Molecular Studies Probe Bipolar Disorder
Authors: M J Friedrich
Journal: JAMA (2005)

SAN DIEGO—After weathering numerous manic attacks and hospitalizations, 20th-century poet Robert Lowell found relief in treatment with lithium carbonate. Lowell commented to his publisher, Robert Giroux, “It’s terrible, Bob, to think that all I’ve suffered, and all the suffering I’ve caused, might have arisen from the lack of a little salt in my brain” (Lowell R. Collected Prose. Giroux R, ed. New York, NY: Farrar Strauss & Giroux; 1987:xiii-xiv). A dash of lithium to season the moods of those who, like Lowell, experience the highs of mania and the depths of depression revolutionized the treatment of bipolar disorder after the drug’s effects were first reported in 1949 and it subsequently came into clinical use. However, neither lithium nor other current treatments for bipolar disorder, such as valproic acid, are without problems. Many patients respond poorly to these mood-stabilizing drugs, and adverse effects often interfere with compliance. None of the medications now in use were developed specifically for the treatment of bipolar disorder, noted Husseini Manji, MD, chief of the laboratory of molecular pathophysiology at the National Institute of Mental Health, Bethesda, Md. He and other researchers are investigating how current moodstabilizing drugs work in the hope of gathering molecular clues that will lead to better therapies for bipolar disorder. Manji described this research at the annual meeting of the Society for Neuroscience here in October. “One of the strategies that I and others have taken is to understand how these seemingly simple molecules [lithium and valproic acid] bring about their beneficial effects,” said Manji. “If we can understand what they do, not only might we understand more about the underlying neurobiology of the illness, we also might be in a position to come up with improved treatments.” Until recently, common scientific wisdom held that bipolar disorder results from an imbalance in neurotransmitters, the chemical messengers that send signals between cells, said Manji. In the last decade, however, researchers have begun to think that the complex phenotypic picture of this disease stems from more than just abnormalities of neurotransmitter systems. Neurotransmitters are certainly involved, Manji said, but the primary abnormality may lie elsewhere—specifically, inside the cell. The evolving biological view accords with the shift in understanding of the clinical picture of bipolar disorder. Traditionally, clinicians viewed the disease as consisting of discrete episodes of depression and mania. But, as Manji explained, investigators have begun to recognize that severe mood disorders such as bipolar disorder and unipolar depression involve more than episodic mood disturbances. “These disorders seem to have ramifications for the whole body,” said Manji. “A lot of data suggest that cardiovascular mortality is increased and diabetes and osteoporosis are affected. So now we’re starting to recognize that the psychological symptoms are just one aspect of the disorder,” said Manji. He noted that while current treatments are adequate for treating the symptoms of acute mania or suicidal depression, they are not as successful at addressing functioning between episodes. “This may be because there is underlying disease progression that we haven’t been paid enough attention to.”