• The incidence of suicidal acts was studied in 68 depressed patients and related to the level of 5-hydroxyindoleacetic acid (5HIAA) in the cerebrospinal fluid. The distribution of 5-HIAA levels was bimodal. Patients in the low 5-HIAA mode (below 15 ng/ml) attempted suicide significantly more often than those in the high mode, and they used more violent means. Two of the 20 patients in the low mode, and none of the 48 patients in the high mode died from suicide.

5-HIAA in the Cerebrospinal Fluid: A Biochemical Suicide Predictor?

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.

• Dysfunction of the central serotonergic system has been variously associated with depression and with suicidal and/or impulsive aggressive behavior. To evaluate central serotonergic function in relation to these variables, prolactin responses to a singledose challenge with fenfluramine hydrochloride (60 mg orally), a serotonin releasing/uptake-inhibiting agent, were examined in 45 male patients with clearly defined major affective (n = 25) and/or personality disorder (n 20) and in 18 normal male control patients. Prolactin responses to fenfluramine among all patients were reduced compared with responses of controls. Reduced prolactin responses to fenfluramine were correlated with history of suicide attempt in all patients but with clinician and selfreported ratings of impulsive aggression in patients with personality disorder only; there was no correlation with depression. These results suggest that reduced central serotonergic function is present in a subgroup of patients with major affective and/or personality disorder and is associated with history of suicide attempt in patients with either disorder, but with impulsive aggression in patients with personality disorder only.

Serotonergic Studies in Patients with Affective and Personality Disorders: Correlates with Suicidal and Impulsive Aggressive Behavior

In an earlier, separate study, the authors found that human aggression and suicide (a specific aggression-related behavior) were associated with lower levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. That study focused on subjects with personality disorders without affective illness. In the present study they examine the life history of aggression and history of suicidal behavior in 12 subjects with borderline personality disorders without major affective disorder. Histories of aggressive behaviors and of suicide attempts were significantly associated with each other, and each was significantly associated with lower 5-HIAA levels. Altered serotonin metabolism may be a highly significant contributing factor to these behaviors in whatever diagnostic group they occur. Language: en

Aggression, suicide, and serotonin: relationships to CSF amine metabolites.

• 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 5-HIAA level below the median.

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=psych&articleId=492558&pdfFileName=archpsyc_38_6_002.pdf

Monoamine metabolites in CSF and suicidal behavior.

5-hydroxytryptamine, noradrenaline, and dopamine in brainstem, hypothalamus, and caudate nucleus of controls and of patients committing suicide by coal-gas poisoning

D.P.H. Yeung

Papers

5-hydroxytryptamine, noradrenaline, and dopamine in brainstem, hypothalamus, and caudate nucleus of controls and of patients committing suicide by coal-gas poisoning