Angelos Halaris

• MD, PhD
• Loyola University Medical Center

Background: Bipolar disorder (BD) is a chronic condition associated with treatment resistance, cognitive decline, structural brain changes, and an approximately 13-year reduction in life expectancy compared to the general population. Depression in BD substantially impairs quality of life, while neuroinflammation and excitotoxicity are thought to co...

• Treatment-resistant bipolar depressive disorder (TRBDD) poses significant challenges in psychiatric practice, often unresponsive to standard treatment strategies. • Immune dysfunction and inflammation play critical roles in the pathophysiology of bipolar disorder. • This study compared baseline BDNF levels between the TRBDD and HC groups and inv...

• NCCP demonstrates a complex relationship between pain, psychological, and physiological factors. • Patients with a history of panic disorder (PD) or generalized anxiety disorder (GAD) who were treated with escitalopram experienced a reduction in their NCCP symptoms. • Escitalopram significantly reduced anxiety (p<0.001), depression (p=0.039), and...

• Our study identified an inverse relationship between baseline BDNF serum levels and PSS-14 scores (p = 0.014). This observation suggests two possible scenarios: perceived stress may reduce BDNF levels, or decreased BDNF levels could increase susceptibility to stress. • Analysis of SNPs (rs6265, rs10835210, and rs1519480) revealed trends suggestin...

• The nervous and immune systems engage in complex communication, which is regulated by multiple mechanisms. This interaction can be disrupted by various triggers such as infections, autoimmune diseases, peripheral and systemic inflammation, traumatic brain injuries, environmental toxins, and stress, potentially leading to neuroinflammation. • Chem...

Objective Autonomic dysregulation is common in many medical conditions and can have a widespread, negative impact on multiple bodily systems, leading to poorer health outcomes. Thus, addressing autonomic dysregulation as part of a comprehensive treatment plan is important. The goal of this paper was to gain a better understanding of the physiologic...

Background: in a recent double-blind, placebo controlled RCT we demonstrated that selective inhibition of cyclo-oxygenase 2 (COX2) is an effective adjunctive strategy in treatment-resistant bipolar depression (TRBDD). To better clarify the mechanisms underlying TRBDD and treatment response, we conducted a retrospective exploratory analysis of the s...

Brain-Derived Neurotrophic Factor (BDNF) is crucial for various aspects of neuronal development and function, including synaptic plasticity, neurotransmitter release, and supporting neuronal differentiation, growth, and survival. It is involved in the formation and preservation of dopaminergic, serotonergic, GABAergic, and cholinergic neurons, faci...

It is well-established that cardiovascular disease and depression are highly comorbid. This study aimed to assess the possible role of the NOD-like receptor protein 3 (NLRP3) inflammasome pathway and the high-sensitivity C-reactive protein (hsCRP) in patients with incident myocardial infarction in the presence or absence of depression. Sixty-eight...

(1) Background: Inflammation is associated with depressive illness and treatment resistance. This study assessed a novel inflammatory index, the Systemic Immune-Inflammation Index (SII), in patients diagnosed with treatment-resistant bipolar depression (TRBDD) before and after treatment with escitalopram (ESC) and celecoxib (CBX) add-on or ESC and...

(2023), Poster Abstracts. Bipolar Disord, 25: 55-116. https://doi.org/10.1111/bdi.13333

Background: : Anger can worsen a person's emotions and increase the severity of an individual's mood state, notably depression. The State-Trait Anger Expression Inventory (STAXI) assessment tool is useful for assessing the experience, expression, and control of anger in normal individuals, and in evaluating anger experienced by patients with a vari...

Background: Affective illness has been associated with a proinflammatory state, and it is generally accepted that the immune system plays a key role in the pathophysiology of mood disorders. Since inflammatory biomarkers are elevated in bipolar disorder, anti-inflammatory combination therapies may enhance response and reverse treatment resistance....

The glutamatergic system is the primary excitatory pathway within the CNS and is responsible for cognition, memory, learning, emotion, and mood. Because of its significant importance in widespread nervous system function, it is tightly regulated through multiple mechanisms, such as glutamate recycling, microglial interactions, and inflammatory path...

ACNP 61st Annual Meeting: Poster Abstracts P271-P540.

Inflammation plays a pivotal role in the etiopathology of Major Depressive Disorder (MDD), at least in a subset of patients. It is crucial to first establish which specific inflammatory biomarkers are of clinical utility. Anti-cardiolipin antibody (aCL IgM) is an inflammatory marker that has the potential to be such a candidate but there are insuff...

Objective: Matrix metalloproteinase is a family of proteases with different pathophysiological roles. Matrix metalloproteinase 9 (MMP9) plays an enzymatic role in the restructuring of the extracellular matrix and adhesion molecules. MMP9 is upregulated in pro-inflammatory states and leads to breakdown of tight junctions thereby increasing blood-bra...

Depressive disorders are characterized by persistent low mood, loss of interest and pleasure, decreased energy, varying levels of social and occupational dysfunction. Depressive symptoms include depressed mood, anhedonia, appetite disturbances and changes in weight, lpss of libido, sleep disturbances, lack of energy, unwarranted guilt, difficulty i...

Esketamine is a novel treatment for Treatment Resistant Depression (TRD) and was approved by the FDA in early 2019. It antagonizes the NMDA receptor providing rapid improvement in symptoms with a complex mechanism of action primarily mediated through glutamatergic activation. Significant barriers exist to widespread use of esketamine including dura...

Background: Taking into account the role of oxidative stress in neurodegeneration, we sought to evaluate the expression of genes for select enzymes with antioxidant properties (paraoxonases PON1, PON2 and PON3 and myeloperoxidase MPO) at the mRNA and protein levels in patients with depressive disorders. We further sought to determine the impact of...

(1) Background: Only 60–70% of depressed patients respond to standard antidepressant treatments. Hence, it is essential to search for new, effective and safe therapies for unmet clinical needs of treatment-resistant depression (TRD). Agents targeting the components of the JAK-STAT signaling pathway have been shown to be relevant in immunology and a...

Aim: To determine the efficacy and safety of vitamin D3 supplementation in reducing depressive symptoms in women with type 2 diabetes (T2D), depression, and low vitamin D. Methods: In this double-blind randomized active comparator-controlled trial, women with significant depressive symptoms as assessed by the Center for Epidemiologic Studies Dep...

Objective: The present study aimed at exploring the potential utility of autonomic regulation as a useful marker in the diagnostic differentiation between unipolar and bipolar depression. Method: Respiratory sinus arrhythmia (RSA), low-frequency (LF) of heart rate variability, and systolic blood pressure (SBP) were assessed in patients with bipo...

Objective: One proposed mechanism to subclassify depressive illness relates oxytocinergic dysregulation, via its effect on social behavior and Hypothalamic-pituitary-adrenal (HPA) axis inhibition. To further investigate the role of oxytocin in Major Depressive Disorder (MDD), we compared plasma oxytocin levels in patients with MDD to healthy contro...

Pharmacogenomic (PGx) testing is being increasingly recognized by clinicians as an essential tool to guide medication decisions for treatment of psychiatric illnesses. Extensive implementation of PGx testing, however, varies by setting and location. In this retrospective study, we reviewed charts from 592 patients diagnosed with a psychiatric disor...

Objectives Serum or plasma levels of C-reactive protein (CRP) and high-sensitivity CRP (hsCRP) are widely used clinical markers of inflammation in other branches of medicine, whereas its clinical use in psychiatry has been limited to research studies. We aimed to assess the possibility of using CRP/hsCRP in psychiatric practice. This is a review an...

Coronavirus may have a negative impact not only on physical, but also on mental wellbeing. Despite the different approaches of countries to stop the spread of the virus and different infection rates, the dynamically developing pandemic has already affected the entire world. The consequences of the coronavirus for our mental health can be divided in...

Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approx...

Background Adjunctive inflammatory treatments improve response and remission rates in treatment-resistant bipolar depression (TRBDD), but underlying mechanisms remain unclear. Given the association between hypothalamic-pituitary-adrenal (HPA) axis dysregulation and treatment-resistant depression, we investigated the pre-treatment HPA-axis profile i...

Background Neuroinflammation plays a role in the pathophysiology of Bipolar Disorder Depression (BDD) and altered levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1, aka CCL2) have been reported. This study reports specifically on MCP-1 levels, as a potential marker of BDD and/or treatment response in patients recei...

Researchers have endeavored to subclassify depressive illness based on pathophysiological mechanism. One model relates to hypothalamic-pituitary-adrenal (HPA) axis overactivation with a shift from corticotropin-releasing hormone (CRH) driven regulation to arginine vasopressin (AVP) driven regulation. Given the mixed literature, we compared plasma A...

Background: Vascular Endothelial Growth Factor (VEGF) has been implicated in the neurotrophic model of depression. We explored the potential role of VEGF in the pathophysiology of bipolar depression and potential utility as a diagnostic or outcome predictive biomarker. Methods: In a double-blind study, treatment-resistant bipolar depressed patie...

Background: Adjunctive inflammatory modulation improved remission rates in treatment-resistant bipolar depression (TRBDD), but reliable biomarkers must be established to characterize the biosignature of TRBDD and the mechanisms underlying treatment response. In this molecular profiling study, we describe TRBDD and treatment response from the stand...

Objective Growing evidence indicates that depressive disorders (DDs) are an important risk factor for atherosclerosis. The aim of this study was to evaluate the presence of common carotid artery (CCA) intima-media thickness (IMT) and circulation inflammation markers in patients with DD. Methods A cross-sectional prospective study was undertaken co...

Background Grand rounds is a formal meeting at which physicians and trainees discuss excellence in medical care. Residents should participate in scholarly activity per Accreditation Council for Graduate Medical Education (ACGME). Consultation-Liaison (CL) psychiatry focuses on caring for patients presenting with psychiatric complications in general...

L-Arginine pathway metabolites appear to play differential roles in the pathogenesis of major depressive disorder (MDD). Studies have revealed an antidepressant and anxiolytic effect of agmatine and putrescine. Possible mechanisms of these effects include inhibition of nitric oxide synthase and N-methyl-D-aspartate receptors. The present study soug...

Objective: The goal of this study was to reduce treatment resistance and enhance antidepressant response in patients with treatment-resistant bipolar depression (TRBDD) by modulating inflammatory activation. Methods: Forty-seven TRBDD patients completed a randomized, double-blind, placebo (PBO)-controlled two-arm study using celecoxib (CBX), a c...

There is increasing recognition in the neurological and psychiatric literature of patients with so-called isolated psychotic presentations (ie, with no, or minimal, neurological features) who have tested positive for neuronal autoantibodies (principally N-methyl-D-aspartate receptor antibodies) and who have responded to immunotherapies. Although th...

Background Adjunctive immune-modulation can be safe and effective for treatment-resistant bipolar depression (TRBDD), but molecular work is needed to further characterize the safety and efficacy involved in treatment response and the reversal of treatment resistance. Here we profiled the kynurenine pathway (KP) for biomarkers associated with TRBDD...

In this review article we present an integrative overview of parameters and mechanisms underlying psychiatric and neuropsychiatric disorders that involve the immune and autonomic nervous systems along with neurotransmission and specific endocrine mechanisms. At the center of these highly complex and interactive mechanisms is stress and stress perce...

Purpose of review: Up until the latter part of the previous century, the monoamine theory guided our understanding of psychiatric disorders, notably depressive illness in its various phenotypic manifestations. The purpose of this review is to provide an overview of newer theories that allow a deeper understanding of brain dysfunction and neuropsyc...

Background: Fibromyalgia (FM) is a chronic medical condition characterized by widespread pain, sleep disturbance, and cognitive dysfunction. Sleep disorders are thought to play a prominent role in the etiology and symptomatic management of FM, specifically obstructive sleep apnea (OSA). In order to provide collaborative care, we need a better under...

Objectives Treatment-resistance is high in bipolar disorder and is associated with a pro-inflammatory state and diversion of tryptophan toward the kynurenine pathway. This study as part of a large clinical trial, sought to determine, if modulation of the inflammatory response by inhibiting cyclooxygenase-2 (COX-2) with celecoxib combined with escit...

This chapter aims to provide an overview of the burgeoning field of psychoneuroimmunology as it relates to psychiatric and neuropsychiatric disorders. It is a relatively young field, having come of age only recently, but the progress that has been made just in the past three decades has exceeded all expectations. It is fair to say that the field ha...

The immune system and inflammatory processes contribute to brain-related pathologies in most, if not all, neurological and psychiatric disorders. Stress is a key factor in inducing immune system dysregulation in conjunction with genetic, epigenetic and environmental factors. Activation of the immune response can alter neurotransmission leading, amo...

Edwin Meresh, John Piletz, Angelos Halaris Department of Psychiatry and Behavioral Neurosciences, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL, USA Background: Noncardiac chest pain (NCCP) is defined as persistent angina-like chest pain with no evidence of cardiac disease. There is some controversy about the long-term m...

Immune system activation and neuroinflammation appear to play a key role in the pathophysiology and treatment of bipolar depression (BDD). This study is the first to analyze blood levels of the pro-inflammatory biomarker C-reactive protein (CRP) in bipolar disorder patients treated with the cyclooxygenase-2 inhibitor, celecoxib (CBX). In this doubl...

The present case report describes a case of serotonin syndrome which developed post septal myectomy in a patient with hypertrophic cardiomyopathy. This case contributes to an emerging awareness of serotonin syndrome in the context of prescribed serotonergic agents, such as SSRIs, and triggered by the addition of fentanyl and methylene blue, particu...

Aims: Autonomic nervous system (ANS) dysregulation is associated with various symptoms of depressive disorder. The beat-to-beat pattern of heart rate (Heart Rate Variability) (HRV) provides a noninvasive portal to ANS function through the quantification of periodic heart rate patterns. In this study we quantified two components of HRV: Respiratory...

Autonomic nervous system (ANS) dysregulation in depression is associated with symptoms associated with the ANS. The beat-to-beat pattern of heart rate defined as heart rate variability (HRV) provides a noninvasive portal to ANS function and has been proposed to represent a means of quantifying resting vagal tone. We quantified HRV in bipolar depres...

Background: In bipolar disorder, the depressive phase most adversely impairs the individual’s quality of life. Failure to respond during anti-depressant therapy has been reported to be 3.4 times more common in bipolar depressed patients. It is thought that the chronic pro-inflammatory state associated with stress and depression may be associated wi...

Background: Vascular Endothelial Growth Factor (VEGF) is involved in brain plasticity and neurogenesis. It has been implicated in the neurotrophic model of depression, which is based on the finding that stress can cause a decline in levels of neurotrophins. In contrast, VEGF levels appear to increase in mood disorders. Notably, VEGF doesn’t cross t...

Background: In connection with the emerging link between treatment resistance and neuroprogression in bipolar disorder, it is increasingly apparent that clinical remission is achieved in part through pharmacologically induced arrest of neuroprogression. Literature increasingly suggests that bipolar and unipolar depression are chronic inflammatory s...

Objectives: Major depressive disorder (MDD) and depression in bipolar disorder (BD) are often difficult to distinguish from each other. Autonomic nervous system (ANS) dysregulation is associated with various depressive symptoms and inflammatory response disinhibition. The beat-to-beat pattern of heart rate (Heart Rate Variability) (HRV) offers a n...

The concept of neuroprogression describes the progressive course of the disorder and stresses the progressive, recurrent, and chronic course of the disease entity under consideration. It subsumes clinical manifestations of the disease process and may also entail morphological, biochemical, neurochemical, immunological, physiological, and genetic as...

Morbidity and mortality of cardiovascular disease (CVD) is exceedingly high worldwide. Depressive illness is a serious psychiatric illness that afflicts a significant portion of the world population. Epidemiological studies have confirmed the high co-morbidity between these two disease entities. The co-morbidity is bidirectional and the mechanisms...

Objectives: The aim of the study was to evaluate baseline plasma VEGF levels as a potential predictor of response to antidepressant pharmacotherapy. The study also sought to determine whether baseline plasma VEGF would be useful in predicting treatment outcome when two pharmacodynamically diverse agents with established antidepressant efficacy, es...

To understand the origin of co-morbidity between neurological disorders and depressive illness, a multifactorial model is in order. Diverse approaches have been undertaken to elucidate the co-morbidity. Of these, the concept that inflammatory processes contribute to brain-related pathologies has been gaining traction. Inflammatory processes have be...

The role of the immune system and interactions between the endocrine, neurotransmitter, and immune systems in affective disorders have opened up new avenues to pursue in psychiatric research. Exploration of a potential causal relationship between inflammation and depression has lent support to the contention that a bidirectional relationship is at...

Type 2 diabetes (T2D) patients are twice as likely to experience depressive symptoms than people without T2D, resulting in greater economic burden, worse clinical outcomes, and reduced quality-of-life. Several overlapping pathophysiological processes including hypothalamic-pituitary-adrenal axis hyperactivity, sympathetic nervous system activation,...

Despite intense research efforts undertaken by investigators throughout the world over the past half century to identify a specific biomarker for major depressive disorder (MDD), none have so far met the rigorous test of specificity, reliability and reproducibility. Vascular Endothelial Growth Factor (VEGF) has been implicated in the neurotrophic m...