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Suicide and some of its neurobiological correlations. Second part
Abstract
Suicidal behavior is a complex and multifactorial phenomenon. At present, growing evidence shows the participation of biological traits in suicidality. Some findings suggest the dysfunction of the serotonin system, since serotonin and some of its receptor subtypes are involved in the modulation of such as affective behavior and cognition, among other behavioral processes. The content of 5-hydroxyindoleacetic acid, the major serotonin metabolite, is reduced in the cerebrospinal fluid of violent suicide attempters, independently of any other previous psychiatric diagnosis. In fact, this reduction may predict future suicide attempts and suicide completion. Post-mortem studies of ventromedial prefrontal cortex from suicide victims show decreased density of the 5-HT1A presynaptic serotonergic receptor subtype, and a compensatory upregulation of the 5-HT2A serotonergic post-synaptic receptor subtype. These observations on suicide strongly suggest a role of the two serotonin receptor subtypes located in this cortical brain region. Dysfunction of this region may support the diathesis concept (vulnerability) associated to suicidal behavior. In fact, some people display impulsive and self-aggressive behavior as part of their suicidality. This dysfunction is associated with alterations in the polymorphisms of tryptophan hydroxylase gene expression, i.e., the rate-limiting enzyme which in turn modifies the biosynthesis of serotonin, contributing to the reduction of serotonergic activity. Since the prefrontal cortex and related structures play a major role in mood regulation, their participation in the pathophysiology of affective disorders and suicide is currently being discussed. A circuit integrated by prefrontal cortex, hippocampus, amygdaloid complex, lateral septal nucleus and other functionally related structures could be involved in the regulation of emotional memory, hedonism and decision-taking. The hippocampus is implicated in cognition and is one of the cerebral structures strongly affected by stress. Structural abnormalities in cortical and hippocampal areas and reduced hippocampal plasticity have been demonstrated in patients suffering from chronic stress and affective disorders. Reduced neurotrophin expression may be associated with structural abnormalities and reduced hippocampal plasticity. A decrease in the content of neurotrophins in the prefrontal cortex and hippocampus could be of relevance in suicidal behavior. Human post-mortem studies supported by living animals studies have demonstrated that antidepressants increase the activity of the brain-derived neurotrophic factor (BDNF) and increase the density of its receptor (BDNF-tyrosine kinase receptor B: trkB), which seems to participate in the therapeutic effects of drugs used in the treatment of depression. On the contrary, the reduction of BNDF trkB-receptor mRNA has been related to suicidal behavior, since a reduction of plasma BNDF levels has been reported in major depression. BNDF levels have also been suggested as a biological marker of suicidal depression. Abnormalities in the ventromedial prefrontal cortex in suicidal individuals largely correlate with the neurochemical deficits reported in this population. In fact, prefrontal hypofunction and impaired serotonergic responsivity are proportional to the lethality of the suicide attempt. Positron emission tomographic studies indicate lower ventromedial prefrontal cortex activity, behaviorally associated with high impulsivity, higher planning of suicidal intent, and higher-lethality suicide attempts. Other studies have also related structural abnormalities in amygdala with suicidality. The function of this region is critical regarding fear, anxiety, aggression and the recognition and response to danger, i.e., some behavioral patterns involved in suicidality. Anxiety commonly follows or precedes depression. Therefore, amygdaline dysfunction may increase the risk of suicidal behavior. For depressive-suicide attempters, the suicide act itself occurs at a moment of extreme anxiety, strongly suggesting amygdaloid complex participation in the process. Lastly, the lateral septal nucleus is related with anhedonia and hopelessness (despair). Since its neuronal firing rate increases after the experimental application of clinically effective antidepressant treatments. The septal nucleus is considered a target of these drugs, a suggestion supported by the observation that anhedonia is one of the main symptoms in depression and lateral septal nucleus activity is involved in hedonic process. Anhedonia, hopelessness and other depressive symptoms are significantly related to suicidal ideation. Taking into account that some patients with major depression are vulnerable to suicide, this vulnerability may result from the interaction of suicidality with environmental precipitants and a lowered threshold for suicidal behavior. Certainly, one of the psychiatric disorders associated with suicide is depression, which suggests a causal relationship and suggests the involvement of these brain structures in suicidality. Then, an anatomic and functional circuit may be expected. In normal conditions, the environment is perceived through the sensorial systems. Sensorial information reaches circuits located in the temporal lobe, such as amygdala and hippocampus, in which a comparison with previous experiences takes place. It is acceptable to consider that emotional memory comparison and acquisition of new information is a continuous process. By pathways arising from amygdala, the forebrain structures related with hedonic processing, such as lateral septal nuclei, may be involved. In species with a low development of frontal cortex (birds, amphibian, reptiles) many of the functions of prefrontal cortex are likely in charge of thalamic nuclei, namely, its association nuclei. In these species, the circuit reached enough functionality for the species surviving, given that when an animal copes with a dangerous situation it needs a comparison with previous experiences. This first learning of adequate responses takes place much time before, around weanling. But it is enough, since an animal scarcely needs to process a decision, simply attack or escape, approaches or avoid. It is simple, but tremendously efficacious. In human beings, the participation of the prefrontal cortex allow us to select a response, and depending on previous experiences, but namely trait, i.e., the actual contingence and the right functionality of all the circuits, the correct response is going to be selected, and survival strategies may succeed. In other case, if any of the anatomical substrates of emotional memory, hedonic processing or taking decisions circuits is deficiently working, the response to cope must be wrong. This may explain some common mistakes in selecting the right response, but also if the previous experiences and personality trait implicate impulsivity, the consequence may be fatal. We ask ourselves, is it suicidality? It might very well. Suicidality is also related to the response to stress. The hypothesis of hypothalamic pituitary adrenal axis hyperactivity in suicide is supported by post-mortem findings showing increased cerebrospinal fluid content of corticotrophin-releasing hormone, combined with reduced receptor binding sites for this hormone in the prefrontal cortex. Although some risk factors have been identified, the complete neurobiological basis of suicide is not well understood yet. Cerebral structures involved in the integration of the affective state, emotional memory, impulsivity and decision-taking may participate in suicide. Therefore, depending on the previous diagnosis, antidepressants, lithium or second-generation antipsychotics may be the first option in the management of suicidality. Atypical antipsychotics produce beneficial effects on depressed mood in patients with major depressive disorder and in patients with bipolar disorder. In schizophrenic patients, a significant amelioration of suicidality using clozapine, among other atypical antipsychotics, has also been reported. The sudden presence of anxiety, agitation and impulsivity must call the attention in patients suffering from depression, bipolar disorder, schizophrenia or schizoaffective disorder to seek pharmacological treatment combined with psychotherapy.
Introduction: During the last decade we have observed important climate changes, especially in environmental temperatures. There is considerable information linking the increase in hot weather and human health. For example, hot weather is associated with an increased risk of suicide in different countries around the world. Objective: To evaluate the relationship between suicide rates and the environmental temperature in Baja California Sur, Mexico, from 1985 to 2008. Method: Suicide mortality data for Baja California Sur (BCS) were obtained for the years 1985-2008 from the Instituto Nacional de Estadística, Geografía e Informática (INEGI). The selected codes were: E950-E959 (ICD-9) and X60-X84, Y87.0 (ICD-10) for BCS. The BCS weather data used was the maximum temperature from 1985 to 2008, obtained from the Extractor Rápido de Información Climatológica (ERIC III). Lineal and quadratic models were used to assess the annual rate changes of suicide and generalized lineal models (GLM) to assess the effect of the climatological variables to the suicide rate. The p≤0.05 was considered significant. Results: In BCS, 582 suicide deaths were reported from 1985 to 2008. The 9% (53) of the total reported were women with a yearly average rate 1.6/100 000; 91% (529) were men with a yearly average rate 16.3/100 000. Lineal and quadratic models explained the tendency of the annual increment observed in the number of suicides in both seasons. The quadratic model better explained such increment during the warmer months (R2=0.64 p<0.01). The temperature was positively correlated with the rate of suicides in both seasons (p<0.01). Two predictive GLMs were created by season. Discussion: These results suggest a potential link between an increase in environmental temperature and the rates of suicide during 24 years in BCS. This relationship is clear during the hot season; however, a positive trend was found during the cold season, perhaps due to the result of warmer winters.
The authors of this paper present a review of actual data on the neurobiological background of suicidal behaviour. The results of epidemiological studies suggest that suicidal behaviours have certain genetic background which do not depend on the presence of concomitant mental disorders. The estimated heritability rate of suicide is about 21-50%, while the heritability rate of suicidal ideation and behaviour is about 30-55%. The genes of serotonergic and noradrenergic systems, as well as the HPA axis genes, have been scrutinised in context of suicidal behaviour. Epigenetic factors are also believed to be involved in the pathogenesis of suicide. Serotonergic, noradrenergic, glutamatergic and GABAergic systems, as well as the HPA axis, are the main neural networks involved in the pathophysiology of suicide. Disorders of opioid and endocannabinoid systems can also be found in suicide victims. Pathogenesis of suicidal behaviour also contains abnormalities of cell signalising and pathology ofglial cells. Neurobiological background of akathisia and impulsivity (clinical issues closely related to the pathogenesis of suicidal behaviour) have also been presented. Most of the available trials on neurobiological background of suicidal behaviour have significant methodological weaknesses, making the results difficult to interpret. Usually they contain small samples and only single biological variables (without adjustment on environmental factors) are being analysed.
Low cholesterol concentrations and cholesterol-lowering therapies have been suggested
to be associated with increased suicidality. This article examined the association of
cholesterol, triglycerides, and body-mass index (BMI) with suicidal ideation and
suicide attempts. Findings are based on a nationally representative community sample
of n ¼ 4,181 subjects (18–65 years) examined with a standardized diagnostic
interview (CIDI) for (DSM-IV) mental disorders. Controlling for age and gender
the study revealed a moderate positive association between cholesterol, triglycerides,
BMI, and suicide attempts in subjects with depressive symptoms during the past
12 months (n ¼ 1,205). The results of this study are compatible with two recent
epidemiological cohort studies showing a positive association between cholesterol
and completed suicide.
Keywords major depressive episode, suicide attempt, cholesterol, body-mass index
Serious suicidal behavior, affective disorders, and a variety of other psychopathologic behaviors and syndromes have been found to correlate with measures of the serotonin system. Clinical studies have employed a range of serotonin indexes, including the cerebrospinal fluid level of 5-hydroxyindoleacetic acid, the prolactin response to serotonin agonists, such as fenfluramine hydrochloride, and platelet serotonin-related proteins or serotonin content. Many of these indexes are correlated with suicidal behavior, but the interrelationship of these biologic measures has been uncertain. We studied the relationship of a series of serotonin indexes in patients in whom these measures were correlated with suicidal behavior. A positive correlation was found between cerebrospinal fluid 5-hydroxyindoleacetic acid and the maximal prolactin response to fenfluramine but not with platelet serotonin2 receptor indexes. The fenfluramine-stimulated maximal prolactin response correlated with platelet serotonin2 receptor number, particularly in older patients. We conclude that cerebrospinal fluid 5-hydroxyindoleacetic acid measurements cannot be replaced but can be complemented by less invasive procedures, such as a fenfluramine challenge test or platelet serotonin2 measures, in the study of the relationship of the serotonin system to psychiatric disorders.
There is an increase in suicidal behaviour in the western world providing a major challenge to health care providers. There is an increase in the number of suicides among elderly people in Europe. The problem of suicides among elderly people is in itself a social problem, not solely a medical one. The general practitioner may be the only source of social contact for the elderly. Elderly individuals often present their problems to doctors as somatic complaints; these complaints must not be taken at face value but understood as expressions of psychosocial and social distress. The rise in suicide rates among young people is also alarming. The warning signs of escalating distress in adolescents are known and a treatment programme coordinating medical initiatives, such that recidivism of suicidal behaviour in adolescents is reduced, is necessary. The general practitioner is urged to sense when the problem presented by the individual stems from a source which is predominantly social, and to suggest an appropriate solution which may entail a family intervention. The general practitioner is in the front line of treatment and he or she may be better advised to treat both the social situation and the individual person in cases of attempted suicide. Medical initiatives must incorporate aspects of social medicine whereby community solutions are found for the management of individual distress. Social disruption, isolation, conflict and neglect are the doors to the house of despair. While medicine must respond to those who enter that house, it is the social level at which we must be the architects of change. People will die.(ABSTRACT TRUNCATED AT 250 WORDS)
Suicidal behavior has been linked to a deficiency in serotonin neurotransmission, but it is not known which brain regions are involved. We determined the pattern of alteration in serotonin 5-HT2 (5-HT2) receptor binding sites in suicide victims in prefrontal cortex compared with temporal cortex using a matched-pairs design to study 11 suicide victims and 11 matched controls, by both membrane binding and quantitative receptor autoradiography. Since a relationship between the serotonergic and noradrenergic systems has been proposed, we also examined beta-adrenergic receptor binding sites. Binding to 5-HT2 and beta-adrenergic sites in slide-mounted sections correlated strongly with binding site number in membrane preparations. A specific laminar distribution of 5-HT2 binding sites was found in both the control and suicide groups, whereas beta-adrenergic binding sites did not differ across cortical layers. A significant increase was found in suicide victims across all cortical layers in both receptor subpopulations in the prefrontal cortex, but only beta-adrenergic sites were increased in the temporal cortex. We conclude that suicide is associated with a localized increase in 5-HT2 binding sites.
A prospective study of 1,958 outpatients found that hopelessness, as measured by the Beck Hopelessness Scale, was significantly related to eventual suicide. A scale cutoff score of 9 or above identified 16 (94.2%) of the 17 patients who eventually committed suicide, thus replicating a previous study with hospitalized patients. The high-risk group identified by this cutoff score was 11 times more likely to commit suicide than the rest of the outpatients. The Beck Hopelessness Scale thus may be used as a sensitive indicator of suicide potential.
Extended previous findings that when rats avoid and/or escape electric shock that is not preceded by a warning signal, considerable gastric ulceration normally develops. In an experiment with 96 male albino sprague-dawley rats, very little ulceration developed under these conditions when ss were given a brief feedback signal after each avoidance-escape response. Ss showed only slightly more ulceration than nonshock controls and much less ulceration than either ss which could also avoid and escape shock but had no feedback signal or yoked "helpless" ss. These results, showing that excellent response feedback will greatly reduce or even eliminate ulceration, support a proposed theory, which also accounts for the "executive" monkey phenomenon. The explanation for this atypical effect is presented.
DOGS WHICH HAD 1ST LEARNED TO PANEL PRESS IN A HARNESS IN ORDER TO ESCAPE SHOCK SUBSEQUENTLY SHOWED NORMAL ACQUISITION OF ESCAPE/AVOIDANCE BEHAVIOR IN A SHUTTLE BOX. IN CONTRAST, YOKED, INESCAPABLE SHOCK IN THE HARNESS PRODUCED PROFOUND INTERFERENCE WITH SUBSEQUENT ESCAPE RESPONDING IN THE SHUTTLE BOX. INITIAL EXPERIENCE WITH ESCAPE IN THE SHUTTLE BOX LED TO ENHANCED PANEL PRESSING DURING INESCAPABLE SHOCK IN THE HARNESS AND PREVENTED INTERFERENCE WITH LATER RESPONDING IN THE SHUTTLE BOX. INESCAPABLE SHOCK IN THE HARNESS AND FAILURE TO ESCAPE IN THE SHUTTLE BOX PRODUCED INTERFERENCE WITH ESCAPE RESPONDING AFTER A 7-DAY REST. THESE RESULTS ARE INTERPRETED AS SUPPORTING A LEARNED "HELPLESSNESS" EXPLANATION OF INTERFERENCE WITH ESCAPE RESPONDING: SS FAILED TO ESCAPE SHOCK IN THE SHUTTLE BOX FOLLOWING INESCAPABLE SHOCK IN THE HARNESS BECAUSE THEY HAD LEARNED THAT SHOCK TERMINATION WAS INDEPENDENT OF RESPONDING.
To study the association of mortality from accidents, suicides, and other violent deaths with serum cholesterol concentration.
Baseline measurements in two randomly chosen independent cohorts were carried out in 1972 and 1977. Mortality was monitored over 10-15 years through the national death registry.
Eastern Finland.
The two cohorts comprised men (n = 10,898) and women (n = 11,534) born between 1913 and 1947. There were 193 deaths due to accidents, suicides, and violence among men and 43 among women.
Mortality from accidents, suicides, and other violent deaths was used as the end point. Deaths from these causes were pooled together in the analyses.
Serum cholesterol concentration was not associated with mortality from accidents, suicides, and other violent deaths in the univariate analyses or in the proportional hazards regression analyses including smoking, systolic blood pressure, alcohol drinking, and education. In both genders smoking was more prevalent among those who died from accidents, suicides, and other violent causes than from other causes. Frequent use of alcohol increased mortality from these causes.
The risk of accidents, suicides, and other violent deaths was not related to serum cholesterol concentration, whereas such deaths were more prevalent in smokers and alcohol drinkers.
Resumen
La existencia de trastornos mentales es casi constante en los sujetos que tratan de quitarse la vida. Además, una mayoría de las personas que intentan suicidarse tiene más de un diagnóstico. Esto es especialmente cierto si se tienen en cuenta los trastornos subumbral del Eje II o el Eje I. La existencia de un trastorno explica en gran parte la asociación entre la mayoría de las variables socioeconómicas (sexo, matrimonio, nivel educativo) y la suicidalidad. Los trastornos depresivos son el factor de riesgo principal, riesgo asociado probablemente a un episodio actual justo antes del intento. La asociación con episodios depresivos de un trastorno de ansiedad o la existencia de rasgos impulsivos (trastorno de la personalidad del grupo B, abuso de drogas o ambos) aumenta el riesgo de actuación. La ideación suicida y los intentos de suicidio muestran curvas de comienzo paralelas con picos entre los 14-20 años de edad, con la existencia de un diagnóstico previo del DSM-III-R como un predictor poderoso. El número de trastornos asociados aumenta linealmente la probabilidad de intentar el suicidio y es el único predictor significativo de la mortalidad. Un tratamiento adecuado de los trastornos mentales podría reducir sustancialmente la suicidalidad.
The term "neurosteroids" applies to those steroids that are both synthesized in the nervous system, either de novo from cholesterol or from steroid hormone precursors, and that accumulate in the nervous system to levels at least in part independent of steroidogenic gland secretion rates. Glial cells play a major role in neurosteroid formation and metabolism. Several neurosteroids are involved in either auto- or paracrine mechanisms implicating both regulation of target gene expression and effects on membrane receptors (including those of neurotransmitters). The neuromodulatory role of neurosteroids in regulating the estrus cycle and pregnancy, stress, memory, developmental and aging processes awaits further investigation.
Abnormalities in the serotonergic system have been implicated in suicidal behavior. Higher numbers of serotonin-2 (5-HT2) receptors have been reported in the post-mortem brain of suicide victims. In order to further examine the role of 5-HT2A receptors in suicidal behavior, the authors studied 5-HT2A receptors in platelets of suicidal and nonsuicidal patients as well as normal comparison subjects.
5-HT2A receptor levels were determined by using [125I]LSD as a radioligand in platelets obtained from hospitalized psychiatric patients (N = 131) and nonhospitalized normal comparison subjects (N = 40) during a drug-free baseline period. Patients were diagnosed according to DSM-III-R criteria, and suicidal behavior was identified by using the Hamilton Depression Rating Scale.
The mean maximum number of binding sites (Bmax) of platelet 5-HT2A receptors for all suicidal patients was significantly higher than for nonsuicidal patients or normal comparison subjects. This significant difference remained when subgroups of suicidal patients with depression, schizophrenia, schizoaffective disorder, or bipolar illness were compared to the other two subject groups. The higher number of platelet 5-HT2A receptors in suicidal patients was independent of diagnosis. While there was no significant difference in Bmax between patients with serious suicidal ideation and those who made suicidal attempts, both groups had significantly higher Bmax than normal comparison subjects.
The observed higher number of platelet 5-HT2A receptors in suicidal patients is independent of diagnosis and appears to be associated with both the brain and the platelets of suicidal patients. These results thus suggest the potential usefulness of platelet 5-HT2A receptors as a biological marker for identifying suicide-prone patients.
The stress–diathesis model posits that suicide is the result of an interaction between state-dependent (environmental) stressors and a trait-like diathesis or susceptibility to suicidal behaviour, independent of psychiatric disorders. Findings from post-mortem studies of the brain and from genomic and in-vivo neuroimaging studies indicate a biological basis for this diathesis, indicating the importance of neurobiological screening and interventions, in addition to cognitive and mood interventions, in the prevention of suicide. Early-life adversity and epigenetic mechanisms might explain some of the link between suicide risk and brain circuitry and neurochemistry abnormalities. Results from a range of studies using diverse designs and post-mortem and in-vivo techniques show impairments of the serotonin neurotransmitter system and the hypothalamic–pituitary–adrenal axis stress-response system in the diathesis for suicidal behaviour. These impairments manifest as impaired cognitive control of mood, pessimism, reactive aggressive traits, impaired problem solving, over-reactivity to negative social signs, excessive emotional pain, and suicidal ideation, leading to suicidal behaviour. Biomarkers related to the diathesis might help to inform risk-assessment procedures and treatment choice in the prevention of suicide.
Background:
It has been hypothesized that depletion of cell membrane n3 polyunsaturated fatty acids (PUFA), particularly docosahexanoic acid (DHA), may be of etiological importance in depression.
Methods:
We measured the fatty acid composition of phospholipid in cell membranes from red blood cells (RBC) of 15 depressive patients and 15 healthy control subjects.
Results:
Depressive patients showed significant depletions of total n3 PUFA and particularly DHA. Incubation of RBC from control subjects with hydrogen peroxide abolished all significant differences between patients and controls.
Conclusions:
These findings suggest that RBC membranes in depressive patients show evidence of oxidative damage. Possible interpretations, and implications for the etiology and treatment of depression, are discussed.
The purpose of this review is threefold. The first objective is to assess from current literature the extent to which depressive symptoms may be associated with peri- and postmenopausal states. Although there have been many studies published addressing this topic, there remains much controversy as to whether there is a true positive correlation of increased depressive symptomatology with the peri- and postmenopausal periods. Second, sex steroid neurobiology will be reviewed. In recent years, improved technology has allowed for much more detail in investigations of the central mechanisms of action of the sex hormones. Ultimately, estrogen appears to play an excitatory role in the central nervous system, whereas progesterone has been shown to be inhibitory. The third objective is to determine whether sex steroids have been shown to clinically affect mood and psychologic function, and if so, how such information might relate to regimens for peri- and postmenopausal hormone replacement. Currently, only large, pharmacologic doses of estrogen have been shown to improve mood in clinically depressed patients. Estrogen has been shown to potentiate the effects of some antidepressants; therefore menopausal women with major depressive disorders may respond to lower doses of antidepressant medications when estrogen replacement is added to the treatment regimen.
Depression is associated with a lowered degree of esterification of serum cholesterol, an increased C20:4ω6/C20:5ω3 ratio and decreases in ω3 fractions in fatty acids (FAs) or in the red blood cell membrane. The aims of the present study were to examine: (i) serum phospholipid and cholesteryl ester compositions of individual saturated fatty acids (SFAs), monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs) in major depressed patients vs. healthy volunteers; (ii) the relationships between the above FAs and lowered serum zinc (Zn), a marker of the inflammatory response in depression; and (iii) the effects of subchronic treatment with antidepressants on FAs in depression. The composition of the FAs was determined by means of thin layer chromatography in conjunction with gas chromatography. Lipid concentrations were assayed by enzymatic colorimetric methods. The oxidative potential index (OPI) of FAs was computed in 34 major depressed inpatients and 14 normal volunteers. Major depression was associated with: increased MUFA and C22:5ω3 proportions and increased C20:4ω6/C20:5ω3 and C22:5ω6/C22:6ω3 ratios; lower C22:4ω6, C20:5ω3 and C22:5ω3 fractions in phospholipids; lower C18:3ω3, C20:5ω3 and total (Σ)ω3 FAs, and higher C20:4ω6/C20:5ω3 and Σω6/Σω3 ratios in cholesteryl esters; lower serum concentrations of phospholipids and cholesteryl esters; and a decreased OPI. In depression, there were significant and positive correlations between serum Zn and C20:5ω3 and C22:6ω3 fractions in phospholipids; and significant inverse correlations between serum Zn and the Σω6/Σω3, C20:4ω6/C20:5ω3, and C22:5ω6/C22:6ω3 ratios in phospholipids. There was no significant effect of antidepressive treatment on any of the FAs. The results show that, in major depression, there is a deficiency of ω3 PUFAs and a compensatory increase in MUFAs and C22:5ω6 in phospholipids. The results suggest that: (i) there is an abnormal metabolism of ω3 PUFAs in depression; (ii) the FA alterations in depression are related to the inflammatory response in that illness; and (iii) the disorders may persist despite successful antidepressant treatment.
Olanzapine and risperidone, both second-generation antipsychotic agents, represent two different pharmacologic strategies. Although they share some in vitro properties, they differ by virtue of their chemical structure, spectrum of receptor binding affinities, animal neuropharmacology, pharmacokinetics, and in vivo neuroimaging profile. Based on such differences, it was hypothesized that the two compounds would show distinct safety and/or efficacy characteristics. To test this hypothesis, an international, multicenter, double-blind, parallel-group, 28-week prospective study was conducted with 339 patients who met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. Results of the study indicated that both olanzapine and risperidone were safe and effective in the management of psychotic symptoms. However, olanzapine demonstrated significantly greater efficacy in negative symptoms (Scale for Assessment of Negative Symptoms summary score), as well as overall response rate (> or = 40% decrease in the Positive and Negative Syndrome Scale total score). Furthermore, a statistically significantly greater proportion of the olanzapine-treated than risperidone-treated patients maintained their response at 28 weeks based on Kaplan-Meier survival curves. The incidence of extrapyramidal side effects, hyperprolactinemia, and sexual dysfunction was statistically significantly lower in olanzapine-treated than risperidone-treated patients. In addition, statistically significantly fewer adverse events were reported by olanzapine-treated patients than by their risperidone-treated counterparts. Thus, the differential preclinical profiles of these two drugs were also evident in a controlled, clinical investigation. Olanzapine seemed to have a risk-versus-benefit advantage.
Our current knowledge about the neurobiology of suicide is still limited. Technical limitations and the complexity of the CNS are major obstacles. However, there is evidence for a hereditary disposition to suicide, which appears to be independent of diagnosis. Clinical, postmortem, genetic, and animal studies suggest that serotonin has a central role. The main regions of interest in the CNS have been the dorsal and median raphe nuclei in the midbrain that host the main serotonergic cell bodies and the prefrontal cortex, particularly the ventral PFC, innervated by the serotonergic system. In vivo and postmortem studies indicate serotonergic hypofunction in suicide and serious suicide attempts. This deficiency in turn can lead to a predisposition to impulsive and aggressive behavior, probably due to a breakdown in the inhibitory function of the ventral prefrontal cortex as a result of less serotonin input. In the context of this predisposition and the development of mental illness or other life stressors, the individual is at risk of acting on suicidal thoughts. Such deficient serotonin input into the PFC may arise as a result of genetic, parenting, head injury, and other effects. Identifying psychiatric, social, and environmental predictors of suicide are studied to improve prediction and prevention of suicide. A better understanding of the neurobiology of suicide can help detect at risk populations and help develop better treatment interventions. Depression and Anxiety 14:164–176, 2001. © 2001 Wiley-Liss, Inc.
Patients with unilateral frontal- or temporal-lobe excisions and control subjects performed a cognitive risk-taking task in which target items (line-drawings or words) had to be guessed on the basis of partial-information clues. For each item, subjects chose to guess with either one, two, three, or all four clues, for a possible reward of 30, 20, 10, or 5 points, respectively. Two clue-presentation conditions were used to allow the differentiation of risk-taking from impulsivity. Whereas no group obtained high risk-taking scores, patients with frontal-lobe lesions demonstrated impulsive behaviour when manual responses were required. Only the left frontal-lobe group was impaired at solving the clues.
Numerous abnormalities have been found in the serotonergic system in suicide attempters and completers. There is considerable evidence that the serotonergic system is partly under genetic control and that as yet unknown genetic factors mediate the risk for suicidal behavior independently of the genetic factors responsible for the heritability of major psychiatric conditions associated with suicide. An argument is made that there is a relationship of genetic variants to intermediate phenotypes, such as impulsivity, psychomotor change, pathological aggression and biological abnormalities including specific gene products. A variety of biological indices have been generated by new approaches using postmortem tissue and in vivo imaging that will provide a rich substrate for further genetic studies.
Suicide and depression are associated with reduced serotonergic neurotransmission. In suicides, there is a reduction in serotonin transporter (SERT) sites and an increase in postsynaptic 5-HT1A receptors in localized regions of the prefrontal cortex. In depression, there is a diffuse decrease in SERT binding throughout the dorsoventral extent of the prefrontal cortex. Serotonergic innervation of the prefrontal cortex arises predominantly from neurons in the brainstem dorsal raphe nucleus (DRN). We, therefore, examined postmortem SERT binding and mRNA expression, as well as 5-HT1A autoreceptor binding in the DRN of 10 matched pairs of controls and depressed suicide victims. The concentration of SERT sites, SERT mRNA, and 5-HT1A binding was not different between controls and suicides (p > .05). In the DRN of suicides, the volume of tissue defined by 5-HT1A binding was 40% smaller than controls. An index of the total number of 5-HT1A receptors (receptor binding × volume of receptor distribution) was 43.3% lower in the DRN of suicides, compared with controls. The suicide group had 54% fewer DRN neurons expressing SERT mRNA compared with controls. In the serotonin neurons that expressed the SERT gene, expression per neuron was greater in suicides. Less total 5-HT1A and SERT binding is consistent with results of in vivo studies in depression. Less feedback inhibition of serotonin DRN firing via 5-HT1A autoreceptors and enhancement of serotonin action due to less uptake of serotonin, is consistent with compensatory changes in response to hypofunction in depressed suicides.
Background:
Serotonin abnormalities have been reported in the brain of suicide victims. Evidence of a serotonin deficiency in suicide attempters is less consistent. We hypothesized that a serotonin deficiency may be present in suicide attempters whose attempt behavior more closely approximates completed suicide.
Method:
Sixty-seven (67) drug-free depressed inpatients (46 suicide attempters, 21 nonattempters) underwent research clinical assessments and a lumbar puncture. Cerebrospinal fluid (CSF) monoamine metabolites were assayed. Degree of medical damage and intent of the most recent suicide attempt were rated.
Results:
CSF amine metabolites did not differentiate suicide attempters as a group from nonattempters. However, reduced serotonergic activity, as indicated by lower levels of CSF-5-hydroxyindoleacetic acid (5-HIAA) was associated with a history of planned suicide attempts and with suicide attempts that resulted in greater medical damage. Other monoamine metabolites did not correlate with seriousness of suicidal behavior, except for low CSF homovanillic acid and higher medical damage. No correlation was found with violent method.
Conclusions:
Planned and more medically damaging suicide attempts appear to be associated specifically with low serotonergic activity and, therefore, resemble completed suicide both behaviorally and biochemically. It remains to be determined whether low levels of CSF 5-HIAA can predict greater medical damage in future suicide attempts.
The amine metabolites, namely homovanillic acid (HVA) and 5-hydroxy indoleacetic acid (5-HIAA) were measured in cerebrospinal fluid (CSF) of depressives (n = 30) and controls (n = 30). Depressed patients had significantly lower HVA levels than controls. No significant differences were noted between the two groups in 5-HIAA levels. However, the differences between the groups for the CSF HVA/5-HIAA ratio were larger than those for the CSF HVA alone (p less than 0.01 versus p less than 0.025, respectively). HVA levels correlated positively with monoamine oxidase activity and adenosine deaminase activity.
CSF findings distinguished 12 elderly depressed patients who attempted suicide from nine depressed patients who did not and from seven normal control subjects. Psychosocial factors and measures of psychopathology did not differentiate suicidal from nonsuicidal patients. Biochemical factors may be important in evaluating suicide risk in the elderly.
Single unit activity was recorded from the lateral and medial septum of rats during aversive Pavlovian differential conditioning. One conditioned stimulus (CS+) was consistently paired with and another (CS-) was explicitly unpaired with a brief shock unconditioned stimulus (US). In the lateral septum single unit activity generally increased in the presence of a conditioned inhibitor of fear (CS-), while unit activity generally decreased in the presence of a conditioned excitor of fear (CS+). Responses in the medial septum were more heterogeneous. Many cells did not show plastic changes to the CSs, others showed responses to the conditioned stimuli opposite to that seen in the lateral septum. A small group of cells showed responses similar to that seen in the lateral septum. Finally, theta bursting cells were seen in the medial septum with some evidence of increased theta activity in the presence of a conditioned inhibitor of fear (CS-). The results were interpreted as consistent with the proposition that the lateral septum mediates the inhibition of aversive emotional states. The medial septum may have some involvement with the activation of fear or anxiety.
Although depression is common among alcoholics, its determinants are poorly understood. Among 339 alcoholics, 111 (33%) had a history of major depression. Depressed, compared with never-depressed alcoholics, had a higher daily alcohol intake, more lifetime diagnoses of other anxiety and affective disorders and drug abuse, more had attempted suicide, and more reported alcoholism in both parents. Depressed alcoholics also had significantly lower cerebrospinal fluid levels of the dopamine metabolite homovanillic acid and of gamma-aminobutyric acid. Among subgroups of depressed alcoholics, secondary compared with primary depressives were more often divorced, of lower social status, with an earlier onset of alcoholism, and higher Michigan Alcohol Screening Test scores. Secondary depressives also had significantly lower cerebrospinal fluid concentrations of homovanillic acid than never depressed alcoholics. These results suggest that certain psychosocial variables, alcohol consumption, and neurochemical variables may be specifically associated with depression in alcoholics.
Six depressed patients free of recent serious suicidal ideation developed intense, violent suicidal preoccupation after 2-7 weeks of fluoxetine treatment. This state persisted for as little as 3 days to as long as 3 months after discontinuation of fluoxetine. None of these patients had ever experienced a similar state during treatment with any other psychotropic drug.
The concentration of 5-hydroxyindoleacetic acid (5-HIAA) in the cerebrospinal fluid (CSF) and psychophysiologic variables, such as habituation of the skin conductance response, were measured in 35 drug-free, suicidal inpatients. Twenty-four patients were hospitalized after a suicide attempt, and another 11 had suicidal ideation. The suicide attempters were classified into nonviolent (drug overdoses taken orally, or a single wrist cut) and violent (all other methods). As in previous studies, the suicide attempters had significantly lower CSF concentrations of 5-HIAA compared with healthy, matched controls. The distribution of habituation rate was bimodal (slow and fast habituators). All violent attempters were fast habituators, as were all four patients who in a one-year follow-up were found to have completed a suicide (all by violent methods). The lowest frequency of fast habituators was found in the group of patients with suicidal ideation. There was no correlation between CSF 5-HIAA and habituation rate. A combination of these two variables yielded a highly significant correlation with type of suicide behavior, both retrospectively and prospectively.
Depressed patients who had attempted suicide (N = 19) had significantly lower CSF homovanillic acid (HVA) levels than patients who had not attempted suicide (N = 8) and control subjects (N = 41). Intergroup levels of 5-hydroxyindoleacetic acid (5-HIAA) were not significantly different. The ratio of CSF HVA to CSF 5-HIAA was significantly lower in both patient groups than in control subjects, and patients who had attempted suicide had CSF HVA/5-HIAA ratios that were nearly 50% those of the control subjects. The combinations of nonsuppression on the dexamethasone suppression test and either a low CSF HVA level or a low CSF HVA/5-HIAA ratio were significantly more common among patients who had attempted suicide than among those who had not.
Studies on neuronal firing have shown a decrease in frequency of firing in structures not directly related to emotional processes. However, studies of the hippocampus have shown increases in firing rate. Other limbic structures not yet explored in regard to the action of antidepressants include the septal nuclei. The present work describes a common effect of various therapeutic antidepressant models. Extracellular unit recordings were obtained from the septal nuclei of rats exposed to different acute treatments: clomipramine, isocarboxazid, trazodone, sleep deprivation, and electroshock. Frequencies and firing intervals were analyzed. After treatment, an increase in firing frequency in cells of the dorsolateral septal nucleus was found. This supports the hypothesis that brain structures related to the phenomenon of self-stimulation participate in the mechanism of antidepressant treatments.
Panic disorder, which is found in about 1.5 percent of the population at some time in their lives, includes recurrent episodes of sudden, unpredictable, intense fear accompanied by symptoms such as palpitations, chest pain, and faintness. Panic attacks, which do not meet these diagnostic criteria fully, are two to three times more prevalent. Since panic symptoms can mimic those of other medical disorders, patients with these symptoms use medical services frequently. To determine the risk of suicidal ideation and suicide attempts in panic disorder and attacks, we studied a random sample of 18,011 adults drawn from five U.S. communities. Subjects who had panic disorder, as compared with other psychiatric disorders, had more suicidal ideation and suicide attempts, with an adjusted odds ratio for suicide attempts of 2.62 (95 percent confidence interval, 1.83 to 3.74). The odds ratio was 17.99 (95 percent confidence interval, 12.18 to 26.58) when the group with panic disorder was compared with subjects who had no psychiatric disorder. Twenty percent of the subjects with panic disorder and 12 percent of those with panic attacks had made suicide attempts. These results could not be explained by the coexistence of major depression or of alcohol or drug abuse. We conclude that panic disorder and attacks are associated with an increased risk of suicidal ideation and suicide attempts. Physicians working in general medical settings and emergency departments should be alert to this problem.
A statistically significant 28 percent increase was found in the number of 5-HT receptor (B(max)) in frontal cortex (Brodmann's area 9) of the suicide group. No differences were found in binding affinity (K(D)). Beta-adrenergic binding in suicide victims was increased 78 percent over control values (p < 0.05, 2-tailed t test). Beta-adrenergic agonist binding was assessed using 125I-iodopindolol as a ligand and l μM isoproterenol. Agonist binding, particularly high affinity agonist binding, is a more sensitive indicator of functionally relevant changes in receptor binding. Both overall beta-adrenergic binding and high affinity agonist binding were increased in tissue pooled from a subgroup of three subjects in the suicide victims compared to three controls.
Differences in serotonin-2 (5-HT2) receptor properties were studied in frontal cortex from suicide victims and controls. The number of 5-HT2 receptors was significantly higher (44%) in the suicide group. The postsynaptic receptor changes were consistent with previous findings of a reduced number of presynaptic serotonin receptors in the same post-mortem series. The combined findings of both studies support the decreased use of serotonin in suicide victims and may also throw light on the mechanism of action of antidepressant drugs.
Cerebrospinal fluid concentrations of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) were measured in 30 psychiatric patients who had attempted suicide and 45 healthy volunteers. The suicide attempters had a significantly lower CSF 5-HIAA level than the controls, especially those who had made more violent attempts. After adjustment for differences in body height and age between controls and patients, the difference in 5-HIAA level became even more marked. Concentrations of 5-HIAA also were lower than normal in suicidal patients who were not diagnosed as depressed at the time of lumbar puncture, while HVA levels were lowered only in the depressives. A follow-up study of these and 89 more patients (depressed and/or suicidal) revealed a 20% mortality by suicide within a year after lumbar puncture in patients with a CSF-HIAA level below the median.
This paper reviews the clinical literature relevant to the association between aggressive behavior and the limbic system in humans. Specific areas of review include aggressive behavior related to: (1) naturally occurring and iatrogenic brain lesions; (2) electrical disturbances; (3) pharmacologic intervention; and (4) central neurochemical concentrations which may implicate limbic lobe involvement.
The neurotransmitter metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured by mass fragmentography in 83 patients with melancholia (diagnosed by the Newcastle Inventory and the Research Diagnostic Criteria), and 66 healthy volunteer controls. After adjustment by analysis of covariance for differences between the subject groups in body height, age and sex distribution, significantly (P less than 0.001) lower concentrations of 5-HIAA and HVA were found in the melancholia patients than in the controls. HMPG did not differ between the groups. The differences could not be accounted for by differences in timing or examination techniques, and not by previously administered drugs (all patients were drug-free at the examination, but a minority had taken small amounts of psychotropic drugs prior to the wash-out period). The differences persisted after excluding the suicidal patients. There were no clear-cut differences between unipolar and bipolar patients. It is suggested that the reduced concentrations of 5-HIAA and HVA in the melancholic patients may be due to altered serotonin and/or dopamine functions in the central nervous system, which may be connected with an increased vulnerability to certain types of affective illness.
There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters. In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover.
Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department. The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors. Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors.
Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations. Compared with healthy volunteers, they showed increased physical activity during the daytime. Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desynchronized diurnal activity rhythm. Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders. Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers.
In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence.
An impressive amount of evidence from many different laboratories using a variety of experimental techniques indicates that the amygdala plays a crucial role in the acquisition, consolidation and retention or expression of conditioned fear. Electrophysiological data are beginning to detail the transmitters and inter-amygdala connections that transmit information to, within, and out of the amygdala. In general, treatments that increase the excitability of amygdala output neurons in the basolateral nucleus (for example, by decreasing opiate and GABA transmission, and increasing noradrenergic transmission) improve aversive conditioning, whereas treatments that decrease excitability of these neurons (by increasing opiate and GABA transmission, and decreasing NMDA and noradrenergic transmission) retard aversive conditioning as well as producing anxiolytic effects in appropriate animal tests. A better understanding of brain systems that inhibit the amygdala, as well as the role of its very high levels of peptides, might eventually lead to the development of more effective pharmacological strategies for treating clinical anxiety and memory disorders.
A review of 27 research reports on the cerebrospinal fluid levels of neurotransmitter metabolites involving 1202 psychiatric patients found strong evidence for the involvement of the serotonin system in suicidal behavior. Attempted suicides, especially those using violent methods, had lower levels of CSF 5-HIAA as compared to psychiatric controls, and those making subsequent suicidal actions also had lower levels of CSF 5-HIAA. The meta-analysis permitted more reliable conclusions to be drawn than did each individual study alone.
Recent results from cholesterol level-lowering trials and some, but not all, observational studies support an intriguing link between low or lowered serum cholesterol levels and violent death. The reasons behind this relationship are far from clear.
In this report, we further investigate this issue by assessing the relationship of baseline serum cholesterol levels with long-term risk of mortality due to trauma and suicide in a cohort of 7309 middle-aged Japanese-American men.
After 23 years of follow-up, a total of 75 traumatic fatalities and 24 deaths by suicide were documented. Rather than an inverse relation, a positive association between serum cholesterol level and risk of suicide death was observed. After controlling for potential confounders, the relative risk of suicide associated with an increment of 0.98 mmol/L (38 mg/dL) in serum cholesterol level (1 SD) was 1.46 (95% confidence interval, 1.04 to 2.05; P = .02). Multivariate analysis of traumatic mortality failed to detect a relation with serum cholesterol level (relative risk = 0.89; 95% confidence interval, 0.70 to 1.13; P = .44). Heavy alcohol consumption (> 1200 mL of alcohol per month, top quintile) was an independent risk factor for trauma death relative to abstinence (relative risk = 1.86; 95% confidence interval, 1.07 to 3.22; P = .02).
These findings contradict the hypothesis of an inverse relation between serum cholesterol level and suicide, but they support the hypothesis that heavy alcohol consumption is a risk factor for traumatic fatal events.
Results of several studies suggest that either a reduction in the serum level of total cholesterol level or a persistently low cholesterol level may be associated with an increase in violent deaths. Although there are several possible explanations for these observations, it has been suggested that the cholesterol level could influence various behaviors. We therefore examined the cross-sectional relation of several psychologic characteristics, assessed by the Diagnostic Interview Schedule and the Minnesota Multiphasic Personality Inventory, to levels of total cholesterol, high-density lipoprotein cholesterol, and triglycerides among 3,490 men aged 31-45 years who were examined in 1985-1986. (All men had served in the US Army between 1965 and 1971). Compared with that of other men, the mean total cholesterol level was 5 mg/dl higher among 697 men diagnosed with generalized anxiety disorder (possibly because of increased catecholamine levels) and 7 mg/dl lower among 325 men with antisocial personality disorder (p < 0.01 for each association). These differences could not be attributed to education, relative weight, cigarette smoking, use of various medications, or other potential confounders. In contrast, cholesterol levels were not significantly associated with major depression or hostility; levels of high-density lipoprotein cholesterol and triglycerides were not related to any diagnosis. If the serum level of total cholesterol is found to be predictive of antisocial personality disorder in longitudinal analyses, this association may have implications for cholesterol-lowering recommendations.
Therapeutic efficacy for depression and panic disorder has been demonstrated with the triazolobenzodiazepine alprazolam. However, potentially serious adverse events, including depression and suicide attempts, have been reported in patients taking this medication. In this paper, reports addressing the association between each of these two events and benzodiazepine use in general and, more specifically, alprazolam use, are reviewed. We conclude that while these adverse events do occur in patients taking alprazolam, the causal relationship remains unclear and requires further study. Fortunately, these events are observed only rarely, so the prudent clinician may continue to safely prescribe this useful medication.
Cerebrospinal fluid (CSF), urine, platelet and neuroendocrine challenge tests of monoaminergic function give evidence of monoamines, especially serotonin, playing an important role in suicidal behavior. However, additional clinical, social and biochemical factors are necessary to better define suicide-prone psychiatric patients.
Changes in neurotrophic factor expression in the brain are part of the stress response. Decreased BDNF may contribute to hippocampal damage that occurs during chronic stress or aging. Stress-induced increases in NT-3 may be important for neural plasticity and adaptation or sensitization to repeated stress. Stress-induced changes in neurotrophic factors may be particularly relevant to the cognitive changes that occur in recurrent depression, aging, and posttraumatic stress disorder.