Joseph, Boney

AbstractBackgroundKetamine is increasingly used for treatment‐resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs).MethodsA comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine.ResultsA total of 1859 abstracts were screened of which 11 were included for full‐text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open‐label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment‐resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post‐infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients.ConclusionsThis systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.

Ketamine has shown rapid antidepressant and anti-suicidal effects in treatment-resistant depression (TRD) with single and serial intravenous (IV) infusions, but the effectiveness for depressive episodes of bipolar disorder is less clear. We conducted an updated systematic review and meta-analysis to appraise the current evidence on the efficacy and tolerability of ketamine/esketamine in bipolar depression. A search was conducted to identify randomized controlled trials (RCTs) and non-randomized studies examining single or multiple infusions of ketamine or esketamine treatments. A total of 2657 articles were screened; 11 studies were included in the systematic review of which 7 studies were included in the meta-analysis (five non-randomized, N = 159; two RCTs, N = 33) with a mean age of 42.58 ± 13.1 years and 54.5% females. Pooled analysis from two RCTs showed a significant improvement in depression symptoms measured with MADRS after receiving a single infusion of ketamine (1-day WMD = −11.07; and 2 days WMD = −12.03). Non-randomized studies showed significant response (53%, p < 0.001) and remission rates (38%, p < 0.001) at the study endpoint. The response (54% vs. 55%) and remission (30% vs. 40%) rates for single versus serial ketamine infusion studies were similar. The affective switch rate in the included studies approximated 2.4%. Esketamine data for bipolar depression are limited, based on non-randomized, small sample-sized studies. Further studies with larger sample sizes are required to strengthen the evidence.

In the original publication [...]

Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40−100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings.

Abstract Objective The factors that influence seizure timing are poorly understood, and seizure unpredictability remains a major cause of disability. Work in chronobiology has shown that cyclical physiological phenomena are ubiquitous, with daily and multiday cycles evident in immune, endocrine, metabolic, neurological, and cardiovascular function. Additionally, work with chronic brain recordings has identified that seizure risk is linked to daily and multiday cycles in brain activity. Here, we provide the first characterization of the relationships between the cyclical modulation of a diverse set of physiological signals, brain activity, and seizure timing. Methods In this cohort study, 14 subjects underwent chronic ambulatory monitoring with a multimodal wrist‐worn sensor (recording heart rate, accelerometry, electrodermal activity, and temperature) and an implanted responsive neurostimulation system (recording interictal epileptiform abnormalities and electrographic seizures). Wavelet and filter–Hilbert spectral analyses characterized circadian and multiday cycles in brain and wearable recordings. Circular statistics assessed electrographic seizure timing and cycles in physiology. Results Ten subjects met inclusion criteria. The mean recording duration was 232 days. Seven subjects had reliable electroencephalographic seizure detections (mean = 76 seizures). Multiday cycles were present in all wearable device signals across all subjects. Seizure timing was phase locked to multiday cycles in five (temperature), four (heart rate, phasic electrodermal activity), and three (accelerometry, heart rate variability, tonic electrodermal activity) subjects. Notably, after regression of behavioral covariates from heart rate, six of seven subjects had seizure phase locking to the residual heart rate signal. Significance Seizure timing is associated with daily and multiday cycles in multiple physiological processes. Chronic multimodal wearable device recordings can situate rare paroxysmal events, like seizures, within a broader chronobiology context of the individual. Wearable devices may advance the understanding of factors that influence seizure risk and enable personalized time‐varying approaches to epilepsy care.

Clonidine, an alpha-2 adrenergic agonist, has been proposed as an antimanic agent that acts by reducing noradrenergic transmission. We conducted a systematic review to examine the efficacy and safety of clonidine for acute mania/hypomania. A comprehensive literature search was performed to identify randomized controlled trials (RCT) and non-randomized studies investigating the efficacy and safety of monotherapy/adjuvant treatment with clonidine for acute mania/hypomania in patients with bipolar disorder (BD). Nine studies (n = 222) met our inclusion criteria, including five RCTs (n = 159) and four non-randomized studies (n = 63). Non-randomized studies showed clonidine to help reduce symptoms of mania. However, data from placebo controlled RCTs were inconsistent. One RCT showed adjuvant clonidine as superior to placebo, whereas another RCT reported that clonidine was not better than placebo. In individual RCTs, lithium and valproate offered better antimanic effects compared to clonidine. Studies reported hypotension, depression, and somnolence as common adverse effects. Significant differences in study design and sample size contributed to high heterogeneity. This systematic review suggests low-grade evidence for clonidine as an adjuvant treatment for acute mania with mood stabilizers and inconclusive efficacy as monotherapy, warranting further well-designed RCTs.

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders.

Abstract Objective Anterior temporal lobectomy (ATL) is a widely performed and successful intervention for drug‐resistant temporal lobe epilepsy (TLE). However, up to one third of patients experience seizure recurrence within 1 year after ATL. Despite the extensive literature on presurgical electroencephalography (EEG) and magnetic resonance imaging (MRI) abnormalities to prognosticate seizure freedom following ATL, the value of quantitative analysis of visually reviewed normal interictal EEG in such prognostication remains unclear. In this retrospective multicenter study, we investigate whether machine learning analysis of normal interictal scalp EEG studies can inform the prediction of postoperative seizure freedom outcomes in patients who have undergone ATL. Methods We analyzed normal presurgical scalp EEG recordings from 41 Mayo Clinic (MC) and 23 Cleveland Clinic (CC) patients. We used an unbiased automated algorithm to extract eyes closed awake epochs from scalp EEG studies that were free of any epileptiform activity and then extracted spectral EEG features representing (a) spectral power and (b) interhemispheric spectral coherence in frequencies between 1 and 25 Hz across several brain regions. We analyzed the differences between the seizure‐free and non–seizure‐free patients and employed a Naïve Bayes classifier using multiple spectral features to predict surgery outcomes. We trained the classifier using a leave‐one‐patient‐out cross‐validation scheme within the MC data set and then tested using the out‐of‐sample CC data set. Finally, we compared the predictive performance of normal scalp EEG‐derived features against MRI abnormalities. Results We found that several spectral power and coherence features showed significant differences correlated with surgical outcomes and that they were most pronounced in the 10–25 Hz range. The Naïve Bayes classification based on those features predicted 1‐year seizure freedom following ATL with area under the curve (AUC) values of 0.78 and 0.76 for the MC and CC data sets, respectively. Subsequent analyses revealed that (a) interhemispheric spectral coherence features in the 10–25 Hz range provided better predictability than other combinations and (b) normal scalp EEG‐derived features provided superior and potentially distinct predictive value when compared with MRI abnormalities (>10% higher F1 score). Significance These results support that quantitative analysis of even a normal presurgical scalp EEG may help prognosticate seizure freedom following ATL in patients with drug‐resistant TLE. Although the mechanism for this result is not known, the scalp EEG spectral and coherence properties predicting seizure freedom may represent activity arising from the neocortex or the networks responsible for temporal lobe seizure generation within vs outside the margins of an ATL.

Abstract Objective This study aims to evaluate the role of scalp electroencephalography (EEG; ictal and interictal patterns) in predicting resective epilepsy surgery outcomes. We use the data to further develop a nomogram to predict seizure freedom. Methods We retrospectively reviewed the scalp EEG findings and clinical data of patients who underwent surgical resection at three epilepsy centers. Using both EEG and clinical variables categorized into 13 isolated candidate predictors and 6 interaction terms, we built a multivariable Cox proportional hazards model to predict seizure freedom 2 years after surgery. Harrell's step‐down procedure was used to sequentially eliminate the least‐informative variables from the model until the change in the concordance index (c‐index) with variable removal was less than 0.01. We created a separate model using only clinical variables. Discrimination of the two models was compared to evaluate the role of scalp EEG in seizure‐freedom prediction. Results Four hundred seventy patient records were analyzed. Following internal validation, the full Clinical + EEG model achieved an optimism‐corrected c‐index of 0.65, whereas the c‐index of the model without EEG data was 0.59. The presence of focal to bilateral tonic‐clonic seizures (FBTCS), high preoperative seizure frequency, absence of hippocampal sclerosis, and presence of nonlocalizable seizures predicted worse outcome. The presence of FBTCS had the largest impact for predicting outcome. The analysis of the models’ interactions showed that in patients with unilateral interictal epileptiform discharges (IEDs), temporal lobe surgery cases had a better outcome. In cases with bilateral IEDs, abnormal magnetic resonance imaging (MRI) predicted worse outcomes, and in cases without IEDs, patients with extratemporal epilepsy and abnormal MRI had better outcomes. Significance This study highlights the value of scalp EEG, particularly the significance of IEDs, in predicting surgical outcome. The nomogram delivers an individualized prediction of postoperative outcome, and provides a unique assessment of the relationship between the outcome and preoperative findings.

Abstract Quantitative volumetric brain MRI measurement is important in research applications, but translating it into patient care is challenging. We explore the incorporation of clinical automated quantitative MRI measurements in statistical models predicting outcomes of surgery for temporal lobe epilepsy. Four hundred and thirty-five patients with drug-resistant epilepsy who underwent temporal lobe surgery at Cleveland Clinic, Mayo Clinic and University of Campinas were studied. We obtained volumetric measurements from the pre-operative T1-weighted MRI using NeuroQuant, a Food and Drug Administration approved software package. We created sets of statistical models to predict the probability of complete seizure-freedom or an Engel score of I at the last follow-up. The cohort was randomly split into training and testing sets, with a ratio of 7:3. Model discrimination was assessed using the concordance statistic (C-statistic). We compared four sets of models and selected the one with the highest concordance index. Volumetric differences in pre-surgical MRI located predominantly in the frontocentral and temporal regions were associated with poorer outcomes. The addition of volumetric measurements to the model with clinical variables alone increased the model’s C-statistic from 0.58 to 0.70 (right-sided surgery) and from 0.61 to 0.66 (left-sided surgery) for complete seizure freedom and from 0.62 to 0.67 (right-sided surgery) and from 0.68 to 0.73 (left-sided surgery) for an Engel I outcome score. 57% of patients with extra-temporal abnormalities were seizure-free at last follow-up, compared to 68% of those with no such abnormalities (P-value = 0.02). Adding quantitative MRI data increases the performance of a model developed to predict post-operative seizure outcomes. The distribution of the regions of interest included in the final model supports the notion that focal epilepsies are network disorders and that subtle cortical volume loss outside the surgical site influences seizure outcome.