Serotonin and the Suicidal

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Serotonin and the Suicidal

Suicide is the eighth leading cause of death in the United States and is among the three leading causes of death for those aged 15 to 34 years. For every person in the U.S. who dies by suicide, 10 people attempt suicide but survive. Suicide attempts are the most serious complication of Major Depressive Disorder, and, in up to forty percent of cases, attempts precede completed suicide. Recent studies in Finland and England suggest that, while Major Depression is a recognizable and treatable disorder, only a small fraction of suicides with Major Depression received adequate antidepressant treatment prior to their deaths. Data from our own studies confirms that most depressed suicide attempters receive inadequate antidepressant treatment. Clinicians cannot easily predict which patients with Major Depression will attempt suicide and which depressives will not. This difficulty also perplexes and demoralizes the families of depressed, suicidal patients that must deal with the consequences of suicidal thoughts and actions.

Dr. John Mann directs the Federally-funded Mental Health Clinical Research Center for the Study of Suicidal Behavior, which was established in 1989. Located at the New York State Psychiatric Institute/Columbia Presbyterian Medical Center, the Research Center is uniquely dedicated to conducting suicide research across the life cycle in order to better understand the behavioral, biological, and genetic mechanisms underlying suicidal behavior.

Because clinical characteristics such as severity of depression so poorly differentiate depressed suicide completers and attempters from depressed nonattempters, we have suggested that a "trait-related suicidal threshold" exists. In vulnerable (low threshold) patients this threshold is exceeded easily following the onset of a depressive episode; the inability to suppress or contain suicidal thoughts then leads to a suicidal act. Because suicidal acts vary in their severity, we have proposed further that suicidal acts closely resembling completed suicide are more likely to provide behavioral and biological clues that define the suicidal threshold.

Since 1976 several studies have reported lower levels of the major metabolite of the neurotransmitter serotonin in the spinal fluid of suicide victims. We and others also have reported that, in depressed patients, prolactin release in response to the serotonin-releasing drug fenfluramine is more blunted in suicide attempters than in nonattempters.

More recently, we have reported that depressed patients whose suicidal acts most closely resemble completed suicide (i.e. more medical damage as a consequence of the suicidal act) have both lower spinal fluid serotonin metabolite levels and a more blunted prolactin response to fenfluramine compared to depressed patients whose suicidal acts inflict minimal medical damage. As we predicted, no differences were found between the groups in other neurotransmitter metabolites or hormonal levels, nor were there any meaningful differences in clinical characteristics such as age, sex, or severity of depression.

This reduction of serotonergic function did not relate to how recently the suicide attempt had been made, which in many cases was several months earlier, and thus it appears to represent a biological trait. Our evidence to date therefore suggests that an underlying serotonin dysfunction may be associated with more serious suicidal behavior and may play a major role in defining the suicidal threshold.

While these biochemical tests provide us with potentially useful information about alterations in brain serotonin activity in suicidal patients, they give us no information about whether any specific brain regions may be responsible. For this answer, we referred to our colleague in the MHCRC, Dr. Victoria Arango, who conducts neurochemical studies on suicide victims' brains that families donated. In these brains, she has identified alterations in serotonergic neuron projections to specific regions of the frontal cortex (the most sophisticated area of the brain and involved in the regulation of mood and impulsiveness).

As clinicians, we then wondered if we could devise a method that would capture a direct image of normal brain response to serotonin release in live, normal subjects. If this were possible, we could apply such technology to visualizing regional serotonin responses in depressed and suicidal patients. To this end, we used positron emission tomography (PET), a new brain imaging technique that can visualize regional brain metabolic activity. We found that serotonin release increased brain metabolic activity in the same region of the prefrontal cortex that Dr. Arango found to be abnormal. The procedure marked the first report of imaging regional serotonin responses in a live human brain.

We recently applied this methodology to depressed patients, predicting that they would have an impaired prefrontal cortical response to serotonin release. Prefrontal brain response was reduced indeed in all depressed patients compared with normal subjects. This study provides the first visualization of the serotonin deficiency hypothesis of depression, which was originally proposed in 1965. We are now conducting brain-imaging and genetic studies on depressed patients who made serious suicide attempts.

Much work still needs to be done. Research of this kind will improve detection of high risk patients and will create novel treatment options. The exciting developments in probing the brain constitute work in progress, and we are currently seeking more depressed and suicidal patients to volunteer for the investigation. Moreover, publicizing the problem is more likely to encourage investment in solutions.

Further reading: Please contact Dr. Kevin Malone at (212) 960-5571, or write to him at P.O. Box 28, New York State Psychiatric Institute, 1051 Riverside Drive, NY, NY, 10032.

Kevin Malone, M.D. is Assistant Professor at the Columbia University College of Physicians and Surgeons. J. John Mann, M.D. is Professor of Psychiatry at the Columbia University College of Physicians and Surgeons and Chief of the Department of Neuroscience at the New York State Psychiatric Institute.

http://www.afsp.org/research/articles/malone.html

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