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JAMA Psychiatry Jan 2023Anxiety disorders are common, highly distressing, and impairing conditions. Effective treatments exist, but many patients do not access or respond to them.... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Anxiety disorders are common, highly distressing, and impairing conditions. Effective treatments exist, but many patients do not access or respond to them. Mindfulness-based interventions, such as mindfulness-based stress reduction (MBSR) are popular and can decrease anxiety, but it is unknown how they compare to standard first-line treatments.
OBJECTIVE
To determine whether MBSR is noninferior to escitalopram, a commonly used first-line psychopharmacological treatment for anxiety disorders.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial (Treatments for Anxiety: Meditation and Escitalopram [TAME]) included a noninferiority design with a prespecified noninferiority margin. Patients were recruited between June 2018 and February 2020. The outcome assessments were performed by blinded clinical interviewer at baseline, week 8 end point, and follow-up visits at 12 and 24 weeks. Of 430 individuals assessed for inclusion, 276 adults with a diagnosed anxiety disorder from 3 urban academic medical centers in the US were recruited for the trial, and 208 completed the trial.
INTERVENTIONS
Participants were 1:1 randomized to 8 weeks of the weekly MBSR course or the antidepressant escitalopram, flexibly dosed from 10 to 20 mg.
MAIN OUTCOMES AND MEASURES
The primary outcome measure was anxiety levels as assessed with the Clinical Global Impression of Severity scale (CGI-S), with a predetermined noninferiority margin of -0.495 points.
RESULTS
The primary noninferiority sample consisted of 208 patients (102 in MBSR and 106 in escitalopram), with a mean (SD) age of 33 (13) years; 156 participants (75%) were female; 32 participants (15%) were African American, 41 (20%) were Asian, 18 (9%) were Hispanic/Latino, 122 (59%) were White, and 13 (6%) were of another race or ethnicity (including Native American or Alaska Native, more than one race, or other, consolidated owing to low numbers). Baseline mean (SD) CGI-S score was 4.44 (0.79) for the MBSR group and 4.51 (0.78) for the escitalopram group in the per-protocol sample and 4.49 (0.77) vs 4.54 (0.83), respectively, in the randomized sample. At end point, the mean (SD) CGI-S score was reduced by 1.35 (1.06) for MBSR and 1.43 (1.17) for escitalopram. The difference between groups was -0.07 (0.16; 95% CI, -0.38 to 0.23; P = .65), where the lower bound of the interval fell within the predefined noninferiority margin of -0.495, indicating noninferiority of MBSR compared with escitalopram. Secondary intent-to-treat analyses using imputed data also showed the noninferiority of MBSR compared with escitalopram based on the improvement in CGI-S score. Of patients who started treatment, 10 (8%) dropped out of the escitalopram group and none from the MBSR group due to adverse events. At least 1 study-related adverse event occurred for 110 participants randomized to escitalopram (78.6%) and 21 participants randomized to MBSR (15.4%).
CONCLUSIONS AND RELEVANCE
The results from this randomized clinical trial comparing a standardized evidence-based mindfulness-based intervention with pharmacotherapy for the treatment of anxiety disorders found that MBSR was noninferior to escitalopram.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03522844.
Topics: Humans; Adult; Female; Male; Mindfulness; Escitalopram; Stress, Psychological; Anxiety Disorders; Anxiety; Treatment Outcome
PubMed: 36350591
DOI: 10.1001/jamapsychiatry.2022.3679 -
International Clinical... Jul 2014It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the... (Comparative Study)
Comparative Study Review
It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter.
Topics: Allosteric Site; Animals; Antidepressive Agents, Second-Generation; Citalopram; Depression; Depressive Disorder, Major; Drug Interactions; Evidence-Based Medicine; Humans; Models, Biological; Nerve Tissue Proteins; Paroxetine; Serotonin Plasma Membrane Transport Proteins; Selective Serotonin Reuptake Inhibitors; Sertraline
PubMed: 24424469
DOI: 10.1097/YIC.0000000000000023 -
The Journal of Clinical Psychiatry Aug 2020Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD); however, their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on response as well as CYP2C19 phenotype on escitalopram pharmacokinetics from February 2015 through November 2018.
METHODS
Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean ± SD age: 14.8 ± 1.7 years) or placebo (n = 25, mean ± SD age: 14.9 ± 1.6 years) for 8 weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUC0-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes.
RESULTS
Escitalopram was superior to placebo for mean ± SD baseline-to-endpoint change in PARS (-8.65 ± 1.3 vs -3.52 ± 1.1, P = .005) and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax (P = .07) and AUC0-24 (P < .05). Vital signs, corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo.
CONCLUSIONS
Escitalopram reduces anxiety symptoms, and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02818751.
Topics: Adolescent; Anti-Anxiety Agents; Anxiety Disorders; Area Under Curve; Child; Citalopram; Cytochrome P-450 CYP2C19; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Selective Serotonin Reuptake Inhibitors; Treatment Outcome
PubMed: 32857933
DOI: 10.4088/JCP.20m13396 -
Clinical Pharmacology and Therapeutics Apr 2022The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The... (Randomized Controlled Trial)
Randomized Controlled Trial
The psychedelic psilocybin is being investigated for the treatment of depression and anxiety. Unclear is whether antidepressant treatments interact with psilocybin. The present study used a double-blind, placebo-controlled, crossover design with two experimental test sessions to investigate the response to psilocybin (25 mg) in healthy subjects after pretreatment with escitalopram or placebo. The treatment order was random and counterbalanced. Pretreatment consisted of 10 mg escitalopram daily for 7 days, followed by 20 mg daily for 7 days, including the day of psilocybin administration, or 14 days of placebo pretreatment before psilocybin administration. Psilocybin treatments were separated by at least 16 days. The outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor (BDNF) levels, electrocardiogram QTc time, whole-blood HTR2A and SCL6A4 gene expression, and pharmacokinetics. Escitalopram pretreatment had no relevant effect on positive mood effects of psilocybin but significantly reduced bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects of psilocybin compared with placebo pretreatment. Escitalopram did not alter the pharmacokinetics of psilocin. The half-life of psychoactive free (unconjugated) psilocin was 1.8 hours (range 1.1-2.2 hours), consistent with the short duration of action of psilocybin. Escitalopram did not alter HTR2A or SCL6A4 gene expression before psilocybin administration, QTc intervals, or circulating BDNF levels before or after psilocybin administration. Further studies are needed with a longer antidepressant pretreatment time and patients with psychiatric disorders to further define interactions between antidepressants and psilocybin.
Topics: Antidepressive Agents; Brain-Derived Neurotrophic Factor; Citalopram; Cross-Over Studies; Double-Blind Method; Escitalopram; Healthy Volunteers; Humans; Psilocybin
PubMed: 34743319
DOI: 10.1002/cpt.2487 -
BMJ (Clinical Research Ed.) Jan 2022To identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of panic disorder with or without agoraphobia.
DESIGN
Systematic review and network meta-analysis.
DATA SOURCES
Embase, Medline, and ClinicalTrials.gov from inception to 17 June 2021.
ELIGIBILITY CRITERIA FOR STUDY SELECTION
Randomised controlled trials that included adults aged ≥18 years with a diagnosis of panic disorder, compared drugs used to treat the panic disorder, and measured the outcomes of interest, including remissions, dropouts, and adverse events.
METHODS
Risk of bias in the included studies was assessed using the revised Cochrane risk of bias tool for randomised trials. Direct meta-analyses were performed using random effects models. A two stage network meta-analysis with surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of drug classes and individual SSRIs.
RESULTS
87 studies including a total of 12 800 participants and 12 drug classes were eligible for inclusion. Almost all the studies (86/87) had some concern or were at high risk of bias. Network meta-analysis of remission with consistent results indicated that tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, SSRIs, and serotonin-noradrenaline reuptake inhibitors (SNRIs) were associated with significantly higher remission rates than placebo, with risk ratios of 1.39 (95% confidence interval 1.26 to 1.54), 1.47 (1.36 to 1.60), 1.30 (1.00 to 1.69), 1.38 (1.26 to 1.50), and 1.27 (1.12 to 1.45), respectively. SUCRAs identified benzodiazepines (84.5%, mean rank=2.4), tricyclic antidepressants (68.7%, 3.8), and SSRIs (66.4%, 4.0) as the top three best treatments for remission. However, tricyclic antidepressants, benzodiazepines, and SSRIs were also significantly associated with increased risk of adverse events compared with placebo, with risk ratios of 1.79 (1.47 to 2.19), 1.76 (1.50 to 2.06), and 1.19 (1.01 to 1.41), respectively. Consistency assumption of adverse events was upheld but could still be present on removal of studies with high percentages of women participants and those with agoraphobia. A SUCRA cluster ranking plot considering both remission and adverse events among all drug classes indicated that SSRIs were associated with high remission and low risk of adverse events. Among individual SSRIs, sertraline and escitalopram provided high remission with an acceptable risk of adverse events.
CONCLUSION
The findings suggest that SSRIs provide high rates of remission with low risk of adverse events for the treatment of panic disorder. Among SSRIs, sertraline and escitalopram were associated with high remission and low risk of adverse events. The findings were, however, based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42020180638.
Topics: Adult; Agoraphobia; Escitalopram; Female; Humans; Induction Chemotherapy; Male; Network Meta-Analysis; Panic Disorder; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors; Sertraline; Treatment Outcome
PubMed: 35045991
DOI: 10.1136/bmj-2021-066084 -
Ugeskrift For Laeger Aug 2023This review aims at RCT's of psychedelics used in the treatment of depression and PTSD. Psilocybin has shown an antidepressant effect in cancer patients that was... (Review)
Review
This review aims at RCT's of psychedelics used in the treatment of depression and PTSD. Psilocybin has shown an antidepressant effect in cancer patients that was sustained at 6- and 12-months follow-up. The effect of psilocybin was comparable to escitalopram in one study. Ketamine has shown effect for the treatment of resistant depression. Phase 2 and 3 trials have shown the effect of MDMA on PTSD. No serious adverse events were reported in controlled settings, but larger studies are needed to establish safety and long-term effects.
Topics: Humans; Hallucinogens; Psilocybin; Ketamine; Mental Disorders; Escitalopram
PubMed: 37615227
DOI: No ID Found -
European Neuropsychopharmacology : the... Jan 2022Inflammation may correlate with a specific subgroup of depression and differential antidepressant response, but no trial has studied changes of many inflammatory markers... (Clinical Trial)
Clinical Trial
Inflammation may correlate with a specific subgroup of depression and differential antidepressant response, but no trial has studied changes of many inflammatory markers over several time points and evaluated symptom-specific antidepressant response and long-term prognosis. We performed secondary analyses among 90 outpatients with moderate-severe depression (71% female, mean age 38 years) treated for 26 weeks with escitalopram or nortriptyline. We measured 27 pro- and anti-inflammatory markers at week 0, 8, 12, and 26 and calculated composite inflammation scores. Three depression rating scales were applied and symptom dimensions of depression calculated. Via Danish nationwide registers, 10 years follow-up were included on psychiatric hospital contacts, indicating relapse. Pearson correlation analyses were performed between baseline inflammatory markers and depressive symptom severity, mixed effects models during the 26-week trial, and Cox regression analyses for the register-based outcomes, adjusted for age, sex, BMI, and smoking. Baseline inflammatory markers correlated with differential severity on specific symptom dimensions but not with overall depression severity. A total of 17 of 27 inflammatory markers decreased significantly during treatment. We found no correlation between baseline nor change in inflammatory markers nor composite inflammation scores with differential treatment response on the MADRS, but small correlations between changes in inflammatory markers and differential response on neurovegetative symptoms. Findings were similar among 59 treatment-naïve patients. Inflammatory markers were not associated with differential risks for 10-year relapse. These findings support the importance of studying specific depressive symptoms to further explore the correlation between inflammation with differential antidepressant response in a subgroup of depression. Clinical Trial Registration number: GENDEP is registered at EudraCT2004-001723-38 (http://eudract.emea.europa.eu) and ISRCTN03693000 (www.controlled-trials.com).
Topics: Adult; Antidepressive Agents; Biomarkers; Citalopram; Depression; Depressive Disorder, Major; Female; Humans; Inflammation; Male; Prognosis; Recurrence; Treatment Outcome
PubMed: 34598835
DOI: 10.1016/j.euroneuro.2021.09.006 -
The Primary Care Companion For CNS... Jul 2021Side effects of selective serotonin reuptake inhibitors (SSRIs), the most commonly used antidepressants, are usually underreported in clinical trials. Systematic...
Side effects of selective serotonin reuptake inhibitors (SSRIs), the most commonly used antidepressants, are usually underreported in clinical trials. Systematic evaluation of side effects associated with SSRIs with structured instruments in a naturalistic setting is an important design to fully understand the side effect profile of various SSRIs. We examined the frequencies of the side effects induced by 3 commonly used SSRIs, sertraline, escitalopram, and fluoxetine, by using a self-rating instrument designed to measure the subjective symptoms of patients in a naturalistic treatment setting. The subjects were outpatients recruited from the psychiatry department of a tertiary care hospital. The subjects were aged ≥ 18 years; were diagnosed with depression, anxiety spectrum disorders, adjustment disorder, hypochondriasis, or impulse control disorder according to criteria; and were on SSRI monotherapy. The assessment instrument included 42 items and was devised using drug package insert data on the most commonly observed side effects of antidepressants released by the US Food and Drug Administration. A total of 100 patients participated in the study. Among them, 70% were women. The most common diagnosis was depression (49%). Of the patients, 53% were taking sertraline, 38% escitalopram, and 8% fluoxetine. The common side effects reported by patients were flatulence (64%), somnolence (59%), memory impairment (51%), decreased concentration (50%), yawning (47%), fatigue (45%), dry mouth (45%), weight gain (45%), light headedness (43%), and sweating (38%). Patients treated with escitalopram had significantly higher incidence of headache, pruritus, memory impairment, decreased concentration, and dizziness. Patients treated with sertraline had significantly decreased appetite. The study results highlight the prevalence and pattern of side effect profiles of 3 commonly used SSRIs and provide baseline data for comparison with other similar studies.
Topics: Antidepressive Agents; Citalopram; Cross-Sectional Studies; Female; Humans; Selective Serotonin Reuptake Inhibitors; Sertraline
PubMed: 34324797
DOI: 10.4088/PCC.20m02747 -
JAMA Psychiatry Nov 2021Anxiety is common among patients with coronary heart disease (CHD) and is associated with worse health outcomes; however, effective treatment for anxiety in patients... (Randomized Controlled Trial)
Randomized Controlled Trial
Effect of Exercise, Escitalopram, or Placebo on Anxiety in Patients With Coronary Heart Disease: The Understanding the Benefits of Exercise and Escitalopram in Anxious Patients With Coronary Heart Disease (UNWIND) Randomized Clinical Trial.
IMPORTANCE
Anxiety is common among patients with coronary heart disease (CHD) and is associated with worse health outcomes; however, effective treatment for anxiety in patients with CHD is uncertain.
OBJECTIVE
To determine whether exercise and escitalopram are better than placebo in reducing symptoms of anxiety as measured by the Hospital Anxiety and Depression-Anxiety Subscale (HADS-A) and in improving CHD risk biomarkers.
DESIGN, SETTING, AND PARTICIPANTS
This randomized clinical trial was conducted between January 2016 and May 2020 in a tertiary care teaching hospital in the US and included 128 outpatients with stable CHD and a diagnosed anxiety disorder or a HADS-A score of 8 or higher who were older than 40 years, sedentary, and not currently receiving mental health treatment.
INTERVENTIONS
Twelve weeks of aerobic exercise 3 times per week at an intensity of 70% to 85% heart rate reserve, escitalopram (up to 20 mg per day), or placebo pill equivalent.
MAIN OUTCOMES AND MEASURES
The primary outcome was HADS-A score. CHD biomarkers included heart rate variability, baroreflex sensitivity, and flow-mediated dilation, along with 24-hour urinary catecholamines.
RESULTS
The study included 128 participants. The mean (SD) age was 64.6 (9.6) years, and 37 participants (29%) were women. Participants randomized to the exercise group and escitalopram group reported greater reductions in HADS-A (exercise, -4.0; 95% CI, -4.7 to -3.2; escitalopram, -5.7; 95% CI, -6.4 to -5.0) compared with those randomized to placebo (-3.5; 95% CI, -4.5 to -2.4; P = .03); participants randomized to escitalopram reported less anxiety compared with those randomized to exercise (-1.67; 95% CI, -2.68 to -0.66; P = .002). Significant postintervention group differences in 24-hour urinary catecholamines were found (exercise z score = 0.05; 95% CI, -0.2 to 0.3; escitalopram z score = -0.24; 95% CI, -0.4 to 0; placebo z score = 0.36; 95% CI, 0 to 0.7), with greater reductions in the exercise group and escitalopram group compared with the placebo group (F1,127 = 4.93; P = .01) and greater reductions in the escitalopram group compared with the exercise group (F1,127 = 4.37; P = .04). All groups achieved comparable but small changes in CHD biomarkers, with no differences between treatment groups.
CONCLUSIONS AND RELEVANCE
Treatment of anxiety with escitalopram was safe and effective for reducing anxiety in patients with CHD. However, the beneficial effects of exercise on anxiety symptoms were less consistent. Exercise and escitalopram did not improve CHD biomarkers of risk, which should prompt further investigation of these interventions on clinical outcomes in patients with anxiety and CHD.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02516332.
Topics: Aged; Anxiety Disorders; Comorbidity; Coronary Disease; Depression; Escitalopram; Exercise Therapy; Female; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Selective Serotonin Reuptake Inhibitors
PubMed: 34406354
DOI: 10.1001/jamapsychiatry.2021.2236 -
Microbiome Aug 2023There is a growing body of evidence suggesting that disturbance of the gut-brain axis may be one of the potential causes of major depressive disorder (MDD). However, the...
BACKGROUND
There is a growing body of evidence suggesting that disturbance of the gut-brain axis may be one of the potential causes of major depressive disorder (MDD). However, the effects of antidepressants on the gut microbiota, and the role of gut microbiota in influencing antidepressant efficacy are still not fully understood.
RESULTS
To address this knowledge gap, a multi-omics study was undertaken involving 110 MDD patients treated with escitalopram (ESC) for a period of 12 weeks. This study was conducted within a cohort and compared to a reference group of 166 healthy individuals. It was found that ESC ameliorated abnormal blood metabolism by upregulating MDD-depleted amino acids and downregulating MDD-enriched fatty acids. On the other hand, the use of ESC showed a relatively weak inhibitory effect on the gut microbiota, leading to a reduction in microbial richness and functions. Machine learning-based multi-omics integrative analysis revealed that gut microbiota contributed to the changes in plasma metabolites and was associated with several amino acids such as tryptophan and its gut microbiota-derived metabolite, indole-3-propionic acid (I3PA). Notably, a significant correlation was observed between the baseline microbial richness and clinical remission at week 12. Compared to non-remitters, individuals who achieved remission had a higher baseline microbial richness, a lower dysbiosis score, and a more complex and well-organized community structure and bacterial networks within their microbiota. These findings indicate a more resilient microbiota community in remitters. Furthermore, we also demonstrated that it was not the composition of the gut microbiota itself, but rather the presence of sporulation genes at baseline that could predict the likelihood of clinical remission following ESC treatment. The predictive model based on these genes revealed an area under the curve (AUC) performance metric of 0.71.
CONCLUSION
This study provides valuable insights into the role of the gut microbiota in the mechanism of ESC treatment efficacy for patients with MDD. The findings represent a significant advancement in understanding the intricate relationship among antidepressants, gut microbiota, and the blood metabolome. Additionally, this study offers a microbiota-centered perspective that can potentially improve antidepressant efficacy in clinical practice. By shedding light on the interplay between these factors, this research contributes to our broader understanding of the complex mechanisms underlying the treatment of MDD and opens new avenues for optimizing therapeutic approaches. Video Abstract.
Topics: Humans; Depressive Disorder, Major; Multiomics; Antidepressive Agents; Treatment Outcome; Escitalopram; Amino Acids
PubMed: 37641148
DOI: 10.1186/s40168-023-01635-6