Adjunctive canakinumab reduces peripheral inflammation markers and improves positive symptoms in people with schizophrenia and inflammation: A randomized control trial.

BACKGROUND: Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1ß) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1ß monoclonal antibody, interferes with the bioactivity of IL-1ß and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. TRIAL DESIGN: We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. METHODS: Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1ß, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1ß, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. RESULTS: Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. CONCLUSIONS: Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.

Antipsychotic-induced prolactin elevation in premenopausal women with schizophrenia: associations with estrogen, disease severity and cognition.

PURPOSE: Antipsychotic-induced prolactin elevation may impede protective effects of estrogens in women with schizophrenia-spectrum disorders (SSD). Our study sought to confirm whether the use of prolactin-raising antipsychotics is associated with lower estrogen levels, and to investigate how estrogen and prolactin levels relate to symptom severity and cognition in premenopausal women with SSD. METHODS: This cross-sectional study included 79 premenopausal women, divided in three groups of women with SSD treated with prolactin-sparing antipsychotics (n = 21) or prolactin-raising antipsychotics (n = 27), and age-matched women without SSD (n = 31). Circulating 17ß-estradiol was compared among groups. In patients, we assessed the relationship between prolactin and 17ß-estradiol, and the relationships of these hormones to symptom severity and cognition, using correlation analyses and backward regression models. RESULTS: In women receiving prolactin-raising antipsychotics, 17ß-estradiol levels were lower as compared to both other groups (H(2) = 8.34; p = 0.015), and prolactin was inversely correlated with 17ß-estradiol (r=-0.42, p = 0.030). In the prolactin-raising group, 17ß-estradiol correlated positively with verbal fluency (r = 0.52, p = 0.009), and 17ß-estradiol and prolactin together explained 29% of the variation in processing speed (ß17ß-estradiol = 0.24, ßprolactin = -0.45, F(2,25) = 5.98, p = 0.008). In the prolactin-sparing group, 17ß-estradiol correlated negatively with depression/anxiety (r = -0.57, p = 0.014), and together with prolactin explained 26% of the variation in total symptoms (ß17ß-estradiol = -0.41, ßprolactin = 0.32, F(2,18) = 4.44, p = 0.027). CONCLUSIONS: In women with SSD, antipsychotic-induced prolactin elevation was related to lower estrogen levels. Further, estrogens negatively correlated with symptom severity and positively with cognition, whereas prolactin levels correlated negatively with cognition. Our findings stress the clinical importance of maintaining healthy levels of prolactin and estrogens in women with SSD.

The association of prolactin and gonadal hormones with cognition and symptoms in men with schizophrenia spectrum disorder: Divergent effects of testosterone and estrogen.

BACKGROUND: Certain antipsychotics elevate prolactin levels in patients with schizophrenia spectrum disorders (SSD), potentially affecting cognition, symptoms, and hormone levels. This study examines the association between prolactin, testosterone, and estrogen and cognition and symptoms in men with SSD, considering antipsychotic medication. METHODS: This cross-sectional study included 128 men with SSD and 44 healthy men from two trials. Patients were divided into a prolactin-sparing (n = 53) and prolactin-raising group (n = 75) based on antipsychotic medication. We examined the association between hormones (testosterone, estrogen and prolactin), and cognition and symptoms using backward linear regression. Three domains of cognition were assessed including: processing speed, verbal fluency, and working memory, while symptoms were measured using the Positive and Negative Syndrome Scale (PANSS). RESULTS: Prolactin levels were highest in the prolactin-raising group, followed by the control group, and lowest in the prolactin-sparing group (H = 45.279, p < .001). Testosterone and estrogen levels did not differ significantly between groups. In the prolactin-raising group, prolactin negatively correlated with testosterone (r(73) = -0.32, p = .005). Higher testosterone predicted better cognitive functioning (working memory: ß = 0.20, p = .007, verbal fluency: ß = 0.30, p = .001) and lower symptom scores (total: ß = -0.21, p = .001; negative: ß = -0.24, p = .002) in men with SSD. Conversely, higher estrogen levels related to slower processing speed (ß = -0.22, p < .001) and higher symptoms scores (ß = 0.23, p = .010) in men with SSD. CONCLUSION: The results suggest positive associations between testosterone and cognition and symptoms in men with SSD, while suggesting that high prolactin levels could relate to lower testosterone levels, possibly worsening cognition and symptoms in men with SSD.

Toll-Like Receptor mRNA Levels in Schizophrenia: Association With Complement Factors and Cingulate Gyrus Cortical Thinning.

BACKGROUND AND HYPOTHESES: Previous studies revealed innate immune system activation in people with schizophrenia (SZ), potentially mediated by endogenous pathogen recognition receptors, notably Toll-like receptors (TLR). TLRs are activated by pathogenic molecules like bacterial lipopolysaccharides (TLR1 and TLR4), viral RNA (TLR3), or both (TLR8). Furthermore, the complement system, another key component of innate immunity, has previously been linked to SZ. STUDY DESIGN: Peripheral mRNA levels of TLR1, TLR3, TLR4, and TLR8 were compared between SZ and healthy controls (HC). We investigated their relationship with immune activation through complement expression and cortical thickness of the cingulate gyrus, a region susceptible to immunological hits. TLR mRNA levels and peripheral complement receptor mRNA were extracted from 86 SZ and 77 HC white blood cells; structural MRI scans were conducted on a subset. STUDY RESULTS: We found significantly higher TLR4 and TLR8 mRNA levels and lower TLR3 mRNA levels in SZ compared to HC. TLRs and complemental factors were significantly associated in SZ and HC, with the strongest deviations of TLR mRNA levels in the SZ subgroup having elevated complement expression. Cortical thickness of the cingulate gyrus was inversely associated with TLR8 mRNA levels in SZ, and with TLR4 and TLR8 levels in HC. CONCLUSIONS: The study underscores the role of innate immune activation in schizophrenia, indicating a coordinated immune response of TLRs and the complement system. Our results suggest there could be more bacterial influence (based on TLR 4 levels) as opposed to viral influence (based on TLR3 levels) in schizophrenia. Specific TLRs were associated with brain cortical thickness reductions of limbic brain structures.