Longitudinal associations between beta-endorphin, nonsuicidal self-injury and comorbid psychopathology.

Homeostasis models posit that nonsuicidal self-injury (NSSI) serves, in part, to upregulate the endogenous opioid system in order to compensate for an opioid deficiency. A few studies have demonstrated lower basal levels of beta-endorphin (BE), an endogenous opioid, in individuals with NSSI. However, longitudinal studies are missing. Hence, the present study aimed to investigate the longitudinal associations between NSSI, comorbid psychopathology (i.e., borderline personality disorder and depressive symptoms), pain sensitivity and basal BE levels in adolescents with NSSI. N = 53 adolescents with NSSI disorder undergoing specialized treatment participated in baseline and one-year follow-up assessments. BE was measured in plasma; pain sensitivity was assessed with a heat pain stimulation paradigm. Associations between BE and change in NSSI, borderline personality disorder and depressive symptoms as well as pain sensitivity were examined using negative binomial and linear regression analyses. We found that an increase in basal BE was significantly associated with a decrease in depressive symptoms. No associations between BE and NSSI, borderline personality disorder symptoms or pain sensitivity were observed. Our findings may confirm a role of plasma BE in the etiology of depressive symptoms but challenge current models of endogenous opioid homeostasis in NSSI.

From the urge to see one's own blood to the urge to drink it: Can hemomania be specified as an impulse control disorder? Two case reports.

At least half of self-mutilative individuals report that seeing their own blood is comforting, while a quarter report that they have tasted it. Bloodletting and blood-drinking behaviors have been discussed in case reports of disorders such as borderline personality disorder, bulimia nervosa, dissociative identity disorder, and psychotic disorder. The role of blood-drinking behavior, however, needs to be clarified in the psychiatric literature. This paper is the first to discuss blood-drinking behavior as a possible impulse control disorder that progresses from a desire to see or taste one's own blood. It presents the cases of two patients who report drawing blood from their own arms via syringe and drinking it. The first patient began to suck her own blood by removing scabs at age 8. The second started cutting his arm during his middle school years to reduce tension. Both eventually began to drink their own blood by draining it impulsively. This paper presents two cases with blood-drinking behavior diagnosed as impulse control disorder not otherwise specified according to the Diagnostic and Statistical Manual of Mental Disorders. We propose the term "hemomania" to describe an impulse control disorder characterized by impaired functioning due to at least one of the following urges: seeing one's own blood, self-bloodletting, and tasting/drinking one's own blood. We argue that hemomania progresses from an urge to see one's own blood to the urge to drink it, though randomized controlled studies are needed to support this claim.

Causal relationships between blood lipids and depression phenotypes: a Mendelian randomisation analysis.

BACKGROUND: The etiology of depression remains poorly understood. Changes in blood lipid levels were reported to be associated with depression and suicide, however study findings were mixed. METHODS: We performed a two-sample Mendelian randomisation (MR) analysis to investigate the causal relationship between blood lipids and depression phenotypes, based on large-scale GWAS summary statistics (N = 188 577/480 359 for lipid/depression traits respectively). Five depression-related phenotypes were included, namely major depression (MD; from PGC), depressive symptoms (DS; from SSGAC), longest duration and number of episodes of low mood, and history of deliberate self-harm (DSH)/suicide (from UK Biobank). MR was conducted with inverse-variance weighted (MR-IVW), Egger and Generalised Summary-data-based MR (GSMR) methods. RESULTS: There was consistent evidence that triglyceride (TG) is causally associated with DS (MR-IVW ß for one-s.d. increase in TG = 0.0346, 95% CI 0.0114-0.0578), supported by MR-IVW and GSMR and multiple r2 clumping thresholds. We also observed relatively consistent associations of TG with DSH/suicide (MR-Egger OR = 2.514, CI 1.579-4.003). There was moderate evidence for positive associations of TG with MD and the number of episodes of low mood. For HDL-c, we observed moderate evidence for causal associations with DS and MD. LDL-c and TC did not show robust causal relationships with depression phenotypes, except for weak evidence that LDL-c is inversely related to DSH/suicide. We did not detect significant associations when depression phenotypes were treated as exposures. CONCLUSIONS: This study provides evidence to a causal relationship between TG, and to a lesser extent, altered cholesterol levels with depression phenotypes. Further studies on its mechanistic basis and the effects of lipid-lowering therapies are warranted.

Proopiomelanocortin (POMC) sequencing and developmental delay: Preliminary evidence for a SNP in the 3' UTR region of the POMC gene-Possible relevance for biological risk and self-injurious behavior.

The proopiomelanocortin (POMC) molecule has been implicated in models of self-injurious behavior (SIB) in neurodevelopmental disorders, but it has never been specifically sequenced in search of base specific polymorphisms. The empirical focus of this preliminary study was to sequence the POMC gene in 11 children (mean age = 41.8 months, range = 12-60 months; 73% male) with clinical concerns regarding global developmental delay, 5 with reported self-injury. Genomic DNA was extracted from blood samples, and the POMC gene was amplified by specific oligonucleotide primers via polymerase chain reaction. The amplified gene products were sequenced by the University of Minnesota Genomic Center, and the results were analyzed using Sequencher software. A single nucleotide polymorphism (SNP), 1130 C>T, was found in the 3' untranslated region (UTR) of two samples (one of whom had SIB). The program TargetScanHuman was used to predict the function of this mutation. Variant c.1130 C<T was predicted to be located in the target site of two microRNAs (miRNAs; hsa-mir-3715 and hsa-mir-1909), and the variant allele T may result in an increased minimum free energy for the two miRNAs. Further work with much larger samples is needed to continue the investigation of POMC's possible function as a risk factor for the development of SIB in children with developmental delay/disability. The findings presented in this study show that the SNP found in the 3' UTR could alter the binding of miRNAs to POMC 3'UTR, thus, increasing POMC expression and affecting several biological systems with high relevance to the biology of self-injury. There was a significant difference in ß-endorphin levels between SIB (M = 169.25 pg/mL) and no SIB (M = 273.5 pg/mL, SD = 15.2) cases (p < .01). Intervention implications are tied to prior observations of individual differences among SIB responders and nonresponders to treatment with the opioid antagonist naltrexone. Stratifying individuals with SIB by POMC mutation status may provide a potential tailoring-like variable to guide the selection of who is more (or less) likely to respond to opiate antagonist treatment. Currently, opioid antagonistic treatment for SIB is empiric (trial and error).

Naturally absorbed polyunsaturated fatty acids, lithium, and suicide-related behaviors: A case-controlled study.

OBJECTIVE: Previous studies have investigated the effects of omega-3, omega-6 and lithium on suicide-related behaviors separately. This study was performed to comprehensively investigate the effects of naturally absorbed EPA, DHA, arachidonic acid and lithium in relation to suicide attempt and deliberate self-harm, with adjustment for each other. METHODS: We analyzed plasma EPA, DHA, arachidonic acid levels and serum lithium levels of 197 patients including 33 patients with suicide attempts, 18 patients with deliberate self-harm, and 146 control patients. RESULTS: Multivariate logistic regression analysis with adjustment for age, gender, EPA, DHA, arachidonic acid and log-transformed lithium levels revealed that the negative associations with EPA levels (adjusted OR 0.972, 95% CI 0.947-0.997, p = 0.031) and log-transformed lithium levels (adjusted OR 0.156, 95% CI 0.038-0.644, p = 0.01) and the positive association with DHA levels (adjusted OR 1.026, 95% CI 1.010-1.043, p = 0.002) were significant in patients with suicide attempts than in control patients. The analysis also demonstrated that the positive association with arachidonic acid levels (adjusted OR 1.015, 95% CI 1.005-1.025, p = 0.004) was significant in patients with deliberate self-harm than in control patients. LIMITATIONS: The limitations are relatively small number of patients and the effects of demographics of individual patients could not be adjusted for the analyses. CONCLUSIONS: The present findings suggest that, as naturally absorbed nutrients, higher EPA and lithium levels may be associated with less suicide attempt, and that higher arachidonic acid levels may be associated with more deliberate self-harm.

May nesfatin-1 be a state marker in major depressive disorder with suicidal ideation?

The best known effects of nesfatin-1 are on appetite and metabolic regulation. Moreover, several research suggest that nesfatin-1 play a role in stress responses. This molecule may be involved in the pathophysiology of mood disorders and suicidal behavior. We compared nesfatin-1 levels between depressed patients with suicidal ideation (n = 32, mean ±â€¯SD, 1,40 ±â€¯0.11), without suicidal ideation(n = 31, 1.46 ±â€¯0.14) and healthy controls (n = 32, 1.52 ±â€¯0.13). Suicidal ideation was assessed with the Suicide Probability Scale, Scale for Suicide Ideation and depressive symptoms were evaluated with the Hamilton Depression Rating Scale. Blood samples were collected to measure serum nesfatin-1levels by using ELISA method. The study revealed that serum nesfatin-1 levels were significantly lower in MDD with suicidal ideation than in healthy volunteers (p < 0.001). There were a negative correlation between the scores of suicidal ideation and nesfatin-1 levels in MDD with SI group (r = -0.215; p = 0.016). In the future, nesfatin-1 levels may one day be applied in predicting and monitoring patients' suicide risk. Further prospective studies are required to elucidate this potential association.

[Dyslipidemia and suicidal risk in patients with psychiatric disorders]. / Dyslipidémie et risque suicidaire chez des patients avec maladies psychiatriques.

The aim of this work is to study the association between dyslipidemia and suicidal risk in patients with psychiatric pathology. Our study has involved 155 patients suffering from major depressive disorder and 124 schizophrenic patients aged 40.58±12.16 and 43.43±10.60 years, respectively. Total cholesterol (TC), triglycerides (TG) and HDL-c were determined by enzymatic methods, LDL-c was calculated by the Friedewald formula. Plasma cholesterol level was significantly lower among suicidal schizophrenic or depressive patients. There were no significant differences in the others lipid levels. The results of our study suggest that total cholesterol values less than 3.59mmol/L could be an indicator of suicide vulnerability in patients with schizophrenia or major depressive disorder.

Do serum BDNF levels vary in self-harm behavior among adolescents and are they correlated with traumatic experiences?

The aim of this study was to compare serum brain-derived neurotrophic factor (BDNF) levels between adolescents that harm themselves, those that receive psychiatric treatment but do not harm themselves, healthy adolescents, and childhood traumas and to investigate the relationship between traumatic experiences and serum BDNF levels. The cases were divided into two groups of 40 adolescents exhibiting self-harm behavior (self-harm/diagnosed group) and 30 adolescents receiving psychiatric treatment but not exhibiting self-harm behaviors (non self-harm/diagnosed group). The control group (healthy control group) consisted of 35 healthy adolescents with no psychiatric disorders or self-harm behaviors. The adolescents were asked to fill in the Inventory of Statements About Self Injury (ISAS) and Childhood Trauma Questionnaire (CTQ). For BDNF measurement, blood samples were taken from the cases and controls. The serum BDNF level of self-harming adolescents who used the self-cutting method was significantly lower than that of other groups, and serum BDNF levels decreased with the increase in the emotional neglect and abuse severity of self-harming adolescents during childhood. In our study, serum BDNF levels decreased with the increase in emotional abuse in self-harming adolescents. This finding may indicate that neuroplasticity can be affected by a negative emotional environment during the early period.

Serum lithium levels and suicide attempts: a case-controlled comparison in lithium therapy-naive individuals.

BACKGROUND: Several epidemiological studies have shown the inverse association of lithium levels in drinking water and suicide rates; however, it is necessary to perform a clinical study dealing with individual patients. METHODS: We analyzed 199 patients including 31 patients with suicide attempts, 21 patients with self-harm, and 147 control patients. All were transferred to a university emergency department suffering from intoxication or injury, were aged 20 or more years, and were alive at the start of the study. The exclusion criteria consisted of suffering from schizophrenia and a past or present history of lithium therapy. These exclusions were applied because it is difficult to determine whether their suicide attempt was induced by the intent to end their life or by psychotic symptoms such as auditory hallucinations, and if the patient had received lithium therapy, the association between the small amount of lithium taken from drinking water and food and serum lithium levels cannot be detected. RESULTS: There was a significant difference (p = 0.043) between the three groups whereby patients with suicide attempts had significantly lower lithium levels than control patients (p = 0.012) in males but not females. Multivariate logistic regression analysis with adjustment for age and gender revealed that patients with suicide attempts had significantly lower lithium levels than control patients (p = 0.032, odds ratio 0.228, 95% CI 0.059-0.883). LIMITATIONS: The limitations of the present study are the nature of observational research which cannot reveal a causal relationship and the relatively small number of subjects. CONCLUSIONS: The present findings suggest that higher serum lithium levels may be protective against suicide attempts in lithium therapy-naive individuals.

Lower cortisol level in response to a psychosocial stressor in young females with self-harm.

BACKGROUND: Self-harm is highly prevalent in adolescence, often serving an emotion regulation function. Social stressors such as bullying are associated with self-harm. The neurobiological background of the relationship between social stressors and self-harm needs to be further understood to inform prevention and therapy. METHODS: Participants were members of an epidemiological cohort study. 130 female participants underwent the Trier Social Stress Test (TSST) at age 19. Of them, 21 reported a history of self-harm as assessed by the Youth Self Report. Psychiatric diagnoses were recorded. RESULTS: Participants with a history of self-harm showed significantly lower blood cortisol levels throughout the TSST. Early psychosocial adversity did not significantly differ between groups with and without self-harm, with self-harming participants reporting more childhood adversities. CONCLUSION: These results add to the limited field of studies showing an altered HPA axis activity in females with self-harm. Future studies need to address the causal mechanisms behind this association.

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation.

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-ß-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

The role of cytokines in the pathophysiology of suicidal behavior.

OBJECTIVE: Immune dysregulation has been implicated in depression and other psychiatric disorders. What is less clear is how immune dysregulation can affect risk of suicidal behavior. We reviewed the scientific literature concerning cytokines related to suicidal ideation, suicidal behavior and suicide, and surveyed clinical and neurobiological factors associated with cytokine levels that may modulate effects of inflammation on suicide risk. METHODS: We searched PubMed, Embase, Scopus and PsycINFO for relevant studies published from 1980 through February, 2015. Papers were included if they were written in English and focused on cytokine measurements in patients with suicidal behaviors. RESULTS: The literature search yielded 22 studies concerning cytokines and suicidal ideation, suicide attempts or suicide completion. The most consistent finding was elevated interleukin (IL)-6, found in 8 out of 14 studies, in CSF, blood, and postmortem brain. In one study, IL-6 in CSF was also found to be higher in violent than nonviolent attempters and to correlate with future suicide completion. Low plasma IL-2 was observed in 2 studies of suicide attempters, while divergent results were seen for tumor necrosis factor (TNF)-α, interferon (IFN)-γ, transforming growth factor (TGF)-ß, IL-4, and soluble Il-2 receptors. CONCLUSIONS: Given the complexity suggested by the heterogenous cytokine findings, putative mediators and moderators of inflammation on suicidal behavior merit further study. Elevated IL-6 was the most robust cytokine finding, associated with suicidal ideation and both nonfatal suicide attempts and suicides. Future studies should evaluate the predictive value of high IL-6, consider how this may alter brain function to impact suicidal behavior, and explore the potential beneficial effects of reducing IL-6 on suicide risk.

Combined Toxoplasma gondii seropositivity and high blood kynurenine--Linked with nonfatal suicidal self-directed violence in patients with schizophrenia.

Toxoplasma gondii (T. gondii) chronic infection and elevated kynurenine (KYN) levels have been individually associated with non-fatal suicidal self-directed violence (NF-SSDV). We aimed to test the hypothesis that the association between T. gondii seropositivity and history of NF-SSDV would be stronger in schizophrenia patients with high plasma KYN levels than in those with lower KYN levels. We measured anti-T. gondii IgG antibodies and plasma KYN in 950 patients with schizophrenia, and used logistic regression to evaluate the relationship between NF-SSDV and KYN in patients who were either seropositive or seronegative for T. gondii. For those with KYN levels in the upper 25th percentile, the unadjusted odds ratio for the association between NF-SSDV history and KYN in T. gondii seropositive patients was 1.63 (95% CI 1.01 to 2.66), p = 0.048; the adjusted odds ratio was 1.95 (95% CI 1.15 to 3.30), p = 0.014. Plasma KYN was not associated with a history of NF-SSDV in T. gondii seronegative patients. The results suggest that T. gondii and KYN may have a nonlinear cumulative effect on the risk of NF-SSDV among those with schizophrenia. If confirmed by future longitudinal studies, this result is expected to have both theoretical and clinical implications for the prevention and treatment of suicidal behavior.

Exploratory associations with tumor necrosis factor-α, disinhibition and suicidal endorsement after traumatic brain injury.

PURPOSE: To examine the relationship of Tumor Necrosis Factor (TNF)-α to disinhibition and suicidal endorsement after traumatic brain injury (TBI). PARTICIPANTS: Adults with moderate to severe TBI (acute serum levels: n=48, n=543 samples; acute CSF levels: n=37, n=389 samples; chronic serum levels: n=48, n=326 samples). MAIN MEASURES: TNFα levels (CSF, Serum) from time of injury to 12 months post-injury; Frontal Systems Behavior Scale - Disinhibition Subscale at 6 and 12 months post-injury; Patient Health Questionnaire at 6 and 12 months post-injury. RESULTS: Participants with TBI had significantly higher CSF and serum TNFα levels than healthy controls (p<0.05). Acute and chronic serum TNFα was significantly associated with disinhibition at 6 months post-injury (p=0.009, p=0.029 respectively), and 6 month disinhibition was associated with suicidal endorsement at both 6 and 12 months (p=0.045, p=0.033 respectively) and disinhibition at 12 months post-injury (p<0.001). CONCLUSION: These preliminary data suggest a biological to behavioral pathway of suicidality after TBI, from TNFα to disinhibition to suicidal endorsement. Future investigation is warranted to validate these findings and clarify what biological mechanisms might underlie these relationships.

Triglycerides as a biological marker of repeated re-hospitalization resulting from deliberate self-harm in acute psychiatry patients: a prospective observational study.

BACKGROUND: Biological factors have been associated with deliberate self-harm (DSH) but have not been integrated with clinical factors in routine risk assessments.This study aimed to examine the incremental validity of lipid levels and platelet serotonin when combined with psychosocial factors in risk assessments for repeated admissions due to DSH. METHODS: In this prospective observational study of 196 acutely admitted patients, results of blood tests performed upon admission and the MINI Suicidal Scale and psychosocial DSH risk factor assessments performed at discharge were compared with the incidence of DSH recorded during the first 3 and 12 months after discharge. RESULTS: High triglyceride levels were found to be a significant marker for patients admitted 3 or more times due to DSH (repeated DSH, DSH-R) when tested against other significant risk factors. When all (9) significant univariate factors associated with 12-month post-discharge DSH-R were analyzed in a multivariate logistic regression, the MINI Suicidal Scale (p = 0.043), a lack of insight (p = 0.040), and triglyceride level (p = 0.020) remained significant. The estimated 12-month area under the curve of the receiver operator characteristic (ROC-AUC) for DSH-R was 0.74 for triglycerides, 0.81 for the MINI, 0.89 for the MINI + psychosocial factors, and 0.91 for the MINI + psychosocial factors + triglycerides. The applied multifaceted approach also significantly discriminated between 12-month post-discharge DSH-R patients and other DSH patients, and a lack of insight (p = 0.047) and triglycerides (p = 0.046) remained significant for DSH-R patients in a multivariate analysis in which other DSH patients served as the reference group (rather than non-DSH patients). CONCLUSION: The triglyceride values provided incremental validity to the MINI Suicidal Scale and psychosocial risk factors in the assessment of the risk of repeated DSH. Therefore, a bio-psychosocial approach appears promising, but further research is necessary to refine and validate this method.

Lower levels of cannabinoid 1 receptor mRNA in female eating disorder patients: association with wrist cutting as impulsive self-injurious behavior.

The cannabinoid 1 (CB 1) receptor as the primary mediator of the endocannabinoid (EC) system was found to play a role in eating disorders (EDs), depression, anxiety, and suicidal behavior. The CB 1 receptor is assumed to play a crucial role in the central reward circuitry with impact on body weight and personality traits like novelty-seeking behavior. In a previous study we found higher levels of CB 1 receptor mRNA in patients with anorexia nervosa (AN) and bulimia nervosa (BN) compared to healthy control women (HCW). The aim of the present study was to investigate the possible influence of the EC and the CB 1 receptor system on wrist cutting as self-injurious behavior (SIB) in women with EDs (n=43; AN: n=20; BN: n=23). Nine ED patients with repetitive wrist cutting (AN, n=4; BN, n=5) were compared to 34 ED patients without wrist cutting and 26 HCW. Levels of CB 1 receptor mRNA were determined in peripheral blood samples using quantitative real-time PCR. ED patients with self-injurious wrist cutting exhibited significantly lower CB 1 receptor mRNA levels compared with ED patients without wrist cutting and HCW. No significant differences were found between ED patients without a history of wrist cutting and HCW. Furthermore, a negative association was detected between CB 1 receptor mRNA levels and Beck Depression Inventory (BDI) scores. To our knowledge, this is the first study reporting a down-regulation of CB 1 receptor mRNA in patients with EDs and wrist cutting as SIB. Due to the small sample size, our results should be regarded as preliminary and further studies are warranted to reveal the underlying mechanisms.

Increased IL-1ß reactivity upon a glucose challenge in patients with deliberate self-harm.

OBJECTIVE: A disturbed glucose metabolism has been observed in patients with aggressive behaviour. Interleukin (IL)-1ß is a pro-inflammatory cytokine that can induce hypoglycaemia, but has also been suggested to be involved in the generation of hostility and aggression. Our group has previously shown an altered glucose metabolism in patients with self-inflicted aggressive behaviour. We investigated the hypothesis that the levels of IL-1ß would be increased in these patients, because this might explain the aberrant glucose metabolism and add further knowledge to the aetiology of self-inflicted aggressive behaviour. METHOD: We investigated plasma cytokine changes in 13 patients with borderline personality disorder and 13 healthy controls during a 5-h glucose challenge. Plasma samples were analysed for cytokines IL-1ß, TNF-α and IL-6 using high-sensitivity multiplex ELISA. Psychiatric symptoms were rated using the Aggression Questionnaire Revised Swedish Version. RESULTS: Basal plasma levels of the three cytokines did not differ between patients and controls. All three cytokines reacted significantly upon the glucose challenge. The increase in IL-1ß levels in response to glucose was significantly greater in patients than in controls. Furthermore, IL-1ß reactivity was associated with symptoms of hostility. CONCLUSION: An increased reactivity of IL-1ß might be part of a pathogenetic mechanism in patients with deliberate self-harm.

TPH2 5'- and 3'-regulatory polymorphisms are differentially associated with HPA axis function and self-injurious behavior in rhesus monkeys.

Tryptophan hydroxylase-2 (TPH2) synthesizes neuronal serotonin and is linked to numerous behavioral traits. We have previously characterized the functionality of polymorphisms (especially 2051A>C) in 3'-untranslated region (3'-UTR) of rhesus monkey TPH2 (rhTPH2). This study further assessed the functionality of additional polymorphisms (-1605T>C, -1491Tn, -1485(AT)n, -1454A>G, -1325In>Del and -363T>G) in rhTPH2 5'-flanking region (5'-FR), and evaluated the effects of rhTPH2 5' and 3' genotypes on central serotonin turnover, hypothalamic-pituitary-adrenal (HPA) axis function and self-injurious behavior (SIB) in 32 unrelated adult male monkeys of Indian origin. Haplotypes of the rhTPH2 5'-FR polymorphisms exert a significant, cell-dependent effect on reporter gene expression, primarily conferred by -1485(AT)n. The -1485(AT)n and 2051A>C polymorphisms interact to influence cerebrospinal fluid (CSF) 5-HIAA and plasma adrenocorticotropic hormone (ACTH) in the afternoon. While -1485(AT)n exerts significant main effects on the afternoon cortisol level and nocturnal HPA negative feedback, 2051A>C has significant main effects on the morning cortisol level and cortisol response to ACTH challenge, as well as marginally significant main effects on the daytime HPA negative feedback and self-biting rate. In addition, the genotype/allele frequency of the 5'-FR -1325Ins>Del differed significantly between the self-wounders and non-wounders, whereas 3'-UTR 2128S>L polymorphism differed significantly in genotype/allele frequency between the high- and low-frequency biters. This study shows the functionality of rhTPH2 5'-FR polymorphisms, and provides evidence for the differential association of rhTPH2 5'-FR and 3'-UTR polymorphisms with HPA axis function and SIB. Our findings shed light on the role of TPH2 gene variance in physiology and behavioral traits, and also contribute to the understanding of the pathophysiology and genetics of SIB.

Relationship between whole blood serotonin and repetitive behaviors in autism.

This study was conducted to examine the relationship between whole blood serotonin level and behavioral symptoms in 78 subjects with autism. No significant associations were found between serotonin level and the primary behavioral outcome measures. However, a significant inverse relationship between serotonin level and self-injury was demonstrated.

L-tryptophan and correlates of self-injurious behavior in small-eared bushbabies (Otolemur garnettii).

Self-injurious behavior (SIB) among captive primates is a recurring problem for those who manage such facilities. Its prevalence highlights the need for research evaluating the effectiveness of potential treatment approaches. In the present study, 4 wk of dietary supplementation with L-tryptophan (100 mg daily) was evaluated for the treatment of self-inflicted wounds in 22 small-eared bushbabies, a prosimian primate, with a history of SIB. The treatment significantly reduced stereotypy and was associated with a reduction in wound area and severity. In terms of physiologic measures, preexisting high levels of cortisol were reduced in bushbabies with SIB, whereas serotonin concentrations were increased after 4 wk of treatment. Results indicate that L-tryptophan as a dietary supplement may be a viable adjunct to standard husbandry procedures for animals exhibiting maladaptive behaviors such as stereotypy and SIB.