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INTRODUCTION: Treatable mental disorders, such as psychotic, major depressive disorder (MDD), and bipolar disorder (BD), contribute to a substantial portion of suicide risk, often accompanied by neurocognitive deficits. We report the association between cognitive function and suicidal ideation/suicide attempts (SI/SA) in individuals with schizoaffective disorder, BD, and MDD. METHODS: A systematic search was conducted on PubMed, Ovid and Scopus databases for primary studies published from inception to April 2024. Eligible articles that reported on the effect size of association between cognition and SI/SA were pooled using a random effects model. RESULTS: A total of 41 studies were included for analysis. There was a negative association between executive functioning and SI/SA in schizoaffective disorder (SA: Corr = -0·78, 95 % CI [-1·00, 0·98]; SI: Corr = -0·06, 95 % CI [-0·85, 0·82]) and MDD (SA: Corr = -0·227, 95 % CI [-0·419, -0·017]; SI: Corr = -0·14, 95 % CI [-0·33, 0·06]). Results were mixed for BD, with a significant positive association between SA and global executive functioning (Corr = 0·08, 95 % CI [0·01, 0·15]) and negative association with emotion inhibition. Mixed results were observed for processing speed, attention, and learning and memory, transdiagnostically. LIMITATIONS: There is heterogeneity across sample compositions and cognitive measures. We did not have detailed information on individuals with respect to demographics and comorbidities. CONCLUSIONS: We observed a transdiagnostic association between measures of cognitive functions and aspects of suicidality. The interplay of cognitive disturbances, particularly in reward-based functioning, may underlie suicidality in individuals with mental disorders. Disturbances in impulse control, planning, and working memory may contribute to self-injurious behavior and suicide.
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BACKGROUND AND OBJECTIVES: Ketamine and esketamine are increasingly prescribed in the treatment of resistant mood disorders and persons at risk of suicide. Ketamine is a drug of misuse with increasing non-therapeutic use in the general population. Herein, our aim was to determine whether ketamine and/or esketamine are disproportionately associated with reports of substance and/or alcohol misuse. METHODS: Replicating a similar analysis recently conducted using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, we identified cases of "alcohol problem, alcoholism, alcohol abuse, substance dependence, substance use disorder (SUD), substance abuse, drug dependence, drug use disorder and drug abuse" in association with ketamine and esketamine reported to the World Health Organization Pharmacovigilance Database (WHO VigiBase). We searched the database from inception to January 2024. The reporting odds ratio (ROR) of each of the aforementioned parameters was calculated; acetaminophen was used as the control. The numerator of the equation represents the number of cases (n) and the denominator represents the total cases of psychiatric disorders (N). Significance was obtained when the lower limit of the 95 % confidence (CI) > 1.0. RESULTS: The RORs for ketamine was increased for most parameters (i.e., alcohol abuse (3.24), substance dependence (12.48), substance use disorder (170.44), substance abuse (2.94), drug dependence (2.88), drug use disorder (11.54) and drug abuse (2.85), respectively). With respect to esketamine, the RORs were observed to be different from ketamine insofar as we observed a reduction in the RORs for three parameters (i.e., substance abuse (0.41), drug dependence (0.083) and drug abuse (0.052), respectively). The IC025 values were significant for ketamine in cases of alcohol abuse (0.35), substance dependence (0.50), substance use disorder (2.77), substance abuse (0.83), drug dependence (0.97), drug use disorder (1.95) and drug abuse (0.94). Additionally, oxycontin showed significant IC025 values for substance use disorder (0.0014), substance abuse (0.042), and drug dependence (0.17). CONCLUSION: Esketamine was not associated with an increased ROR for any parameter of alcohol and/or substance use disorder. Mixed results were observed with ketamine with some RORs increased and others decreased. Estimating RORs using a pharmacovigilance database does not establish causation in the case of elevated RORs and cannot be assumed to be a therapeutic effect when lower RORs were observed.
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Alcoolismo , Bases de Dados Factuais , Ketamina , Farmacovigilância , Transtornos Relacionados ao Uso de Substâncias , Organização Mundial da Saúde , Ketamina/efeitos adversos , Humanos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Masculino , Alcoolismo/epidemiologia , Adulto , Feminino , Pessoa de Meia-Idade , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricosRESUMO
OBJECTIVE: Recovery from a COVID-19 infection can lead to post-COVID-19 condition (PCC), which causes a multitude of debilitating symptoms that negatively affect an individual's health-related quality of life, including depressive and anxiety symptoms. We aim to examine the mediatory effects of anxiety on depressive symptoms in persons with PCC receiving vortioxetine. METHODS: We performed a post-hoc analysis of a randomized, double-blinded, placebo-controlled clinical trial investigating vortioxetine treatment on cognitive functioning in persons with PCC. Anxiety and depressive symptoms were measured by the 7-Item Generalized Anxiety Disorder (GAD-7) Scale and the 16-Item Quick Inventory of Depressive Symptomatology (QIDS-SR-16), respectively. RESULTS: Based on data of 147 participants, GAD-7 scores were significantly positively associated with QIDS-SR-16 scores (ß=0.038, 95 % CI [0.029,0.047], p < 0.001). After adjusting for covariates, a significant group (χ2=176.786, p < 0.001), time (χ2=8.914, p = 0.003), and treatment x time x GAD-7 score interaction (χ2=236.483, p < 0.001) effect was observed. Vortioxetine-treated participants had a significant difference in overall change in depressive symptoms (mean difference=-3.15, SEM=0.642, 95 % CI [-4.40,-1.89], p < 0.001). CONCLUSION: Anxiety symptoms were significantly associated with depressive symptoms in persons with PCC. Antidepressant efficacy on ameliorating depressive symptoms is dependent on improving anxiety symptoms, underscoring significant implications in improving treatment efficacy and patient quality of life.
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Ansiedade , COVID-19 , Depressão , Vortioxetina , Humanos , Vortioxetina/farmacologia , Vortioxetina/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Depressão/etiologia , Método Duplo-Cego , Adulto , COVID-19/complicações , COVID-19/psicologia , Qualidade de Vida , Transtornos de Ansiedade/tratamento farmacológico , Idoso , Antidepressivos/uso terapêutico , Antidepressivos/farmacologiaRESUMO
BACKGROUND: Major depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin's acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression. METHODS: Fifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures. DISCUSSION: This study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin's antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.
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Afeto , Encéfalo , Transtorno Depressivo Maior , Psilocibina , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , Psilocibina/uso terapêutico , Psilocibina/efeitos adversos , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Afeto/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/tratamento farmacológico , Imageamento por Ressonância Magnética , Fatores de Tempo , Resultado do Tratamento , Adulto , Plasticidade Neuronal/efeitos dos fármacos , Adulto Jovem , Masculino , Antidepressivos/uso terapêutico , Feminino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Approximately 30 % of persons with Major Depressive Disorder (MDD) inadequately respond to conventional antidepressants. Kappa opioid receptor (KOR) antagonists, aticaprant and navacaprant, are in development as treatments for MDD. Herein, we aim to comprehensively evaluate the safety, efficacy and pharmacology of aticaprant and navacaprant for MDD. METHODS: We performed a systematic review of primary research investigating aticaprant and navacaprant on PubMed, OVID, and Scopus databases from inception to April 2024. Studies that reported on the pharmacological profile and/or safety and efficacy of aticaprant and navacaprant were included. RESULTS: Navacaprant monotherapy and aticaprant adjunctive therapy are in development for MDD. Navacaprant exhibits 300-fold selectivity for the KOR compared to the mu-opioid receptor, while aticaprant exhibits 30-fold selectivity. At clinically-relevant doses, navacaprant and aticaprant occupy 87-95 % and 73-94 % of KORs, respectively. Clinical trials of the foregoing agents (navacaprant as monotherapy and actiprant as adjunctive therapy) reported significant improvement in depressive symptoms and may clinically benefit measures of anhedonia. Both agents appear well-tolerated, with most adverse events mild and no known safety concerns. LIMITATIONS: Aticaprant and navacaprant treatment for MDD are in early stages of clinical trials and results from Phase 3 pivotal trials are not yet available. CONCLUSIONS: Kappa opioid receptor antagonists may serve as mechanistically-novel treatments for MDD and persons who inadequately respond to index conventional antidepressants. Anhedonia is debilitating and insufficiently treated with conventional antidepressants. Future research vistas should establish the efficacy and safety of KORAs in phase 3 studies in both acute and maintenance paradigms.
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Antidepressivos , Transtorno Depressivo Maior , Receptores Opioides kappa , Animais , Humanos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Benzamidas , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Entorpecentes/uso terapêutico , Antagonistas de Entorpecentes/farmacologia , Pirrolidinas , Receptores Opioides kappa/antagonistas & inibidoresRESUMO
BACKGROUND: Psilocybin-assisted psychotherapy (PAP) is a promising treatment option for depression, with randomized controlled trials (RCTs) providing preliminary support for its safety and efficacy. However, there is a lack of consistency across existing treatment protocols and psychotherapeutic approaches. The objective of this review is to summarize and compare current psychotherapy methods of PAP in treating depression and distress in life-threatening illnesses. We sought to comprehensively summarize published psychotherapy protocols from clinical trials to provide insights for future practices. METHODS: A systematic search of four databases (Embase, MEDLINE, PsycINFO, CINAHL) for data relating to psychotherapy protocols was conducted by two independent reviewers. RESULTS: In total, our search identified 1869 articles; after removing duplicates, we screened 1107 articles. We included 70 articles in the full-text review and determined that 28 were eligible for the final review. All protocols include sessions before (preparatory) and after (integration) the psychedelic dosing session with supportive monitoring. However, there was substantial variability and inconsistencies in all other aspects of therapy protocols (e.g., duration and number of sessions, model of therapy). Additionally, significant limitations were identified in the frequent need for more clarity in the description of therapeutic approaches. CONCLUSION: In published clinical trials, PAP has consisted of preparation, supportive dosing, and integration sessions. Beyond this basic framework, significant heterogeneity and lack of clarity were identified in reported psychotherapy protocols, meaning a validated and universally agreed upon protocol for PAP currently does not exist. Future studies should more clearly define and report psychotherapeutic components to identify the safest and most efficacious approaches to PAP.
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Alucinógenos , Psilocibina , Psicoterapia , Humanos , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Psicoterapia/métodos , Alucinógenos/administração & dosagem , Depressão/terapia , Depressão/tratamento farmacológico , Protocolos Clínicos , Transtorno Depressivo/terapia , Transtorno Depressivo/tratamento farmacológicoRESUMO
BACKGROUND: Bipolar disorder (BD) has a high disease burden and the highest mortality risk in BD comes from suicide. Bipolar disorder type II (BD-II) has been described as a milder form of bipolar disorder; however, extant literature is inconsistent with this description and instead describe illness burden and notably suicidality comparable to persons with bipolar I disorder (BD-I). Towards quantifying the hazard of BD-II, herein we aim via systematic review and meta-analysis to evaluate the rates of completed suicide in BD-I and BD-II. METHOD: We conducted a literature search on PubMed, OVID (Embase, Medline) and PsychINFO databases from inception to June 30th, 2023, according to PRISMA guidelines. Articles were selected based on the predetermined eligibility criteria. A meta-analysis was performed, comparing the risk of completed suicide between individuals diagnosed with BD-I to BD-II. RESULTS: Four out of eight studies reported higher suicide completion rates in persons living with BD-II when compared to persons living with BD-I; however, two of the studies reported non-significance. Two studies reported significantly higher suicide completion rates for BD-I than BD-II. The pooled odds ratio of BD-II suicide rates to BD-I was 1.00 [95 % CI = 0.75, 1.34]. LIMITATIONS: The overarching limitation is the small number of studies and heterogeneity of studies that report on suicide completion in BD-I and BD-II. CONCLUSION: Our study underscores the severity of BD-II, with a risk for suicide not dissimilar from BD-I. The greater propensity to depression, comorbidity and rapid-cycling course reported in BD-II are contributing factors to the significant mortality hazard in BD-II.
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Transtorno Bipolar , Suicídio Consumado , Humanos , Transtorno Bipolar/mortalidade , Transtorno Bipolar/psicologia , Suicídio Consumado/estatística & dados numéricosRESUMO
OBJECTIVE: Post-COVID-19 Condition (PCC) is a prevalent, persistent and debilitating phenomenon occurring three or more months after resolution of acute COVID-19 infection. Fatigue and depressive symptoms are commonly reported in PCC. We aimed to further characterize PCC by assessing the relationship between fatigue and depressive symptom severity in adults with PCC. METHODS: A post hoc analysis was conducted on data retrieved from a randomized, double-blinded, placebo-controlled study evaluating vortioxetine for cognitive deficits in persons with PCC. We sought to determine the relationship between baseline fatigue [i.e. Fatigue Severity Scale (FSS) total score] and baseline depressive symptom severity [i.e. 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR-16) total score] in adults with PCC. RESULTS: The statistical analysis included baseline data from 142 participants. After adjusting for age, sex, education, employment status, history of major depressive disorder (MDD) diagnosis, self-reported physical activity, history of documented acute SARS-CoV-2 infection and body mass index (BMI), baseline FSS was significantly correlated with baseline QIDS-SR-16 (ß = 0.825, p = .001). CONCLUSION: In our sample, baseline measures of fatigue and depressive symptoms are correlated in persons living with PCC. Individuals presenting with PCC and fatigue should be screened for the presence and severity of depressive symptoms. Guideline-concordant care should be prescribed for individuals experiencing clinically significant depressive symptoms. Fatigue and depressive symptom severity scores were not pre-specified as primary objectives of the study. Multiple confounding factors (i.e. disturbance in sleep, anthropometrics and cognitive impairment) were not collected nor adjusted for in the analysis herein. TRIAL REGISTRATION: Unrestricted Research Grant from H. Lundbeck A/S, Copenhagen, Denmark. ClinicalTrials.gov Identifier: NCT05047952.
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COVID-19 , Depressão , Fadiga , Humanos , Feminino , Masculino , Fadiga/etiologia , COVID-19/complicações , COVID-19/psicologia , Pessoa de Meia-Idade , Depressão/epidemiologia , Adulto , Síndrome de COVID-19 Pós-Aguda , Método Duplo-Cego , SARS-CoV-2 , Idoso , Índice de Gravidade de DoençaRESUMO
INTRODUCTION: Replicated evidence indicates that ketamine and esketamine reduce measures of suicidality in persons with treatment-resistant depression (TRD). It remains uncertain whether individuals experience worsening of preexisting suicidality with either agent. RESEARCH DESIGN AND METHODS: The Food and Drug Administration Adverse Event Reporting System (FAERS) database was searched from 1970 and 2019 to 30 September 2023 for reports of suicidal ideation, depression suicidal, suicidal behavior, suicidal attempt, and completed suicide in association with ketamine and esketamine exposure, respectively. We present reporting odds ratios (ROR) significance was determined when the lower limit of the 95% confidence interval (CI) exceeded 1.0. Lithium was used as the control agent. RESULTS: Observed a higher ROR for suicidal ideation (ROR 7.58, 95% CI 6.34-9.07) and depression suicidal (ROR 14.19, 95% CI 1.80-112.07) with esketamine. Significantly lower RORs were observed for suicide attempt with ketamine (ROR 0.15, 95% CI 0.11-0.21) and esketamine (ROR 0.57, 95% CI 0.48-0.67). CONCLUSIONS: Mixed RORs across aspects of suicidality were observed with ketamine and esketamine. Limitations of the FAERS database prevent any determination of causal effects new onset suicidality to either agent. The lower RORs for suicide attempt with ketamine and esketamine is noted but cannot be interpreted as a direct therapeutic effect.
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BACKGROUND: Package inserts for the FDA-approved dual orexin receptor antagonists (DORAs) suvorexant, lemborexant and daridorexant state that suicide risk should be monitored. It remains unknown whether suicidality is attributed to DORAs. We aim to evaluate suicidality associated with DORAs reported to the FDA Adverse Event Reporting System (FAERS). METHODS: The reporting odds ratio (ROR) was determined with trazodone as the control. Significant disproportionate reporting was determined when 95% confidence intervals (CIs) did not encompass 1.0. We used information components (ICs) to calculate the lower limit of the 95% CI (IC025). IC was significantly increased when the IC025 ≥0. RESULTS: Suvorexant (0.025 ROR), lemborexant (0.019 ROR) and daridorexant (0.002 ROR) were significantly associated with lower odds of reported completed suicides compared to trazodone (p < 0.05). There was no significantly increased RORs for the DORAs regarding suicidal ideation, depression suicidal, suicidal behavior and suicide attempts. Nonsignificant associations between all parameters of suicidality were observed for each DORA using IC025. CONCLUSION: We did not find a significant association between any parameter of suicidality captured in the FAERS for each DORA. All persons treated for insomnia pharmacologically/non-pharmacologically should be evaluated for emergence/worsening of any suicidality aspect.
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Prescription of vesicular monoamine transporter 2 (VMAT2) inhibitors, valbenazine, deutetrabenazine, and tetrabenazine, is becoming increasingly common in persons treated with antipsychotics. Reported suicidality and parkinsonism are safety concerns with VMAT2 inhibitors. Herein, we aim to evaluate the aforementioned safety outcomes using the FDA Adverse Event Reporting System. Reporting odds ratios (RORs) and lower limits of 95% confidence intervals of information components (IC025) were calculated to quantify VMAT2 inhibitor-associated adverse events. Acetaminophen was the reference agent. Suicidal ideation was significantly associated with VMAT2 inhibitors, with RORs ranging from 2.38 to 10.67 and IC025 ranging from 0.73 to 2.39. Increased odds of suicidal behavior was observed with tetrabenazine (ROR 3.011, IC025 0.0087), but not deutetrabenazine or valbenazine. Decreased odds of suicide attempts and completed suicide were observed with VMAT2 inhibitors, with RORs ranging from 0.011 to 0.10 (all IC025â <â 0). Increased odds of parkinsonism were reported for all VMAT2 inhibitors, with RORs and IC025 ranging from 19.49 to 25.37 and 1.66 to 2.93, respectively. The mixed results with VMAT2 inhibitor-associated suicidality and parkinsonism do not establish causal relationships. The parameters of suicidality may be explained by underlying psychiatric disorders.
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BACKGROUND: The Canadian Network for Mood and Anxiety Treatments (CANMAT) last published clinical guidelines for the management of major depressive disorder (MDD) in 2016. Owing to advances in the field, an update was needed to incorporate new evidence and provide new and revised recommendations for the assessment and management of MDD in adults. METHODS: CANMAT convened a guidelines editorial group comprised of academic clinicians and patient partners. A systematic literature review was conducted, focusing on systematic reviews and meta-analyses published since the 2016 guidelines. Recommendations were organized by lines of treatment, which were informed by CANMAT-defined levels of evidence and supplemented by clinical support (consisting of expert consensus on safety, tolerability, and feasibility). Drafts were revised based on review by patient partners, expert peer review, and a defined expert consensus process. RESULTS: The updated guidelines comprise eight primary topics, in a question-and-answer format, that map a patient care journey from assessment to selection of evidence-based treatments, prevention of recurrence, and strategies for inadequate response. The guidelines adopt a personalized care approach that emphasizes shared decision-making that reflects the values, preferences, and treatment history of the patient with MDD. Tables provide new and updated recommendations for psychological, pharmacological, lifestyle, complementary and alternative medicine, digital health, and neuromodulation treatments. Caveats and limitations of the evidence are highlighted. CONCLUSIONS: The CANMAT 2023 updated guidelines provide evidence-informed recommendations for the management of MDD, in a clinician-friendly format. These updated guidelines emphasize a collaborative, personalized, and systematic management approach that will help optimize outcomes for adults with MDD.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/terapia , Canadá , AdultoRESUMO
INTRODUCTION: Ketamine and esketamine have been proven to be effective in treating adults with treatment resistant depression (TRD). Preliminary evidence indicates that, when combined with behavioral and psychological interventions, both agents may offer benefits for individuals with substance use disorder (SUD) and alcohol use disorder (AUD). Notwithstanding, concerns have been raised as to whether either or both agents are associated with abuse and/or gateway activity. METHODS: Herein, we evaluate disproportionate reporting expressed as reporting odds ratios (ROR) for esketamine and ketamine. The outcomes of interest include alcohol problem, alcoholism, alcohol abuse, substance dependence, SUD, substance abuse, drug dependence, drug use disorder and drug abuse as codified by the Medical Dictionary for Regulatory Activities (MedDRA) within the FAERS. The IC025 values were significant for ketamine in cases of alcohol abuse (0.28), substance dependence (1.88), substance use disorder (0.996), substance abuse (0.61), drug dependence (0.56), drug use disorder (1.17) and drug abuse (1.22). Additionally, oxycontin showed significant IC025 values for substance dependence (0.067), substance use disorder (0.094), substance abuse (0.035), and drug dependence (0.27). RESULTS: We observed significant increases in the reporting odds ratios (RORs) for ketamine with respect to various outcomes: alcohol abuse (ROR 2.84, 95 % CI 1.53-5.28; p = 0.0010), substance dependence (ROR 18.72, 95 % CI 8.49-41.30; p ≤ 0.0001), SUD (ROR 11.40, 95 % CI 4.24-30.65; p ≤ 0.0001), substance abuse (ROR 2.29, 95 % CI 1.73-3.04; p ≤ 0.0001), drug dependence (ROR 1.99, 95 % CI 1.64-2.42; p ≤ 0.0001), drug use disorder (ROR 4.50, 2.94-6.88; p ≤ 0.0001) and drug abuse (ROR 3.72, 3.36-4.12; p ≤ 0.0001). For esketamine, we observed that the ROR was significantly reduced for substance abuse (ROR 0.37, 95 % CI 0.22-0.63; p = 0.0003), drug dependence (ROR 0.13, 95 % CI 0.076-0.23; p ≤ 0.0001) and drug abuse (ROR 0.048, 95 % CI 0.030-0.078; p ≤ 0.0001). To our knowledge, this is the first report of spontaneous adverse events related to these outcomes of interest in the FAERS. CONCLUSION: Mixed RORs were observed across aspects of SUD and AUD for both ketamine and esketamine. Due to limitations in the FAERS, establishing causal links between new onset alcohol and substance misuse with either agent remains inconclusive. Possible beneficial effects on measures of SUD and AUD were observed. It is currently unclear, but possible, whether both agents have differential ameliorative effects across dimensions of SUD and AUD, which is a focus of ongoing research.
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Alcoolismo , Ketamina , Transtornos Relacionados ao Uso de Substâncias , United States Food and Drug Administration , Ketamina/efeitos adversos , Humanos , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Estados Unidos , Adulto , Masculino , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Feminino , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Individuals who have recovered from the acute stage of SARS-CoV-2 infection may be at risk of developing post-COVID-19 condition (PCC), characterised by a spectrum of persisting, non-specific, and functionally impairing symptoms across multiple organ systems. Obesity has been implicated as a risk factor for PCC, mediated by chronic systemic inflammation. The foregoing has also been separately reported to mediate cognitive dysfunction in PCC. METHODS: This is a post-hoc analysis of a randomised, double-blinded, placebo-controlled clinical trial evaluating vortioxetine treatment for cognitive impairments in persons with PCC who received vortioxetine or placebo for eight weeks. This analysis comprises baseline data, examining the impact of BMI on cognitive functioning measured by the Digit Symbol Substitution Test (DSST) and Trails Making Tests (TMT)-A/B, as well as inflammation, via serum c-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). RESULTS: Complete data from 70 participants were statistically analysed and adjusted for age and sex. BMI was negatively correlated with performance on the DSST (ß = -0.003, p = 0.047), TMT-A (ß = -0.006, p = 0.025), and TMT-B (ß = -0.006, p = 0.002). BMI was positively correlated with serum CRP (unstandardized ß = 0.193, standardized ß = 0.612, p < 0.001) and ESR (ß = 0.039, p < 0.001) levels. CONCLUSION: We observed a significant negative correlation between BMI and cognitive functioning, and a significant positive correlation between BMI and inflammation in persons with PCC, suggesting a bidirectional interplay between BMI, PCC, and cognitive function; individuals with an elevated BMI may be at a greater risk of developing PCC and/or presenting with greater cognitive deficits mediated by chronic systemic inflammation.
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OBJECTIVES: Clinicians are often hesitant to prescribe psychostimulants in bipolar disorder (BD) due to concerns of inducing (hypo)mania, despite limited published evidence on associations between prescribed psychostimulant use and recurrence of mood episodes in BD. The current systematic review and meta-analysis evaluated the emergence of (hypo)manic symptoms in patients with BD receiving prescribed psychostimulants or other pro-cognitive medications in euthymic or depressive states. METHODS: A systematic search was performed of MEDLINE, Embase, and PsychINFO from inception to April 5, 2023 and search of Clinicaltrials.gov and Clinicaltrialsregister.eu for unpublished data. References of included studies were hand-searched. Randomized trials and prospective longitudinal studies that evaluated psychostimulants and non-stimulant medications recommended for the treatment of ADHD by the Canadian ADHD practice guidelines were included. The review was reported in line with PRISMA guidelines and was preregistered on PROSPERO (CRD42022358588). RESULTS: After screening 414 unique records, we included 27 studies, of which five reported data that was quantitatively synthesized (n = 1653). The use of psychostimulants in BD was not associated with increased scores on the Young Mania Rating Scale in patients who were in a euthymic or depressed state (SMD IV -0.17; 95% CI, -0.40 to 0.06) compared to placebo. There was a high degree of study-level heterogeneity (I2 = 80%). A qualitative synthesis of studies revealed a limited risk of medication-induced manic symptoms. CONCLUSIONS: Our review provides preliminary evidence to suggest psychostimulants and non-stimulant ADHD medications have a limited risk of precipitating (hypo)mania symptoms. More extensive studies evaluating the safety and efficacy of these medications are warranted.
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Transtorno Bipolar , Estimulantes do Sistema Nervoso Central , Mania , Humanos , Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Mania/tratamento farmacológico , RecidivaRESUMO
BACKGROUND: Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS: We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS: Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS: The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS: Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Alucinógenos , Ketamina , Dietilamida do Ácido Lisérgico , Psilocibina , Humanos , Psilocibina/farmacologia , Psilocibina/administração & dosagem , Psilocibina/uso terapêutico , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , Ketamina/uso terapêutico , Ketamina/administração & dosagem , Ketamina/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Alucinógenos/administração & dosagem , Alucinógenos/efeitos adversos , Alucinógenos/farmacologia , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Voluntários Saudáveis , Eletroencefalografia/efeitos dos fármacosRESUMO
BACKGROUND: Major depressive disorder (MDD) is a heterogeneous group of mood disorders. A prominent symptom domain is anhedonia narrowly defined as a loss of interest and ability to experience pleasure. Anhedonia is associated with depressive symptom severity, MDD prognosis, and suicidality. We perform a systematic review and meta-analysis of extant literature investigating the effects of anhedonia on health-related quality of life (HRQoL) and functional outcomes in persons with MDD. METHODS: A literature search was conducted on PubMed, OVID databases, and SCOPUS for published articles from inception to November 2023, reporting on anhedonia and patient-reported outcomes in persons with MDD. The reported correlation coefficients between anhedonia and self-reported measures of both HRQoL and functional outcomes were pooled using a random effects model. RESULTS: We identified 20 studies that investigated anhedonia with HRQoL and/or functional outcomes in MDD. Anhedonia as measured by the Snaith-Hamilton Pleasure Scale (SHAPS) scores had a statistically significant correlation with patient-reported HRQoL (r = -0.41 [95 % CI = -0.60, -0.18]) and functional impairment (r = 0.39 [95 % CI = 0.22, 0.54]). LIMITATIONS: These preliminary results primarily investigate correlations with consummatory anhedonia and do not distinguish differences in anticipatory anhedonia, reward valuation or reward learning; therefore, these results require replication. CONCLUSIONS: Persons with MDD experiencing symptoms of anhedonia are more likely to have worse prognosis including physical, psychological, and social functioning deficits. Anhedonia serves as an important predictor and target for future therapeutic and preventative tools in persons with MDD.
Assuntos
Anedonia , Transtorno Depressivo Maior , Qualidade de Vida , Humanos , Anedonia/fisiologia , Transtorno Depressivo Maior/psicologia , Transtorno Depressivo Maior/fisiopatologia , Qualidade de Vida/psicologiaRESUMO
BACKGROUND: Ketamine has been established as efficacious in adults living with Treatment-resistant Depression (TRD). Toward providing a quantifiable estimate of the clinical meaningfulness of the therapeutic benefit of ketamine, herein, we conduct a systematic review that aims to report the Number Needed to Treat (NNT) and the Number Needed to Harm (NNH). METHODS: This systematic review searched Embase, Medline/Pubmed, PsycINFO and ClinicalTrials.gov from inception up to October 15th 2023, for placebo-controlled, Randomized Controlled Trials (RCTs) assessing racemic ketamine or esketamine therapy for unipolar TRD. We calculated NNT and NNH for ketamine treatments over various time points. RESULTS: A total of 21 studies with 2042 participants were included. Racemic ketamine treatments had pooled NNTs for response of 7 at 4 h, 3 from one day to one week and 9 for studies at four weeks. Esketamine treatment was found to have a similar efficacy with an NNT of 2 at one day and 11 at four weeks. NNH values indicated low risk for ketamine treatments. LIMITATIONS: Limitations in the data used include the possibility of functional unblinding and selective reporting bias. Moreover, the meta-analysis may have been limited in its precision by including low threshold definitions of treatment resistance (≥ 1 failed antidepressant) and low-dose ketamine treatments. CONCLUSION: Herein, we determined that the NNT for ketamine treatment in adults living with TRD across different intervals of observation was <10. We conclude that the NNTs observed herein are highly clinically meaningful in this difficult to treat disorder.
Assuntos
Antidepressivos , Transtorno Depressivo Resistente a Tratamento , Ketamina , Ketamina/uso terapêutico , Ketamina/administração & dosagem , Humanos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antidepressivos/uso terapêutico , Adulto , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
INTRODUCTION: To date, there are no therapeutics that have gained regulatory approval by the United States Food and Drug Administration (FDA) for the treatment of post-COVID-19 condition (PCC), a debilitating condition characterized by cognitive impairment and mood symptoms. Additionally, persistent inflammation, metabolic dysfunction, and risks associated with an elevated body mass index (BMI) have been observed. Herein, we aimed to assess the efficacy of vortioxetine in improving depressive symptoms among individuals with PCC, as modulated by inflammation, metabolic dysfunction, and BMI. METHODS: In this post-hoc analysis, we present preliminary data obtained from an 8-week randomized, double-blind, placebo-controlled trial. Participants included adults aged 18 years and older residing in Canada who were experiencing symptoms of World Health Organization (WHO)-defined PCC. Recruitment began November 2021 and ended January 2023. Of the 200 participants enrolled, 147 were randomized (1:1) to receive vortioxetine (5-20 mg, n = 73) or placebo (n = 74) for daily treatment under double-blind conditions. The primary outcome measure was the change from baseline to endpoint in the 16-Item Quick Inventory of Depressive Symptomatology Self-Report Questionnaire (QIDS-SR-16). RESULTS: Our findings revealed significant effects for time (χ2 = 9.601, p = 0.002), treatment (χ2 = 9.135, p = 0.003), and the treatment × time × CRP × TG-HDL × BMI interaction (χ2 = 26.092, p < 0.001) on PCC-related depressive symptoms in the adjusted model. Moreover, the between-group analysis showed a significant improvement with vortioxetine at endpoint as compared to placebo (mean difference = - 5.41, SEM = 1.335, p < 0.001). CONCLUSION: Overall, vortioxetine significantly improved depressive symptoms among participants with PCC in the adjusted model. Notably, individuals with baseline markers of increased inflammation, metabolic disruption, and elevated BMI exhibited a more pronounced antidepressant effect at endpoint. TRIAL REGISTRATION NUMBER: NCT05047952 (ClinicalTrials.gov).
Assuntos
Índice de Massa Corporal , Inflamação , Vortioxetina , Humanos , Vortioxetina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Método Duplo-Cego , Feminino , Inflamação/tratamento farmacológico , Adulto , Depressão/tratamento farmacológico , Idoso , COVID-19/psicologia , SARS-CoV-2 , Antidepressivos/uso terapêuticoRESUMO
Converging evidence has suggested that treatment augmentation with a second-generation atypical antipsychotic (SGA) may improve treatment outcomes in major depressive disorder (MDD) patients after an incomplete response to a first-line antidepressant. Cariprazine is a recently approved SGA for MDD augmentation. Herein, we evaluate both continuous (ie, change in depressive symptom severity scores over time) and categorical (ie, remission and response rates) outcomes. Following a full-text review, four randomized controlled trials (RCTs) were included in our meta-analysis, while five studies were included for a qualitative review. Risk ratios (RRs) were calculated for all included randomized controlled studies to determine the relative response and remission rates of cariprazine compared to placebo augmentation. The RR for all-cause dropout was also determined as a proxy for overall acceptability. Two studies found a statistically significant treatment response using cariprazine augmentation. One study observed depressive symptom remission for cariprazine compared to placebo. Our random-effects model revealed moderate antidepressant effects of cariprazine, with a standardized mean difference (SMD) in Montgomery-Åsberg Depression Rating Scale (MADRS) scores of -1.79 (95% CI): -2.89, -0.69). Our pooled response RR and remission RR were calculated as 1.21 (95% CI: 1.05, 1.39, P=0.008) and 0.99 (95% CI: 0.84, 1.17, P=0.91), respectively. The RR for response was statistically significant (P<0.05). However, the RR for remission was not statistically significant. The findings from our meta-analysis include a variable magnitude of effects. Evidence suggests cariprazine may be an effective treatment for MDD; however, further results are needed to clarify this relation.