J. John Mann, MD DIRECTOR OF THE MOLECULAR IMAGING AND NEUROPATHOLOGY DIVISION COLUMBIA UNIVERSITY NEW YORK STATE PSYCHIATRIC INSTITUTE

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1 J. John Mann, MD DIRECTOR OF THE MOLECULAR IMAGING AND NEUROPATHOLOGY DIVISION COLUMBIA UNIVERSITY NEW YORK STATE PSYCHIATRIC INSTITUTE PAUL JANSSEN PROFESSOR OF TRANSLATIONAL NEUROSCIENCE DEPARTMENT OF PSYCHIATRY COLUMBIA UNIVERSITY Do not use or distribute without obtaining permission 1

2 Neurobiology of the Predisposition to Suicidal Behavior J. John Mann MD Paul Janssen Professor of Translational Neuroscience Columbia University New York State Psychiatric Institute

3 Who is at risk for suicidal behavior? Suicide and most nonfatal suicide attempts are made by people suffering from untreated psychiatric illness. The most common illness is a mood disorder which accounts for about 60% of suicides in the USA. The rate of suicide in the USA is at present about the same as it was in the 1950s. There is an urgent need for more basic research to improve prevention.

4 The Predisposition to Suicidal Behavior Clinicians have observed that only a minority of those with mood disorders ever attempt suicide. Those who do suicide or make suicide attempts do so early in the course of illness. This indicates a predisposition to suicidal behavior. Suicidal behavior and this predisposition are transmitted in families.

5 Brent DA, Oquendo M, Birmaher B, Greenhill L, Kolko D, Stanley B, Zelazny J, Brodsky B, Bridge J, Ellis S, Salazar JO, Mann JJ: Familial pathways to early-onset suicide attempt: risk for suicidal behavior in offspring of mooddisordered suicide attempters. Arch Gen Psychiatry 2002

6 A model of suicidal behavior We propose a model of suicidal behavior where in high-risk patients the response to psychiatric illness and current adverse life events is abnormally intense. Problem solving is impaired, leading to greater emotional distress and more severe suicidal ideation, and all of which are combined with a greater tendency to act on emotions including suicidal thoughts. The causes are genetic and early childhood adversity.

7 Genetics, Major Depression and Suicidal Behavior Major psychiatric disorders and mood disorders are moderately heritable. Suicidal behavior predisposition is also heritable. Specific genes are being sought for both illness and predisposition. Genes and early childhood experiences can combine to contribute to a predisposition in terms of response to current life stressors.

8 Connecting Genes to Suicidal Behavior This is like constructing a tunnel from two opposite ends. It involves drilling from two opposite directions towards each other. At one end there are genes and their interaction with childhood environment. At the other end there is suicidal behavior. In between is this predisposition. We need to find some genes to find a starting point. It is easier to find genes related to the predisposition.

9 Biology of Predisposition to Suicide and Stress Response is More Closely Related to Genes Early onset recurrent mood disorder < low serotonin function, high cortisol Pessimism< low norepinephrine function Cognitive deficits< high cortisol and other neurotransmitters Acting on feelings<low serotonin, higher dopamine, low norepinephrine

10 Stress Related Neural Circuitry and Suicidal Behavior Cortisol

11 Corticosteroid Stress Response and Suicidal Behavior High cortisol predicts mood instability and increases the risk of suicide more than four times (Currier, Mann and others). High cortisol also underlies greater impulsive aggression and impaired cognition (childhood adversity or genes). Childhood adversity permanently altered the function of genes in this basic stress response system.

12 Some relevant neural circuitry Serotonin neurons

13 Arango et al 2002 Serotonin Transporter (a) and 5-HT 1A Receptor (b) in Suicide

14 Low Serotonin Transporter Binding (PET with 11C-DASB) in MDD Suicide Attempters controls MDD nonattempters MDD nonattempters MDD attempters Miller et al (in press)

15 Future Focus on offspring of suicide attempters in at-risk families. Study antecedents of suicidal behavior as potential targets for preventative interventions such as decisionmaking, aggression and early onset mood disorders. Evaluate biological antecedents such as abnormal stress responses or abnormal brain scans. Design prevention efforts to target at-risk family members before the onset of major depression or manifestation of suicidal behavior.

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