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Background There is growing evidence for complement system involvement in the pathophysiology of schizophrenia, although the extent and magnitude of complement factor disturbances has not been fully reported. It also remains unclear whether complement abnormalities are characteristic of all patients with schizophrenia or whether they are representative of a subgroup of patients who show signs of heightened inflammation. The aim of the present study was to quantify and compare the levels of a range of complement factors, receptors and regulators in healthy controls and people with schizophrenia and to determine the extent to which the levels of these peripheral molecules relate to measures of brain structure, particularly cortical thickness. Method Seventy-five healthy controls and 90 patients with schizophrenia or schizoaffective disorder were included in the study. Peripheral blood samples were collected from all participants and mRNA expression was quantified in 20 complement related genes, four complement proteins, as well as for four cytokines. T1-weighted structural MRI scans were acquired and analysed to determine cortical thickness measures. Results There were significant increases in peripheral mRNA encoding receptors (C5ar1, CR1, CR3a), regulators (CD55, C59) and protein concentrations (C3, C3b, C4) in people with schizophrenia relative to healthy controls. C4a expression was significantly increased in a subgroup of patients displaying elevated peripheral cytokine levels. A higher inflammation index score derived from mRNA expression patterns predicted reductions in cortical thickness in the temporal lobe (superior temporal gyrus, transverse temporal gyrus, fusiform gyrus, insula) in patients with schizophrenia and healthy controls. Conclusions Analysis of all three major complement pathways supports increased complement activity in schizophrenia and also shows for the first time that peripheral C4a up-regulation is related to increased peripheral pro-inflammatory cytokines in schizophrenia. Our region-specific, neuroimaging findings linked to an increased peripheral complement mRNA expression pattern suggests a role for complement in cortical thinning. Further studies are required to further clarify clinical and neurobiological consequences of aberrant complement levels in schizophrenia and related psychoses.

While high levels of glucocorticoids are generally neuro-damaging, a related adrenal steroid, dehydroepiandrosterone (DHEA), has anti-glucocorticoid and neuroprotective properties. Previous work has shown increased circulating levels of DHEA and abnormal cortisol/DHEA ratios in people with schizophrenia, however reports are limited and their relationship to neuropathology is unclear. We performed the largest study to date to compare levels of serum DHEA and cortisol/DHEA ratios in people with schizophrenia and healthy controls, and investigated the extent to which cortisol/DHEA ratios predict brain volume. Serum cortisol and DHEA were assayed in 94 people with schizophrenia and 81 healthy controls. T1-weighted high-resolution anatomical scans were obtained using a 3 T Achieva scanner on a subset of 59 people with schizophrenia and 60 healthy controls. Imaging data were preprocessed and analyzed using SPM12. People with schizophrenia had significantly increased serum DHEA levels (p = 0.002), decreased cortisol/DHEA ratios (p = 0.02) and no difference in cortisol levels compared to healthy controls. Cortisol/DHEA ratios were inversely correlated with hippocampal (r = -0.33 p = 0.01) and dorsolateral prefrontal cortex (r = -0.30, p = 0.02) volumes in patients. Our findings suggest that the cortisol/DHEA ratio may be a molecular blood signature of hippocampal and cortical damage. These results further implicate the role of DHEA and hypothalamic-pituitary-adrenal axis dysfunction in the pathophysiology of schizophrenia.

Lower testosterone levels are associated with greater negative symptoms in men with schizophrenia. Testosterone signals via androgen receptor (AR). A functional variant in the AR gene (CAG trinucleotide repeat polymorphism) is associated with circulating testosterone and mood-related symptoms in healthy people. Raloxifene increases testosterone in healthy males and reduces symptom severity and improves cognition in schizophrenia; however, whether raloxifene increases testosterone in men with schizophrenia is unknown. We assessed the interaction of a functional AR gene variant and adjunctive raloxifene on peripheral testosterone and symptom severity in schizophrenia. Patients with schizophrenia (59 males and 38 females) participated in a randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene (120 mg/day). Healthy adults (46 males and 41 females) were used for baseline comparison. Baseline circulating testosterone was decreased in male patients compared to male controls and positively correlated with CAG repeat length in male controls and female patients. Male patients with short, compared to long, CAG repeat length had higher stress scores. Raloxifene treatment increased testosterone in male patients, but was unrelated to AR CAG repeat length, suggesting that raloxifene’s effects may not depend on AR activity. Sex-specific alterations of the relationship between AR CAG repeat length and testosterone suggest that altered AR activity may impact perceived stress in men with schizophrenia.

Growing evidence suggests that testosterone may play a role in the pathophysiology of schizophrenia given that testosterone has been linked to cognition and negative symptoms in schizophrenia. Here, we determine the extent to which serum testosterone levels are related to neural activity in affective processing circuitry in men with schizophrenia. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as 32 healthy controls and 26 people with schizophrenia performed a facial emotion identification task. Whole brain analyses were performed to determine regions of differential activity between groups during processing of angry versus non-threatening faces. A follow-up ROI analysis using a regression model in a subset of 16 healthy men and 16 men with schizophrenia was used to determine the extent to which serum testosterone levels were related to neural activity. Healthy controls displayed significantly greater activation than people with schizophrenia in the left inferior frontal gyrus (IFG). There was no significant difference in circulating testosterone levels between healthy men and men with schizophrenia. Regression analyses between activation in the IFG and circulating testosterone levels revealed a significant positive correlation in men with schizophrenia (r=.63, p=.01) and no significant relationship in healthy men. This study provides the first evidence that circulating serum testosterone levels are related to IFG activation during emotion face processing in men with schizophrenia but not in healthy men, which suggests that testosterone levels modulate neural processes relevant to facial emotion processing that may interfere with social functioning in men with schizophrenia.

Older adults who experience loneliness have an increased risk of all-cause mortality and morbidity [1], and among the biological mechanisms implicated, increases in inflammation might contribute. In older adults reporting high levels of loneliness and/or psychological stress, nuclear factor (NF)-κB shows increased activity [2]. NF-κB is a transcription factor that may be an important mediator for the translation of social stress into inflammation [3] as NF-κB controls the expression of genes that code for multiple inflammatory cytokines [4], and stress activation of the sympathetic nervous system stimulates NF-κB [3]. A meditation technique, Tai Chi Chih (TCC), is thought to act on stress response pathways [5] that may be sensitized in lonely individuals due to hypervigilance for social threat and feelings of vulnerability. TCC is a multidimensional behavioral therapy that integrates moderate physical activity, deep breathing and meditation to promote regulation of emotional and affective responses to stress, with downregulation of sympathetic nervous system outflow [6]. Findings show that TCC and other meditation forms also reduce markers of inflammation [6, 7] and the expression of genes bearing NF-κB response elements [8]. However, the effect of TCC on levels of the NF-κB transcription factor has not been examined. Given evidence that chronic stress leads to a progressive rise in inflammation in older adults [9], and that both stress and increased expression of genes bearing NF-κB response elements are associated with loneliness, we hypothesized that TCC would reduce stress and slow the rate of increase in NF-κB levels in lonely older adults, as compared to those who receive a stress and health education (SHE) intervention. Twenty-six older adults (≥ 60 years), naive to Tai Chi, who scored ≥ 40 on the UCLA Loneliness Scale, participated in this study approved by the UCLA Institutional Review Board (NCT01204021). Excluded were those with current psychotherapy, behavioral therapy and/or use of antidepressants, current DSM-IV (SCID-IV) psychiatric disorder, body mass index >33, cognitive impairment (Mini-Mental State Examination 3 standard deviations from the mean were dropped from analysis. One subject refused blood sampling and all NF-κB values were missing for this single case. The TCC intervention consisted of 20 guided meditative movements under the instruction of a certified teacher as previously detailed [11]. SHE controlled for nonspecific treatment effects of time, attention, expectancy and group support, similar to prior protocols [11]. The session format was didactic, with guest presenters lecturing on health (e.g. stress, aging, exercise and nutrition). Intention-to-treat analyses were performed in SPSS version 20 (IBM Corp., Armonk, N.Y., USA). Changes in PSS and levels of NF-κB from pre- to postintervention time points were tested using linear mixed modeling, adjusted for pre-intervention levels. Twenty-six enrollees were evenly randomized to treatment and provided pre-intervention data, 22 (85%) completed the postintervention visit (10 in TCC and 12 in SHE). The two treatment groups showed similar demographic and clinical characteristics (table 1). Psychological stress as indexed by the PSS significantly differed between the two groups after intervention [F(1, 23.92) = 4.49, p = 0.04] covarying for pre-intervention levels. From pre- to postintervention visits, decreases in PSS were observed in the TCC group (p < 0.01) but not in the SHE control (p = 0.75; fig. 1 a). NF-κB significantly differed between the two groups after intervention [F(1, 106.79) = 5.24, p = 0.02] covarying for pre-intervention levels. From pre- to postintervention visits, increases in NF-κB levels were observed in the SHE group (p < 0.05), but not in the TCC group (p = 0.34; fig. 1 b). The pre- to postintervention changes in PSS levels were correlated with changes in NF-κB levels (Spearman's r = 0.46, p = 0.05, n = 19, fig. 2). Fig. 1 a Estimated PSS levels (±SE), covarying for pre-intervention PSS score. b Estimated NF-κB activation (±SE), covarying for pre-intervention NF-κB; * p < 0.05 for difference between groups. Fig. 2 Correlation between changes from pre- to postintervention visits in PSS and NF-κB activation for the participants in the TCC and SHE control groups, Spearman's r = 0.46, p = 0.05, n = 19. Table 1 Pre-intervention characteristics of the lonely older adult sample Our findings show that among lonely older adults who received a health education control, levels of psychological stress persisted, and these elderly showed significant increases in nuclear levels of activated NF-κB from pre- to postintervention time points. Conversely, among lonely older adults who received TCC, psychological stress decreased, while NF-κB levels remained constant. Further, change in psychological stress was correlated with change in NF-κB activation from pre- to postintervention examinations, which together suggests that treatment-induced reduction in stress may attenuate increases in NF-κB activation. Previous work indicates that chronic stress in older adults is associated with an accelerated rate of increase in inflammatory markers such as interleukin-6 [9]. Lonely adults show elevated psychological stress scores as well as physiological indicators of stress, and they have been conceptualized as a chronically stressed population [12]. Ours is the first study to show that TCC has the capacity to alter stress levels in lonely older adults and to attenuate the rate of increase in a key transcription factor, NF-κB, involved in the upstream inflammatory cascade. Limitations of this study include its small sample size and the predominance of women, which limit the generalizability of our results; hence, these findings require future replication. A larger sample would enable more appropriate tests of whether changes in stress mediate the changes in NF-κB. History of loneliness was not assessed, so the chronic nature of stress in the sample was unknown. Future studies should account for a previous history of loneliness. Levels of NF-κB were only measured in peripheral blood mononuclear cells, and it is possible that the changes in NF-κB reported here are due to changes in lymphocyte subset distribution. However, such changes in immune cell trafficking occur primarily in the context of acute stress manipulation, and chronic stress has not been associated with changes in immune cell numbers. The meditation intervention TCC significantly reduced psychological stress and attenuated the rise of NF-κB activation that is otherwise found in lonely older adults.

This study examined differences between Asians and non-Hispanic Whites (Whites) in pain sensitivity, and its relationship to mean arterial pressure (MAP) and heart rate (HR). In 30 Whites (50% female) and 30 Asians (50% female), experimental pain sensitivity was assessed with a hand cold pressor task, yielding measures of pain threshold, tolerance, intensity, and unpleasantness. Mean arterial pressure and HR measurements taken at rest and in response to speech stress were assessed. Perceived stress, anxiety, perfectionism, parental criticism, parental expectations and depressive symptoms were also measured. The results indicated that for the cold pain test, Asians demonstrated significantly lower pain threshold and tolerance levels than Whites. Although no ethnic differences were seen for MAP or HR responses to stress, for Whites higher stress MAP levels were correlated with reduced pain sensitivity, while for Asians higher baseline and stress HR levels were correlated with reduced pain sensitivity. Asians reported higher parental expectations and greater parental criticism than Whites. For Asians only, higher levels of perfectionism were related to more depressive symptoms, anxiety and perceived stress. These results indicate that Asian Americans are more sensitive to experimental pain than Whites and suggest ethnic differences in endogenous pain regulatory mechanisms (e.g. MAP and HR). The results may also have implications for understanding ethnic differences in clinical pain.