HONOLULU— Suicidal behavior is at least partly due to a serotonin transporter defect in the prefrontal cortex, and that defect may be what links stress and suicide in some patients. J. John Mann, MD, Chief of the Division of Neuroscience, Columbia University, New York City, said the serotonin defect is similar in subjects who survive a serious suicide attempt compared with those who succeed. Both have evidence of deficient serotonin input into the part of the brain governing impulsivity and restraint. Dr. Mann reported at the 14th Annual Meeting of the American Neuropsychiatric Association that the defect is also reflected in altered numbers of the 5-HT1A and 5-HT2A serotonin receptors.

“Neither pathological violence nor suicide is understandable solely as a response to stress. Suicidal behavior requires an underlying predisposition, without which the probability for suicide is small, even in patients with psychiatric illness such as recurrent unipolar depression. Most individuals with a psychiatric disorder, including mood disorders, never attempt suicide,” Dr. Mann explained.

In attempting to learn why some people exhibit suicidal behavior but others do not, Dr. Mann first looked for differences between individuals with a psychiatric illness who had a history of suicide attempts and those with a psychiatric illness who had never made such an attempt.

IMPULSIVITY AND INTENT

“The objective psychiatric pathology was no different between the attempters and the nonattempters. Faced with the same severe objective illness and the same number of life events, individuals with a history of suicidal behavior reported feeling more severely depressed, seeing fewer reasons for living, and having more suicidal ideation. They were also more aggressive and impulsive in a variety of behaviors in their lives. The impulsivity element appears to mediate both the risk for suicidal behavior and the risk for aggressive behaviors. We found that impulsivity seems to determine the probability of attempting suicide, whereas suicidal intent determines lethality of the attempt,” Dr. Mann said.

As serotonin dysfunction has been associated with mood disorders and with suicidal behavior, Dr. Mann thought it a good candidate for further study and set out to map serotonergic components of depression and suicide. He and his colleagues Victoria Arango, PhD, and Mark Underwood, PhD, mapped the serotonin transporter, which can be labeled with a selective serotonin reuptake inhibitor (SSRI). The transporter is responsible for reuptake of the transmitter, terminating the signal.

Dr. Mann explained that when less serotonin is released, the nerve terminal internalizes and removes the serotonin transporter. “That is an attempt to amplify the signal. Less transporter usually means either fewer terminals or less serotonin being released which the brain is trying to make an adjustment for. Either way, less transporter probably equals less serotonin activity in most situations,” Dr. Mann surmised.

Positron emission tomography (PET) scan studies by Dr. Mann and his colleague, Ramin Parsey, MD, PhD, in patients with depression have found lower levels of serotonin transporter in the brainstem, ventral striatum, and anterior cingulate—areas involved in mood regulation. In postmortem studies, they have reported a widespread deficit of serotonin transporter throughout the prefrontal cortex and anterior cingulate of subjects with a history of a major depressive episode.

The level of 5-HT2A receptor expression is higher in individuals who are more aggressive. This might be due to 5-HT2B-mediated aggressive behavior or because the brain is trying to compensate for low levels of 5-HT1A. Dr. Mann mentioned that this receptor is also expressed at high levels in suicidal people and is blocked with particular effectiveness by antipsychotic drugs such as clozapine. “That may explain the anti-aggression and anti-suicidal effects of clozapine,” he noted.

CAUSE AND EFFECT

The lower level of serotonin transporter has different causes in depression and in suicidal behavior. In patients with depression, there are abnormally few neurons in the affected areas of the prefrontal cortex, and there is less serotonergic input. In patients with suicidal behavior, the number of neurons is not reduced, but there is an even greater deficit in the serotonin coming into the specific brain region involved in behavioral restraint.

PET scans can map serotonin-induced changes in brain activity. Dr. Mann said that there is an area of abnormality that distinguished depressed suicide attempters. “The size of the abnormality is proportional to the suicidal intent and thereby enforces suicidal lethality. The more lethal the suicidal behavior, the less activity we found in the anterior cingulate and in the lateral prefrontal cortex. On the other hand, activity was higher when impulsivity was higher. These particular brain changes explain how intent and impulsiveness determine how lethal suicidal behavior is,” he said.

In depressed suicidal patients only half as many cells in this region express serotonin transporter as in nonsuicidal controls, but the cells that are turned on express the protein to excess. “That suggests to us that there is a regulatory defect that can result in underexpression in some cells but overexpression in others. That regulatory defect might be a target for therapeutic manipulation,” Dr. Mann said. “Stress, pessimism, and suicidal ideation all are reflective of a diathesis that determines whether or not interaction of depression with temperament will result in suicide. Impaired serotonergic transmission in the prefrontal cortex predisposes some patients to acting suicidally and acts on other powerful emotions such as anger. Stress can lead to excessive noradrenergic changes, which may explain the excessive hopelessness we see in many of these patients.”

—Janis Kelly

Suggested Reading
Oquendo MA, Placidi GPA, Malone KM, et al. Positron emission tomography of regional brain metabolic responses to a serotonergic challenge and lethality of suicide attempts in major depression. Arch Gen Psychiatry. 2003;60:14-22.

Return to table of contents