Bipolar disorder falls into a category of psychopathological conditions known as affective disorders. These conditions manifest themselves with inappropriate and disproportionate exaggerations in mood state. Bipolar disorder itself consists of the swinging between major depressive and manic episodes. The manic episodes of bipolar disorder are the distinguishing factor that enable diagnosis. In many individuals however, manic episodes occur infrequently making diagnosis challenging. As a result, many patients are first diagnosed with depression and this leads to problems with treatment.
Circadian Rhythms and Bipolar Disorder
Patients with bipolar disorder suffer from disturbances in their circadian rhythms. In depressive episodes insomnia or hypersomnia are common factors, and in manic episodes there is a decreased “need for sleep”. The rhythm of sleep is also altered, in particular REM and slow wave stages of sleep. The normal rhythms of activity, hormonal secretions and appetite are also affected. Indeed the normalization of the sleep/wake cycle and exogenous zeitgebers plays an important part in treating many individuals suffering with the illness (Plante 2008). Recently SNPs (signal nucleotide polymorphisms) have been identified in genes that encode crucial components of our endogenous pacemakers associated with mood disorders (Benedetti 2008). In addition to this, lithium and valproate, the most common mood stabilizing treatments both have known targets and effects in circadian rhythm biology. Lithium for example has been shown in many organisms to lengthen the circadian day and valproate to alter the expression of several circadian proteins.
Animal model of mania
CLOCK is a protein that is thought to play an important part in the molecular feedback mechanisms that make up our endogenous pacemaker. Described in this publication is a mouse model in which CLOCK was mutated to inhibit its interaction with BMAL1, its transcription regulatory complex partner. In the original paper several tests were employed to demonstrate that the mice exhibited different diagnostic criteria of mania (Roybal 2007). One symptom of mania in humans is feelings of extreme euphoria. In mice this was examined by assessing helplessness in forced swim experiments. Positively the results indicated less helplessness in the mutants. Anxiety tests were also utilized and results were indicative of this second symptom of mania. The mutant mice also show a greater preference for rewarding stimuli, similar to the manic states in bipolar. This was examined by assessing the level of intracranial self-stimulation to the medial forebrain bundle. Finally disrupted circadian rhythms, hyperactivity and decreased sleep were also observed in the mice. Perhaps the most intriguing part of this model is the lithium sensitivity. Treatment with lithium was shown to ameliorate the mood-related effects of the mutation to wild type levels (in the helplessness and anxiety tests).
Evaluation (My Thoughts)
One major weakness in this model is the identification of CLOCK null mutant mice that exhibit normal circadian functioning (Jason 2006). This suggests that the CLOCK 19 mice dysfunction may result from new functions of the mutant CLOCK or a desynchronization of function or parallel function of CLOCK, with the mutations failing to completely inhibit CLOCKs function.
There is no evidence that suggests that mutations in the circadian system are required for the development of bipolar disorder in humans and therefore it could be argued that this model lacks any relevance to the human condition.
Bipolar disorder is more complex that the behavior displayed by these mice, which exhibit no cycling between mood states. These mice are at best a model of constant mania but their utility in predicting therapeutic efficacy remains unclear. At worst this model has no biological relevance for bipolar disorder. The observed influence of lithium in alleviating the effects of the mutation may be attributed to its intrinsic polypharmacology. In addition, in this study lithium was not able to restore all behavioral phenomena to wild type levels.
Despite these reservations it must be acknowledged that circadian rhythm dysfunction is an important factor in bipolar disorder and models that can be used in the development of drugs to “normalize” this are useful.
Blog written by: James Noble
- Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, Campori E, Smeraldi E Am J Med Genet B Neuropsychiatr Genet, 2003, 123:23–26.
- David T. Plante, John W. Winkelman, Sleep Disturbance in Bipolar Disorder: Therapeutic Implications Am J Psychiatry 2008; 165:830–843
- Jason P. DeBruyne, Elizabeth Noton, Christopher M. Lambert, Elizabeth S. Maywood, David R. Weaver, Steven M. Reppert, A Clock Shock: Mouse CLOCK Is Not Required for Circadian Oscillator Function, Neuron, 2006, 50 (3), 465-477
- Kole Roybal, David Theobold, Ami Graham, Jennifer A. DiNieri, Scott J. Russo, Vaishnav Krishnan, Sumana Chakravarty, Joseph Peevey, Nathan Oehrlein, Shari Birnbaum, Martha H. Vitaterna, Paul Orsulak, Joseph S. Takahashi, Eric J. Nestler, William A. Carlezon, Jr, and Colleen A. McClung,Mania-like behavior induced by disruption of CLOCK, PNAS 2007, 104 (15), 6406-6411