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Objectives: Serum or plasma levels of C-reactive protein (CRP) and highsensitivity 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 and evaluation of various lines of evidence supporting the concept of CRP as a biomarker for psychiatric disorders in certain conditions. Methods: We searched the literature for studies which assessed CRP/hsCRP levels in various psychiatric disorders. Results: The accumulating evidence from large studies and meta-analyses allows us to understand the role of CRP in major psychiatric disorders and increase our understanding of specific symptoms and subtypes of disorders. CRP may be considered a “psychiatric biomarker” which can alert clinicians about neuroinflammation, adverse effects of medications, cardiometabolic status, comorbidities, and may also predict clinical outcomes and guide optimal treatment selection. Conclusion: Although the underlying pathophysiological role of CRP and hsCRP is still elusive and the association between CRP and psychiatric disorders is inconsistent, CRP holds promise to become a psychiatric biomarker. WOS:000684418100001 34323645 Q2

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 standpoint of interleukin-1 Beta (IL-1β) and KYN/TRP.47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg-40 mg daily dose range) + celecoxib (CBX) (200 mg twice daily), or ESC (10 mg-40 mg daily dose range) + placebo (PBO) (twice daily). Plasma cytokine levels were measured in both treatment arms at baseline and week 8, and in a healthy control (HC) group of subjects (N = 43) once. A linear mixed model (LMM) was applied to evaluate whether clinical outcome is related to CBX and changes to biomarkers throughout treatment. A binary logistic regression model was formulated from this series to predict both the primary outcome of treatment response to CBX, and the secondary outcome of diagnosis of TRBDD using age, BMI, gender, and IL-1β at baseline.Patients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT = 3, and 15.300 times more likely to remit (p 0.001) with NNT = 2, compared with ESC + PBO patients. Patient BMI (p = 0.003), baseline IL-1β (p = 0.004), and baseline KYN/TRP (p = 0.001) were most predictive of TRBDD diagnosis. By Week 8, responders showed a downtrend in IL-1β compared to non-responders in the ESC + CBX treatment arm. However, there was no statistical difference in the IL-1β or KYN/TRP change after treatment between placebo and ESC + CBX group responders/non-responders (p = 0.239, and p = 0.146, respectively). While baseline IL-1β was elevated in TRBDD compared to HC (p 0.001), there was no difference in IL-1β between treatment responders at Week 8 compared to HC (p = 0.067).Elevated IL-1β and low KYN/TRP at baseline are components of the TRBDD molecular signature. CBX but not baseline IL-1β or KYN/TRP predict treatment response. Change in IL-1β and KYN/TRP did not predict treatment response.

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 AVP levels in healthy controls to patients with major depressive disorder (MDD). Plasma samples from 33 patients and 12 controls were collected at baseline, 8 weeks, and 12 weeks of treatment and measured by immunochemical assay. Patients who were treatment responders trended toward lower AVP levels than non-responders. Patients were stratified into low and high AVP groups based on median split. Within the low AVP group, patients whose current episode lasted longer than a year had significantly higher baseline AVP levels than patients whose current episode was less than 6 months. Female patients in the low AVP group had significantly higher baseline AVP levels than male patients. Given the association between stress, HPA axis activation, immune dysregulation, and depression, we also measured concentrations of inflammatory biomarkers. We found a significant negative correlation between IL-10 and baseline AVP levels, within the low AVP subgroup. Given inconsistent data, HPA axis overactivation may be present within a subset of depressed patients.

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 cyclooxygenase 2 (COX-2) inhibitor, in combination with escitalopram (ESC). The Hamilton Depression (17-Item) and the Hamilton Anxiety Rating Scales were used to quantify symptom severity. Self-rating instruments included BDI, BAI and QLES-Q questioner. An adverse events inventory was used, and the possibility of bleeding diathesis was monitored. Complete blood count (CBC), prothrombin time (PT), and activated partial thromboplastin time (APTT) were determined. Comparison of mood scores between the CBX and PBO groups were conducted using a mixed ANOVA and an Independent Sample Student t-test. Results The CBX adjunctive treatment produced significantly more responders and remitters than the PBO arm. Compared to the PBO group (n = 20), the CBX group (n = 27) experienced lower depression severity through the entire course of the study, showing significant decrease in depression and anxiety scores as early as week 1. Except for initial mild nausea, no adverse events were reported and study medications were well tolerated. Conclusions Modulation of the inflammatory response through targeted inhibition of the enzyme COX-2 by means of CBX reduces TRBDD and augments and accelerates treatment response in an efficacious and safe manner. Future studies should replicate these findings and additionally investigate whether prolonged administration of CBX is required to maintain remission by adding a discontinuation phase to the study design. Trial Registration Clinicaltrials.gov ID: NCT01479829.

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 comparing 40 patients with DD to 40 individuals free of depression, matched for age and gender. The Beck Depression Inventory questionnaire, serum total cholesterol, triglycerides, high-sensitivity C-reactive protein, interleukin-6, tumor necrosis factor α, P-selectin, and E-selectin levels were measured. The CCA-IMT was assessed with duplex sonography. Results: Patients with DD were more likely to smoke (65% vs 40%; P = .03) and have higher levels of serum total cholesterol (211 mg/dL vs 181 mg/dL; P = .010), triglycerides (138 mg/dL vs 97 mg/dL; P = .005), and P-selectin (0.87 ng/mL vs 0.61 ng/mL; P = .05) and lower levels of interleukin 6 (4.4 ± 2.1 pg/mL vs 10.3 ± 1.1 pg/mL; P = .002). The CCA-IMT was similar in both groups (0.07 ± 0.02 cm vs 0.06 ± 0.01 cm; P = .31). Among those with CCA-IMT in the upper quartile, subjects in the DD group had lower levels of interleukin 6 ( P = .05) and triglycerides ( P = .01) and higher levels of soluble P-selectin ( P = .03). Conclusion: Patients with DD do not present with higher CCA-IMT than a control group, although smoking and a higher level of serum lipids are present. Inflammatory biomarkers seem to be higher in patients with DD.

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 hospital. Post-residency subspecialty CL fellowship training plays a big role in creating future leaders in CL. Our program decided to conduct annual CL grand rounds fully allotted to discuss complex CL psychiatry cases in medical setting. Methods We conducted a retrospective review of resident's interest in pursuing CL fellowship. We compared the number of residents pursuing CL fellowship after the CL grand rounds to the previous years starting 2005 when CL was recognized as an ACGME approved subspecialty. We also compared our program residents pursuing CL psychiatry fellowship to national trend obtained from National Residency Matching Program (NRMP). Results From 2013 to 2018, CL grand rounds n=8, Number of residents graduated from 2013 to 2018 n=26. Number of residents pursued CL fellowship from 2013 to 2018 n=3 (11.5%) compared to no residents pursuing CL fellowship before 2013. Fisher's exact test to compare and examine the data from the residents pursuing CL fellowship after implementation of the CL grand rounds is 0.0668 (p value < 0.10). When combining all the available NRMP match results for CL from 2015 to 2019, a total of 531 positions were offered and 359 positions were filled (fill rate of 67.6%). In our program, after we implemented the annual CL grand rounds, 11.5% of the residents from 2013 to 2018 pursued CL fellowship, which is higher than the likely national average of 5.7%. Conclusion Our residency program grand rounds educational module appears to nurture and sustain interest in CL subspecialty compared to previous years. Prospective studies are required.

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 disorder at the Loyola University Medical Center, for whom PGx testing was performed. Information collected included demographics at the time of testing, psychiatric diagnosis, medical and psychiatric history and medications prior and after PGx testing. Of the 592 charts analyzed, the most common primary diagnoses were depression (52%) and anxiety (12%). Prior to PGx testing, 72% of patients were prescribed three or more medications, whereas, after testing, only 44% were prescribed three or more medications included in the test panel (p &lt, 0.0001). The most common clinical consideration on the PGx reports was recommendation to reduce dosages (33%). After PGx testing, the proportion of patients taking incongruent medications decreased from 26% to 19% and that of patients taking congruent medications increased from 74% to 81% (p = 0.006). The results from this retrospective data analysis demonstrated a reduction in polypharmacy and an increase in recommendation-congruent medication prescribing resulting from implementation of PGx testing.

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 into those related to strategies for the prevention of infection, like isolation, quarantine, limitation of social contacts, and remote work, and those related to the direct impact of infection on our nervous system. This review aims to highlight the global effects of the Coronavirus Disease 2019 (COVID-19) pandemic on public mental health following social restrictions, to identify how infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may have direct neurophysiological effects and to compare the impact on public mental health between the USA, Australia, and Poland with Taiwan and Thailand.

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 in relation to treatment response. Methods: This is a secondary analysis of 31 TRBDD patients with moderately severe depression scores as assessed with the Hamilton Depression Rating Scale 17 (HAMD17), who were randomized to receive either escitalopram (ESC) (10–40 mg daily) + celecoxib (CBX) (200 mg twice daily), or ESC (10–40 mg daily) + placebo (PBO) (twice daily). Salivary cortisol was measured at baseline. A multivariate linear regression model was applied to evaluate whether depression scores at Week 8 were related to CBX and baseline salivary cortisol, adjusting for sex, age, BMI, and baseline depression scores. We utilized the HAMD17 and Montgomery-Asberg Depression Rating Scale (MADRS). Results: Coefficient of determination (R2) for week 8 MADRS and HAMD17 scores were 0.907 and 0.624 (both p-value

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 neuropsychiatric disease entities such as depressive illness. One such key theory is the theory of inflammation as a result of stress-induced immune system activation. Recent findings Stress activates the hypothalamic-pituitary-adrenal axis and the sympathetic branch of the autonomic nervous system [sympathetic branch (SNS)] with a concomitant reduction in vagal tone. This homeostatic imbalance makes a simultaneous dual contribution to the resulting proinflammatory state of depression. SNS stimulation results in upregulation of proinflammatory signaling, whereas diminution in parasympathetic tone affects the body's immune response. The resulting proinflammatory status has been closely associated with multiple organ dysfunction and comorbid conditions. Summary The advent of innovative theories about the pathophysiology of psychiatric disorders has ushered in a new era on the basis of the role of the immune system and inflammation in mediating depression in its multifaceted manifestations. Extensive studies have confirmed the proinflammatory status in depression and causal relationships with neurotransmitter dysregulation. Equally importantly the role the autonomic nervous system plays in this complex and multifactorial interplay of body systems is being increasingly elucidated.

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 and treatment response to celecoxib (CBX)-augmentation. Methods 47 TRBDD patients with moderately severe HAMD-17 scores were randomized to receive either escitalopram (ESC) (10 mg twice daily) + CBX (200 mg twice daily), or ESC (10 mg twice daily) + placebo (PBO) (twice daily). Plasma kynurenine pathway (KP) metabolite levels were measured at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. Results Patients receiving ESC + CBX had 4.278 greater odds of responding (p = 0.021) with NNT=3, and 15.300 greater odds of remitting (p Conclusion Clinical response to CBX augmentation is not associated with altered neurotoxic or neuroprotective indices within the time frame of this study. TRBDD revealed alterations in neuroprotective and neurotoxic indices, in the context of low kynurenine/tryptophan and high tryptophan. Treatment responders revealed a depletion in tryptophan by week 8, without concomitant kynurenine pathway (KP) activation.

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 perception by the afflicted individual. Stress reactivity is governed by genetic and epigenetic factors that have yet to be fully clarified. Stress is defined as a state of threatened homeostasis following exposure to extrinsic or intrinsic adverse forces. The major pathways activated by stressors are the HPA axis and the autonomic nervous system. Loss of dynamic variability in the autonomic nervous system, during which one branch dominates over the other for extended periods of time and across multiple environmental demands, is associated with illness and eventually chronic disease. This state of dysregulation can be achieved by excessive sympathetic activation, too little parasympathetic activation, or some combination of both. Autonomic dysregulation leads to immune system dysregulation which in turn interferes with the metabolism of tryptophan leading to the formation of toxic and diabetogenic metabolites. We introduce the concept of neuroprogression as a suitable conceptual framework that allows integration of the complex component mechanisms that contribute to recurrence and chronicity of mental disorders if left untreated or undertreated. The complex interactions among the autonomic, endocrine, immune and metabolic systems and associated cascades provide unique opportunities for development of novel therapeutic agents.

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 escitalopram, would convert treatment-resistant bipolar depression to response or remission and whether blood levels of quinolinic acid (QA) differ from healthy controls and change with treatment response. Methods This was a randomized, double-blind, two-arm, placebo-controlled study. Subjects who met study criteria were randomized to receive escitalopram + celecoxib, or escitalopram + placebo. Inflammation biomarkers and kynurenine pathway intermediates were determined at baseline and weeks 4 and 8. Results Patients receiving the celecoxib combination showed improved response and higher remission rate. All patients had significantly lower QA levels at baseline compared to healthy controls. QA values did not change significantly over time, but a downtrend was noted through treatment. Responders had marginally lower QA values than non-responders. Factors that might have led to low QA levels may include prior exposure to a variety of psychoactive agents. Conclusions Although QA did not significantly change, symptom reduction and remission occurred more frequently in the celecoxib group, demonstrating the beneficial effect of inflammation modulation.

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 understanding of any overlapping presentation of FM and OSA. We conducted a site-wide review of patients from 2012-2016 to identify FM patients diagnosed with OSA. Methods: Charts were reviewed in patients aged 18 and above from 2012-2016 using ICD codes from a clinical data repository. Intersection of patients with a diagnosis of FM and OSA in clinics of psychiatry, sleep, rheumatology, and other outpatient clinics was compared. Polysomnography order patterns for FM patients were investigated. Results: Co-morbidity was highest in the sleep clinic (85.8%) compared to psychiatry (42.0%), rheumatology (18.7%), and other outpatient clinics (3.6%) (p

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 approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.

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 these individuals are sometimes described as having atypical, mild, or attenuated forms of autoimmune encephalitis, some authors feel that that these cases are sufficiently different from typical autoimmune encephalitis to establish a new category of so-called autoimmune psychosis. We briefly review the background, discuss the existing evidence for a form of autoimmune psychosis, and propose a novel, conservative approach to the recognition of possible, probable, and definite autoimmune psychoses for use in psychiatric practice. We also outline the investigations required and the appropriate therapeutic approaches, both psychiatric and immunological, for probable and definite cases of autoimmune psychoses, and discuss the ethical issues posed by this challenging diagnostic category.

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 receiving combination treatment with the cyclooxygenase-2 inhibitor, celecoxib (CBX). Methods In this randomized, 10-week, double-blind, two-arm, placebo-controlled study, 47 patients with treatment resistant BDD received either escitalopram (ESC) + CBX, or ESC + placebo (PBO). Plasma MCP-1 levels were measured at 3 time points in the BDD subjects, and in a healthy control (HC) group. Depression severity was quantified using the Hamilton Depression Scale (HAMD-17). Results The CBX group had significantly lower HAMD-17 scores vs. PBO at week 4 (P = 0.026) and week 8 (P = 0.002). MCP-1 levels were not significantly different in BDD vs. HC subjects at baseline (P = 0.588), nor in CBX vs. PBO groups at week 8 (P = 0.929). Week 8 HAMD-17 scores and MCP-1 levels were significantly negatively correlated in treatment non-responders to CBX or PBO (P = 0.050). Non-responders had significantly lower MCP-1 levels vs. responders at weeks 4 (P = 0.049) and 8 (P = 0.014). MCP-1 was positively correlated with pro-inflammatory analytes in the PBO group and with anti-inflammatory analytes in the CBX group. Conclusions Combination treatment reduced treatment resistance and augmented antidepressant response. Baseline plasma MCP-1 levels were not altered in BDD patients. Since non-responders had lower levels of MCP-1, elevated MCP-1 may indicate a better response to CBX + SSRI treatment.

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, among others, to serotonin deficiency, and increased production of neurotoxic substances contributing to disease progression. The concept of neuroprogression is gaining acceptance among clinicians and researches as it seeks to explain the mechanism(s) responsible for disease chronicity, recurrence and treatment resistance. Therefore, measurement of neuroinflammatory biomarkers along with assessment of neurotoxic metabolites, oxidative stress and neuroplasticity impairment, will ultimately be useful tools to predict and possibly prevent the development and progression of neuropsychiatric disorders as well as to identify the most efficacious treatments.

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 wi...

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 patients received Escitalopram and were randomized to receive add-on Celecoxib (26 participants) or Placebo (21 participants). There were 32 healthy controls. Plasma levels of VEGF were determined at three timepoints over eight weeks. Results Bipolar patients had significantly higher VEGF levels at baseline compared to healthy controls. Logistic regression analysis revealed that the AUC is 0.67 and the VEGF cut point is 8.21. At all timepoints, patients receiving Celecoxib had comparable VEGF levels to those receiving Placebo. VEGF levels did not change significantly over time. Baseline VEGF was a poor predictor of treatment response with an AUC of 0.53. Conclusions The increased VEGF in bipolar depression agrees with similar findings in major depressive disorder. A high VEGF level tended to accurately predict bipolar disorder, with apparent differential VEGF expression. Baseline VEGF did not predict treatment response, and levels did not change with treatment. Plasma VEGF may have diagnostic utility and guide personalized treatment.

Background: Affective disorders, including bipolar depression (BDD), have high medical comorbidity, especially cardiovascular disease (CVD). The link between BDD and CVD is bidirectional, with involvement of inflammation. Inflammation in BDD may promote endothelial dysfunction and arterial stiffness. This study utilized noninvasive Applanation Tonometry (AT) to examine the link between inflammation, endothelial dysfunction, and CVD risk in BDD patients. It was an exploratory study as part of a study aimed at testing the hypothesis that modulation of inflammation improves treatment resistance. Methods: BDD subjects (N=47) enrolled in a double-blind study to receive Escitalopram (ESC) + Celecoxib (CBX) or ESC + Placebo (PBO) for eight weeks. ESC was given at daily doses of 20-30 mg and CBX at 400 mg. AT was used to measure the Augmentation Index (AIx). Healthy subjects served as controls. Results: BDD subjects had a higher mean AIx at baseline than healthy subjects but after controlling for confounding variables, no difference emerged. There was no correlation between severity of depression and augmentation index at baseline. CBX did not decrease AIx over the study period. Age is a significant confounding variable for AIx in all subjects, but young BDD subjects had significantly higher AIx than young healthy subjects. Conclusions: AIx is a marker of endothelial dysfunction and arterial stiffness. Several factors impact AIx, including natural aging, and inflammation. Among young BDD patients, the contributory effect of age is minimized, and the effect of depression unmasked. It is important to understand the inflammatory effects of depression, as contributory to CVD risk.

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 Sinus Arrhythmia (RSA), and Low Frequency HRV (LF-HRV). Both of these components have been extensively reported in studies of depression and have been at least partially associated with reduction in vagal nerve tone. We quantified RSA and LF-HRV in patients with Major Depressive Disorder (MDD) as measures of ANS regulation seeking to establish the utility of components of HRV as potential diagnostic and prognostic biomarkers for treatment outcome. Methods: Sixty-six MDD patients were enrolled. In two separate and consecutively run studies they received either Escitalopram or Quetiapine fumarate ER over 12 weeks. Forty-one patients completed the studies. RSA and LF-HRV were assessed at pretreatment and end of study. Thirty-six healthy subjects served as controls. RSA and LF-HRV were quantified using an algorithm that incorporates time and frequency domains to address the non-stationarity of the beat-to-beat heart rate pattern. Results: No significant differences in baseline RSA or LF-HRV were found between MDD and healthy controls. However, baseline RSA and LF-HRV were significantly higher in treatment responders (lnRSA = 6.20, lnLF-HRV = 5.76) than non-responders (lnRSA = 4.75, lnLF-HRV = 4.53) (p = 0.005, p = 0.006). No significant changes in RSA or LF-HRV were detected over the course of either treatment. Conclusions: Components of HRV may be predictive of antidepressant response in MDD patients.

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, particularly in conjunction cardiological procedures. Clinicians should be aware of such interactions which increase the emergence of the serotonin syndrome and the appropriate management of comorbid delirium post-serotonin syndrome.

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 depressed (BDD) patients as a measure of ANS dysregulation seeking to establish HRV as a potential diagnostic and prognostic biomarker for treatment outcome. Forty-seven BDD patients were enrolled. They were randomized to receive either escitalopram–celecoxib or escitalopram-placebo over 8 weeks in a double-blind study design. Thirty-five patients completed the HRV studies. Thirty-six healthy subjects served as controls. HRV was assessed at pretreatment and end of study and compared with that of controls. HRV was quantified and corrected for artifacts using an algorithm that incorporates time and frequency domains to address non-stationarity of the beat-to-beat heart rate pattern. Baseline high frequency-HRV (i.e., respiratory sinus arrhythmia) was lower in BDD patients than controls, although the difference did not reach significance. Baseline low-frequency HRV was significantly lower in BDD patients (ln4.20) than controls (ln = 5.50) (p

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 been identified in most, if not all, neurological conditions. Similarly, major depressive disorder has been associated with a chronic proinflammatory status. Activation of the immune response can alter neurotransmission leading, among others, to serotonin deficiency, and increased production of neurotoxic substances contributing to primary disease progression. Therefore, inflammatory factors might serve as biomarkers to predict and ultimately prevent the development and progression of neuropsychiatric disorders as well as to identify the most efficacious treatments.

A pro-inflammatory state and a dysregulation in the tryptophan/kynurenine pathway have been documented in depression. This study examined whether treatment with the SSRI, escitalopram (ESC), could suppress inflammation and favorably shift metabolites of the kynurenine pathway in patients with major depressive disorder (MDD) within the utilized treatment period. Twenty seven healthy control subjects were included for comparison. Thirty patients were enrolled after completing baseline assessments. They received a 12-week ESC monotherapy. Twenty subjects were completers. Clinical assessments were carried out at each visit using the HAM-D, HAM-A, CGI and BDI rating scales. Blood samples were collected at each assessment and stored until analyzed. Cytokines were analyzed with Randox multiplex assay and tryptophan and kynurenine metabolites were analyzed using HPLC/GCMS. Baseline plasma concentrations of hsCRP, TNF alpha IL6 and MCP-1 were significantly higher in patients compared to healthy controls. IL10 trended toward an increase. Baseline plasma IL1 beta correlated significantly with IL1 alpha, and IL4. Patients showed significant improvement in all outcome measures with a high remission rate. Significant correlations were obtained between specific symptoms and certain biomarkers at baseline but these correlations must be viewed as very preliminary. During ESC treatment concentrations of inflammatory biomarkers did not change except for TNF alpha that trended lower. Metabolites and ratios of the tryptophan/kynurenine pathway showed reductions of the neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, 3-hydroxykynurenine/kynurenine, quinolinic acid/tryptophan, kynurenic acid/quinolinic acid and quinolinic acid/3-hydroxylcynurenine. The results indicate that ESC may exert its antidepressant effect in part through inhibition of synthesis of certain neurotoxic kynurenine metabolites and possibly also through reduction of the inflammatory response, although there was no concordance in the time course of changes between antidepressant efficacy and reversal of the pro-inflammatory status.

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 model of depression and several studies have assessed VEGF levels in depressed patients. The results have been discrepant largely due to design and assay differences among studies. The aim of this study was to assess plasma VEGF levels in a cohort of MDD subjects prior to treatment with psychotropic medication and compare them to those of healthy control (HC) subjects. Prospective study participants underwent extensive medical and psychiatric assessments before they were enrolled. Plasma concentrations of VEGF were measured by the technique marketed by Randox Technologies. The mean baseline VEGF for the healthy and depressed groups was 5.91 pg/ml (SD: 3.04) and 10.51 pg/ml (SD: 9.04), respectively, and this difference was statistically significant (p = 0.001). We detected a very low univariate relationship between VEGF and demographic and clinical variables. Using the Optimal Data Analysis a cut score of 6.64 pg/ml for baseline plasma VEGF distinguished depressed from healthy subjects with a 63% overall accuracy. We conclude these results support a role of plasma VEGF as a useful biomarker of depression that can be measured with a routine blood draw at the point of service. The specificity of this potential biomarker must be confirmed in studies that include other psychiatric disease entities.

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 double-blind study, 47 consenting patients with BDD were randomized to receive either escitalopram (10 mg twice/day) + CBX (200 mg twice/day), or escitalopram (10 mg twice/day) + placebo (twice/day). Plasma CRP levels were measured in both patient groups at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. Symptoms were rated using the 17-item Hamilton Depression Scale (HAMD-17). The CBX group had significantly lower HAMD-17 scores vs. placebo at week 4 (P = 0.026) and week 8 (P = 0.002). Therefore, SSRI + CBX is more effective than SSRI + placebo in reversing treatment resistance and augmenting antidepressant response in BDD. Baseline CRP levels were significantly increased amongst BDD patients versus HC subjects, indicating that CRP may be a useful biomarker for BDD (P = 0.044). No significant differences in CRP levels were measured between CBX and placebo groups at baseline (P = 0.156), but by week 8 CRP was significantly decreased in the CBX group vs. placebo (P = 0.003). This indicates reduced inflammation in CBX-treated patients, and that CRP may be a useful biomarker for monitoring treatment response in BDD patients during SSRI + CBX combination treatment. CRP and IL-6 levels were positively correlated in the CBX group, and CRP levels were positively correlated with BMI.

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 aspects that contribute to the progressive course of the disease in question. In an attempt to identify the appropriate agent or method that could arrest neuroprogression in psychiatric patients, we conducted an evaluation of the use of anti-inflammatory drugs under the perspective of current pharmacological and neurophysiological data. This evaluation included the use of nonsteroidal anti-inflammatory drugs (NSAIDs) as adjunctive treatment to conventional pharmacotherapy as well as the use of natural products exerting anti-inflammatory properties (i.e., ω-3 fatty acids) given as adjunctive or monotherapeutic treatments in less severe cases. The therapeutic significance of nonpharmacological methods, such as psychotherapy, physical exercise, and body-mind therapies, was also considered and will be discussed in this chapter. In conclusion, the role of psychotropic and select anti-inflammatory drugs in arresting neuroprogression is a very promising new frontier in psychiatric research and clinical practice. Modulators of a specific prostanoid synthase or receptor across the cyclooxygenase (COX)-2 downstream pathway along with new multitarget NSAIDs are expected to be tested by the pharmaceutical industry as potential agents to antagonize neuroprogression. Meanwhile, salicylates and selective COX-2 inhibitors could still be used in carefully selected subgroups of patients. Psychotherapy and nonpharmacological, stress-relieving methods should be considered as adjunctive tools to aid in arresting neuroprogression.