The McClung Lab

Department of Psychiatry

Translational Neuroscience Program

University of Pittsburgh Medical Center


Our laboratory is interested in discovering the molecular mechanisms of bipolar disorder, major depression and drug addiction. We are particularly interested in studying the association between these various psychiatric disorders and the circadian clock.

It has been suggested for some time that mood disorders are associated with, and may even arise from, abnormalities in the circadian system (Bunney and Bunney, 2000; Hallonquist et al., 1986; Healy and Williams, 1989; Jones, 2001; Kripke et al., 1978; Mansour et al., 2005; Mitterauer, 2000; Wirz-Justice, 2006). Seasonal affective disorder (SAD) or “winter depression” is clearly associated with a disruption of biological rhythms. As well, major depression is most common in areas of the world that receive little sunlight for extended periods of time and depression symptoms are at their worst typically in the early morning (Booker et al., 1991; Rusting and Larsen, 1998).

Our laboratory is interested in discovering the molecular mechanisms of bipolar disorder, major depression and drug addiction. We are particularly interested in studying the association between these various psychiatric disorders and the circadian clock.

It has been suggested for some time that mood disorders are associated with, and may even arise from, abnormalities in the circadian system (Bunney and Bunney, 2000; Hallonquist et al., 1986; Healy and Williams, 1989; Jones, 2001; Kripke et al., 1978; Mansour et al., 2005; Mitterauer, 2000; Wirz-Justice, 2006). Seasonal affective disorder (SAD) or “winter depression” is clearly associated with a disruption of biological rhythms. As well, major depression is most common in areas of the world that receive little sunlight for extended periods of time and depression symptoms are at their worst typically in the early morning (Booker et al., 1991; Rusting and Larsen, 1998).

Individuals suffering from depression usually have major alterations in circadian functions including sleep, activity, hormonal secretions and appetite. This is also true of people suffering from bipolar disorder. Bipolar cycling between mania and depression can be somewhat regular in pattern or even seasonal, suggesting a circadian component to its pathology (Cassano et al., 1999). In addition, normalization of both sleep/wake cycles and social zeitgebers often is essential for mood stabilization; while disruptions in these rhythms can trigger bipolar episodes (Leibenluft and Suppes, 1999).

There are also many indications that drug addiction and alcoholism is associated with the circadian system. Successful treatments for mood disorders, including bright light therapy and total sleep depravation rely on altering the circadian cycle (Giedke and Schwarzler, 2002; Postolache and Oren, 2005; Terman and Terman, 2005; Wirz-Justice and Van den Hoofdakker, 1999). Lithium treatment lengthens the circadian period in drosophila, mice and humans, and this effect is thought to be important in its therapeutic efficacy (Klemfuss, 1992)

Recently, studies in human populations have begun to identify polymorphisms, haplotypes, and mutations in certain circadian genes that associate with mood disorders. Multiple studies in bipolar patients have identified polymorphisms in both Clock and Bmal1 that associate with the occurrence, frequency and severity of bipolar episodes (Benedetti et al., 2003; Mansour et al., 2006; Nievergelt et al., 2006; Serretti et al., 2003). Variations in Period3 (Per3) have also been found to associate with bipolar disorder (Nievergelt et al., 2006). As well, a polymorphism in NPAS2 has been identified that associates with seasonal affective disorder (Johansson et al., 2003) and a variant in the Per2 gene has been found to associate with alcoholism (Spanagel et al., 2005). These results suggest that variations in certain circadian clock proteins may result in an increased vulnerability for developing a mood disorder.

Circadian Clock

As well, antidepressant treatment in rodents is able to alter the expression of individual members of the circadian clock. In the hippocampus, chronic (14 day) treatment with fluoxetine leads to an increase in the expression of Clock, Bmal1 and NPAS2 (Manev and Uz, 2006). Acute treatment had no effect on the expression of these genes suggesting that they may be important in the long-term placticity needed for the therapeutic efficacy of antidepressant treatment.

Though it seems certain that circadian rhythms and the genes that make up the clock are important in the development and treatment of mood disorders and addiction, their exact functions remain unknown. Our laboratory combines molecular and behavioral assays to determine more specifically how circadian rhythms and individual circadian genes regulate mood and addiction.