A randomised clinical trial of methotrexate points to possible efficacy and adaptive immune dysfunction in psychosis.

NMDA autoantibody encephalitis presenting as schizophrenia suggests the possible role of adaptive cell-mediated immunity in idiopathic schizophrenia. However, to our knowledge there have been no trials of the immune-suppressant methotrexate in schizophrenia. We tested if low-dose methotrexate as used in the treatment of systemic autoimmune disorders would be tolerable and effective in people with schizophrenia in a feasibility study. Ninety-two participants within 5 years of schizophrenia diagnosis were recruited from inpatient and outpatient facilities in Karachi, Pakistan. They were randomised to receive once weekly 10-mg oral methotrexate (n = 45) or matching placebo (n = 47) both with daily 5-mg folic acid, in addition to treatment as usual for 12 weeks. There were eight dropouts per group. Side effects were non-significantly more common in those on methotrexate and were not severe. One person developed leukopenia. Positive symptom scores improved more in those receiving methotrexate than placebo (ß = -2.5; [95% CI -4.7 to -0.4]), whereas negative symptoms were unaffected by treatment (ß = -0.39; [95% CI -2.01 to 1.23]). There were no immune biomarkers but methotrexate did not affect group mean leucocyte counts or C-reactive protein. We conclude that further studies are feasible but should be focussed on subgroups identified by advances in neuroimmune profiling. Methotrexate is thought to work in autoimmune disorders by resetting systemic regulatory T-cell control of immune signalling; we show that a similar action in the CNS would account for otherwise puzzling features of the immuno-pathogenesis of schizophrenia.

A comparison of salivary cortisol in chronic fatigue syndrome, community depression and healthy controls.

BACKGROUND: Previous studies reporting cortisol hyposecretion in chronic fatigue syndrome may have been confounded by venepuncture, fasting and hospitalisation. METHODS: Morning and evening salivary cortisol were obtained on consecutive days in the first 3 days of the menstrual cycle and compared in three samples of women taking no medication and matched for age: 14 patients with chronic fatigue syndrome, 26 community cases of ICD-10 current depressive episodes and 131 healthy community controls. RESULTS: The mean evening cortisol was significantly lower in the chronic fatigue syndrome patients compared to controls with depression (P = 0.02) and healthy controls (P = 0.005). Chronic fatigue syndrome patients without psychiatric disorder had significantly lower morning salivary cortisols compared to controls (P = 0.009). CONCLUSION: Chronic fatigue syndrome patients display cortisol hyposecretion in saliva as well as plasma compared to patients with depression and healthy controls. LIMITATIONS: Small samples of female patients with cortisol estimated at only two time points in the day. Cortisol secretion may be secondary to other neurotransmitter abnormalities or other physiological or lifestyle factors in chronic fatigue syndrome patients. CLINICAL RELEVANCE: Chronic fatigue syndrome is biochemically distinct from community depression.