Biochemical Imbalances and Micronutrient Intervention in Violent and Aggressive Male Children and Adolescents

Abstract

Violence and aggression in children and adolescents is of worldwide public health concern.1 Given the multitude of serious implications associated with violent crime such as costs to victims, taxpayer dollars and heightened safety concerns; early intervention is particularly important.2 Psychiatry is at an important juncture with few psychiatric pharmaceuticals on the horizon and unfavourable, long-term, risk-benefit profiles for many of the existing agents. The use of pharmaceuticals in violent and aggressive children and adolescents is limited due to the negative impact on growth and development, risk of adverse effects and lack of safety and efficacy data available.3 Evidence-based effective and safe therapies for the management of youth with violent and aggressive behavioural disorders are crucially needed. In recent years there has been an increase in both the quantity and methodological quality of research exploring the relationship between micronutrients and mental health.4 Neuroscientists have identified nutrients required for the synthesis of neurotransmitters, gene regulation and antioxidant protection.5,6 Changes in concentrations of different micronutrients as well as other organic and inorganic compounds may contribute to aggressive behaviour.7,8 The need for novel diagnostic techniques and interventions for children and adolescents with violent and aggressive behavioural disorders has been identified.9,10 Micronutrients that target biochemical imbalances that are identified by clinical examination and pathology may be a novel therapeutic option to improve behaviour, with minimal side effects.10,11 Due to the individualised nature of diagnosis and treatment, the use of micronutrient therapy to target biochemical imbalances has primarily anecdotal evidence. A retrospective review of prescribing patterns, diagnostic instruments and patient outcomes was conducted to evaluate available evidence and identify key trends for micronutrient therapy in violent and aggressive males. This study led to the development of a data collection instrument, and highlighted elevated urinary hydroxyhemopyrroline-2-one (HPL) and elevated plasma copper/zinc ratios as common biochemical imbalances present in violent and aggressive youth. It was also identified in the retrospective review that micronutrients such as zinc, vitamin B6, vitamin E, vitamin C and chromium were often prescribed at doses above the Australian recommended daily intake12 and paediatric guidelines,13,14 but appeared to be well tolerated. There is no ‘gold-standard’ outcome measure for the evaluation of violent and aggressive behaviours in youth receiving pharmacological intervention.9,15 In addition, findings from the retrospective review emphasised the need to identify appropriate efficacy outcome measures used in this population. Therefore, a review to evaluate the psychometric and administrative properties, and the applicability of instruments used to measure the efficacy of pharmacotherapy in violent and aggressive youth was conducted. The review identified that the majority of instruments contained few items specific to violent and aggressive behaviours, and that these behaviours were often conflated with oppositional and defiant symptoms. It was found that all items in the Children’s Aggression Scale (CAS) and the Modified Overt Aggression Scale (MOAS) could be used to measure violent and/or aggressive behaviours. The CAS was the most psychometrically sound and useful instrument that could be used to exclusively measure aggressive behaviours in youth. A 16 week, open-label, clinical trial of 31 males aged four to 14 who displayed ongoing violent and aggressive behaviours was conducted. The participants received a standardised micronutrient intervention containing vitamin E, vitamin C, biotin, chromium, pyridoxal-5-phosphate, vitamin B6, selenium and zinc. Primary outcomes were ratings of violent and aggressive behaviours, measured using the CAS and the MOAS. Secondary outcomes were health-related quality of life (HRQoL) and family functioning. Plasma zinc, plasma copper, copper/zinc ratio and urinary HPL tests were conducted at baseline and endpoint. Micronutrient therapy significantly improved parent reported aggressive and violent behaviours measured using the CAS for all domains except the use of weapons, with medium to large effect size, and the MOAS, with large effect size. Parent reported HRQoL and family functioning also significantly improved. Micronutrient therapy appeared well tolerated, with a favourable side effect profile. The feasibility study identified important strengths in the open-label study that should be replicated in future studies and suggestions for the successful conduct of future research including randomised controlled trials, longitudinal or follow-up studies. This is the first investigation of a standardised micronutrient intervention for violent and aggressive behaviour disorders in male children and adolescents. Significant improvements in parent reported violent and aggressive behaviours as well as HRQoL and family functioning were found which could potentially bridge a therapeutic gap and change current practices in mainstream medicine. Results from the systematic review, evaluation of outcome measures and feasibility analysis should assist, and have an impact on, future research and clinical trials.