Aggression, Suicide, and Lithium Treatment

To the Editor: In the April 2008 issue of the Journal, Larry J. Siever, M.D. comprehensively reviewed important studies regarding the neurobiology of aggression and violence (1) . Dr. Siever suggested that the processing of stimuli in relation to past emotional conditioning encoded in the amygdala and related limbic regions will trigger the “bottom-up drive” to an aggressive action, while the orbital frontal cortex and anterior cingular gyrus will provide “top-down brakes” of the aggressive action.

Dr. Siever did not explicitly mention suicide, which is the most dangerous self-directed aggressive behavior. In studies of suicide, the orbital prefrontal cortex and anterior cingulate gyrus have been reported to play important roles in suppressing aggression via inhibitory projection to the amygdala (2) . Actually, positron emission tomography studies have shown reduced response in the prefrontal cortex and anterior cingulate gyrus after fenfluramine challenge to individuals who have attempted suicide (2) .

Although Dr. Siever briefly reviewed pharmacological treatment, lithium was regrettably omitted. Recent meta-analyses have revealed that lithium has antisuicidal effects (3, 4), which are probably stronger than those of other mood stabilizers such as valproate and gabapentin (5) . As Dr. Siever pointed out, valproate and gabapentin may decrease limbic irritability (“bottom-up drive”) and thereby improve both mood and aggression. On the other hand, lithium seems to reduce the rate of suicidal behavior independently of its mood-stabilizing effects (2) . Taking the fact into consideration that lithium has been reported to increase the volume of the prefrontal cortex and anterior cingulate gyrus (6), it seems likely that lithium may at least partially exert its antisuicidal effect via reinforcing “top-down brakes” of aggressive action. Since lithium has been shown to increase the volume and function of the limbic system, such as the hippocampus (7), antisuicidal effects of lithium may consist of both reinforcing “top-down brakes” and decreasing “bottom-up drive.” Therefore, lithium may have superior antisuicidal effects relative to other mood stabilizers.