Previous Major Depressive Episodes Research Articles

Effectiveness of vortioxetine for major depressive disorder in real-world clinical practice: US cohort results from the global RELIEVE study.

Effective treatment of major depressive disorder (MDD) involves addressing both depressive and functional symptoms, increasing patients' overall sense of well-being and quality of life (QoL). RELIEVE was an international observational, prospective study in patients ≥18 years with a current diagnosis of a major depressive episode (MDE) initiating vortioxetine in routine clinical practice; outcomes for the cohort of participants from the United States are presented here. Functioning was assessed at weeks 12 and 24 versus baseline using the Sheehan Disability Scale (SDS). Secondary effectiveness analyses assessed changes from baseline to weeks 12 and 24 in functioning, depression severity, cognitive symptoms, sexual function, and QoL. 244 participants had an average of 8.2 previous MDEs; mean duration of their current MDE at baseline was 93.5 weeks. Vortioxetine was used as second- or later-line treatment for 80.5% of participants. Least-squares mean (SE) SDS total score significantly decreased from baseline by 7.19 (0.52) points at week 12 and 8.19 (0.56) points at week 24 (p < 0.0001 for both). Significant improvements were also reflected across SDS subscores, depression severity, cognitive function, sexual function, and QoL. Healthcare resource utilization and productivity parameters also improved. Adverse events were observed in 21.8% of patients, with nausea being the most common (7.3%). This real-world study demonstrated improvements in functioning, depressive symptoms, and cognitive function in patients with MDD treated with vortioxetine in routine clinical practice in the cohort of patients enrolled in the United States. Outcomes were consistent with the efficacy and safety profile of vortioxetine in randomized controlled trials.

Vortioxetine 5, 10, and 20 mg significantly reduces the risk of relapse compared with placebo in patients with remitted major depressive disorder: The RESET study

BackgroundMaintenance therapy for major depressive disorder (MDD) is typically recommended at the dose on which the patient was stabilized. However, for some patients, dose alteration may be required. We investigated multiple vortioxetine doses versus placebo for relapse prevention in patients achieving remission with vortioxetine 10 mg daily. MethodsIn this US-based, randomized withdrawal study, outpatients (N = 1106, aged 18–75 years) with recurrent MDD (Montgomery-Åsberg Depression Rating Scale [MADRS] score ≥26), a current major depressive episode (MDE) (8 weeks–18 months’ duration), and ≥2 previous MDEs were treated with open-label vortioxetine 10 mg once daily orally for 16 weeks. Responders at week 8 (≥50% MADRS score reduction) achieving remission (MADRS score ≤12) at weeks 14 and 16 (N = 580) were randomized to vortioxetine 5, 10, or 20 mg or placebo in a 32-week double-blind period. The primary outcome was time to first relapse over the first 28 weeks; secondary outcomes (relapse, change in total MADRS, Clinician Global Impression-Severity [CGI-S]) were evaluated at 32 weeks. ResultsTime to relapse was longer and cumulative relapse rates were lower for vortioxetine 5 mg (19.3%), 10 mg (17.9%), and 20 mg (17.4%) versus placebo (32.5%) over 28 weeks (p<0.05 for all). CGI-S scores remained stable and adverse events were generally mild-to-moderate. LimitationsExtrapolation of results to patients achieving remission with vortioxetine doses other than 10 mg should be made with caution. ConclusionFor patients with MDD achieving symptomatic remission at 10 mg/day, all doses of vortioxetine were effective for relapse prevention, with acceptable tolerability.

Effects of bilateral transcranial direct current stimulation on working memory and global cognition in older patients with remitted major depression: A pilot randomized clinical trial.

To assess the effects of a 10-day course of bilateral anodal transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) on working memory and global cognition in elderly participants with remitted major depressive disorder at 14 days (primary outcome) and 90 days (secondary outcome) post intervention. Randomized double blind controlled trial (clinicaltrials.gov # NCT02212366). Community dwelling outpatient setting. Sixty or older with previous single or recurrent episodes of major depression currently in full remission. A 10 day course of active or sham bilateral DLPFC anodal tDCS. (a) Working memory assessed by a computerized N back task, and (b) global cognition assessed by a standard paper and pencil neuropsychological test battery. Thirty-three participants, (mean (SD) age = 66. 5 (5.7) year) were enrolled, out of which 18 (mean (SD) age = 66. 3 (5.8) year) were randomized to active tDCS and 15 (mean (SD) age = 66. 7 (5.8) years) to sham tDCS. All randomized participants except one from the sham group -completed the tDCS course. There were no differences between the groups on working memory performance or global cognition at 14 or 90 days post intervention. Both groups showed promising changes in working memory and global cognition over time. tDCS was well tolerated in older patients with remitted MDD, however, as compared to the sham group, it did not improve working memory or global cognition. Future studies should investigate tDCS with alternative parameters to enhance cognition in this population.

Predictors ofrecurrence of major depressive disorder.

A total of 201 patients with major depressive disorder from four hospitals in Malaysia were followed up for 5 years to determine the prognostic factors of recurrent major depressive disorder that could potentially contribute to improving the management of MDD patients. For each individual patient, at the time of recruitment as part of a case-control study, information was collected on recent threatening life events, personality and social and occupational functioning, while blood samples were collected to genotype single nucleotide polymorphisms of vitamin D receptor (VDR), zinc transporter-3 (ZnT3), dopamine transporter-1 (DAT1), brain-derived neurotropic factor (BDNF), serotonin receptor 1A (HT1A) and 2A (HT2A) genes. Kaplan-Meier and Cox-regression were used to estimate hazard functions for recurrence of major depressive disorder. Individuals with severe MDD in previous major depressive episodes had five and a half times higher hazard of developing recurrence compared to mild and moderate MDD (HR = 5.565, 95% CI = 1.631-18.994, p = 0.006). Individuals who scored higher on social avoidance had three and a half times higher hazard of recurrence of MDD (HR = 3.525, 95% CI = 1.349-9.209; p = 0.010). There was significant interaction between ApaI +64978C>A single nucleotide polymorphism and severity. The hazard ratio increased by 6.4 times from mild and moderate to severe MDD for A/A genotype while that for C/A genotype increased by 11.3 times. Social avoidance and severity of depression at first episode were prognostic of recurrence. Screening for personality factors at first encounter with MDD patients needs to be considered as part of the clinical practice. For those at risk of recurrence in relation to social avoidance, the psychological intervention prescribed should be customized to focus on this modifiable factor. Prompt and appropriate management of severe MDD is recommended to reduce risk of recurrence.

Risk Factors of Relapse After Successful Electroconvulsive Therapy for Taiwanese Patients With Major Depression.

Major depressive disorder is a recurrent illness. Treatment strategies are generally focused on achieving remission and preventing relapse/recurrence. The aim of this study was to explore the risk factors associated with relapse for remitted patients during the 12-week follow-up. This was an open-label trial for major depressive disorder patients receiving acute treatments with electroconvulsive therapy (ECT) and continuation medication in the 12-week follow-up. Symptom severity and psychosocial functioning were assessed using the 17-item Hamilton Rating Scale for Depression (HAMD-17) and the Work and Social Adjustment Scale at each visit. Remission was defined as a HAMD-17 of 7 or less after acute treatment. Relapse was defined as a HAMD-17 of 14 or greater. Subjects achieving remission after acute treatments were included for analysis. Survival analysis was used to investigate the factors associated with relapse. Sixty patients receiving ECT for acute treatment were enrolled for 12-week follow-up. Using Cox regression analysis, a greater number of previous major depressive episodes and greater baseline Work and Social Adjustment Scale scores were significantly associated with shorter time to relapse. The goal of acute treatment should focus on functional remission to prevent relapse. Further studies related to more effective treatments to prevent relapse after acute ECT are required in the future.

The association between the number of previous episodes and modifiable vulnerability factors in remitted patients with recurrent depression.

ObjectiveRemitted patients with a history of several previous major depressive episodes have a higher risk of relapse/recurrence than patients with fewer previous episodes, and the probability of another episode increases progressively with each successive episode. This study examines the association between the number of previous episodes and modifiable vulnerability factors in remitted patients with recurrent depression.MethodsPatients with recurrent depression (DSM-IV-diagnosed) who were in remission (N = 214) were recruited between September 2011 and July 2016. The association was examined between the number of previous episodes and the following factors: i.e. interpersonal functioning, daily stress, sense of mastery, coping and dysfunctional beliefs.ResultsA history of more previous episodes was associated with higher levels of interpersonal problems (P < .001), daily stress (P = .04) and a lower sense of mastery (P = .05). Interpersonal problems were most strongly associated with more previous episodes in a Generalized Linear Regression model. In the domain of interpersonal problems, the subscales that showed the strongest relationship were domineering/controlling, vindictive/self-centred, socially inhibited and self-sacrificing.ConclusionsPatients with a history of more depressive episodes reported higher levels of interpersonal problems, daily stress and a lower sense of mastery. Future studies should examine these factors in a longitudinal cohort and look at whether the effect of interventions to prevent relapse can be explained by targeting these psychological factors.Trial registrationNetherlands Trial Register: 2599.

The TRKB rs2289656 genetic polymorphism is associated with acute suicide attempts in depressed patients: A transversal case control study.

IntroductionSuicide Attempts (SA) are the main complications of Major Depressive Episodes (MDE) and are difficult to predict. Suicide is associated with the expression of Receptor Tyrosin-Kinase B (TRKB), the receptor of the Brain Derived Neurotrophic Factor (BDNF) involved in MDE. However, the impact of its genetic polymorphisms as predictive factors of SA should be clarified. Our main aim is to assess the association of 8 TRKB genetic polymorphisms and SA in depressed patients.Material and methodsIn 624 patients currently experiencing an MDE in the context of Major Depressive Disorder (MDD) (METADAP study), we assessed the association between 8 TRKB genetic polymorphisms (rs1778933, rs1187352, rs2289658, rs2289657, rs2289656, rs3824519, rs56142442 and rs1439050) and acute (previous month) or past (older than one month) SA. Bonferroni corrections and multivariate analysis adjusted for age, sex, level of education, marital status, Hamilton Depression Rating Scale score and previous MDE were used.ResultsThe rs2289656 was associated with acute SA (CC = 28.5%, CT = 15.0% and TT = 11.5%, p = 0.0008). However, the other SNPs were not. Patients with the CC genotype had a higher rate of acute SA (28.5%) as compared to T carriers (14.6%) (adjusted OR = 2.2, CI95% [1.4; 3.5], p<0.0001).ConclusionThe TRKB rs2289656 CC genotype is associated with a 2.2 fold higher risk of acute SA in depressed patients. If this result could be confirmed, this TRKB SNP may be assessed to contribute to the prediction of SA in depressed patients.

Switch from previous major depression comorbid with CLIPPERS to mania-like episode following glucocorticosteroid therapy: a case report

Bipolar disorder is associated with high rates of general medical conditions, but few cases of overlap between bipolar disorder and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids...

Effectiveness of long-term vortioxetine treatment of patients with major depressive disorder

To investigate the effectiveness, safety, and tolerability of vortioxetine in patients treated at therapeutic doses (5–20mg/day) for both acute and maintenance treatment, patient-level data were pooled from 5 long-term (52-week), open-label extension studies of major depressive disorder. The mean (±standard deviation) MADRS total score improved from 17.1±10.2 at the start of maintenance therapy to 7.6±8.2 (observed cases [OC]) or 10.3±9.9 (last observation carried forward [LOCF]) at week 52. The mean HAM-A total scores improved from 11.3±6.9 to 6.0±6.0 (OC) or 7.5±6.7 (LOCF) and the mean CGI-S score improved from 3.11±1.20 to 1.94±1.08 (OC) or 2.27±1.26 (LOCF) at week 52. Response and remission rates increased over time. At week 52, the total response rate was 75.4% (n=916/1215, LOCF) and the total remission rate was 60.7% (n=738/1215, LOCF). There were no differences in effectiveness as assessed by MADRS total scores at week 52 in subgroups based on gender, age (<55 vs ≥55 years), baseline HAM-A total score (<20 vs ≥20), baseline MADRS total score (<30 vs ≥30), previous major depressive episodes (MDEs) (<3 vs ≥3) or current MDE duration (<6 vs ≥6 months) at the start of the lead-in studies, or response status (≥50% decrease in MADRS total score during the lead-in study). The most commonly reported adverse event during the maintenance period was nausea.

Facial recognition of happiness among older adults with active and remitted major depression

Biased emotion processing in depression might be a trait characteristic independent of mood improvement and a vulnerable factor to develop further depressive episodes. This phenomenon of among older adults with depression has not been adequately examined. In a 2-year cross-sectional study, 59 older patients with either active or remitted major depression, or never-depressed, completed a facial emotion recognition task (FERT) to probe perceptual bias of happiness. The results showed that depressed patients, compared with never depressed subjects, had a significant lower sensitivity to identify happiness particularly at moderate intensity of facial stimuli. Patients in remission from a previous major depressive episode but with none or minimal symptoms had similar sensitivity rate to identify happy facial expressions as compared to patients with an active depressive episode. Further studies would be necessary to confirm whether recognition of happy expression reflects a persistent perceptual bias of major depression in older adults.

Treatment resistant depression or dementia: a case report.

Summary: The current case describes a 78-year-old female with two previous episodes of major depression who presented with both symptoms of depression (amotivation and flattened affect) and typical symptoms of dementia (impaired memory and executive functioning). Even after a detailed clinical exam and neuropsychiatric testing, it remained difficult to definitively classify the diagnosis as either treatment-resistant depression or old-age dementia. After 8 weeks of inpatient treatment, including changing her reserpine-based antihypertensive medication, adjusting her antidepressants, and providing psychotherapy, her depressive and anxiety symptoms improved, but most of her cognitive symptoms persisted. Her symptoms did not change over 7 months of post-hospitalization follow-up. She subsequently developed advanced breast cancer and started chemotherapy; at this point her depressive and cognitive symptoms became more pronounced. We conclude that it will take two-to-three years of follow-up to determine whether the cognitive symptoms are residual to her depression or a newly emerging dementia (or both). This case shows that for elderly patients who have symptoms of both depression and dementia, detailed clinical examination and neuropsychiatric testing may need to be combined with longitudinal assessment of their responsiveness to treatment before a definitive diagnosis can be assigned.

Recurrent Major Depressive Disorder of a Young Woman.

Questions are presented at “consideration points” that follow a section that gives information about the case. One or more choices may be correct for each question; make your choices on the basis of your clinical knowledge and the history provided. Read all of the options for each question before making any selections. You are given points on a graded scale for the best possible answer(s), and points are deducted for answers that would result in a poor outcome or delay your arriving at the right answer. Answers that have little or no impact receive zero points. At the end of the exercise, you will add up your points to obtain a total score.

First manic episode in a patient with a frontal meningioma

IntroductionPsychiatric symptoms are common among brain tumor patients. Meningiomas are the most common benign brain tumors accounting for 13 to 26% of all intracranial tumors and might present exclusively with psychiatric symptoms. To diagnose a manic episode according to DSM-5 criteria the episode must not be attributable to the physiological effects of a substance or to another medical condition.Objectives/aimsDescribe a case of first manic episode with a frontal meningioma along with a brief review of available literature.MethodsThe case we report is based on information collected from interviews with the patient and the family members as well as from the clinical files. The literature review was performed using the PubMed database.ResultsWe describe the case of a 58-year-old woman presenting with symptoms of a first manic episode with psychotic features. There were no previous hypomanic or major depressive episodes. In order to exclude organic causes a brain CT scan was performed that revealed a possible frontal lesion. A brain MRI confirmed the presence of a frontal meningioma with an approximate diameter of 1.4 cm.ConclusionsThe majority of the cases described in the literature refer to large tumors presenting with major depressive symptoms. Given the absence of similar cases in the literature, it seems unlikely that such a small benign lesion may cause a manic episode with psychotic features. Nevertheless, we cannot exclude that possibility.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Real-world determinants of adjunctive antipsychotic prescribing for patients with major depressive disorder and inadequate response to antidepressants: a case review study.

IntroductionPatients with major depressive disorder (MDD) often fail to respond to first-line antidepressant treatments (ADTs); subsequent strategies include dosage increase, switch to a different ADT, or addition of another ADT or other drug. The objective of this prospective, case review study was to identify factors that influence the decision to prescribe adjunctive antipsychotics for patients with MDD and inadequate response to ADT.MethodsPsychiatrists or primary care physicians (n = 411) based in the USA and Europe each completed an online survey for ten consecutive adults with MDD and inadequate response to ADTs, and for whom a treatment change was considered. A t test was used to compare survey responses between groups of patients.ResultsThe survey was completed for 4018 patients; an adjunctive antipsychotic was considered for 961/4018 patients (23.9%) and actually prescribed for 514/4018 (12.8%). Compared with patients not considered for an adjunctive antipsychotic, those who were considered for this treatment had more previous major depressive episodes (MDEs), longer duration of the current MDE, more severe illness both at ADT initiation and current consultation, and more treatment changes. Patients who were prescribed adjunctive antipsychotics had at baseline more functional impairment and absences from work than those considered for but not prescribed this treatment. Key symptoms that prompted physicians to consider antipsychotics were psychotic symptoms, psychomotor agitation, hostility, irritability, impulsivity, and anger bursts. Anxious mood and irritability were mentioned significantly more often by physicians who actually prescribed adjunctive antipsychotics. Obstacles to prescribing included a tendency to wait to see if symptoms improved and concern over side effects.ConclusionThis real-world study suggested that the decision to prescribe an adjunctive antipsychotic for patients with MDD and inadequate response to ADT is influenced by a broad spectrum of factors, predominantly related to severity of illness, functional impairment, and symptom profile.FundingOtsuka Pharmaceutical Development & Commercialization, Inc. (Princeton, USA) and H. Lundbeck A/S (Valby, Denmark).Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0207-3) contains supplementary material, which is available to authorized users.

Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial

Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months. In this single-blind, parallel, group randomised controlled trial (PREVENT), we recruited adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants, from primary care general practices in urban and rural settings in the UK. Participants were randomly assigned to either MBCT-TS or maintenance antidepressants (in a 1:1 ratio) with a computer-generated random number sequence with stratification by centre and symptomatic status. Participants were aware of treatment allocation and research assessors were masked to treatment allocation. The primary outcome was time to relapse or recurrence of depression, with patients followed up at five separate intervals during the 24-month study period. The primary analysis was based on the principle of intention to treat. The trial is registered with Current Controlled Trials, ISRCTN26666654. Between March 23, 2010, and Oct 21, 2011, we assessed 2188 participants for eligibility and recruited 424 patients from 95 general practices. 212 patients were randomly assigned to MBCT-TS and 212 to maintenance antidepressants. The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months (hazard ratio 0·89, 95% CI 0·67-1·18; p=0·43), nor did the number of serious adverse events. Five adverse events were reported, including two deaths, in each of the MBCT-TS and maintenance antidepressants groups. No adverse events were attributable to the interventions or the trial. We found no evidence that MBCT-TS is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence. Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence, residual depressive symptoms, and quality of life. National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula.

Association of testosterone levels and future suicide attempts in females with bipolar disorder

BackgroundConsiderable evidence suggests that testosterone may play a role in the pathophysiology of mood disorders in females. This is the first prospective study to examine whether blood testosterone levels predict suicide attempts in females with bipolar disorder. MethodsFemales with a DSM-IV diagnosis of a bipolar disorder in a depressive or mixed episode with at least one past suicide attempt were enrolled. Demographic and clinical parameters were assessed and recorded. Plasma testosterone was assayed using a double antibody radioimmunoassay procedure. Patients were followed up prospectively for up to 2.5 years. ResultsAt baseline, testosterone levels positively correlated with the number of previous major depressive episodes and suicide attempts. Cox proportional hazards regression analysis found that higher baseline testosterone levels predicted suicide attempts during the follow-up period. LimitationsA limitation of the study is that the sample size is modest. Another limitation is that we did not have a bipolar nonattempter or healthy volunteer control group for comparison. ConclusionTestosterone levels may predict suicidal behavior in women with bipolar disorder.

Successful Use of Agomelatine in the Treatment of Major Depression in a Woman Taking Tamoxifen

The selective estrogen receptor modulator, tamoxifen, is extensively used for the endocrine treatment of all stages of hormone receptor-positive breast cancer. Tamoxifen is a mainly inactive prodrug, necessitating metabolism by the cytochrome P450 (CYP450) pathway, predominantly the Cytochrome P450 2D6 (CYP2D6), into the active metabolites 4-hydroxytamoxifen and, in particular, endoxifen to achieve its therapeutic effect. As several women treated with tamoxifen may experience depressive symptoms or may have a previous or actual major depressive episode with ongoing antidepressant treatment or need for a new-onset therapy, the coprescription of an antidepressant drug may be particularly problematic as several antidepressants are potent CYP2D6-inhibiting drugs. We herein report a case of a patient with major depression and concurrent tamoxifen therapy successfully treated with agomelatine monotherapy.

Maintenance Cognitive-Behavioral Therapy and Manualized Psychoeducation in the Treatment of Recurrent Depression: A Multicenter Prospective Randomized Controlled Trial

This multicenter study compared the relapse and recurrence outcomes of two active treatments, maintenance cognitive-behavioral therapy (CBT) and manualized psychoeducation, both in addition to treatment as usual, in patients in remission from depression. This was a multicenter prospective randomized observer-blinded study with two parallel groups. The authors assessed 180 patients with three or more previous major depressive episodes who met remission criteria over a 2-month baseline period and who were randomly assigned to 16 sessions of either maintenance CBT or manualized psychoeducation over 8 months and then followed up for 12 months. The main outcome measure was time to first relapse or recurrence of a major depression, based on DSM-IV criteria, as assessed by blinded observers with the Longitudinal Interval Follow-Up Evaluation. Cox regression analysis showed that time to relapse or recurrence of major depression did not differ significantly between treatment conditions, but a significant interaction was observed between treatment condition and number of previous episodes (<5 or ≥5). Within the subsample of patients with five or more previous episodes, maintenance CBT was significantly superior to manualized psychoeducation, whereas for patients with fewer than five previous episodes, no significant treatment differences were observed in time to relapse or recurrence. The results indicate that maintenance CBT has significant effects on the prevention of relapse or recurrence only in patients with a high risk of depression recurrence. For patients with a moderate risk of recurrence, nonspecific effects and structured patient education may be equally effective.

Reduced Serum Nerve Growth Factor in Patients With Late-Life Depression

Nerve growth factor (NGF) is one of the most abundant neurotrophic factors in the central nervous system and has been involved in several neuropsychiatric disorders. We recruited 77 age- and gender-matched elderly subjects (38 with late-life depression, 17 with previous major depressive episode, and 22 healthy subjects in the comparison group). Serum concentration of NGF was determined by enzyme-linked immunosorbent assay. NGF levels were significantly reduced in the depressed patients (p = 0.002) as compared with healthy elderly controls. Elderly control subjects with previous depressive episode also showed a significant reduction in NGF levels as compared with controls (p <0.01); NGF levels were similar between patients with current depressive episode and previous depressive episode (p = 0.2). The present findings provide additional evidence to the relevance of reduced neurotrophic support in the pathophysiology of late-life depression. Also, reduced serum NGF level may be a state marker of depression in elderly subjects.

Bipolar Spectrum Disorder: Origins and State of the Art

The threshold chosen by categorical mental health classifications like DSM-IV-TR or ICD-10 for the diagnosis of bipolar disorders (BP) is too high, elevating the risk of misdiagnosing cases that closely resemble BP under several clinical variables like “major depressive disorder”. Acknowledging and providing the necessary weight to the BP subthreshold forms may improve the clinical practice and reduce the number of patients with misdiagnosis, creating opportunities for better treatment. Increasing evidence support the bipolar spectrum disorder (BPS) concept and factors such us earlier onset age of the first major depressive episode (MDE), brief duration of MDEs, rapid onset of MDEs, more than five previous MDEs, family history of BP, treatment-resistant depression, suicidal behavior, postpartum depression, atypical features, psychotic traits, irritability, overactivity, comorbidity with anxiety disorders, substance abuse, borderline personality disorder, migraine, and irritable temperament are well validated differentiators between unipolar and bipolar depressive disorders. Identifying those factors could increase the lifetime prevalence of BPS to at least 4.8%. New studies on the diagnosis and management of BP should focus on the development of diagnostics dimensional models with categorical benchmarks to recognize BP sub-threshold forms, on the selection of biomarkers for early identification of patients with BPS, especially those with BP family history, and on the promotion of joint efforts between academia, industry, government, and community to search new interventions in BPS management. Keywords: Temperament, Bipolar Disorder, Bipolar Depression, Hypomania, Bipolar Spectrum, Cyclothymia