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More than two decades of reports have linked low serotonin levels in the brain to depression, aggressive behavior and a tendency toward impulsiveness, but the evidence has been particularly confusing with regard to suicide. A number of studies have found reductions in serotonin in the brains of suicides, whereas others have not. Some have observed a lack of serotonin in one part of the brain but not elsewhere. Still others have described increases in the number of receptors for serotonin or deficits in the chain of chemical events that convey the serotonin signal from those receptors to the inside of a neuron.
Despite the inconsistencies, the bulk of evidence points strongly to a problem in the brains of suicides involving the serotonin system. That line of thinking has been bolstered by the recent findings of Arango and Mann.
In a second-floor laboratory at the upper tip of Manhattan, Arango's technician leans into an open freezer to use a machine called a microtome to pare a feather-light slice from a frozen brain donated by grieving relatives anxious to help science address the mystery of suicide. Using a chilled brush, she delicately coaxes the rime of icy tissue onto a glass slide the size of a snapshot. With the body heat from her own gloved hands, she then melts the brain sliver onto the glass; observing the process is reminiscent of watching bright sunlight on a frigid winter day dissolve frost on a window.
The scientists working with the Columbia collection divide the brains into left and right hemispheres and then carefully section each hemisphere into 10 or 12 blocks from front to back. Once frozen and put through the microtome, every block yields roughly 160 slices that are thinner than a human hair.
The chief benefit of this approach is that Arango's and Mann's groups can perform several different biochemical tests on the same brain slice and know the exact anatomical locations of the variations they find. By reassembling the slices virtually, they can compile an overall model of how those abnormalities might work in concert to affect a complex behavior.
At a conference of the American College of Neuropsychopharmacology in 2001, Arango reported that the brains of people who were depressed and died by suicide contained fewer neurons in the orbital prefrontal cortex, a patch of brain just above each eye. What is more, in suicide brains, that area had one third the number of presynaptic serotonin transporters that control brains had but roughly 30 percent more postsynaptic serotonin receptors.
Together the results suggest that the brains of suicides are trying to make the most of every molecule of serotonin they have, by increasing the molecular equipment for sensing the neurotransmitter while decreasing the number of transporters that absorb it back again. "We believe there is a deficiency in the serotonergic system in people who commit suicide," Arango concludes. "They can be so sick Prozac can't help them." Inhibiting the reuptake of serotonin isn't always enough to prevent suicide: it wasn't for my mother, who died despite taking 40 milligrams of Prozac a day.
Mann and his colleagues are now trying to devise a positron emission tomography (PET) test that might one day aid doctors in determining which among their depressed patients have the most skewed serotonin circuitry--and are therefore at highest risk of suicide. PET scans mirror brain activity by monitoring which brain regions consume the most blood glucose; administering drugs, such as fenfluramine, that cause the release of serotonin can help scientists zero in on active brain areas using serotonin.
In the January Archives of General Psychiatry, Mann and his co-workers reported a relation between activity in the prefrontal cortex of people who had attempted suicide and the potential deadliness of the attempt. Those who had used the most dangerous means--for example, by taking the most pills or jumping from the highest point--had the least serotonin-based activity in the prefrontal cortex. "The more lethal the suicide attempt, the bigger the abnormality," Mann observes.
Ghanshyam N. Pandey of the University of Illinois agrees that the brain's serotonin system is key to understanding suicide. "There is a lot of evidence to suggest serotonin defects in suicide, but these defects do not exist in isolation but in concert with other deficits," he says. "The whole system appears to be altered."
The serotonin hypothesis does not rule out important contributions by other neurotransmitters, however. Serotonin is only one molecule in the intricate biochemical network named the hypothalamic-pituitary-adrenal (HPA) axis, in which the hypothalamus and pituitary glands in the brain communicate with the adrenal glands atop the kidneys. The HPA is responsible for the so-called fight-or-flight response exemplified by the racing heartbeat and sweaty palms you get after a close scrape while driving, say. In particular, corticotrophin-releasing factor, which the hypothalamus releases in times of stress, causes the anterior pituitary to make adrenocorticotropic hormone, which in turn causes the adrenal cortex to produce glucocorticoids such as cortisol. Cortisol prepares the body for stress by raising blood sugar concentrations, increasing heart rate and inhibiting the overreaction of the immune response.
Serotonin fits into the HPA because it modulates the threshold of stimulation. Researchers such as Charles B. Nemeroff of the Emory University School of Medicine and his colleagues are finding that extremely adverse early life experiences, such as child abuse, can throw the HPA axis off kilter, literally leaving biochemical imprints on the brain that make it vulnerable to depression as a result of overreacting to stress later on.
In 1995 Pandey's group reported indications that the abnormalities in serotonin circuitry present in those at risk for suicide could be detectable using a relatively simple blood test. When he and his co-workers compared the number of serotonin receptors on platelets (clotting cells) in the blood of suicidal people with those of nonsuicidal people, they observed that individuals considering suicide had many more serotonin receptors. (Platelets just happen to have receptors for serotonin, although it is unclear why.)
Pandey says that his group concluded that the boost in receptors reflects a similar increase in the suicide-prone brains--a vain attempt to garner as much serotonin as possible. To prove the link, Pandey would like to determine whether the association holds up in people who go on to take their own lives. "We want to know if platelets can be used as markers for identifying suicidal patients," Pandey says. "We are making progress, but it's slow."
A Curse of Generations
Until researchers can develop tests to forecast those at highest risk for suicide, doctors might concentrate their efforts on the biological relatives of suicide victims. In the September 2002 issue of Archives of General Psychiatry, Mann, David A. Brent of the Western Psychiatric Institute and Clinic in Pittsburgh and their colleagues reported that the offspring of suicide attempters have six times the risk of people whose parents never attempted suicide. The link appears in part to be genetic, but efforts to pin down a predisposing gene or genes have not yet yielded any easy answers. In studies in the early 1990s Alec Roy of the Department of Veterans Affairs Medical Center in East Orange, N.J., observed that 13 percent of the identical twins of people who died by suicide also eventually took their own lives, whereas only 0.7 percent of fraternal twins traveled the same path as their suicidal siblings.
http://www.sciam.com/print_version.cfm?articleID=0006AF90-5BC7-1E1B-8B3B809EC588EEDF
If anyone wants to know anything about depression/suicide I am more than willing to answer their questions. I am seriously considering volunteering as a Suicide Prevention Counsellor, (given the appropriate training of course).
Despite the inconsistencies, the bulk of evidence points strongly to a problem in the brains of suicides involving the serotonin system. That line of thinking has been bolstered by the recent findings of Arango and Mann.
In a second-floor laboratory at the upper tip of Manhattan, Arango's technician leans into an open freezer to use a machine called a microtome to pare a feather-light slice from a frozen brain donated by grieving relatives anxious to help science address the mystery of suicide. Using a chilled brush, she delicately coaxes the rime of icy tissue onto a glass slide the size of a snapshot. With the body heat from her own gloved hands, she then melts the brain sliver onto the glass; observing the process is reminiscent of watching bright sunlight on a frigid winter day dissolve frost on a window.
The scientists working with the Columbia collection divide the brains into left and right hemispheres and then carefully section each hemisphere into 10 or 12 blocks from front to back. Once frozen and put through the microtome, every block yields roughly 160 slices that are thinner than a human hair.
The chief benefit of this approach is that Arango's and Mann's groups can perform several different biochemical tests on the same brain slice and know the exact anatomical locations of the variations they find. By reassembling the slices virtually, they can compile an overall model of how those abnormalities might work in concert to affect a complex behavior.
At a conference of the American College of Neuropsychopharmacology in 2001, Arango reported that the brains of people who were depressed and died by suicide contained fewer neurons in the orbital prefrontal cortex, a patch of brain just above each eye. What is more, in suicide brains, that area had one third the number of presynaptic serotonin transporters that control brains had but roughly 30 percent more postsynaptic serotonin receptors.
Together the results suggest that the brains of suicides are trying to make the most of every molecule of serotonin they have, by increasing the molecular equipment for sensing the neurotransmitter while decreasing the number of transporters that absorb it back again. "We believe there is a deficiency in the serotonergic system in people who commit suicide," Arango concludes. "They can be so sick Prozac can't help them." Inhibiting the reuptake of serotonin isn't always enough to prevent suicide: it wasn't for my mother, who died despite taking 40 milligrams of Prozac a day.
Mann and his colleagues are now trying to devise a positron emission tomography (PET) test that might one day aid doctors in determining which among their depressed patients have the most skewed serotonin circuitry--and are therefore at highest risk of suicide. PET scans mirror brain activity by monitoring which brain regions consume the most blood glucose; administering drugs, such as fenfluramine, that cause the release of serotonin can help scientists zero in on active brain areas using serotonin.
In the January Archives of General Psychiatry, Mann and his co-workers reported a relation between activity in the prefrontal cortex of people who had attempted suicide and the potential deadliness of the attempt. Those who had used the most dangerous means--for example, by taking the most pills or jumping from the highest point--had the least serotonin-based activity in the prefrontal cortex. "The more lethal the suicide attempt, the bigger the abnormality," Mann observes.
Ghanshyam N. Pandey of the University of Illinois agrees that the brain's serotonin system is key to understanding suicide. "There is a lot of evidence to suggest serotonin defects in suicide, but these defects do not exist in isolation but in concert with other deficits," he says. "The whole system appears to be altered."
The serotonin hypothesis does not rule out important contributions by other neurotransmitters, however. Serotonin is only one molecule in the intricate biochemical network named the hypothalamic-pituitary-adrenal (HPA) axis, in which the hypothalamus and pituitary glands in the brain communicate with the adrenal glands atop the kidneys. The HPA is responsible for the so-called fight-or-flight response exemplified by the racing heartbeat and sweaty palms you get after a close scrape while driving, say. In particular, corticotrophin-releasing factor, which the hypothalamus releases in times of stress, causes the anterior pituitary to make adrenocorticotropic hormone, which in turn causes the adrenal cortex to produce glucocorticoids such as cortisol. Cortisol prepares the body for stress by raising blood sugar concentrations, increasing heart rate and inhibiting the overreaction of the immune response.
Serotonin fits into the HPA because it modulates the threshold of stimulation. Researchers such as Charles B. Nemeroff of the Emory University School of Medicine and his colleagues are finding that extremely adverse early life experiences, such as child abuse, can throw the HPA axis off kilter, literally leaving biochemical imprints on the brain that make it vulnerable to depression as a result of overreacting to stress later on.
In 1995 Pandey's group reported indications that the abnormalities in serotonin circuitry present in those at risk for suicide could be detectable using a relatively simple blood test. When he and his co-workers compared the number of serotonin receptors on platelets (clotting cells) in the blood of suicidal people with those of nonsuicidal people, they observed that individuals considering suicide had many more serotonin receptors. (Platelets just happen to have receptors for serotonin, although it is unclear why.)
Pandey says that his group concluded that the boost in receptors reflects a similar increase in the suicide-prone brains--a vain attempt to garner as much serotonin as possible. To prove the link, Pandey would like to determine whether the association holds up in people who go on to take their own lives. "We want to know if platelets can be used as markers for identifying suicidal patients," Pandey says. "We are making progress, but it's slow."
A Curse of Generations
Until researchers can develop tests to forecast those at highest risk for suicide, doctors might concentrate their efforts on the biological relatives of suicide victims. In the September 2002 issue of Archives of General Psychiatry, Mann, David A. Brent of the Western Psychiatric Institute and Clinic in Pittsburgh and their colleagues reported that the offspring of suicide attempters have six times the risk of people whose parents never attempted suicide. The link appears in part to be genetic, but efforts to pin down a predisposing gene or genes have not yet yielded any easy answers. In studies in the early 1990s Alec Roy of the Department of Veterans Affairs Medical Center in East Orange, N.J., observed that 13 percent of the identical twins of people who died by suicide also eventually took their own lives, whereas only 0.7 percent of fraternal twins traveled the same path as their suicidal siblings.
http://www.sciam.com/print_version.cfm?articleID=0006AF90-5BC7-1E1B-8B3B809EC588EEDF
If anyone wants to know anything about depression/suicide I am more than willing to answer their questions. I am seriously considering volunteering as a Suicide Prevention Counsellor, (given the appropriate training of course).
