Genetic and clinical factors predict lithium's effects on PER2 gene expression rhythms in cells from bipolar disorder patients.

Bipolar disorder (BD) is associated with abnormal circadian rhythms. In treatment responsive BD patients, lithium (Li) stabilizes mood and reduces suicide risk. Li also affects circadian rhythms and expression of 'clock genes' that control them. However, the extent to which BD, Li and the circadian clock share common biological mechanisms is unknown, and there have been few direct measurements of clock gene function in samples from BD patients. Hence, the role of clock genes in BD and Li treatment remains unclear. Skin fibroblasts from BD patients (N=19) or healthy controls (N=19) were transduced with Per2::luc, a rhythmically expressed, bioluminescent circadian clock reporter gene, and rhythms were measured for 5 consecutive days. Rhythm amplitude and period were compared between BD cases and controls with and without Li. Baseline period was longer in BD cases than in controls. Li 1 mM increased amplitude in controls by 36%, but failed to do so in BD cases. Li 10 mM lengthened period in both BD cases and controls. Analysis of clock gene variants revealed that PER3 and RORA genotype predicted period lengthening by Li, whereas GSK3ß genotype predicted rhythm effects of Li, specifically among BD cases. Analysis of BD cases by clinical history revealed that cells from past suicide attempters were more likely to show period lengthening with Li 1 mM. Finally, Li enhanced the resynchronization of damped rhythms, suggesting a mechanism by which Li could act therapeutically in BD. Our work suggests that the circadian clock's response to Li may be relevant to molecular pathology of BD.

Non-aversive reduction of cigarette smoking in two adult men in a residential setting.

Two middle-aged men with mental retardation, addicted to smoking cigarettes, operated spinners that determined the probability with which they could obtain cigarettes and other items. Absence of several maladaptive behaviors permitted the operation of the spinners hourly (i.e., DRO 60 min), 16 h per day, 7 days per week. The actual frequencies of obtaining cigarettes followed the theoretical probabilities of obtaining cigarettes in all phases of the study. Presumed smoking frequencies were reduced by about 50% with associated medical benefits. Low frequencies of maladaptive behaviors were maintained throughout.

Cyclical self-injurious behavior, contingent water mist treatment, and the possibility of rapid-cycling bipolar disorder.

Cyclical self-injurious behavior (SIB) in the form of self-slapping was treated in a 45-year-old, profoundly retarded woman who had a life-long history of SIB. Her SIB alternated between high (mean = 8.54 responses per min; SD = 6.77 and low (mean = 0.05 responses per min; SD = 0.20) frequencies every 8 weeks on average. Instances of self-slapping produced water mist treatment paired with a verbal command, "No hitting". Absence of self-slapping and/or completion of a work task led to a variety of outcomes, including brief back rubs, sips of water, small edibles, and praise. Water mist treatment reduced the frequency of SIB within treatment days during high frequency periods, but produced no reduction across treatment days. Treatment onset was associated with a slight increase in the frequency of SIB during three of the five low frequency periods. However, water mist treatment suppressed SIB completely in sessions during low frequency periods and the suppression continued across treatment days. Water mist treatment produced no discernible changes in the length of the high and low frequency periods of SIB.