Trial of Psilocybin versus Escitalopram for Depression.

BACKGROUND: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking. METHODS: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6. RESULTS: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups. CONCLUSIONS: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants. (Funded by the Alexander Mosley Charitable Trust and Imperial College London's Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075.).

Real-World Use of Trazodone in Older Persons in Long Term Care Setting: A Retrospective Study.

BACKGROUND: Trazodone, an antidepressant drug is also largely used in several medical contexts. Insomnia, behavioral disorders, and anxiety may be underlying symptoms for prescribing trazodone. This cross-sectional study aims to identify reasons for trazodone prescription, assess the efficacy, as well as identify any related side effects in older persons living in long term care facilities (LTCFs). METHODS: Older adults aged ≥ 60 years, at risk of or affected with Covid-19 and enrolled in the GeroCovid Observational study from LTCFs, and using trazodone were included. A structured questionnaire was administered to treating physicians regarding reasons for trazodone prescription, discontinuation, possible adverse events and benefits. RESULTS: Thirty-seven out 74 LTCFs participating in both the GeroCovid and GeroCovid Vax studies completed the questionnaire regarding trazodone use. Of the 427 participants included in this study analysis, we found that 43% had diagnoses of dementia and depression, 33% had dementia, no behavioral and psychological symptoms of dementia (BPSD) and no depression, 14% had dementia with BPSD and no depression, and < 11% had only depression. The main reasons for trazodone prescription included agitation, insomnia, depression and anxiety. Trazodone use was reported as partially or totally effective in more than 90% of participants using the drug. Falls were the most frequent adverse event (30% of participants). CONCLUSIONS: Our data suggest that trazodone behaves as an eclectic antidepressant that, in the clinical practice, may also be used for BPSD and insomnia, especially in older people with dementia.

Nonpharmacologic and Pharmacologic Treatments of Adult Patients With Major Depressive Disorder: A Systematic Review and Network Meta-analysis for a Clinical Guideline by the American College of Physicians.

BACKGROUND: Primary care patients and clinicians may prefer alternative options to second-generation antidepressants for major depressive disorder (MDD). PURPOSE: To compare the benefits and harms of nonpharmacologic treatments with second-generation antidepressants as first-step interventions for acute MDD, and to compare second-step treatment strategies for patients who did not achieve remission after an initial attempt with antidepressants. DATA SOURCES: English-language studies from several electronic databases from 1 January 1990 to 8 August 2022, trial registries, gray literature databases, and reference lists to identify unpublished research. STUDY SELECTION: 2 investigators independently selected randomized trials of at least 6 weeks' duration. DATA EXTRACTION: Reviewers abstracted data about study design and conduct, participants, interventions, and outcomes. They dually rated the risk of bias of studies and the certainty of evidence for outcomes of interest. DATA SYNTHESIS: 65 randomized trials met the inclusion criteria; eligible data from nonrandomized studies were not found. Meta-analyses and network meta-analyses indicated similar benefits of most nonpharmacologic treatments and antidepressants as first-step treatments. Antidepressants had higher risks for discontinuation because of adverse events than most other treatments. For second-step therapies, different switching and augmentation strategies provided similar symptomatic relief. The certainty of evidence for most comparisons is low; findings should be interpreted cautiously. LIMITATIONS: Many studies had methodological limitations or dosing inequalities; publication bias might have affected some comparisons. In some cases, conclusions could not be drawn because of insufficient evidence. CONCLUSION: Although benefits seem to be similar among first- and second-step MDD treatments, the certainty of evidence is low for most comparisons. Clinicians and patients should focus on options with the most reliable evidence and take adverse event profiles and patient preferences into consideration. PRIMARY FUNDING SOURCE: American College of Physicians. (PROSPERO: CRD42020204703).

BUPROPION MISUSE BY NASAL INSUFFLATION WITH A FATAL OUTCOME: CASE REPORT AND REVIEW.

Bupropion is the only FDA - approved synthetic cathinone, with increasing popularity in clinical practice due to its wide range of action, and lack of sexual side effects. However, its stimulant effect similar to amphetamines has growing the concern regarding its recreational use.

The Timing of Clinical Effects of Bupropion Misuse Via Insufflation Reported to a Regional Poison Center.

BACKGROUND: Bupropion is an antidepressant medication with expanding indications including smoking cessation, weight loss, attention-deficit/hyperactivity disorder, seasonal affective disorder, and amphetamine dependence. Despite its increasing popularity among providers, it has a well-known narrow therapeutic window that can lead to delayed onset of symptoms with extended-release formulations and devastating consequences in overdose. We have noticed some patients misusing bupropion via insufflation, which added a layer of complexity with regards to the therapeutic application of the drug. This route of use created difficult decisions regarding clinical monitoring in these patients. OBJECTIVES: To determine if prolonged observation is required after insufflation of bupropion and to further describe effects from this route of use. METHODS: This is a retrospective observational study reviewing all the cases of insufflated bupropion use reported to a single poison center without any other coingestants. RESULTS: The majority (85.7%) of patients had mild or moderate effects, and seizures occurred in 19.6% of cases; and the vast majority of patients were symptomatic by the time of the initial call to the poison center. We did not encounter any delayed effects after this route of use. CONCLUSIONS: This report describes the clinical effects reported, and the timing of these effects, after insufflation of bupropion.

The effects of trazodone on human cognition: a systematic review.

Trazodone is a widely used antidepressant that is also useful in the control of agitation and insomnia in Alzheimer's disease. This drug is now recognized as having a new mechanism of action, an effect on the unfolded protein response (UPR) pathway, restoring protein translation and slowing neurodegenerative progression in mice. This mechanism may have a role in dementia-modifying treatment. To explore the effects of trazodone on human cognition and to search for clinical evidence of its putative benefits in human neurodegenerative diseases, a systematic review was conducted for studies that evaluated the effect of a minimum dose of 25 mg of trazodone daily, for at least 1 week, on cognition in adult humans. The search was run in MEDLINE, Web of Science, and CENTRAL from the Cochrane databases, yielding a total of 16 studies after selection. Overall, seven studies showed no effect of trazodone on cognition, five showed a beneficial effect by improving or reducing cognitive decline, and four evidenced impaired cognitive function. Our analysis highlights the possibility of a dose-independent dual effect of trazodone on human cognition, with acute utilization associated with impaired cognitive function and long-term use with preventing cognitive deterioration. There was no clinical evidence that trazodone could be used as a specific treatment of neurodegenerative diseases. Future studies should explore the role of trazodone in the UPR pathway and the implications in neurodegenerative diseases in humans.

Antidepressants for functional abdominal pain disorders in children and adolescents.

BACKGROUND: Functional Abdominal Pain Disorders (FAPDs) present a considerable burden to paediatric patients, impacting quality of life, school attendance and causing higher rates of anxiety and depression disorders. There are no international guidelines for the management of this condition. A previous Cochrane Review in 2011 found no evidence to support the use of antidepressants in this context. OBJECTIVES: To evaluate the current evidence for the efficacy and safety of antidepressants for FAPDs in children and adolescents. SEARCH METHODS: In this updated review, we searched the Cochrane Library, PubMed, MEDLINE, Embase, PsycINFO and two clinical trial registers from inception until 03 February 2020. We also updated our search of databases of ongoing research, reference lists and 'grey literature' from inception to 03 February 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing antidepressants to placebo, to no treatment or to any other intervention, in children aged 4 to 18 years with a FAPD diagnosis as per the Rome or any other defined criteria (as defined by the authors). The primary outcomes of interest included treatment success (as defined by the authors), pain severity, pain frequency and withdrawal due to adverse events. DATA COLLECTION AND ANALYSIS: Two review authors checked all citations independently, resolving disagreement with a third-party arbiter. We reviewed all potential studies in full text, and once again made independent decisions, with disagreements resolved by consensus. We conducted data extraction and 'Risk of bias' assessments independently, following Cochrane methods. Where homogeneous data were available, we performed meta-analysis using a random-effects model. We conducted GRADE analysis. MAIN RESULTS: We found one new study in this updated search, making a total of three trials (223 participants) eligible for inclusion: two using amitriptyline (AMI) and one using citalopram. For the primary outcome of treatment success, two studies used reports of success on a symptom-based Likert scale, with either a two-point reduction or the two lowest levels defined as success. The third study defined success as a 15% improvement in quality of life (QOL) ratings scales. Therefore, meta-analysis did not include this final study due to the heterogeneity of the outcome measure. There is low-certainty evidence that there may be no difference when antidepressants are compared with placebo (risk ratio (RR) 1.17, 95% confidence interval (CI) 0.87 to 1.56; 2 studies, 205 participants; I2 = 0%). We downgraded the evidence for significant imprecision due to extremely sparse data (see Summary of findings table 1). The third study reported that participants receiving antidepressants were significantly more likely than those receiving placebo to experience at least a 15% improvement in overall QOL score at 10 and 13 weeks (P = 0.007 and P = 0.002, respectively (absolute figures were not given)). The analysis found no difference in withdrawals due to adverse events between antidepressants and placebo: RR 3.17 (95% CI 0.65 to 15.33), with very low certainty due to high risk of bias in studies and imprecision due to low event and participant numbers. Sensitivity analysis using a fixed-effect model and analysing just for AMI found no change in this result. Due to heterogeneous and limited reporting, no further meta-analysis was possible. AUTHORS' CONCLUSIONS: There may be no difference between antidepressants and placebo for treatment success of FAPDs in childhood. There may be no difference in withdrawals due to adverse events, but this is also of low certainty. There is currently no evidence to support clinical decision making regarding the use of these medications. Further studies must consider sample size, homogenous and relevant outcome measures and longer follow up.

Second-generation antidepressants for treatment of seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is a seasonal pattern of recurrent depressive episodes that is often treated with second-generation antidepressants (SGAs), light therapy, or psychotherapy. OBJECTIVES: To assess the efficacy and safety of second-generation antidepressants (SGAs) for the treatment of seasonal affective disorder (SAD) in adults in comparison with placebo, light therapy, other SGAs, or psychotherapy. SEARCH METHODS: This is an update of an earlier review first published in 2011. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 1) in the Cochrane Library (all years), Ovid MEDLINE, Embase, and PsycINFO (2011 to January 2020), together with the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR) (all available years), for reports of randomised controlled trials (RCTs). We hand searched the reference lists of all included studies and other systematic reviews. We searched ClinicalTrials.gov for unpublished/ongoing trials. We ran a separate update search for reports of adverse events in the Ovid databases.  SELECTION CRITERIA: For efficacy we included RCTs of SGAs compared with other SGAs, placebo, light therapy, or psychotherapy in adult participants with SAD. For adverse events we also included non-randomised studies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and full-text publications against the inclusion criteria. Data extraction and 'Risk of bias' assessment were conducted individually. We pooled data for meta-analysis where the participant groups were similar, and the studies assessed the same treatments with the same comparator and had similar definitions of outcome measures over a similar duration of treatment. MAIN RESULTS: In this update we identified no new RCT on the effectiveness of SGAs in SAD patients. We included 2 additional single-arm observational studies that reported on adverse events of SGAs.  For efficacy we included three RCTs of between five and eight weeks' duration with a total of 204 participants. For adverse events we included two RCTs and five observational (non-randomised) studies of five to eight weeks' duration with a total of 249 participants. All participants met the DSM (Diagnostic and Statistical Manual of Mental Disorders) criteria for SAD. The average age ranged from 34 to 42 years, and the majority of participants were female (66% to 100%). Results from one trial with 68 participants showed that fluoxetine (20/36) was numerically superior to placebo (11/32) in achieving clinical response; however, the confidence interval (CI) included both a potential benefit as well as no benefit of fluoxetine (risk ratio (RR) 1.62, 95% CI 0.92 to 2.83, very low-certainty evidence). The number of adverse events was similar in both groups (very low-certainty evidence). Two trials involving a total of 136 participants compared fluoxetine versus light therapy. Meta-analysis showed fluoxetine and light therapy to be approximately equal in treating seasonal depression: RR of response 0.98 (95% CI 0.77 to 1.24, low-certainty evidence), RR of remission 0.81 (95% CI 0.39 to 1.71, very low-certainty evidence). The number of adverse events was similar in both groups (low-certainty evidence). We did not identify any eligible study comparing SGA with another SGA or with psychotherapy. Two RCTs and five non-randomised studies reported adverse event data on a total of 249 participants who received bupropion, fluoxetine, escitalopram, duloxetine, nefazodone, reboxetine, light therapy, or placebo. We were only able to obtain crude rates of adverse events, therefore caution is advised regarding interpretation of this information. Between 0% and 100% of participants who received an SGA suffered an adverse event, and between 0% and 25% of participants withdrew from the study due to adverse events. AUTHORS' CONCLUSIONS: Evidence for the effectiveness of SGAs is limited to one small trial of fluoxetine compared with placebo showing a non-significant effect in favour of fluoxetine, and two small trials comparing fluoxetine against light therapy suggesting equivalence between the two interventions. The lack of available evidence precluded us from drawing any overall conclusions on the use of SGAs for SAD. Further, larger RCTs are required to expand and strengthen the evidence base on this topic, and should also include comparisons with psychotherapy and other SGAs. Data on adverse events were sparse, and a comparative analysis was not possible. The data we obtained on adverse events is therefore not robust, and our confidence in the data is limited. Overall, up to 25% of participants treated with SGAs for SAD withdrew from the study early due to adverse events.

Effects of fluoxetine on functional outcomes after acute stroke (FOCUS): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Results of small trials indicate that fluoxetine might improve functional outcomes after stroke. The FOCUS trial aimed to provide a precise estimate of these effects. METHODS: FOCUS was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were aged 18 years or older, had a clinical stroke diagnosis, were enrolled and randomly assigned between 2 days and 15 days after onset, and had focal neurological deficits. Patients were randomly allocated fluoxetine 20 mg or matching placebo orally once daily for 6 months via a web-based system by use of a minimisation algorithm. The primary outcome was functional status, measured with the modified Rankin Scale (mRS), at 6 months. Patients, carers, health-care staff, and the trial team were masked to treatment allocation. Functional status was assessed at 6 months and 12 months after randomisation. Patients were analysed according to their treatment allocation. This trial is registered with the ISRCTN registry, number ISRCTN83290762. FINDINGS: Between Sept 10, 2012, and March 31, 2017, 3127 patients were recruited. 1564 patients were allocated fluoxetine and 1563 allocated placebo. mRS data at 6 months were available for 1553 (99·3%) patients in each treatment group. The distribution across mRS categories at 6 months was similar in the fluoxetine and placebo groups (common odds ratio adjusted for minimisation variables 0·951 [95% CI 0·839-1·079]; p=0·439). Patients allocated fluoxetine were less likely than those allocated placebo to develop new depression by 6 months (210 [13·43%] patients vs 269 [17·21%]; difference 3·78% [95% CI 1·26-6·30]; p=0·0033), but they had more bone fractures (45 [2·88%] vs 23 [1·47%]; difference 1·41% [95% CI 0·38-2·43]; p=0·0070). There were no significant differences in any other event at 6 or 12 months. INTERPRETATION: Fluoxetine 20 mg given daily for 6 months after acute stroke does not seem to improve functional outcomes. Although the treatment reduced the occurrence of depression, it increased the frequency of bone fractures. These results do not support the routine use of fluoxetine either for the prevention of post-stroke depression or to promote recovery of function. FUNDING: UK Stroke Association and NIHR Health Technology Assessment Programme.

Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression.

BACKGROUND: We compared transcranial direct-current stimulation (tDCS) with a selective serotonin-reuptake inhibitor for the treatment of depression. METHODS: In a single-center, double-blind, noninferiority trial involving adults with unipolar depression, we randomly assigned patients to receive tDCS plus oral placebo, sham tDCS plus escitalopram, or sham tDCS plus oral placebo. The tDCS was administered in 30-minute, 2-mA prefrontal stimulation sessions for 15 consecutive weekdays, followed by 7 weekly treatments. Escitalopram was given at a dose of 10 mg per day for 3 weeks and 20 mg per day thereafter. The primary outcome measure was the change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score (range, 0 to 52, with higher scores indicating more depression). Noninferiority of tDCS versus escitalopram was defined by a lower boundary of the confidence interval for the difference in the decreased score that was at least 50% of the difference in the scores with placebo versus escitalopram. RESULTS: A total of 245 patients underwent randomization, with 91 being assigned to escitalopram, 94 to tDCS, and 60 to placebo. In the intention-to-treat analysis, the mean (±SD) decrease in the score from baseline was 11.3±6.5 points in the escitalopram group, 9.0±7.1 points in the tDCS group, and 5.8±7.9 points in the placebo group. The lower boundary of the confidence interval for the difference in the decrease for tDCS versus escitalopram (difference, -2.3 points; 95% confidence interval [CI], -4.3 to -0.4; P=0.69) was lower than the noninferiority margin of -2.75 (50% of placebo minus escitalopram), so noninferiority could not be claimed. Escitalopram and tDCS were both superior to placebo (difference vs. placebo, 5.5 points [95% CI, 3.1 to 7.8; P<0.001] and 3.2 points [95% CI, 0.7 to 5.5; P=0.01], respectively). Patients receiving tDCS had higher rates of skin redness, tinnitus, and nervousness than did those in the other two groups, and new-onset mania developed in 2 patients in the tDCS group. Patients receiving escitalopram had more frequent sleepiness and obstipation than did those in the other two groups. CONCLUSIONS: In a single-center trial, tDCS for the treatment of depression did not show noninferiority to escitalopram over a 10-week period and was associated with more adverse events. (Funded by Fundação de Amparo à Pesquisa do Estado de São Paulo and others; ELECT-TDCS ClinicalTrials.gov number, NCT01894815 .).

The Effect of Second-Generation Antidepressant Treatment on the Memory of Patients With Major Depressive Disorder: A Meta-analysis Study With Structural Equation Models.

BACKGROUND: Major depressive disorder (MDD) has been linked to episodic memory deficits that may be improved after pharmacological treatment, but it is unclear whether there is a class of antidepressants that is more effective than others to ameliorate these deficits in MDD. In addition, the possible effects of clinical and sociodemographic variables on the improvement of MDD memory deficits after pharmacological treatment are currently unknown. Our aims are to study the possible neuropsychological effects of second-generation antidepressant classes on the episodic memory of MDD patients and to study the potential effects of clinical and demographic variables as moderators of the effects of antidepressants on the memory of depressed patients through a meta-analysis approach. PROCEDURES: Nine articles were included in our study. A structural equation model meta-analysis was performed. RESULTS: Our results suggest that selective serotonin reuptake inhibitors and serotonine-noradrenaline reuptake inhibitors would bring about a substantial improvement in the memory of depressed patients, whereas other antidepressant classes would cause rather modest effects. Our results also suggest that clinical and demographic variables play a very important role as mediators of memory improvement after MDD treatment. Thus, a relatively low level of symptom severity, a high degree of clinical improvement, a younger age, and more years of education were positively related to memory improvement after MDD treatment. CONCLUSIONS: Although antidepressant class is an important variable linked to memory improvement in MDD, overall, the degree of memory amelioration in depression is very closely related to clinical and demographic variables of patients with depression.

Trazodone as an Alternative Treatment for Neuroleptic-Associated Akathisia: A Placebo-Controlled, Double-Blind, Clinical Trial.

BACKGROUND: Akathisia is a distressing extrapyramidal complication that follows the use of antipsychotic medications. Early treatment of neuroleptic-associated akathisia (NAA) is of great importance because it may lead to poor therapeutic response and ultimately treatment noncompliance. Considering the lack of adequate response of some patients to conventional treatments and the assumption that serotonin might be involved in the pathophysiology of the disease in addition to dopaminergic mechanisms, we aimed to evaluate the effectiveness of trazodone as an antidepressant agent with strong antagonistic effects on serotonin receptors in the treatment of akathisia. METHODS: In a double-blind clinical trial, 52 patients receiving antipsychotic medications who were diagnosed to have mild to severe NAA using Barnes Akathisia Rating Scale were treated with trazodone 50 mg daily for 5 days and compared with the placebo control group. RESULTS: Patients receiving trazodone did not show a significant difference compared with the control group in terms of the severity of akathisia symptoms until the third day of the study. In contrast, at the end of the fifth day, there was a significant improvement in objective (P = 0.01) and subjective (P = 0.001) symptoms of akathisia and the global clinical assessment of akathisia scale (P = 0.001). Moreover, there was no clear difference between trazodone and placebo group in terms of adverse effects. CONCLUSIONS: Considering the antagonistic effect of trazodone on postsynaptic 5-hydroxytryptamine2A receptors as a possible mechanism of efficacy of this agent in the treatment of NAA, this study suggests that trazodone might be an effective and relatively safe drug.

Citalopram in Treatment of Pregnant Women With Panic Disorder: A Retrospective Study.

PURPOSE: The study aimed to investigate efficacy of citalopram in pregnant women with panic disorder. METHODS: The study data with 22 patients were retrospectively collected from clinical registers. The study was conducted in patients with and without comorbid major depression. The patients were evaluated using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, the Clinical Global Impression-Improvement Scale, the Hamilton Depression Rating Scale, and the Hamilton Rating Scale for Anxiety. FINDINGS: The Hamilton Depression Rating Scale and the Hamilton Rating Scale for Anxiety scores were significantly reduced after treatment with citalopram at 20 mg/d for 8 weeks. The response rate based on Clinical Global Impression-Improvement Scale was 68.2%. Patients with comorbid major depression seemed to have a lower response rate compared with nondepressed patients. IMPLICATIONS: The current study suggests that citalopram may be beneficial for in pregnant women with panic disorder.

Antidepressants and the Risk of Cardiovascular Events in Elderly Affected by Cardiovascular Disease: A Real-Life Investigation From Italy.

PURPOSE: The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. METHODS: A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. FINDINGS: Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. IMPLICATIONS: Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.

Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternal-fetal pharmacokinetics of fexofenadine. METHODS: Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. RESULTS: The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0-∞R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(-)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. CONCLUSIONS: A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(-)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.

The Cost-Effectiveness of Cognitive Behavioral Therapy Versus Second-Generation Antidepressants for Initial Treatment of Major Depressive Disorder in the United States: A Decision Analytic Model.

Background: Most guidelines for major depressive disorder recommend initial treatment with either a second-generation antidepressant (SGA) or cognitive behavioral therapy (CBT). Although most trials suggest that these treatments have similar efficacy, their health economic implications are uncertain. Objective: To quantify the cost-effectiveness of CBT versus SGA for initial treatment of depression. Design: Decision analytic model. Data Sources: Relative effectiveness data from a meta-analysis of randomized controlled trials; additional clinical and economic data from other publications. Target Population: Adults with newly diagnosed major depressive disorder in the United States. Time Horizon: 1 to 5 years. Perspectives: Health care sector and societal. Intervention: Initial treatment with either an SGA or group and individual CBT. Outcome Measures: Costs in 2014 U.S. dollars, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Results of Base-Case Analysis: In model projections, CBT produced higher QALYs (3 days more at 1 year and 20 days more at 5 years) with higher costs at 1 year (health care sector, $900; societal, $1500) but lower costs at 5 years (health care sector, -$1800; societal, -$2500). Results of Sensitivity Analysis: In probabilistic sensitivity analyses, SGA had a 64% to 77% likelihood of having an incremental cost-effectiveness ratio of $100 000 or less per QALY at 1 year; CBT had a 73% to 77% likelihood at 5 years. Uncertainty in the relative risk for relapse of depression contributed the most to overall uncertainty in the optimal treatment. Limitation: Long-term trials comparing CBT and SGA are lacking. Conclusion: Neither SGAs nor CBT provides consistently superior cost-effectiveness relative to the other. Given many patients' preference for psychotherapy over pharmacotherapy, increasing patient access to CBT may be warranted. Primary Funding Source: Department of Veterans Affairs, National Institute of Mental Health.

Effectiveness of Paroxetine for Poststroke Depression: A Meta-Analysis.

OBJECTIVE: The purpose of our study is to evaluate the efficacy of paroxetine in poststroke depression (PSD) patients by conducting a meta-analysis. METHODS: We searched Web of Science (science and social science citation index), PubMed, the Cochrane Central Register of Controlled Trials, Embase up to August 2019. Randomized controlled trials that paroxetine compared to other antidepressants or control treatments as monotherapy for patients with PSD. RESULTS: This review identified a total of 4 studies including 212 patients. This meta-analysis presented that paroxetine exhibits beneficial efficacy than routine treatment in PSD patients in terms of the reducing score of Hamilton Depression Scale (HAMD). Control treatment is more effective than paroxetine. No significant advantage was found with paroxetine. CONCLUSIONS: The efficacy of paroxetine maybe not very significant compared to other pharmacological and nonpharmacological interventions. Further high quality and large sample size studies are needed to evaluate the efficacy and safety of paroxetine in treating PSD in future.

Trazodone use and risk of dementia: A population-based cohort study.

BACKGROUND: In vitro and animal studies have suggested that trazodone, a licensed antidepressant, may protect against dementia. However, no studies have been conducted to assess the effect of trazodone on dementia in humans. This electronic health records study assessed the association between trazodone use and the risk of developing dementia in clinical practice. METHODS AND FINDINGS: The Health Improvement Network (THIN), an archive of anonymised medical and prescribing records from primary care practices in the United Kingdom, contains records of over 15 million patients. We assessed patients from THIN aged ≥50 years who received at least two consecutive prescriptions for an antidepressant between January 2000 and January 2017. We compared the risk of dementia among patients who were prescribed trazodone to that of patients with similar baseline characteristics prescribed other antidepressants, using a Cox regression model with 1:5 propensity score matching. Patients prescribed trazodone who met the inclusion criteria (n = 4,716; 59.2% female) were older (mean age 70.9 ± 13.1 versus 65.6 ± 11.4 years) and were more likely than those prescribed other antidepressants (n = 420,280; 59.7% female) to have cerebrovascular disease and use anxiolytic or antipsychotic drugs. After propensity score matching, 4,596 users of trazadone and 22,980 users of other antidepressants were analysed. The median time to dementia diagnosis for people prescribed trazodone was 1.8 years (interquartile range [IQR] = 0.5-5.0 years). Incidence of dementia among patients taking trazodone was higher than in matched users of other antidepressants (1.8 versus 1.1 per 100 person-years), with a hazard ratio (HR) of 1.80 (95% confidence interval [CI] 1.56-2.09; p < 0.001). However, our results do not suggest a causal association. When we restricted the control group to users of mirtazapine only in a sensitivity analysis, the findings were very similar to the results of the main analysis. The main limitation of our study is the possibility of indication bias, because people in the prodromal stage of dementia might be preferentially prescribed trazodone. Due to the observational nature of this study, we cannot rule out residual confounding. CONCLUSIONS: In this study of UK population-based electronic health records, we found no association between trazodone use and a reduced risk of dementia compared with other antidepressants. These results suggest that the clinical use of trazodone is not associated with a reduced risk of dementia.

Pharmacokinetic and pharmacodynamic of bupropion: integrative overview of relevant clinical and forensic aspects.

Bupropion is an atypical antidepressant of the aminoketone group, structurally related to cathinone, associated with a wide interindividual variability. An extensive pharmacokinetic and pharmacodynamic review of bupropion was performed, also focusing on chemical, pharmacological, toxicological, clinical and forensic aspects of this drug without a limiting period. Bupropion is a chiral, basic, highly lipophilic drug, clinically used as racemate that undergoes extensive stereoselective metabolism. Its major active metabolites, hydroxybupropion, threohydrobupropion, and erythrohydrobupropion reach higher plasma concentrations than bupropion. Bupropion exerts its effects mainly by inhibiting dopamine and norepinephrine reuptake and by blocking several nicotinic receptors. Recent reports highlight recreational use of bupropion via intranasal insufflation and intravenous use. Seizures, insomnia, agitation, headache, dry mouth, and nausea are some of the reported adverse effects. Neurologic effects are major signs of intoxication that should be carefully managed. Finally, the characterization of the polymorphic enzymes involved in the metabolism of bupropion is essential to understand factors that may influence the interindividual and intraindividual variability in bupropion metabolite exposure, including the evaluation of potential drug-drug interactions and pharmacogenetic implications.

The Course of Adverse Events in Venlafaxine XR Treatment in Generalized Anxiety Disorder.

PURPOSE: The time course of adverse events is an important factor for patient management. Clinicians are better able to prepare patients for specific adverse events, which leads to better treatment adherence. METHODS: Adverse events were followed longitudinally for 6 months during the open-label phase of a relapse prevention trial with 264 patients with generalized anxiety disorder. Adverse events were assessed at each treatment visit using a 21-item checklist. Logistic regression modeling, continuation ratio modeling, and hierarchical linear modeling were used to determine whether adverse events led to early attrition and whether adverse events decreased in enrolled patients over time. FINDINGS: Adverse events were found to have decreased highly significantly during treatment. A highly significant race effect was found in that whites had a significantly higher adverse event rate than did nonwhites. Early attrition rates were predicted by presence of nausea and fatigue, late attrition by dizziness, nervousness, and sexual dysfunction. IMPLICATIONS: Our findings provide information for clinicians on the course of adverse events over treatment, useful to prepare patients for treatment adherence.