Body Clock Strength Impacts Bipolar Disorder

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Bipolar Disorder, also known as manic–depressive disorder, is a condition characterized by alternating states of elevated energy, cognition and mood, with periods of irritable mood and depression. The extreme mood swings experienced by patients with bipolar disorder have been strongly associated with disruptions in circadian rhythms — the 24-hour cycle of biological processes that govern our day and night activity.

Lithium is one of the most common treatments for bipolar disorder. However, little research has been done to find out if and how lithium impacts the brain and peripheral body clockwork. A new study published in the open access journal PLoS ONE reveals a novel link between lithium, bipolar disorder and circadian rhythms [1].

All species have a body clock that controls periods of activity and rest. These clocks, known as circadian rhythms, refer to the cycle of physiological and biological processes that alternate on an approximately 24-hour schedule. Although many people refer to circadian rhythms as a single process, there are actually a number of body clocks that fluctuate throughout the day and include alertness, physical strength and sleep-wake rhythms. Two clusters of approximately 20,000 neurons called the suprachiasmatic nuclei (SCN) in a region at the base of the brain called the anterior hypothalamus controls the body’s many circadian rhythms.

Bipolar disorder is a brain disorder that affects between 1% and 3% of the general population and is the fifth leading cause of disability worldwide. For the last 60 years, lithium has been the mainstay treatment for bipolar disorder. Past research has shown that lithium lengthens both the period of behavioral circadian rhythms in rodents and humans, and the circadian firing rate rhythms in dispersed SCN neurons [2-3]. The impacts of lithium on the dynamics of clock gene/protein rhythms in the SCN and surrounding tissues have not been critically investigated.

To learn whether the lengthening of behavioral circadian rhythms is the major effect of lithium within circadian clockwork, and if so, what biological pathways are involved, researchers from the University of Manchester in the U.K. evaluated locomotor activity rhythms of mice treated chronically with lithium and, separately in cell culture, monitored clock gene/protein dynamics in real-time following acute lithium treatment.

Consistent with other studies, mice chronically treated with lithium at a dosage close to the therapeutic blood level in humans showed a mild but significant increase in circadian period, as measured by an increase in wheel running time. This result demonstrates that lithium lengthens circadian period in locomotor activity rhythms.

In cell culture (both brain and peripheral tissue slices/cells), lithium lengthened circadian period and increased the expression of a gene/protein called period homolog 2 (Per2). This result suggests that lithium acts on clock protein dynamics.

To more directly address the action of lithium, researchers treated cells with specific protein inhibitors independently or in the presence of lithium, and measured Per2 expression. Although inhibition of a protein called glycogen synthase kinase 3 beta (GSK3-beta) shortened clock period (as opposed to lengthening it as lithium did), it increased Per2 expression and oscillation amplitude. Oscillation amplitude or strength was measured as the difference between high and low levels of Per2 gene expression 24–48 hrs after drug treatment. There was no additive effect of the GSK3 inhibitor plus lithium, suggesting that inhibition of GSK3 may be the causal mechanism for induction of PER2 protein rhythms by lithium.

Lead author Dr. Qing-Jun Meng commented on the results [4]:

Our findings are important for two reasons: firstly, they offer a novel explanation as to how lithium may be able to stabilise mood swings in bipolar patients; secondly, they open up opportunities to develop new drugs for bipolar disorder that mimic and even enhance the effect lithium has on GSK3 without the side-effects lithium salts can cause.

Lithium salts have a ranges of side-effects including nausea, acne, thirstiness, muscle weakness, tremor, sedation and/or confusion.

There are two limitations to this study. First, in peripheral tissues, the concentrations of lithium used were well above the therapeutic range of serum levels. Second, only the potential roles of two protein pathways in mediating lithium actions on the circadian clockwork were addressed. Nevertheless, the data show that increased expression and strength of Per2 rhythms by lithium in the SCN and peripheral tissues/cells is associated with decelerated behavioural and molecular pacemaking.

The findings shed new light on the cellular and molecular mechanisms underlying therapeutic actions of lithium in Bipolar Disorder, and suggest that specific targeting of GSK3-beta may offer novel treatment solutions for patients. Several GSK3 inhibiting drugs are already in development as they have been shown to be important in other diseases, including diabetes and Alzheimer’s disease.

References

1. Li et al. Lithium Impacts on the Amplitude and Period of the Molecular Circadian Clockwork. PLoS ONE 7(3): e33292. 2012.
2. Klemfuss H. Rhythms and the pharmacology of lithium. Pharmacol Ther. 1992;56(1):53-78.
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3. Abe et al. Lithium lengthens the circadian period of individual suprachiasmatic nucleus neurons. Neuroreport. 2000 Sep 28;11(14):3261-4.
   View abstract
4. Body clocks may hold key for treatment of bipolar disorder. The University of Manchester. 2012 Mar 13.