The association between plasma tryptophan catabolites and depression: The role of symptom profiles and inflammation.

BACKGROUND: Tryptophan catabolites ("TRYCATs") produced by the kynurenine pathway (KP) may play a role in depression pathophysiology. Studies comparing TRYCATs levels in depressed subjects and controls provided mixed findings. We examined the association of TRYCATs levels with 1) the presence of Major Depressive Disorder (MDD), 2) depressive symptom profiles and 3) inflammatory markers. METHODS: The sample from the Netherlands Study of Depression and Anxiety included participants with current (n = 1100) or remitted (n = 753) MDD DSM-IV diagnosis and healthy controls (n = 642). Plasma levels of tryptophan (TRP), kynurenine (KYN), kynurenic acid (KynA), quinolinic acid (QA), C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured. Atypical/energy-related symptom (AES), melancholic symptom (MS) and anxious-distress symptom (ADS) profiles were derived from questionnaires. RESULTS: After adjustment for age, sex, education, smoking status, alcohol consumption and chronic diseases, no significant differences in TRYCATs were found comparing MDD cases versus controls. The MS profile was associated (q < 0.05) with lower KynA (ß = -0.05), while AES was associated with higher KYN (ß = 0.05), QA (ß = 0.06) and TRP (ß = 0.06). Inflammatory markers were associated with higher KYN (CRP ß = 0.12, IL-6 ß = 0.08, TNF ß = 0.10) and QA (CRP ß = 0.21, IL-6 ß = 0.12, TNF ß = 0.18). Significant differences against controls emerged after selecting MDD cases with high (top 30%) CRP (KYN d = 0.20, QA d = 0.33) and high TNF (KYN d = 0.24; QA d = 0.39). CONCLUSIONS: TRYCATs levels were related to specific clinical and biological features, such as atypical symptoms or a proinflammatory status. Modulation of KP may potentially benefit a specific subset of depressed patients. Clinical studies should focus on patients with clear evidence of KP dysregulations.

Bupropion for the treatment of apathy in Huntington's disease: A multicenter, randomised, double-blind, placebo-controlled, prospective crossover trial.

OBJECTIVE: To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS: In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS: At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION: Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION: ClinicalTrials.gov 01914965.

A randomized exploratory phase 2 study in patients with chemotherapy-related peripheral neuropathy evaluating whole-body vibration training as adjunct to an integrated program including massage, passive mobilization and physical exercises.

BACKGROUND: Chemotherapy-induced polyneuropathy (CIPN) is a common toxicity after chemotherapy, immunomodulatory drugs or proteasome inhibitors, which is difficult to treat and may also have impact on quality of life. The objective of the study was to evaluate whole-body vibration (WBV) on the background of an integrated program (IP) including massage, passive mobilization and physical exercises on CIPN. PATIENTS AND METHODS: In an exploratory phase-2 study patients with CIPN (NCI CTC grade 2/3) were randomized for WBV plus IP (experimental) to IP alone (standard). 15 training sessions within 15 weeks were intended. As primary endpoint we used chair-rising test (CRT) to assess physical fitness and coordination. In addition, locomotor and neurological tests and self-assessment tools were performed. RESULTS: A total 131 patients with CIPN were randomized (standard, n = 65; experimental, n = 66). The median age was 60 (range 24-71) years; 44 patients had haematological neoplasms and 87 solid tumors. At baseline, all patients presented with an abnormal CRT. Fifteen (standard) and 22 (experimental) patients left the program due to progression/relapse or concomitant disease. There was no significant difference in the proportion of patients with normal CRT (<10 s) at follow up between experimental (68%) and standard (56%) (p = 0.20). All patients experienced less symptoms and pain (p < 0.001) and had improved CRT (p < 0.001) over time. WBV was significantly associated with a higher reduction of time needed for CRT (p = 0.02) and significantly improved warm-detection-threshold comparing baseline to follow-up assessment (p = 0.02). CONCLUSION: Whole-body vibration on the background of an IP may improve physical fitness and coordination in patients suffering from CIPN. Trial registration Retrospectively registered at http://www.iscrtn.com (ISRCTN 51361937) and http://www.clinicaltrials.gov (NCT02846844).

Patterns of TH1/TH2 cytokines predict clinical response in multiple sclerosis patients treated with glatiramer acetate.

The patterns of Th1/Th2 cytokines in relapsing-remitting multiple sclerosis were analyzed to evaluate their relevance as biomarkers of therapy response to glatiramer acetate (GA). Serum interferon-γ (IFN-γ), osteopontin and interleukin (IL)-2, IL-4, and IL-10 were measured in 19 relapsing-remitting multiple sclerosis patients treated with GA in a prospective study over 3 years. The quotient (IL-2 + IFN-γ)/(IL-4 + IL-10) was elevated in patients with relapses as compared to relapse-free patients after 12 (p = 0.04), 24 (p = 0.02) and 36 months (p = 0.04). Our study indicates that specific patterns of Th1/Th2 cytokines predict the response to GA therapy.

Cerebrospinal fluid biomarkers in Guillain-Barré syndrome--where do we stand?

Guillain-Barré syndrome (GBS) is an acute inflammatory polyneuropathy affecting the myelin-protein sheathing and the axons themselves to various degrees. Damage to these structures causes biomarkers to be released into the adjacent body fluid compartment. In case of the proximal nerve roots these biomarkers diffuse into the cerebrospinal fluid (CSF). Here we review the literature on CSF biomarkers in GBS, including a discussion of CSF basic findings, myelin sheath-associated markers (myelin basic protein), axonal damage markers (neurofilaments, tau, anti-ganglioside antibodies), glial and neuronal markers (neuron specific enolase, 14-3-3 proteins, S100B, hypocretin-1), immunological markers (different chemokines and complement factors, cystatin C, tumor necrosis factor-alpha) as well as recent advances in the field of CSF proteome analysis in GBS. Second, the different pathophysiological mechanisms reflected by these biomarkers are discussed. Finally, candidate biomarkers are reviewed with regard to their clinical relevance to act as a surrogate for the disease process, their value for improving prognostic accuracy and their potential to be used as predictors of treatment response.