CCPR: Welcome, Dr. Krause. Tell us a little bit about the recent paper you coauthored called Pharmacologic Management of Autism Spectrum Disorder: A Review of Seven Studies (Kothadia RJ et al, Current Psychiatry 2021;20(1):33–38).
Dr. Krause: Our study was a review of reviews. The aim was to see if we could find any new insights into medication treatment in autism. Medication is a supplemental intervention in autism. We reserve it for challenging situations due to neurologic, metabolic, behavioral, and other side effects. Still, medications can be very beneficial when implemented appropriately. Our AACAP practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder emphasizes the developmental assessment screening, a thorough diagnostic evaluation, multidisciplinary assessment, and structured educational and evidence-based behavioral health treatment, all ahead of pharmacotherapy.

CCPR: What do you see as the main goals in treating autism with medications?
Dr. Krause: The main goal is to target secondary symptoms, such as irritability, anger, self-injurious behavior, anxiety, and depressed mood. Because of the heterogeneity of autism, we need to look at the associated symptoms and comorbid diagnoses before electing which direction to go with medication. Medications for autism are not curative, but they can alter the trajectory of the outcomes, quiet things down so patients can reach their goals. Often medication resets that baseline to get them to function to the best of their capabilities.

CCPR: What did you learn in your review of reviews?
Dr. Krause: The big news is sort of no news. Antipsychotics have the most data, and risperidone outperformed aripiprazole, lurasidone, and placebo on the Autism Behavior Checklist-Iceberg (ABC-I). This supports what most of us are already doing. But the other news is that SSRIs show mixed results. Fluoxetine worked for 75% of patients with positive changes on the Autism Behavior Checklist (ABC), Autism Treatment Evaluation Checklist (ATEC), Clinical Global Impression scale (CGI), and Yale-Brown Obsessive Compulsive checklist (YBOC) but with frequent behavioral activation. Sertraline, on the other hand, was well tolerated but ineffective on measures of expressive language or any other outcomes. Donepezil plus choline helped expressive language in 5- to 10-year-olds but not older children, who also had worse behavior on the treatment. And in the supplement realm, both Vitamin D and omega-3 fatty acids each separately reduced hyperactivity and were well tolerated.

CCPR: What else was interesting?
Dr. Krause: There is a wide variety of medications and natural supplements employed for the management of autism-related symptoms. I was intrigued by all the neurotransmitter and biological targets, including dopamine and serotonin, but also GABA-glutamate pathways. The bumetanide trial could represent a potential breakthrough. It is one of the first of its kind to study the core feature deficits in social communication and restricted range of interests.

CCPR: Tell us more about bumetanide.
Dr. Krause: It could be a game-changer. Bumetanide is actually a loop diuretic similar to furosemide that acts by antagonizing ion channel transporter systems in renal tissue but also in the central nervous system. Low-dose bumetanide improved social communication as well as restricted interests. The three trials included 208 patients ages 2–18 years in randomized controlled trials, but used different outcome measures including CARS, CGI, the ABC, the Social Responsiveness Scale, and the ADOS, making it difficult to draw specific conclusions (James BJ et al, Ann Pharmacother 2019;53(5):537–544). So, based on that alone, am I ready to recommend bumetanide? Probably not.

CCPR: It still sounds hopeful. Were there side effects with bumetanide?
Dr. Krause: With higher doses, there was hypokalemia and polyurea. Apart from that, it was pretty well tolerated.

CCPR: What’s the message of your paper for everyday clinical practice?
Dr. Krause: Begin where we have the most evidence and branch out from there to options with limited or anecdotal evidence. Off-label prescribing is OK; however, we should have a low threshold to discontinue treatment at the first sign of significant side effects or clinical worsening.

CCPR: What should we tell patients and families about the use of medications for autism?
Dr. Krause: Medication is a tool that should be used when it might help. Tell them how it may help some problems, such as irritability and perhaps attention, but is unlikely to help the core problems with social communication and the narrow range of interests. Talk about the available evidence in a way that families can understand. I talk about the goal to strengthen the quality of life and mental well-being of patients and perhaps lessen the burden on parents and guardians, educators, and others involved in the day-to-day life of the child.

CCPR: What do you tell them about side effects?
Dr. Krause: We need to monitor closely because medications in this population often do not have the expected and desired effects. One example is that SSRIs have a higher likelihood of behavioral activation. Medications don’t work the same in the autism population as they do in others, and so close follow-up and psychoeducation are important.

CCPR: Parents often want to use medication only as a last resort, pursuing things that have less evidence such as herbals, acupuncture, and chiropractic. How do you respond to this?
Dr. Krause: I use the AACAP practice parameters to offer what we know of the evidence for various treatments (www.tinyurl.com/kd6mwxss). At the same time, you have to respect families’ wishes. I always say: “We want to try whatever we can and if there’s newer options, it’s intriguing.” Don’t discount it completely. Some families will come in and say they’ve started something—for example, CBD—and they feel it’s working. I will say: “I hear you that you are finding it useful. I can’t recommend a certain product or a certain dose.” Then I offer the AACAP stance. There are ethical nuances in not recommending or recommending against a “treatment,” and in not interfering with parents’ choices for their children. We have to find ways to work safely with families.

CCPR: What cultural or equity impacts do you see at play in the use of medication for kids with autism?
Dr. Krause: Racial and socioeconomic disparities are particularly problematic for autism when considering the importance of early detection, screening, identification, and treatment. African American children are diagnosed a year and a half later than the general population, and minority children tend to receive fewer services, which really puts them at a disadvantage. They are also more likely to be given medications as first-line options because prescribing trends for autism increase with age. Furthermore, more Medicaid-insured children are prescribed medication relative to those who have a commercial payer source. Taken together, a delay in diagnosis plus limited access to resources results in increased pressure on psychiatrists to play catch-up in the form of medication management, which often leads to polypharmacy (Constantino JN et al, Pediatrics 2020;146(3):e20193629).

CCPR: Any thoughts on how to get earlier diagnosis and access to treatment for minority populations?
Dr. Krause: We need to ensure minority and underserved populations have appropriate access to primary care. Going back a step, we also need to ensure that women receive timely prenatal and perinatal care, especially when autism risk factors may already be present within the family. A key component as well is education of personnel at childcare/school, where kids spend so much of their time and where their social interactions and play tendencies can be closely observed from a very young age.

CCPR: What’s your bottom-line message about medication treatment for kids with autism spectrum disorder?
Dr. Krause: As psychiatrists, we need to be compassionate but up front with families about the indications and expectations of medication treatment for autism spectrum disorder.

CCPR: Thank you for your time, Dr. Krause.