Progress in Neuro-Psychopharmacology and Biological Psychiatry
Moderators of treatment response in adults with ADHD treated with a vitamin–mineral supplement☆
Introduction
Attention-Deficit/Hyperactivity Disorder (ADHD) in adulthood has become increasingly recognized as an important disorder to treat, with prevalence rates for adult ADHD estimated between 4 and 5% (Kessler et al., 2006) and poor long-term outcomes documented for those followed to adulthood (Klein et al., 2012). Predictors of treatment response are confined to medication trials with symptom severity, gender, co-occurring disorders, and academic achievement shown to influence outcome (Buitelaar et al., 2011, Torgersen et al., 2008). The most common risk factors studied are genetic; however, this emphasis has led to an overall neglect in considering the role that the environment might play in the expression of the symptoms (Calarge et al., 2010). Although there has been a recent interest in the role that nutrients play in the expression and treatment of ADHD (Milte et al., 2012, Nigg et al., 2012), as well as studies showing associations between nutrient levels and ADHD behaviours (Arnold et al., 2005), to date no study on broad-based micronutrient supplementation has investigated whether nutrient levels can be useful at predicting treatment response.
Biochemical markers or biomarkers are becoming increasingly studied in attempts to identify those who might be at risk for ADHD as well as to identify possible areas for intervention (Scassellati et al., 2012). Some biomarkers are modifiable and thus may lead to targeted treatments. Individual nutrients have been the focus of studies attempting to determine the role that they may play in the expression of ADHD in children. The most studied candidates have been iron and zinc, with some positive and some negative results (Akhondzadeh et al., 2004, Arnold et al., 2011, Bilici et al., 2004, Cortese et al., 2009, Konofal et al., 2008, Oner and Oner, 2008, Oner et al., 2010, Sever et al., 1997, Uckardes et al., 2009). The rationale for supplementing with these nutrients includes the role that iron plays as a coenzyme of tyrosine hydroxylase, critical for dopamine synthesis (Oner and Oner, 2008), and the role that zinc plays in regulating the dopamine transporter, among its many functions (Lepping and Huber, 2010). There have been no studies looking at the impact of nutrient levels on the expression of ADHD in adults. Nutrient biomarkers seem a potentially profitable way forward to predict treatment responders, given that mechanisms by which nutrient treatments might work implicate nutrients working at the cellular level, either through improving mitochondrial functioning (Gardner and Boles, 2005), correcting in-born errors of metabolism (Kaplan et al., 2007), possibly addressing compromised gastrointestinal functioning (Jackson et al., 2012) or inflammation (Donev and Thome, 2010), or acting as cofactors for various metabolic activities in the body (Ames et al., 2002). Deficiencies in nutrients in particular may identify individuals who may benefit from micronutrient treatment.
This study presents the first investigation looking at whether nutrient biomarkers taken prior to a broad-based micronutrient treatment are useful for predicting treatment response in adults with ADHD. These predictors were explored alongside more common predictors such as demographic variables, developmental history, and clinical correlates (Buitelaar et al., 2011, Torgersen et al., 2008). This study aligns well with the National Institute of Mental Health's (NIMH) Research Domain Criteria (RDoC), which encourages research that aims to uncover laboratory-based evaluations that can assist with prognosis and treatment (Insel et al., 2010).
Section snippets
Study design
The study received ethical approval from both the National Upper South A Health and Disability Ethics Committee and the Human Ethics Committee at the University of Canterbury. After describing the experimental nature of the trial and explaining the other treatment options available in the community, written informed consent was obtained from all participants. The trial was prospectively registered (ACTRN12609000308291).
Study details have been described previously (Rucklidge et al., in press).
Patient characteristics
Baseline demographics, clinical features and nutrient levels are shown in Table 2, Table 3. Other than vitamin D, most participants entered the trial with serum nutrient levels within the normal reference ranges. Correlations between nutrient levels and baseline psychiatric variables (e.g., mood, ADHD scores, GAF) revealed only one significant association: baseline iron was significantly correlated with baseline MADRS (r = 0.323, p = 0.009), with higher baseline MADRS scores associated with higher
Discussion
This study investigated predictors of response to a micronutrient treatment for adults with ADHD, which produced significant changes in all outcome measures from pre- to post-supplementation. These findings are consistent with a large body of international literature showing the benefit of micronutrients as a treatment for psychiatric disorders (Rucklidge and Kaplan, 2013). Three baseline vitamin/nutrient levels showed an association with treatment response: ferritin, vitamin D, and copper.
Conclusions
This is the first study to investigate the associations among serum nutrient levels and other presenting features with treatment response to a micronutrient intervention for ADHD in adults. The aim of identifying the factors that predict better treatment response is to target therapy to those who may benefit from the treatment. Those included in the analyses were largely a compliant group who we felt confident had been exposed to nutrients for an 8 week period, and even under these ideal
Acknowledgements
None of the authors have any financial disclosures or competing interests to declare. Thanks to the Vic Davis Memorial Trust (E5672), Marie Lockie for her private donation, the Department of Psychology, University of Canterbury for ongoing research support, and three summer studentships awarded by the University of Canterbury. Thanks also to Dr Nic Ward, Rachel Harrison, Heather Gordon, Ellen Sole, Sarah Anticich, Sarah Dymond and Dr Petra Hoggarth for assistance with data collection and entry;
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Trial registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12609000308291.