Depressive Phase Of Bipolar Disorder Research Articles

Pharmacogenomic overlap between antidepressant treatment response in major depression & antidepressant associated treatment emergent mania in bipolar disorder

There is increasing interest in individualizing treatment selection for more than 25 regulatory approved treatments for major depressive disorder (MDD). Despite an inconclusive efficacy evidence base, antidepressants (ADs) are prescribed for the depressive phase of bipolar disorder (BD) with oftentimes, an inadequate treatment response and or clinical concern for mood destabilization. This study explored the relationship between antidepressant response in MDD and antidepressant-associated treatment emergent mania (TEM) in BD. We conducted a genome-wide association study (GWAS) and polygenic score analysis of TEM and tested its association in a subset of BD-type I patients treated with SSRIs or SNRIs. Our results did not identify any genome-wide significant variants although, we found that a higher polygenic score (PGS) for antidepressant response in MDD was associated with higher odds of TEM in BD. Future studies with larger transdiagnostic depressed cohorts treated with antidepressants are encouraged to identify a neurobiological mechanism associated with a spectrum of depression improvement from response to emergent mania.

Effectiveness of internet delivered cognitive behaviour therapy provided as routine care for people in the depressed phase of bipolar disorder treated with Lithium.

There is little research reporting the outcome of internet delivered cognitive behaviour therapy, (iCBT), which helps patients identify and modify unhelpful cognitions and behaviours, for the depressed phase of bipolar disorder as part of routine care. Demographic information, baseline scores and treatment outcomes were examined for patients of MindSpot Clinic, a national iCBT service who reported taking Lithium and their clinic records confirmed the diagnosis of bipolar disorder. Outcomes were completion rates, patient satisfaction and changes in measures of psychological distress, depression and anxiety measured by the Kessler-10 item (K-10), Patient Health Questionnaire 9 Item (PHQ-9), and Generalized Anxiety Disorder Scale 7 Item (GAD-7), compared to clinic benchmarks. Out of 21,745 people who completed a MindSpot assessment and enrolled in a MindSpot treatment course in a 7 year period, 83 reported taking Lithium and had a confirmed a diagnosis of bipolar disorder. Outcomes of reductions in symptoms were large on all measures (effect sizes > 1.0 on all measures, percentage change between 32.4% and 40%), and lesson completion and satisfaction with the course were also high. MindSpot treatments appear to be effective in treating anxiety and depression in people diagnosed with bipolar, and suggest that iCBT has the potential to overcome the under-use of evidence based psychological treatments of people with bipolar depression.

Stimulants in Bipolar Depression: Risks and Benefits

While mania is the illness hallmark, the depressive phase of bipolar disorder is the main driver of treatment resistance, functional disability, and suicidality. The 5 FDA approved anti-psychotic treatments for bipolar depression represent an important milestone for a clinical evidence base, but new ways of framing and rethinking care management for the depressive phase in bipolar disorder are needed. This article reviews the controversy surrounding the use of stimulants for bipolar depression. We summarize approved recommendations, discuss mechanisms of action, and compare risks and benefits to provide a new perspective and direction as how to individualize care and consider novel treatment strategies for patients with bipolar depression. [ Psychiatr Ann . 2023;53(2):73–78.]

Study on effect of Chronotherapy in depressive phase of Bipolar Disorder

Study on effect of Chronotherapy in depressive phase of Bipolar Disorder

A Case of Ruminative Hypomania Induced by High Dose Venlafaxine

IntroductionObsessive phenomena, when present, are usually seen in the depressive phase of bipolar disorder.ObjectivesThe peculiar case with aggravation in ruminative and obsessive thinking with simultaneous hypomania may widen our understanding of the phenomenology of antidepressant induced hypomanic symptoms.MethodsWe present a case of ruminative hypomania induced by high dose venlafaxine. Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D) and Yale Brown Obsessive Compulsive Scale (YBOCS) were used for symptom ratings.ResultsThe patient was 30 years old and she had treatment history of depression for 3 months. She had two consecutive suicide attempts with drugs in the week before she was hospitalized for suicidal risk. She was using venlafaxine 300 mg/day and olanzapin 2,5 mg/day; continuous ruminative thinking about the past and imaginary sexual affairs with former friends were apparent with an unremitting pattern, leading to intense psychomotor agitation and suicide attempts. Irritable mood, and increased energy was observed with continuous ruminations. She was diagnosed with bipolar-II-disorder, with mixed features and anxious distress (YMRS:17, HAM-D:22, YBOCS:34). After discontinuing venlafaxine and starting anti-manic treatment with haloperidol 10 mg/day in the first week, both affective symptoms and ruminations were improved (YMRS:2, HAM-D:4, YBOCS:8). Aripiprazol 20 mg/day and quetiapine 100 mg/day which were given for continuation treatment were also effective for preserving full remission.ConclusionsWhen prescribing high dose venlafaxine for treatment resistant depression, it should be remembered that this may induce hypomanic symptoms and prominent ruminative thinking which can be ameliorated with anti-manic treatment.DisclosureNo significant relationships.

Abstracts

Abstracts

A unified model of the pathophysiology of bipolar disorder.

This work provides an overview of the most consistent alterations in bipolar disorder (BD), attempting to unify them in an internally coherent working model of the pathophysiology of BD. Data on immune-inflammatory changes, structural brain abnormalities (in gray and white matter), and functional brain alterations (from neurotransmitter signaling to intrinsic brain activity) in BD were reviewed. Based on the reported data, (1) we hypothesized that the core pathological alteration in BD is a damage of the limbic network that results in alterations of neurotransmitter signaling. Although heterogeneous conditions can lead to such damage, we supposed that the main pathophysiological mechanism is traceable to an immune/inflammatory-mediated alteration of white matter involving the limbic network connections, which destabilizes the neurotransmitter signaling, such as dopamine and serotonin signaling. Then, (2) we suggested that changes in such neurotransmitter signaling (potentially triggered by heterogeneous stressors onto a structurally-damaged limbic network) lead to phasic (and often recurrent) reconfigurations of intrinsic brain activity, from abnormal subcortical-cortical coupling to changes in network activity. We suggested that the resulting dysbalance between networks, such as sensorimotor networks, salience network, and default-mode network, clinically manifest in combined alterations of psychomotricity, affectivity, and thought during the manic and depressive phases of BD. Finally, (3) we supposed that an additional contribution of gray matter alterations and related cognitive deterioration characterize a clinical-biological subgroup of BD. This model may provide a general framework for integrating the current data on BD and suggests novel specific hypotheses, prompting for a better understanding of the pathophysiology of BD.

Inferior frontal gyrus seed-based resting-state functional connectivity and sustained attention across manic/hypomanic, euthymic and depressive phases of bipolar disorder

ObjectiveSeed-based resting-state functional connectivity (rs-FC) of inferior frontal gyrus (IFG), as well as sustained attention cognitive deficit are consistently reported to be impaired in bipolar disorders. However, whether these deficits exist across mood states and euthymic state are lacking. We compared rs-FC of IFG and sustained attention of bipolar patients in (hypo) mania, depression and euthymia, with controls. We also explored the interrelationships between clinical, cognitive, and imaging measurements. MethodsParticipants included 110 bipolar subjects: 46 manic/hypomanic, 35 euthymic, and 29 depressed, matched with 41 healthy controls (HCs) underwent structural magnetic resonance imaging (MRI) and resting-state functional MRI scans. Seed-based functional connectivity analyses were performed focused on bilateral IFG seeds. Clinical symptoms and sustained attention function were measured. Stepwise linear regression analysis was conducted to explore predictors of sustained attention measurements. ResultsIncreased rs-FC between right IFG and bilateral frontal pole/superior frontal gyrus, precuneus, and posterior cingulate gyrus, as well as decreased rs-FC between right IFG and sensorimotor areas, anterior middle cingulate gyrus were found in all three bipolar subgroups compared with HCs. Impaired sustained attention measurement was found in bipolar manic/hypomanic and depressive subgroups compared with HCs. Linear regression analyses revealed a significant impact of the manic symptoms and psychotic symptoms on the performance of sustained attention task. ConclusionsOur results revealed that IFG seed-based resting-state functional networks involved in emotion regulation and cognitive function were trait-like deficit in bipolar patients. Higher manic levels and psychotic symptoms were predictors of a worse sustained attention performance.

Opposing Changes in the Functional Architecture of Large-Scale Networks in Bipolar Mania and Depression.

Manic and depressive phases of bipolar disorder (BD) show opposite symptoms in psychomotor, thought, and affective dimensions. Neuronally, these may depend on distinct patterns of alterations in the functional architecture of brain intrinsic activity. Therefore, the study aimed to characterize the spatial and temporal changes of resting-state activity in mania and depression, by investigating the regional homogeneity (ReHo) and degree of centrality (DC), in different frequency bands. Using resting-state functional magnetic resonance imaging (fMRI), voxel-wise ReHo and DC were calculated-in the standard frequency band (SFB: 0.01-0.10 Hz), as well as in Slow5 (0.01-0.027 Hz) and Slow4 (0.027-0.073 Hz)-and compared between manic (n = 36), depressed (n = 43), euthymic (n = 29) patients, and healthy controls (n = 112). Finally, clinical correlations were investigated. Mania was mainly characterized by decreased ReHo and DC in Slow4 in the medial prefrontal cortex (as part of the default-mode network [DMN]), which in turn correlated with manic symptomatology. Conversely, depression was mainly characterized by decreased ReHo in SFB in the primary sensory-motor cortex (as part of the sensorimotor network [SMN]), which in turn correlated with depressive symptomatology. Our data show a functional reconfiguration of the spatiotemporal structure of intrinsic brain activity to occur in BD. Mania might be characterized by a predominance of sensorimotor over associative networks, possibly driven by a deficit of the DMN (reflecting in internal thought deficit). Conversely, depression might be characterized by a predominance of associative over sensorimotor networks, possibly driven by a deficit of the SMN (reflecting in psychomotor inhibition).

Abnormal Functional Relationship of Sensorimotor Network With Neurotransmitter-Related Nuclei via Subcortical-Cortical Loops in Manic and Depressive Phases of Bipolar Disorder.

Manic and depressive phases of bipolar disorder (BD) show opposite psychomotor symptoms. Neuronally, these may depend on altered relationships between sensorimotor network (SMN) and subcortical structures. The study aimed to investigate the functional relationships of SMN with substantia nigra (SN) and raphe nuclei (RN) via subcortical-cortical loops, and their alteration in bipolar mania and depression, as characterized by psychomotor excitation and inhibition. In this resting-state functional magnetic resonance imaging (fMRI) study on healthy (n = 67) and BD patients (n = 100), (1) functional connectivity (FC) between thalamus and SMN was calculated and correlated with FC from SN or RN to basal ganglia (BG)/thalamus in healthy; (2) using an a-priori-driven approach, thalamus-SMN FC, SN-BG/thalamus FC, and RN-BG/thalamus FC were compared between healthy and BD, focusing on manic (n = 34) and inhibited depressed (n = 21) patients. (1) In healthy, the thalamus-SMN FC showed a quadratic correlation with SN-BG/thalamus FC and a linear negative correlation with RN-BG/thalamus FC. Accordingly, the SN-related FC appears to enable the thalamus-SMN coupling, while the RN-related FC affects it favoring anti-correlation. (2) In BD, mania showed an increase in thalamus-SMN FC toward positive values (ie, thalamus-SMN abnormal coupling) paralleled by reduction of RN-BG/thalamus FC. By contrast, inhibited depression showed a decrease in thalamus-SMN FC toward around-zero values (ie, thalamus-SMN disconnection) paralleled by reduction of SN-BG/thalamus FC (and RN-BG/thalamus FC). The results were replicated in independent HC and BD datasets. These findings suggest an abnormal relationship of SMN with neurotransmitters-related areas via subcortical-cortical loops in mania and inhibited depression, finally resulting in psychomotor alterations.

Quantitative separation of the depressive phase of bipolar disorder and major depressive disorder using electrovestibulography

Objectives: No electrophysiological, neuroimaging or genetic markers have been established that strongly relate to the diagnostic separation of bipolar disorder (BD) and major depressive disorder (MDD). This paper’s objective is to describe the potential of features, extracted from the recording of electrical activity from the outer ear canal, in a process called electrovestibulography (EVestG), for identifying depressed and partly remitted/remitted MDD and BD patients from each other.Methods: From EVestG data four sensory vestibulo-acoustic features were extracted from both background (no movement) and using a single supine-vertical translation stimulus to distinguish 27 controls, 39 MDD and 43 BD patients.Results: Using leave-one-out-cross-validation, unbiased parametric and non-parametric classification routines resulted in 78–83% (2–3 features), 80–81% (1–2 features) and 66–68% (3 features) accuracies for separation of MDD from BD, controls from depressed (BD & MDD) and the 3-way separation of BD from MDD from control groups, respectively. The main limitations of this study were the inability to fully disentangle the impact of prescribed medication from the responses and also the limited sample size.Conclusions: EVestG features can reliably identify depressed and partly remitted/remitted MDD and BD patients from each other.

Serum BICC1 levels are significantly different in various mood disorders.

PurposeMood disorders are recurrent chronic disorders with fluctuating mood states and energy, and misdiagnosis is common when based solely on clinical interviews because of overlapping symptoms. Because misdiagnosis may lead to inappropriate treatment and poor prognosis, finding an easily implemented objective tool for the discrimination of different mood disorders is very necessary and urgent. However, there has been no accepted objective tool until now. Recently, BICC1 has been identified as a candidate gene relating to major depressive disorder (MDD). Therefore, the aim of this study is to evaluate the ability of serum BICC1 to discriminate between various mood disorders, including MDD and the manic and depressive phases of bipolar disorder, namely bipolar mania (BM) and bipolar depression (BD).Patients and methodsSerum BICC1 levels in drug-free patients with MDD (n=30), BM (n=30), and BD (n=13), and well-matched healthy controls (HC, n=30) were measured with ELISA kits. Pearson correlation analyses were used to analyze the correlations between serum BICC1 levels and clinical information. Receiver operating characteristic (ROC) curve analysis was used to analyze the differential discriminative potential of BICC1 for different mood disorders.ResultsOne-way ANOVA indicated that serum BICC1 levels were significantly increased in all patient groups compared with the HC group and significantly different between each pair of patient groups. Correlation analyses found no relationship between serum BICC1 levels and any clinical variables in any study group. ROC curve analysis showed that serum BICC1 could discriminate among all three mood disorders from each other accurately with fair-to-excellent discriminatory capacity (area under the ROC curve from 0.787 to 1.0).ConclusionThe findings of this preliminary study indicated significant differences in serum BICC1 levels in patients with different mood disorders. This study provides preliminary evidence that serum BICC1 may be regarded as a promising, objective, easy-to-use tool for diagnosing different mood disorders.

Opposing patterns of neuronal variability in the sensorimotor network mediate cyclothymic and depressive temperaments.

Affective temperaments have been described since the early 20th century and may play a central role in psychiatric illnesses, such as bipolar disorder (BD). However, the neuronal basis of temperament is still unclear. We investigated the relationship of temperament with neuronal variability in the resting state signal-measured by fractional standard deviation (fSD) of Blood-Oxygen-Level Dependent signal-of the different large-scale networks, that is, sensorimotor network (SMN), along with default-mode, salience and central executive networks, in standard frequency band (SFB) and its sub-frequencies slow4 and slow5, in a large sample of healthy subject (HC, n = 109), as well as in the various temperamental subgroups (i.e., cyclothymic, hyperthymic, depressive, and irritable). A replication study on an independent dataset of 121 HC was then performed. SMN fSD positively correlated with cyclothymic z-score and was significantly increased in the cyclothymic temperament compared to the depressive temperament subgroups, in both SFB and slow4. We replicated our findings in the independent dataset. A relationship between cyclothymic temperament and neuronal variability, an index of intrinsic neuronal activity, in the SMN was found. Cyclothymic and depressive temperaments were associated with opposite changes in the SMN variability, resembling changes previously described in manic and depressive phases of BD. These findings shed a novel light on the neural basis of affective temperament and also carry important implications for the understanding of a potential dimensional continuum between affective temperaments and BD, on both psychological and neuronal levels.

Mapping the Human Brain in Frequency Band Analysis of Brain Cortex Electroencephalographic Activity for Selected Psychiatric Disorders.

There are still no good quantitative methods to be applied in psychiatric diagnosis. The interview is still the main and most important tool in the psychiatrist work. This paper presents the results of electroencephalographic research with the subjects of a group of 30 patients with psychiatric disorders compared to the control group of healthy volunteers. All subjects were solving working memory task. The digit-span working memory task test was chosen as one of the most popular tasks given to subjects with cognitive dysfunctions, especially for the patients with panic disorders, depression (including the depressive phase of bipolar disorder), phobias, and schizophrenia. Having such cohort of patients some results for the subjects with insomnia and Asperger syndrome are also presented. The cortical activity of their brains was registered by the dense array EEG amplifier. Source localization using the photogrammetry station and the sLORETA algorithm was then performed in five EEG frequency bands. The most active Brodmann Areas are indicated. Methodology for mapping the brain and research protocol are presented. The first results indicate that the presented technique can be useful in finding psychiatric disorder neurophysiological biomarkers. The first attempts were made to associate hyperactivity of selected Brodmann Areas with particular disorders.

Simultaneous analysis of olanzapine, fluoxetine, and norfluoxetine in human plasma using liquid chromatography-mass spectrometry and its application to a pharmacokinetic study

Adjunctive therapy with olanzapine and fluoxetine has been shown to be beneficial in treatment-resistant depression and the depressive phase of bipolar disorder. Consensus guidelines issued by the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie strongly recommend that patients taking olanzapine undergo therapeutic drug monitoring (TDM), and suggest that TDM is useful for patients taking fluoxetine. The aim of the current study was to develop and validate a sensitive, practical, and robust liquid chromatography-tandem mass spectrometry method (LC-MS/MS) for simultaneous determination of olanzapine, fluoxetine, and norfluoxetine in human plasma for routine TDM. Simple liquid-liquid extraction using ethyl acetate was used to extract olanzapine, fluoxetine, and norfluoxetine from 200 μL of pre-basified human plasma. Analytes were separated on an Agilent Eclipse Plus C18 column (4.6 × 100 mm, 5 μm) eluted with a mobile phase consisting of methanol:20 mM ammonium formate buffer (82.5:17.5, v/v), and then quantified using an electrospray ionization source operated in positive ion multiple reaction monitoring mode. The linear range for the analytes was 0.2–25 ng/mL, covering the vast majority of levels encountered in real-life samples. A weighting factor of 1/x2 best fit the calibration curves. The mean internal standard-normalized matrix effects for all analytes were 99.5%–110%. The extraction recoveries were 75%–85% for olanzapine and olanzapine‑d3, and 58%–69% for fluoxetine, norfluoxetine, and their deuterated internal standards. Accuracy and precision values also met the acceptance criteria. The stability assessments showed that QC samples containing the three analytes were stable for at least 1 d at room temperature, 21 d at −70 °C, and through three freeze-thaw cycles. Post-preparation storage for 2 d in the autosampler did not cause obvious degradation of the investigated compounds. This validated high performance LC-MS/MS method was successfully applied to a pharmacokinetic study in healthy male volunteers.

Increased oxidative stress in the mitochondria isolated from lymphocytes of bipolar disorder patients during depressive episodes

The present study aims to investigate the oxidative stress parameters in isolated mitochondria, as well as looking at mitochondrial complex activity in patients with Bipolar Disorder (BD) during depressive or euthymic episodes. This study evaluated the levels of mitochondrial complex (I, II, II-III and IV) activity in lymphocytes from BD patients. We evaluated the following oxidative stress parameters: superoxide, thiobarbituric acid reactive species (TBARS) and carbonyl levels in submitochondrial particles of lymphocytes from bipolar patients. 51 bipolar patients were recruited into this study: 34 in the euthymic phase, and 17 in the depressive phase. Our results indicated that the depressive phase could increase the levels of mitochondrial superoxide, carbonyl and TBARS, and superoxide dismutase, and could decrease the levels of mitochondrial complex II activity in the lymphocytes of bipolar patients. It was also observed that there was a negative correlation between the Hamilton Depression Rating Scale (HDRS) and complex II activity in the lymphocytes of depressive bipolar patients. In addition, there was a positive correlation between HDRS and superoxide, superoxide dismutase, TBARS and carbonyl. Additionally, there was a negative correlation between complex II activity and oxidative stress parameters. In conclusion, our results suggest that mitochondrial oxidative stress and mitochondrial complex II dysfunction play important roles in the depressive phase of BD.

Efficacy of vestibular stimulation treatment in the depressive phase of bipolar disorder: study protocol for a randomized, double-blind, controlled trial

Background and objectives: Bipolar disorder (BD) is a neuropsychiatric disorder characterized by the oscillation of mood states between hypoactive/pessimistic (depressive phase) and hyperactive/optimistic states (manic/hypomanic phase). Previous studies evidenced that a particular technique of neuro-vestibular stimulation is an effective treatment for major depression. This study will investigate the efficacy of the said vestibular stimulation technique in the depressive phase of BD, and will compare it with sham vestibular stimulation. Design: A double-blind, randomized controlled study. Methods: One hundred and twenty patients with bipolar type I or II, currently undergoing a depressive phase, will be randomized into the experimental group (n = 60) or control group (n = 60), receiving three sessions of real/sham vestibular stimulation. Outcome measures: The primary outcome is the change in Montgomery Asberg Depression Rating Scale scores from baseline to post 4 and 12 weeks. The secondary outcome is the vestibular activity assessed at baseline, post 4 and 2 weeks. Discussion: Currently, no treatment has proved efficacy for bipolar depression. Studies have demonstrated that lateralized neuro-vestibular stimulation is an effective treatment for mayor depression but has not been studied in the depressive phase of bipolar disorder. This investigation will give the first evidence supporting or denying the use of vestibular stimulation treatment in BD depression. Ethics and dissemination: This study protocol was approved by the Ethics Committee of SSMO (Servicio de Salud Metropolitano Oriente) in Santiago, Chile (approval No. 08032016) on March 8, 2016. The results of the study will be published in scientific journals and other media. Trial registration: ClinicalTrials.gov Identifier: NCT02778256.

Pharmacologic Treatment Options for Bipolar Disorder in Children and Adolescents

Purpose of review Bipolar disorder is a chronic and disabling condition that often presents in adolescence and leads to significant functional impairment, especially in the areas of emotional, cognitive, and social development. Pharmacotherapy is a vital component of the complex treatment of this disorder.The purpose of this review is to provide an overview of the available data on the management of bipolar disorder and the most common comorbid conditions in youth. Recent findings Several medications such as lithium and second-generation antipsychotics (risperidone, aripiprazole, olanzapine, quetiapine, and asenapine) are currently approved by the FDA for the management of acute mixed or manic phases of pediatric bipolar disorder. Very limited data are available on continuation treatment and management of depressive phases of bipolar disorder. There is some evidence that supports the use of a combination of an antipsychotic with lithium or an anticonvulsant for treatment of resistant cases. Summary Monotherapy with an atypical antipsychotic or lithium is the preferable initial treatment of acute manic or mixed episodes. The available evidence supports the use of an olanzapine/fluoxetine combination for the treatment of bipolar depression, which has also been approved by the FDA for this purpose. Additional studies are needed to evaluate safety and efficacy of psychopharmacological interventions, especially focusing on treatment of the depressive and maintenance phases of bipolar disorder.

Depression and Mania in Bipolar Disorder.

: Background: Episode duration, recurrence rates, and time spent in manic and depressive phases of bipolar disorder (BD) is not well defined for subtypes of the disorder.Methods: We reviewed the course, timing, and duration of episodes of mania and depression among 1130 clinically treated DSM-IV-TR BD patients of various types, and compared duration and rates as well as total proportion of time in depressive versus manic episodes during 16.7 average years at risk.Results: As expected, episodes of depressions were much longer than manias, but episode-duration did not differ among BD diagnostic types: I, II, with mainly mixed-episodes (BD-Mx), or with psychotic features (BD-P). Recurrence rates (episodes/year) and proportion of time in depression and their ratios to mania were highest in BD-II and BD-Mx subjects, with more manias/year in psychotic and BD-I subjects. In most BD-subtypes, except with psychotic features, there was more time in depressive than manic morbidity, owing mainly to longer depressive than manic episodes. The proportion of time in depression was highest among those who followed a predominant DMI course, whereas total time in mania was greatest in BD with psychotic features and BD-I. and with an MDI course.Conclusions: Subtypes of BD patients differed little in episode-duration, which was consistently much longer for depression. The findings underscore the limited control of bipolar depression with available treatments.

Pharmacotherapy of Acute Bipolar Depression in Adults: An Evidence Based Approach.

In the majority of cases of bipolar disorder, manic episodes are usually brief and typically responsive to currently available psychopharmacological agents. In contrast, depressive manifestations are more prevalent and persistent, and can present as major depressive/mixed episodes or residual interepisode symptoms. The depressive phase is often associated with other neuropsychiatric conditions, such as anxiety spectrum disorders, substance use disorders, stressor-related disorders, and eating disorders. It is viewed as a systemic disease with associated ailments such as metabolic syndrome, diabetes mellitus, and cardiovascular disease. There is an increased rate of mortality not only from suicide, but also from concomitant physical illness. This scenario is made worse by the fact that depressive symptoms, which represent the main disease burden, are often refractory to existing psychotropic drugs. As such, there is a pressing need for novel agents that are efficacious in acute depressive exacerbations, and also have applicable value in preventing recurrent episodes. The rationale of the present review is to delineate the pharmacotherapy of the depressive phase of bipolar disorder with medications for which there is evidence in the form of observational, open-label, or double-blind randomized controlled studies. In the treatment of acute bipolar depression in adults, a comprehensive appraisal of the extant literature reveals that among mood stabilizers, the most robust proof of efficacy exists for divalproex sodium; while atypical antipsychotics, which include olanzapine, quetiapine, lurasidone, and cariprazine, are also effective, as demonstrated in controlled trials.