August 2023 Newsletter: Donanemab for Alzheimer’s Disease, Atypical Psychopharmacologic Strategies for Youth, and Pharmacologic Therapies for Fibromyalgia

This newsletter presents the findings of a phase 3 trial for donanemab—a groundbreaking drug engineered to battle Alzheimer’s disease. The trial results highlight donanemab’s promise in decelerating the progression of early-stage Alzheimer’s disease.

We also discuss updates on atypical psychopharmacologic strategies for youth, key points from a presentation on pharmacologic therapies for fibromyalgia, and our practical research summaries of adult, child, and adolescent psychiatry (Quick Takes and CAP Smart Takes).

Donanemab for Early Symptomatic Alzheimer’s Disease

Donanemab—an innovative drug developed to combat Alzheimer’s disease—has shown promising results in the disease’s early stages. According to the TRAILBLAZER-ALZ phase 2 trial, donanemab offered significant cognitive and functional improvements.

As of July 17, 2023, the phase 3 results have been published, indicating a significant deceleration of clinical progression at 76 weeks.

How does donanemab work?
- Donanemab is a monoclonal antibody designed to selectively target and facilitate the removal of brain plaques by identifying a modified version of beta-amyloid known as N3pG, a distinctive form of the beta-amyloid protein.

How does donanemab differ from aducanumab and lecanemab?
- All 3 work by targeting forms of beta-amyloid. However, they target slightly different forms of this protein and have different properties.
- Aducanumab targets aggregated forms of beta-amyloid, reducing amyloid plaques.
- Lecanemab selectively targets large, soluble beta-amyloid protofibrils, which might help to slow the formation of plaques.

Which patients are candidates for treatment with donanemab?
- Patients with early symptomatic Alzheimer’s disease

What makes donanemab more effective in earlier than later stages of Alzheimer’s disease?
- In the early stages of Alzheimer’s, there may be fewer plaques.
- In later stages, significant neuronal damage has already occurred. This damage is irreversible, and donanemab may not be able to reverse the cognitive decline associated with this damage.
- Also, the progression of Alzheimer’s disease is often faster and more severe in the later stages.

What do we know about its efficacy?
- By the conclusion of the 76-week trial:
  - 80% of the participants in the donanemab group had a clearance of amyloid plaques.
  - Although all participants observed a persistent decline in cognition and daily function, the administration of donanemab successfully delayed the advancement of symptoms by approximately 4 months.

What are the risks associated with the use of donanemab?
- Amyloid-related imaging abnormalities (ARIA) include 2 types: ARIA-E and ARIA-H.
  - ARIA-E (brain swelling) occurred in 24% of cases, with 6.1% symptomatic.
  - ARIA-H (brain microbleeds) occurred in 31.4% of cases.
  - Most ARIA cases were mild to moderate and managed effectively. However, severe ARIA led to 3 deaths in the study.
- Infusion-related reactions occurred in 8.7% of participants, with most cases being mild to moderate. You can learn more here.

It will be important to consider whether the potential benefits of donanemab, which includes an average delay in disease progression of about 4 months, outweigh the financial costs and the impact on the patient’s quality of life.

Atypical Psychopharmacologic Strategies for Children and Adolescents, With David Rosenberg, M.D.

In this interview, Dr. David Rosenberg discusses practical considerations when it comes to atypical psychopharmacologic strategies in children and adolescents and tackles common concerns, such as dosing considerations, possible adverse effects, and tapering strategies. He also addresses questions regarding the use of atypical psychopharmacologic agents for specific clinical concerns, such as insomnia, obsessive-compulsive disorder, and self-injurious behaviors.

Interview highlights include the following:

Low-dose topiramate is generally better tolerated by children and adolescents compared with adults, but it is still important to watch out for side effects, such as cognitive impairment.
Use of antihistamines for the management of insomnia and sleep difficulties should be limited to the short term and always complemented with sleep hygiene techniques.

Learn more and earn 0.75 CME credits here.

Nociplastic Pain Syndromes: Focus on Fibromyalgia

In this video lecture, Dr. Clauw imparts his expertise on nociceptive pain syndromes, emphasizing fibromyalgia. He elucidates the various pain mechanisms and outlines the process for identifying and diagnosing patients with fibromyalgia. Furthermore, he also explores pharmacologic and nonpharmacologic treatment approaches, offering valuable clinical pearls for effectively managing patients with chronic pain.

Pharmacologic Therapies for Fibromyalgia

The recommended pharmacologic therapies for nociplastic pain include:
- Tricyclic drugs.
- SNRIs.
- Gabapentinoids.

Learn more and earn 0.75 CME credits here.

Quick Takes: Research, Digested

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) Recommendations for the Management of Patients With Bipolar Disorder With Mixed Presentations

The CANMAT-ISBD guidelines present mixed states as “dimensional”; any admixture of manic and depressive symptoms is possible.
According to Dr. Roger McIntyre, the most clinically important symptoms of mixed states are the “4 A’s”: Agitation, anger, anxiety, and attention problems.
This makes it extremely difficult to make the differential diagnosis of mixed states vs major depression plus generalized anxiety disorder, PTSD, borderlinity, or MDD plus attention-deficit/hyperactivity disorder.
But selecting among treatment options is not so impossible. After exhausting nonmedication options, it’s about whether to use an antidepressant—or whether to taper the one that’s already there. Learn more.

Listen to or read the full volume, and earn 0.5 CME credits here.

CAP Smart Takes: Research, Digested

Prescribing Stimulants for Youth With ADHD and Co-Occurring Cannabis Use

Chronic cannabis use starting in childhood or adolescence is associated with long-term problems in attention, cognition, impulse control, executive functioning, and intellectual ability.
There is concern that cannabis use may worsen preexisting symptoms in youth with ADHD.
Motivational enhancement interviewing can help gauge the adolescent’s insight into how cannabis use may complicate ADHD treatment. Nonstimulant medications and close substance use/abuse monitoring may be appropriate in some cases. Learn more.