Early Study of N-Acetylcysteine to Treat Deliberate Self-Harm in Adolescents

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.

The study consists of two components: treatment with N-acetyl cysteine and brain imaging. Participants will be invited to participate in either or both, depending on the distinct eligibility criteria of the two components (see below.)

Treatment component:

The treatment component of the study consists of eight weeks of open label N-Acetylcysteine (NAC). All eligible study subjects will be treated with 600mg of NAC twice a day for 2 weeks, then the dose will be increased to 1200mg twice a day for two weeks, and to 1800mg twice a day for 4 weeks. weeks. Subjects will be seen every two weeks during the 8-week study. Efficacy and safety assessments will be performed at each visit.

Imaging component: A brain imaging session will take place before and after the treatment with NAC. For individuals that either chose not to compete the treatment component or who did not meet entry criteria, they will only have the baseline scan.

The healthy group will only participate in assessment and neuroimaging, not in the treatment or the second scan.

All participants will undergo a comprehensive clinical assessment which will include the following interviews/rating scales/tests:

1. KSADS interview (adolescents and parents) or SCID (adult participants)
2. Child Depression Rating Scale-Revised (CDRS-R)
3. Columbia Suicide Severity Rating Scale (CSSRS) (patients only)
4. Inventory of Statements About Self-Harm (ISAS) (patients only)
5. The Deliberate Self Harm Inventory (DSHI) (patients only)
6. Deliberate Self Harm Questionnaire (DSHQ) (patients only)
7. Beck Depression Inventory-II (BDI-11)
8. Wechsler Abbreviated Scale of Intelligence (WASI)
9. Edinburgh Handedness inventory
10. Iowa Gambling Task (IGT)
11. NIH Toolbox
12. Tanner Questionnaire
13. Eating Questionnaire (EDEQ)
14. Personality Assessment Inventory (PAI)
15. Symptom Check-List-90-R (SCL-90)
16. Barrett Impulsivity Scale (BIS)
17. Difficulties in Emotion Regulation Scale (DERS)
18. Satisfaction with Life Questionnaire
19. Toronto Alexithymia scale
20. Rejection Sensitivity Questionnaire - Adolescent (RSQ-A)

All participants will be invited to undergo an MRI session that includes a structural scan, a resting state fMRI scan, an emotion task fMRI scan, diffusion tensor imaging, and magnetic resonance spectroscopy in the anterior cingulate cortex.

Every two weeks the following assessments will be utilized to assess the efficacy of current treatment on NAC participants:

1. Inventory of Statements About Self-Injury Since Last Visit version (ISAS - SLV)
2. Self-Injury Assessment Scale (SIAS)
3. Deliberate Self Harm Inventory Clinical Change Version (DSHI - CCV)
4. Columbia Suicide Severity Rating Scale Since Last Visit version (CSSRS - SLV)

At the end of the 8 week administration of NAC participants will complete:

1. Inventory of Statements About Self-Injury Since Last Visit version (ISAS - SLV)
2. Self-Injury Assessment Scale (SIAS)
3. Deliberate Self Harm Inventory Clinical Change Version (DSHI - CCV)
4. Columbia Suicide Severity Rating Scale Since Last Visit version (CSSRS - SLV)
5. Barrett Impulsivity Scale (BIS)
6. SCL-90
7. DERS
8. Satisfaction with Life Questionnaire
9. BDI-II
10. Iowa Gambling Task (IGT)
11. The same MRI protocol as described above.