Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.

Allelic Variation of Human Serotonin Transporter Gene Expression

Objective. —To determine if the diagnosis of major depression in patients hospitalized following myocardial infarction (Ml) would have an independent impact on cardiac mortality over the first 6 months after discharge. Design. —Prospective evaluation of the impact of depression assessed using a modified version of the National Institute of Mental Health Diagnostic Interview Schedule for major depressive episode. Cox proportional hazards regression was used to evaluate the independent impact of depression after control for significant clinical predictors in the data set. Setting. —A large, university-affiliated hospital specializing in cardiac care, located in Montreal, Quebec. Patients. —All consenting patients (N=222) who met established criteria for Ml between August 1991 and July 1992 and who survived to be discharged from the hospital. Patients were interviewed between 5 and 15 days following the MI and were followed up for 6 months. There were no age limits (range, 24 to 88 years; mean, 60 years). The sample was 78% male. Primary Outcome Measure. —Survival status at 6 months. Results. —By 6 months, 12 patients had died. All deaths were due to cardiac causes. Depression was a significant predictor of mortality (hazard ratio, 5.74; 95% confidence interval, 4.61 to 6.87;P=.0006). The impact of depression remained after control for left ventricular dysfunction (Killip class) and previous Ml, the multivariate significant predictors of mortality in the data set (adjusted hazard ratio, 4.29; 95% confidence interval, 3.14 to 5.44;P=.013). Conclusion. —Major depression in patients hospitalized following an Ml is an independent risk factor for mortality at 6 months. Its impact is at least equivalent to that of left ventricular dysfunction (Killip class) and history of previous Ml. Additional study is needed to determine whether treatment of depression can influence post-MI survival and to assess possible underlying mechanisms. (JAMA. 1993;270:1819-1825)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=JAMA&articleId=408863&pdfFileName=jama_270_15_029.pdf

Depression Following Myocardial Infarction: Impact on 6-Month Survival

This article reviews the burgeoning literature on the relationship of mood disorders and heart disease. Major depression and depressive symptoms, although commonly encountered in medical populations, are frequently underdiagnosed and undertreated in patients with cardiovascular disease (CVD). This is of particular importance because several studies have shown depression and its associated symptoms to be a major risk factor for both the development of CVD and death after an index myocardial infarction. This review of the extant literature is derived from MEDLINE searches (1966-1997) using the search terms "major depression," "psychiatry," "cardiovascular disease," and "pathophysiology." Studies investigating pathophysiological alterations related to CVD in depressed patients are reviewed. The few studies on treatment of depression in patients with CVD are also described. Treatment of depression in patients with CVD improves their dysphoria and other signs and symptoms of depression, improves quality of life, and perhaps even increases longevity. Recommendations for future research are proposed.

The relationship of depression to cardiovascular disease: epidemiology, biology, and treatment.

Multiple sources of evidence support a role for diminished dopaminergic neurotransmission in major depression. The physiological alterations underlying reduced dopamine(DA)signalingcouldresultfromeitherdiminishedDAreleasefrompresynaptic neuronsorimpairedsignaltransduction,eitherduetochangesinreceptornumberor functionand/oralteredintracellularsignalprocessing.Therearedatasupportingeachofthesemechanisms,althoughinterpretationofpreviousresearchisconfoundedbyissuesaroundstudypopulation, medication status, and technological limitations. In some patients with depression, DA-related disturbances improve by treatment with antidepressants, presumably by acting on serotonergic or noradrenergic circuits, which then affect DA function. However, most antidepressant treatments do not directly enhance DA neurotransmission, which may contribute to residual symptoms, including impaired motivation, concentration, and pleasure. Animal models of major depression show considerable responsiveness to manipulations of DA neurotransmission. Several studies, including postmortem investigations, particularly of subjects with severe depression, have demonstrated reduced concentrations of DA metabolites both in the cerebrospinal fluid and in brain regions that mediate mood and motivation. Although the neuroimaging findings are not unequivocal, several studies support the hypothesis that major depression is associated with a state of reduced DA transmission, possiblyreflectedbyacompensatoryup-regulationofD2receptors.ThesealterationsinDAsignalingmay underlie the findings of increased “liking” or “high” feelings reported by severely depressed subjects treated with d-amphetamine compared with the response of less severely ill and normal control subjects. The efficacy of medications that directly act on DA neurons or receptors, such as monoamine oxidase inhibitors and pramipexole, suggests that subtypes of depression stemming from a primary DA dysfunction exist. Further research on the contribution of DA to the pathophysiology of depressionisjustifiedtoimproveoutcomesforpatientswithtreatment-resistantandnonremittingdepression.

/pdf/the-role-of-dopamine-in-the-pathophysiology-of-depression-3c9024azkx.pdf

The role of dopamine in the pathophysiology of depression.

About one million suicides and ten million suicide attempts occur worldwide each year. Suicide is not simply a response to stress, but generally a complication of a psychiatric disorder. A proposed stress–diathesis model is described in clinical and neurobiological terms. Neurobiological correlates of the diathesis for suicidal acts point to the involvement of the serotonergic and noradrenergic systems, and the ventromedial prefrontal cortex. Some treatments seem to reduce suicide risk independently of an effect on the primary psychiatric disorder, perhaps by reducing the diathesis.

Neurobiology of suicidal behaviour.

The authors determined serotonin2 (5-HT2) binding in the frontal cortex of 32 suicide victims and 37 subjects who died from nonpsychiatric causes. The maximum number of binding sites (Bmax) and the affinity (Kd) were significantly higher in subjects who had committed suicide than in control subjects. However, there was no difference in Kd between these two groups after the influence of age, race, sex, and postmortem delay was covaried. The Bmax of subjects who had committed violent suicide was significantly greater than that of control subjects. Language: en

Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects.

Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients

The density of 5-HT1A binding using3H-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) as binding ligand, was studied in human frontal cortex of suicide victims and normal controls who died due to medical disease or accidentally. There was no difference in the maximum number of binding site (Bmax) or Kd (an inverse measure of affinity) of 5-HT1A receptor binding sites between normal controls and the entire group of suicide victims. However, nonviolent suicides had significantly higher Bmax (22—25%) compared to both controls and violent suicides. A negative correlation between age and Bmax of 5-HT1A binding sites was found in male controls but not in female controls or suicide victims. This relationship was less apparent among the male controls over age 60.

Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims.

Six serotonergic measures in blood platelets, Km and Vmax of serotonin (5-HT) uptake, Kd and Bmax of 3H-imipramine binding, 5-HT content, and MAO activity, were measured in depressed and other psychiatric patients and related to Hamilton Depression Scale suicide ratings. Km was negatively correlated with the suicide rating while Kd was positively correlated with it. Multivariate analyses showed that Km, Kd, Vmax, and MAO activity were significant predictors of Hamilton Depression Scale suicide ratings. Low platelet MAO activity was present in seven nondepressed females who had made suicide attempts in the current episode. The direction of the association between the platelet measures and suicide ratings indicated diminished presynaptic serotonergic activity in patients with high suicide ratings, if the platelet findings could be extrapolated to 5-HT nerve terminals.

Platelet markers of suicidality.

Imipramine binding (desipramine- and serotonin-sensitive) was determined in the frontal cortex of suicide victims and nonpsychiatric controls who died due to medical disease or accidents. There were no differences in Kd or Bmax of imipramine binding between controls and suicides. The Kd and Bmax values of serotonin-sensitive imipramine binding were significantly lower than desipramine-sensitive imipramine binding, both in controls and suicides. There were significant correlations between Kd and Bmax of serotonin-sensitive imipramine binding and desipramine-sensitive imipramine binding in suicides but not in controls.

Ramesh C. Arora

Papers

Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects.

Increased serotonin2 (5-HT2) receptor binding as measured by 3H-lysergic acid diethylamide (3H-LSD) in the blood platelets of depressed patients

Serotonergic measures in suicide brain: 5-HT1A binding sites in frontal cortex of suicide victims.

Platelet markers of suicidality.

3H-imipramine binding in the frontal cortex of suicides