Subthreshold Hypomanic Symptoms Research Articles

White matter abnormalities in adults with bipolar disorder type-II and unipolar depression

Discerning distinct neurobiological characteristics of related mood disorders such as bipolar disorder type-II (BD-II) and unipolar depression (UD) is challenging due to overlapping symptoms and patterns of disruption in brain regions. More than 60% of individuals with UD experience subthreshold hypomanic symptoms such as elevated mood, irritability, and increased activity. Previous studies linked bipolar disorder to widespread white matter abnormalities. However, no published work has compared white matter microstructure in individuals with BD-II vs. UD vs. healthy controls (HC), or examined the relationship between spectrum (dimensional) measures of hypomania and white matter microstructure across those individuals. This study aimed to examine fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) across BD-II, UD, and HC groups in the white matter tracts identified by the XTRACT tool in FSL. Individuals with BD-II (n = 18), UD (n = 23), and HC (n = 24) underwent Diffusion Weighted Imaging. The categorical approach revealed decreased FA and increased RD in BD-II and UD vs. HC across multiple tracts. While BD-II had significantly lower FA and higher RD values than UD in the anterior part of the left arcuate fasciculus, UD had significantly lower FA and higher RD values than BD-II in the area of intersections between the right arcuate, inferior fronto-occipital and uncinate fasciculi and forceps minor. The dimensional approach revealed the depression-by-spectrum mania interaction effect on the FA, RD, and AD values in the area of intersection between the right posterior arcuate and middle longitudinal fasciculi. We propose that the white matter microstructure in these tracts reflects a unique pathophysiologic signature and compensatory mechanisms distinguishing BD-II from UD.

Irritable Mood and Subthreshold Hypomanic Episodes Correlate with More Severe Major Depression

Introduction: Irritable mood (IM) and subthreshold hypomanic symptoms are reported in half and two-fifths of major depressed subjects respectively, but their clinical and prognostic meanings remain unclear. The aim of this study was to test the clinical usefulness of 2 specifiers in DSM-IV major depressive disorder (MDD): IM occurring during an index episode (IM+) and lifetime episodes of elated mood or IM with at least 2 concurrent hypomanic symptoms (subthreshold hypomanic episodes [SHEs]). Method: We included 482 outpatients with MDD participating in the Combining Medications to Enhance Depression Outcome study (mean age 43.14 ± 12.46 years, 144 males – 30%). The main aim of the original study was to test whether 2 different medications when given in combination as the first treatment step, compared to 1 medication, would improve antidepressant response. Results: IM + subjects (N = 349; 70%) were younger and more often females, with a more severe depression, a more marked social impairment, and more psychiatric comorbidities. The IM + group was also characterized by higher levels of suicidal ideation and more cases of emotional abuse. The combination of IM+ and SHEs was associated with an even more severe clinical picture. Limitations include the post hoc method, incomplete assessment of bipolar validators (e.g., family history of bipolar illness), personality disorders and suicide attempts. Conclusions: The presence of IM and SHEs in MDD correlate with an overall more severe clinical condition.

Differential response to SSRI versus Placebo and distinct neural signatures among data-driven subgroups of patients with major depressive disorder

Objective: To identify data-driven subgroups in Major Depressive Disorder (MDD) in order to elucidate underlying neural correlates and determine if these subgroups have utility in predicting response to antidepressant versus placebo. Methods: Using 27 clinical measures at baseline of Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study, participants with MDD (n=244) were sub grouped using principal component (PC) analysis. Baseline-to-week-8 changes in depression severity with sertraline versus placebo were compared in these subgroups. Resting-state functional connectivity of these subgroups were compared to those of healthy controls (n=38). Results: Eight subgroups were identified from four PCs: (PC1) severity of depression-associated symptoms, (PC2) sub-threshold mania and anhedonia, (PC3) childhood trauma, medical comorbidities, and sexual dysfunction, and (PC4) personality traits of openness and agreeableness. Participants with high childhood trauma experienced greater improvement with sertraline (Cohen's d=0.87), whereas those with either higher levels of subthreshold hypomanic symptoms (Cohen's d=0.67) or with lower levels of agreeableness and openness experienced greater improvement with placebo (Cohen's d=0.71). Participants with high childhood trauma had greater connectivity between salience and dorsal attention networks, whereas those with higher levels of subthreshold hypomanic symptoms and lower levels of agreeableness and openness had greater connectivity within limbic network and that of visual network with hippocampus and dorsal attention network. Conclusion: Assessing history of childhood trauma, presence of subthreshold hypomanic symptoms and personality traits may help to identify subgroups of patients with MDD who respond differentially to sertraline or placebo and have distinct neural signatures.

Depression Preceding Diagnosis of Bipolar Disorder.

This paper focuses on depression that precedes an onset of manifest bipolar disorder as early stage bipolar disorder. First, we review how to pragmatically identify the clinical characteristics of patients presenting with an episode of depression who subsequently go on to develop episodes of mania or hypomania. The existing literature shows a strong consensus: accurate identification of depression with early onset and recurrent course with multiple episodes, subthreshold hypomanic and/or mixed symptoms, and family history of bipolar disorder or completed suicide have been shown by multiple authors as signs pointing to bipolar diagnosis. This contrasts with relatively limited information available to guide management of such “pre-bipolar” (pre-declared bipolar) patients, especially those in the adult age range. Default assumption of unipolar depression at this stage carries significant risk. Antidepressants are still the most common pharmacological treatment used, but clinicians need to be aware of their potential harm. In some patients with unrecognized bipolar depression, antidepressants can not only produce switch to (hypo)mania, but also mixed symptoms, or worsening of depression with an increased risk of suicide. We review pragmatic management strategies in the literature beyond clinical guidelines that can be considered for this at-risk group encompassing the more recent child and adolescent literature. In the future, genetic research could make the early identification of bipolar depression easier by generating informative markers and polygenic risk scores.

How to Manage Young Depressed Patients with Subthreshold Manic Symptoms

Patients with major depressive disorder (MDD) and subthreshold hypomanic symptoms are at an elevated risk for conversion to bipolar disorder. In

Research Roundup

Subthreshold hypomanic symptoms affect antidepressant response ECT shows efficacy in treating clozapine‐resistant schizophrenia Meta‐analysis: SSRIs decrease risk of myocardial infarction Cannabidiol could help patients at high risk for psychosis Nicotine shows promise in elderly with mood and depressive symptoms Atypical antipsychotics compare favorably on measures of hostility Antidepressants in elderly generate no increased risk of dementia

Do baseline sub-threshold hypomanic symptoms affect acute-phase antidepressant outcome in outpatients with major depressive disorder? Preliminary findings from the randomized CO-MED trial.

Sub-threshold hypomanic symptoms are common in major depressive disorder. This study evaluated the prevalence, the clinical and sociodemographic correlates, and the overall and differential effects of the presence/absence of sub-threshold hypomanic symptoms at baseline on acute-phase treatment outcomes with bupropion-plus-escitalopramcombination, escitalopram monotherapy, and venlafaxine-plus-mirtazapine combination. Combining medications to enhance depression outcomes (CO-MED) trial participants (n = 665) were designated as sub-threshold hypomanic symptoms present (Altman Self-Rating Mania Scale score (ASRM) ≥ 1) or absent (ASRM = 0) and compared on clinical and sociodemographic features and remission rates. Participants with sub-threshold hypomanic symptoms (n = 335/665, 50.4%) were more likely to be black and non-Hispanic, have comorbid medical and psychiatric disorders, experience longer index episodes, and report lower depression severity and psychosocial impairment. Intent-to-treat remission rates were lower overall (absent = 42.7%, present = 34.0%, p = 0.02), with escitalopram monotherapy (absent = 45.8%, present = 31.6%, p = 0.03), and with venlafaxine-XR-plus-mirtazapinecombination (absent = 44.4%, present = 30.1%, p = 0.03) but not with bupropion-plus-escitalopramcombination (absent = 37.7%, present = 40.0%, p = 0.73). Participants without sub-threshold hypomanic symptoms were more likely to remit than those with such symptoms overall [odds ratio (OR) = 1.49], with escitalopram monotherapy (OR = 1.71), and with venlafaxine-plus-mirtazapinecombination (OR = 1.97) but not with bupropion-plus-escitalopramcombination (OR = 0.96), even after controlling for baseline depression severity, psychosocial impairment, and number of comorbid psychiatric disorders. Sub-threshold hypomanic symptoms (found in about 50% of patients in this report) were associated with lower remission rates with escitalopram monotherapy and with venlafaxine-plus-mirtazapine combination but not with the bupropion-plus-escitalopram combination.

Effect of Lurasidone on Sexual Function in Major Depressive Disorder Patients With Subthreshold Hypomanic Symptoms (Mixed Features): Results From a Placebo-Controlled Trial.

The aim of this secondary analysis was to evaluate whether treatment with lurasidone was associated with impairment in sexual functioning in major depressive disorder (MDD) patients with subthreshold hypomanic symptoms (mixed features). Patients meeting DSM-IV-TR criteria for MDD, who presented with 2 or 3 protocol-specified manic symptoms, were randomized to 6 weeks of double-blind treatment with flexible doses of either lurasidone 20-60 mg/d (n = 109) or placebo (n = 100). The study was conducted between September 2011 and October 2014. Change in sexual functioning was assessed utilizing the 14-item self-report Changes in Sexual Functioning Questionnaire (CSFQ-14) administered at baseline and week 6 endpoint. Change from baseline to week 6 in depression severity was assessed utilizing the Montgomery-Asberg Depression Rating Scale (MADRS) total score, the primary efficacy endpoint. Lurasidone significantly reduced mean MADRS total scores at week 6 endpoint (-20.5 vs -13.0; P < .001). Treatment with lurasidone was associated with significant endpoint improvement in CSFQ total scores versus placebo (+5.1 vs +3.1; P < .05). Fewer patients treated with lurasidone versus placebo shifted from normal to abnormal sexual function. The proportion of patients with a baseline-to-endpoint shift from normal to abnormal sexual function was smaller for lurasidone versus placebo (1.9% vs 4.3%; CSFQ criteria) at study endpoint. Use of higher lurasidone doses was not associated with greater impairment in sexual functioning. No treatment-emergent adverse events related to sexual function were reported during lurasidone treatment. In this secondary analysis of a placebo-controlled trial involving patients with MDD and mixed features, lurasidone was not associated with treatment-related sexual dysfunction. These findings were consistent across both structured assessments using a validated sexual functioning questionnaire (CSFQ) as well as adverse event reporting. ClinicalTrials.gov identifier: NCT01421134.

Ratings surveillance and reliability in a study of major depressive disorder with subthreshold hypomania (mixed features)

Site-independent ratings surveillance assessed ratings reliability in a clinical trial. Inter-rater reliability was assessed at the screen visit in a 6-week, double-blind, placebo-controlled study of lurasidone for the treatment of major depressive disorder (MDD) with subthreshold hypomanic ("mixed") symptoms (clinicaltrials.gov NCT01421134). Site-based Montgomery-Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) interviews were paired with 184 site-independent ratings derived from audio-digital recordings. The paired MADRS and YMRS scores were highly correlated (r=0.708 and 0.885, respectively) and generated minimal scoring discordance. The surveillance program identified 14 MADRS scores (7.6% of this sample) that were below the study entry criterion (MADRS ≥26) and resulted in screen failure. When present, paired scoring discordance was associated with symptom severity, interview length, interview quality, and the level of patient cooperation. Higher severity scores (MADRS ≥40 and YMRS ≥15) were associated with greater paired scoring discordance. Further, MADRS scores <30 and short MADRS interviews conducted in ≤12min revealed significantly more pairs of discordant outliers (p=0.04 and 0.009, respectively). The findings suggest that MDD patients with mixed features can be reliably assessed, that paired site-based and site-independent assessments were generally concordant, and that ratings surveillance may reinforce ratings precision.

Lurasidone in post-menopausal females with major depressive disorder with mixed features: Post-hoc analysis of a placebo-controlled trial

BackgroundSeveral studies have found that depressed, post-menopausal females may respond differently to antidepressants compared to pre-menopausal females. The atypical antipsychotic lurasidone, whose mechanism of action differs from SSRIs and other standard antidepressants, was shown in a 6-week randomized, flexible-dose, placebo-controlled study (n=209), to be effective in treating major depressive disorder (MDD) with mixed features (subthreshold hypomanic symptoms). This post-hoc analysis assessed the efficacy of lurasidone in this study by menopausal status. MethodsThe main outcome measure for this post-hoc analysis was change in MADRS score from baseline to week 6 endpoint for two lurasidone-treated subgroups: presumptive pre-menopausal (<52years) and presumptive post-menopausal (≥52years) patients, compared to placebo treatment, using a mixed-model for repeated-measures analysis, and calculation of the effect size for each subgroup. Additional efficacy assessments included the CGI-S, HAM-A and YMRS. An exploratory analysis was also conducted removing presumptive peri-menopausal women (ages 45–51years) to allow for clearer definition of pre- and post-menopausal status. ResultsA total of 56 lurasidone-treated and 47 placebo-treated pre-menopausal females, and 17 lurasidone-treated and 25 placebo-treated post-menopausal females were available from the larger study for comparison on key outcome measures. The pre- and post-menopausal subgroups had similar demographic and clinical characteristics at study baseline (other than age), including number of past major depressive episodes as well as depressive and manic symptom severity. Mean daily lurasidone dose was similar for each subgroup during the study. Both the primary and exploratory analyses showed that both lurasidone-treated post-menopausal and pre-menopausal females responded significantly compared to placebo (p=0.016 or less) on the MADRS, and that post-menopausal patients had a numerically larger response (effect size=0.96) than pre-menopausal patients (effect size=0.64). All other secondary outcome measures for lurasidone compared with placebo treatment were significant (p=0.045 or less) for both subgroups. ConclusionsIn this post-hoc analysis, lurasidone was found to be effective in treating post-menopausal MDD patients with mixed features (subthreshold hypomanic symptoms).

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension-CORRIGENDUM.

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension—CORRIGENDUM - Volume 22 Issue 4

Remission and recovery associated with lurasidone in the treatment of major depressive disorder with subthreshold hypomanic symptoms (mixed features): post-hoc analysis of a randomized, placebo-controlled study with longer-term extension.

This post-hoc analysis assessed rates of symptomatic and functional remission, as well as recovery (combination of symptomatic and functional remission), in patients treated with lurasidone for major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features). Patients with MDD plus two or three manic symptoms (defined as per the DSM-5 mixed-features specifier) were randomly assigned to flexible-dose lurasidone 20-60 mg/day (n=109) or placebo (n=100) for 6 weeks, followed by a 3-month open-label, flexible-dose extension study for U.S. sites only (n=48). Cross-sectional recovery was defined as the presence of both symptomatic remission (Montgomery-Åsberg Depression Rating Scale score ≤ 12) and functional remission (all Sheehan Disability Scale [SDS] domain scores ≤3) at week 6, and at both months 1 and 3 of the extension study ("sustained recovery"). A significantly higher proportion of lurasidone-treated patients (31.3%) achieved recovery (assessed cross-sectionally) compared to placebo (12.2%, p=0.002) at week 6. The number of manic symptoms at baseline moderated the effect size for attaining cross-sectional recovery for lurasidone treatment (vs. placebo) (p=0.028). Sustained recovery rates were higher in patients initially treated with lurasidone (20.8%) versus placebo (12.5%). In this post-hoc analysis of a placebo-controlled study with open-label extension that involved patients with MDD and mixed features, lurasidone was found to significantly improve the rate of recovery at 6 weeks (vs. placebo) that was sustained at month 3 of the extension study. The presence of two (as opposed to three) manic symptoms moderated recovery at the acute study endpoint.

The association between self-reported and clinically determined hypomanic symptoms and the onset of major mood disorders.

BackgroundHypomanic symptoms may be a useful predictor of mood disorder among young people at high risk for bipolar disorder.AimsTo determine whether hypomanic symptoms differentiate offspring of parents with bipolar disorder (high risk) and offspring of well parents (control) and predict the development of mood episodes.MethodHigh-risk and control offspring were prospectively assessed using semi-structured clinical interviews annually and completed the Hypomania Checklist-32 Revised (HCL-32). Clinically significant sub-threshold hypomanic symptoms (CSHS) were coded.ResultsHCL-32 total and active or elated scores were higher in control compared with high-risk offspring, whereas 14% of high-risk and 0% of control offspring had CSHS. High-risk offspring with CSHS had a fivefold increased risk of developing recurrent major depression (P=0.0002). The median onset of CSHS in high-risk offspring was 16.4 (6–31) years and was before the onset of major mood episodes.ConclusionsCSHS are precursors to major mood episodes in high-risk offspring and could identify individuals at ultra-high risk for developing bipolar disorder.Declaration of interestNone.Copyright and usage© The Royal College of Psychiatrists 2017. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) license.

Lurasidone effective in treating depression with mixed features

In what is believed to be the first placebo‐controlled trial of a medication treatment for patients with depression and subthreshold hypomanic symptoms, researchers have found that the atypical antipsychotic lurasidone was safe and effective over a 6‐week treatment period. Lurasidone demonstrated efficacy across a range of core mood symptoms associated with the disorder, the researchers reported.

Major depressive disorder with subthreshold hypomania (mixed features): Clinical characteristics of patients entered in a multiregional, placebo-controlled study

Major depressive disorder (MDD) associated with subthreshold hypomanic symptoms (mixed features), has been identified as a distinct nosological entity in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). We identified the predominant manic symptoms present at baseline in a multiregional, placebo-controlled trial involving 211 patients with MDD with mixed features (Clinicaltrials.govNCT01421134). Patients with 2 or 3 DSM-5 criteria defined manic symptoms were eligible for the study. At study baseline, increased talkativeness (pressure to keep talking) and flight of ideas (racing thoughts) were endorsed by approximately 65% of patients and a decreased need for sleep was endorsed by 40% of patients. Approximately 60% of patients also endorsed irritability and distractibility at baseline although these symptoms are not generally counted as part of the “mixed” depression diagnosis as they may overlap with criteria for MDD. Thus, five clinical symptoms characterized the manic presentation in the majority of patients diagnosed as having MDD with “mixed” features in this first placebo-controlled trial examining the use of a psychotropic medication (lurasidone) in this population. Our findings support the designation of MDD with mixed features specifier and suggest that this subpopulation of depressed patients may warrant additional medication beyond antidepressants.

Lurasidone for the Treatment of Major Depressive Disorder With Mixed Features: A Randomized, Double-Blind, Placebo-Controlled Study

Accumulating evidence indicates that manic symptoms below the threshold for hypomania (mixed features) are common in individuals with major depressive disorder. This form of depression is often severe and is associated with an increased risk for recurrence, suicide attempts, substance abuse, and functional disability. This study evaluated the efficacy and safety of lurasidone in major depressive disorder with mixed features. Patients meeting DSM-IV-TR criteria for major depressive disorder who presented with two or three protocol-defined manic symptoms were randomly assigned to 6 weeks of double-blind treatment with either lurasidone at 20-60 mg/day (N=109) or placebo (N=100). Changes from baseline in Montgomery-Åsberg Depression Rating Scale score (MADRS; primary outcome measure) and Clinical Global Impressions severity subscale score (CGI-S; key secondary outcome measure) were evaluated using a mixed model for repeated-measures analysis. Lurasidone significantly improved depressive symptoms and overall illness severity, assessed by least squares mean change at week 6 in the MADRS and CGI-S scores: -20.5 compared with -13.0 (effect size, 0.80) and -1.8 compared with -1.2 (effect size, 0.60), respectively. Significant improvement in manic symptoms, assessed by the Young Mania Rating Scale, was also observed, in addition to other secondary efficacy endpoints. Rates of discontinuation due to adverse events were low. The most common adverse events were nausea (6.4% and 2.0% in the lurasidone and placebo groups, respectively) and somnolence (5.5% and 1.0%). Lurasidone was effective and well tolerated in this study involving patients with major depressive disorder associated with subthreshold hypomanic symptoms (mixed features).

Risk of bipolar disorder and psychotic features in patients initially hospitalised with severe depression

Severe depression may be a risk factor for diagnostic conversion into bipolar disorder (BD), and psychotic depression (PD) has been consistently associated with BD. The aims of the present study were to investigate the stability of the diagnosis of severe depression and the differences between PD and non-psychotic severe depression (non-PD), as well as to assess the effectiveness of electroconvulsive therapy (ECT). Patients who were hospitalised for severe depression (diagnosed according to ICD-10) both with and without psychotic symptoms (n=89; mean age=55.6 years, SD=13.9) from 2001 to 2010 were retrospectively assessed. By the 75th month of follow-up assessments, 11(12.4%) patients had developed BD. Among these 11 converters, nine had developed BD within 1 year after admission. Only sub-threshold hypomanic symptoms were significantly related to developing BD. The number of depressive episodes and history of physical diseases were significantly increased in non-PD compared with PD patients, whereas ECT was significantly increased in PD compared with non-PD patients. There was a significant association between length of stay at the hospital and the number of days between admission and ECT. Sub-threshold hypomanic symptoms may represent a prodrome of BD or an indicator of an already manifest phenotype, especially in older patients, which suggests cautious use of antidepressants. In severe depression, non-PD may often occur secondary to physical diseases and patients may experience increased recurrences compared with PD patients, which may be a more 'primary' disorder and often requires ECT treatments. ECT is effective for severe depression regardless of the presence of any psychotic feature; the earlier ECT is introduced, the better the expected treatment outcome.

Major Depressive Disorder: Long-Term Course, Treatment, and Complications

Major Depressive Disorder: Long-Term Course, Treatment, and Complications

THE IMPORTANCE OF ANXIETY IN BOTH MAJOR DEPRESSION AND BIPOLAR DISORDER

Generalized anxiety disorder (GAD) is frequently co-morbid with major depression (MDD), and this becomes more so when the duration requirement is relaxed. Both anxiety diagnoses and anxious symptoms are more common in both unipolar and bipolar depression. This paper explores the relationship between anxious symptoms and GAD with both unipolar and bipolar depression. MDD and bipolar disorder (BPD) are compared in three important respects: the extent of their co-morbidity with anxious symptoms and GAD, the effects that anxiety has on outcome of MDD and BPD, and the effects that anxiety has on the probability of suicide in each disorder. Anxious diagnoses occur frequently in association with depressive disorders, albeit to a different extent in the various subtypes of depression. In both disorders, anxiety affects the outcome and makes suicidal thoughts, and completed suicide more likely. Anxious phenomena should be assessed whenever a depressive disorder is diagnosed. It is likely that the raised expectancy of anxious phenomena is related to an individual's premorbid level of negative affect, and it is possible that suicidal phenomena are related to subthreshold hypomanic symptoms.

Broadening bipolar diagnostic criteria: why not start with hypomania?

Broadening bipolar diagnostic criteria: why not start with hypomania?