The Noradrenaline Metabolite MHPG Is a Candidate Biomarker from the Manic to the Remission State in Bipolar Disorder I: A Clinical Naturalistic Study

Abstract

Remission is the primary goal of treatment for bipolar disorder I (BDI). Metabolites of noradrenaline and dopamine, 3-methoxy-4-hydroxyphenylglycol (MHPG) and homovanillic acid (HVA), respectively, are reduced by treatment with antipsychotics, but whether these phenomena are caused by antipsychotics or by the pathophysiology of BDI is not known. Interactions between brain-derived neurotrophic factor (BDNF) and mood disorders have also been suggested. We conducted a multifaceted study in BDI patients to ascertain if biological markers are associated with the manic state. Patients with Young Mania Rating Scale (YMRS) scores >20 participated in the study. Final analyses involved 24 BDI patients (13 men and 11 women). We used YMRS scores to identify mania stages in individual BDI patients (i.e., manic syndrome, response and remission stages). Statistical analyses were done using one-way repeated-measures analyses of variance (rep-ANOVA) throughout manic syndrome, response and remission stages. Plasma concentrations of MHPG and HVA were analyzed by high-performance liquid chromatography with electrochemical detection. Plasma levels of BDNF were measured by sandwich enzyme-linked immunosorbent assay. BDI patients had significantly reduced plasma levels of MHPG throughout manic syndrome, response and remission stages (rep-ANOVA, p = 0.002). Without a case of response state, there was a significant positive correlation between YMRS scores and plasma levels of MHPG (ρ = 0.33, p = 0.033, n = 48). Plasma levels of HVA and BDNF were not significantly altered throughout manic syndrome, response and remission stages. These data suggest that the peripheral level of MHPG (which is associated with noradrenaline levels in the brain) could be used as a biomarker for the manic state in BDI. The MHPG level is likely to reflect the clinical characteristics of the manic syndrome in BDI, and noradrenaline may reflect the pathophysiology from manic to remission states.

Peripheral blood brain-derived neurotrophic factor in bipolar disorder: a comprehensive systematic review and meta-analysis

“…Thirtyfive studies, comprising a total of 2238 bipolar disorder patients and 1560 healthy control subjects, were eligible for review and included in the meta-analysis with a minimum of one pair-wise comparison each. [11][12][13][19][20][21]26, Exclusion of full 63 text articles and reports were based on (a) data on BDNF levels were unavailable, [66][67][68] (b) patients not suffering from bipolar disorder, [69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84] (c) the study not evaluating peripheral BDNF levels, (d) the study being a review or a comment, [107][108][109][110][111][112][113][114][115][116][117][118][119] (e) the study not comparing states or comparing bipolar patients with healthy control subjects [120][121][122] and/or (f) the study investigated treatment of experimental nature 123,124 and (g) the study presenting duplicate data presented in an included article. …”

“…11,13,19,20,26,[38][39][40][41][42] Ten studies provided data for comparisons between affective states in bipolar disorder patients, 12,19,20,26,38,41,42,46,48,65 of which two studies 12,26 included within-subject comparisons between a manic and euthymic state and one study 26 included withinsubjects comparisons between a depressed and euthymic state and a depressed and manic state (Supplementary Table 2-4S). Seven studies investigated changes in BDNF levels before and after treatment of an acute affective episode, 12,21,43,46,47,57,64 with follow-up periods ranging from 4 to 52 weeks. In five studies the intervention included a combination or different medication types (lithium, antipsychotics and anticonvulsants), 12,46,47,57,64 one study investigated BDNF changes before and after lithium treatment 43 and one study investigated changes before and after valproate treatment 21 (Supplementary Table 5-6S).…”

“…Seven studies investigated changes in BDNF levels before and after treatment of an acute affective episode, 12,21,43,46,47,57,64 with follow-up periods ranging from 4 to 52 weeks. In five studies the intervention included a combination or different medication types (lithium, antipsychotics and anticonvulsants), 12,46,47,57,64 one study investigated BDNF changes before and after lithium treatment 43 and one study investigated changes before and after valproate treatment 21 (Supplementary Table 5-6S). Of the included studies, 33 were published as peer-reviewed articles, while two were available as conference abstracts only.…”

“…41,42,44,45,48,49,64 Fifteen studies investigated plasma BDNF levels and twenty studies investigated serum BDNF levels. Ten studies reported the time of day blood samples were obtained, 12,19,21,26,39,45,52,53,56,61 ranging from 0800 to 1700 h. Six studies reported obtaining blood samples in a fasting state, 21,26,53,56,61,62 with the remaining studies providing no information regarding fasting state. Blinding of laboratory staff to the clinical state of participants was reported in eight studies.…”

“…[7][8][9] Early investigations reported low peripheral blood BDNF levels in manic and depressed patients with bipolar disorder and suggested that levels normalized after treatment of an acute illness episode. 10 Later findings from individual case-control studies and cohort studies of BDNF in bipolar disorder show large variation and are based on studies with generally small sample sizes, [11][12][13] likely lacking statistical power. In such cases metaanalysis provides a way of investigating the body of evidence, applying a systematic and rigorous analytic approach in analysis of the overall association, combining results from individual studies in potentially increasing power to detect true effects.…”