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

30 Participants Needed

Trial Summary

What is the purpose of this trial?

The investigators will recruit 30 children and adolescents (15 per group x 2 groups) aged 6 to 17 years with ASD and significant repetitive behaviors that cause problems to them and to others around them. Subjects will be randomized to either amitriptyline (AMI), dosed flexibly according to response and tolerability with a maximum dose of 100mg per day or 1.5mg/kg/day, in divided doses to minimize side effects, or placebo in look-alike capsules, for 10 weeks. Rating scales will be used to measure outcomes.

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 amitriptyline generally safe for humans?

Amitriptyline has been used for many years to treat various conditions, but it can cause heart-related side effects, especially in children, and may increase the risk of sudden cardiac death. It's important to have a heart check-up before starting this medication, particularly in children, to avoid serious heart problems. ^{1 2 3 4 5}

How is the drug amitriptyline unique for treating autism?

Amitriptyline is unique for treating autism because it is primarily known as a tricyclic antidepressant that works by inhibiting the reuptake of serotonin and norepinephrine, which are chemicals in the brain that affect mood. This mechanism is different from other treatments for autism, which may not focus on these neurotransmitters. ^{4 5 6 7 8}

Research Team

Jessica A. Hellings, MD

Principal Investigator

University of Kansas City-Missouri and Truman Behavioral Health

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

References

1. Austria pubmed.ncbi.nlm.nih.gov

[Amitriptyline and imipramine poisoning]. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Significance of screening electrocardiogram before the initiation of amitriptyline therapy in children with functional abdominal pain. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Effects of Low-Dose Amitriptyline on Epigastric Pain Syndrome in Functional Dyspepsia Patients. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Classics in Chemical Neuroscience: Amitriptyline. [2022]

5. Denmark pubmed.ncbi.nlm.nih.gov

Fetal teratogenicity in a rhesus macaque (Macaca mulatta): Association with the chronic maternal treatment of amitriptyline. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Intravenous amitriptyline in pediatrics. [2019]

7. England pubmed.ncbi.nlm.nih.gov

Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep. [2019]

8. England pubmed.ncbi.nlm.nih.gov

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