Violent offenders respond to provocations with high amygdala and striatal reactivity.

The ability to successfully suppress impulses and angry affect is fundamental to control aggressive reactions following provocations. The aim of this study was to examine neural responses to provocations and aggression using a laboratory model of reactive aggression. We used a novel functional magnetic resonance imaging point-subtraction aggression paradigm in 44 men, of whom 18 were incarcerated violent offenders and 26 were control non-offenders. We measured brain activation following provocations (monetary subtractions), while the subjects had the possibility to behave aggressively or pursue monetary rewards. The violent offenders behaved more aggressively than controls (aggression frequency 150 vs 84, P = 0.03) and showed significantly higher brain reactivity to provocations within the amygdala and striatum, as well as reduced amygdala-prefrontal and striato-prefrontal connectivity. Amygdala reactivity to provocations was positively correlated with task-related behavior in the violent offenders. Across groups, striatal and prefrontal reactivity to provocations was positively associated with trait anger and trait aggression. These results suggest that violent individuals display abnormally high neural sensitivity to social provocations, a sensitivity related to aggressive behavior. These findings provide novel insight into the neural pathways that are sensitive to provocations, which is critical to more effectively shaped interventions that aim to reduce pathological aggressive behavior.

Serotonin 1B Receptor Binding Is Associated With Trait Anger and Level of Psychopathy in Violent Offenders.

BACKGROUND: The involvement of serotonin in aggression has traditionally been attributed to impaired prefrontal serotonergic inhibitory control of emotional reactions to provocations in antisocial individuals. However, it is unclear which specific serotonergic receptors are involved in the effects. A large body of preclinical research supports a specific role of serotonin 1B receptors (5-HT1BRs) in aggression and impulsivity, but this has never been evaluated in humans. METHODS: Nineteen incarcerated violent offenders and 24 healthy control nonoffenders were included and examined with positron emission tomography, using the radioligand [11C]AZ10419369 for quantification of cerebral 5-HT1BR binding in three regions of interest: the anterior cingulate cortex, orbitofrontal cortex, and striatum. RESULTS: Group status significantly moderated the association between striatal 5-HT1BRs and trait anger (difference in slopes, pcorrected = .04). In the violent offender group, striatal 5-HT1BR binding was positively correlated with self-reported trait anger (p = .0004), trait psychopathy (p = .008), and level of psychopathy according to the Psychopathy Checklist-Revised (p = .02). We found no group differences in 5-HT1BR binding. CONCLUSIONS: Our data demonstrate for the first time in humans a specific involvement of 5-HT1BR binding in anger and psychopathy. 5-HT1BRs putatively represent a molecular target for development of pharmacologic antiaggressive treatments.

Association between genetic polymorphisms in the serotonergic system and comorbid personality disorders among patients with first-episode depression.

Studies on the association between genetic polymorphisms and personality disorders have provided inconsistent results. Using the "enriched sample method," the authors of the present study aimed to assess the association between polymorphisms in the serotonergic transmitter system and comorbid personality disorders in patients recently diagnosed with first-episode depression. A total of 290 participants were systematically recruited via the Danish Psychiatric Central Research Register. Diagnoses of personality disorders were assessed by a SCID-II interview, and polymorphisms in the genes encoding the serotonin transporter, serotonin receptors 1A, 2A, 2C, and tryptophan hydroxylase 1 were genotyped. The authors found a significant effect of the length polymorphism in the serotonin transporter gene (5-HTTLPR) on cluster B personality disorder (mainly borderline disorder), but no influence on cluster C personality disorder, and no associations between other polymorphisms and personality disorders. The study adds evidence to the effect of the serotonin transporter gene specifically on cluster B personality disorders.

The effect of prolonged duration of untreated depression on antidepressant treatment outcome.

BACKGROUND: The duration of untreated illness has been considered a likely predictor of the course of psychotic disorders. However, there is only sparse data concerning the influence of treatment delay on the outcome of mood disorders. The present study aimed to assess the effect of prolonged untreated depression on the outcome of antidepressant treatment. METHOD: Patients aged 18-70 years with recent onset of the first lifetime depressive episode were systematically recruited by the Danish Psychiatric Central Research Register during a 2-year period. A total number of 399 individuals out of 1006 potential participants in the Register were interviewed, and 270 fulfilled the inclusion criteria. The validity of the diagnosis, duration of untreated illness, remission on first-line antidepressant treatment and a number of covariates, including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, and family history of psychiatric illness, were assessed by structured interviews. RESULTS: The remission rate was significantly decreased among patients with six months or more of untreated depression as compared to patients who were treated with antidepressant medication earlier after onset (21.1% versus 33.7%, OR=0.5, 95% CI 0.3 to 0.9, p=0.03). The negative influence of a prolonged DUI on the outcome did not seem confounded by any of a wide range of demographic and clinical variables. LIMITATIONS: The outcome was evaluated retrospectively. The findings cannot be generalized to patients outside hospital settings. CONCLUSION: Initiation of antidepressant treatment more than six months after onset of first episode depression reduces the chance of obtaining remission. The results emphasize the importance of early recognition and treatment of patients suffering from depression.

Promoter variants in IL18 are associated with onset of depression in patients previously exposed to stressful-life events.

BACKGROUND: Depression is accompanied by an inflammatory reaction and activation of cell mediated immunity (CMI) and stressors may induce the cytokine network in humans. The proinflammatory cytokine interleukin-18 (IL-18) is less investigated in depression but highly relevant since it is produced by activated macrophages and expressed in the brain. METHODS: The distribution of six polymorphisms in IL10, IL18 and NF was compared between patients with a single episode of depression either preceded by a stressful life event (n=182), or occurring without a prior stressful life event (n=106) and a group of healthy control individuals (n=335). RESULTS: The major C allele of the IL18 rs187238 and the major G allele of rs1946518 had a significantly higher prevalence among the patients with a stressful life event prior to onset of disease than both patients without a stressful life event and compared with the healthy controls individuals. None of the examined IL10 or NF alleles were differently distributed among these groups. LIMITATIONS: Data are nominally significant and not resistant to correction for multiple testing. CONCLUSION: The major C allele of the IL18 rs187238 and the major G allele rs1946518 have previously been associated with higher expression of IL-18 mRNA. Our data suggest that this genetic trend towards higher IL-18 production may increase the susceptibility to depression in response to stressful life events.

Association of the leucine-7 to proline-7 variation in the signal sequence of neuropeptide Y with major depression.

OBJECTIVE: There is clear evidence of a genetic component in major depression, and several studies indicate that neuropeptide Y (NPY) could play an important role in the pathophysiology of the disease. A well-known polymorphism encoding the substitution of leucine to proline in the signal peptide sequence of NPY (Leu7Pro variation) was previously found to protect against depression. Our study aimed at replicating this association in a large Danish population with major depression. METHOD: Leu7Pro was studied in a sample of depressed patients and ethnically matched controls, as well as psychiatric disease controls with schizophrenia. Possible functional consequences of Leu7Pro were explored in vitro. RESULTS: In contrast to previous studies, Pro7 appeared to be a risk allele for depression, being significantly more frequent in the depression sample (5.5%, n = 593; p = 0.009; odds ratio, OR: 1.46) as compared to ethnically matched controls (3.8%, n = 2912), while schizophrenia patients (4.1%, n = 503) did not differ. In vitro, the Pro7 substitution appeared to be associated with reduced levels of NPY without affecting its mRNA level. CONCLUSION: The Leu7Pro variation may increase the risk of major depression, possibly by affecting the biosynthesis of NPY.

Differences between early and late onset adult depression.

BACKGROUND: It is unclear, whether age-of-onset identifies subgroups of depression. AIM: To assess the clinical presentation of depression with onset in the early adult age (18-30 years) as compared to depression with later onset (31-70 years). METHOD: A total number of 301 patients with first episode depression were systematically recruited. Characteristics including psychiatric co-morbidity, personality disorders and traits, stressful life events prior to onset, family history, and treatment outcome were assessed by structured interviews and compared by chi-square tests for categorical data, t-tests for continuous parametric data and Mann-Whitney U-test for continuous nonparametric data. Logistic and multiple regression analyses were used to adjust the analyses for potentially confounding variables. RESULTS: Patients with early onset of depression were characterised by a higher prevalence of co-morbid personality disorders, higher levels of neuroticism, and a lower prevalence of stressful life events preceding onset compared to patients with later age-of-onset. There were no differences in severity of the depressive episode, treatment outcome or family loading of psychiatric illness. CONCLUSION: Early adult onset of depression is associated with co-morbid personality deviances, whereas late onset is associated with environmental risk factors.

Clinical utility of Standardised Assessment of Personality - Abbreviated Scale (SAPAS) among patients with first episode depression.

BACKGROUND: Personality disorder frequently co-occurs with depression and seems to be associated with a poorer outcome of treatment and increased risk for recurrences. However, the diagnosing of personality disorder can be lengthy and requires some training. Therefore, a brief screening interview for comorbid personality disorder among patients suffering from depression would be of clinical use. METHOD: The present study aimed to assess the utility of the Standardised Assessment of Personality - Abbreviated Scale (SAPAS) as a screen for personality disorder in a population of patients recently diagnosed with first episode depression. A total number of 394 patients with an ICD-10 diagnosis of a single depressive episode were sampled consecutively via the Danish Psychiatric Central Research Register during a 2years inclusion period and assessed by the screening interview and, subsequently, by the Structured Clinical Interview for DSM-IV Personality Disorders. RESULTS: We found, that a cut-off of 3 on the screen correctly identified the presence of comorbid personality disorder in 73.1% of the patients. The sensitivity and specificity were 0.80 and 0.70, respectively. LIMITATIONS: The findings cannot be generalized to patients outside hospital settings. CONCLUSION: The study provides evidence for the clinical utility of SAPAS as a screening interview for comorbid personality disorder in a population of patients with a primary diagnosis of depression.

The influence of comorbid personality disorder and neuroticism on treatment outcome in first episode depression.

BACKGROUND: It has never been investigated whether comorbid personality disorder or neuroticism predicts a poor treatment outcome in first episode depression. METHODS: Medically treated patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. The patients participated in an extensive interview including the Schedules for Clinical Assessment in Neuropsychiatry, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders and a detailed assessment of medical treatment history using standardised procedures (Treatment Response to Antidepressants Questionnaire, TRAQ). Remission was defined as a score of < or =7 on the Hamilton Depression Rating Scale, 17 items, and a score of > or =4 on the TRAQ following (1) a first adequate trial of antidepressant treatment, and (2) 2 trials of antidepressant treatment. Further personality traits were assessed by means of the Eysenck Personality Questionnaire. RESULTS: Among a total of 301 patients with a single depressive episode, 31.9% fulfilled diagnostic criteria for at least 1 personality disorder of any kind. Comorbid personality disorder was associated with a 2.2-times (95% CI: 1.1-4.2) increased risk of non-remission following the first antidepressant trial, whereas no effect was found following the second antidepressant trial (OR: 1.6; 95% CI: 0.8-3.4). A high level of neuroticism was associated with non-remission in first as well as second trials. CONCLUSION: Comorbid personality disorder and high levels of neuroticism in first episode depression predict an increased risk of non-remission from depression.

Gender differences among patients with a single depressive episode.

BACKGROUND: Studies on gender differences in depression have usually included a mixture of patients with first-episode, chronic and recurrent depression. Consequently, the results might be confounded by the history of depression among participants. The present study evaluated gender differences in sociodemographic, clinical and treatment variables among patients suffering exclusively from single-episode depression. METHOD: Systematic recruitment of 301 participants via the Danish Psychiatric Central Research Register and assessment by means of questionnaires and interviews regarding psychiatric diagnoses, personality traits and disorders, stressful life events, family history, and treatment response. RESULTS: Female patients showed a higher level of neuroticism and more residual anxiety symptoms after treatment of the depression. There were no gender differences in severity of depression, psychiatric co-morbidity (including personality disorders), stressful life events prior to onset, family loading of psychiatric disorders, or treatment outcome. CONCLUSION: The results provide evidence for a higher level of anxiety and neuroticism among females with a recent onset of depression, whereas other clinical characteristics of first-episode depression were equivalent between male and female patients. Only patients with contact to a psychiatric hospital were included; thus, the results cannot be generalized to patients in primary care.

Does bereavement-related first episode depression differ from other kinds of first depressions?

BACKGROUND: It has never been investigated whether first depression differs in patients who have experienced bereavement compared to patients who have not. METHOD: Patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. Patients participated in an extensive interview including the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and the Interview of Recent Life Events (IRLE). RESULTS: Among 301 patients with a first depression, 26 patients (4.7%) had experienced death of a first degree relative (parent, sibling, child) or a near friend, 163 patients (54.2%) had experienced other moderate to severe stressful life events and 112 patients had not experienced stressful life events in a 6 months period prior to the onset of depression. Patients who had experienced bereavement did not differ from patients with other stressful life events or from patients without stressful life events in socio-demographic variables or in the phenomenology of the depression, psychiatric comorbidity, family history or response to antidepressant treatment. CONCLUSION: Bereavement-related first episode depression does not differ from other kinds of first depression.

No interactions between genetic polymorphisms and stressful life events on outcome of antidepressant treatment.

Genetic polymorphisms seem to influence the response on antidepressant treatment and moderate the impact of stress on depression. The present study aimed to assess, whether allelic variants and stressful life events interact on the clinical outcome of depression. In a sample of 290 systematically recruited patients diagnosed with a single depressive episode according to ICD-10, we assessed the outcome of antidepressant treatment and the presence of stressful life events in a 6-month period preceding onset of depression by means of structured interviews. Further, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophan hydroxylase, and the serotonin receptors 1A, 2A, and 2C. We found no evidence that the effects of the genetic polymorphisms on treatment outcome were dependent on stressful life events experienced by the individual prior to onset of depression.

Antidepressive-drug-induced bodyweight gain is associated with polymorphisms in genes coding for COMT and TPH1.

Bodyweight gain is a common side effect of treatment with antidepressive drugs; however, little is known about the mechanisms behind this weight gain. Genetic differences may contribute to the susceptibility for bodyweight gain during antidepressive treatment. The objective of this study was to examine the association of antidepressive-drug-induced bodyweight gain with polymorphisms in genes within the serotonin or catecholamine systems. Participants (N = 165) were selected from the Danish Psychiatric Central Research Register from June 2005 through May 2007 as patients with a diagnosis of a single depressive episode and who were under antidepressive treatment. Weight gainers were identified based on rating with the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale. Polymorphisms in catechol-O-methyltransferase, tryptophan hydroxylase (TPH1), serotonin receptor 2C (HTR2C) and serotonin transporter (SLC6A4) genes were identified and associated with bodyweight gain during treatment. The AG genotype of catechol-O-methyltransferase rs4680 and the AA genotype of TPH1 rs18532 were significantly associated with bodyweight gain during antidepressive treatment, when adjusted for age and sex. These new findings may aid the understanding of susceptibility to side effects such as weight gain during clinical antidepressive treatment.

Interaction between genetic polymorphisms and stressful life events in first episode depression.

BACKGROUND: A polymorphism in the serotonin transporter (5-HTT) gene seems to moderate the influence of stressful life events on depression. However, the results from previous studies of gene-environment interactions in depression are inconsistent and might be confounded by the history of depression among participants. METHOD: We applied a case-only design, including 290 ethnically homogeneous patients suffering exclusively from first episode depression. Psychiatric mo-morbidity, personality traits and disorders and stressful life events in a six months period preceding onset of depression were evaluated by means of interviews and questionnaires. Additionally, we genotyped nine polymorphisms in the genes encoding the serotonin transporter, brain derived neurotrophic factor, catechol-O-methyltransferase, angiotensin converting enzyme, tryptophane hydroxylase, and the serotonin receptors 1A, 2A, and 2C. RESULTS: The low activity variants of the 5-HTT-linked polymorphic region in the serotonin transporter gene and the Met-allele of a single nucleotide polymorphism (Val66Met) in the gene encoding brain derived neurotrophic factor were independently associated with the presence of stressful life events prior to onset of depression, also when corrected for the effect of age, gender, marital status, personality disorder, neuroticism, and severity of depressive symptoms at the time of interview. CONCLUSION: Polymorphisms in the genes encoding the serotonin transporter and the brain derived neurotrophic factor interact with recent stressful life events on depression among patients with no history of previous depressive episodes.

Do stressful life events predict medical treatment outcome in first episode of depression?

BACKGROUND: It is unclear whether medical treatment outcome in first episode depression differ for patients with and without stressful life events prior to onset of depression. METHODS: Patients discharged with a diagnosis of a single depressive episode from a psychiatric in- or outpatient hospital setting were consecutively sampled from the Danish Psychiatric Central Research Register. Patients participated in an extensive interview including the schedules for clinical assessment in neuropsychiatry (SCAN), the Structured Clinical Interview for DSM-IV axis II personality disorders (SCID-II) and the interview of recent life events (IRLE). Medical treatment history was assessed in detail using standardised procedures (TRAQ). Remission was defined as a score or= 4 on TRAQ following (1) first trial of antidepressant treatment (2) two adequate trials of antidepressant treatment. RESULTS: A total of 399 patients participated in the interview and among these 301 patients obtained a SCAN diagnosis of a single depressive episode. A total of 62.8% of the 301 patients experienced at least one moderate to severe stressful life event in a 6 months period prior to symptom onset. The presence of a stressful life event or the number of stressful life events did not predict remission from first or second antidepressant drug trial-nor when adjusted for differences in age, gender or prevalence of co-morbid personality disorders. CONCLUSIONS: Medical treatment outcome in first episode depression does not depend on the prevalence of moderate to severe stressful life events prior to symptom onset.

Validity of the diagnosis of a single depressive episode in a case register.

OBJECTIVE: To validate the ICD-10 diagnosis of a single depressive episode as used in daily clinical psychiatric practice and as recorded in the Danish Psychiatric Central Research Register. METHODS: Patients discharged with a diagnosis of a single depressive episode were consecutively sampled from the register and diagnosed according to an interview using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN). RESULTS: A total of 75.4% of 399 patients with a register diagnosis of a single depressive episode also got this diagnosis according to the SCAN interview (82.8% for severe type of a single depression, 76.0% for moderate type of a single depression and 65.2% for mild type of a single depression). CONCLUSION: The ICD-10 diagnosis of a single depressive episode can be used in daily clinical practice with sufficient precision. The validity of the diagnosis is highest for severe and moderate type of depression and decreases for mild depression.

The once-daily human GLP-1 analog, liraglutide, reduces olanzapine-induced weight gain and glucose intolerance.

Therapeutic use of atypical antipsychotic agents is often associated with weight gain and impaired glucose tolerance. The once-daily human GLP-1 analog liraglutide improves glycemic control and reduces body weight. We have investigated the ability of liraglutide to improve olanzapine-induced metabolic effects in female rats. Female Sprague-Dawley rats were implanted with subcutaneous osmotic mini pumps for delivery of olanzapine (1.75 mg/24 h) or vehicle for 28 days (n=20). After 14 days, ten animals from each group were given liraglutide (0.2 mg/kg) or vehicle twice daily for the remainder of the study. Compared to vehicle treated animals, olanzapine infusion for 4 weeks significantly increased end point cumulated food intake (667.3+/-7.0 versus 593.2+/-13.2g, p<0.01), body weight (306.6+/-4.2 versus 276.4+/-3.6 g, p<0.001), subcutaneous inguinal fat (3.4+/-0.3 versus 1.9+/-0.1 g, p<0.001), mesenteric fat (3.1+/-0.2 versus 1.7+/-0.2g, p<0.001), retroperitoneal fat (6.2+/-0.6 versus 2.8+/-0.3 g, p<0.001), and impaired glucose tolerance, measured as total area under the glucose curve during an oral glucose tolerance test (1906+/-66 versus 1770+/-28 mMxmin, p<0.05). These olanzapine-induced elevations were significantly reduced by liraglutide (cumulated food intake: 601.8+/-20.4 g, p<0.01; body weight: 280.2+/-5.6 g, p<0.001; subcutaneous inguinal fat: 2.4+/-0.2 g, p<0.001; mesenteric fat: 1.8+/-0.1 g, p<0.001; retroperitoneal fat: 3.5+/-0.4 g, p<0.001; AUC: 1764+/-32 mMxmin, p<0.05). In conclusion, subcutaneous olanzapine infusion in female rats leads to weight gain and metabolic changes of which several are reversed following liraglutide treatment. It may therefore be relevant to study these effects of liraglutide in patients treated with atypically antipsychotics.

[The influence of genetic variations on the effect of selective serotonin reuptake inhibitors]. / Genetiske variationers betydning for effekten af selektive serotoningenoptagelseshaemmere.

The outcome of psychopharmacological treatment may depend on genetic polymorphisms of various neurotransmitter systems. We summarize studies of associations between genetic variations with relation to the serotonin system and response to selective serotonin reuptake inhibitors. The results are still preliminary but suggest that treatment response to antidepressant drugs is influenced by genetic factors. They also indicate that the genetic component is polygenic and highly complex and might manifest itself in interaction with other biological and environmental factors.