Structural brain plasticity and inflammation are independently related to changes in depressive symptoms six months after an index ECT course.

BACKGROUND: Electroconvulsive therapy (ECT) is effective for treatment-resistant depression and leads to short-term structural brain changes and decreases in the inflammatory response. However, little is known about how brain structure and inflammation relate to the heterogeneity of treatment response in the months following an index ECT course. METHODS: A naturalistic six-month study following an index ECT course included 20 subjects with treatment-resistant depression. Upon conclusion of the index ECT course and again after six months, structural magnetic resonance imaging scans and peripheral inflammation measures [interleukin-6 (IL-6), IL-8, tumor necrosis factor (TNF-α), and C-reactive protein] were obtained. Voxel-based morphometry processed with the CAT-12 Toolbox was used to estimate changes in gray matter volume. RESULTS: Between the end of the index ECT course and the end of follow-up, we found four clusters of significant decreases in gray matter volume (p < 0.01, FWE) and no regions of increased volume. Decreased HAM-D scores were significantly related only to reduced IL-8 level. Decreased volume in one cluster, which included the right insula and Brodmann's Area 22, was related to increased HAM-D scores over six months. IL-8 levels did not mediate or moderate the relationship between volumetric change and depression. CONCLUSIONS: Six months after an index ECT course, multiple regions of decreased gray matter volume were observed in a naturalistic setting. The independent relations between brain volume and inflammation to depressive symptoms suggest novel explanations of the heterogeneity of longer-term ECT treatment response.

Interleukin-8 and depressive responses to an inflammatory challenge: secondary analysis of a randomized controlled trial.

Emerging evidence suggests that interleukin (IL)-8 has a protective role in the context of depression. Higher levels of IL-8 are associated with lower depressive symptom severity among depressed patients, and treatment-related increases in IL-8 correlate with a positive response in depressed patients. This study (a secondary analysis of a completed randomized controlled trial) aimed to examine whether higher levels of IL-8 mitigate increases in depressed mood in response to an experimental model of inflammation induced depression. Given epidemiologic relationships identified between IL-6, tumor necrosis factor (TNF)- α, and subsequent depression, levels of these pro-inflammatory cytokines were also explored as potential moderators of depressed mood response to endotoxin. Secondary analyses were completed on data from healthy adults (n = 114) who completed a double-blind, placebo-controlled randomized trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). IL-8, as well as IL-6 and TNF- α, were measured at baseline prior to infusion, and depressed mood and feelings of social disconnection were assessed approximately hourly. Baseline levels of IL-8, but not IL-6 or TNF-α, moderated depressed mood (ß = - 0.274, p = .03) and feelings of social disconnection (ß = - 0.307, p = .01) responses, such that higher baseline IL-8 was associated with less increase in depressed mood and feelings of social disconnection in the endotoxin, but not placebo, condition. IL-8 had threshold effects, in which highest quartile IL-8 (≥ 2.7 pg/mL) attenuated increases in depressed mood in response to endotoxin as compared to lower IL-8 quartiles (p = .02). These findings suggest that IL-8 may be a biological factor that mitigates risk of inflammation-associated depression. Clinical trials registration: ClinicalTrials.gov NCT01671150, registration date 23/08/2012.

Interleukin-8 and lower severity of depression in females, but not males, with treatment-resistant depression.

INTRODUCTION: In cross-sectional studies of depressed patients, relationships between depression and levels of IL-8 are inconsistent, and have not been examined in relation to sex. Given identified sex differences in longitudinal data, it is important to evaluate sex-specific cross-sectional relationships between IL-8 and depressive symptoms, which may explain some inconsistency in the extant literature. It is further unknown whether IL-8 levels may relate to specific symptom profiles among depressed patients, with or without regard to sex. METHODS: Among 108 patients with treatment resistant depression (50 females), we evaluated cross-sectional relationships between IL-8 and depression severity, as measured by the Hamilton Depression Rating Scale [HAM-D] Score, and examined sex-specific relationships, as well as relationships with depressive symptom profiles. Other inflammatory markers (IL-6, IL-10, TNF-α, CRP) were also explored in relation to HAM-D. RESULTS: Higher IL-8 was associated with lower total HAM-D score (standardized ß = -0.19, p = 0.049). Sex-specific effects were identified (IL-8 x sex interaction: p = 0.03), in which higher IL-8 related to lower HAM-D score in females (standardized ß = -0.41, p = 0.004, effect size (sr2) = 0.17), but not males (standardized ß = 0.02, p = 0.91). Among a subset of 94 patients (41 females) who had individual HAM-D items available, we evaluated relationships between IL-8 and HAM-D factor subscores. Across sexes, higher IL-8 was associated with lower anxiety/hypochondriasis subscores (standardized ß = -0.31, p = 0.002; sex interaction: p = 0.99). Sex differences were identified for relationships between IL-8 and two other HAM-D factor subscores. CONCLUSIONS: IL-8 may be related to anxiety symptoms across sexes, but may have a sex-specific relationship with other depressive symptoms. Further evaluation of sex-specific relationships between IL-8, depression symptom profiles, treatment response, and potential neurobiological correlates, may inform mechanisms of depression pathophysiology and aid in development of precision medicine strategies.

Depression treatment response to ketamine: sex-specific role of interleukin-8, but not other inflammatory markers.

Inflammation plays a role in depression pathophysiology and treatment response, with effects varying by sex and therapeutic modality. Lower levels of interleukin(IL)-8 predict depression response to antidepressant medication and to electroconvulsive therapy (ECT), although ECT effects are specific to females. Whether IL-8 predicts depression response to ketamine and in a sex-specific manner is not known. Here, depressed patients (n = 46; female, n = 17) received open label infusion of ketamine (0.5 mg/kg over 40 min; NCT02165449). Plasma levels of IL-8 were evaluated at baseline and post-treatment. Baseline levels of IL-8 had a trending association with response to ketamine, depending upon sex (responder status × sex interaction: p = 0.096), in which lower baseline levels of IL-8 in females (p = 0.095) but not males (p = 0.96) trended with treatment response. Change in levels of IL-8 from baseline to post-treatment differed significantly by responder status (defined as ≥50% reduction in Hamilton Depression Rating Scale [HAM-D] Score), depending upon sex (responder status × sex × time interaction: F(1,42)=6.68, p = 0.01). In addition, change in IL-8 interacted with sex to predict change in HAM-D score (ß = -0.63, p = 0.003); increasing IL-8 was associated with decreasing HAM-D score in females (p = 0.08) whereas the inverse was found in males (p = 0.02). Other inflammatory markers (IL-6, IL-10, tumor necrosis factor-α, C-reactive protein) were explored with no significant relationships identified. Given these preliminary findings, further evaluation of sex differences in the relationship between IL-8 and treatment response is warranted to elucidate mechanisms of response and aid in the development of personalized approaches to depression treatment.

Non-Convulsive Status Epilepticus in the Presence of Catatonia: A Clinically Focused Review.

INTRODUCTION: Catatonia is classically associated with psychiatric conditions but may occur in medical and neurologic disorders. Status epilepticus (SE) is a seizure lasting more than five minutes or two or more seizures within a five-minute period without interictal recovery of consciousness. Non-convulsive status epilepticus (NCSE) is SE without prominent motor activity that may present with catatonic symptoms. The relevance of NCSE as a potential etiology for catatonia is not clear in the literature. METHODS: A systematic review was completed to evaluate the literature on NCSE presenting with catatonia. PubMed and PsycInfo databases were searched and articles were reviewed for the presence of catatonia and NCSE. RESULTS: 15 articles describing 27 cases meeting inclusion criteria were identified. The authors add 1 case to the literature. The most common catatonic symptoms identified in NCSE were mutism and stupor. Clinical features frequent in NCSE presenting with catatonia included new catatonic symptoms, age over 50 years, comorbid neurological conditions, or a change in medications that affect seizure threshold. A documented psychiatric history was also common and may contribute to delayed diagnosis. DISCUSSION/CONCLUSION: It is important to consider NCSE in the differential diagnosis of new catatonic symptoms. A suggested approach to diagnostic evaluation is provided.

Inflammation and depression treatment response to electroconvulsive therapy: Sex-specific role of interleukin-8.

Females suffer from depression at twice the rate of males and have differential neural and emotional responses to inflammation. However, sex-specific evaluation of relationships between inflammation and response to depression treatments are lacking. Some data suggest that interleukin(IL)-8 predicts treatment response to antidepressants and has a relationship with depressive symptom severity. This study examines whether IL-8 predicts treatment response to electroconvulsive therapy (ECT), and whether there are sex specific effects. In 40 depressed patients (22 female), plasma levels of IL-8, as well as other markers of inflammation including IL-6, IL-10, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) were obtained prior to administration of ECT and after completion of the index treatment series. Depression treatment response was defined as ≥ 50% reduction in Hamilton Depression Rating Scale (HAM-D) Score. Baseline levels of IL-8 differed by responder status, depending on sex (group × sex interaction: ß = -0.571, p = 0.04), with female responders having lower levels of IL-8 at baseline as compared to female non-responders [t(20) = 2.37, p = 0.03]. Further, IL-8 levels from baseline to end of treatment differed by responder status, depending on sex (group × sex × time interaction: [F(1,36) = 9.48, p = 0.004]), and change in IL-8 from baseline to end of treatment was negatively correlated with percentage change in HAM-D score in females (ß = -0.458, p = 0.03), but not in males (ß = 0.315, p = 0.20). Other inflammatory markers did not differ in relation to responder status and sex. Further evaluation of sex differences in the relationship between IL-8, depression, and treatment response, across disparate treatment modalities, may inform mechanisms of response and aid in development of personalized medicine strategies.

Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study.

Inflammation has an important physiological influence on mood and behavior. Kynurenine metabolism is hypothesized to be a pathway linking inflammation and depressed mood, in part through the impact of kynurenine metabolites on glutamate neurotransmission in the central nervous system. This study evaluated whether the circulating concentrations of kynurenine and related compounds change acutely in response to an inflammatory challenge (endotoxin administration) in a human model of inflammation-induced depressed mood, and whether such metabolite changes relate to mood change. Adults (n = 115) were randomized to receive endotoxin or placebo. Mood (Profile of Mood States), plasma cytokine (interleukin-6, tumor necrosis factor-α) and metabolite (kynurenine, tryptophan, kynurenic acid, quinolinic acid) concentrations were repeatedly measured before the intervention, and at 2 and 6 h post-intervention. Linear mixed models were used to evaluate relationships between mood, kynurenine and related compounds, and cytokines. Kynurenine, kynurenic acid, and tryptophan (but not quinolinic acid) concentrations changed acutely (p's all <0.001) in response to endotoxin as compared to placebo. Neither kynurenine, kynurenic acid nor tryptophan concentrations were correlated at baseline with cytokine concentrations, but all three were significantly correlated with cytokine concentrations over time in response to endotoxin. Quinolinic acid concentrations were not correlated with cytokine concentrations either before or following endotoxin treatment. In those who received endotoxin, kynurenine (p = 0.049) and quinolinic acid (p = 0.03) positively correlated with depressed mood, although these findings would not survive correction for multiple testing. Changes in tryptophan and kynurenine pathway metabolites did not mediate the relationship between cytokines and depressed mood. Further work is necessary to clarify the pathways leading from inflammation to depressed mood in humans.

Inflammation and Improvement of Depression Following Electroconvulsive Therapy in Treatment-Resistant Depression.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most robust acute treatment for severe major depressive disorder, yet clinical response is variable. Inflammation is associated with depression, especially in women, and levels of C-reactive protein (CRP) and interleukin (IL)-6 predict response to antidepressant medications. This study evaluated whether markers of inflammation predicted response to electroconvulsive therapy (ECT) in patients with treatment-resistant depression and to what extent this association differed between men and women. METHODS: In patients (N = 29) who had a current major depressive episode diagnosed using DSM-IV-TR criteria and were scheduled to undergo ECT at an academic referral center, levels of CRP, IL-6, IL-8, and tumor necrosis factor-α and severity of depressive symptoms (Montgomery-Asberg Depression Rating Scale [MADRS]) were prospectively evaluated before ECT treatment, after the second ECT session, and again at the completion of the index treatment series. Data were collected between December 2011 and December 2014. The primary outcome was end-of-treatment MADRS score. RESULTS: In multivariate analyses, higher levels of IL-6 at baseline, but not other inflammatory markers or clinical variables, were associated with lower end-of-treatment MADRS score (P = .01). When stratified by sex, IL-6 remained a significant predictor of end-of-treatment MADRS for women (P = .02) but not men (P = .1), and CRP emerged as a significant predictor for women (P = .04) but not men (P = .66). CRP and IL-6 increased from baseline to the second ECT session (P values < .01) and returned to baseline levels at end of treatment; these changes did not relate to MADRS score over the course of ECT. CONCLUSIONS: Levels of IL-6 prior to ECT treatment may be useful in identifying those depressed patients most likely to benefit from ECT treatment. In contrast, acute changes in IL-6 and CRP may reflect spikes in inflammatory response related to the initiation of seizure therapy, but not mood. Assessment of pretreatment inflammatory biomarkers, especially in women, might be useful in guiding treatment decision-making in treatment-resistant depression.

Long-term risk of myocardial infarction and stroke in bipolar I disorder: A population-based Cohort Study.

OBJECTIVES: To estimate the risk of fatal and non-fatal myocardial infarction (MI) and stroke in patients with bipolar I disorder compared to people without bipolar I disorder. METHOD: Utilizing a records-linkage system spanning 30 years (1966-1996), a population-based cohort of 334 subjects with bipolar I disorder and 334 age and sex-matched referents from Olmsted County, Minnesota, U.S. was identified. Longitudinal follow-up continued until incident MI or stroke (confirmed by board-certified cardiologist/neurologist), death, or study end date (December 31, 2013). Cox proportional hazards models assessed the hazard ratio (HR) for MI or stroke, adjusting for potential confounders. RESULTS: There was an increased risk of fatal or non-fatal MI or stroke (as a composite outcome) in patients with bipolar I disorder [HR 1.54, 95% confidence interval (CI) 1.02, 2.33; p=0.04]. However, after adjusting for baseline cardiovascular risk factors (alcoholism, hypertension, diabetes, and smoking), the risk was no longer significantly increased (HR 1.19, 95% CI 0.76, 1.86; p=0.46). LIMITATIONS: Small sample size for the study design. Findings were not retained after adjustment for cardiovascular disease risk factors. Psychotropic medication use during the follow-up was not ascertained and was not included in the analyses. CONCLUSION: This study in a geographically defined region in the U.S. demonstrated a significant increased risk of MI or stroke in bipolar I disorder, which was no longer significant after adjustment for cardiovascular risk factors.

Psychiatric Autoimmunity: N-Methyl-D-Aspartate Receptor IgG and Beyond.

BACKGROUND: Descriptions of psychiatric autoimmunity beyond N-methyl-D-aspartate (NMDA) receptor encephalitis are sparse. OBJECTIVE: To report the autoimmune psychiatric spectrum currently recognized in Mayo Clinic practice. METHODS: Medical record review, testing of stored serum and cerebrospinal fluid for IgGs reactive with synaptic receptors and ion channels, neuronal nuclear and cytoplasmic antigens (including glutamic acid decarboxylase 65-kDa isoform) and case-control comparison were conducted. Patients were categorized into group 1, all adult psychiatric inpatients tested for neural autoantibodies (2002-2011; n = 213), and group 2, all Mayo NMDA receptor IgG-positive patients (2009-2013; n = 13); healthy control subjects were also included (n = 173). RESULTS: In group 1, at least 1 serum autoantibody (but not NMDA receptor IgG) was detected in 36 of 213 psychiatric inpatients. In total, 12 patients were determined retrospectively to have high-likelihood autoimmune encephalitic diagnoses. The most commonly detected autoantibody specificities were voltage-gated potassium channel ([Kv1] VGKC) complex (6) and calcium channel (P/Q type or N type; 5). Symptoms seen were as follows: depressive (8), anxious (7), psychotic (7), disorganized (5), suicidal (3), manic (1) and catatonic (1). In group 2, among 13 NMDA receptor IgG-positive patients, 12 had encephalitis; their psychiatric symptoms were as follows: depressive (9), catatonic (9), disorganized (8), anxious (8), psychotic (7), manic (6), and suicidal (3). Catatonic symptoms were more common in the 12 NMDA receptor IgG-positive patients than in the 12 group 1 patients with high likelihood of encephalitis (p = 0.002). Antibody positivities were usually low positive in value among healthy controls (12 of 16 vs 3 of 12 group 1 encephalitis cases, p = 0.025). NMDA receptor IgG was not detected in any healthy control subject. CONCLUSIONS: A spectrum of psychiatric autoimmunity beyond NMDA-R IgG may be under-recognized. Diagnosis is facilitated by combining results of comprehensive psychiatric, laboratory, radiologic, and electrophysiologic evaluations.

Sick and tired: mood, fatigue, and inflammation in cancer.

Cancer patients commonly experience depression and fatigue before, during, and after treatment. Symptoms can be debilitating, and the risks associated with unrecognized or inadequately treated depression are substantial. Inflammation may be important in the genesis of depression and fatigue in cancer patients; potential neurobiological mechanisms of inflammation-related behavioral symptoms are reviewed. Randomized studies of pharmacologic treatments for depression in cancer populations are limited, but available data are generally encouraging. Studies of pharmacologic treatments for cancer-related fatigue have been more numerous but with mixed results. A practical approach to pharmacologic treatment of depression and fatigue in cancer patients involves weighing the potential risks and benefits of specific agents, including potential for adverse or advantageous side effects. Progress in understanding the neurobiological mechanisms underlying inflammation-related behavioral symptoms will provide opportunities for the development of novel and targeted treatments.

Anti-N-methyl-D-aspartate receptor encephalitis: a targeted review of clinical presentation, diagnosis, and approaches to psychopharmacologic management.

BACKGROUND: Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis was formally described in 2007 and includes a range of psychiatric and neurologic symptoms. Most patients with anti-NMDAR encephalitis initially present to psychiatrists for diagnosis and treatment. However, there is limited literature summarizing treatment strategies for psychiatric symptoms. In an effort to improve identification and treatment, this review article provides an overview of anti-NMDAR encephalitis, with a focus on psychopharmacologic treatment strategies. Two case reports provide a clinical context for the literature review. METHODS: The authors conducted a PubMed search. RESULTS: Prominent psychiatric symptoms of anti-NMDAR encephalitis include psychosis, agitation, insomnia, and catatonia. Neuroleptics may be helpful for managing psychosis and agitation, but may exacerbate movement abnormalities. Diphenhydramine and benzodiazepines are helpful for agitation and insomnia. In addition, the anticholinergic affinity of diphenhydramine can improve dystonia or rigidity attributable to anti-NMDAR encephalitis, while benzodiazepines and electroconvulsive therapy have been used for catatonia associated with this condition. CONCLUSIONS: Psychiatrists play an important role in the diagnosis and treatment of anti-NMDAR encephalitis. Recognizing the typical clinical progression and closely monitoring for accompanying neurologic symptoms will facilitate diagnosis and timely treatment. Careful selection of psychopharmacological interventions may reduce suffering.