Examining the usefulness of the brain network marker program using fMRI for the diagnosis and stratification of major depressive disorder: a non-randomized study protocol.

BACKGROUND: Although many studies have reported the biological basis of major depressive disorder (MDD), none have been put into practical use. Recently, we developed a generalizable brain network marker for MDD diagnoses (diagnostic marker) across multiple imaging sites using resting-state functional magnetic resonance imaging (rs-fMRI). We have planned this clinical trial to establish evidence for the practical applicability of this diagnostic marker as a medical device. In addition, we have developed generalizable brain network markers for MDD stratification (stratification markers), and the verification of these brain network markers is a secondary endpoint of this study. METHODS: This is a non-randomized, open-label study involving patients with MDD and healthy controls (HCs). We will prospectively acquire rs-fMRI data from 50 patients with MDD and 50 HCs and anterogradely verify whether our diagnostic marker can distinguish between patients with MDD and HCs. Furthermore, we will longitudinally obtain rs-fMRI and clinical data at baseline and 6 weeks later in 80 patients with MDD treated with escitalopram and verify whether it is possible to prospectively distinguish MDD subtypes that are expected to be effectively responsive to escitalopram using our stratification markers. DISCUSSION: In this study, we will confirm that sufficient accuracy of the diagnostic marker could be reproduced for data from a prospective clinical study. Using longitudinally obtained data, we will also examine whether the "brain network marker for MDD diagnosis" reflects treatment effects in patients with MDD and whether treatment effects can be predicted by "brain network markers for MDD stratification". Data collected in this study will be extremely important for the clinical application of the brain network markers for MDD diagnosis and stratification. TRIAL REGISTRATION: Japan Registry of Clinical Trials ( jRCTs062220063 ). Registered 12/10/2022.

Verification of the brain network marker of major depressive disorder: Test-retest reliability and anterograde generalization performance for newly acquired data.

BACKGROUND: Recently, we developed a generalizable brain network marker for the diagnosis of major depressive disorder (MDD) across multiple imaging sites using resting-state functional magnetic resonance imaging. Here, we applied this brain network marker to newly acquired data to verify its test-retest reliability and anterograde generalization performance for new patients. METHODS: We tested the sensitivity and specificity of our brain network marker of MDD using data acquired from 43 new patients with MDD as well as new data from 33 healthy controls (HCs) who participated in our previous study. To examine the test-retest reliability of our brain network marker, we evaluated the intraclass correlation coefficients (ICCs) between the brain network marker-based classifier's output (probability of MDD) in two sets of HC data obtained at an interval of approximately 1 year. RESULTS: Test-retest correlation between the two sets of the classifier's output (probability of MDD) from HCs exhibited moderate reliability with an ICC of 0.45 (95 % confidence interval,0.13-0.68). The classifier distinguished patients with MDD and HCs with an accuracy of 69.7 % (sensitivity, 72.1 %; specificity, 66.7 %). LIMITATIONS: The data of patients with MDD in this study were cross-sectional, and the clinical significance of the marker, such as whether it is a state or trait marker of MDD and its association with treatment responsiveness, remains unclear. CONCLUSIONS: The results of this study reaffirmed the test-retest reliability and generalization performance of our brain network marker for the diagnosis of MDD.

Disrupted Brain Activation and Deactivation Pattern during Semantic Verbal Fluency Task in Patients with Major Depression.

BACKGROUND: Patients with major depressive disorder (MDD) exhibit cognitive impairment, and evidence suggests that the semantic version of the verbal fluency task is a reliable cognitive marker of the disorder. Here, using functional magnetic resonance imaging (fMRI), we investigated the dysfunction of neural processing in acute depression and examined the effects of a 6-week pharmacological intervention. METHODS: Sixteen patients with MDD participated in 2 fMRI sessions, and 16 healthy control (HC) subjects participated in 1 fMRI session. During each fMRI session, the participants performed a semantic verbal fluency task. Brain activity during the task was compared between groups (MDD 1st fMRI vs. HC) and times (MDD 1st fMRI vs. 2nd fMRI). RESULTS: Significant brain hypoactivation was observed in MDD patients at the prefrontal, lateral parietal, and limbic regions compared to HC, and MDD patients exhibited hyperactivation at the left precuneus compared to HC. Hypoactivity of the left dorsolateral prefrontal cortex (DLPFC) and hyperactivity of the precuneus were normalized with treatment. CONCLUSIONS: Hypoactivation of the left DLPFC and hyperactivation of the precuneus should be considered as dysregulation of anticorrelated brain networks during a cognitive demanding task. This failure of network regulation may be an important factor in the pathophysiology of MDD.

The valproate serum level in maintenance therapy for bipolar disorder in Japan.

The appropriate therapeutic serum valproate level in maintenance therapy for bipolar disorder is not well known. We studied the serum valproate levels in seventeen bipolar I and twenty-four bipolar II disorder outpatients who had been treated with stable doses of valproate successfully for at least 12 months as prophylactic therapy. The trough serum valproate levels were 52.2 +/- 20.4 microg/ml in bipolar I, and 41.0 +/- 18.3 microg/ml in bipolar II disorder patients, respectively. A greater trend towards a higher trough level (p = 0.07) was indicated in the bipolar I disorder group. We speculate that these valproate levels may be an approximation to the appropriate valproate levels in maintenance therapy and that there may be a correlation between the level of valproate required for stabilization and the subtype of the bipolar disorder. However, when interpreting these findings, certain limitations to this study? Need to be taken into account as follows. The sample size was small. We could not look at a group on valproate that had relapsed and a group that had dropped out of maintenance therapy. Further studies are needed.

One-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment.

OBJECTIVE: The aim of the study was to investigate one-year outcomes of unipolar depression patients with manic or hypomanic switch during acute antidepressant treatment. METHODS: A review of medical records revealed 37 consecutive patients admitted from 1997 to 2002 who underwent an antidepressant-induced manic or hypomanic switch fulfilling DSM-IV criteria. Their clinical courses were retrospectively investigated after discharge. RESULTS: Of the 37 patients, 33 (89.2%) were followed up for 1 year after discharge. None developed a manic episode, while seven developed a hypomanic episode, including 1 patient who was lost after emerging from a hypomanic episode within 6 months after discharge. Only one of those seven patients developed hypomania during acute antidepressant treatment for a recurrent depressive episode under maintenance mood stabilizer treatment. Furthermore, bipolar conversion occurred in four patients within the first 6 months and in another two patients, including 1 with rapid cycling, over the subsequent 6 months after discharge. Of these 33 patients, 28 received continuous maintenance treatment with mood stabilizers for the one-year period after discharge. CONCLUSIONS: The subjects were considered to have a bipolar nature according to the prevalence rate of bipolar conversion over a one-year period. Longer follow-up studies appear warranted determine the diagnostic issues of antidepressant-induced switch in unipolar depression.

Manic/hypomanic switch during acute antidepressant treatment for unipolar depression.

A significant proportion of patients with unipolar depression clinically develop manic or hypomanic switch during acute antidepressant treatment. Elucidation of its prevalence and predicting factors is of clinical relevance during acute antidepressant treatment of such patients. We retrospectively studied patients with unipolar depression who were admitted to our department during the 6-year period from 1997 to 2002 and who had fewer than 3 previous episodes before admission. The clinical background of the consecutive patients with manic/hypomanic switch (n = 37) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria was compared with that of patients without manic/hypomanic switch (n = 245). The prevalence rate of manic/hypomanic switch was 13.1%. The switch group was composed of 23 men and 14 women, whose average age was 48.8 +/- 12.3 years (range, 26-78 years). Manic/hypomanic switch was most frequently observed between 2 and 3 weeks after the antidepressant was increased to the ongoing dose. Antidepressants were decreased in 13 patients and discontinued in 23. Manic/hypomanic episodes lasted from 1 to 8 weeks. The patients in the switch group included a greater proportion of male subjects and had a higher frequency of family history of bipolar disorders than those in the nonswitch group. The mean doses of antidepressants were not significantly different between these groups. The higher frequency of manic/hypomanic switch occurring around the period when antidepressants begin to show clinical effects and the higher frequency of family history of bipolar disorders might suggest a biological susceptibility to antidepressants in patients of the switch group.