Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories.

In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up to 27% of patients with MDD and is associated with a more severe, chronic, and treatment-resistant trajectory. Inflammation is not unique to depression and has transdiagnostic effects suggesting a shared etiological risk factor underlying psychopathologies and metabolic disorders. Research supports an association but not necessarily a causation with depression. Putative mechanisms link chronic stress to dysregulation of the HPA axis and immune cell glucocorticoid resistance resulting in hyperactivation of the peripheral immune system. The chronic extracellular release of DAMPs and immune cell DAMP-PRR signaling creates a feed forward loop that accelerates peripheral and central inflammation. Higher plasma levels of inflammatory cytokines, most consistently interleukin IL-1ß, IL-6, and TNF-α, are correlated with greater depressive symptomatology. Cytokines sensitize the HPA axis, disrupt the negative feedback loop, and further propagate inflammatory reactions. Peripheral inflammation exacerbates central inflammation (neuroinflammation) through several mechanisms including disruption of the blood-brain barrier, immune cellular trafficking, and activation of glial cells. Activated glial cells release cytokines, chemokines, and reactive oxygen and nitrogen species into the extra-synaptic space dysregulating neurotransmitter systems, imbalancing the excitatory to inhibitory ratio, and disrupting neural circuitry plasticity and adaptation. In particular, microglial activation and toxicity plays a central role in the pathophysiology of neuroinflammation. Magnetic resonance imaging (MRI) studies most consistently show reduced hippocampal volumes. Neural circuitry dysfunction such as hypoactivation between the ventral striatum and the ventromedial prefrontal cortex underlies the melancholic phenotype of depression. Chronic administration of monoamine-based antidepressants counters the inflammatory response, but with a delayed therapeutic onset. Therapeutics targeting cell mediated immunity, generalized and specific inflammatory signaling pathways, and nitro-oxidative stress have enormous potential to advance the treatment landscape. Future clinical trials will need to include immune system perturbations as biomarker outcome measures to facilitate novel antidepressant development. In this overview, we explore the inflammatory correlates of depression and elucidate pathomechanisms to facilitate the development of novel biomarkers and therapeutics.

The Psychological Impact of COVID-19 on Hospital Staff.

INTRODUCTION: The coronavirus 2019 (COVID-19) pandemic has created a mental health crisis among hospital staff who have been mentally and physically exhausted by uncertainty and unexpected stressors. However, the mental health challenges and complexities faced by hospital staff in the United States has not been fully elucidated. To address this gap, we conducted this study to examine the prevalence and correlates of depression and anxiety among hospital staff in light of the COVID-19 pandemic. METHODS: The design is a single-center, cross-sectional, online survey evaluating depression and anxiety among all hospital employees (n = 3,500) at a safety-net hospital with a moderate cumulative COVID-19 hospitalization rate between April 30-May 22, 2020. We assessed depression with the Patient Health Questionnaire-9. Anxiety was measured with the Generalized Anxiety Disorder-7 scale. Logistic regression analyses were calculated to identify associations with depression and anxiety. RESULTS: Of 3,500 hospital employees, 1,246 (36%) responded to the survey. We included 1,232 individuals in the final analysis. Overall, psychological distress was common among the respondents: 21% and 33% of staff reported significant depression and anxiety, respectively, while 46% experienced overwhelming stress due to COVID-19. Notably, staff members overwhelmed by the stress of COVID-19 were seven and nine times more likely to suffer from depression and anxiety, respectively. In addition to stress, individuals with six to nine years of work experience were two times more likely to report moderate or severe depression compared to those with 10 or more years of work experience. Moreover, ancillary staff with direct patient contact (odds ratio [OR] 8.9, confidence interval (CI), 1.46, 173.03) as well as administrative and ancillary staff with indirect patient contact (OR 5.9, CI, 1.06, 111.01) were more likely to be depressed than physicians and advanced providers. CONCLUSION: We found that a considerable proportion of staff were suffering from psychological distress. COVID-19-associated depression and anxiety was widespread among hospital staff even in settings with comparatively lower COVID-19 hospitalization rates. Ancillary staff, administrative staff, staff with less job experience, and staff overwhelmed by the stress of COVID-19 are particularly susceptible to negative mental health outcomes. These findings will help inform hospital policymakers on best practices to develop interventions to reduce the mental health burden associated with COVID-19 in vulnerable hospital staff.

Tramadol: Understanding the Risk of Serotonin Syndrome and Seizures.

Tramadol is commonly prescribed for pain control because it presents a lower risk for addiction and respiratory depression compared to other opioids. However, tramadol's serotonin and norepinephrine reuptake inhibitory effects result in a unique adverse effect profile. Two such adverse events are serotonin syndrome and seizures. The prevalence of tramadol-induced serotonin syndrome and seizures is modest in the general population, but if left untreated, the morbidity and mortality can be high; therefore, prompt recognition and management is essential. Various risk factors such as medical comorbidities, use or abuse of supratherapeutic doses of tramadol, and concomitant administration of proconvulsant serotonergic cytochrome P-450 inhibitors will help clinicians identify individuals at an elevated risk for serotonin toxicity and seizures. Serotonin syndrome and seizures can be effectively treated by administering benzodiazepines, providing supportive care, and discontinuing tramadol and other contributing agents. Cyproheptadine should be administered in moderate to severe cases of serotonin syndrome. Our objective is to summarize the literature on the pharmacology, epidemiology, risk factors, clinical presentations, and evidence-based management of tramadol-related seizures and serotonin syndrome.

The Evaluation of Medical Inpatients Who Are Admitted on Long-term Opioid Therapy for Chronic Pain.

Individuals who are on long-term opioid therapy (LTOT) for chronic noncancer pain are frequently admitted to the hospital with acute pain, exacerbations of chronic pain, or comorbidities. Consequently, hospitalists find themselves faced with complex treatment decisions in the context of uncertainty about the effectiveness of LTOT as well as concerns about risks of overdose, opioid use disorders, and adverse events. Our multidisciplinary team sought to synthesize guideline recommendations and primary literature relevant to assessing medical inpatients on LTOT, with the objective of assisting practitioners in balancing effective pain treatment and opioid risk reduction. We identified no primary studies or guidelines specific to assessing medical inpatients on LTOT. Recommendations from outpatient guidelines on LTOT and guidelines on pain management in acute-care settings include the following: evaluate both pain and functional status, differentiate acute from chronic pain, investigate the preadmission course of opioid therapy, obtain a psychosocial history, screen for mental health conditions, screen for substance use disorders, check state prescription drug monitoring databases, order urine drug immunoassays, detect use of sedative-hypnotics, and identify medical conditions associated with increased risk of overdose and adverse events. Although approaches to assessing medical inpatients on LTOT can be extrapolated from related guidelines, observational studies, and small studies in surgical populations, more work is needed to address these critical topics for inpatients on LTOT.

A pilot study of body image perceptions, and attitudes toward obesity in hospitalized psychotic and non-psychotic patients.

OBJECTIVE: Body image perceptions, and attitudes toward obesity were examined and compared between psychotic and non-psychotic patients with a mood disorder. METHODS: 80 psychotic patients and 36 non-psychotic patients with a mood disorder admitted to an acute inpatient psychiatric unit participated in the study. On admission, each patient completed a visual silhouettes scale of actual self and ideal self, as well as the Attitudes Toward Obese Persons (ATOP) scale. RESULTS: Analogous to the general population, psychotic and non-psychotic patients had similar body image perceptions, and experienced discrepancy between actual and ideal body image. Female patients with serious mental illness (SMI) picked a heavier actual self body image, and experienced greater discrepancy between actual and ideal body image compared to male patients with SMI. Psychotic and non-psychotic patients experienced similar mostly neutral attitudes toward obese persons, however there was a trend for depressed patients to have more negative attitudes toward obese persons compared to non-depressed patients. DISCUSSION: The presence of an acute psychotic episode did not affect body perceptions, or obesity attitudes; however depressed patients had more negative obesity attitudes. Similar to the general population, females with SMI overassessed their body size, and experienced more body dissatisfaction compared to males with SMI.

Overcoming Barriers to Initiating Medication-assisted Treatment for Heroin Use Disorder in a General Medical Hospital: A Case Report and Narrative Literature Review.

Deaths due to heroin overdoses are increasing and are the leading cause of death among intravenous heroin users. Although medication-assisted treatment (MAT) improves morbidity and mortality in patients with opioid use disorders, it is underutilized. Most efforts to expand access to MAT have focused on outpatient settings. Although the inpatient medical setting presents a critical opportunity to initiate treatment, general hospitals are often unfamiliar with MAT, creating a number of barriers to its use. In this report, we describe the case of a woman with heroin use disorder who was initiated on buprenorphine maintenance treatment while hospitalized for cardiac disease related to her intravenous heroin use. Barriers to initiating buprenorphine in this case included patient, practitioner, and organizational factors, and, ultimately, shared misperceptions about the feasibility of administering buprenorphine in a general medical hospital. These barriers were addressed, buprenorphine was initiated, and the patient demonstrated reduced craving, improved postoperative pain control, improved overall well-being, increased engagement in discharge planning, and acceptance of referral for addiction specialty aftercare. Our experience with this patient suggests that it is feasible to initiate buprenorphine in acute medical settings and that such treatment can improve patient outcomes. Our review of the literature reveals emerging evidence supporting the value of this practice.

Reversible Valproic Acid-Induced Parkinsonism and Cognitive Impairment in an Elderly Patient With Bipolar Disorder I. / Bipolar Bozukluk I Tanisi Olan Yasli Bir Hastada Valproik Asit Kullanimina Bagli Gelisen Geri Dönüsümlü Parkinsonizm ve Bilissel Bozulma.

Valproic acid (VPA) is approved by the Food and Drug Administration (FDA) for the treatment of manic or mixed episodes associated with bipolar disorder. VPA is also used off-label to treat other conditions in psychiatry such as impulse control disorders, major depression, and posttraumatic stress disorder (PTSD). Although VPA is mostly well-tolerated, common adverse effects include gastrointestinal symptoms (nausea, vomiting, diarrhea), neurological symptoms (sedation, ataxia, tremor), weight gain, and alopecia. Less common adverse effects include VPA-induced parkinsonism and cognitive impairment. We describe a patient who developed parkinsonism and cognitive impairment eight years after starting divalproex sodium for bipolar disorder, type I. Over time, the patient's parkinsonian symptoms progressed, and the motor symptoms were partially responsive to carbidopa/levodopa. Her mild cognitive impairment was, for the most part, stable on donepezil. Rapid discontinuation of divalproex sodium resolved the parkinsonian symptoms as well as the cognitive impairment. A brief review of the literature regarding VPA-induced parkinsonism and cognitive impairment in adults is included. Given the reversible nature and potential severity of VPA-induced parkinsonism, improved recognition in psychiatric populations is critical, particularly after extended VPA exposure. To the best of our knowledge there are no reports describing the onset of VPA-induced parkinsonism in psychiatric patients more than eight years after starting VPA.

A narrative review: The effects of opioids on sleep disordered breathing in chronic pain patients and methadone maintained patients.

BACKGROUND AND OBJECTIVES: Opioids increase the risk for sleep disordered breathing (SDB), but there are few studies examining the prevalence and risk factors for SDB, specifically central sleep apnea (CSA), and obstructive sleep apnea (OSA) in chronic pain patients on opioids as well as methadone maintained patients (MMPs). METHODS: A literature review was conducted in which SDB was confirmed by polysomnography (PSG) in chronic pain patients on opioids as well as patients with a diagnosis of an opioid use disorder or opioid dependence on methadone maintenance treatment (MMT). RESULTS: About 22 reports were included. Six were with MMPs, and 16 were with chronic pain patients on opioids. Among MMPs, the prevalence of SDB ranged from 42.3% to 70%; 0-60% had CSA and 10-35.2% had OSA. In chronic pain patients on opioids, the prevalence of SDB ranged from 71% to 100%; 17-80% had CSA and 20-39% had OSA. In MMPs, studies found a positive association between BMI, weight gain, duration of MMT, non-Caucasian race and the number of obstructive apneas, as well as blood methadone concentrations and the number of central apneas. In chronic pain patients on opioids, older age, higher BMI, male gender, and higher opioid doses predicted more obstructive apneas; older age, lower BMI, male gender, higher pain levels, higher benzodiazepine doses, and higher opioid doses predicted more central apneas. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: CSA and OSA are common in MMPs and chronic pain patients on opioids. Among chronic pain patients, higher opioid doses appear to be a risk factor for CSA, and to a lesser extent OSA. Therefore, it is important for providers to screen these patient populations for SDB. (Am J Addict 2016;25:452-465).

Reversal of cerebral glucose hypometabolism on positron emission tomography with electroconvulsive therapy in an elderly patient with a psychotic episode.

AB, a 74-year-old Caucasian woman, was admitted for acute onset of psychosis, anxiety, and cognitive impairment. Pharmacotherapy was unsuccessful and the patient was referred for electroconvulsive therapy (ECT). Pre-ECT, 18 F-fluorodeoxyglucose-positron emission tomography (PET)/computed tomography showed extensive frontal, parietal, and temporal cortical hypometabolism suggestive of a neurodegenerative disease. After eight ECT sessions, the psychotic and anxiety symptoms as well as the cognitive impairment resolved. The rapid improvement in symptoms was more suggestive of a psychotic episode rather than dementia. Two days after the ECT course, 18 F-fluorodeoxyglucose-PET/computed tomography showed improvements in cerebral cortical hypometabolism, especially in the left parietal cortex, left temporal/occipital cortex. and bifrontal regions. At a follow-up visit 2 months after the ECT course, the psychotic episode was still in remission, and 18 F-fluorodeoxyglucose-PET/computed tomography continued to show improved cerebral cortical hypometabolism in these areas. This case illustrated the effect of ECT in reversing cerebral glucose hypometabolism on PET. The improvement in cerebral glucose hypometabolism may represent the neurophysiological mechanism of ECT in the treatment of a psychotic episode. Improved cerebral glucose hypometabolism was present 2 months post-ECT, which suggests that ECT caused sustained functional neural changes.

A preoperative interdisciplinary biopsychosocial opioid reduction program in patients on chronic opioid analgesia prior to spine surgery: A preliminary report and case series.

BACKGROUND: Spine surgery candidates are commonly treated with long-term opioid analgesia. However, chronic opioid analgesia is associated with poor pain control, psychological distress, decreased functional status and operative complications. Therefore, our medical centre piloted an outpatient biopsychosocial interdisciplinary opioid reduction program for spine surgery candidates on chronic opioid analgesia. METHODS: Our case series reviews the outcomes of the first 5 interdisciplinary program completers. Data was collected on admission to the program, preoperatively at completion of the program, and 1 month postoperatively. We recorded changes in pain interference scores, physical functioning, and symptoms of depression and anxiety as captured by the Patient-Reported Outcome Measurement Information System (PROMIS-29) Profile. RESULTS: The mean duration of the preoperative opioid reduction program was 6-7 weeks. The mean morphine equivalent daily dose (SD) decreased from 238.2 (226.9)mg on admission to 157.1 (161.0)mg preoperatively and 139.1 (84.0)mg one month postoperatively. Similarly, the mean pain interference score (SD) decreased from 72.4 (5.1) on admission to 66.5 (6.9) preoperatively and 67.7 (5.4) one month postoperatively. The preoperative opioid dose and pain interference scores decreased in all 5 patients, but one month postoperatively increased in one patient related to a surgical complication. Pre- and post-operative depression, anxiety and fatigue improved in all patients. Satisfaction with participation in social roles, sleep disturbances, and physical functioning improved in most patients. CONCLUSIONS: Pre- and post-operative pain improved despite the opioid dose being tapered. These preliminary data suggest that a short-term outpatient preoperative interdisciplinary biopsychosocial opioid reduction program is safe, feasible, and improves patient-centred outcomes. IMPLICATIONS: Our preliminary data support the rationale for expansion of the opioid reduction program; opioid use and pain should be evaluated in all surgical candidates. These findings need to be replicated in larger studies.

Augmentation Therapy With Serial Intravenous Ketamine Over 18 Months in a Patient With Treatment Resistant Depression.

Major depressive disorder is a severe illness that affects 3% to 7% of adults annually in the United States. About 30% of these individuals are refractory to multiple treatment trials. Recent reports have found a significant and almost immediate improvement in depressive symptoms after single or multiple ketamine intravenous infusions (IVIs) in such patients. We present the case of A.B., a patient with treatment-resistant depression (TRD) including to subgenual deep brain stimulation, who went into remission after augmentation with 6 ketamine IVIs (0.5 mg/kg) over a 3-week period. However, she had a reemergence of depressive symptoms 4 months later and received a second series of 3 ketamine IVIs over the course of a week. A.B. again went into remission and maintained this for the next 8 months. At this time, she experienced a reemergence of depressive symptoms and was treated with the third series of ketamine IVIs (3 infusions over the course of a week). Because A.B. has now been in remission for 6 months. A.B. has received a total of 12 ketamine IVIs over the course of 18 months. No significant adverse events have occurred. To our knowledge, this is the first case of long-term ketamine efficacy as augmentation therapy in TRD over the course of 18 months. There is a need for studies examining the long-term management of TRD with IV ketamine. Guidelines for maintenance ketamine IVIs in TRD also need to be developed.

Examining the role of psychological distress in linking childhood maltreatment and alcohol use in young adulthood.

BACKGROUND AND OBJECTIVES: Childhood maltreatment is related to alcohol use as well as psychological distress in young adulthood. Few studies have examined whether psychological distress mediates the relationship between child maltreatment and alcohol use. We examined the role of psychological distress in linking child maltreatment subtypes (ie, emotional abuse, physical abuse, sexual abuse, neglect) to four patterns of alcohol use, including frequency of alcohol use, binge drinking, alcohol-related problems, and alcohol dependence. METHODS: We used a community sample of young adults (N = 337), who completed an interview assessing exposure to childhood maltreatment, current psychological distress, and drinking behaviors. RESULTS: Emotional abuse was associated with psychological distress, whereas psychological distress was related to more pathological drinking behaviors such as alcohol-related problems and alcohol dependence. Subsequent analyses indicated significant mediated effects between emotional abuse and alcohol-related problems and alcohol dependence via psychological distress, even after controlling for demographic factors, other maltreatment subtypes, parental alcoholism, and peer alcohol use. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Findings suggest that among four types of childhood maltreatment, emotional abuse might be the major driver of pathological drinking among child maltreatment victims. Interventions aimed at negative emotionality may be useful in preventing and treating problematic drinking among the victims of childhood emotional abuse.

QTc Prolongation in Veterans With Heroin Dependence on Methadone Maintenance Treatment.

BACKGROUND: QTc prolongation and Torsade de Ppointes have been reported in patients on methadone maintenance. OBJECTIVES: In this study, QTc was compared before and after the veteran (n = 49) was on a stable dosage of methadone for 8.72 ± 4.50 years to treat heroin dependence. Risk factors were correlated with the QTc once the veteran was on a stable dose of methadone. Differences in the clinical risk factors in subgroups of veterans with below and above mean QTc change was compared. PATIENTS AND METHODS: ECG data was obtained from a 12-lead electrocardiogram (pre-methadone and on methadone) on 49 veterans. Data and risk factors were retrospectively collected from the medical records. RESULTS: The mean QTc at baseline (pre-methadone) was 426 ± 34 msec and after being on methadone for an average of 8.72 ± 4.50 years was significantly higher at 450 ± 35 msec. No significant relationships were found between QTc prolongation and risk factors except for calcium. The methadone dosage was significantly higher in veterans with a QTc change above the mean change of ≥ 24 msec (88.48 ± 27.20 mg v.s 68.96 ± 19.84 mg). None of the veterans experienced cardiac arrhythmias. CONCLUSIONS: The low complexity of medical co-morbidities may explain the lack of a significant correlation between any risk factor with the QTc except calcium and methadone dosage. The absence of TdP may be explained by the low prevalence of QTc values > 500 msec as well as the retrospective design of the study. During long-term methadone treatment, there was a slight increase in the QTc interval but we did not find evidence of increased cardiac toxicity as a reason for treatment termination.

A brief analysis of suicide methods and trends in Virginia from 2003 to 2012.

BACKGROUND: The objective is to analyze and compare Virginia suicide data from 2003 to 2012 to US suicide data. METHODS: Suicide trends by method, age, gender, and race were obtained from Virginia's Office of the Chief Medical Examiner's annual reports. RESULTS: Similar to US suicide rates, suicide rates in Virginia increased between 2003 and 2012 from 10.9/100,000 people to 12.9/100,000 people. The most common methods were firearm, asphyxia, and intentional drug overdose, respectively. The increase in asphyxia (r = 0.77, P ≤ 0.01) and decrease in CO poisoning (r = -0.89, P ≤ 0.01) were significant. Unlike national trends, intentional drug overdoses decreased (r = -0.55, P = 0.10). Handgun suicides increased (r = 0.61, P = 0.06) and are the most common method of firearm suicide. Hanging was the most common method of asphyxia. Helium suicides also increased (r = 0.75, P = 0.05). Middle age females and males comprise the largest percentage of suicide. Unlike national data, the increase in middle age male suicides occurred only in the 55-64-year-old age group (r = 0.79, P ≤ 0.01) and decreased in the 35-44-year-old age group (r = -0.60, P = 0.07) and 10-14-year-old age group (r = -0.73, P = 0.02). Suicide in all female age ranges remained stable. Caucasians represent the highest percentage of suicide. CONCLUSION: There has been a rise in suicide in Virginia and suicide rates and trends have closely resembled the national average albeit some differences. Suicide prevention needs to be enhanced.

Delayed Onset and Prolonged ECT-Related Delirium.

Electroconvulsive therapy (ECT) is effective in the treatment of depression. Delayed post-ECT delirium is rare but can occur in a small subset of patients with risk factors and in most cases resolves with the use of psychotropic medications. We report a unique presentation of a patient who developed a delayed post-ECT delirium with fecal incontinence that commenced 24 hours after the administration of ECT. The condition resolved spontaneously after 48 hours without the use of psychotropic medications.

General coping strategies and their impact on quality of life in older adults with schizophrenia.

BACKGROUND: Both symptom specific and general coping strategies may affect the well-being of persons with schizophrenia. There are little data on how older adults with schizophrenia employ various coping styles. This study examines the types of general coping strategies used by older persons with schizophrenia and examines the extent to which the various coping strategies affect quality of life. METHODS: The schizophrenia group consisted of 198 persons aged 55 and over living in the community who developed schizophrenia before age 45. A community comparison group (n=113) was recruited using randomly selected block-groups. Cognitive, instrumental, and avoidant coping scales were created based on a principal component analysis with equamax rotation of items from a self-report coping inventory. A modified version of Yanos and Moos' integrative model was used to assess the direct and mediating effects of each of the coping strategies scales on the Quality of Life Index. RESULTS: Older adults with schizophrenia and their age peers in the general community most commonly use cognitive coping strategies, and there was no significant difference in their scores on this scale. For persons with schizophrenia, the active coping strategies--cognitive and instrumental--were used more frequently than the avoidant strategies. Both active and avoidant strategies mediated the impact of psychiatric symptoms on quality of life as well as contributing independently to improving life quality; however, they had no impact on the other stressor variables. CONCLUSION: This study suggests that general coping strategies, especially more active approaches, may be useful in diminishing the adverse impact of psychiatric symptoms on quality of life as well as having direct effects on life quality. Such strategies can complement symptom specific approaches.