Salivary cortisol awakening levels are reduced in human subjects with intermittent explosive disorder compared with controls.

BACKGROUND: The role of the hypothalamic-pituitary-adrenal (HPA) axis in human aggressive behavior is poorly characterized, though some studies report that, unlike depression, circulating or salivary levels of cortisol are low compared with controls. METHODS: In this study, we collected three salivary cortisol levels (two in the morning and one in the evening) on three separate days in 78 adult study participants with (n = 28) and without (n = 52) prominent histories of impulsive aggressive behavior. Plasma C-Reactive Protein (CRP) and Interleukin-6 (IL-6) were also collected in most study participants. Aggressive study participants meet DSM-5 criteria for Intermittent Explosive Disorder (IED) while non-aggressive participants either had a history of a psychiatric disorder or no such history (Controls). RESULTS: Morning, but not evening, salivary cortisol levels were significantly lower in IED (p < 0.05), compared with control, study participants. In addition, salivary cortisol levels correlated with measures of trait anger (partial r = -0.26, p < 0.05) and aggression (partial r = -0.25, p < 0.05) but not with measures of impulsivity, psychopathy, depression, history of childhood maltreatment, or other tested variables that often differ in individuals with IED. Finally, plasma CRP levels correlated inversely with morning salivary cortisol levels (partial r = -0.28, p < 0.05); plasma IL-6 levels showed a similar, though not statistically significant (rp = -0.20, p = 0.12) relationship with morning salivary cortisol levels. CONCLUSION: The cortisol awakening response appears to be lower in individuals with IED compared with controls. In all study participants, morning salivary cortisol levels correlated inversely with trait anger, trait aggression, and plasma CRP, a marker of systemic inflammation. This suggests the present of a complex interaction between chronic-low level inflammation, the HPA axis, and IED that warrants further investigation.

Plasma and cerebrospinal fluid inflammatory markers and human aggression.

A growing body of work suggests that individuals with aggressive behavior and/or aggressive tendencies have evidence of chronic, low level, inflammation as manifested by elevated circulating levels of acute phase reactant proteins and pro-inflammatory cytokines. While animal studies report that direct application of pro-inflammatory proteins in brain increase aggressive behavior, there is no data on the relationship of central levels of these proteins and aggression in human subjects. We simultaneously measured levels of both plasma and lumbar cerebrospinal fluid (CSF) C-Reactive Protein (CRP) and IL-6, IL-8, and TNF-α in 77 medically healthy, drug-free, individuals with varying degrees of aggression including 22 individuals with DSM-5 Intermittent Explosive Disorder (IED). Aggression was assessed using the Life History of Aggression (LHA) and the Buss-Perry Aggression Questionnaire (BPAQ). Plasma and CSF levels of CRP, IL-8, and TNF-α, but not IL-6, correlated significantly with each other. Aggressive individuals with IED displayed elevated plasma, but not CSF, levels of proinflammatory markers and this relationship was specific to IED. Similarly, composite aggression scores correlated significantly with plasma, but not CSF, pro-inflammatory markers. Aggressive behavior in humans is correlated with Plasma, but not CSF, proinflammatory markers despite the observation that these two sets of markers are significantly correlated. Since the direct application of proinflammatory proteins in brains of animals increase aggressive behavior, proinflammatory proteins likely influence brain-based behavior in a manner not reflected in lumbar CSF.

Associations of agression and use of caffeine, alcohol and nicotine in healthy and aggressive individuals.

BACKGROUND: Caffeine, alcohol, and nicotine are the three most commonly used psychoactive substances in the world. Given the known propensity of these substances to influence behavior, the relationship between these substances and aggressive and impulsive behaviors, in particular is of interest. METHODS: 1062 adult individuals participated in this study including those with Intermittent Explosive Disorder (IED) and non-aggressive healthy (HC) and psychiatric (PC) controls. Data regarding current and life use of caffeine, alcohol, and nicotine were recorded as were responses on measures of aggression, anger, and impulsivity. RESULTS: Dimensional measures of aggression, anger, and impulsiveness were variably but significantly related to the consumption of these commonly used psychoactive substances. These findings were generally mirrored when using the categorical construct of IED. Finally, these findings were not due to comorbidity with other psychiatric disorders. CONCLUSIONS: These data confirm a link between these externalizing behaviors and these three legal and commonly consumed psychoactive substances in clinically relevant individuals.

Narcissistic and Borderline Personality Disorders: Relationship With Oxidative Stress.

The authors hypothesized that personality disorders characterized by interpersonal hypersensitivity would be associated with an elevated concentration of 8-hydroxy-2'-deoxyguanosine (8-OH-DG), the oxidized form of guanine, and a biomarker of oxidative stress burden. One hundred ninety-five male and female adults underwent semistructured diagnostic interviews, completed questionnaire measures of social cognition and emotional attribution, and had blood drawn for determination of plasma 8-OH-DG. A hierarchical linear regression model revealed that narcissistic and borderline personality disorders predicted 8-OH-DG level independently of the effects of age, gender, recent alcohol and cigarette use, current major depression, and posttraumatic stress disorder. In all subjects, 8-OH-DG level was also correlated with the number of borderline personality disorder symptoms present. Narcissistic and borderline personality disorders predicted oxidative stress burden independently of potentially confounding factors.

Role of the kynurenine pathway and the endocannabinoid system as modulators of inflammation and personality traits.

BACKGROUND: Kynurenine pathway metabolites and endocannabinoids both exert potent regulatory effects on the immune system, but the relationship between these molecules is unknown. The role of these immunobiological mediators in emotionality and personality traits is not previously characterized. METHODS: Interleukin-6 (IL-6), 2-arachidonoylglycerol (2-AG) and picolinic acid (PIC) were measured in the plasma of physically healthy individuals who had history of mood, anxiety, and personality disorders (n = 96) or who had no history of any psychiatric disorder (n = 56) by DSM-5 Criteria. Dimensional assessments of personality were performed using the Eysenck Personality Questionnaire (EPQ) and the Tridimensional Personality Questionnaire (TPQ). RESULTS: Plasma IL-6 levels were significantly associated with plasma 2-AG levels and plasma PIC levels across all subjects. PIC levels were also negatively associated with 2-AG levels across all subjects, independent of IL-6 levels. In our analysis of the biological determinants of personality factors, we identified significant associations between IL-6 and novelty seeking assessment, and between PIC and neuroticism assessment. CONCLUSIONS: These data provide evidence of a biological link between metabolites of the kynurenine pathway, the endocannabinoid system and IL-6 and suggest that these factors may influence personality traits.

Aggression directed towards others vs. aggression directed towards the self: clinical differences between intermittent explosive disorder and nonsuicidal self-injury

Objective: To investigate the clinical differences between intermittent explosive disorder (IED) (disorder of aggression primarily directed towards others) and nonsuicidal self-injury (NSSI) (disorder of aggression predominantly directed towards the self) in order to better understand the different clinical subtypes of aggression. Methods: We used treatment-seeking samples to compare demographic and clinical correlates between 82 participants with IED and 55 participants with NSSI. Results: The IED group was older, more likely to be male, in a relationship, and employed than the NSSI group. With respect to clinical variables, the NSSI group had more severe depressive symptoms and more social adjustment difficulties. Regarding psychiatric co-morbidities, the IED group had higher rates of generalized anxiety disorder. On the other hand, the NSSI group had higher rates of major depressive disorder, agoraphobia, substance use disorder, and bulimia nervosa. Conclusions: Individuals with NSSI may benefit from better management of psychiatric comorbidities, specifically depressive symptoms and social adjustment difficulties. Conversely, the treatment of individuals with IED may be improved by targeting comorbid generalized anxiety disorder. Our results provide important insight for the development of tailored interventions for specific subtypes of aggression.

Intermittent Explosive Disorder and Substance Use Disorder: Analysis of the National Comorbidity Survey Replication Sample.

OBJECTIVE: A relationship between aggression and substance use has been debated for many years. While substance use increases the risk of aggressive behavior, no studies have reported on the relationship between impulsive aggression and substance use/disorder, specifically. METHODS: We analyzed data from the community-based National Comorbidity Survey Replication (N = 9,282 subjects) in order to examine the relationship between current DSM-5 intermittent explosive disorder (IED), a disorder of impulsive aggression, and current substance use disorders (SUDs), overall, and with regard to alcohol, tobacco, and cannabis use disorders and nondisordered use. RESULTS: Occurrence of current SUD was elevated in current IED versus non-IED adult subjects, and onset of IED preceded that of SUD in 92.5% of comorbid IED + SUD cases. This relationship was not due to the presence, or absence, of current depressive or anxiety disorders. Examination of the severity of IED and of SUD revealed that the presence of IED increases SUD severity but that the presence of SUD does not increase IED severity. CONCLUSIONS: Subjects with IED are at increased risk of developing SUD, compared with those without IED. This suggests that history of recurrent, problematic, impulsive aggression is a risk factor for the later development of SUD rather than the reverse. If so, effective treatment of impulsive aggression, before the onset of substance misuse, may prevent, or delay, the development of SUD in young people.

Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects.

Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.

Childhood trauma and parental style: Relationship with markers of inflammation, oxidative stress, and aggression in healthy and personality disordered subjects.

Recent studies suggest that early life trauma is associated with elevations in circulating markers of inflammation in human subjects. History of aggression as a behavior, or aggression as a personality trait, is also associated with elevations of these inflammatory markers. Since early life trauma is associated with the development and maintenance of aggression in later life we examined the relationship of early life adversity, plasma inflammation markers (IL-6 and CRP) and oxidative stress markers (8-OH-DG and 8-ISO), and aggression in adult subjects with (n=79) and without (n=55) personality disorder. We used a series of mediated and moderated path models to test whether the effects of early adversity on later aggression may be mediated through markers of inflammation. Childhood abuse and parental control were associated with basal IL-6 and CRP concentrations. Path modeling suggested that childhood abuse was associated with aggression indirectly through CRP while parental control influenced aggression indirectly through IL-6 and CRP. Furthermore, these effects were independent of the effect of current depression. The results suggest that disruption of inflammatory processes represent one pathway by which early adversity influences aggression.

Inflammatory markers and chronic exposure to fluoxetine, divalproex, and placebo in intermittent explosive disorder.

Intermittent Explosive Disorder (IED) is a disorder of impulsive aggression affecting 4-7% of the U.S. population during some period of life. In addition to other biological correlates, elevations of plasma inflammatory markers have been reported in IED, compared with control, subjects. In this study we sought to explore if treatment exposure to anti-aggressive agents, compared with placebo, would be associated with a reduction in circulating levels of inflammatory markers. Thirty IED subjects, from a 12-week, double-blind, randomized, placebo-controlled trial of fluoxetine and divalproex, in which both pre- and post-treatment levels of C-Reactive Protein (CRP), interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α were obtained. Efficacy measures included the Overt Aggression Scale-Modified (OAS-M) score for Aggression and for Irritability, rate of Clinical Global Impression of Improvement (CGI-I), and rate of IED Remitters at study completion. As compared to placebo, neither fluoxetine nor divalproex reduced any of the measures of aggression. In addition, levels of CRP and pro- and anti-inflammatory cytokines showed no changes from pre- to post-treatment for any treatment condition. Correlations between pre- and post- treatment plasma CRP/cytokines were substantial (mean r=0.71, r(2)=0.50, p<0.001). Overall, circulating markers of inflammation markers were unaffected by treatment with fluoxetine or divalproex, consistent with the absence of change in measures of impulsive aggression.

Cerebrospinal fluid inflammatory cytokines and aggression in personality disordered subjects.

BACKGROUND: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters and neuromodulators such as cytokines. While animal studies of cytokines suggest an aggression-facilitating role for central cytokines, especially for interleukin-1ß and other cytokines, no cerebrospinal fluid studies of cytokines have yet been reported in regard to human aggression. METHODS: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with DSM-5 Personality Disorder and assayed for cerebrospinal fluid interleukin-6 (log IL-6) and cerebrospinal fluid soluble IL-1 Receptor II protein in the context of their relationship with measures of aggression. RESULTS: Cerebrospinal fluid soluble interleukin-1 Receptor II (r=.35, r(2) = .12, P= .03), but not log interleukin-6 (r = -.05, r(2) = .00, P= .76), levels were positively correlated with a composite measure of aggression. Adding relevant covariates, including cerebrospinal fluid levels of serotonin and dopamine metabolites, to the statistical model doubled the strength of this relationship (partial r = .54, r(2) = .29, P= .002). No relationship was seen with history of suicidal behavior or with any measure of impulsivity, negative affectivity, or of general dimensions of personality. CONCLUSION: These data suggest a positive relationship between at least one inflammatory cytokine in the central nervous system and aggression in human subjects. This finding adds to the complex picture of the central neurochemistry of impulsive aggression in human subjects.

Elevated plasma inflammatory markers in individuals with intermittent explosive disorder and correlation with aggression in humans.

IMPORTANCE: Neurochemical studies in human aggression point to a modulatory role for a variety of central neurotransmitters. Some of these neurotransmitters play an inhibitory role, while others play a facilitatory role modulating aggression. Preclinical studies suggest a facilitatory role for inflammatory markers in aggression. Despite this, to our knowledge, no studies of aggression and inflammatory markers have been reported in psychiatric patients or in individuals with recurrent, problematic, impulsive aggressive behavior. OBJECTIVE: To test the hypothesis that plasma inflammatory markers will correlate directly with aggression and will be elevated in individuals with recurrent, problematic, impulsive aggressive behavior. DESIGN, SETTING, AND PARTICIPANTS Case-control study in a clinical research program in impulsive aggressive behavior at an academic medical center. Participants were physically healthy individuals with intermittent explosive disorder (n = 69), nonaggressive individuals with Axis I and/or II disorders (n = 61), and nonaggressive individuals without history of an Axis I or II disorder (n = 67). MAIN OUTCOMES AND MEASURES: Plasma levels of C-reactive protein and interleukin 6 were examined in the context of measures of aggression and impulsivity and as a function of intermittent explosive disorder. RESULTS: Both plasma C-reactive protein and interleukin 6 levels were significantly higher in participants with intermittent explosive disorder compared with psychiatric or normal controls. In addition, both inflammatory markers were directly correlated with a composite measure of aggression and, more specifically, with measures reflecting history of actual aggressive behavior in all participants. CONCLUSIONS AND RELEVANCE: These data suggest a direct relationship between plasma inflammatory processes and aggression in humans. This finding adds to the complex picture of the central neuromodulatory role of aggression in humans.

Heritability of performance deficit accumulation during acute sleep deprivation in twins.

STUDY OBJECTIVES: To determine if the large and highly reproducible interindividual differences in rates of performance deficit accumulation during sleep deprivation, as determined by the number of lapses on a sustained reaction time test, the Psychomotor Vigilance Task (PVT), arise from a heritable trait. DESIGN: Prospective, observational cohort study. SETTING: Academic medical center. PARTICIPANTS: There were 59 monozygotic (mean age 29.2 ± 6.8 [SD] yr; 15 male and 44 female pairs) and 41 dizygotic (mean age 26.6 ± 7.6 yr; 15 male and 26 female pairs) same-sex twin pairs with a normal polysomnogram. INTERVENTIONS: Thirty-eight hr of monitored, continuous sleep deprivation. MEASUREMENTS AND RESULTS: Patients performed the 10-min PVT every 2 hr during the sleep deprivation protocol. The primary outcome was change from baseline in square root transformed total lapses (response time ≥ 500 ms) per trial. Patient-specific linear rates of performance deficit accumulation were separated from circadian effects using multiple linear regression. Using the classic approach to assess heritability, the intraclass correlation coefficients for accumulating deficits resulted in a broad sense heritability (h(2)) estimate of 0.834. The mean within-pair and among-pair heritability estimates determined by analysis of variance-based methods was 0.715. When variance components of mixed-effect multilevel models were estimated by maximum likelihood estimation and used to determine the proportions of phenotypic variance explained by genetic and nongenetic factors, 51.1% (standard error = 8.4%, P < 0.0001) of twin variance was attributed to combined additive and dominance genetic effects. CONCLUSION: Genetic factors explain a large fraction of interindividual variance among rates of performance deficit accumulations on PVT during sleep deprivation.

Lifetime history of cigarette smoking associated with aggression and impulsivity in both healthy and personality disordered volunteers.

Cigarette smoking has been associated with several personality and behavioral traits including impulsivity and aggression, primarily in adolescents and/or pregnant women. In this study, the authors tested the hypothesis that history of cigarette smoking is also associated with dimensional measures of aggression and impulsivity in adult subjects. Subjects were 179 personality disordered (PD), and healthy volunteer control (HV), subjects in whom history of cigarette smoking and measures of both aggression and impulsivity were collected. Scores on measures of both aggression and impulsivity were elevated as a function of personality disorder status and history of cigarette smoking status; no interaction between these two factors were noted on these measures. Including socio-economic status and global psychosocial functioning in the model eliminated the difference associated with diagnostic grouping and impulsivity but not the difference in aggression associated with lifetime history of smoking. These data suggest that lifetime history of cigarette smoking is associated with elevations in life history of aggression regardless of the presence of psychiatric disorder in nontreatment seeking individuals.

Unhealthy aggression: intermittent explosive disorder and adverse physical health outcomes.

OBJECTIVE: To examine the relationship between Intermittent Explosive Disorder (IED; a psychiatric diagnosis characterized by episodes of affective aggression) and adverse physical health outcomes. DESIGN: A large epidemiological sample drawn from the Collaborative Psychiatric Epidemiological Surveys (N = 10,366), was used to compare participants with a lifetime diagnosis of IED (n = 929) to those without any history of IED (n = 9,437) on demographic variables (age, education, gender, race) common risk factors (smoking status, body mass index, substance use disorders, past accident or injury requiring treatment, major depression) and the presence of 12 adverse health outcomes. MAIN OUTCOME MEASURES: History of heart attacks, coronary heart disease, hypertension, stroke, lung disease, diabetes, cancer, arthritis, back/neck pain, ulcer, headaches, and other chronic pain. RESULTS: Logistic regression analysis controlling for demographic and other risk factors indicated that IED was associated with 9 of the 12 adverse physical health outcomes (coronary heart disease, hypertension, stroke, diabetes, arthritis, back/neck pain, ulcer, headaches, and other chronic pain). Only cancer, heart attacks, and lung disease were not significantly related to IED. CONCLUSION: IED may be a risk factor for several significant adverse physical health outcomes.

Evidence for a dysfunctional prefrontal circuit in patients with an impulsive aggressive disorder.

Humans with lesions to the orbital/medial prefrontal cortex and interconnected areas display impulsive aggressive behavior. To examine further the relationship between impulsive aggression and orbital/medial prefrontal dysfunction, we measured the behavioral performance of psychiatric patients with a disorder characterized by impulsive aggression, Intermittent Explosive Disorder (IED). Presently, no evidence exists for a localized brain lesion in IED subjects. However, on the basis of the location of brain lesions that produce acquired impulsive aggression, we hypothesized that IED subjects would exhibit test performance similar to patients with lesions to the orbital/medial prefrontal cortex. Subjects with IED and controls were administered three tests sensitive to lesions of the orbital/medial prefrontal circuit: the Iowa Gambling Task, facial emotion recognition, and odor identification, and two control tests of working memory. On the gambling task, IED subjects continued to make disadvantageous decisions throughout the 100 trials, whereas controls learned to avoid disadvantageous decisions. On the facial recognition test, IED subjects were impaired at recognizing "anger," "disgust," and "surprise," and they were biased to label neutral faces with "disgust" and "fear." On odor identification, IED subjects were mildly anosmic and were impaired relative to controls. However, on the working memory control tests, both groups performed similarly. Across tests, the performance of IED subjects resembles the performance of patients with orbital/medial prefrontal lesions in previous studies. These results extend the link between dysfunction of the orbital/medial prefrontal circuit and impulsive aggressive behavior.