N-Acetylcysteine in the Treatment of Deliberate Self-Harm in Adolescents: An Open Label Pilot Study

Deliberate Self-Harm (DSH) among adolescents is a serious behavioral problem associated with significant morbidity and mortality, impaired functioning, reduced quality of life, and high rates of psychiatric hospitalizations. Rates of DSH among high-school adolescents range between 14% and 21%, highlighting the need for effective behavioral and pharmacological interventions . Because DSH has been closely linked to Borderline Personality Disorder (BPD), treatments that have been used successfully for BPD such as Dialectical Behavior Therapy (DBT) have been used to treat adolescents with DSH. While DSH has not been shown to have a direct link to suicide attempts themselves, there is a clear link between individuals who engage in DSH and overall rates of suicide. In addition to these high rates of DSH in adolescents, research is continuing to show that similar to adult patients; adolescent DSH is related to high levels of impulsivity.

Considerable advances in the understanding of the neurobiology of risk and reward and impulsivity have improved the general understanding of the neuropathology of a behavior such as DSH. Our previous neuroimaging research of DSH in BPD found that frontal white matter integrity was significantly impaired in these individuals. One conceptualization of DSH is that it represents an imbalance between a strong desire for the reward of DSH (i.e. an overactive ventral tegmental area [VTA]) and an inability to inhibit the drive (i.e. impaired inferior frontal cortex). If the frontal cortex is impaired due to inadequate white matter integrity as our earlier study demonstrated, then reducing the drive for DSH may be the most beneficial target for treatment. Glutamate is known to activate dopamine neurons in the VTA. Because such activation can increase dopamine release in mesocorticolimbic targets, this glutamate-dopamine interaction in the VTA may underlie the chronic reward-seeking that underlies DSH. In fact, dysregulated prefrontal cortex-nucleus accumbens synaptic glutamate transmission appears to underlie the unmanageable motivation to engage in DSH.

Because interactions of glutamate with the dopaminergic system within the VTA mediate reward, N-acetyl cysteine (NAC), a glutamate modulating agent, should attenuate the rewarding properties of DSH by interfering with DSH-induced stimulation of the mesolimbic dopaminergic pathway. NAC increases the activity of cysteine-glutamate antiporters in the nucleus accumbens and abolishes reward-seeking behavior. Behaviorally, NAC administration should lead to diminished urges to engage in DSH. Increased extracellular glutamate by NAC may correct the underlying pathophysiology and symptoms of this compulsive drive to self-injure. NAC has been extensively studied in a variety of medical problems (e.g., cocaine dependence, acetaminophen overdose, AIDS, gambling), and its lack of significant side effects may present a marked advantage over pharmacological agents.

There is a need to develop effective treatment options that are well tolerated, widely available, and do not have prohibitive costs. NAC is an amino acid, available in health food stores, cheaper than the cost of most insurance co-payments, and is easily tolerated. If effective, NAC could be a treatment option available to people throughout the country that do not currently have insurance but are suffering from DSH.

The population to be studied for this trial is 40 men and women, ages 13-21, who engage in deliberate self-harm behaviors at least twice a month. We will also add a sample of 40 matched healthy adolescents to serve as a comparison group for the baseline neuroimaging measures. Study participants will be recruited from outpatient mental health clinics and from the community through advertisements.