Prediction Of Early Antidepressant Treatment Response In First Episode Major Depressive Disorder

BackgroundMajor depressive disorder（MDD）is a mental illness that has a significant impact on human health and quality of life worldwide.Currently,about 350 million people worldwide suffer from MDD,which is one of leading causes of years lived with disability（YLDs）.MDD is mainly characterized by low interest,lack of pleasure,decreased energy,sleep disorders,impaired cognitive function,and even suicidal intentions and behaviors.In the clinical practice,the diagnosis of MDD is mainly based on the cluster of symptoms with high heterogeneity across different patients with MDD.The heterogeneity of these symptoms leads to a low homogeneity of the samples recruited in clinical studies,thereby weakening the validity and sensitivity of genetic and imaging studies.At present,the treatment of MDD is mainly based on 2^nd generation antidepressants,such as selective serotonin reuptake inhibitor（SSRI）,serotonin-norepinephrine reuptake inhibitors（SNRI）and adrenalin and specific serotonergic antidepressants（NaSSA）,supplemented by psychotherapy（e.g.,behavioral cognitive therapy,balanced psychotherapy）,physical therapy（e.g.,repetitive transcranial magnetic stimulation,modified electroconvulsive therapy）,as well as the Chinese traditional medicine.It is worth noting that in the current clinical practice,whether it is single drug therapy or combination therapy of drug and psychotherapy or physical therapy,the overall effective rate is still less than 50%,and nearly half of MDD patients are suffer chronic disease course or become treatment refractory depression.Based on the current“monoamine hypothesis”,antidepressants take about 2-4 weeks after be prescribed to regulate neurotransmitter release and reuptake,including serotonin/5-hydroxyptamine（5-HT）and norepinephrine.The Antidepressants can keep a a preliminary balance in the peripheral and central synaptic clefts,resulting in an antidepressant effect.However,this viewpoint is based on the average onset time of the MDD population study.In fact,some patients in clinical practice have more obvious symptoms improvement in the first week of treatment,such as sleep disorders and lack of energy.Meanwhile,there are still quite a few patients who have not shown obvious symptoms improvement even after using antidepressants for more than 6 weeks.Therefore,guiding the clinical use of drugs through the average onset time in previous clinical studies is clearly not conducive to the individualized treatment of MDD patients.Especially in the current framework of precision medicine,the individual characteristics of MDD patients should be considered comprehensively,including age,gender,duration of disease,genetic characteristics,and brain imaging features.The patient’s condition should be integrated before or during the initial treatment.Evaluate and make a more optimal treatment strategy based on personalized therapy.This aspect will help reduce the patient’s disease suffering and suicide risk,and on the other hand,it will help to consolidate the reciprocal trust between physicians and patients,improve patient compliance,and reduce medical resources waste.The existing research evidence indicates that the structural and functional changes of critical brain’s regions or networks are deeply involved in regulating the occurrence and development of MDD,including the emergence and aggravation of symptoms,and the improvement during the treatment.The networks with extensive research are default mode network（DMN）and reward network.The DMN comprising the medial prefrontal cortex,posterior cingulate gyrus,precuneus,hippocampus,and cerebellum,which plays important role in the maladaptive rumination process in the neuropathology of MDD,and deeply participates in the regulation of negative reappraisal bias and the preservation and extraction of negative memory in daily life events.The reward network mainly including the nucleus accumbens and prefrontal cortex,which implicated in the negative evaluation of positive life events,leading to the appearance of anhedonia.During the treatment of antidepressant,the functional regulation of the above structures is particularly important for the patient’s emotional and cognitive resilience,thus existing that patients with different network characteristics exhibit different therapeutic responses to the antidepressant.In addition,as a type of complex disorder,MDD has a relatively low heritability of about 30-40%.Its onset and outcome are not regulated by one or several genes,but may be co-regulated by dozens,and even hundreds of minor genes.However,the current genome-wide association study（GWAS）has included 500,000 to 2 million single nucleotide polymorphisms（SNPs）sites for screening analysis,thus requiring a larger sample size,and it is easier to screen out those minor genes during further false positive corrections because of the need for tighter thresholds.Therefore,for MDD,a low-genetic complex disease,the use of hypothesis-based genetic pathway studies may be more efficient and sensitive.In the process of MDD occurrence and outcome,the most important thing is the 5-HT system,which not only directly regulates the emotional regulation process,but also indirectly affects other neurotransmitter systems,such as the dopaminergic system,the gamma-aminobutyric acid system,and the function of the glutamatergic system.It is generally believed that one of the most important genetic factors affecting the function of the 5-HT system is the multiple genes of the 5-HT pathway,such as the 5-HT receptor gene,the serotonin transporter gene,the tryptophan hydroxylase gene,etc.These genes are deeply involved in the regulation of the synthesis,release,transport and reuptake of 5-HT.These genes are widely expressed in key brain regions of mood regulation,mainly distributed in the aforementioned DMN and the reward circuit regions.Therefore,in the process of evaluating and predicting the efficacy of antidepressant therapy and early optimization of the treatment strategy,if we can adopt the hypothesis-driven method and the pointcut of imaging intermediate phenotype,focusing on certain characteristic phenotype（such as curative effect）or symptom cluster（such as a lack of pleasure）,taking into account genetic and neuroimaging indicators,will help to more comprehensive understand the important factors in the treatment of MDD.This will provide a more practical and operational assessment framework for individualized antidepressant treatment in clinical practice in the future.Therefore,this study will adopt a step-by-step approach to study the following three aspects:1)From the level of local functional changes in brain regions of MDD,including voxel-mirrored homotopic connectivity（VMHC）,time variability,amplitude of low-frequency fluctuation（ALFF）,and cerebral blood flow（CBF）.Preliminary investigate the functional changes in the above-mentioned local regions and the potential relevance with the early treatment efficacy of antidepressants,and the power of early efficacy prediction.Furthermore,we try to combine bimodal indicators for analysis to understand whether there is a synchronous change in cerebral blood flow and local brain activity,and the impact of these changes on early efficacy.And we also attempt to employ machine learning technology to incorporate bimodal comprehensive indicators to the classification and prediction of early efficacy;2)From the level of brain network,we aim to further explore the difference of the topological attribute of the DMN and the functional connection of the reward network between the RD and the NRD group,and to examine the potential impact and predictive value of this difference on the early antidepressants efficacy;3)Finally,the imaging genetics（IGs）analysis strategy will be utilized to comprehensively analyze the data on multi-locus genes in the 5-HT pathway multiple sites.The interaction of genetic polymorphisms and changes in regional CBF on the early efficacy in MDD patients.The above three aspects（six parts）of study will be comprehensively explored the imaging genetic indicators that can be applied for early efficacy prediction in the treatment of antidepressants,from the point to the face,from the local region to the whole network,from the point of pre-treatment to after medication.Part 1 Early efficacy prediction of antidepressants based on local-level brain functional characteristics at baselineChapter 1 Prognostic value of imbalanced interhemispheric functional coordination in early therapeutic efficacy in major depressive disorderObjective:This study aims to explore the early response of antidepressant therapy by measuring the voxel-mirrored homotopic connectivity（VMHC）in major depressive disorder（MDD）.Methods:Eighty-two MDD patients[n=42 treatment-responsive depression（RD）and n=40non-responding depression（NRD）]and N=50 normal controls（NC）underwent clinical measures and a magnetic resonance imaging scan,and the VMHC values were calculated.Receiver operating characteristic（ROC）curve analysis was applied to determine the capability of altered VMHC to distinguish the NRD group.Results:The NRD group showed significantly decreased VMHC in the bilateral precuneus（PCU）and inferior temporal gyrus（ITG）,and increased VMHC in middle frontal gyrus（MFG）and caudate nucleus as compared to the RD group.When compared with the NC group,the NRD group exhibited reduced VMHC in the bilateral cerebellum anterior lobe,thalamus and postcentral gyrus.Moreover,the VHMC in the medial frontal gyrus,postcentral gyrus and precentral gyrus were significantly decreased in the RD group.Correlation analysis showed that reduced VMHC in PCU was negatively correlated with the baseline Hamilton depression rating scale（HAMD）score of the NRD group.The ROC curve indicated that the combined changes of the three regional VMHC（PCU,ITG and MFG）could effectively identify depressed patients with poor treatment response.Conclusion:The current study suggests that decreased interhemispheric connectivity represents a novel neural trait underlying the prediction of the early therapeutic outcome of MDD.Chapter 2 Increased temporal variability of striatum region facilitating the early antidepressant response in patients with major depressive disorderObjective: The aim of this study is to identify the difference of temporal variability among MDD patients（with different early antidepressant responses）and HC,and further explore the relationship between pre-treatment temporal variability and early antidepressant response.Methods: At baseline,77 treatment-naive inpatients with MDD and 42 matched HC received clinical assessments and 3.0 Tesla resting-state functional magnetic resonance imaging scans.After 2 weeks of antidepressant treatment,the patients were subgrouped into the RD（n = 40）and the NRD（n = 37）group based on the reduction of HAMD.The temporal variability of 90 brain nodes was calculated for further analysis.Results: Compared with the HC group,both the RD and NRD subjects showed greater baseline temporal variability（i.e.,greater dynamic）in the left inferior occipital gyrus.Significantly greater temporal variability in the left pallidum was found in the RD group than the NRD and the HC groups,and the higher variability of left pallidum correlated positively with the HAMD reduction at week 2.Moreover,the pooled MDD（i.e.,RD and NRD）group showed greater baseline temporal variability in the right inferior frontal gyrus,the left inferior occipital gyrus,the bilateral fusiform gyri and the left Heschl gyrus than the HC group.Conclusion: The distinctive pattern of dynamically reorganized networks may provide a crucial scaffold to facilitate early antidepressant response,and the temporal variability may serve as a promising indicator for the personalized therapy of MDD.Chapter 3 Distinct features of regional cerebral blood flow and spontaneous low-frequency oscillation as integrated predictor of early antidepressants response in major depressive disorderObjective: To explore the potential power of bimodal functional features in discriminating the early antidepressant response.Methods: Eighty treatment-na?ve MDD patients and forty-two HC underwent pulsed arterial spin labeling and resting-state functional magnetic resonance imaging scans and clinical assessment.After 2 weeks of antidepressants treatment,the MDD group was divided into the RD and the NRD based on a 50 percent reduction in HAMD score.The cerebral blood flow（CBF）and amplitude of low-frequency fluctuation（ALFF）values were calculated for further group-comparisons and differentiating analysis.Results: Compared with the HC,the RD and the NRD groups both exhibited lower CBF and ALFF in right cerebellum posterior lobe.Compared with the NRD,the RD group showed a distinct CBF pattern in the left frontostriatal and right frontal-sensorimotor-cerebellum areas,as well as a distinct ALFF pattern in the left frontoparietal-striatum and right frontotemporal-sensorimotorstriatal-cerebellum regions.Furthermore,the ROC analyses revealed that the AUC of the combined measures in each modality（i.e.,CBF and ALFF）was 0.749 and 0.757,respectively.When taking into account the measures of both ASL and rs-f MRI modalities,the results demonstrated an optimal performance with balanced specificity（89%）and sensitivity（72%）in discriminating the NRD from the RD group（area under curve（AUC）= 0.823,P < 0.001）.When the two modal（ASL and rs-f MRI）indicators were further integrated to distinguish between the NRD and RD groups,the results demonstrated an optimal performance than single indicator with balanced specificity（89%）and sensitivity（72%）in discriminating the NRD from the RD group（AUC = 0.823,P < 0.001）The SVM classifier further validated the favorable differentiated performance by the combined bimodal indicators（accuracy = 0.713）.Conclusion: Abnormal CBF and ALFF in the frontal-striatal network might serve as promising neuroimaging predictor for identifying MDD patients with blunted treatment responsiveness,which will facilitate the personalized antidepressants therapy.Part 2 Early efficacy prediction of antidepressants based on changes in brain network level characteristics at baselineChapter 4 Divergent topological architecture of the default mode network as a pretreatment predictor of early antidepressant response in major depressive disorderObjective: To identify robust pretreatment neuroimaging markers that would be helpful for the selection of an optimal therapy for patients with MDD.Methods: We recruited 82 MDD patients（RD,n = 42 and NRD,n = 40）and 50 HC for this study.The default mode network was constructed based on the thresholded partial correlation matrices of 58 specific brain regions,and graph theory approach was applied to analyze the topological properties.Results: When compared to the HC,both the RD and the NRD patients exhibited a lower nodal degree（Dnodal）in the left anterior cingulate gyrus;as for RD,the Dnodal of the left superior medial orbitofrontal gyrus was significantly reduced,but the right inferior orbitofrontal gyrus was increased（all P < 0.017,FDR corrected）.Moreover,the nodal degree in the right dorsolateral superior frontal cortex（SFGdor）was significantly lower in the RD than in the NRD.Receiver operating characteristic curve analysis demonstrated that the λ and nodal degree in the right SFGdor exhibited a good ability to distinguish nonresponding patients from responsive patients,which could serve as a specific maker to predict an early response to antidepressants.Conclusion: The disrupted topological configurations in the present study extend the understanding of pretreatment neuroimaging predictors for antidepressant medication.Chapter 5 Distinctive pretreatment features of bilateral NAcc networks predict early antidepressants response in major depressive disorderObjective: The pretreatment neuroimaging markers parsing resting-state brain network that could predict the early antidepressants response are still unrevealed.The aim of present study was to identify the performance of reward network features on discriminating patients with poor treatment response.Methods: 81 MDD patients（44 RD and 37 NRD）and 43 HC underwent rs-f MRI scan and clinical estimates.The bilateral nucleus accumbens（NAcc）based networks were constructed for further functional connectivity（FC）analysis.Results: Compared with the NRD,in the left NAcc network,the RD group showed decreased positive FC with left superior temporal gyrus（STG.L）,right superior frontal gyrus（SFG.R）and left parahippocampus but increased positive FC with bilateral postcentral gyrus,left medial frontal gyrus and right middle cingulate gyrus.In the right NAcc network,compared with NRD,RD group exhibited decreased positive FC in SFG.L but increased positive FC in right cingulate gyrus（all FDR-corrected,P < 0.05）.Among the MDD group,the Pearson’s correlation analysis revealed that the FC of left NAcc and right SFG was positively related to the baseline HAMD score（r = 0.367,P = 0.001）and negatively associated with to the HAMD reductive rate（r=-0.372,P = 0.001）.The FC of SFG.R（AUC = 0.837,P < 0.001）and left parahippocampus（AUC = 0.770,P < 0.001）within the left NAcc reward network,as well as the FC of SFG.L（AUC = 0.827,P < 0.001）in the right NAcc reward network could distinguishing the NRD from the RD subjects relatively well.Combinedly,when took into account the distinctive connectional pattern of bilateral reward circuits,the synthetical differentiating effect was achieved to a better performance on discriminating the NRD patients（AUC = 0.869,P < 0.001）,with balanced sensitivity（0.838）and specificity（0.818）.Conclusion: The distinct pretreatment characteristics of reward network make specific contributions to early antidepressants response and establish a promising imaging predictor for the classification of early efficacy.Part 3 The effects of polymorphisms in 5-hydroxytryptamine（5-HT）pathway genes on cerebral blood flow and its potential value in early prediction of antidepressant efficacyChapter 6 The interaction of 5-HT pathway genes and pretreatment regional cerebral blood flow of DMN modulating early antidepressants response in major depressive disorderObjective: To examine whether the pathway genetic polymorphisms and the pretreatment regional CBF potential interact with the early treatment response,and further explore whether the distinct CBF features can effectively predict the early antidepressant response.Methods: Twenty-two RD and twenty-two NRD subjects received 5-hydroxytryptamine（5-HT）pathway gene sequencing and paused arterial spin labeling（p ASL）and T1 images scan in 3.0 Tesla scanner.The interactions were determined by efficacy × SNPs analysis of covariance.The regional CBF interacted with SNPs in 5-HT pathway genes and early treatment response were selected for further correlation and ROC analyses.Results: Twelve SNPs of eleven genes showed significant interactions with early antidepressant response on regional CBF.Significant correlations were revealed between the regional CBF in left cerebellum Posterior Lobe,right medial frontal gyrus（Me FG_R）,left middle temporal gyrus（MTG_L）and short-term or mid-term antidepressant response.When combined three metrics of CBF in Me FG_R（interacted with the SNP of HTR3 D rs12493550）,the Ce PL_R（HTR1A rs878567）and the Precuneus_L（TPH2 rs11178998）for ROC analysis,an optimized discrimination power was revealed in classifying the NRD patients from the RD subjects.Conclusion: The interaction between multilocus SNPs and early efficacy can be revealed on the dimension of CBF,and the short-term and middle-term efficacy may be mediated by different loci in 5-HT pathway and brain regions.The features of 5-HT pathway and the CBF may provide a comprehensive perspective and novel indicator for the treatment modification in the early stage,thus potentially contributing to the development of individualized antidepressant medication.