Bipolar disorder is manifested as severe dysregulation of mood with recurrent manic and major depressive episodes. It is associated with psychiatric and medical comorbidities, inadequate response to currently available pharmacological agents and a progressively deteriorating course in many patients. The index episode is often depressive in nature, while the first manic or hypomanic episode may occur several years later in the course of the disorder causing delay in diagnosis and use of inappropriate treatment strategies. Staging has been used to great advantage in other branches of medicine like cardiology and oncology. There is growing realization that major mental disorders are fundamentally progressive, with simpler treatment requirements and better prognosis during initial stages of the illness. Defining these conditions into clinically applicable stages not only helps in better understanding the trajectory of a particular disorder, but also assists in management. Patients with a chronic, recalcitrant condition like bipolar disorder are likely to greatly benefit from this approach. If the illness is correctly identified early in its course, proper treatment can be instigated arresting progression to latter phases which are associated with myriad complications in the biopsychosocial realm. With these considerations, a search of the MEDLINE data base was conducted to seek out literature pertaining to staging models in bipolar disorder. A thorough scrutiny of the existing research work revealed that a number of investigators have endeavored to stage define bipolar disorder. This paper outlines staging proposals for bipolar disorder which have the greatest supporting evidence in the literature.
Allostasis ; Biomarkers ; Bipolar Disorder* ; Cardiology ; Comorbidity ; Diagnosis ; Humans ; Mental Disorders ; Prognosis ; Research Personnel

Major depressive disorder and bipolar disorders are among the commonest neuropsychiatric conditions, affecting persons of both sexes which belong to all age groups. Comorbidity is the rule rather than the exception; anxiety spectrum disorders, somatoform disorders, eating disorders and substance use disorders frequently co-exist with mood disorders. Catatonia is a serious complication of the latter and every patient with a severe affective exacerbation should be assessed for the presence of catatonic signs and symptoms. In a significant minority of patients, symptoms show treatment resistance; many patients experience severe hopelessness and suicidal ideation, causing high rates of morbidity and mortality in afflicted individuals. Pharmacological management is challenging and currently available psychotropic agents often fall short of inducing remission. Second generation antipsychotics have been shown in a number of studies as having an antidepressant and mood stabilizing effect. Aripiprazole is a novel antipsychotic which is being increasingly used in difficult to treat mood disorders patients. Several controlled and uncontrolled studies have shown the efficacy and safety of this medication in subjects of all ages. Here a case series of three patients is presented who suffered from refractory mood disorders but responded to aripiprazole with complete remission of affective symptoms.
Affective Symptoms ; Antipsychotic Agents ; Anxiety ; Bipolar Disorder ; Catatonia ; Comorbidity ; Depressive Disorder, Major ; Feeding and Eating Disorders ; Humans ; Mood Disorders* ; Mortality ; Somatoform Disorders ; Substance-Related Disorders ; Suicidal Ideation ; Aripiprazole

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.
Adult* ; Anticonvulsants ; Antipsychotic Agents ; Anxiety ; Bipolar Disorder* ; Cardiovascular Diseases ; Depression ; Diabetes Mellitus ; Drug Therapy* ; Eating ; Humans ; Lurasidone Hydrochloride ; Mortality ; Psychotropic Drugs ; Quetiapine Fumarate ; Substance-Related Disorders ; Suicide ; Valproic Acid

Bipolar disorder is a chronic, recurrent condition with the usual onset during adolescence or early adulthood. In the Diagnostic and Statistical Manual of Mental Disorders 5th edition, it is conceptualized as a spectrum disorder usually associated with such comorbidities as anxiety disorders and substance use disorders. It is a relatively prevalent condition often complicated by mixed episodes, rapid cycling, subsyndromal symptoms, and treatment refractoriness. In spite of carrying substantial morbidity and mortality, effective treatments are few and far between and conventional mood stabilizers are often unsuccessful in controlling the various manifestations of the disorder. In this scenario, second generation antipsychotics are emerging as treatments with valid efficacy in all phases of bipolar disorder. Quetiapine is a versatile atypical antipsychotic which was first approved for the treatment of schizophrenia, but latter on the basis of controlled studies earned United States Food and Drug Administration's approval for acute as well as maintenance treatment of this difficult to treat condition. In this review, recently published studies in the last 10 years were examined to update the knowledge about the efficacy and safety of quetiapine in the treatment of bipolar disorder. The medication's clinical pharmacology was first considered followed by a literature review summarizing its uses in bipolar disorder. The conclusion was that quetiapine was efficacious in manic, mixed and depressive episodes and as a maintenance agent with a good tolerability profile.
Adolescent ; Antipsychotic Agents ; Anxiety Disorders ; Bipolar Disorder* ; Comorbidity ; Diagnostic and Statistical Manual of Mental Disorders ; Drug Therapy* ; Humans ; Mortality ; Pharmacology, Clinical ; Schizophrenia ; Substance-Related Disorders ; United States ; Quetiapine Fumarate

Bipolar disorder is a severe and enduring psychiatric condition which in many cases starts during early adulthood and follows a relapsing and remitting course throughout life. In many patients the disease follows a progressive path with brief periods of inter-episode recovery, sub-threshold symptoms, treatment resistance and increasing functional impairment in the biopsychosocial domains. Knowledge about the neurobiology of bipolar disorder is increasing steadily and evidence from several lines of research implicates immuno-inflammatory mechanisms in the brain and periphery in the etiopathogenesis of this illness and its comorbidities. The main findings are an increase in the levels of proinflammatory cytokines during acute episodes with a decrease in neurotrophic support. Related to these factors are glial cell dysfunction, neuro-endocrine abnormalities and neurotransmitter aberrations which together cause plastic changes in the mood regulating areas of the brain and neuroprogression of the bipolar diathesis. Research in the above mentioned areas is providing an opportunity to discover novel biomarkers for the disease and the field is reaching a point where major breakthroughs can be expected in the not too distant future. It is hoped that with new discoveries fresh avenues will be found to better treat an otherwise recalcitrant disease.
Biomarkers* ; Bipolar Disorder* ; Brain ; Comorbidity ; Cytokines ; Disease Susceptibility ; Hope ; Humans ; Inflammation* ; Nerve Growth Factors ; Neurobiology ; Neuroglia ; Neurotransmitter Agents ; Plastics

The neurobiology of bipolar disorder, a chronic and systemic ailment is not completely understood. The bipolar phenotype manifests in myriad ways, and psychopharmacological agents like lithium have long term beneficial effects. The enzyme glycogen synthase kinase 3 (GSK3) has come into focus, as lithium and several other mood stabilizing medications inhibit its activity. This kinase and its key upstream modulator, Wnt are dysregulated in mood disorders and there is a growing impetus to delineate the chief substrates involved in the development of these illnesses. In May 2016, a comprehensive literature search was undertaken which revealed that there is over activity of GSK3 in bipolar disorder with deleterious downstream effects like proinflammatory status, increased oxidative stress, and circadian dysregulation leading to declining neurotrophic support and enhanced apoptosis of neural elements. By developing specific GSK3 inhibitors the progressive worsening in bipolar disorder can be forestalled with improved prospects for the sufferers.
Apoptosis ; Bipolar Disorder* ; Chronobiology Disorders ; Glycogen Synthase Kinase 3 ; Lithium ; Mood Disorders ; Neurobiology ; Oxidative Stress ; Phenotype ; Phosphotransferases ; Proto-Oncogene Proteins c-akt ; Wnt Signaling Pathway

OBJECTIVE: Staging of psychiatric disorders is gaining momentum and the purpose of this review is to examine whether major mood disorders can be defined according to stages. METHODS: In April 2018 the PubMed electronic data base was scrutinized by a combination of various search terms like “major depressive disorder and staging,”“bipolar disorder and neuroprogression,” etc. To incorporate the latest findings the search was limited to the last 10 years. Both original and review articles were examined by reading the abstracts, and papers which were found to be particularly applicable were read in full and their reference lists were also consulted. RESULTS: A significant increase occurred in the number of papers published on the topic of staging of mood disorders. Staging formats were found for both major mood disorders, with the caveat that many more articles were discovered for bipolar disorder. Current evidence points to allostatic load and neuroprogression as the basis for staging of mood disorders. CONCLUSION: Principal affective illnesses may be characterized by distinct stages, for instance early, intermediate and late. These phases inform the management so that clinicians should incorporate the staging schema into everyday practice and implement treatment strategies according to the phase of the illness.
Allostasis ; Bipolar Disorder ; Depressive Disorder ; Depressive Disorder, Major ; Mood Disorders*

Many bipolar disorder patients exhibit mixed affective states, which portend a generally more severe illness course and treatment resistance. In the previous renditions of Diagnostic and Statistical Manual mixed states were narrowly defined in the context of bipolar I disorder, but with the advent of DSM-5 the term “mixed episode” was dropped and replaced by “mixed features” specifier which could be broadly applied to manic, hypomanic and depressive episodes in both the bipolar spectrum and major depressive disorders. This paradigm shift reflected their significance in the prognosis and overall management of mood disorders, so that the clinicians should thoroughly familiarize themselves with the contemporary notions surrounding these conditions. The purpose of this manuscript is to bring to light the current conceptualizations regarding the etiology, pathogenesis and treatment of mixed states. To achieve this goal, in June 2016 an extensive literature search was undertaken using the PubMed database. Some exploratory terms utilized included “mixed states”, “mixed episodes”, “switching”, “rapid cycling” cross referenced with “bipolar disorder”. Focusing on the most relevant and up to date studies, it was revealed that mixed states result from genetic susceptibility in the circadian and dopamine neurotransmission apparatuses and disturbance in the intricate catecholamine-acetylcholine neurotransmission balance which leads to mood fluctuations. The management of mixed states is challenging with atypical antipsychotics, newer anticonvulsants and electroconvulsive therapy emerging as the foremost treatment options. In conclusion, while progress has been made in the neurobiological understanding of mixed states, the currently available therapeutic modalities have only shown limited effectiveness.
Acetylcholine ; Anticonvulsants ; Antipsychotic Agents ; Bipolar Disorder ; Catecholamines ; Depressive Disorder, Major ; Dopamine ; Electroconvulsive Therapy ; Genetic Predisposition to Disease ; Humans ; Mood Disorders ; Prognosis ; Synaptic Transmission

Bipolar disorder is a heterogeneous condition with myriad clinical manifestations and many comorbidities leading to severe disabilities in the biopsychosocial realm. The objective of this review article was to underline recent advances in knowledge regarding the neurobiology of bipolar disorder. A further aim was to draw attention to new therapeutic targets in the treatment of bipolar disorder. To accomplish these goals, an electronic search was undertaken of the PubMed database in August 2015 of literature published during the last 10 years on the pathophysiology of bipolar disorder. A wide-ranging evaluation of the existing work was done with search terms such as "mood disorders and biology," "bipolar disorder and HPA axis," "bipolar disorder and cytokines," "mood disorders and circadian rhythm," "bipolar disorder and oxidative stress," etc. This endeavor showed that bipolar disorder is a diverse condition sharing neurobiological mechanisms with major depressive disorder and psychotic spectrum disorders. There is convincing evidence of crosstalk between different biological systems that act in a deleterious manner causing expression of the disease in genetically predisposed individuals. Inflammatory mediators act in concert with oxidative stress to dysregulate hormonal, metabolic, and circadian homeostasis in precipitating and perpetuating the illness. Stress, whether biologically or psychologically mediated, is responsible for the initiation and progression of the diathesis. Bipolar spectrum disorders have a strong genetic component; severe life stresses acting through various paths cause the illness phenotype.
Bipolar Disorder ; Circadian Rhythm ; Comorbidity ; Depressive Disorder, Major ; Disease Susceptibility ; Homeostasis ; Neurobiology ; Oxidative Stress ; Phenotype ; Stress, Psychological

Bipolar disorder (BD) is a severe psychiatric condition which affects innumerable people across the globe. The etiopathogenesis of BD is multi-faceted with genetic, environmental and psychosocial factors playing a role. Hitherto, the diagnosis and management of BD are purely on empirical grounds as we lack confirmed biomarkers for this condition. In this regard, hypothesis-driven investigations have been unable to identify clinically applicable biomarkers, steering the field towards newer technologies. Innovative, state-of-the-art techniques like multiplex immunoassays and mass spectrometry can potentially investigate the entire proteome. By detecting up or down regulated proteins, novel biomarkers are identified and new postulates about the etiopathogenesis of BD are specified. Hence, biological pathways are uncovered which are involved in the initiation and advancement of the disease and new therapeutic targets are identified. In this manuscript, the extant literature is thoroughly reviewed and the latest findings on candidate BD biomarkers are provided, followed by an overview of the proteomic approaches. It was found that due to the heterogeneous nature of BD no single biomarker is feasible, instead a panel of tests is more likely to be useful. With the application of latest technologies, it is expected that validated biomarkers will be discovered which will be useful as diagnostic tools and help in the delivery of individually tailored therapies to the patients.