| Background:As a pandemic psychiatric disorder,major depressive disorder(MDD),also known alternatively as depression,is endangering human life quality all around the world.According to data recently published by the World Health Organization(WHO),there are now approximately 355 million people suffering from MDD,which are estimated to be 4.4 % of the global population.According to the severity of the disease,depression can be divided into mild,moderate,and severe depression.At its worst,people with depression may have suicidal thoughts or behaviors.It is conservatively estimated that 100,000 people die from suicide every year.Moreover,there is a worsening trend year after year.Reports from WHO warn that depressive disorders are reckoned as the largest single source of non-fatal health loss(7.5 % of all YLD,Years Lived with Disability).Until now,pharmacotherapy remains the major strategy for most psychiatric disorders including MDD.Within this field,various guidelines for the management of depression unexceptionally recommend the selective serotonin reuptake inhibitors(SSRIs),serotonin noradrenaline reuptake inhibitors(SNRIs),and some other antidepressants as first-line pharmaceutical choices.However,although abundant drugs are ready for use,the efficiency remains unsatisfying,nearly two-thirds of depressive patients did not remit after the initial treatment session.Meanwhile,about one-third of them failed to achieve remission even after four continuous courses of treatment.Besides,slow-start clinical effects which take weeks awaiting treatment response are also challenging the classical therapeutic strategy based on the monoamine hypothesis.To some extent,the current status should be partly attributed to the elusive complexity and heterogeneity of pathogenesis.Despite the conventional monoaminergic mechanisms,researchers postulated innovative hypotheses,e.g.neurotrophic deficiency,neuronal circuit disturbance,hypothalamic-pituitary-adrenal axis malfunction,and proinflammatory cytokine overload.Since the introduction of the cytokine hypothesis,decades passed and emerging studies on account of this theory have attracted great attention.As several meta-analyses indicated,excessive cytokines,such as interleukin-1?,-6(IL-1?,IL-6),tumor necrosis factor-?(TNF-?)and interferon-?(IFN-?),were detected in peripheral blood samples of MDD patients when compared with healthy controls.Moreover,alterations of inflammation associated biomarkers like C-reactive protein(CRP)during antidepressant applications were found to correlate with the treatment response.In a clinical trial,although Raison et al.failed to acquire an overall efficacy of TNF-? antagonist infliximab in treatment-resistant depression,they discovered that patients with relatively high baseline inflammations responded better to infliximab treatment.Therefore the promoted clinical effect,probably controversial,is related to the inflammatory status,considering CRP was detected elevated in patients with MDD,especially treatment-resistant ones.Furthermore,Felger and colleagues found that plasma CRP was strongly correlated with cerebrospinal fluid CRP,and also pointed out reliable correlations between CRP and several inflammatory biomarkers,both peripherally and centrally.In line with the evidence,baseline inflammation(primarily determined by CRP)was proposed as a feasible marker to inform antidepressant therapy.According to our preclinical findings,NLRP3 inflammasome,which cleaves pro-IL-1? into its active form,is involved in the pathogenesis of depressive-like behaviors in mice via its effect on modulating systemic inflammation.In-depth studies on the priming and upstream regulation of inflammasome confirmed that alarmins(DAMPs)could initiate a widespread immune response,thereby resulted in overwhelming chronic mild inflammation.High mobility group box 1(HMGB1)is a special alarmins protein discovered decades ago,known for its late-phase and long-lasting effect on priming and amplifying neuroinflammation.Concerned with the complexity and interconnection of the inflammatory network,Weber et al.considered damaged cells would release HMGB1 to prime NLRP3 inflammasome in responding to stressors.In consistence with this viewpoint,we provided conclusive evidence suggesting disulfide-HMGB1 induced rodent depressive behavior by facilitating secretions of proinflammatory cytokines including TNF-?.In a later study,we demonstrated Glycyrrhizic acid(glycyrrhizin,GZA),a natural herbal extract and direct inhibitor of HMGB1,might have a promising prospect in ameliorating depression.Of note,GZA is commonly used to treat patients with chronic hepatitis,also widely accepted as a well-tolerable and effective suppressor of inflammation and a protective agent for liver cell injury.Collectively,there is a growing body of pharmacotherapy choices primarily based upon the classical monoaminergic imbalance theory.It is undeniable that these medications greatly relieve clinical symptoms,even if accompanied by an unpredictable and unstable process.To date,the most appropriate antidepressant therapy for each patient is largely determined by a trial-and-error strategy,which means to postpone remission,prolong suffering,decrease compliance,facilitate adverse effect,and also increase the economic burden.Besides,the aforementioned slow-start clinical effect and unsatisfactory response rate are calling for an urgent need of integrating various hypotheses to yield preferable therapeutic effects.Along with that,we still lack acceptable low-cost and easy-detected biomarker to either assist diagnosis or inform prognosis,or even help with the customization of antidepressants.In short,based on the research on the inflammatory mechanism of depression,we hope to upgrade the current strategy for the diagnosis and treatment of depression.In detail,we suggest determining the inflammatory status at the first visit of each patient.As to those with high levels of proinflammatory cytokines,we recommend them to receive(adjunctive)anti-inflammatory therapy,which helps make better solutions of the issues including slow onset,low response rate and high recurrence rate regarding treatment-resistant depression,especially those involved with high inflammation.In line with that,we designed this clinical trial,recruited 56 patients and treated them with routine SSRIs plus placebo or SSRIs combining glycyrrhizic acid.Contents:1.Glycyrrhizic acid improves depressive symptomsThe Hamilton Depression Scale was assessed at the time of enrollment,the first weekend,the second weekend,and the fourth weekend.At each checkpoint,the difference in the degree of symptomatic improvement between the two groups was observed and evaluated.2.Glycyrrhizic acid improves cognitive function in patients with depressionThe Montreal Cognitive Assessment Scale was assessed at the time of enrollment,the first weekend,the second weekend,and the fourth weekend to identify changes in cognitive function and their relationship with the improvement of the depressive symptom.3.Glycyrrhizic acid improves sleep symptoms in patients with depressionThe Pittsburgh Sleep Quality Index was evaluated at the time of enrollment,the second weekend,and the fourth weekend to determine the changes of the patients' sleep qualities and their relationship with the improvement in depressive symptoms.4.Relationship between depression,cognitive function,and sleep disordersAccording to the above results,the relationships between depressive symptoms,cognitive functions,and sleep qualities were analyzed to explore how glycyrrhizic acid exerted its therapeutic effects.5.Effect of glycyrrhizin on serum biomarkers in patients with depressionSeveral inflammatory factors(CRP,TNF-?,IL-1?,IL-6,IFN-?,etc.)and glucocorticoid levels were measured at the time of enrollment,the second weekend,and the fourth weekend.6.Clinical safety and side effects of glycyrrhizic acid against depressionThe Side Effect Rating Scale(SERS)was evaluated at the time of enrollment,the first weekend,the second weekend,and the fourth weekend to confirm the clinical safety and side effects of glycyrrhizic acid.Results:1.Glycyrrhizic acid improved depressive symptoms1.1 Baseline sociodemographic and clinical featuresThere were no statistical differences in gender,marital status,only-child status,smoking history,age,educational experience,BMI,waist circumference and HAMD scale.It suggested that the two groups of patients are comparable in subsequent clinical trials.1.2 Comparison of cumulative reductions of HAMD scores from baseline between the two groupsCovariance analysis was performed on the cumulative reductions of HAMD scores of the two groups(baseline scores were defined as covariates).The results showed that the cumulative reductions of HAMD scores in the SSRI+GZA group were higher than those in the SSRI+PBO group on the second weekend and the fourth weekend.1.3 Comparison of treatment efficiency and response rate at different time points between the two groupsSimilar to the results of reductions of HAMD scores,at the fourth weekend,the patients treated with SSRI+GZA had higher rates of response(66.7 %)and remission(46.7 %)when comparing with the SSRI+PBO group.2.Glycyrrhizin improved cognitive function in patients with depressionCovariance analysis was performed on cumulative increases of MoCA scores of the two groups(baseline scores were defined as covariates).The results showed that SSRI+GZA group had better improvement of MoCA scores than SSRI+PBO group at the observation points of the second and fourth week.3.Glycyrrhizin ameliorated sleep disorders in patients with depressionCovariance analysis was performed on the cumulative reductions of PSQI scores of the two groups(baseline scores were defined as covariates).The results indicated that,at the time points of the second and fourth week,SSRI+GZA group got more cumulative reductions of PSQI scores than that of SSRI+PBO group.4 Relationship between depression,cognition,and sleepAt baseline,the second weekend,and the fourth weekend,a positive relationship was found between the total score of HAMD and the total score of PSQI,whereas a negative relationship was detected between the total score of HAMD and the total score of MoCA.Meanwhile,the total score of MoCA negatively correlated with the total score of PSQI at the aforementioned time points.5 Effect of glycyrrhizin on serum biomarkers in patients with depression5.1 Comparison of CRP between the two groups at different time pointsFor the convenience of subsequent analysis,the CRP concentrations were logarithmically transformed.Results regarding variance analysis of continuous measurements suggested no significant difference between groups.However,there existed an overall conspicuous effect of time,suggesting lg CRP decreased across continuous weeks.In spite of the fact that both effects of time and treatment assignment were found regarding serum IL-1?,we failed to draw similar conclusions in the Bonferroni's multiple comparisons test of each week.5.2 Comparison of cumulative reduction values of serum biological indicators at different time points between the two groupsCovariance analysis was performed on the cumulative reduction of serum biological indicators.The results showed that at the end of the fourth week,the cumulative reductions of TNF-? and IL-1? in the SSRI+GZA group were higher than those in the SSRI+PBO group.This indicates that the overall inflammatory state of the SSRI+GZA group will be more improved.More importantly,differences in serum biomarkers were consistent with changes in the HAMD scores.5.3 Exploratory analysisTo explore the potential interaction between GZA treatment,inflammation,and antidepressant efficacy,we further carried out a mediational analysis.Results showed that TNF-? reduction partially mediates the association between GZA treatment and HAMD score reduction.5.4 Retrospective efficacy analysis by CRP levelConsidering that combined anti-inflammatory treatment can produce a better anti-depression effect,and CRP is a good indicator of the recent inflammation level of the body,the above-mentioned patients were divided into high-and low-inflammatory subgroups according to CRP levels.A retrospective analysis was performed at 3 mg/L.Covariance analysis was performed on HAMD cumulative scores at various time points.The results suggest that there is no statistically significant difference in the effects of SSRI+PBO and SSRI+GZA in patients with low-inflammation;in patients with hyperinflammation,the cumulative scores for HAMD in the SSRI+GZA group at the second and fourth weekends Both were significantly higher than the SSRI+PBO group,suggesting that anti-inflammatory treatment in patients with hyperinflammation can produce better results.6 Clinical safety of glycyrrhizic acid in the treatment of depressionFrequencies of adverse events were comparable across the treatment groups.No patient in either group experienced severe adverse events,nor was there a participant discontinued the trial owing to drug adverse events.Conclusions:In conclusion,based on the cytokines hypothesis of the pathophysiology of depression,we performed a clinical trial to evaluate the potential clinical effects of combined antidepressant therapy.Present results demonstrate that compared with placebo,adjunctive GZA leads to impressively greater symptomatic improvement and better treatment response in depressive patients.The mediation analysis indicates that TNF-? reduction partially mediated the association between GZA treatment and the decrease in HAMD scores.Furthermore,we propose to categorize patients according to their inflammatory state by detecting serum concentrations of CRP.Generally,high levels of serum CRP(> 3 mg/L)inform combined antidepressant therapy with anti-inflammatory agents like GZA.This study does shed light on a novel strategy for the diagnosis,categorization,individualization,and prognosis regarding antidepressant therapy. |
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