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.
1.Siever LJ: Neurobiology of aggression and violence. Am J Psychiatry 2008; 165:429–442
2.Mann JJ: Neurobiology of suicidal behaviour. Nat Rev Neurosci 2003; 4:819–828
3.Cipriani A, Pretty H, Hawton K, Geddes JR: Lithium in the prevention of suicide behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry 2005; 162:1805–1819
4.Baldessarini RJ, Tondo L, Davis P, Pompili M, Goodwin FK, Hennen J: Decreased risk of suicides and attempts during long-term lithium treatment: a meta-analytic review. Bipolar Disord 2006; 8:625–639
5.Collins JC, McFarland BH: Divalproex, lithium and suicide among Medicaid patients with bipolar disorder. J Affect Disord 2008; 107:23–28
6.Monkul ES, Matsuo K, Nicoletti MA, Dierschke N, Hatch JP, Dalwani M, Brambilla P, Caetano S, Sassi RB, Mallinger AG, Soares JC: Prefrontal gray matter increases in healthy individuals after lithium treatment: a voxel-based morphometry study. Neurosci Lett 2007; 429:7–11
7.Yucel K, McKinnon MC, Taylor VH, Macdonald K, Alda M, Young LT, MacQueen GM: Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study. Psychopharmacology 2007; 195: 357–367
Dr. Terao reports no competing interests.
This letter (doi: 10.1176/appi.ajp.2008.08040598) was accepted for publication in June 2008.