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Selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitors and epidemiological characteristics associated with prenatal diagnosis of congenital heart disease.
Melov, SJ, Shetty, PS, Pasupathy, D, Kirby, A, Sholler, GF, Winlaw, DS, Alahakoon, TI
Prenatal diagnosis. 2021;(1):35-42
Abstract
OBJECTIVE Identify early pregnancy associations of congenital heart disease (CHD) in a multiethnic cohort. METHODS This retrospective observational cohort study compared the general obstetric population to women who gave birth at a referral centre in Australia between 2012 and 2017, after 20 weeks' of gestation, with a pregnancy affected by CHD. We defined mood disorder and anxiety as a history of self-reported or medically diagnosed anxiety, depression, postpartum depression or bipolar disorder. RESULTS We compared epidemiological factors between 30 842 general obstetric patients and 470 obstetric patients with a foetus affected by CHD. Multivariate analysis showed independent associations between CHD and use of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) in the first trimester (relative risk [RR] 4.14, 95% CI 2.58-6.65), history of anxiety or mood disorder with no SSRI/SNRI first trimester (RR 2.20, 95% CI 1.77-2.74), folate and/or pregnancy multivitamin use in the first trimester (RR 0.69, 95% CI 0.55-0.87) and increased risk with maternal age >40 years (RR 2.30, 95% CI 1.57-3.38). CONCLUSIONS Our data show maternal mood disorders with and without SSRI or SNRI use, maternal age >40 years and lack of multivitamin/folate use to be independently associated with CHD in pregnancy.
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Glutamatergic medications as adjunctive therapy for moderate to severe obsessive-compulsive disorder in adults: a systematic review and meta-analysis.
Hadi, F, Kashefinejad, S, Kamalzadeh, L, Hoobehfekr, S, Shalbafan, M
BMC pharmacology & toxicology. 2021;(1):69
Abstract
BACKGROUND Obsessive-compulsive disorder (OCD) is among the most disabling neuropsychiatric conditions characterized by the presence of repetitive intrusive thoughts, impulses, or images (obsessions) and/or ritualized mental or physical acts (compulsions). Serotonergic medications, particularly Selective Serotonin Reuptake Inhibitors (SSRIs), are the first-line treatments for patients with OCD. Recently, dysregulation of glutamatergic system has been proposed to be involved in the etiology of OCD. We designed this systematic review and meta-analysis to evaluate clinical efficacy of glutamatergic medications in patients with OCD, according to the guidelines of Cochrane collaboration. METHOD We searched Medline, Scopus, and Cochrane library without applying any language filter. Two of the authors independently reviewed search results for irrelevant and duplicate studies and extracted data and assessed methodological quality of the studies. We transformed data into a common rubric and calculated a weighted treatment effect across studies using Review Manager. RESULTS We found 476 references in 3 databases, and after exclusion of irrelevant and duplicate studies, 17 studies with total number of 759 patients with OCD were included. In the present review we found evidence for several drugs such as memantine, N-acetylcysteine (NAC), Minocycline, L-carnosine and riluzole. Glutamaterigic drug plus SSRIs were superior to SSRI+ Placebo with regard to Y-BOCS scale [standardized mean difference (SMD = - 3.81 95% CI = - 4.4, - 3.23). CONCLUSION Augmentation of glutamatergic medications with SSRIs are beneficial in obsessive-compulsive patients, no harmful significant differences in any safety outcome were found between the groups.
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Efficacy of Traditional Chinese Medicine Combined with Selective Serotonin Reuptake Inhibitors on the Treatment for Parkinson's Disease with Depression: A Systematic Review and Meta-Analysis.
Feng, ST, Wang, XL, Wang, YT, Yuan, YH, Li, ZP, Chen, NH, Wang, ZZ, Zhang, Y
The American journal of Chinese medicine. 2021;(3):627-643
Abstract
Depression is a common neuropsychiatric symptom of Parkinson's disease (PD), resulting in a lower quality of life and cognitive impairment in PD patients. Traditional Chinese medicine (TCM) formulas have been widely used in neurodegenerative disease and neuropsychic disorders to improve life quality of patients in ethnomedicine. TCM formulas combined with selective serotonin reuptake inhibitors (SSRIs) also have a positive effect on depressed PD compared with SSRIs as reported by several clinical studies. However, the results are discordant and failed to be conclusive. We aim to evaluate the efficacy of TCM formulas combined with SSRIs for depressed PD in this systematic review. We searched literatures from PubMed, Web of Science, Medline, Embase, Google Scholar, Chinese National Knowledge Infrastructure, Wanfang Database, and VIP Information Database before July 2020. We included randomized controlled trials investigating the efficacy of TCM formulas combined with SSRIs on depressed PD patients. This analysis was according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Eleven randomized clinical trials involving 861 subjects were enrolled in this analysis. The overall results showed that TCM formulas combined with SSRIs significantly improved the depression score [weighted mean difference (WMD): -4.920, 95% confidence interval (CI): (-5.999, -3.840); [Formula: see text]¡ 0.001] and had a statistical significance on Unified Parkinson's Disease Rating Scale II score [WMD: -1.209, 95% CI: (-1.561, -0.857); [Formula: see text] < 0.001]. Furthermore, we observed that Chai-Hu-Shu-Gan Powder combined with SSRIs had a significant improvement on the depressive symptom in PD compared to the SSRIs alone [WMD: -5.390, 95% CI: (-7.66, -3.11); [Formula: see text] < 0.001]. No severe side events were reported in these included trials. This systematic review provided the evidences that TCM formulas combined with SSRIs might be helpful and safe in the treatment of depression of PD, including Chai-Hu-Shu-Gan Powder. Also, more randomized double-blinded trials with reliable design are required in the future.
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Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens: A Randomized Clinical Trial.
Nabbout, R, Mistry, A, Zuberi, S, Villeneuve, N, Gil-Nagel, A, Sanchez-Carpintero, R, Stephani, U, Laux, L, Wirrell, E, Knupp, K, et al
JAMA neurology. 2020;(3):300-308
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Abstract
IMPORTANCE Fenfluramine treatment may reduce monthly convulsive seizure frequency in patients with Dravet syndrome who have poor seizure control with their current stiripentol-containing antiepileptic drug regimens. OBJECTIVE To determine whether fenfluramine reduced monthly convulsive seizure frequency relative to placebo in patients with Dravet syndrome who were taking stiripentol-inclusive regimens. DESIGN, SETTING, AND PARTICIPANTS This double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted in multiple centers. Eligible patients were children aged 2 to 18 years with a confirmed clinical diagnosis of Dravet syndrome who were receiving stable, stiripentol-inclusive antiepileptic drug regimens. INTERVENTIONS Patients with 6 or more convulsive seizures during the 6-week baseline period were randomly assigned to receive fenfluramine, 0.4 mg/kg/d (maximum, 17 mg/d), or a placebo. After titration (3 weeks), patients' assigned dosages were maintained for 12 additional weeks. Caregivers recorded seizures via a daily electronic diary. MAIN OUTCOMES AND MEASURES The primary efficacy end point was the change in mean monthly convulsive seizure frequency between fenfluramine and placebo during the combined titration and maintenance periods relative to baseline. RESULTS A total of 115 eligible patients were identified; of these, 87 patients (mean [SD], age 9.1 [4.8] years; 50 male patients [57%]; mean baseline frequency of seizures, approximately 25 convulsive seizures per month) were enrolled and randomized to fenfluramine, 0.4 mg/kg/d (n = 43) or placebo (n = 44). Patients treated with fenfluramine achieved a 54.0% (95% CI, 35.6%-67.2%; P < .001) greater reduction in mean monthly convulsive seizure frequency than those receiving the placebo. With fenfluramine, 54% of patients demonstrated a clinically meaningful (≥50%) reduction in monthly convulsive seizure frequency vs 5% with placebo (P < .001). The median (range) longest seizure-free interval was 22 (3.0-105.0) days with fenfluramine and 13 (1.0-40.0) days with placebo (P = .004). The most common adverse events were decreased appetite (19 patients taking fenfluramine [44%] vs 5 taking placebo [11%]), fatigue (11 [26%] vs 2 [5%]), diarrhea (10 [23%] vs 3 [7%]), and pyrexia (11 [26%] vs 4 [9%]). Cardiac monitoring demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary arterial hypertension. CONCLUSIONS AND RELEVANCE Fenfluramine demonstrated significant improvements in monthly convulsive seizure frequency in patients with Dravet syndrome whose conditions were insufficiently controlled with stiripentol-inclusive antiepileptic drug regimens. Fenfluramine was generally well tolerated. Fenfluramine may represent a new treatment option for Dravet syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02926898.
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Cortical Connectivity Moderators of Antidepressant vs Placebo Treatment Response in Major Depressive Disorder: Secondary Analysis of a Randomized Clinical Trial.
Rolle, CE, Fonzo, GA, Wu, W, Toll, R, Jha, MK, Cooper, C, Chin-Fatt, C, Pizzagalli, DA, Trombello, JM, Deckersbach, T, et al
JAMA psychiatry. 2020;(4):397-408
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IMPORTANCE Despite the widespread awareness of functional magnetic resonance imaging findings suggesting a role for cortical connectivity networks in treatment selection for major depressive disorder, its clinical utility remains limited. Recent methodological advances have revealed functional magnetic resonance imaging-like connectivity networks using electroencephalography (EEG), a tool more easily implemented in clinical practice. OBJECTIVE To determine whether EEG connectivity could reveal neural moderators of antidepressant treatment. DESIGN, SETTING, AND PARTICIPANTS In this nonprespecified secondary analysis, data were analyzed from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinic Care study, a placebo-controlled, double-blinded randomized clinical trial. Recruitment began July 29, 2011, and was completed December 15, 2015. A random sample of 221 outpatients with depression aged 18 to 65 years who were not taking medication for depression was recruited and assessed at 4 clinical sites. Analysis was performed on an intent-to-treat basis. Statistical analysis was performed from November 16, 2018, to May 23, 2019. INTERVENTIONS Patients received either the selective serotonin reuptake inhibitor sertraline hydrochloride or placebo for 8 weeks. MAIN OUTCOMES AND MEASURES Electroencephalographic orthogonalized power envelope connectivity analyses were applied to resting-state EEG data. Intent-to-treat prediction linear mixed models were used to determine which pretreatment connectivity patterns were associated with response to sertraline vs placebo. The primary clinical outcome was the total score on the 17-item Hamilton Rating Scale for Depression, administered at each study visit. RESULTS Of the participants recruited, 9 withdrew after first dose owing to reported adverse effects, and 221 participants (150 women; mean [SD] age, 37.8 [12.7] years) underwent EEG recordings and had high-quality pretreatment EEG data. After correction for multiple comparisons, connectome-wide analyses revealed moderation by connections within and between widespread cortical regions-most prominently parietal-for both the antidepressant and placebo groups. Greater alpha-band and lower gamma-band connectivity predicted better placebo outcomes and worse antidepressant outcomes. Lower connectivity levels in these moderating connections were associated with higher levels of anhedonia. Connectivity features that moderate treatment response differentially by treatment group were distinct from connectivity features that change from baseline to 1 week into treatment. The group mean (SD) score on the 17-item Hamilton Rating Scale for Depression was 18.35 (4.58) at baseline and 26.14 (30.37) across all time points. CONCLUSIONS AND RELEVANCE These findings establish the utility of EEG-based network functional connectivity analyses for differentiating between responses to an antidepressant vs placebo. A role emerged for parietal cortical regions in predicting placebo outcome. From a treatment perspective, capitalizing on the therapeutic components leading to placebo response differentially from antidepressant response should provide an alternative direction toward establishing a placebo signature in clinical trials, thereby enhancing the signal detection in randomized clinical trials. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01407094.
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Randomized Controlled Trial of Riluzole Augmentation for Posttraumatic Stress Disorder: Efficacy of a Glutamatergic Modulator for Antidepressant-Resistant Symptoms.
Spangler, PT, West, JC, Dempsey, CL, Possemato, K, Bartolanzo, D, Aliaga, P, Zarate, C, Vythilingam, M, Benedek, DM
The Journal of clinical psychiatry. 2020;(6)
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Abstract
OBJECTIVE Current pharmacologic treatments for posttraumatic stress disorder (PTSD) have shown limited efficacy, prompting a call to investigate new classes of medications. The current study investigated the efficacy of glutamate modulation with riluzole augmentation for combat-related PTSD symptoms resistant to treatment with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). METHODS A randomized, double-blind, placebo-controlled, parallel trial was conducted at Walter Reed National Military Medical Center and Syracuse VA Medical Center between December 2013 and November 2017. Veterans and active duty service members with combat-related PTSD (per the Clinician Administered PTSD Scale [CAPS]) who were not responsive to SSRI or SNRI pharmacotherapy were randomized to 8-week augmentation with a starting dose of 100 mg/d of riluzole (n = 36) or placebo (n = 38) and assessed weekly for PTSD symptoms, anxiety, depression, disability, and side effects. RESULTS Intent-to-treat analyses (N = 74) of the primary outcome (CAPS for DSM-IV) showed no significant between-group difference in change in overall PTSD symptoms (F = 0.64, P = .422), with a small effect size (d = 0.25). There was clinically significant within-group improvement in overall PTSD symptoms in both groups, with a greater mean (SD) decrease in CAPS score in the riluzole group (-21.1 [18.9]) than in the placebo group (-16.7 [17.2]). Exploratory analyses of PTSD symptom clusters showed significantly greater improvement on hyperarousal symptoms in the riluzole group as measured by the PTSD Checklist-Specific-Subscale D (d = 0.48) and near-significant findings on the CAPS Subscale D. Riluzole augmentation was not superior to placebo on change in depression, anxiety, or disability severity. CONCLUSIONS Although preliminary, the exploratory findings of this study offer some evidence that riluzole augmentation of an SSRI or SNRI may selectively improve PTSD hyperarousal symptoms without changes in overall PTSD symptoms, depression, anxiety, or disability. Additional investigation of the mechanism of the efficacy of riluzole for hyperarousal symptoms is warranted. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02155829.
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Metabolomic signature of exposure and response to citalopram/escitalopram in depressed outpatients.
Bhattacharyya, S, Ahmed, AT, Arnold, M, Liu, D, Luo, C, Zhu, H, Mahmoudiandehkordi, S, Neavin, D, Louie, G, Dunlop, BW, et al
Translational psychiatry. 2019;(1):173
Abstract
Metabolomics provides valuable tools for the study of drug effects, unraveling the mechanism of action and variation in response due to treatment. In this study we used electrochemistry-based targeted metabolomics to gain insights into the mechanisms of action of escitalopram/citalopram focusing on a set of 31 metabolites from neurotransmitter-related pathways. Overall, 290 unipolar patients with major depressive disorder were profiled at baseline, after 4 and 8 weeks of drug treatment. The 17-item Hamilton Depression Rating Scale (HRSD17) scores gauged depressive symptom severity. More significant metabolic changes were found after 8 weeks than 4 weeks post baseline. Within the tryptophan pathway, we noted significant reductions in serotonin (5HT) and increases in indoles that are known to be influenced by human gut microbial cometabolism. 5HT, 5-hydroxyindoleacetate (5HIAA), and the ratio of 5HIAA/5HT showed significant correlations to temporal changes in HRSD17 scores. In the tyrosine pathway, changes were observed in the end products of the catecholamines, 3-methoxy-4-hydroxyphenylethyleneglycol and vinylmandelic acid. Furthermore, two phenolic acids, 4-hydroxyphenylacetic acid and 4-hydroxybenzoic acid, produced through noncanconical pathways, were increased with drug exposure. In the purine pathway, significant reductions in hypoxanthine and xanthine levels were observed. Examination of metabolite interactions through differential partial correlation networks revealed changes in guanosine-homogentisic acid and methionine-tyrosine interactions associated with HRSD17. Genetic association studies using the ratios of these interacting pairs of metabolites highlighted two genetic loci harboring genes previously linked to depression, neurotransmission, or neurodegeneration. Overall, exposure to escitalopram/citalopram results in shifts in metabolism through noncanonical pathways, which suggest possible roles for the gut microbiome, oxidative stress, and inflammation-related mechanisms.
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The Experience Sampling Method-Evaluation of treatment effect of escitalopram in IBS with comorbid panic disorder.
Vork, L, Mujagic, Z, Drukker, M, Keszthelyi, D, Conchillo, JM, Hesselink, MAM, van Os, J, Masclee, AAM, Leue, C, Kruimel, JW
Neurogastroenterology and motility. 2019;(1):e13515
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BACKGROUND Confirming treatment response in clinical trials for irritable bowel syndrome (IBS) is challenging, due to the lack of biomarkers and limitations of the currently available symptom assessment tools. The Experience Sampling Method (ESM) might overcome these limitations by collecting digital assessments randomly and repeatedly during daily life. This study evaluated differences in change in abdominal pain between real-time (ie, ESM) and retrospective (ie, Gastrointestinal Symptom Rating Scale [GSRS] and an end-of-day symptom diary) measurements, using data of an RCT on escitalopram vs placebo in patients with IBS and comorbid panic disorder. METHODS Twenty-nine IBS patients with comorbid panic disorder were included in a 6-month RCT. The GSRS, diary, and ESM were completed at baseline (t = 0) and after 3 (t = 3) and 6 months (t = 6). Linear mixed models were used. KEY RESULTS Experience Sampling Method analyses revealed a significant interaction between escitalopram and time, and ESM abdominal pain scores were 1.4 points lower in the escitalopram group compared to placebo at t = 6 (on a 1-to-7 scale; P = 0.021). When including the interaction with momentary anxiety, the reduction in abdominal pain scores in escitalopram vs placebo was even more pronounced for higher levels of anxiety. Average GSRS- and end-of-day abdominal pain scores were not significantly different between escitalopram and placebo at t = 3 and 6. CONCLUSIONS & INFERENCES Real-time ESM has the potential to capture treatment response more sensitively compared to a retrospective end-of-day GI symptom diary and the GSRS, by taking into account day-to-day symptom variability as well as momentary factors that might moderate treatment effect, such as anxiety.
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Premenstrual Dysphoric Disorder.
Lanza di Scalea, T, Pearlstein, T
The Medical clinics of North America. 2019;(4):613-628
Abstract
Premenstrual dysphoric disorder (PMDD) comprises emotional and physical symptoms and functional impairment that lie on the severe end of the continuum of premenstrual symptoms. Women with PMDD have a differential response to normal hormonal fluctuations. This susceptibility may involve the serotonin system, altered sensitivity of the GABAA receptor to the neurosteroid allopregnanalone, and altered brain circuitry involving emotional and cognitive functions. Serotonin reuptake inhibitors are considered the first-line treatment. Second-line treatments include oral contraceptives containing drospirenone, other ovulation suppression methods, calcium, chasteberry, and cognitive-behavioral therapy.
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Facets of shared decision-making on drug treatment for adults with an eating disorder.
Himmerich, H, Bentley, J, Lichtblau, N, Brennan, C, Au, K
International review of psychiatry (Abingdon, England). 2019;(4):332-346
Abstract
Shared decision-making (SDM) means that clinicians and the patient make decisions about the treatment together. Regarding drug treatment in eating disorders (EDs), such decisions may include psychopharmacological treatment for the ED itself, medications for potential co-morbid psychiatric disorders, pharmacological strategies to alleviate the health consequences of an ED, or 'pro re nata' (PRN) medication which is given in acute care when required. Decisions regarding drug treatment in EDs should be specific in terms of the active pharmacological substance, its dose, its route of administration, and the duration of treatment. Decisions should be made with regard to the specific health risks of patients with EDs and the entire treatment approach, and should take alternative measures, additional therapies, and specific combinations of therapies into account. The differences in the expectations of patients, carers, and clinicians towards drug treatment, the lack of specific suggestions in clinical practice guidelines, and the lack of approved psychopharmacological treatment options make SDM necessary, but also a challenge. However, SDM may be limited due to the patient's impaired insight or limited capacity due to the ED. Thus, the legal framework must be taken into consideration.