Medication in 22q11DS

As briefly presented earlier, prevalence of psychopathology in 22q11DS is very high, with 73-79% of individuals presenting with at least one psychiatric diagnosis (Green et al., 2009; Tang et al., 2014). Furthermore, comorbidity of psychiatric diagnosis is also very high with 42-50%

of individuals presenting with two or more psychiatric diagnosis and 16% with at least three (Tang et al., 2014; Yi et al., 2015). Because of the increased risk of psychopathology, many 22q11DS carriers are required to take a medication in the course of their lives. However, a large study including 112 individuals with 22q11DS suggest that this population is rather undertreated for their diagnosed psychiatric illnesses (Tang et al., 2014). The authors report that only 42% of individuals with a psychotic disorder are taking antipsychotic medication.

Additionally, 34% of individuals diagnosed with ADHD take stimulants or alpha-2 agonist, and 36% of people diagnosed with mood or anxiety disorder take antidepressants or anxiolytics and 13% take mood stabilizers. It has been suggested that due to medical conditions associated with 22q11DS (e.g., heart defect, hypocalcemia), certain clinicians are reluctant to prescribe medication (Dori, Green, Weizman, & Gothelf, 2017). This is why it is of utmost importance to conduct studies on safety and efficacy of medication in 22q11DS to help guide the care and management of these patients.

Medications most frequently prescribed in 22q11DS include antipsychotics, antidepressants, and stimulants. Paradoxically, studies on the effects of these medications and the short- to long-term outcome are still scarce. In a retrospective study examining 190 records of patients with 22q11DS, Dori et al. (2017) found that treatments with antipsychotics and antidepressants are effective and relatively safe in this population. In a longitudinal study including 62 participants with 22q11DS followed-up 2 to 4 times, Mancini, Maeder et al. (2020) demonstrate that long-term treatment with an antidepressant (Selective Serotonin Reuptake Inhibitor, SSRI) - alone or in combination with atypical antipsychotics - ameliorates cognitive performances (measured by IQ scores) and has a promising effect on brain development (increased volume of dentate gyrus, frontal and cingulate regions).

As for the use of stimulants in 22q11DS, two studies have looked at the effects of methylphenidate (MPH), known under the trade name Ritalin®, Concerta® or Medikinet®, which is the first-line medication for the treatment of ADHD according to Anglo-Saxon recommendations (National Institute for Health and Care Excellence, NICE Guidelines, March 2018). In a first study, Gothelf et al. (2003) evaluated the effects of low dose of MPH (0.3mg/kg) in 12 individuals, aged 5 to 20 years old, with 22q11DS and ADHD. They found that MPH significantly diminished core symptoms of ADHD and improved cognitive measures of attention in a sub-group of 6 participants. In a follow-up after 4 weeks, treatment was shown

to be effective and safe with no significant change in cardiac measures or participants exhibiting psychotic symptoms. Side effects were very common (92%) but never server enough to warrant discontinuation of medication. Similar to other studies on idiopathic ADHD, the most common reported side effect was poor appetite, but other effects were also relatively frequent (irritability, sadness, stomachaches, talking little with others and proneness to crying). In a second study from the same group, the authors evaluated in more detail the effects of MPH on cognition, including working memory, inhibition, mental flexibility and visual attention (Green et al., 2011). The studies included a larger sample (N=34) aged 5 to 20 years old and effects of MPH were compared to a placebo group (respectively N=22 vs. N=12). The results show that a single dose of MPH (0.5 mg/kilo) is associated with an increase in cognitive functions underpinned by the frontal lobes. The authors showed that performance on the cognitive task only taxing working memory was not affected by MPH, while tasks taxing both working memory and inhibition improved significantly with medication, compared to a placebo. After 6 months of regular treatment, the authors re-evaluated the psychiatric diagnosis, observing decrease in core ADHD symptoms of 40%. They also observed that the treatment was well tolerated by the participants (stable side effects) and that cardiovascular side effects were minimal. However, number of participants who continued treatment after the initial dose was small (N=15).

Altogether these two studies provide evidence for effectiveness and safety of MPH in 22q11DS.

Since they included small sample size, results should be confirmed in a larger sample and long-term effect (chronic users) should be differentiated from short-long-term effects (single dose). Both studies found encouraging effects both on core ADHD symptoms and associated cognitive measures however, the effect of MPH on specific cognitive measures is still limited with few domains of attention and EF explored.

Finally, omega-3 supplements are also worth mentioning given their safety, tolerability and positive effects reported on cognitive measures of attention (distractibility) in 22q11DS

(Armando et al., 2020). Furthermore, in the sample of 62 patients aged 8-25 years old, individuals with an omega-3 treatment showed less risk of developing an UHR status and lower conversion rate to psychosis. However, results were obtained from an observational analysis and should be confirmed in a randomized clinical trial.

In sum, because of the increased risk for developing psychiatric disorders and the cognitive impairments observed in 22q11DS, medication represents an important aspect of treatment and care of this population. However, as a rare genetic condition, research evaluating benefits of medications specifically for 22q11DS individuals are still scarce with limited number of studies, limited sample size or results derived from observational analysis. This demonstrates the need to conduct more clinical trials in this population.