By Linnea Sepe-Forrest, Indiana University
Antipsychotic medications have revolutionized the pediatric psychiatry field, placating children with severe disruptive behavior disorders and ameliorating psychosis symptoms that can torture developing children (Jensen et al., 2007; Scotto Rosato et al., 2012). These drugs can improve extreme difficulties in functioning by altering neurochemical levels, particularly for the dopamine neurotransmitter (Solmi et al., 2017). The most commonly used antipsychotic medications primarily function by reducing dopamine levels in regions that are thought to contribute to the presence of unwanted aberrant symptoms (e.g., hallucinations), while increasing dopamine release in regions that facilitate adaptive behaviors (e.g., reward response) that are often diminished in psychosis (Juckel, 2016; Loy et al., 2017; Stahl, 2001) At the same time, antipsychotics are one of the most toxic psychiatric medications prescribed to youth, with recipients being more than 4 times as likely to die of cardiovascular or metabolic events (Ray et al., 2019). Extensive evidence has indicated these drugs cause severe weight gain, hormonal changes, and increased risks of movement disorders (Briles et al., 2012; Brown et al., 2021). These medications can be especially damaging for children and adolescents, who may experience worse metabolic effects and extrapyramidal symptoms compared to adults (Kryzhanovskaya et al., 2012; Vitiello et al., 2009). It is therefore critical for doctors to know the true drug benefits that can be weighed against the likely metabolic and other costs.
The probable detrimental effects of antipsychotics are often justified by citing potential benefits. A number of relatively short, randomized control trials (RCTs) support the use of risperidone (Risperdal) and aripiprazole (Abilify) for treatment of irritability seen in autism spectrum disorder (ASD) (Fallah et al., 2019). Furthermore, a review on RCTs, with a median length of 8 weeks, suggests antipsychotics may have a small beneficial effect on delusions, hallucinations, and other psychotic symptoms among youth (Stafford et al., 2015). While there are far fewer studies examining long-term effects of antipsychotics on psychopathology, a number of RCTs claim that the improved symptoms reported in short term trials are sustained over time (Singappuli et al., 2022). Specifically, 3 clinical trials reported greater sustained improvements for risperidone in ASD and aripiprazole in bipolar disorder compared to placebo (Findling et al., 2012; Luby et al., 2006; Nagaraj et al., 2006). Studies have additionally reported sustained benefits of antipsychotics for treating children with early schizophrenia or conduct disorders, two of the primary populations receiving antipsychotics, based on long-term extension studies that followed youth over time (≥ 6 months) and found better outcomes at the end of the study compared to the beginning (Masi & Liboni, 2011; McKinney & Renk, 2011).
If the benefits claimed in this study were to be true, this would be extremely promising as it would mean there are concrete solutions to reduce suffering in children and families who are dealing with severe psychiatric problems. However, in my view, there are many weaknesses in the current studies that have limited the conclusions that can be drawn. Perhaps the largest factor limiting the current evidence on efficacy is pervasive, unaccounted-for attrition bias (Loy et al., 2017; Stafford et al., 2015). Most studies report drug benefits based on outcomes from the final fraction of children who did not drop out of the trial due to severe side effects or worsening symptoms (Stafford et al., 2015). This is especially true for long-term studies, as most are “open-label extension trials” without comparison groups, limited to only those individuals who tolerated and responded to the drug well during an initial trial (Boyce et al., 2018; Gorwood, 2006). When comparing results between the same individuals, it is unclear to what degree the antipsychotics may be improving symptoms compared to individual factors influencing a child, such as concurrent treatments or natural changes due to maturation (Joseph et al., 2015; Moerman & Jonas, 2002). Furthermore, critics have argued that these extension trials may be “pharmaceutical company propaganda”, with a focus on reporting benefits of the drugs while neglecting to assess and adequately discuss poor outcomes (Day & Williams, 2007).
The flaws highlighted in these studies do not indicate whether a drug is or is not beneficial towards psychopathology, but rather suggest that the potential benefits among youth remain unclear. This is in contrast with the metabolic and other physiological adverse effects, which have been extensively studied in both rodent and human models (Almandil et al., 2013; Boyda et al., 2010). This is to be expected, as it is much more difficult to assess causal impacts on psychological outcomes than on weight gain, hormone alterations, or other physiological changes that are easier to measure and observe across species (Carter et al., 2017; Moore, 2010). These studies on psychological benefits can be improved by increasing the sample sizes, lengthening the follow-up time, accounting for dropouts, and including a comparison group in clinical trials. However, conducting large, long-term randomized control trials on antipsychotic use in pediatric populations is exceedingly challenging and costly (Caldwell et al., 2004). For this reason, experts have suggested leveraging the use of advanced causal inference methods in large healthcare datasets that capture real world outcomes (Bérard, 2021). Although no observational method can definitively identify the true (causal) benefits, improved estimates are needed for professionals across healthcare teams to understand the extent to which clinical improvement can be attributed to medication effects compared with concurrent interventions (e.g., psychotherapy). This information is also essential for doctors to accurately weigh the costs and benefits of providing antipsychotic prescriptions.
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