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Saving Lives in New York Volume 2: Approaches and Special Populations While serotonergic function and both aggressive and suicidal behavior are under substantial genetic control 37 it is also subject to environmental influences. Demonstrating the interaction of genetics and environment, peer-reared monkeys, in comparison with maternally raised monkeys, develop lower serotonergic activity that persists into adulthood and is reflected in greater impulsivity and aggression. Thus, effects of rearing are superimposed on genetic effects. Given that a history of child abuse is associated with a greater risk for suicidal behavior in adult life, and extrapolating from these monkey studies, one can hypothesize that adverse rearing such as child abuse, resets serotonergic function at a lower level, an effect that persists into adulthood, contributing to the increased risk for suicidal behavior. Other neurobiological systems are also implicated in the diathesis for suicidal behavior, though their role is less clear than the sertonergic system. Abnormal function of the dopamine neurotransmitter system has been associated with major depression and while the influence of dopamine on suicidal behavior is unclear 38-39 , it may be related to impulsivity and decision making. Studies have also found evidence of noradrenergic neurotransmitter system dysfunction in suicide victims 40;41 . The noradrenergic system mediates acute stress responses to circumstances such as a psychiatric illness or severe suicidal ideation and overactivity of that system has been associated with both severe anxiety or agitation and higher suicide risk 42 . The hypothalamicpituitary-adrenal (HPA) axis is another major stress response system. Major depression is often associated with hyperactivity of the HPA axis 43 , and suicide victims exhibit HPA axis abnormalities 44;45 . Studies of both the HPA axis and noradrenergic activity indicate biological responses to stress that may reflect the risk for suicide. Genetic and Familial Influences There is an important genetic contribution to the propensity for suicidal behavior as shown by several lines of researchers. Individuals who commit suicide or make suicide attempts have a higher rate of familial suicide acts 46 . Both twin 47;48 and adoption 49 studies have noted a heritability of suicidal behavior independent of psychiatric disorders 50 . As yet, the specific genes that contribute to suicide risk are unknown. However since serotonin activity is related to suicidal behavior, and under partial genetic control, investigators have examined the relationship between genetic variation in serotonin-related genes and both suicidal behavior and impulsive aggression. To date candidate gene association findings are inconsistent and unlikely to bear fruit without directly sequencing candidate genes. Non-genetic familial factors that may contribute to diathesis for suicidal behavior include the impact of parenting . Adults reporting childhood abuse experiences have a higher rate of suicidal behavior and greater impulsivity in adulthood, consistent with findings in peer-reared monkeys. We have observed familial transmission of impulsivity where greater parental impulsivity and/or greater provocation from an impulsive child may increase the probability of physical or sexual abuse 51 . Overly sensitive stress response systems in the brain and body are reported in abused populations and may be the neurobiological consequences of abuse and neglect, as demonstrated in animal studies of maternal separation 52 . Thus adverse rearing might contribute to the neurobiological anomalies associated with components, such as impulsivity and aggression, in the diathesis for suicidal behavior in adulthood. Treatment and prevention If suicidal behavior occurs as the outcome of stress-diathesis, management of suicidal patients necessitates addressing both aspects; diagnosis and treatment of psychiatric disorders which act as stressors, and treatment to reduce the diathesis, or propensity, to attempt suicide. As we have seen, diathesis, or predisposition, has an element of biological determination. Diathesis includes more hopelessness or pessimism perhaps related to the noradregergic system, and more lifetime impulsivity partly related to impaired serotonergic input into ventromedial prefrontal cortex region of the brain. Because it is 2 Neurobiological Aspects of Suicide
Saving Lives in New York Volume 2: Approaches and Special Populations related to these biological systems, the diathesis or propensity for suicidal behavior is a potential therapeutic target, and a reduction of the diathesis for suicidal behavior has been observed in the clinical effects of lithium, clozapine and psychotherapy called dialectical behavior therapy, which have been shown to reduce suicidal behavior 53-57 . Both lithium and clozapine act on the serotonergic system and raising serotonergic activity may reduce risk of serious suicidal behavior by decreasing aggressive behavior and impulsivity 58 . There are many promising areas for future neurobiological research into reducing the diathesis for suicidal behavior. These include genetic and neurochemical studies, efforts to identify a genetic haplotype indicating risk for suicidal behavior, development of brain imaging and neuropsychological tests of decision making to measure risk of attempting suicide when depressed, and the development of treatments to ameliorate the risk of suicidal acts while waiting for antidepressants and antipsychotic medications to work. Another promising direction is use of animal models of impulsive and aggressive behaviors in the identification of candidate genes, investigation of genetic and rearing effects, and testing pharmacological treatments to ameliorate aggressive/impulsive behavior that extrapolation may reduce probability of suicidal behavior. References 1. Barraclough, B., Bunch, J., Nelson, B., Sainsbury, P. One hundred cases of suicide. Clinical aspects. Br J Psychiatry. 1974; 125:355-373. 2. Beautrais, A.L., Joyce, P.R., Mulder, R.T., Fergusson, D.M., Deavoll, B.J., Nightingale, S.K. Prevalence and comorbidity of mental disorders in persosn making serious suicide attempts: A case-control study. Am J Psychiatry. 1996; 153:1009-1014 3. Shaffer, D., Gould, M.S., Fisher, P., Trautman, P., Moreau, D., Kleinman, M., Flory, M. Psychiatric diagnosis in child and adolescent suicide. Arch Gen Psychiatry. 1996;53:339-348. 4. Robins, E., Murphy, G.E., Wilkinson, R.H., Jr., Gassner, S., Kayes, J. Some clinical considerations in the prevention of suicide based on a study of 134 successful suicides. Am J Public Health. 1959;49:888-899. 5. Rich, C.L., Fowler, R.C., Fogarty, L.A., Young, D. San Diego suicide study. III. Relationships between diagnoses and stressors. Arch Gen Psychiatry. 1988;45:589-592. 6. Dorpat, T.L., Ripley, H.S. A study of suicide in the Seattle area. Compr Psychiatry. 1960;1:349-359. 7. Isometsa, E., Henriksson, M., Marttunen, M., Heikkinen, M., Aro, H., Kuoppasalmi, K., Lonnqvist, J. Mental disorders in young and middle aged men who commit suicide. BMJ. 1995;310:1366-1367. 8. Roy, A., Linnoila, M. Alcoholism and suicide. Suicide Life Threat Behav. 1986;16:244-273. 9. Roy, A., Lamparski, D., DeJong, J., Moore, V., Linnoila, M. Characteristics of alcoholics who attempt suicide. Am J Psychiatry. 1990;147:761-765. 10. Roy, A., Lamparski, D., DeJong, J., Adinoff, B., Ravitz, B., George, D.T., Nutt, D., Linnoila, M. Cerebrospinal fluid monoamine metabolites in alcoholic patients who attempt suicide. Acta Psychiatr Scand. 1990;81:58-61. 11. Murphy, G.E., Wetzel, R.D. The lifetime risk of suicide in alcoholism. Arch Gen Psychiatry. 1990;47:383-392. 12. Murphy, G.E., Wetzel, R.D., Robins, E., McEvoy, L. Multiple risk factors predict suicide in alcoholism. Arch Gen Psychiatry. 1992;49:459-463. 13. Murphy, G.E. Suicide and substance abuse. Arch Gen Psychiatry. 1988;45:593-594. 14. Dulit, R.A., Fyer, M.R., Haas, G.L., Sullivan T., Frances, A.J. Substance use in borderline personality disorder. Am J Psychiatry. 1990;147:1002-1007. 15. Marzuk, P.M., Mann, J.J. Suicide and substance abuse. Psychiatric Annals. 1988;18:639-645. 16. Pezawas, L., Stamenkovic, M., Jagsch, R., Ackerl, S., Putz, C., Stelzer, B., Moffat, R.R., Schindler, S., Aschauer, H., Kasper, S. A longitudinal view of triggers and thresholds of suicidal behavior in depression. J Clin Psychiatry. 2002;63:866-873. 17. Brodsky, B.S., Malone, K.M., Ellis, S.P., Dulit, R.A., Mann, J.J. Characteristics of borderline personality disorder associated with suicidal behavior. Am J Psychiatry. 1997;154:1715-1719. 18. Brent, D.A. Overrepresentation of epileptics in a consecutive series of suicide attempters seen at a Children’s Hospital, 1978-1983. J Am Acad Child Psychiatry. 1986;25(2):242-246. 19. Breslau, N., Davis, G.C., Andreski, P. Migraine, psychiatric disorders, and suicide attempts: An epidemiologic study of young adults. Psychiatry Res. 1991;37:11-23. 20. Schoenfeld, M., Myers, R.H., Cupples, L.A., Berkman, B., Sax, D.S., Clark, E. Increased rate of suicide among patients with Huntington’s disease. J Neurol Neurosurg Psychiatry. 1984;47:1283-1287. 21. Farrer, L.A. Suicide and attempted suicide in Huntington disease: Implications for preclinical testing of persons at risk. Am J Med Genet. 1986;24:305-311. 22. Breslau, N. Migraine, suicidal ideation, and suicide attempts. Neurology. 1992;42:392-395. 23. Breslau, N., Kilbey, M.M., Andreski, P. Nicotine dependence, major depression, and anxiety in young adults. Arch Gen Psychiatry. 1991;48:1069-1074. 24. Breslau, N., Kilbey, N.M., Andreski, P. Nicotine dependence and major depression: New evidence from a prospective investigation. Arch Gen Psychiatry. 1993;50:31-35. 25. Mann, J.J., Waternaux, C., Haas, G.L., Malone, K.M. Towards a clinical model of suicidal behavior in psychiatric patients. Am J Psychiatry. 1999;156:181-189. 26. Glassman, A.H., Helzer, J.E., Covey, L.S., Cottler, L.B., Stetner, F., Tipp, J.E., Johnson, J. Smoking, smoking cessation, and major depression. J Am Med Assoc. 1990;254:1546-1549. 27. Glassman, A.H. Cigarette smoking: Implications for psychiatric illness. Am J Psychiatry. 1993;150:546-553. 28. Stanley, M., Virgilio, J., Gershon, S. Tritiated imipramine binding sites are decreased in the frontal cortex of suicide. Sci. 1982;216:1337-1339. 29. Stanley, M., Mann, J.J. Increased serotonin-2 binding sites in frontal cortex of suicide victims. Lancet. 1983;i:214-216. 30. Arango, V., Underwood, M.D., Gubbi, A.V., Mann, J.J. Localized alterations in pre-and postsynaptic serotonin binding sites in the ventrolateral prefrontal cortex of suicide victims. Brain Res. 1995;688:121-133. 31. Ono, H., Shirakawa, O., Kitamura, N., Hashimoto, T., Nishiguchi, N., Nishimura, A., Nushida, H., Ueno, Y., Maeda, Neurobiological Aspects of Suicide 3
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