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.

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.

Behavioral Activation Contributed to the Total Reduction of Depression Symptoms in the Smartphone-based Cognitive Behavioral Therapy: A Secondary Analysis of a Randomized, Controlled Trial.

Objective: The contribution of components in cognitive behavior therapy (CBT) to the total reduction of depression symptoms has not been well elucidated, and previous studies couldn't exclude the human factors in the therapy. Design: This is a secondary analysis of a randomized, controlled trial comparing automated smartphone CBT without human factors plus antidepressant switch against antidepressant switch alone among patients with antidepressant-resistant depression. The present CBT consisted of self-monitoring, behavioral activation, and cognitive restructuring. We used linear regression to predict the overall pre- to post-symptom improvement based on improvement achieved by sessions teaching each cognitive or behavioral skill. The overall improvement was measured with the Beck Depression Inventory-II and the session-to-session improvement with K6. Results: Of the 164 participants originally enrolled in the study, 94 participants who completed all K6 evaluation were included in the primary analyses. The results indicated that K6 score reduction in the first half of behavioral activation significantly predicted BDI-II score reduction. The sensitivity analysis including 162 participants did not change the result. K6 score reductions after other CBT sessions did not significantly predict BDI-II score reduction. Conclusion: The behavioral activation seems to contribute to the total reduction of depressive symptoms even if human factors are excluded by using automated smartphone CBT.

Predicting relapse in major depression after successful initial pharmacological treatment.

BACKGROUND: Identifying the predictors of relapse could help to develop more individualized treatment strategies for major depression. The study aim was to explore predictors of depression relapse after remission using data from our previous multicenter randomized practical trial of patients with major depression. METHODS: Our cohort comprised subjects with Patient Health Questionnaire (PHQ-9) scores less than 5 after antidepressant treatment for 9 weeks. Relapse was defined as a PHQ-9 score of 5 or more at week 25. We examined patient demographic and clinical characteristics at baseline (age, sex education, job status, marital status, onset age at first depressive episode, number of previous episodes, length of current episode, scores on the nine PHQ-9 criteria at week 0) and Frequency, Intensity, and Burden of Side Effects Rating Scale and PHQ-9 total scores at week 9 (residual symptoms) as potential predictors of depression relapse at week 25. RESULTS: Of 494 patients remitted at week 9, 71 (14.4%) experienced relapse at week 25. Logistic regression analysis showed that lower PHQ-9 depressive mood score at week 0, higher suicidal ideation score at week 0, and total PHQ-9 score at week 9, and greater severity of side effects at week 9 were significant predictors. On the other hand, when relapse was defined as a PHQ-9 score of 10 or more at week 25, there were no significant predictors. LIMITATIONS: There may be other important predictors that this study failed to identify and the findings obtained may be sensitive to the specific definition of relapse. CONCLUSIONS: Approximately one-seventh of subjects who remitted after 2 months of acute-phase treatment experienced depression relapse within 4 months of remission. Lower depressive mood and higher suicidal ideation upon development of the current depression episode, the presence of residual symptoms, and greater severity of side effects at remission may predict subsequent depression relapse.

Correction: Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/jmir.8602.].

Optimising first- and second-line treatment strategies for untreated major depressive disorder - the SUN☺D study: a pragmatic, multi-centre, assessor-blinded randomised controlled trial.

BACKGROUND: For patients starting treatment for depression, current guidelines recommend titrating the antidepressant dosage to the maximum of the licenced range if tolerated. When patients do not achieve remission within several weeks, recommendations include adding or switching to another antidepressant. However, the relative merits of these guideline strategies remain unestablished. METHODS: This multi-centre, open-label, assessor-blinded, pragmatic trial involved two steps. Step 1 used open-cluster randomisation, allocating clinics into those titrating sertraline up to 50 mg/day or 100 mg/day by week 3. Step 2 used central randomisation to allocate patients who did not remit after 3 weeks of treatment to continue sertraline, to add mirtazapine or to switch to mirtazapine. The primary outcome was depression severity measured with the Patient Health Questionnaire-9 (PHQ-9) (scores between 0 and 27; higher scores, greater depression) at week 9. We applied mixed-model repeated-measures analysis adjusted for key baseline covariates. RESULTS: Between December 2010 and March 2015, we recruited 2011 participants with hitherto untreated major depression at 48 clinics in Japan. In step 1, 970 participants were allocated to the 50 mg/day and 1041 to the 100 mg/day arms; 1927 (95.8%) provided primary outcomes. There was no statistically significant difference in the adjusted PHQ-9 score at week 9 between the 50 mg/day arm and the 100 mg/day arm (0.25 point, 95% confidence interval (CI), - 0.58 to 1.07, P = 0.55). Other outcomes proved similar in the two groups. In step 2, 1646 participants not remitted by week 3 were randomised to continue sertraline (n = 551), to add mirtazapine (n = 537) or to switch to mirtazapine (n = 558): 1613 (98.0%) provided primary outcomes. At week 9, adding mirtazapine achieved a reduction in PHQ-9 scores of 0.99 point (0.43 to 1.55, P = 0.0012); switching achieved a reduction of 1.01 points (0.46 to 1.56, P = 0.0012), both relative to continuing sertraline. Combination increased the percentage of remission by 12.4% (6.1 to 19.0%) and switching by 8.4% (2.5 to 14.8%). There were no differences in adverse effects. CONCLUSIONS: In patients with new onset depression, we found no advantage of titrating sertraline to 100 mg vs 50 mg. Patients unremitted by week 3 gained a small benefit in reduction of depressive symptoms at week 9 by switching sertraline to mirtazapine or by adding mirtazapine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01109693 . Registered on 23 April 2010.

Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled Trial.

BACKGROUND: In the treatment of major depression, antidepressants are effective but not curative. Cognitive behavioral therapy (CBT) is also effective, alone or in combination with pharmacotherapy, but accessibility is a problem. OBJECTIVE: The aim is to evaluate the effectiveness of a smartphone CBT app as adjunctive therapy among patients with antidepressant-resistant major depression. METHODS: A multisite, assessor-masked, parallel-group randomized controlled trial was conducted in 20 psychiatric clinics and hospitals in Japan. Participants were eligible if they had a primary diagnosis of major depression and were antidepressant-refractory after taking one or more antidepressants at an adequate dosage for four or more weeks. After a 1-week run-in in which participants started the medication switch and had access to the welcome session of the app, patients were randomized to medication switch alone or to medication switch plus smartphone CBT app via the centralized Web system. The smartphone app, called Kokoro-app ("kokoro" means "mind" in Japanese), included sessions on self-monitoring, behavioral activation, and cognitive restructuring presented by cartoon characters. The primary outcome was depression severity as assessed by masked telephone assessors with the Patient Health Questionnaire-9 (PHQ-9) at week 9. The secondary outcomes included the Beck Depression Inventory-II (BDI-II) and Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER). RESULTS: In the total sample (N=164), 81 participants were allocated to the smartphone CBT in addition to medication change and 83 to medication change alone. In the former group, all but one participant (80/81, 99%) completed at least half, and 71 (88%) completed at least six of eight sessions. In the intention-to-treat analysis, patients allocated the CBT app scored 2.48 points (95% CI 1.23-3.72, P<.001; standardized mean difference 0.40) lower on PHQ-9 than the control at week 9. The former group also scored 4.1 points (95% CI 1.5-6.6, P=.002) lower on BDI-II and 0.76 points (95% CI -0.05 to 1.58, P=.07) lower on FIBSER. In the per-protocol sample (comfortable with the smartphone app, still symptomatic, and adherent to medication with mild or less side effects after run-in), the intervention group (n=60) scored 1.72 points (95% CI 0.25-3.18, P=.02) lower on PHQ-9, 3.2 points (95% CI -0.01 to 6.3, P=.05) lower on BDI-II, and 0.75 points (95% CI 0.03-1.47, P=.04) lower on FIBSER than the control (n=57). The treatment benefits were maintained up to week 17. CONCLUSIONS: This is the first study to demonstrate the effectiveness of a smartphone CBT in the treatment of clinically diagnosed depression. Given the merits of the mobile mental health intervention, including accessibility, affordability, quality control, and effectiveness, it is clinically worthwhile to consider adjunctive use of a smartphone CBT app when treating patients with antidepressant-resistant depression. Research into its effectiveness in wider clinical contexts is warranted. TRIAL REGISTRATION: Japanese Clinical Trials Registry UMIN CTR 000013693; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000015984 (Archived by WebCite at http://www.webcitation.org/6u6pxVwik).

Strategic use of new generation antidepressants for depression: SUN(

BACKGROUND: SUN(^_^)D, the Strategic Use of New generation antidepressants for Depression, is an assessor-blinded, parallel-group, multicenter pragmatic mega-trial to examine the optimum treatment strategy for the first- and second-line treatments for unipolar major depressive episodes. The trial has three steps and two randomizations. Step I randomization compares the minimum and the maximum dosing strategy for the first-line antidepressant. Step II randomization compares the continuation, augmentation or switching strategy for the second-line antidepressant treatment. Step III is a naturalistic continuation phase. The original protocol was published in 2011, and we hereby report its updated protocol including the statistical analysis plan. RESULTS: We implemented two important changes to the original protocol. One is about the required sample size, reflecting the smaller number of dropouts than had been expected. Another is in the organization of the primary and secondary outcomes in order to make the report of the main trial results as pertinent and interpretable as possible for clinical practices. Due to the complexity of the trial, we plan to report the main results in two separate reports, and this updated protocol and the statistical analysis plan have laid out respective primary and secondary outcomes and their analyses. We will convene the blind interpretation committee before the randomization code is broken. CONCLUSION: This paper presents the updated protocol and the detailed statistical analysis plan for the SUN(^_^)D trial in order to avoid reporting bias and data-driven results. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01109693 (registered on 21 April 2010).

Yokukansan treatment of chronic renal failure patients receiving hemodialysis, with behavioral and psychological symptoms of dementia: an open-label study.

OBJECTIVE: The efficacy and safety of yokukansan (YKS) for chronic renal failure (CRF) patients receiving hemodialysis with behavioral and psychological symptoms of dementia (BPSD) was evaluated. METHODS: Twelve CRF patients receiving hemodialysis with BPSD were recruited and 7.5 g of YKS powder was added to ongoing therapy with antipsychotics. Neuropsychiatric Inventory (NPI) criteria and Barthel Index before and after 4-week YKS treatment were compared. RESULTS: Analysis of the mean score for NPI revealed a significant improvement during the period of YKS administration (25.3 ± 17.6 versus 8.36 ± 4.46; p = 0.0069). The mean score for the Barthel Index showed no significant difference during the period of YKS administration. Mean level of serum potassium was still within the normal range. No subjects had severe adverse reactions necessitating discontinuation from the study. CONCLUSION: Yokukansan significantly improved the symptoms of BPSD in CRF patients receiving hemodialysis without critical side effects.

p53 directly represses Id2 to inhibit the proliferation of neural progenitor cells.

Neural progenitor cells (NPCs) have the capacity to proliferate and give rise to all major central nervous system cell types and represent a possible cell of origin in gliomagenesis. Deletion of the tumor suppressor gene Tp53 (p53) results in increased proliferation and self-renewal of NPCs and is a common genetic mutation found in glioma. We have identified inhibitor of DNA binding 2 (Id2) as a novel target gene directly repressed by p53 to maintain normal NPC proliferation. p53((-/-)) NPCs express elevated levels of Id2 and suppression of Id2 expression is sufficient to inhibit the increased proliferation and self-renewal which results from p53 loss. Elevated expression of Id2 in wild-type NPCs phenocopies the behavior of p53((-/-)) NPCs by enhancing NPC proliferation and self-renewal. Interestingly, p53 directly binds to a conserved site within the Id2 promoter to mediate these effects. Finally, we have identified elevated Id2 expression in glioma cell lines with mutated p53 and demonstrated that constitutive expression of Id2 plays a key role in the proliferation of glioma stem-like cells. These findings indicate that Id2 functions as a proproliferative gene that antagonizes p53-mediated cell cycle regulation in NPCs and may contribute to the malignant proliferation of glioma-derived tumor stem cells.

Higher incidence of hysterectomy and oophorectomy in women suffering from clinical depression: retrospective chart review.

The aim of the present study was to retrospectively evaluate women who were admitted to Hiroshima University Hospital, Department of Psychiatry and Neurosciences, from 1979 to 2008. The women were classified as 'depressed women' (n = 159; mean age, 52.3 +/- 5.7 years) or 'non-depressed women' (n = 182; mean age, 51.5 +/- 4.5 years). A total of 14.5% of the depressed women and 3.3% of the non-depressed women had a hysterectomy and/or oophorectomy; this difference was statistically significant (P = 0.0003). This is consistent with previous reported information as well as clinical experience that depressed women had a higher incidence of hysterectomy and/or oophorectomy.

A role for Id2 in regulating photic entrainment of the mammalian circadian system.

Inhibitor of DNA binding genes (Id1-Id4) encode helix-loop-helix (HLH) transcriptional repressors associated with development and tumorigenesis [1, 2], but little is known concerning the function(s) of these genes in normal adult animals. Id2 was identified in DNA microarray screens for rhythmically expressed genes [3-5], and further analysis revealed a circadian pattern of expression of all four Id genes in multiple tissues including the suprachiasmatic nucleus. To explore an in vivo function, we generated and characterized deletion mutations of Id2 and of Id4. Id2(-/-) mice exhibit abnormally rapid entrainment and an increase in the magnitude of the phase shift of the pacemaker. A significant proportion of mice also exhibit disrupted rhythms when maintained under constant darkness. Conversely, Id4(-/-) mice did not exhibit a noticeable circadian phenotype. In vitro studies using an mPer1 and an AVP promoter reporter revealed the potential for ID1, ID2, and ID3 proteins to interact with the canonical basic HLH clock proteins BMAL1 and CLOCK. These data suggest that the Id genes may be important for entrainment and operation of the mammalian circadian system, potentially acting through BMAL1 and CLOCK targets.

Id2 is required for specification of dopaminergic neurons during adult olfactory neurogenesis.

Understanding the biology of adult neural stem cells has important implications for nervous system development and may contribute to our understanding of neurodegenerative disorders and their treatment. We have characterized the process of olfactory neurogenesis in adult mice lacking inhibitor of DNA binding 2(-/-) (Id2(-/-)). We found a diminished olfactory bulb containing reduced numbers of granular and periglomerular neurons with a distinct paucity of dopaminergic periglomerular neurons. While no deficiency of the stem cell compartment was detectable, migrating neuroblasts in Id2(-/-) mutant mice prematurely undergo astroglial differentiation within a disorganized rostral migratory stream. Further, when evaluated in vitro loss of Id2 results in decreased proliferation of neural progenitors and decreased expression of the Hes1 and Ascl1 (Mash1) transcription factors, known mediators of neuronal differentiation. These data support a novel role for sustained Id2 expression in migrating neural progenitors mediating olfactory dopaminergic neuronal differentiation in adult animals.

Id4 regulates neural progenitor proliferation and differentiation in vivo.

The mechanisms that determine whether a precursor cell re-enters the cell cycle or exits and differentiates are crucial in determining the types and numbers of cells that constitute a particular organ. Here, we report that Id4 is required for normal brain size, and regulates lateral expansion of the proliferative zone in the developing cortex and hippocampus. In its absence, proliferation of stem cells in the ventricular zone (VZ) is compromised. In early cortical progenitors, Id4 is required for the normal G1-S transition. By contrast, at later ages, ectopically positioned proliferating cells are found in the mantle zone of the Id4-/- cortex. These observations, together with evidence for the premature differentiation of early cortical stem cells, indicate that Id4 has a unique and complex function in regulating neural stem cell proliferation and differentiation.