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Elliott Kyung Lee,1,2 Naomi Spitale,2,3 Rebecca Robillard2 1Department of Psychiatry, University of Ottawa, Ottawa, Ontario, Canada; 2Sleep Research Unit, Institute for Mental Health Research (IMHR), Ottawa, Ontario, Canada; 3Department of Medicine, University of Ottawa, Ottawa, Ontario, CanadaCorrespondence: Elliott Kyung Lee, Department of Psychiatry, University of Ottawa, Office 3124, Royal Ottawa Mental Health Center, 1145 Carling Avenue, Ottawa, Ontario, K1Z-7K4, Canada, Tel +1 613-722-6521 x 6226, Fax +1 613-798-2980, Email elliott.lee@theroyal.caPurpose: Restless Legs Syndrome (RLS) is a sensorimotor disorder associated with an unpleasant urge to move the limbs, relieved with movement, occurring in the evenings and with prolonged rest/inactivity. Treatment with dopamine agonists is effective for up to 60– 90% of affected individuals. However, augmentation, ie, the paradoxical worsening of RLS symptoms after prolonged RLS treatment, is frequently reported, typically after 3– 10 years of treatment. Here, we present 4 patients with RLS who were successfully treated with dopamine agonists but later developed augmentation. A trial of aripiprazole, a dopamine receptor partial agonist (DRPA), was initiated for treatment of augmentation symptoms.Patients and Methods: Four patients treated for RLS with dopamine agonists developed augmentation. In each instance, augmentation symptoms did not respond adequately to a variety of medications including α 2δ drugs, opioids or other agents. A trial of aripiprazole was initiated for each patient, and effects were evaluated.Results: All four patients with severe RLS and augmentation with dopamine agonists achieved symptom control with aripiprazole. Patients endorsed 90– 100% efficacy with aripiprazole by subjective self-report after failures with other agents. Further evaluation with the International Restless Legs Syndrome Study Group RLS Rating Scale (IRLS-SGRS) showed that benefits (from moderate to very severe, to mild to moderate severity) were largely maintained for 1– 2 years. Aripiprazole doses to control augmentation symptoms were low (1– 4 mg). No significant side effects were reported.Conclusion: Aripiprazole may have utility for augmentation in RLS. We speculate that the partial agonist and antagonist properties of aripiprazole may limit potential for dopamine hyposensitization to progress to cause augmentation. Further research is needed to see if aripiprazole and/or other DRPAs are a viable long-term treatment option for patients experiencing augmentation and/or severe RLS with dopamine agonist therapy.Keywords: partial dopamine agonist, Willis Ekbom disease, dopamine treatment, dopamine receptor partial agonist, augmentation, restless legs syndrome, aripiprazole

Addo Boafo,1,2 Stephanie Greenham,1,3 Shuliweeh Alenezi,1,2 Rébecca Robillard,3,4 Kathleen Pajer,1,2 Paniz Tavakoli,1 Joseph De Koninck3,4 1Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada; 2Department of Psychiatry, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada; 3School of Psychology, University of Ottawa, Ottawa, ON, Canada; 4Sleep Research Unit, Royal’s Institute of Mental Health Research, Ottawa, ON, Canada Abstract: Exogenous melatonin can be used to treat sleep disturbance in adults, children, and adolescents. While its short-term use is considered safe, there are some concerns that long-term use might delay children’s sexual maturation, possibly by disrupting the decline in nocturnal melatonin levels that occur at the onset of puberty. This narrative review aimed to summarize some of the current knowledge about the potential effects of exogenous melatonin on puberty. We found no clinical studies that experimentally tested the effects of melatonin on pubertal timing in children, but we reviewed the small number of observational studies. We also drew on animal data to try to answer our question. The photoperiod and melatonin-mediated seasonal transitions in sexual activity and breeding in some mammals across the seasons have been used as a model of sexual development in mammals, including humans. The switch from non-sexual activity (in the non-breeding period) to sexual activity (in the breeding period) has been likened to the onset of puberty as there are similarities between the two. We conclude that to investigate an association between melatonin and pubertal timing, it will be important to conduct long-term randomized controlled trials of latency age children and also examine the cellular and systems-level interactions between melatonin and kisspeptin, a recently identified neuropeptide with a locus of action at the gonadotropin releasing hormone neurons that is important in contributing to the timing of puberty onset. Keywords: melatonin, puberty, hypothalamic-pituitary-gonadal-axis, kisspeptin, sleep disturbance

Kathleen Biard,1,2 Alan B Douglass,2,3 Rébecca Robillard,2 Joseph De Koninck1,2 1School of Psychology, University of Ottawa, 2University of Ottawa Institute for Mental Health Research, 3Royal Ottawa Mental Health Center, University of Ottawa Institute for Mental Health Research, Ottawa, ON, Canada Rationale: The serotonergic and cholinergic systems are jointly involved in regulating sleep but this system is theorized to be disturbed in depressed individuals. We previously reported that cholinergic and serotonergic agents induce sleep changes partially consistent with monoamine models of sleep disturbances in depression. One potential cause of disturbed neurotransmission is genetic predisposition. The G(-1019) allele of the serotonin-1A (5-HT1A) receptor promoter region predicts an increased risk for depression compared to the wild-type C(-1019) allele. Objective: The goal of this study was to investigate how serotonin-1A receptor genotypes mediate sleep sensitivity to pharmacological probes modeling the serotonergic/cholinergic imbalance of depression. Methods: Seventeen healthy female participants homozygous for either C (n=11) or G (n=6) alleles aged 18–27 years were tested on four nonconsecutive nights. Participants were given galantamine (an anti-acetylcholinesterase), buspirone (a serotonergic agonist), both drugs together, or placebos before sleeping. Results: As reported previously, buspirone significantly increased rapid eye movement (REM) latency (P