The Discovery of Clinically Applicable Biomarkers for Bipolar Disorder: A Review of Candidate and Proteomic Approaches.

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.

Kynurenine Pathway of Tryptophan Metabolism in Neuropsychiatric Disorders: Pathophysiologic and Therapeutic Considerations.

Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by the kynurenine pathway (KP) to yield the ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy requirements. Importantly, the intermediaries of KP exert crucial effects throughout the body, including the central nervous system. Besides, KP metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body of research indicates that the KP plays a pathogenic role in major psychiatric diseases like mood disorders and schizophrenia. Triggered by inflammatory processes, the balance between neurotoxic and neuroprotective branches of the KP is disturbed. In preclinical models these discrepancies result in behaviors reminiscent of depression and psychosis. In clinical samples, recent studies are discovering key kynurenine pathway abnormalities which incriminate it in the pathogenesis of the main psychiatric disorders. Harnessing this knowledge has the potential to find disease biomarkers helpful in identifying and prognosticating neuropsychiatric disorders. Concurrently, earnest research efforts directed towards manipulating the KP hold the promise of discovering novel pharmacological agents that have therapeutic value. In this manuscript, an in-depth appraisal of the extant literature is done to understand the working of KP as this applies to neuropsychiatric disorders. It is concluded that this pathway plays an overarching role in the development of major psychiatric disorders, the KP metabolites have the potential to serve as disease markers and new medications based on KP modulation can bring lasting cures for patients suffering from these intractable conditions.

Interventions Addressing the Telomere-Telomerase System.

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder, and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis, or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time, this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.

Telomere Biology in Mood Disorders: An Updated, Comprehensive Review of the Literature.

Major psychiatric disorders are linked to early mortality and patients afflicted with these ailments demonstrate an increased risk of developing physical diseases that are characteristically seen in the elderly. Psychiatric conditions like major depressive disorder, bipolar disorder and schizophrenia may be associated with accelerated cellular aging, indicated by shortened leukocyte telomere length (LTL), which could underlie this connection. Telomere shortening occurs with repeated cell division and is reflective of a cell's mitotic history. It is also influenced by cumulative exposure to inflammation and oxidative stress as well as the availability of telomerase, the telomere-lengthening enzyme. Precariously short telomeres can cause cells to undergo senescence, apoptosis or genomic instability; shorter LTL correlates with compromised general health and foretells mortality. Important data specify that LTL may be reduced in principal psychiatric illnesses, possibly in proportion to exposure to the ailment. Telomerase, as measured in peripheral blood monocytes, has been less well characterized in psychiatric illnesses, but a role in mood disorder has been suggested by preclinical and clinical studies. In this manuscript, the most recent studies on LTL and telomerase activity in mood disorders are comprehensively reviewed, potential mediators are discussed, and future directions are suggested. An enhanced comprehension of cellular aging in psychiatric illnesses could lead to their re-conceptualizing as systemic ailments with manifestations both inside and outside the brain. At the same time this paradigm shift could identify new treatment targets, helpful in bringing about lasting cures to innumerable sufferers across the globe.

Endoplasmic Reticulum Stress: Implications for Neuropsychiatric Disorders.

The Endoplasmic reticulum (ER), an indispensable sub-cellular component of the eukaryotic cell carries out essential functions, is critical to the survival of the organism. The chaperone proteins and the folding enzymes which are multi-domain ER effectors carry out 3-dimensional conformation of nascent polypeptides and check misfolded protein aggregation, easing the exit of functional proteins from the ER. Diverse conditions, for instance redox imbalance, alterations in ionic calcium levels, and inflammatory signaling can perturb the functioning of the ER, leading to a build-up of unfolded or misfolded proteins in the lumen. This results in ER stress, and aiming to reinstate protein homeostasis, a well conserved reaction called the unfolded protein response (UPR) is elicited. Equally, in protracted cellular stress or inadequate compensatory reaction, UPR pathway leads to cell loss. Dysfunctional ER mechanisms are responsible for neuronal degeneration in numerous human diseases, for instance Alzheimer's, Parkinson's and Huntington's diseases. In addition, mounting proof indicates that ER stress is incriminated in psychiatric diseases like major depressive disorder, bipolar disorder, and schizophrenia. Accumulating evidence suggests that pharmacological agents regulating the working of ER may have a role in diminishing advancing neuronal dysfunction in neuropsychiatric disorders. Here, new findings are examined which link the foremost mechanisms connecting ER stress and cell homeostasis. Furthermore, a supposed new pathogenic model of major neuropsychiatry disorders is provided, with ER stress proposed as the pivotal step in disease development.

Frequency of Primary Headache Syndromes in Patients with a Major Depressive Disorder.

Purpose The primary objective of this study was to assess the overall frequency of primary headaches in subjects with a moderate to severe major depressive disorder. A further objective was to determine the frequency of primary headache sub-types in this population. Materials and methods This descriptive, cross-sectional study was conducted at the outpatients' clinic of the department of psychiatry, Pakistan Railways Teaching Hospital, an affiliate of Islamic International Medical College, Rawalpindi. The duration of the study was from December 2016 to May 2017. One hundred and ten consecutive patients with a major depressive disorder (MDD) were assessed for a primary headache, according to the diagnostic criteria of International Classification of Headache Disorders second edition (ICHD-2). MDD patients with moderate to severe depression according to the diagnostic and statistical manual of mental disorders (DSM-5) were enrolled in the study. A semi-structured proforma was designed to gather information on sociodemographic variables. The data was analyzed by utilizing Statistical Package for Social Sciences, version 22 (IBM Corp., Armonk, NY, US). Results Of the 110 MDD patients enrolled, a primary headache was present in 45 (40.90%) cases. Additionally, five of these patients had a migraine with aura (11.11%), 12 had a migraine without aura (26.66%), and 28 had a tension-type headache (62.22%). In the females, migraines with or without aura was frequent (35.29%), while a tension-type headache was more common in males (72.72%). Conclusion More than one-third of the sample had a primary headache syndrome, which shows a high comorbidity between a migraine and its variants and MDD. There is a need to undertake further studies with larger samples to elucidate this relationship.

The Staging of Major Mood Disorders: Clinical and Neurobiological Correlates.

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.

Frequency of obsessive compulsive symptoms in depression: A hospital-based cross-sectional study.

OBJECTIVE: To determine the frequency of obsessive compulsive symptoms in patients suffering from depression. METHODS: This cross-sectional study was conducted at the Allama Iqbal Memorial Teaching, Sialkot, Pakistan, from February 2014 to March 2017, and comprised patients suffering from depression. Every patient was examined by a consultant psychiatrist or a senior medical officer in psychiatry, and a psychologist to establish clinical diagnosis of depression according to the tenth revision of the International Statistical Classification of Diseases and Related Health Problems. Adult patients suffering from depression were included. Patients with severe physical illnesses, other psychiatric illnesses, current, past or family history of obsessive compulsive disorder and drug abuse were excluded. Beck Depression Inventory and Yale Brown Obsessive Compulsive Scale were also administered. Data was analysed using SPSS 21. RESULTS: Of the 5,127 patients, 2,318(45.21%) were males and 2,809(54.79%) females. The mean age of the male and female patients was 35.17±12.39 years (range: 18-73 years) and 33.67±13.27 years (range: 18-70 years), respectively. Besides, 1,991(38.83%) patients had moderate depression, 1,647(32.13%) had mild depression and 1,489(29.04%) had severe depression. Moreover, 1,673(32.63%) patients had obsessive compulsive symptoms, including 497(29.70%) patients with mild depression, 599(35.80%) with moderate depression and 577(34.49%) with severe depression. CONCLUSIONS: Around one-third participants had obsessive compulsive symptoms.

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications.

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.

Mixed States in Bipolar Disorder: Etiology, Pathogenesis and Treatment.

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.

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.

The Treatment of Adult Bipolar Disorder with Aripiprazole: A Systematic Review.

Bipolar disorder is characterized by exacerbations of opposite mood polarity, ranging from manic to major depressive episodes. In the current nosological system of the Diagnostic and Statistical Manual - 5(th) edition (DSM-5), it is conceptualized as a spectrum disorder consisting of bipolar disorder type I, bipolar disorder type II, cyclothymic disorder, and bipolar disorder not otherwise specified. Treatment of all phases of this disorder is primarily with mood stabilizers, but many patients either show resistance to the conventional mood stabilizing medications or are intolerant to their side-effects. In this setting, second-generation antipsychotics have gained prominence as many bipolar subjects who are otherwise treatment refractory show response to these agents. Aripiprazole is a novel antipsychotic initially approved for the treatment of schizophrenia but soon found to be effective in bipolar disorder. This drug is well studied, as randomized controlled trials have been conducted in various phases of bipolar disorders. Aripiprazole exhibits the pharmacodynamic properties of partial agonism, functional selectivity, and serotonin-dopamine activity modulation - the new exemplars in the treatment of major psychiatric disorders. It is the first among a new series of psychotropic medications, which now also include brexpiprazole and cariprazine. The current review summarizes the data from controlled trials regarding the efficacy and safety of aripiprazole in adult bipolar patients. On the basis of this evidence, aripiprazole is found to be efficacious in the treatment and prophylaxis of manic and mixed episodes but has no effectiveness in acute and recurrent bipolar depression.

Staging Models in Bipolar Disorder: A Systematic Review of the Literature.

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.

The Neurobiology of Bipolar Disorder: An Integrated Approach.

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: Role of Inflammation and the Development of Disease Biomarkers.

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.

A Rare Neuropsychiatric Presentation of Adult-Onset Wilson's Disease.

Wilson's disease is characterised by deposition of copper in various tissues of the body, most markedly in the liver and the brain. Cerebral involvement, evident as neuropsychiatric symptoms, may be the presenting form of the illness in up to 50% of the adults. When patients present initially with psychiatric manifestations, the correct diagnosis is frequently missed. This case report describes an adult in his late 20's who presented with symptoms of major depressive disorder, but failed to respond to standard antidepressant treatment. He instead developed neurologic symptoms like tremor, gait disturbance, weakness of grip and clumsiness. Diagnosed as a case of conversion disorder, brain MRI showed abnormalities in the basal ganglia. Further investigations revealed that he had adult-onset Wilson's disease. Because of rarity, adult Wilson's disease patients with initial psychiatric presentations are frequently misdiagnosed and definitive treatment with chelating agents is not offered with continual organ damage from copper accumulation.

Pharmacotherapy of bipolar disorder with quetiapine: a recent literature review and an update.

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.

Aripiprazole in the treatment of refractory mood disorders: a case series.

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.