Michael Stanley

Attempted suicide characteristics and cerebrospinal fluid amine metabolites in depressed inpatients.

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.

Suicide and the self-harm continuum: phenomenological and biochemical evidence

The thrust of biological research in psychiatry has generally followed the classic approach which aims at identifying biochemical differences between individuals who make up one diagnostic group and either normal controls or patients from another diagnostic group (e.g. schizophrenia vs. normal controls or schizophrenia vs. depression). The focus of our research, and in more recent years, of others, has been one of identifying specific behaviors common to many diagnostic groups and biochemical events which correlate with them (e.g. suicide). In this report we review the phenomenological and biochemical evidence that suicide, self-mutilation and trichotillomania may represent points along a continuum of self-harm.

Platelet imipramine binding in children and adolescents with impulsive behavior

The serotonergic system has been implicated in the regulation of impulsive aggressive behavior either toward oneself or others. Imipramine binding sites were measured in the platelets of 23 impulsive aggressive children. Subjects ratings of total behavior, externalizing behavior, hostility, and aggression, as measured by the Child Behavior Checklist, were inversely correlated with the platelet imipramine binding. These findings are consistent with previous studies that suggest that decreased serotonergic activity is associated with impulsive aggressive behavior.

Negative and depressive symptoms in suicidal schizophrenics

The aim of this study was to determine the value of positive, negative and depressive symptoms, and of the dexamethasone suppression test (DST), in differentiating schizophrenics with and without a history of suicide. Fifty‐seven hospitalized patients with schizophrenia were assessed at the end of a neuroleptic free interval with the Brief Psychiatric Rating Scale (BPRS), the Hamilton Rating Scale for Depression (HRSD), and with a dexamethasone challenge. Suicide attempters were significantly more likely to meet criteria for major depression than nonattempters. Scores on the HRSD differentiated the two groups whereas the sums of positive and negative symptom items from the BPRS did not. DST a.m. and p.m. cortisol values differentiated suicide attempters from nonattempters and HRSD scores correlated significantly with cortisol levels. This study confirms the importance of depressive symptoms in schizophrenic patients with a history of suicide. Assessment of the hypothalamic‐pituitary‐adrenal axis in schizophrenia may also provide useful information.

CSF corticotropin-releasing factor (CRF) in Alzheimer's disease: its relationship to severity of dementia and monoamine metabolites

The concentration of corticotropin-releasing factor-like immunoreactivity (CRF-LI) in the cerebrospinal fluid (CSF) of 15 probable Alzheimers disease (AD) patients with mild to moderate dementia and 10 neurologically normal age-matched controls was examined. There were no significant alterations in the mean CSF CRF-LI concentration in AD compared to controls. However, in the AD group, CSF CRF-LI correlated significantly with the global neuropsychological impairment ratings, suggesting that greater cognitive impairment was associated with lower CSF CRF-LI concentrations. There was a significant reduction in the CSF concentration of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) in the AD patients, and there was a positive correlation between the concentration of CRF-LI and 5-HIAA in CSF. This latter finding suggests that serotoninergic neuronal systems may interact with CRF-containing neurons.

Biochemical aspects of suicidal behavior

1. In completed suicides, studies of brain regions and CSF indicate a dysfunction of the serotonergic system. 2. In suicidal patients, regardless of diagnoses, analyses of monoamine metabolites in lumbar CSF reveal decreased concentrations of the serotonin metabolite 5-HIAA. 3. In depressed suicidal patients, both low CSF 5-HIAA and low concentrations of the dopamine metabolite HVA are associated with suicidality. In addition, pathological dexamethasone-tests may indicate an increased suicide-risk in these patients. 4. In depressed patients, there is evidence that the association between CSF 5-HIAA and corticosteroids is in contrast to findings in depressed suicidal patients.

Differential visualization of dopamine D2 and D3 receptors in rat brain

The mRNA for the dopamine D3 receptor is confined to limbic regions and the D3 receptor may be a target for antipsychotic medications. We used quinpirole and domperidone to try to visualize D3 and dopamine D2 receptors selectively in rat brain, using in vitro autoradiography and digital subtraction. We used 125I-sulpiride, a ligand with high affinity for the D2 receptor in brain and for the D3 and D2 receptors in transfected cells. Our data indicate that the D2 receptor is present in much greater density than the D3 receptor in rat brain, even in limbic regions.

Brainstem serotonergic hyperinnervation modifies behavioral supersensitivity to 5-hydroxytryptophan in the rat

Rat pups were injected intracisternally (i.c.) or intraperitoneally (i.p.) with 5,7-dihydroxytryptamine (5,7-DHT) or saline and challenged 2 and 14 weeks later with the 5-HT precursor 5-hydroxytryptophan (5-HTP), which evokes behavioral supersensitivity in adult rats, 5,7-DHT induced transient postinjection convulsions in rats injected i.c. but not i.p. Rats with either type of 5,7-DHT lesions displayed supersensitive behavioral responses to 5-HTP. However, rats lesioned by i.p. injections exhibited significantly greater shaking behavior (+1445%) in response to 5-HTP than their i.c. counterparts, who instead showed more forepaw myoclonus (+250%) and head weaving (+270%), the core features of the 5-HT syndrome. Differences in 5-HT syndrome behaviors were already present 2 weeks after lesioning, whereas the difference in shaking behavior was not. After 14 weeks, 5-HT was selectively depleted (-43 to -92%) in hippocampus, spinal cord, and frontal cortex, and differences between i.c. and i.p. 5,7-DHT routes were insignificant except in frontal cortex. Brainstem 5-HT concentrations were significantly increased (+35%) after i.p. 5,7-DHT injections in contrast to reduction (-89%) after i.c. 5,7-DHT; 5-hydroxyindole acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) ratios were decreased (-20%) with either route. These data suggest that brainstem 5-HT hyperinnervation following i.p. 5,7-DHT injection modifies the functional consequences of injury in abating the 5-HT syndrome, but does not result in complete recovery since shaking behavior is enhanced. Loss of presynaptically mediated autoregulation or receptor dysregulation may play a major role in behavioral supersensitivity induced by 5-HTP in rats with 5,7-DHT lesions. To the extent that the 5-HT syndrome is mediated by 5-HT1A receptors and shaking behavior by 5-HT2 sites, differential responses to injury of 5-HT1A and 5-HT2 receptors may contribute to these behavioral differences.

Loss of the cortisol response to naltrexone in Alzheimer's disease

The administration of a single dose of the opiate antagonist naltrexone (NT) was accompanied by significant elevations in plasma cortisol in normal elderly subjects; in contrast, the cortisol response to NT was absent in individuals of comparable age with Alzheimers disease (AD). The differential effect of AD on the cortisol response was not accompanied by a significant group difference in plasma prolactin in response to NT administration. Furthermore, this differential cortisol response to NT was not associated with any evident differences in age, sex ratio, plasma levels of naltrexone or its major metabolite beta-naltrexol, or with differences in measures of nonspecific stress, such as plasma free MHPG, pulse, or blood pressure, between the two groups. The absence of the well-characterized cortisol response to NT in AD, together with other reports of abnormal responses to other pharmacological challenges, suggests that neuroendocrine abnormalities might be an important concomitant and possibly a central contributor to the pathophysiology of Alzheimers disease.

Regional studies of serotonin and dopamine metabolism and quantification of serotonin uptake sites in human cerebral cortex

An increasing number of studies have indicated that neuronal metabolism of serotonin (5-HT) and other monoamines may be altered in patients with affective disorders and in completed suicides. However, studies have yielded discordant results. The purpose of this study was to determine the regional variation of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), (5-HT) and 5-HT uptake sites within the human cerebral cortex. Our sample consisted of 19 patients who died suddenly and accidently. Cortical concentrations of 5-HIAA, HVA and 5-HT were measured in six regions using an HPLC. 5-HT uptake sites in cortex were examined using [3H] Paroxetine. 5-HT values within each brain were fairly constant in cortical regions studied except for the posterior parietal areas. By contrast, 5-HIAA values showed a trend towards a rostro-caudal increase, with peak values seen at sections corresponding to the post-central gyrus and the occipital pole. Using the ratio of 5-HIAA/5-HT as a crude index of 5-HT turnover, there was a progressive rostro-caudal increase of values which achieved statistical significance: the posterior superior parietal area and the occipital pole displayed a greater ratio than the other four cortical regions. HVA values were highest in the pre-central region and decreased both rostrally and caudally. 5-HIAA and HVA values were correlated positively in 5 of 6 cortical areas, while 5-HIAA and 5-HT were correlated in areas 4 and 5. Results obtaining using [3H]-Paroxetine suggest that 5-HT uptake sites in the human cortex are distributed rather uniformally and are not correlated with 5-HT levels.