and teens aged 6-17 with autism who experience significant repetitive behaviors that disrupt daily life. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires that participants stop taking other psychotropic medications (drugs that affect mood, perception, or behavior) except for melatonin for sleep or lorazepam for severe outbursts.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that amitriptyline, a medication commonly used for depression, is being studied for its potential to help with autism symptoms, especially repetitive behaviors.

In earlier studies, small doses of amitriptyline showed promise for children and teens with autism who struggle with hyperactivity and impulsivity. These studies suggest using the drug carefully, particularly at doses around 1 mg per kilogram of body weight per day, to ensure effectiveness while reducing side effects.

Although detailed safety information about using amitriptyline specifically for autism is limited, the drug is generally used for other conditions and is considered safe when dosed carefully. However, like any medication, it can have side effects, which may vary from person to person. Always consult a healthcare provider about any concerns. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for autism?

Amitriptyline is unique because, unlike standard autism treatments that typically focus on behavioral therapy or medications targeting symptoms like hyperactivity or irritability, it acts on neurotransmitters in the brain, potentially improving a wider range of symptoms. This medication, traditionally used as an antidepressant, targets the brain's serotonin and norepinephrine levels, which may have beneficial effects on mood and social interaction in individuals with autism. Researchers are excited about amitriptyline because it could offer a novel approach by addressing the underlying neurological aspects of autism, rather than just managing individual symptoms.

What evidence suggests that amitriptyline might be an effective treatment for autism?

Studies have shown that amitriptyline, a type of antidepressant, can help with certain behaviors in people with autism. It reduces impulsive aggression, self-injury, and anxiety, which are common challenges for those with autism. Research suggests that it works by affecting brain chemicals like serotonin. A retrospective study also suggested that low doses of amitriptyline can be promising for young people with autism who haven't responded well to other treatments. These findings make it a potential option for managing repetitive behaviors in autism spectrum disorders. In this trial, participants will receive either amitriptyline or a placebo to further evaluate its effectiveness. ^{1 2 3 4 6}

Who Is on the Research Team?

Jessica A. Hellings, MD

Principal Investigator

University of Kansas City-Missouri and Truman Behavioral Health

Are You a Good Fit for This Trial?

This trial is for children and adolescents aged 6-17 with Autism Spectrum Disorder (ASD) who exhibit significant repetitive behaviors. Participants must have a confirmed diagnosis of ASD, a moderate problem rating on the CGI-S scale, and score at least an 8 on the CYBOCS-PDD for compulsive behaviors. They should not have severe intellectual disability, bipolar disorder, past psychosis, certain heart issues (QTc of 440+), or recent seizures.

Inclusion Criteria

If you have a condition that affects your ability to think and learn, it should be no worse than moderate, which means your IQ should be higher than 35.

You have a rating of at least "Moderate" on a scale that measures the severity of your problem.

You have a score of 8 or higher on a test that measures compulsive behaviors.

Exclusion Criteria

You are allergic to amitriptyline.

You have a medical condition that is not well controlled or is changing a lot.

I have had seizures in the last 3 months.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive amitriptyline or placebo for 10 weeks, with flexible dosing and regular monitoring

10 weeks

9 visits (in-person) at weeks 0, 1, 2, 3, 4, 5, 6, 8, and 10

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Amitriptyline

Trial Overview

The study tests amitriptyline against a placebo in managing repetitive behaviors in ASD patients over ten weeks. The drug's dose will be adjusted based on response and side effects but won't exceed 100mg/day or 1.5mg/kg/day. Outcomes are measured using rating scales to track changes in behavior.

How Is the Trial Designed?

Group I: amitriptyline Active Control 1 Intervention

Subjects will receive active amitriptyline compounded into look-alike capsules to resemble placebo capsules. Dosing will be as tolerated, up to tid and maximum of 100mg/day or 1.5mg/kg/day, for 10 weeks.

Group II: placebo Placebo Group 1 Intervention

Subjects in this arm will receive placebo compounded into capsules that resemble the compounded amitriptyline capsules, up to 4 capsules a day (1 qam, 1 q4pm and 2 capsules qhs), for 10 weeks.

Amitriptyline is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Elavil for:

• Depression
• Anxiety and Stress
• Chronic Pain
• Fibromyalgia
• Headache
• Migraine Prevention
• Neuropathic Pain

Approved in European Union as Amitriptyline for:

• Depression
• Anxiety disorders
• Chronic pain
• Fibromyalgia
• Headache
• Migraine prevention
• Neuropathic pain

Approved in Canada as Elavil for:

• Depression
• Anxiety and stress
• Chronic pain
• Fibromyalgia
• Headache
• Migraine prevention
• Neuropathic pain

Who Is Running the Clinical Trial?

University of Missouri, Kansas City

Lead Sponsor

Trials

73

Recruited

34,600+

Published Research Related to This Trial

Amitriptyline, introduced in 1961 as Elavil, is an effective treatment for major depressive disorder, working by inhibiting the reuptake of serotonin and norepinephrine, which helps in managing mood disorders.

Despite its therapeutic benefits, amitriptyline poses a risk of cardiotoxicity due to its off-target effects on various receptors, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Classics in Chemical Neuroscience: Amitriptyline. McClure, EW., Daniels, RN.[2022]

In a double-blind trial involving 40 patients, maprotiline demonstrated a statistically significant earlier onset of antidepressant effects compared to amitriptyline (p < 0.001).

Both medications showed equal long-term effectiveness and no greater side effects, suggesting that maprotiline could be a safer and faster-acting alternative for treating depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of maprotiline (Ludiomil) and amitriptyline (1). Dell, AJ.[2013]

Two cases of severe poisoning from tricyclic antidepressants (Amitriptyline and Imipramine) were reported in children aged 3 and 11, showing serious cardiovascular and neurological symptoms.

In one case, physostigmine was successfully used as an antidote, highlighting its potential role in treating such poisonings, while also suggesting the need for alternative treatments for childhood enuresis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Amitriptyline and imipramine poisoning]. Paul, H., Ehrenthal, W., Wahlen, W.[2013]

In a study of 760 EKGs from children with irritable bowel syndrome, only 3 showed a true prolonged QTc interval, highlighting the importance of careful manual interpretation by a pediatric cardiologist, as these cases were missed by computer-generated readings.

The findings emphasize the necessity of performing screening EKGs before starting amitriptyline therapy in children to prevent potential cardiac risks, as amitriptyline is known to increase the risk of arrhythmias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Significance of screening electrocardiogram before the initiation of amitriptyline therapy in children with functional abdominal pain. Patra, KP., Sankararaman, S., Jackson, R., et al.[2019]

Amitriptyline, a tricyclic antidepressant used for pain and sleep disorders, has been reported to have teratogenic effects when exposed to a fetus during pregnancy.

This case highlights the potential risks associated with maternal-fetal exposure to amitriptyline, emphasizing the need for caution in its use during pregnancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fetal teratogenicity in a rhesus macaque (Macaca mulatta): Association with the chronic maternal treatment of amitriptyline. Hunter, CE., Stammen, RL., Hamlet, T., et al.[2021]

A retrospective review of 8 children (ages 5-16.6 years) showed that intravenous (IV) amitriptyline was used for various conditions, including neuropathic pain and depression, in patients who could not take oral medications.

One patient experienced an extrapyramidal reaction, which was managed effectively, highlighting the need for further controlled studies to evaluate the safety and efficacy of IV amitriptyline in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous amitriptyline in pediatrics. Collins, JJ., Kerner, J., Sentivany, S., et al.[2019]

A study involving six Lacaune ewes found that amitriptyline (AMI) has low intrathecal (IT) bioavailability (1.3%) when administered epidurally (EPI), indicating limited effectiveness in reaching the spinal space from the EPI route.

In contrast, AMI showed a higher bioavailability (55%) when administered intrathecally, suggesting that direct IT administration is more effective for achieving therapeutic concentrations in the spinal area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep. Ratajczak-Enselme, M., Grégoire, N., Estebe, JP., et al.[2019]

In a study of 60 patients with epigastric pain syndrome, low-dose amitriptyline (25 mg) significantly improved dyspepsia symptoms and reduced the time to fall asleep compared to routine treatment with pantoprazole (40 mg) over a 4-week period.

While amitriptyline showed benefits in symptom relief and sleep onset, it did not have a significant impact on psychological distress or overall sleep quality compared to pantoprazole.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Low-Dose Amitriptyline on Epigastric Pain Syndrome in Functional Dyspepsia Patients. Liu, J., Jia, L., Jiang, SM., et al.[2023]

Citations

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Amitriptyline is a tricyclic antidepressant being studied off-label here for repetitive behaviors in autism spectrum disorders. · Other Names: Elavil.

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Amitriptyline often improves impulsive aggression, self-injury, sleep, anxiety and enuresis. This article recommends additional older drug ...

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Elavil (Amitriptyline)

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Cautious use of low dose AMI shows promise for treatment-resistant youth with ASD accompanied by hyperactivity, impulsivity, aggression and self injury.

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A Retrospective Study of Amitriptyline in Youth with Autism ...

Low-dose amitriptyline shows promise for treatment resistance in children, adolescents and adults with ASD, an observation initially made at the ...