Melatonin Effects on Sleep and Circadian Rhythm in Youth and Young Adults With At-risk Symptoms

Context: Sleep disturbances and circadian dysrhythmias have been associated with psychotic
symptom severity in Psychosis Spectrum (PS) youths. Supplemental melatonin is a safe
over-the-counter dietary supplement, and several studies have found that melatonin improves
sleep across several childhood neuropsychiatric disorders.

Objectives: Investigators seeks to determine whether supplemental melatonin improves sleep
and circadian alignment in PS youth. Investigators will also investigate whether supplemental
melatonin affects psychotic symptoms, neurocognition, and peripheral inflammatory and
oxidative stress markers.

Study Design: Parallel group, double-blind, randomized, placebo-controlled trial
Setting/Participants: 40 PS youths ages 11-30 years old (throughout the protocol we use
"youth" to describe this age group) with sleep disturbances will be recruited from an extant
cohort of PS youths followed by our lab in the Philadelphia Neurodevelopmental Cohort (PNC),
Children's Hospital of Philadelphia (CHOP), University of Pennsylvania (UPenn), and the
surrounding community. The study will be conducted at CHOP and UPenn.

Study Interventions and Measures: Youths will be randomized to receive pill placebo or oral
melatonin. Participants will take melatonin (or placebo) at the same time every evening for 2
weeks (final dose range 2.5-10 mg nightly). Outcomes will be assessed at 1 week, 2 weeks, and
6-months. Primary outcomes will be changes in self-reported sleep and actigraph-measured
sleep and circadian rhythm. Secondary outcomes will be psychotic symptoms, neurocognition,
and peripheral blood markers of inflammation and oxidative stress.

Inclusion Criteria:

- Males or females age 11-30 years old and patient at the Children's Hospital of
Philadelphia (CHOP), University of Pennsylvania (UPenn), or member of the surrounding
community

- Subthreshold psychosis-risk positive symptoms (e.g. hallucinations or unusual beliefs)
on the Structured Interview of Psychosis-Risk Syndromes (SIPS)

- At least mild sleep disturbances on the SIPS (>=1 on the SIPS sleep item (G1)) with
difficulties with

- Must have difficulties with sleep onset, sleep awakenings, or maintaining a regular
sleep schedule.

- Willingness to report all changes in medications and therapy during the study

- Intelligence Quotient (IQ) > 70

- If female, not breastfeeding and not pregnant and willing to use effective birth
control for the duration of the study (e.g. abstinence or oral contraception).

- Medically healthy

- Fluent in English

Exclusion Criteria:

- Psychiatric symptoms with imminent safety concern (e.g. intractable and escalating
suicidal ideation)

- Currently taking melatonin, having taken melatonin daily within the 2 weeks prior to
Visit 1, or having a history of an intolerance or allergy to melatonin.

- Medication or treatment changes in the 4 weeks prior to Visit 1 .

- Anticipated medication or other treatment (e.g. type of psychotherapy) changes in the
three weeks after study enrollment.

- IQ <70

- Taking any medication whose potential interactions with melatonin present a
significant risk or limit the effect of melatonin in the judgment of the
investigators.