Polygenic risk for schizophrenia and bipolar disorder in relation to cardiovascular biomarkers.

Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration.

Lifetime Cannabis Use Is Not Associated With Negative Beliefs About Medication in Patients With First Treatment Psychosis.

Objective: Cannabis use is common among patients with psychosis, and along with negative beliefs about medication, it has been found to predict poor adherence to antipsychotic drug treatment. Such lack of adherence to antipsychotic drug treatment increases the risk of poor clinical outcomes and relapse in patients with first treatment for psychosis (FTP). However, to date, it is unclear whether cannabis use may be related to negative perceptions about antipsychotic drug treatment. Methods: A cross-sectional sample of 265 FTP patients with schizophrenia spectrum disorder underwent extensive clinical assessments. Three measures of cannabis use were obtained: lifetime, current and meeting diagnostic criteria for abuse or addiction. For the primary analyses we focused on lifetime cannabis use. The Beliefs about Medication Questionnaire (BMQ) was employed to assess the patients' specific concerns and perceptions of antipsychotic medications, as well as general beliefs about pharmacotherapy. The relationship between lifetime cannabis use and BMQ scores was investigated with general linear model (GLM) analyses, controlling for age and sex. Results: Patients with lifetime use of cannabis ≥10 times were more likely to be male, younger at the age of onset of psychosis and with higher levels of alcohol use and daily tobacco smoking, as compared to the non-users (p < 0.05). Neither lifetime use of cannabis, current use nor a cannabis abuse diagnosis was associated with negative beliefs about medicines as measured by the BMQ questionnaire. Conclusion: Use of cannabis is not linked to negative perceptions about antipsychotic medicines in patients with FTP. Other reasons for poor compliance to antipsychotic drug treatment in cannabis users need to be further investigated.

Childhood trauma is associated with poorer social functioning in severe mental disorders both during an active illness phase and in remission.

BACKGROUND: Impaired social functioning is a core feature of schizophrenia spectrum (SZS) and bipolar spectrum disorders (BDS). Childhood traumatic events are more frequent in SZS and BDS than in healthy individuals (HC), and could represent a cumulative risk for reduced social functioning beyond experiencing ongoing clinical symptoms. METHODS: The study comprised 1039 individuals (SZS [n = 348]; BDS [n = 262], and HC [n = 429]). Childhood trauma and level of social functioning was assessed by the Childhood Trauma Questionnaire (CTQ) and the Social Functioning Scale (SFS), respectively. Diagnosis was obtained by the Structured Clinical Interview (SCID) for the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV). RESULTS: Patients had poorer social functioning (F = 819.18, p Ë‚ 0.001, Cohen's d = 0.44) and reported more childhood trauma experiences than HC (X2 = 289.0, p < .001) than HC. Patients with at least one moderate to severe trauma had poorer social functioning than patients without childhood trauma (F = 8.16, p = .004, Cohen's d = 0.17). Within the patients, a cumulative relationship was observed in that more severe childhood trauma was associated with lower social functioning (F = 2.65, p = .02, Cohen's d = 0.20). No significant associations were observed for having at least one moderate to severe trauma or cumulative traumas on social functioning in the HC. Follow-up analysis showed that patients in remission childhood trauma also had poorer social functioning. CONCLUSION: Patients who reported childhood trauma experiences had poorer social functioning both during an active illness phase and in remission.

Adiponectin Is Related to Cardiovascular Risk in Severe Mental Illness Independent of Antipsychotic Treatment.

Background: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) associated with elevated cardiovascular disease (CVD) risk, including obesity. Leptin and adiponectin are secreted by adipose tissue, with pro- and anti-inflammatory properties, respectively. The second generation antipsychotics (AP) olanzapine, clozapine, and quetiapine have been associated with high leptin levels in SMI. However, the link between inflammatory dysregulation of leptin and adiponectin and CVD risk in SMI, and how this risk is influenced by body mass and AP medication, is still not completely understood. We investigated herein if leptin, adiponectin or their ratio (L/A ratio) could predict increased CVD risk in SCZ, BD, and in subgroups according to use of antipsychotic (AP) treatment, independent of other cardio-metabolic risk factors. Methods: We measured fasting plasma levels of leptin and adiponectin, and calculated the L/A ratio in n = 1,092 patients with SCZ and BD, in subgroups according to AP treatment, and in n = 176 healthy controls (HC). Differences in the levels of adipokines and L/A between groups were examined in multivariate analysis of covariance, and the correlations between adipokines and body mass index (BMI) with linear regression. CVD risk was defined by total cholesterol/high-density lipoprotein (TC/HDL) and triglyceride/HDL (TG/HDL) ratios. The adipokines and L/A ratios ability to discriminate individuals with TG/HDL and TC/HDL ratios above threshold levels was explored by ROC analysis, and we investigated the possible influence of other cardio-metabolic risk factors on the association in logistic regression analyses. Results: We observed higher leptin levels and L/A ratios in SMI compared with HC but found no differences in adiponectin. Both adipokines were highly correlated with BMI. The low adiponectin levels showed a fair discrimination in ROC analysis of individuals with CVD risk, with AUC between 0.7 and 0.8 for both TC/HDL and TG/HDL, in all groups examined regardless of diagnosis or AP treatment. Adiponectin remained significantly associated with an elevated TC/HDL and TG/HDL ratio in SMI, also after further adjustment with other cardio-metabolic risk factors. Conclusions: Adiponectin is not dysregulated in SMI but is associated with CVD risk regardless of AP treatment regime.

Physical activity and childhood trauma experiences in patients with schizophrenia or bipolar disorders.

BACKGROUND: Physical activity promotes resilience and reduces stress. Here we aimed to clarify the impact of physical activity and childhood trauma experiences on current mood and cognitive function in patients with schizophrenia (SZ) or bipolar disorders (BD). METHODS: Three-hundred-and-six patients with DSM-IV schizophrenia (SZ) or bipolar disorder (BD) were included in the study. Diagnoses were assessed using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Physical activity was measured as hours spent on any regular physical activity per week. All patients underwent a neuropsychological test battery. History of Childhood trauma was assessed using the Childhood Trauma Questionnaire and mood symptoms were assessed with the Inventory of Depressive Symptoms. RESULTS: Patients with childhood trauma who were physically inactive (˂90 min per week) had the most severe clinical profile, characterised by the highest depressive symptoms (p ˂ 0.001) and lowest performance on working memory tasks (p ˂ 0.001). Among patients with childhood trauma, those who were physically active (≥90 min per week) had better working memory performance than physically inactive patients (p = 0.02). DISCUSSION: A history of childhood trauma was associated with poorer working memory and more depressive symptoms only in patients who were physically inactive, suggesting a possible protective factor of physical activity in severe mental disorder.

Atherogenic Lipid Ratios Related to Myeloperoxidase and C-Reactive Protein Levels in Psychotic Disorders.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of premature death in patients with psychotic disorders, where dyslipidemia occurs frequently. In the pathogenesis of these serious mental disorders, a low-grade inflammation seems to be a possible contributor. Concurrently, systemic inflammation and its interplay with dyslipidemia is a central driver in the pathogenesis of CVD. We hypothesize that evaluation of atherogenic lipid ratios together with inflammatory markers reflecting different inflammatory pathways with relevance for atherogenesis, could give novel information on immune-related mechanisms involved in early CVD risk in patients with psychotic disorders. METHODS: As a measure for CVD risk we calculated atherogenic lipid ratios using established sex-specific cut-offs: Total cholesterol/high-density lipoprotein; HDL-c (TC/HDL) and triglyceride/HDL-c (TG/HDL) were evaluated in 571 schizophrenia (SCZ) and 247 bipolar disorder (BD) patients, and in 99 healthy controls (HC). In addition, as a measure of low-grade inflammation, we measured fasting plasma levels of nine stable atherogenic inflammatory markers in patients (SCZ, BD) and in HC. The elevated inflammatory markers and CVD risk in patients, as reflected by TC/HDL and TG/HDL, were further assessed in multivariable analyses adjusting for comorbid cardio-metabolic risk factors. RESULTS: A markedly higher proportion (26%-31%) of patients had increased TC/HDL and TG/HDL ratios compared with HC. Plasma levels of high-sensitivity C-reactive protein (hs-CRP) and myeloperoxidase (MPO) were higher (p<0.05, p<0.001) in patients with psychotic disorders than in HC, and hs-CRP and MPO were independently associated with atherogenic lipid ratios in the multivariable analyses. CONCLUSIONS: Our findings suggest that low-grade inflammation and abnormal neutrophil activation may cause increased CVD risk in patients with psychotic disorders. These mechanisms should be further examined to determine the potential for development of novel risk evaluation strategies.

Increased interleukin 18 activity in adolescents with early-onset psychosis is associated with cortisol and depressive symptoms.

OBJECTIVE: Evidence indicates that the pathophysiology of adult psychosis involves immune dysregulation, but its associations with stress are often not considered. The inflammatory cytokine interleukin (IL)-18, which is elevated in adult schizophrenia, is suggested to be sensitive to stress. We compared the associations of IL-18 with cortisol and clinical variables in adolescents with early-onset psychosis (EOP) aged 12-18 years and age-matched healthy controls (HC). METHOD: We measured serum IL-18, IL-18 binding protein (IL-18BP), IL-18 receptor accessory protein (IL-18RAP), IL-18 receptor 1 (IL-18R1) and cortisol, and calculated the IL-18/IL-18BP ratio in patients (n = 31) and HC (n = 60). Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale and depressive symptoms by the Mood and Feelings Questionnaire-Child version (MFQ-C). Bivariate correlation analysis was used to explore relationships between IL-18/IL-18BP ratio and cortisol, depression and other clinical characteristics. Hierarchical multiple linear regression analysis was used to assess their individual contributions to the variance of the IL-18/IL-18BP ratio. RESULTS: Patients had significantly higher IL-18 levels and IL-18/IL-18BP ratios than HC, but similar IL-18BP, IL-18RAP and IL-18R1. Both cortisol (R2 change = 0.05) and the MFQ-C score (R2 change = 0.09) contributed significantly to the variance in IL-18/IL-18BP ratios after controlling for confounders. CONCLUSION: We found increased IL-18 system activity in adolescents with EOP. Cortisol and depressive symptoms each contributed to the variance in the IL-18/IL-18BP ratio. Our findings support activation of inflammatory pathways in adolescent psychosis and suggest interactions between stress, inflammation and depressive symptoms in EOP.

Inflammatory markers are altered in severe mental disorders independent of comorbid cardiometabolic disease risk factors.

BACKGROUND: Inflammation and immune activation have been implicated in the pathogenesis of severe mental disorders and cardiovascular disease (CVD). Despite high level of comorbidity, many studies of the immune system in severe mental disorders have not systematically taken cardiometabolic risk factors into account. METHODS: We investigated if inflammatory markers were increased in schizophrenia (SCZ) and affective (AFF) disorders independently of comorbid CVD risk factors. Cardiometabolic risk factors (blood lipids, body mass index and glucose) and CVD-related inflammatory markers CXCL16, soluble interleukin-2 receptor (sIL-2R), soluble CD14 (sCD14), macrophage inhibitory factor and activated leukocyte cell adhesion molecule (ALCAM) were measured in n = 992 patients (SCZ, AFF), and n = 647 healthy controls. We analyzed the inflammatory markers before and after controlling for comorbid cardiometabolic risk factors, and tested for association with psychotropic medication and symptom levels. RESULTS: CXCL16 (p = 0.03) and sIL-2R (p = 7.8 × 10-5) were higher, while sCD14 (p = 0.05) were lower in patients compared to controls after controlling for confounders, with significant differences in SCZ for CXCL16 (p = 0.04) and sIL-2R (p = 1.1 × 10-5). After adjustment for cardiometabolic risk factors higher levels of sIL-2R (p = 0.001) and lower sCD14 (p = 0.002) remained, also in SCZ (sIL-2R, p = 3.0 × 10-4 and sCD14, p = 0.01). The adjustment revealed lower ALCAM levels (p = 0.03) in patients. We found no significant associations with psychotropic medication or symptom levels. CONCLUSION: The results indicate that inflammation, in particular enhanced T cell activation and impaired monocyte activation, are associated with severe mental disorders independent of comorbid cardiometabolic risk factors. This suggests a role of novel pathophysiological mechanisms in severe mental disorders, particularly SCZ.

Adipokine levels are associated with insulin resistance in antipsychotics users independently of BMI.

BACKGROUND: The prevalence of obesity, metabolic syndrome and type 2 diabetes mellitus is increased among patients with severe mental disorders, and particularly use of second generation antipsychotic drugs is associated with metabolic side effects. Antipsychotics have been found to alter levels of adipokines which regulate insulin sensitivity, but their role in antipsychotic-associated insulin resistance is not established, and it is unclear whether adipokines affect insulin resistance independently of body mass index (BMI). METHODS: We included 1050 patients with severe mental disorders and 112 healthy controls aged 18-65 years from the Oslo area, Norway. Clinical variables, BMI and use of medication were assessed, fasting blood samples were obtained for calculation of the leptin/adiponectin ratio (L/A ratio) and estimate of insulin resistance using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Case-control analyses were followed by mediation analyses to evaluate the possible direct effect of antipsychotics on HOMA-IR and indirect effect mediated via the L/A ratio. This was performed both with and without adjustment for BMI, in the total sample and in an antipsychotic monotherapy subsample (N = 387). RESULTS: BMI, L/A ratio and HOMA-IR were significantly higher in patients than controls (p < 0.001-p = 0.01). There was a significant direct effect from use of antipsychotics in general on HOMA-IR both without (b = 0.03, p = 0.007) and with adjustment for BMI (b = 0.03, p = 0.013), as well as a significant mediating effect via L/A ratio both without (b = 0.03, p < 0.001) and with adjustment for BMI (b = 0.01, p = 0.041). Use of olanzapine (b = 0.03, p < 0.001) or aripiprazole (b = 0.04, p < 0.001) in monotherapy showed significant effects on HOMA-IR mediated via L/A ratio. CONCLUSIONS: The study suggests that use of antipsychotics may alter adipokine levels, and that increased L/A ratio may play a role in the development of insulin resistance associated with use of antipsychotics also independently of BMI.

Elevated hair cortisol is associated with childhood maltreatment and cognitive impairment in schizophrenia and in bipolar disorders.

BACKGROUND: The neural diathesis-stress model is useful to understand schizophrenia (SZ) and bipolar (BD) disorders. Childhood maltreatment could affect the Hypothalamic-Pituitary-Adrenal (HPA)-axis and lead to chronic changes in stress-sensitivity, which can be measured with hair cortisol concentrations (HCC), representing long-term, cumulative cortisol levels. Here we investigated if childhood trauma experiences are associated with chronic changes in the HPA axis in severe mental disorders. METHODS: Participants with SZ or BD (N = 63) and healthy controls (N = 94) were included, and HCC was measured by ELISA. History of childhood maltreatment was assessed using the Childhood Trauma Questionnaire (CTQ). Global function and symptom levels were obtained using the Global Assessment of Functioning (GAF) Scale and the Positive and Negative Syndrome Scale (PANSS). A neuropsychological test battery (MATRICS) was performed to assess cognitive functions. RESULTS: Our study shows for the first time that patients with a history of childhood maltreatment have higher HCC relative to both healthy controls and patients without a history of childhood maltreatment (P = 0.01, ƞp2 = 0.046). In addition, patients experiencing a mood episode had higher HCC than patients in remission (P = 0.03). Lastly, we are the first to show that patients with higher HCC had poorer cognitive performance, specifically working memory (P = 0.01). All associations were irrespective of diagnostic group. A factor analysis confirmed a subgroup within the patients characterized by childhood maltreatment and elevated HCC. CONCLUSIONS: Findings support the neural diathesis-stress model in SZ and BD pointing to long-term changes in HPA-axis following childhood maltreatment experiences.

Reduced brain-derived neurotrophic factor is associated with childhood trauma experiences and number of depressive episodes in severe mental disorders.

BACKGROUND: Although several studies have found reduced plasma BDNF levels in patients with severe mental disorders, the sample sizes have been small and have exhibited variation and heterogeneity. Furthermore, long-term neurobiological changes following childhood trauma and clinical severity have been linked to a reduction in BDNF levels. Accordingly, we aim to clarify, using the largest sample size to date, the role of plasma BDNF in individuals with severe mental disorders in relation to the number of episodes, current remission status, and childhood trauma experiences. METHODS: The study sample comprised 1446 individuals (schizophrenia: SZ [n = 589]; bipolar disorder: BD [n = 254]; and healthy control: HC [n = 603]) all recruited from the same catchment area. A subsample (N = 629) of this larger group had a history of childhood trauma, and some (N = 195) participated in a one-year follow-up study. The level of BDNF in plasma was measured, and childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Diagnoses and episodes were obtained using the Structured Clinical Interview (SCID). RESULTS: Patients with SZ or BD had lower levels of plasma BDNF than did the HC group (p = 0.002, p = 0.003, respectively). Within patients, reduced plasma BDNF levels were associated with more depressive episodes (p = 0.04). Longer time in remission after depressive episodes was associated with higher plasma BDNF levels (p = 0.02), and patients reporting childhood sexual abuse exhibited lower plasma BDNF levels (p = 0.049) than patients without sexual abuse. CONCLUSION: Our study confirms that patients with a severe mental disorder exhibit reduced BDNF levels. While the strongest reduction in BDNF was observed in patients reporting childhood sexual abuse, reduced BDNF levels were also associated with more depressive episodes. Accordingly, further studies are warranted to determine whether treatment that increases BDNF levels may be beneficial to these individuals.

The relationship between physical activity, clinical and cognitive characteristics and BDNF mRNA levels in patients with severe mental disorders.

Background: Here we aimed to clarify the association of physical activity with cognitive function and current mood in severe mental disorders in the most extensive sample to date. Secondly, we aimed to investigate the relationship between physical activity and BDNF mRNA levels.Methods: Three hundred and six patients with a DSM-IV schizophrenia (SZ) or bipolar disorder (BD) spectrum diagnosis were included. Clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV. Depressive symptomatology was measured using the Inventory of Depressive Symptoms (IDS-C) and the Calgary Depression Scale for Schizophrenia (CDSS). All patients underwent neuropsychological assessment. Physical activity was measured as hours spent on any regular physical activity (≥ or ˂90 min) per week. BDNF mRNA was measured in plasma using standardised procedures.Results: Patients with ≥90 min of physical activity per week had fewer depressive symptoms (P ˂0.001, Cohen's d = 0.48) and performed significantly better on working memory (P Ë‚ 0.001, d = 0.44) and executive functioning tasks (P ˂ 0.001, d = 0.50) compared to the ˂90-min group. BDNF mRNA was positively associated with physical activity (P = 0.046) and cognitive functioning (P = 0.037).Conclusions: Our study suggests a positive association between self-reported physical activity, cognitive function, mood and BDNF mRNA levels in severe mental disorders.

Free thyroxine and thyroid-stimulating hormone in severe mental disorders: A naturalistic study with focus on antipsychotic medication.

BACKGROUND: Disturbances in thyroid function have been associated with use of psychotropic drugs, including antipsychotics. Still, the thyroid function in relation to commonly prescribed antipsychotic drugs and polypharmacy is not fully known. We investigated thyroid function associated with use of antipsychotics in patients with psychotic disorders compared with healthy controls. METHODS: We included 1345 patients and 989 healthy controls from the Thematically Organized Psychosis (TOP) study, recruiting participants between 18 and 65 years of age in the Oslo-area. All patients underwent a thorough clinical investigation and assessment of medication data. Thyroid function was determined from plasma levels of free thyroxin (fT4) and thyroid-stimulating hormone (TSH). Multiple linear regression analyses were performed to evaluate the association between thyroid parameters and use of antipsychotics, and monotherapy users of olanzapine, quetiapine, aripiprazole or risperidone (N = 473) were investigated separately. RESULTS: We found lower levels of fT4 (median 13.70 vs 14.00, p < 0.001) in patients compared to healthy controls, and a prevalence of 12.9% of previously undiagnosed deviant thyroid states in the patient group. Lower fT4 levels was associated with use of antipsychotics in general (p = 0.001), and quetiapine (p = 0.003) and olanzapine (p = 0.018) in particular, while the associations with TSH were non-significant. Using antipsychotics in combination with other psychotropic drugs, and with antidepressants in particular, was associated with lower fT4 level (p < 0.001) than use of antipsychotics alone. CONCLUSIONS: Our findings indicate an association between use of antipsychotics and lower fT4. Clinicians should be aware that patients using quetiapine, olanzapine or antipsychotics in psychotropic polypharmacy are especially at risk.

Microscopy of Stained Urethral Smear in Male Urethritis; Which Cutoff Should be Used?

BACKGROUND: The microscopical diagnosis of male urethritis was recently questioned by Rietmeijer and Mettenbrink, lowering the diagnostic criteria of the diagnosis to ≥2 polymorphonuclear leucocytes (PMNL) per high power field (HPF), and adopted by Centers for Disease Control and Prevention in their 2015 STD Treatment Guidelines. The European Non-Gonococcal Urethritis Guideline advocates a limit of ≥5 PMNL/HPF. OBJECTIVE: To determine if syndromic treatment of urethritis should be considered with a cutoff value of ≥2 PMNL/HPF in urethral smear. METHODS: The design was a cross-sectional study investigating the presence and degree of urethritis relative to specific infections in men attending an STI clinic as drop-in patients. RESULTS: The material included 2 cohorts: a retrospective study of 13,295 men and a prospective controlled study including 356 men. We observed a mean chlamydia prevalence of 2.3% in the 0-9 stratum, and a 12-fold higher prevalence (27.3%) in the strata above 9. Of the chlamydia cases, 89.8% were diagnosed in strata above 9. For Mycoplasma genitalium, the prevalence was 1.4% in the 0-9 stratum and 11.2% in the stratum ≥10, and 83.6% were diagnosed in strata above 9. For gonorrhea, a significant increase in the prevalence occurred between the 0-30 strata and >30 strata from 0.2% to 20.7%. The results of the prospective study were similar. CONCLUSIONS: Our data do not support lowering the cutoff to ≥2 PMNL/HPF. However, a standardization of urethral smear microscopy seems to be impossible. The cutoff value should discriminate between low and high prevalence of chlamydia, mycoplasma, and gonorrhea to include as many as possible with a specific infection in syndromic treatment, without overtreating those with few PMNL/HPF and high possibility of having nonspecific or no urethritis.

Urethral inflammatory response to ureaplasma is significantly lower than to Mycoplasma genitalium and Chlamydia trachomatis.

A non-syndromic approach to treatment of people with non-gonococcal urethritis (NGU) requires identification of pathogens and understanding of the role of those pathogens in causing disease. The most commonly detected and isolated micro-organisms in the male urethral tract are bacteria belonging to the family of Mycoplasmataceae, in particular Ureaplasma urealyticum and Ureaplasma parvum. To better understand the role of these Ureaplasma species in NGU, we have performed a prospective analysis of male patients voluntarily attending a drop in STI clinic in Oslo. Of 362 male patients who were tested for NGU using microscopy of urethral smears, we found the following sexually transmissible micro-organisms: 16% Chlamydia trachomatis, 5% Mycoplasma genitalium, 14% U. urealyticum, 14% U. parvum and 5% Mycoplasma hominis. We found a high concordance in detecting in turn U. urealyticum and U. parvum using 16s rRNA gene and ureD gene as targets for nucleic acid amplification testing (NAAT). Whilst there was a strong association between microscopic signs of NGU and C. trachomatis infection, association of M. genitalium and U. urealyticum infections in turn were found only in patients with severe NGU (>30 polymorphonuclear leucocytes, PMNL/high powered fields, HPF). U. parvum was found to colonise a high percentage of patients with no or mild signs of NGU (0-9 PMNL/HPF). We conclude that urethral inflammatory response to ureaplasmas is less severe than to C. trachomatis and M. genitalium in most patients and that testing and treatment of ureaplasma-positive patients should only be considered when other STIs have been ruled out.