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From melatonin for sleep-onset insomnia to electroconvulsive therapy for severe adolescent mood disorder to steroid-induced psychosis to the risk of stimulant-induced psychosis in youth with ADHD, and MORE! In this two-part series, Mara and Dr. Feder will tackle various research topics in the field of child psychiatry. 

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Published On: 12/9/2021

Duration: 14 minutes, 35 seconds

Referenced Articles: 

“Risk of Psychosis With Stimulants in ADHD Patients,” The Carlat Child Psychiatry Report, May/June/July/August 2021

“Vitamin D for ADHD?,” The Carlat Child Psychiatry Report, October/November/December 2020

“Efficacy and Safety of SSRIs and SNRIs for Child and Adolescent Psychiatric Disorders,” The Carlat Child Psychiatry Report, January/February 2018

Joshua Feder, MD, and Mara Goverman, LCSW, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

Transcript:

Dr. Feder: Hello! I’m Dr. Joshua Feder, the Editor-in-Chief of The Carlat Psychiatry Report, and in this episode, brought to you by The Carlat Child Psychiatry team, Mara and I will tackle various research studies in child psychiatry. These studies focused on research topics ranging from the risk of stimulant-induced psychosis in youth with ADHD to the efficacy and safety of SSRIs and SNRIs for youth psychiatric disorders. We will also cover another study that set out to answer whether vitamin D supplementation is beneficial for ADHD.

Dr. Feder: Now onto the risk of psychosis with stimulant use in children with ADHD. 

In 2007, the FDA required stimulant manufacturers to warn of possible psychosis with stimulants. But what is the real incidence?

Mara: The goal of this study was to determine if there’s any differences in incidence of psychosis between methylphenidate and amphetamine classes of medications. 

Drawing from two large commercial insurance databases, researchers looked at over 333,000 patients with ADHD ages 13–25 years who were prescribed a stimulant between 2004 and 2015, matching 110,923 methylphenidate users with an equal number of amphetamine users.

Dr. Feder: The authors excluded patients with confounding variables (eg, glucocorticoid prescription) and adjusted for unmeasured confounders (eg, cannabis use). They defined “stimulant-induced psychosis” as a new psychotic illness within the follow-up period (median 4–5 months) along with a prescription for an antipsychotic within 60 days of that diagnosis.

Mara: Over the years 2005 to 2014, prescription of amphetamine salts increased 3.8 times, while that of methylphenidates increased only 1.6 times. It was notable that internists and family practice doctors tended to use amphetamines most often, prescribing amphetamines in 72.5% of stimulant prescriptions, with psychiatrists at 62.7% and pediatricians 51.6%.

Dr. Feder: The overall risk of psychosis was 1 in 660, with onset of psychotic symptoms occurring after a median 128 days. The risk of psychotic symptoms in the amphetamine group was about double that of the methylphenidate group, having 237 episodes vs 106 episodes, respectively.

Mara: Amphetamine-related psychosis occurred more in younger children and those treated by ­non-psychiatrists (about 80% of patients). In the hands of internists and family practice doctors, the hazard ratio was 1.78, for pediatricians it was 1.7, and for psychiatrists it was 1.38.

Dr. Feder: Overall, amphetamines, such as Adderall, are more likely to lead to psychosis than methylphenidate, though the actual prevalence is quite low. We recommend extra caution in the use of stimulants (especially amphetamines) in those with other risk factors for psychosis (eg, family history of psychosis, cognitive or behavioral signs of prodromal psychosis, or concurrent cannabis use). In the broader picture, methylphenidate is usually better tolerated in any case and probably a ­better first-line medication.

Mara: Since the 2004 FDA black-box warning on all antidepressants for pediatric use, controversy continues over the use of SSRIs and SNRIs in children and adolescents. Both classes of medication are still commonly used for pediatric depressive disorders, anxiety disorders, and obsessive-compulsive disorder. A 2017 systematic review and meta-analysis took another look at the evidence substantiating the use of these medications in youth with various psychiatric disorders. 

Dr. Feder: The authors reviewed 36 randomized, double-blind, placebo-controlled trials with 6,778 participants (48.6%/51.4% boy/girl, average age ~13 years). Each study compared an SSRI or an SNRI versus placebo for children or adolescents with a diagnosis of depressive disorder (17 studies), anxiety disorder (10 studies), OCD (8 studies), or PTSD (1 study). Effect sizes were calculated as standardized mean differences, and risk ratios for adverse events were also addressed. A good rule for interpreting effect sizes is that ≥ 0.8 is considered a large effect, 0.5 a medium effect, and ≤ 0.2 a small effect.

The authors found medium to small effect sizes for the disorders examined: 0.56 for anxiety disorders, 0.39 for obsessive-compulsive disorders, and 0.20 for depressive disorders. However, the single study for PTSD showed no statistical significant treatment effect size. 

Mara: For all disorders grouped together, the SSRIs and SNRIs were more beneficial than placebo by only a small to medium effect size of 0.32. However, compared with participants receiving placebo, patients receiving an antidepressant reported a statistically significant increase in adverse effects, including headache, nausea, and suicidal thoughts and behaviors, although the clinical significance of these differences is less clear.

Dr. Feder: These results are not particularly surprising. Clinicians have long noticed that serotonergic agents work better for anxiety disorders in kids than they do for depression—in line with the higher effect sizes reported for anxiety disorders (a fairly impressive 0.56) in this study. Especially given the elevated risk for serious side effects, the small effect size of 0.20 for depression is disquieting. This is yet another reminder that we should think carefully before using SSRIs and SNRIs for depression in children. 

Mara: Lastly, let’s talk about the vitamin D supplementation in children and adolescents with ADHD.

Many children do not respond to or tolerate standard pharmacotherapy, which drives continued interest in supplements for many conditions, including ADHD. Vitamin D plays a role in healthy brain development, and vitamin D deficiency causes neurotransmitter alterations in pathways underlying ADHD pathogenesis. But is there a link between ADHD and lower vitamin D levels?

Dr. Feder: In 2019, Gan and colleagues conducted a systematic review and meta-analysis to assess the strength of evidence supporting vitamin D supplementation in ADHD. The study looked at four randomized controlled trials (n = 256) studying vitamin D supplementation for ADHD (1,000 international units [IU] daily–50,000 IUs weekly) vs placebo as an adjunct to methylphenidate for children (5–18 years). Trial durations lasted 6–12 weeks.

Mara: The researchers assessed ADHD symptom severity level based on a variety of parent-only rating scales as the primary outcome. The secondary outcomes were adverse effects of supplementation and vitamin D status afterwards.

Dr. Feder: Adjunctive vitamin D supplementation yielded a small but statistically significant improvement in ADHD total score and inattention, hyperactivity, and behavior subscales. Scores for oppositional behaviors were unchanged except in a subgroup analysis of high-dose vitamin D supplementation (> 2,000 IUs daily). 

Mara: Notably, one study found that children with baseline vitamin D deficiency or insufficiency were more likely to respond to adjunctive vitamin D supplementation. Only one trial reported on adverse events, which were mild and similar between groups. Not surprisingly, vitamin D supplementation increased vitamin D levels and also increased the ratio of patients with sufficient vitamin D levels.

Dr. Feder: This paper used excellent methodological procedures for conducting systematic reviews and meta-analyses. Unfortunately, the RCTs were of very low to low quality. Randomization procedures were not clear, the total population was less than 400, and statistical methods varied. All of these trials were carried out in the Middle East, but children’s ethnicities were not reported, so generalizability is unclear.

Mara: Vitamin D supplementation is a relatively low-risk and low-cost intervention with general health benefits. We recommend you consider trying it both in children with vitamin D deficiency and in combination with standard ADHD treatment. 

Dr. Feder: It’s unclear whether similar results would extend to non-methylphenidate stimulants. More research is needed using higher-quality evidence that examines whether vitamin D dose, administration frequency, and baseline status influences outcomes. Do take care to avoid mega-doses, though, as this can disrupt calcium metabolism.

These research updates are available for subscribers to read in The Carlat Child Psychiatry Report. Subscribers get print issues in the mail and email notifications when new issues are available on the website. Subscriptions also come with full access to all the articles on the website and CME credits. 

Mara: And everything from Carlat Publishing is independently researched and produced. There’s no funding from the pharmaceutical industry. 

Dr. Feder: Yes, the newsletters and books we produce depend entirely on reader support. There are no ads and our authors don’t receive industry funding. That helps us to bring you unbiased information that you can trust. 

Mara: Go to www.thecarlatreport.com to sign up. You can get a full subscription to any of our four newsletters for $30 off using the coupon code LISTENER.

As always, thanks for listening and have a great day!

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