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The Genetics of Suicide
Sylvia G. Simpson, M.D.
Bibliography
Slide
Presentation
Until recently, clinical studies were the only
means of exploring the role that genetic factors play in suicidal behavior.
Family studies showed that relatives of persons who commit suicide are at
increased risk of suicidal behavior compared
the relatives of controls. A recent study demonstrated a familial aggregation of
suicide attempts in the families of adolescent suicide victims even after
controlling for the increased rate of Axis I and II disorders in relatives. Twin
studies have found monozygotic twins to have a significantly greater concordance
than dizygotic twins for both suicide and suicide attempts, and adoption studies
have revealed that significantly more adoptees with affective disorder than
controls committed suicide.
Decreased serotonin (5-HT) turnover in the brain,
thought to be associated with increased impulsivity, has been implicated as a
factor in suicide. Strategies for studying the serotonergic system in suicide
include examining cerebrospinal fluid (CSF) and platelets of suicidal
individuals as well as postmortem brain samples. Low concentrations of CSF
5-hydroxyindoleacetic acid (5- HIAA), the principal metabolite of serotonin,
have been found to be associated with suicidality as well as with depression,
alcoholism, and violence. Many of the genes involved in controlling serotonin
metabolism have been cloned, including those for tryptophan hydroxylase (TPH),
the serotonin transporter, and several serotonin receptors. An earlier report of
an association between a polymorphism in intron 7 of the TPH gene and
suicidality in a group of violent alcoholic Finnish offenders has been
replicated, and some evidence for linkage of TPH to suicidality was found.
Molecular genetic methods hold the promise of being able to better identify
individuals at increased risk of suicide. An updated report of these studies
will be presented.
Neuropathology of Suicide
Susan E. Bachus, Ph.D.
Bibliography
Thomas M. Hyde, M.D.
Mary M. Herman, M.D.
Joel E. Kleinman, M.D.
Slide
Presentation
Recently developed molecular biological methods
that can be applied to postmortem studies of human brain have opened new avenues
for the exploration of neuroanatomical substrates of pathology that might
contribute to vulnerability to suicide. A review of the literature will
illustrate application of such techniques as quantitative receptor
autoradiography, immunohistochemistry, cell morphometry, in situ hybridization
histochemistry, and genotyping to the elucidation of causality of suicide.
Examples will be described from our research
effort in the Clinical Brain Disorders Branch utilizing in situ hybridization
histochemistry. While dysfunctional limbic cortex (specifically in entorhinal
cortex/hippocampus [ERC/HPC] and dorsolateral prefrontal cortex [DLPFC]) has
previously been implicated in the neuropathology of suicide and affective
disorders, glutamate neurons in these regions have heretofore received very
little attention in this field. We have made serendipitous findings implicating
limbic cortical glutamate abnormalities in suicide and affective disorders in
the course of our postmortem studies of the involvement of this circuitry in
schizophrenia, in which we included groups of nonpsychotic suicides and of
patients afflicted with bipolar affective disorder as control groups for
diagnostic specificity. In our studies of the possible role of glutamate
synaptic function within limbic circuitry in schizophrenia, we have recently
added several findings to the evidence that these neurons may be aberrant in
suicide as well: 1) mRNA for cholecystokinin (CCK), a neuromodulator which is
co-localized with glutamate in some of these neurons, is elevated in suicides
relative to both normal controls and schizophrenics, in DLPFC; 2) mRNA for
thyrotropin releasing hormone TRH), another neuromodulator co-localized with
glutamate in some of these neurons, is reduced in ERC in suicides, and also in
patients with bipolar affective disorder, relative to normal controls; 3) mRNA
for the transporter for the comodulator l-proline is reduced in ERC/HPC in a
group of affective disorder cases (suicides and bipolars) relative to normal
controls, 4) mRNA for the transporter for the comodulator glycine is reduced in
superior temporal gyrus (STG) in suicides relative to normals, schizophrenics
and bipolars; 5) mRNA for the GluR1 subunit of the AMPA glutamate receptor in
the sulcal region of ERC is elevated in suicides relative to both normal
controls and schizophrenics; and 6) mRNA for the "flip" variant of the
GluR3 subunit of the AMPA receptor in STG is elevated relative to normals.
Finally, by way of contrast, we also have some evidence that the GABA
interneurons in these same regions may also be abnormal in suicide, inasmuch as
levels of mRNA for preprosomatostatin, a marker for GABA neurons, are decreased
in ERC in suicides and bipolars relative to normals and in DLPFC in a group of
"affective disorders" cases (suicides and bipolars).
We propose that the confluence of the
availability of suitable postmortem samples and this augmentation of our
armamentarium of techniques promises the attainment of important new insights
into the biological underpinnings of suicide from postmortem research. It is to
be hoped that this new knowledge might inspire novel pharmacotherapeutic
strategies for the prevention of suicide.
Reduced Risk of Suicidal Behavior in Bipolar
Disorder Patients during Long-term Treatment with Lithium
Ross J. Baldessarini, M.D.
Bibliography
Leonardo Tondo,M.D.
John Hennen, Ph.D.
Slide
Presentation
Introduction:
Mortality in bipolar (BP) disorders is increased owing to suicide, effects of
stress-related medical illnesses, and complications of comorbid substance abuse.
Impact of modern medical treatments on mortal risk has been unclear. Methods:
Rates of suicidal behavior in 21 reported studies were compared for 16,200
lithium-treated and untreated manic-depressive patients. New data from our
international clinical study yielded quantitative estimates of life-threatening
suicide attempts before, during, and after discontinuing long-term lithium
treatment in 310 DSM-IV BP I and II patients. Results: In published
studies, rates of suicidal acts were 7-fold lower during lithium maintenance
treatment (0.25% of patients/year) than without it (1.8%/year). In Sardinian BP
patients, we found 90 suicide attempts (8 fatal) over 5,200 patient-years, with
7.7-fold lower risk during vs. before lithium (0.35% vs. 2.7% of patients/year).
Most attempts occurred within the 8.3-year latency to maintenance treatment
(longest in bipolar-II women). Attempts were associated with current depression/dysphoria
(89%), previous severe depression and attempts, and early illness-onset.
Survival analysis indicated 8-fold reduction of 15-year cumulative risk of
suicide attempts on lithium. After discontinuing lithium, suicidal act-rates
rose 22-fold within the first year (halved with slow discontinuation), to levels
2.5-times over very similar later and prelithium rates, and fatalities increased
by nearly 14-fold after discontinuing lithium. Conclusions: The findings
indicate powerful, long-sustained protective effects of lithium against suicidal
behavior, not demonstrated for alternative treatments, with sharply,
time-limited, increased suicidal risk shortly after discontinuing lithium,
particularly rapidly. These results encourage improved, earlier identification
and treatment of BP depression/dysphoria.
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