ABSTRACT
OBJECTIVE: To evaluate the comparative effectiveness and acceptability of oral monotherapy using psychedelics and escitalopram in patients with depressive symptoms, considering the potential for overestimated effectiveness due to unsuccessful blinding. DESIGN: Systematic review and Bayesian network meta-analysis. DATA SOURCES: Medline, Cochrane Central Register of Controlled Trials, Embase, PsycINFO, ClinicalTrial.gov, and World Health Organization's International Clinical Trials Registry Platform from database inception to 12 October 2023. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials on psychedelics or escitalopram in adults with depressive symptoms. Eligible randomised controlled trials of psychedelics (3,4-methylenedioxymethamphetamine (known as MDMA), lysergic acid diethylamide (known as LSD), psilocybin, or ayahuasca) required oral monotherapy with no concomitant use of antidepressants. DATA EXTRACTION AND SYNTHESIS: The primary outcome was change in depression, measured by the 17-item Hamilton depression rating scale. The secondary outcomes were all cause discontinuation and severe adverse events. Severe adverse events were those resulting in any of a list of negative health outcomes including, death, admission to hospital, significant or persistent incapacity, congenital birth defect or abnormality, and suicide attempt. Data were pooled using a random effects model within a Bayesian framework. To avoid estimation bias, placebo responses were distinguished between psychedelic and antidepressant trials. RESULTS: Placebo response in psychedelic trials was lower than that in antidepression trials of escitalopram (mean difference -3.90 (95% credible interval -7.10 to -0.96)). Although most psychedelics were better than placebo in psychedelic trials, only high dose psilocybin was better than placebo in antidepression trials of escitalopram (mean difference 6.45 (3.19 to 9.41)). However, the effect size (standardised mean difference) of high dose psilocybin decreased from large (0.88) to small (0.31) when the reference arm changed from placebo response in the psychedelic trials to antidepressant trials. The relative effect of high dose psilocybin was larger than escitalopram at 10 mg (4.66 (95% credible interval 1.36 to 7.74)) and 20 mg (4.69 (1.64 to 7.54)). None of the interventions was associated with higher all cause discontinuation or severe adverse events than the placebo. CONCLUSIONS: Of the available psychedelic treatments for depressive symptoms, patients treated with high dose psilocybin showed better responses than those treated with placebo in the antidepressant trials, but the effect size was small. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42023469014.
Subject(s)
Banisteriopsis , Bayes Theorem , Escitalopram , Hallucinogens , Lysergic Acid Diethylamide , Network Meta-Analysis , Psilocybin , Humans , Psilocybin/therapeutic use , Psilocybin/administration & dosage , Psilocybin/adverse effects , Lysergic Acid Diethylamide/therapeutic use , Lysergic Acid Diethylamide/administration & dosage , Lysergic Acid Diethylamide/adverse effects , Hallucinogens/therapeutic use , Hallucinogens/administration & dosage , Hallucinogens/adverse effects , Escitalopram/therapeutic use , Escitalopram/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/administration & dosage , N-Methyl-3,4-methylenedioxyamphetamine/adverse effects , N-Methyl-3,4-methylenedioxyamphetamine/therapeutic use , Depression/drug therapy , Administration, Oral , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
OBJECTIVE: To examine the long-term safety and tolerability of off-label high-dose serotonin reuptake inhibitors (OLHD-SRIs) in the treatment of obsessive-compulsive disorder (OCD). METHODS: A retrospective longitudinal study was performed on 105 randomly selected outpatients diagnosed with OCD and were treated with OLHD-SRIs for at least 6 months. Patients received sertraline >200 mg/day, escitalopram >20 mg/day, fluvoxamine >300 mg/day, and fluoxetine >60 mg/day, combined with exposure and response prevention therapy. Patients were divided into three dosing groups: sertraline equivalent dose (SED) ≤ 200 mg/day (n = 26, 24.7%), 201-400 mg/day (n = 51, 48.5%) and 401-650 mg/day (n = 28, 26.6%). Safety and tolerability were assessed with an electrocardiogram, blood biochemistry, complete blood count, and side-effects monitoring. RESULTS: SED ranged from 100 to 650 mg/day and the mean duration of OLHD-SRI treatment was 20.8 months. The most common side-effects reported were sexual dysfunction (n = 36, 34%), weight gain (n = 28, 27%), sedation (n = 27, 26%), hyperhidrosis (n = 20, 19%), and tremor (n = 11, 10%). Abnormal ECG was documented in one patient, and another patient experienced a first-time seizure, whereas elevated liver enzymes were seen in 4.8% of the sample (n = 5). None of the patients had serotonin syndrome or drug-induced liver injury. Side-effects did not differ among the three dosing groups. CONCLUSION: OLHD-SRIs appear to be safe and well tolerated in OCD patients in SED ≤ 650 mg/day doses and the side-effects did not differ between the three dosing groups.
Subject(s)
Fluvoxamine , Obsessive-Compulsive Disorder , Off-Label Use , Selective Serotonin Reuptake Inhibitors , Sertraline , Humans , Obsessive-Compulsive Disorder/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effects , Female , Adult , Male , Retrospective Studies , Fluvoxamine/therapeutic use , Fluvoxamine/administration & dosage , Fluvoxamine/adverse effects , Sertraline/therapeutic use , Sertraline/administration & dosage , Sertraline/adverse effects , Middle Aged , Longitudinal Studies , Fluoxetine/therapeutic use , Fluoxetine/administration & dosage , Fluoxetine/adverse effects , Escitalopram/therapeutic use , Escitalopram/administration & dosage , Young Adult , Treatment Outcome , Dose-Response Relationship, DrugABSTRACT
INTRODUCTION: Major Depressive Disorder (MDD) is a mental health issue that significantly affects patients' quality of life and functioning. Despite available treatments, many patients continue to suffer due to incomplete symptom resolution and side effects. AREAS COVERED: This manuscript examines Vortioxetine's role in Major Depressive Disorder (MDD) treatment, highlighting its potential to reshape therapeutic strategies due to its unique Multimodal action and proven broad-spectrum efficacy in multiple depressive domains. A detailed examination of Vortioxetine's pharmacological aspects, including indications, dosage, pharmacodynamics, and pharmacokinetics, is provided, emphasizing its safety and effectiveness. The discussion extends to Vortioxetine's role in acute-phase treatment and maintenance of MDD and its profound impact on specialized depression domains. EXPERT OPINION: Vortioxetine is distinguished for its novel multimodal serotonin modulation mechanism, showcasing significant promise as an innovative treatment for MDD. Its efficacy, which is dose-dependent, along with a commendable tolerability profile, positions it as a potential leading option for initial treatment strategies. The discourse on dosage titration, particularly the strategy of initiating treatment at lower doses followed by gradual escalation, underscores the approach toward minimizing initial adverse effects while optimizing therapeutic outcomes, aligning with the principles of personalized medicine in psychiatric care.
Subject(s)
Depressive Disorder, Major , Vortioxetine , Antidepressive Agents/administration & dosage , Antidepressive Agents/therapeutic use , Anxiety/complications , Cognitive Dysfunction/complications , Cognitive Dysfunction/drug therapy , Depressive Disorder, Major/complications , Depressive Disorder, Major/drug therapy , Depressive Disorder, Major/psychology , Emotions/drug effects , Escitalopram/administration & dosage , Escitalopram/therapeutic use , Post-Acute COVID-19 Syndrome/complications , Precision Medicine , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/therapeutic use , Serotonin/metabolism , Vortioxetine/administration & dosage , Vortioxetine/adverse effects , Vortioxetine/pharmacokinetics , Vortioxetine/pharmacology , Vortioxetine/therapeutic use , Humans , Neurotransmitter Agents/metabolism , AnimalsABSTRACT
BACKGROUND: There is growing evidence for the therapeutic effects of the psychedelic drug psilocybin for major depression. However, due to the lack of safety data on combining psilocybin with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and concerns that there may be a negative interaction on efficacy, participants enrolling in psychedelic trials are usually required to discontinue SNRI/SNRIs prior to enrolling. AIMS: Using data from a recent clinical trial examining the comparative efficacy the psychedelic drug psilocybin (P) combined with approximately 20 h of psychological support to a 6-week (daily) course of the SSRI escitalopram plus matched psychological support for major depressive disorder, we explored the effects of discontinuing SSRI/SNRIs prior to study enrolment on study outcomes. METHODS: Exploratory post hoc analyses using linear mixed effects model were performed to investigate the discontinuation effect on various validated depression symptom severity scales and well-being. The impact of SSRI/SNRIs discontinuation on the acute psychedelic experience was also explored. RESULTS/OUTCOMES: In the psilocybin group, there was a reduced treatment effect on all outcome measures for SSRI/SNRIs discontinuers compared with unmedicated patients at trial entry. However, no effects of discontinuation on measures of the acute psychedelic experience were found. CONCLUSION: Discontinuation of SSRI/SNRIs before psilocybin might diminish response to treatment; however, as we did not test SSRI/SNRI continuation in our trial, we cannot infer such causation. Moreover, the exploratory nature of the analyses makes them hypothesis generating, and not confirmatory. A controlled trial of SSRI/SNRI discontinuation versus continuation prior to psilocybin is urgently required.
Subject(s)
Depressive Disorder, Major , Escitalopram , Hallucinogens , Psilocybin , Selective Serotonin Reuptake Inhibitors , Humans , Psilocybin/administration & dosage , Psilocybin/pharmacology , Psilocybin/adverse effects , Depressive Disorder, Major/drug therapy , Adult , Male , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effects , Selective Serotonin Reuptake Inhibitors/pharmacology , Female , Hallucinogens/administration & dosage , Hallucinogens/adverse effects , Hallucinogens/pharmacology , Escitalopram/administration & dosage , Escitalopram/pharmacology , Middle Aged , Treatment Outcome , Drug Therapy, CombinationABSTRACT
AIMS: Cilostazol (CLS) has shown antidepressant effect in cardiovascular patients, post-stroke depression, and animal models through its neurotrophic and antiinflammatory activities. Consequently, we aimed to investigate its safety and efficacy in patients with MDD by conducting double-blind, randomized, placebo-controlled pilot study. METHODS: 80 participants with MDD (DSM-IV criteria) and Hamilton Depression Rating Scale (HDRS) score >20 were treated with CLS 50 mg or placebo twice daily plus escitalopram (ESC) 20 mg once daily for six weeks. Patients were evaluated by HDRS scores (weeks 0, 2, 4, and 6). Serum levels of CREB1, BDNF, 5-HT, TNF-α, NF- κB, and FAM19A5 were assessed pre- and post-treatment. RESULTS: Co-administration of CLS had markedly decreased HDRS score at all-time points compared to the placebo group (p < 0.001). Early improvement, response, and remission rates after 6 weeks were significantly higher in the CLS group (90%, 90%, 80%, respectively) than in the placebo group (25%, 65%, 50% respectively) (p < 0.001). Moreover, the CLS group was superior to the placebo group in modulation of the measured neurotrophic and inflammatory biomarkers. CONCLUSION: CLS is safe and effective short-term adjunctive therapy in patients with MDD with no other comorbid conditions. Trial registration ID:NCT04069819.
Subject(s)
Cilostazol/pharmacology , Depressive Disorder, Major/drug therapy , Escitalopram/pharmacology , Phosphodiesterase 3 Inhibitors/pharmacology , Selective Serotonin Reuptake Inhibitors/pharmacology , Adult , Cilostazol/administration & dosage , Cilostazol/adverse effects , Depressive Disorder, Major/blood , Double-Blind Method , Drug Therapy, Combination , Escitalopram/administration & dosage , Female , Humans , Inflammation/blood , Inflammation/drug therapy , Male , Middle Aged , Outcome Assessment, Health Care , Phosphodiesterase 3 Inhibitors/administration & dosage , Phosphodiesterase 3 Inhibitors/adverse effects , Pilot Projects , Selective Serotonin Reuptake Inhibitors/administration & dosageABSTRACT
BACKGROUND: Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. METHODS: In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5-p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90-92 rats were evaluated in the behavioral and biochemical tests. RESULTS: BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. CONCLUSION: The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.
Subject(s)
Aripiprazole/pharmacology , Brain-Derived Neurotrophic Factor/genetics , Escitalopram/pharmacology , Schizophrenia/drug therapy , Animals , Animals, Newborn , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacology , Aripiprazole/administration & dosage , Behavior, Animal/drug effects , Brain/drug effects , Brain/growth & development , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Therapy, Combination , Escitalopram/administration & dosage , Glutathione/deficiency , Male , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Schizophrenia/physiopathology , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/pharmacologyABSTRACT
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.
Subject(s)
Anxiety Disorders/therapy , Coronary Disease/psychology , Depression/therapy , Escitalopram/pharmacology , Exercise Therapy , Outcome Assessment, Health Care , Selective Serotonin Reuptake Inhibitors/pharmacology , Aged , Anxiety Disorders/drug therapy , Anxiety Disorders/epidemiology , Comorbidity , Coronary Disease/epidemiology , Depression/drug therapy , Depression/epidemiology , Escitalopram/administration & dosage , Escitalopram/adverse effects , Female , Humans , Male , Middle Aged , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/adverse effectsABSTRACT
Background: Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear. Methods: We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a doubleblind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period. Results: Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback. Limitations: We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward. Conclusion: Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry.
Subject(s)
Caudate Nucleus/drug effects , Escitalopram/administration & dosage , Escitalopram/pharmacology , Neurons/drug effects , Punishment , Reward , Thalamus/drug effects , Adult , Caudate Nucleus/cytology , Female , Humans , Magnetic Resonance Imaging , Male , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/pharmacology , Thalamus/cytology , Young AdultABSTRACT
BACKGROUND: Non-response to first-line treatment for major depressive disorder (MDD) is common; for such individuals, quality of life (QoL) impairments can be severe. Identifying predictors of QoL changes may support the management of cases with persistent depressive symptoms despite adequate initial pharmacological/psychological treatment. OBJECTIVE: The present study aimed to explore predictors of domain-specific QoL improvement following adjunctive aripiprazole treatment for inadequate response to initial antidepressant therapy. METHODS: We evaluated secondary QoL outcomes from a CAN-BIND (Canadian Biomarker Integration Network in Depression) study in patients with MDD who did not respond to an initial 8 weeks of escitalopram and received a further 8 weeks of adjunctive aripiprazole (n = 96). Physical, psychological, social, and environmental QoL domains were assessed using the World Health Organization QoL Scale Brief Version (WHOQOL-BREF). Clinician-rated depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Functioning was measured with the Sheehan Disability Scale (SDS). Satisfaction with medication was assessed with a single item from the Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF). Exploratory t-tests were used to describe domain score changes. A hierarchical linear regression was used to explore demographic, clinical, and treatment-related predictors of improvement. RESULTS: Across domains, QoL improved with adjunctive aripiprazole treatment. Satisfaction with medication and MADRS and SDS scores similarly improved. Symptom reduction was a predictor for positive change to physical and psychological QoL; functioning improvements were predictive of increases to all QoL domains. Satisfaction with medication predicted improvements to physical and psychological domains, whereas number of medication trials was a predictor of worsening QoL in the physical domain. CONCLUSION: The final model explained the most variance in psychological (68%) and physical (67%) QoL. Less variance was explained for environmental (43%) and social QoL (33%), highlighting a need for further exploration of predictors in these domains. Strategies such as functional remediation may have potential to support QoL for individuals with persistent depressive symptoms. CLINICAL TRIALS REGISTRY: ClinicalTrials.gov identifier: NCT016557.