HPA-related CSF neuropeptides in suicide attempters.

Corticotropin-releasing hormone (CRH), somatostatin (SOM), delta-sleep-inducing peptide (DSIP), neuropeptide Y (NPY), beta-endorphin (beta-END), and vasopressin (AVP), which are regarded as being involved in the HPA-regulation were investigated in lumbar CSF of 44 suicide attempters. The patients were diagnosed according to the DSM-III-R, and rated with the MADRS. The neuropeptides were compared with the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF and with post-dexamethasone plasma cortisol. We found strong correlations between CRH and the peptides SOM and beta-END. The latter also correlated positively with SOM. There were no differences between men and women. Patients with major depressive disorders had significantly lower SOM, CRH, and DSIP than other patients. Both SOM and beta-END correlated negatively with post dexamethasone plasma cortisol in all patients. We found no significant relationships between neuropeptides and CSF 5-HIAA. Patients who had made previous suicide attempts had significantly lower CRH than those who had not. No other significant associations between neuropeptides and suicidal subgroups of patients appeared, and there was no indication of specific neuropeptide patterns in patients who later completed suicide. Intercorrelations of some neuropeptides and low SOM and DSIP in major depressed patients are findings in line with those by others.     

Vasopressin in CSF and plasma in depressed suicide attempters: preliminary results.

Increased plasma arginine vasopressin (AVP) concentrations have been reported in depressed suicide attempters. Plasma AVP is primarily produced by the magnocellular system in response to increased plasma osmolality, and central AVP may be independently regulated. In the present study we investigated cerebrospinal fluid (CSF) and plasma AVP concentrations in depressed patients and controls. Nineteen drug-free depressed psychiatric inpatients (nine suicide attempters) and nine neurological control subjects underwent lumbar puncture and psychiatric evaluation. CSF and plasma concentrations of AVP, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol were assayed. In 15 depressed patients (eight suicide attempters), the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed to examine the hypothalamic-pituitary-adrenocortical (HPA) system. There were no differences between depressed subjects and controls in all parameters measured. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF.     

CSF 5-HIAA,cortisol and DHEAS levels in suicide attempters

The serotonin system and the hypothalamic–pituitary–adrenal (HPA) axis are involved in the biological vulnerability to suicidal behaviour. Altered levels of dehydroepiandrosterone (DHEA) and its sulphate ester DHEAS have been reported in neuropsychiatric conditions. The aim of this study was to investigate CSF levels of 5-Hydroxyindoleacetic acid (5-HIAA) and CSF and plasma levels of cortisol and DHEAS in 28 medication free suicide attempters and 19 healthy volunteers. Another aim was to investigate the relationship between neuroendocrine measures and childhood trauma in suicide attempters. As the study design includes a longitudinal part, we investigated whether CSF cortisol, 5-HIAA or DHEAS would predict subsequent suicide. We hypothesized higher cortisol levels in suicide attempters and lower CSF 5-HIAA levels and higher cortisol levels in suicide victims. Suicide attempters had higher CSF and plasma cortisol levels compared to healthy volunteers. Male suicide attempters had higher CSF DHEAS levels and female suicide attempters had lower CSF 5-HIAA levels compared to male and female healthy volunteers respectively. Exposure to interpersonal violence as a child showed a negative correlation with CSF cortisol/DHEAS ratio adjusted for age, gender and depression severity in a regression analysis. Suicide victims tended to have low CSF 5-HIAA and high CSF cortisol. Abused suicide victims had higher CSF cortisol compared to suicide victims with low exposure to interpersonal violence as a child. The results underlie the important role of the serotonergic system and HPA axis in suicidal behaviour and suggest that CSF DHEAS may be elevated in male suicide attempters.     

Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in suicide attempters. Monoamine metabolites in 120 suicide attempters and 47 controls.

Dysfunctions of central monoaminergic systems are important elements of the leading biological hypotheses of suicide and depression. The purpose of the present paper was to study the levels and the relationships between the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid (HVA) and the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in the cerebrospinal fluid (CSF) in 120 hospitalised suicide attempters and 47 controls (healthy volunteers or patients admitted for minor surgery). The suicide attempters showed significantly lower HVA levels (174+/-82 vs. 216+/-96 nmol/L, P=0.004), HVA/5HIAA ratios (1.6+/-0.5 vs. 2.1+/-0.6, P=0.0001) and HVA/MHPG ratios (4.2+/-2.1 vs. 4.8+/-1.7, P=0.02) than the controls. The correlations between the monoamine metabolites were markedly lower in patients than in controls. CSF 5-HIAA showed no significant differences between patients and controls (107+/-40 vs. 108+/-51 nmol/L) or between violent and non-violent attempters (112+/-58 vs. 105+/-33 nmol/L). The monoamine metabolites showed no significant differences between survivors and patients who subsequently completed suicide, or between suicide attempters subgrouped by psychiatric diagnoses. The results suggest that low HVA levels and altered relationships between the monoamine metabolites are associated with suicidal behaviour.     

Impulsivity related to brain serotonin transporter binding capacity in suicide attempters.

Altered monoaminergic activity has earlier been associated with violent suicidal behaviour. In this study whole brain binding potential of the serotonin transporter (5HTT) and dopamine transporter (DAT) was measured by single photon emission computerised tomography (SPECT) in 12 patients after a serious suicide attempt and in 12 age, sex and season matched healthy controls. Clinical and temperamental assessments were analysed for possible associations with 5HTT and DAT. We found no significant 5HTT or DAT differences between patients and controls. In patients, but not in controls, there was a significant correlation between whole brain 5HTT and DAT. Impulsiveness according to the Marke Nyman Temperament (MNT) was significantly correlated to 5HTT in suicide attempters, but not in controls. Neither of the transporters could be regarded as a marker for serious suicidal behaviour. A previously discussed connection between serotonin and dopamine was replicated in this study. In suicide attempters, low 5HTT was associated with impulsivity and to some extent with depressive disorder-key factors for suicidal behaviour.     

Recent general practice contacts of hospitalised suicide attempters

This study investigated the timing of recent medical contact in 150 patients hospitalised for a suicide attempt. The research also examined the proportion of attempters complaining of feeling depressed or suicidal to their doctor at that recent consultation. Seventy-three percent of attempters had seen their doctor in the past three months. Contact with general practitioners was most common in the week before their attempt with 32% of all attempters visiting their doctor during this time and 56% visiting in the previous month. Of those attempters who had consulted their general practitioner prior to their attempt, only 35% had complained about feeling depressed or suicidal to their doctor. Several factors that hinder the successful identification of suicidal risk in the general practitioner-patient relationship are identified. The implications of these findings for suicide prevention are discussed.     

A follow up study of suicide attempters: increase of CSF-somatostatin but no change in CSF-CRH.

Concentrations of somatostatin and corticotrophin releasing hormone (CRH), measured in cerebrospinal fluid (CSF) have been reported to be low in suicidal patients with major depressive disorder (MDD). Often have MDD patients in general, high CSF-CRH and low CSF-somatostatin concentrations, which both seem to normalise with clinical recovery. The present study was designed to look for CSF-CRH and CSF-somatostatin alterations along with clinical changes in patients studied repeatedly after a suicide attempt. Sixteen patients with different diagnoses, initially inpatients after a suicide attempt (baseline), participated. Lumbar punctures and ratings according to the Suicidal Assessment Scale (SUAS) and the Montgomery-Asberg Depression Rating Scale (MADRS) were performed while patients were drug-free (baseline) and after a median of 7 (5 to 9) months. At follow up MADRS- and SUAS-scores were significantly decreased (P<0.05), whereas CSF-somatostatin was significantly increased (P=0.013) and CSF-CRH had not changed significantly. Thus, the patients showed long-lasting low CSF-CRH concentrations, in spite of changed CSF-somatostatin concentrations and clinical amelioration.     

Cerebrospinal neuropeptide Y and substance P in suicide attempters during long-term antidepressant treatment

This study describes cerebrospinal fluid (CSF), neuropeptide Y (NPY) and substance P (SP) in patients with a recent suicide attempt and during antidepressant treatment. Seven out of 13 patients received antidepressants. The patients were examined on three separate occasions, i.e. at pre-treatment, followed by every 3 or 4 months. Antidepressant treatment seemed to affect the levels of CSF NPY, which decreased significantly between the second and last lumbar puncture despite no significant changes of clinical scores. When the whole group was taken into consideration, both CSF NPY and SP decreased significantly. At pre-treatment, Brief Scale of Anxiety scores were significantly and negatively correlated to CSF SP and tended to be negatively correlated to CSF NPY. There were also significant positive correlations between CSF NPY and SP during the entire study in the whole group, possibly reflecting an inter-relationship between these neuropeptides.     

Association of the serotonin transporter promotor polymorphism with suicide attempters with a high medical damage.

Serotonergic neurotransmission has been implicated in suicidal behavior, including inconsistent results concerning the serotonin transporter promoter polymorphism (5-HTTLPR). Here, we analyzed the 5-HTTLPR in suicide attempters (n=85). Comparing the presence of SS with SL+LL genotypes showed a significantly higher prevalence of the SS genotype in suicide attempters with high medical damage scores (chi2=9.054, df=1, p=0.0026). The results suggest that the S-allele may predispose for suicidal behavior characterized by high determination.     

Seasonal variation in CSF 5-HIAA concentrations in male rhesus macaques.

Seasonal changes in cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) concentrations were assessed on multiple occasions in 103 free-ranging male rhesus macaques (Macaca mulatta). At the time of sampling subjects ranged between the ages of 2 and 6 years. CSF samples were collected between the hours of 0900 and 1600 throughout the Fall, Winter, and Spring from 1990 through 1994. Data were analyzed in a general linear mixed model with random intercepts. Results indicated that CSF 5-HIAA concentrations decreased with age. CSF 5-HIAA concentrations were significantly increased in the Fall (October and November), which is the height of the breeding season, with no evidence of differences between Winter and Spring. There was also some evidence that the seasonal variation in CSF 5-HIAA concentrations was blunted in younger, more immature subjects.     

Alcohol abuse and eventual suicide: a 5- to 10-year prospective study of alcohol-abusing suicide attempters

Of 161 alcohol-abusing patients who were hospitalized for suicide attempts (attempters) between 1970 and 1975 and followed until 1982, 18 eventually committed suicide. The 143 nonsuiciders were compared to the 18 with respect to 27 background characteristics including their psychiatric diagnosis, Beck Depression Inventory, Hopelessness Scale, and Suicidal Intent Scale (SIS) scores. Only the SIS precautions subscale differentiated those who did and did not eventually commit suicide: the patients who eventually killed themselves had described taking more precautions against discovery at the time of their index attempts than did those who did not commit suicide. Possible explanations for the absence of a relationship between hopelessness or depression with ultimate suicide are discussed.     

alpha-[11C]Methyl-L-tryptophan trapping in the orbital and ventral medial prefrontal cortex of suicide attempters.

Low serotonin neurotransmission is thought to increase vulnerability to suicidal behavior. To test this hypothesis, we measured brain regional serotonin synthesis, as indexed by PET and alpha-[(11)C]methyl-L-tryptophan trapping, in 10 patients who had made a high-lethality suicide attempt and 16 healthy controls. Compared to healthy controls, suicide attempters had reduced normalized alpha-[(11)C]methyl-L-tryptophan trapping in orbital and ventromedial prefrontal cortex. alpha-[(11)C]Methyl-L-tryptophan trapping in these regions correlated negatively with suicide intent. Low serotonin synthesis in the prefrontal cortex might lower the threshold for suicidal behavior.     

CSF monoamine metabolites and lethality of suicide attempts in depressed patients with alcohol dependence.

BACKGROUND: Alcohol dependence (alcoholism) and major depressive disorder are frequently comorbid and are risk factors for suicidal behavior. Monoaminergic abnormalities have been implicated in the pathophysiology of depression, alcohol dependence, and suicidal behavior. Lower cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-HIAA) levels are associated with higher lethality of suicide attempts in major depression and predict a higher rate of future suicide. We sought to study the relationship of CSF monoamine metabolites to lethality of suicidal acts in depressed subjects with comorbid alcoholism. METHODS: We compared 16 high- and 16 low-lethality drug-free depressed suicide attempters with comorbid alcoholism. Subjects were free from any substance use disorder for at least two months. Demographic and clinical parameters, and CSF 5-HIAA, homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG) levels were examined. RESULTS: The two groups did not differ with regard to the demographic characteristics. CSF 5-HIAA levels were lower in high-lethality attempters compared to low-lethality attempters. There were no group difference in CSF HVA or MHPG levels. CONCLUSION: Higher lethality of suicidal behavior in depressed patients with alcoholism is related to lower serotonergic activity.     

Structured diagnostic assessment and depot fluphenazine treatment of multiple suicide attempters in the emergency department

The aim of this study was to compare the efficacy of two doses of monthly intramuscular (i.m.) injections of fluphenazine decanoate in reducing self-harm behaviours in outpatients with histories of multiple suicide attempts. Fifty-eight patients who presented to a psychiatric emergency service after an attempted suicide and who had histories of multiple suicide attempts, were randomized to receive monthly i.m. injections of fluphenazine decanoate. Thirty patients received monthly 12.5 mg ('low' dose), and 28 patients received monthly 1.5 mg ('ultra low' dose) under double-blind conditions. DSM-III-R diagnoses were obtained on all patients using the Structured Clinical Interview for DSM-III-R-Patient Version (SCID-P) and SCID for DSM-III-R Personality Disorders (SCID-II). Outcomes were assessed by the Parasuicide History Inventory and the Abnormal Involuntary Movement Scale, collected monthly for 6 months. Patients had an average of six current Axis I and 2.6 Axis II diagnoses, with borderline personality (85%) and alcohol dependence (58%) occurring most frequently in the sample. Both the low dose and ultra-low dose groups showed a marked reduction in self-harm behaviours. For 'serious' self-harm behaviours, there was a trend for a greater effect of the low dose over the ultra-low dose group, however, the differences did not reach statistical significance. A survival analysis indicated that the presence of 'acute' stressors at baseline and female sex were risk factors for continuing (post-randomization) 'serious' self-harm behaviours, while younger age and the absence of concurrent general medical conditions were risk factors for all self-harm behaviours.     

Association between catechol-O-methyltransferase functional polymorphism and male suicide completers.

Suicide has been suggested to involve catecholaminergic dysfunction and to be related to genetics. Catechol-O-methyltransferase (COMT) 158Val/Met polymorphism (GenBank Accession No. Z26491) is a polymorphism of the gene encoding COMT, a major enzyme in catecholamine inactivation. The COMT 158Val/Met polymorphism affects COMT activity, that is, the alleles encoding Val and Met are associated with relatively high and relatively low COMT activity, respectively. In this study, we hypothesized that the COMT 158Val/Met polymorphism is associated with suicide. The study population consisted of 163 suicide completers (112 males and 51 females). We found that the genotype distribution of the COMT 158Val/Met polymorphism was significantly different between male suicide completers and male controls (p=0.036), while the frequency of the Val/Val genotype, a high-activity COMT genotype, was significantly less in male suicide completers than in male controls (OR: 0.52; 95% CL: 0.31-0.89; p=0.016). However, this was not the case in females. Our results suggest that the Val/Val genotype is a protective factor against suicide in males.     

Effects of maneb on testosterone release in male rats

Maneb (Manganese ethylene-bis-dithiocarbamate) is a widely used fungicide in agriculture. In order to investigate its effect on male reproductive function, rats were intraperitonealy injected with maneb (1 and 4 mg/kg) for 9 or 18 days. After 6 and 14 days of treatment, the animals received human chorionic gonadotropin (hCG) via a jugular catheter and blood samples were collected at several intervals subsequent to the challenge. They were thereafter decapitated after 9 or 18 days, and organs (i.e., liver, seminal vesicles, and kidneys) were weighed. Leydig cells prepared from rats after 18 days of treatment were incubated with or without different stimulators or precursors [hCG, A23187, 25-OH-cholesterol (25-OH-C), or androstenedione] for 1 hour, and the media were analyzed for testosterone or pregnenolone. Liver glutathione and thiobarbituric acid reactive substances (TBARS) as well as serum alanine aminotransferase (ALT) activity were also measured. Further, Leydig cells and testicular interstitial cells (TICs) prepared from normal rats were incubated with maneb (3-100 μM) for 1 or 2 hours, and testosterone release was assessed. The results showed that administration of maneb (4 mg/kg) for 9 and 18 days did not alter liver function, but resulted in a decrease of basal level of plasma testosterone (P < 0.01). In addition, basal testosterone and pregnenolone release by Leydig cells prepared from maneb 18-day treated animals were significantly reduced (P < 0.05). However, acute in vitro exposure of TIC or Leydig cells to maneb did not alter their testosterone release. These results suggested that maneb alters testosterone production, at least in part, through inhibition of CYP11A1 activitiy.     

Sexual behavior in castrated male rats treated with monoamine synthesis inhibitors and testosterone.

Castrated male rats treated daily with the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA, 20 mg/kg) started to display mounts, intromissions and ejaculations more rapidly in response to daily treatment with testosterone propionate (TP, 0.15 mg/kg) than NaCl-treated rats. Daily treatment with the catecholamine (CA) synthesis inhibitor alpha-methyl-p-tyrosine (alpha-MT, 20 mg/kg) had no effect on the behavioral response to subsequent TP treatment. The acceleration of TP-induced sexual behavior by PCPA pretreatment was inhibited by pretreatment with DL-5-HTP (20 mg/kg) but not with L-DOPA (12.5 mg/kg). Analyses of brain monoamines showed that the PCPA treatment reduced brain 5-HT levels and produced a marked inhibition of the 5-HT synthesis. The 5-HTP treatment restored brain 5-HT levels to normal. Daily treatment with PCPA also reduced brain CA levels and inhibited the CA synthesis but these biochemical effects were not related to the effects of PCPA on sexual behavior. Daily treatment with PCPA (40 mg/kg for 12 days) or treatment with 126 mg/kg PCPA for 3 days induced the complete pattern of sexual behavior in 5 of 9 and 19 of 30 castrated rats respectively without concurrent TP treatment. It is suggested that 5-HT exerts a modulating influence on sexual behavior in male rats.     

Circulating androgens enhance sensitivity to testosterone self-administration in male hamsters

Young adult men are more likely to abuse steroids than individuals with low testosterone, including women, boys and older men. This suggests that circulating testosterone may enhance sensitivity to exogenous androgens. This hypothesis was tested using intracerebroventricular (i.c.v.) testosterone self-administration in orchidectomized males without testosterone (Orchx, n=8) and in orchidectomized males with chronic physiologic testosterone replacement (Orchx+T, n=8). Beginning 1 week after surgery, hamsters self-administered testosterone for 4 h/day in operant chambers at three doses (0.1, 1.0 and 2.0 microg/microl), each for 8 days. Afterwards, testosterone was replaced with vehicle for 8 days to test extinction. At 1.0 and 2.0 microg/microl, Orchx+T and Orchx males self-administered similar amounts of testosterone. However, at 0.1 microg/microl testosterone, only Orchx+T males showed a significant preference for the active nose-poke (Orchx+T active: 35.1+/-8.4 responses/4 h [mean+/-S.E.M.] vs. inactive: 16.5+/-1.7 responses/4 h, p<0.05; Orchx active: 16.7+/-4.9 responses/4 h vs. inactive: 13.5+/-3.1 responses/4 h, p>0.05). There was little change in operant behavior during extinction in Orchx+T males. However, when vehicle replaced testosterone, Orchx males extinguished their preference for the active nose-poke hole by day 6. These results support our hypothesis that circulating androgens enhance sensitivity to testosterone self-administration.     

Intracranial cycloheximide: effect on male mouse sexual behavior and plasma testosterone.

Cycloheximide (Cyclo), an inhibitor of protein synthesis, infused bilaterally into the preoptic area (POA) of intact B6D2F male mice significantly inhibited male sexual behavior when the males were presented with receptive females 12 hr after treatment. The few males that ejaculated appeared to copulate normally. This finding suggests that Cyclo acts primarily by inhibiting sexual arousal rather than sexual performance. The inhibition of sexual behavior was not observed when the males were tested 84 hr after treatment. After exposure to an estrous female, plasma testosterone levels were measured in males with POA infusions of Cyclo or saline vehicle. No significant difference was found, but both groups had significantly higher levels of plasma testosterone than males not exposed to estrous females. It is suggested that the interference with sexual behavior by Cyclo was not due to interference with the neuroendocrine mechanisms controlling blood andorgen levels, but due to Cyclo acting directly on the neural circuits controlling sexual responsiveness.