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Aims: Venlafaxine is used to treat depression worldwide. Previous reviews have demonstrated that venlafaxine lowers scores on depression rating scales, producing statistically significant results but the relevance to patients remains uncertain. Knowledge of the incidence of the adverse effects associated with venlafaxine has previously been based on the results of non-randomised studies. Our primary objective was to assess the risks of adverse events with venlafaxine in the treatment of adults with major depressive disorder in randomised trials., Methods: We searched relevant databases and other sources from inception to 7 March 2024 for randomised clinical trials comparing venlafaxine versus placebo or no intervention in adults with major depressive disorder. Data were synthesised using meta-analysis and Trial Sequential Analysis. The primary outcomes were suicides or suicide attempts, serious adverse events and non-serious adverse events., Results: We included 28 trials randomising 6,253 participants to venlafaxine versus placebo. All results were at high risk of bias, and the certainty of the evidence was very low. All trials assessed outcomes at a maximum of 12 weeks after randomisation. Meta-analysis and Trial Sequential Analysis showed insufficient information to assess the effects of venlafaxine on the risks of suicides or suicide attempts. Meta-analysis showed evidence of harm of venlafaxine versus placebo on serious adverse events (risk ratio: 2.66; 95% confidence interval: 1.67-4.25; p < 0.01; 22 trials), mainly due to a higher risk of sexual dysfunction and anorexia. Meta-analysis showed that venlafaxine also increased the risk of several non-serious adverse events: nausea, dry mouth, dizziness, sweating, somnolence, constipation, nervousness, insomnia, asthenia, tremor and decreased appetite., Conclusions: Short-term results show that venlafaxine has uncertain effects on the risks of suicides but increases the risks of serious adverse events (especially sexual dysfunction and anorexia) and many non-serious adverse events. The long-term effects of venlafaxine for major depressive disorder are unknown. It is a particular cause for concern that there are no data on the long-term adverse effects of venlafaxine given that so many people use these drugs for several years.

Aim: To determine the proportion of referrals to a General Neurology New Patient Clinic which meet the diagnostic criteria of Persistent Postural Perceptual Dizziness (PPPD) and to gauge patient-perceived response to treatment., Methods: Referral letters, n=1315, to a General Neurology New Patient Clinic from 2021-2023 were screened for terms 'dizziness', 'vertigo', 'unsteadiness' and 'vestibular'. A chart review was performed to establish study outcomes., Results: 202 (15.4%) patients were referred with 'dizziness', 'vertigo' or 'unsteadiness', 22 (11%) of which fulfilled the diagnostic criteria. Venlafaxine was offered in 10 (45.5%) patients and conferred ≥50% benefit in 8 (80%). Vestibular physiotherapy improved symptoms by ≥25% in all 7 (100%) patients with access to the intervention. Cognitive behavioural therapy and effective communication of the diagnosis alleviated symptoms by 50% in 3 (14%) patients respectively., Discussion: PPPD is increasingly recognised in patients with chronic vestibular symptoms and can cause significant functional morbidity. Venlafaxine may independently improve symptoms1., Competing Interests: None declared.

Background: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults., Methods: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests., Results: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores., Limitations: The conversion tables should be used with caution when comparing depression severity at the individual level., Conclusions: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales., Competing Interests: Declaration of competing interest The original clinical trial was supported by a Patient-Centered Outcomes Research Institute (PCORI) Award (TRD-1511-33321). Dr. Lenze received additional support from the Taylor Family Institute for Innovative Psychiatric Research at Washington University School of Medicine, as well as the Washington University Institute of Clinical and Translational Sciences grant (UL1TR002345) from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH). Dr. Blumberger reports grants from Canadian Institutes of Health Research (CIHR) and the Temerty family through the Centre for Addiction and Mental Health (CAMH) Foundation during the conduct of the study; nonfinancial support from Magventure (in-kind equipment support for investigator-initiated research); grants from Brainsway (principal investigator of an investigator-initiated study and site principal investigator for sponsored clinical trials), National Institutes of Health (NIH), Brain Canada Foundation, Campbell Family Research Institute, and Patient-Centered Outcomes Research Institute outside the submitted work; received medication supplies for an investigator-initiated trial from Indivior; and has participated in advisory boards for Janssen and Welcony. Dr. Flint has received grant support from the US National Institutes of Health, the Patient-Centered Outcomes Research Institute, the Canadian Institutes of Health Research, Brain Canada, the Ontario Brain Institute, and Alzheimer's Association. Dr. Miller has no financial relationships with commercial interests. Dr. Mulsant received additional support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He holds and receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He currently receives or has received research support from Brain Canada, the CAMH Foundation, the Canadian Institutes of Health Research, and the US National Institutes of Health (NIH); research support from Bristol-Myers Squibb (medications for an NIH-funded clinical trial), Eli Lilly and Company (medications for an NIH-funded clinical trial), Pfizer (medications for an NIH-funded clinical trial), Capital Solution Design LLC (software used in a study funded by CAMH Foundation), and HAPPYneuron (software used in a study funded by Brain Canada). Dr. Lavretsky received support from grants (K24 AT009198, R01 AT008383, and R01 MH114981) from the NIH. Dr. Brown received additional support from the National Institute of Mental Health OPTIMUM NEURO grant (5R01MH114980). Dr. Reynolds receives payment from the American Association of Geriatric Psychiatry as Editor-in-Chief of the American Journal of Geriatric Psychiatry and royalty income for intellectual property as co-inventor of the Pittsburgh Sleep Quality Index. Other authors have no conflict of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299., (© 2024. The Author(s).)

Objective: Migraine, as a primary headache disorder, stands as one of the primary causes of disability worldwide. Consequently, prophylactic treatments are highly recommended for individuals experiencing recurrent migraine episodes. Our study aimed to compare the efficacy and safety profiles of venlafaxine and nortriptyline in the prophylactic management of migraine., Methods: In this single-center, randomized, double-blind clinical trial, 210 migraine patients were allocated into two groups in a 1:1 ratio. One group received venlafaxine (37.5 mg, orally twice daily), while the other group administered nortriptyline (25 mg, orally once daily). A neurologist documented (1) headache intensity using the Visual Analog Scale (VAS) and 6-point Behavioral Rating Scale (BRS-6), (2) headache frequency (per month), and (3) headache duration (in hours) of participants on days 0, 45, and 90 of the intervention., Results: Following the 90-day intervention, a significant decrease was observed in VAS, BRS-6, frequency, and duration of headaches within both groups (all with p-values <0.001). No difference in VAS, BRS-6, or headache durations was observed between the two groups after 45 and 90 days of treatment (all p-values > 0.05). Although the headache frequency exhibited no difference between the groups after 45 days (p-value = 0.097), a significantly lower frequency in the venlafaxine group was observed at day 90 of the intervention (p-value = 0.011). The reductions in attack parameters in the 0-45- and 0-90-day intervals did not meet statistical significance between the two groups (p-values > 0.05). 77.0 % of the participants in the venlafaxine group and 79.2 % in the nortriptyline group experienced a minimum of 50 % improvement in all attack parameters. Venlafaxine demonstrated a statistically significant lower incidence of adverse reactions in comparison to nortriptyline (p-value = 0.005). A total of 33 adverse drug reactions were documented in the venlafaxine group and 53 in the nortriptyline group, with insomnia observed in the former and xerostomia in the latter as the most prevalent side effects., Conclusions: Venlafaxine and nortriptyline demonstrate clinically significant and comparable therapeutic efficacy for migraine patients in reducing the intensity, frequency, and duration of headache attacks. Venlafaxine may be preferred to nortriptyline in the context of migraine preventive treatment under comparable conditions due to its lower incidence of adverse effects., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Venlafaxine is frequently prescribed for patients with depression. To control the concentration of venlafaxine within the therapeutic window for the best treatment effect, a model to predict venlafaxine concentration is necessary., Aim: Our objective was to develop a prediction model for venlafaxine concentration using real-world evidence based on machine learning and deep learning techniques., Method: Patients who underwent venlafaxine treatment between November 2019 and August 2022 were included in the study. Important variables affecting venlafaxine concentration were identified using a combination of univariate analysis, sequential forward selection, and machine learning techniques. Predictive performance of nine machine learning and deep learning algorithms were assessed, and the one with the optimal performance was selected for modeling. The final model was interpreted using SHapley Additive exPlanations., Results: A total of 330 eligible patients were included. Five influential variables that affect venlafaxine concentration were venlafaxine daily dose, sex, age, hyperlipidemia, and adenosine deaminase. The venlafaxine concentration prediction model was developed using the eXtreme Gradient Boosting algorithm (R 2  = 0.65, mean absolute error = 77.92, root mean square error = 93.58). In the testing cohort, the accuracy of the predicted concentration within ± 30% of the actual concentration was 73.49%. In the subgroup analysis, the prediction accuracy was 69.39% within the recommended therapeutic range of venlafaxine concentration within ± 30% of the actual value., Conclusion: The XGBoost model for predicting blood concentration of venlafaxine using real-world evidence was developed, guiding the adjustment of regimen in clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Tramadol and venlafaxine share similar pharmacological characteristics that may allow for overlapping therapeutic indications for them. The objective of this study was to compare the efficacy of venlafaxine and naltrexone in the treatment of tramadol abuse. This comparative trial included 95 patients with tramadol abuse who were detoxified for 2 weeks. Twenty-eight participants underwent the maintenance phase, while the remaining participants (n = 67) dropped out. The patients were randomized to use 50 mg/day of naltrexone or 225 mg/day of venlafaxine for 8 weeks. All participants were interviewed using SCID-I (DSM-IV-TR) criteria for diagnosing substance use and other psychiatric disorders. The proportion of relapsed patients was comparable between the naltrexone and venlafaxine groups (29.4% vs. 30.4%, P  = 0.9). However, participants in the venlafaxine group stayed in treatment longer than participants in the naltrexone group, and the difference was significant (22.9 ± 7.89 days vs. 16.9 ± 3.4 days, P = 0.01). Only psychiatric comorbidity was found to be significantly associated with retention in treatment (80% vs. 22%, P  = 0.005). Venlafaxine is as effective as naltrexone in preventing relapse in patients with tramadol abuse. Venlafaxine was more effective than naltrexone in treatment retention., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Serotonin norepinephrine reuptake inhibitors (SNRIs) have been postulated to afford benefits in alleviating anhedonia and amotivation. This post hoc pooled analysis evaluated the effect of venlafaxine XR, an SNRI, on these symptoms in patients with major depressive disorder (MDD)., Methods: Data was pooled from five short-term randomized, placebo-controlled studies of venlafaxine XR for the treatment of MDD, comprising 1087 (venlafaxine XR, n = 585; placebo, n = 502) adult subjects. The change from baseline score in the MADRS anhedonia factor (based on items 1 [apparent sadness], 2 [reported sadness], 6 [concentration difficulties], 7 [lassitude], and 8 [inability to feel]) for anhedonia, and in motivational deficits (based on 3 items of HAM-D17: involvement in work and activities, psychomotor retardation, and energy level [ie, general somatic symptoms]) for amotivation, were measured through 8 weeks. Mixed model repeated measures (MMRMs) were used to analyze changes over time and ANCOVA to analyze the change from baseline at week 8 with LOCF employed to handle missing data., Results: At the end of 8 weeks, the change from baseline was significantly greater in patients on venlafaxine XR in both anhedonia (mean, 95% CI: -2.73 [-3.63, -1.82], p  < 0.0001) and amotivation scores (mean, 95% CI: -0.78 [-1.04, -0.52], p  < 0.0001) than those on placebo. For both measures, the between-group separation from baseline was statistically significant starting from week 2 onwards, and it increased over time., Conclusion: This analysis demonstrates that venlafaxine XR is effective in improving symptoms of anhedonia and motivational deficits in patients with MDD.

Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to treatment, falling into the category of treatment-resistant depression (TRD). This underscores the need for the exploration of novel therapeutic options. Our work aims to study the effect of chronic administration of the pyridoindole derivative SMe1EC2M3, a triple reuptake inhibitor, and the combination of zoletil and venlafaxine under conditions of stress induced by a 4-week chronic mild stress (CMS) procedure in Wistar-Kyoto male rats as an animal model of TRD. Therefore, we investigated the possible effect of the selected compounds in four experimental groups, i.e., stress + vehicle, stress + venlafaxine, stress + zoletil + venlafaxine and stress + SMe1EC2M3. The following variables were assessed: anhedonia in sucrose preference test (SPT), spontaneous locomotion and exploration in open field test (OF), anxiety-like behavior in elevated plus maze test (EPM), motivation and depressive-like behavior in forced swim test (FST) and nociception in tail flick test. We also evaluated cognition, particularly recognition memory, in the novel object recognition test (NOR). Sucrose preference was significantly increased in the SMe1EC2M3 group ( p < 0.05) in comparison with the venlafaxine animals. In the OF, we observed a significantly higher number of entries into both the central and peripheral zones in the venlafaxine ( p < 0.05 central zone; p ≤ 0.05 periphery zone) and SMe1EC2M3 ( p < 0.05 central zone; p < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST ( p < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group ( p < 0.05) compared to the control and venlafaxine groups. Analyses of the tail flick test showed a significant increase in reaction time to painful stimuli in the SMe1EC2M3 group ( p < 0.05) in comparison to both the control and venlafaxine groups. Our findings suggest that SMe1EC2M3 has the potential to ameliorate some behavioral changes associated with TRD, and the venlafaxine + zoletil combination treatment was not a promising treatment alternative in the animal model of TRD.

In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine., (© 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Research on long-term pharmacotherapy for trauma-affected refugees is scarce. The purpose of this follow-up study of a randomised trial was to investigate the effects of sertraline compared to venlafaxine in combination with psychotherapy, 6 and 18 months after end of trial., Method: The primary outcome was PTSD symptoms, measured by the Harvard Trauma Questionnaire (HTQ). The secondary outcomes included: Hopkins Symptom Checklist-25 (HSCL-25), somatisation items of the Symptoms Checklist-90 (SCL), pain on a visual analogue scale, well-being on the WHO-5, Sheehan Disability Scale, Hamilton Depression and Anxiety scales and Global Assessment of Functioning. Moreover, the shorter version of the Recent Life Events (IRLE) was adopted to obtain information regarding the patients' treatment and life events between the follow-up periods., Results: Out of 195 patients eligible for intention-to-treat analyses during trial, 116 participated in the 6-month follow-up and 97 participated in the 18-month follow-up. The results of our intention-to-treat analyses revealed no significant long-term differences between the groups on the primary outcome assessing PTSD symptoms (HTQ). For the secondary outcomes significant differences were found at the 18-month follow-up in favour of venlafaxine assessing symptoms of anxiety, depression and somatisation (HSCL-25 and SCL), although only in intention-to-treat and not per-protocol analyses., Conclusions: No conclusions could be drawn due to conflicting results between our intention-to-treat and per-protocol analyses.

Background: Depressive episodes in adolescents are often accompanied by various physical symptoms, but few studies have explored the association between depression and fever, This case study is the first to report the relationship between unexplained recurrent high fever and depression., Case Presentation: H is a 15 year old adolescent female currently in junior year. 2 + months ago, H gradually felt depressed after a class change. Around the time, the patient suddenly developed chills with no obvious trigger and fever. H was treated with anti-infective and anti-viral treatments all of which did not show significant improvement. No significant abnormality was seen in any of the related examinations. Considering that the patient's anxiety, depression and somatic symptoms were obvious during the course of the disease, she was given venlafaxine hydrochloride extended-release capsule 75 mg/d; tandospirone citrate capsule 10 mg Bid; alprazolam tablets 0.4 mg qn to improve mood and sleep; supplemented with transcranial repetitive magnetic stimulation therapy 2 times/d; visible light therapy 1 time/d and psychological counseling once. Over the 6 days of treatment, the patient's body temperature gradually returned to the normal range and her mood improved significantly., Conclusion: Depression should be considered a potential cause of unexplained recurrent fevers in adolescents, even when the temperature is significantly outside the normal range., (© 2024. The Author(s).)

Introduction: Recent publications relate the presence of hypoglycemia in venlafaxine (VLX) poisoning depending on the dose. Our aim was to analyze the clinical characteristics of patients who presented hypoglycemia induced by VLF overdose., Patients and Methods: Retrospective study carried out in the Balearic Islands (2020-2023)., Inclusion Criteria: serum concentrations of VLX + O-desmethyl-venlafaxine (O-VLX)>800 ng/mL. The characteristics of patients with and without hypoglycemia were compared., Results: Twenty-one patients were included, 8 (38.1%) with hypoglycemia. No differences were found in the doses referred to in both groups. Peak concentrations of VLX + O-VLX (ng/mL) were 9,783 [4,459-17,976] in patients with hypoglycemia and 1,413 [930-1,719] in patients without hypoglycemia (p<0.0001). The presence of hypoglycemia was associated with: lower age and level of consciousness; and higher frequency of suicide attempts, seizures, mydriasis, tachycardia and serotonin syndrome, invasive respiratory support, fluid therapy and ICU admission (p<0.05)., Conclusions: The detection of hypoglycemia in a VLX overdose case is a readily available marker to suspect the severity of the patient. In any case, serum concentrations when available allow us to confirm intoxication., (Copyright © 2023. Published by Elsevier España, S.L.U.)

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = -0.32, p = 0.0023, n = 88) and remission (r = -0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression., (© 2024. The Author(s).)

Aims: To explore the pharmacological treatment of vascular depression (VaDep) and whether the blood levels of neurotransmitters can reflect the VaDep severity., Methods: VaDep patients with somatic symptoms were enrolled and randomly received venlafaxine + tandospirone (Combined Group) or venlafaxine (Monotherapy Group). The treatment efficacy was assessed by Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Patient Health Questionnaire-15 (PHQ-15). The levels of blood monoamine neurotransmitters were measured by enzyme-linked immunosorbent assay., Results: Both groups reported a progressive decrease in HAMD, HAMA, and PHQ-15 scores to below the baseline after the respective treatment. Compared with the Monotherapy Group, the Combined Group reported a significant decrease in HAMD score at week 2 and markedly lower HAMA and PHQ-15 scores at weeks 1, 2, 4, and 8. Both groups showed a decrease in the levels of blood monoamine neurotransmitters at weeks 4 and 8 when compared with the baseline. A strong positive association was evident between the plasma 5-HT levels and the HAMD score., Conclusion: The combined therapy rapidly acts on VaDep comorbid with anxiety and somatic symptoms and significantly alleviates the anxiety and somatic symptoms. The plasma levels of 5-HT may serve as potential objective candidates in evaluating VaDep severity and the efficacy of the undertaken treatment regimen., (© 2024 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Introduction: The selective serotonin and norepinephrine reuptake inhibitor venlafaxine is among the most prescribed antidepressant drugs worldwide and, according to guidelines, its dose titration should be guided by drug-level monitoring of its active moiety (AM) which consists of venlafaxine (VEN) plus active metabolite O-desmethylvenlafaxine (ODV). This indication of therapeutic drug monitoring (TDM), however, assumes a clear concentration/effect relationship for a drug, which for VEN has not been systematically explored yet., Objectives: We performed a systematic review and meta-analysis to investigate the relationship between blood levels, efficacy, and adverse reactions in order to suggest an optimal target concentration range for VEN oral formulations for the treatment of depression., Methods: Four databases (MEDLINE (PubMed), PsycINFO, Web of Science Core Collection, and Cochrane Library) were systematically searched in March 2022 for relevant articles according to a previously published protocol. Reviewers independently screened references and performed data extraction and critical appraisal., Results: High-quality randomized controlled trials investigating concentration/efficacy relationships and studies using a placebo lead-in phase were not found. Sixty-eight articles, consisting mostly of naturalistic TDM studies or small noncontrolled studies, met the eligibility criteria. Of them, five cohort studies reported a positive correlation between blood levels and antidepressant effects after VEN treatment. Our meta-analyses showed (i) higher AM and (ii) higher ODV concentrations in patients responding to VEN treatment when compared to non-responders (n = 360, k = 5). AM concentration-dependent occurrence of tremor was reported in one study. We found a linear relationship between daily dose and AM concentration within guideline recommended doses (75-225 mg/day). The population-based concentration ranges (25-75% interquartile) among 11 studies (n = 3200) using flexible dosing were (i) 225-450 ng/ml for the AM and (ii) 144-302 ng/ml for ODV. One PET study reported an occupancy of 80% serotonin transporters for ODV serum levels above 85 ng/ml. Based on our findings, we propose a therapeutic reference range for AM of 140-600 ng/ml., Conclusion: VEN TDM within a range of 140 to 600 ng/ml (AM) will increase the probability of response in nonresponders. A titration within the proposed reference range is recommended in case of non-response at lower drug concentrations as a consequence of VEN's dual mechanism of action via combined serotonin and norepinephrine reuptake inhibition. Drug titration towards higher concentrations will, however, increase the risk for ADRs, in particular with supratherapeutic drug concentrations., (© 2023. The Author(s).)

Major depressive disorder (MDD) is a highly prevalent psychiatric disorder, but chances for remission largely decrease with each failed treatment attempt. It is therefore desirable to assign a given patient to the most promising individual treatment option as early as possible. We used a polygenic score (PGS) informed electroencephalography (EEG) data-driven approach to identify potential predictors for MDD treatment outcome. Post-hoc we conducted exploratory analyses in order to understand the results in depth. First, an EEG independent component analysis produced 54 functional brain networks in a large heterogeneous cohort of psychiatric patients (n = 4,045; 5-84 yrs.). Next, the network that was associated to PGS for antidepressant-response (PRS-AR) in an independent sample (n = 722) was selected: an age-related posterior alpha network that explained >60 % of EEG variance, and was highly stable over recording time. Translational analyses were performed in two other independent datasets to examine if the network was predictive of psychopharmacotherapy (n = 535) and/or repetitive transcranial magnetic stimulation (rTMS) and concomitant psychotherapy (PT; n = 186) outcome. The network predicted remission to venlafaxine (p = 0.015), resulting in a normalized positive predicted value (nPPV) of 138 %, and rTMS + PT - but in opposite direction for women (p = 0.002) relative to men (p = 0.018) - yielding a nPPV of 131 %. Blinded out-of-sample validations for venlafaxine (n = 29) and rTMS + PT (n = 36) confirmed the findings for venlafaxine, while results for rTMS + PT could not be replicated. These data suggest the existence of a relatively stable EEG posterior alpha aging network related to PGS-AR that has potential as MDD treatment predictor., Competing Interests: Declaration of Competing Interest MA is unpaid chairman of the Brainclinics Foundation, a minority shareholder in neuroCare Group (Munich, Germany), and a co-inventor on 4 patent applications related to EEG, neuromodulation and psychophysiology, but receives no royalties related to these patents. EG is founder and receives income as CEO and chairman for Brain Resource Ltd. and he has stock options in Brain Resource Ltd. All other authors declare no competing financial or non-financial interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Venlafaxine has been demonstrated to treat diseases such as social anxiety disorder and depression. Most of antidepressants including venlafaxine have a certain effect, but significant side effects. Therefore, it is necessary for us to research the development of novel antidepressants for effective treatment in practice. MicroRNA-204 (miR-204) is highly expressed in brain tissue, and plays a critical role in the synaptic plasticity of hippocampal neurons in rats. However, the underlying molecular mechanism of miR-204 remains unclear to date, this study aims to offer unique insights into depression and provide a theoretical basis for clinical physicians., Methods: A chronic social defeat stress (CSDS) was initially adopted for establishing a mice model of depression in this research and depression-like behaviors were evaluated by a series of behavioral experiments including the sucrose preference test (SPT), the tail suspension test (TST), the forced swim test (FST) and the social interaction test (SIT). Quantitative real-time reverse transcription PCR (qRT-PCR) was also conducted to test the expression levels of miR-204 and BDNF in the hippocampus of mice. Finally, gene interference of miR-204-5p was further adopted to test whether miR-204-5p played an effective role in the antidepressant effects of venlafaxine in mice., Results: Our data implicated that CSDS significantly increased the miR-204-5p but not miR-204-3p levels in the hippocampus of mice. The treatment of venlafaxine obviously relieved depression- like behaviors of CSDS-induced mice. The usage of venlafaxine abolished the increasing effects on the expression of miR-204-5p but up-regulated the BDNF expression level in CSDS-exposured mice. More importantly, we found that genetic overexpression of miR-204-5p decreased the reverse effects of venlafaxine on depressive-like behaviors and genetic knockdown of hippocampal miR-204-5p relieved the depressive-like behaviors and neurogenesis in CSDS-induced mice., Conclusion: miR-204-5p played an effective role in the antidepressant effects of venlafaxine in CSDS-induced mice., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To investigate the relationship between lean muscle mass and treatment response in treatment-resistant late-life depression (TR-LLD). We hypothesized that lower lean muscle mass would be associated with older age, higher physical comorbidities, higher depressive symptom severity, and poorer treatment response., Design: Secondary analysis of a randomized, placebo-controlled trial., Setting: Three academic hospitals in the United States and Canada., Participants: Adults aged 60+ years with major depressive disorder who did not remit following open treatment with venlafaxine extended-release (XR) (n = 178)., Measurements: We estimated lean muscle mass using dual-energy X-ray absorptiometry (DEXA) scans prior to and following randomized treatment with aripiprazole or placebo added to venlafaxine XR. Multivariate regressions estimated influence of demographic and clinical factors on baseline lean muscle mass, and whether baseline lean muscle mass was associated with treatment response, adjusted for treatment arm., Results: Low lean muscle mass was present in 22 (12.4%) participants. Older age and female sex, but not depressive symptom severity, were independently associated with lower lean muscle mass at baseline. Marital status, baseline depressive symptom severity, and treatment group were associated with improvement of depressive symptoms in the randomized treatment phase. Baseline lean muscle mass was not associated with improvement, regardless of treatment group., Conclusion: As expected, older age and female sex were associated with lower lean muscle mass in TR-LLD. However, contrary to prior results in LLD, lean muscle mass was not associated with depression severity or outcome. This suggests that aripiprazole augmentation may be useful for TR-LLD, even in the presence of anomalous body composition.clinicaltrials.gov Identifier: NCT00892047.

Background: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines., Objectives: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis., Search Methods: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022., Selection Criteria: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo., Data Collection and Analysis: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses., Main Results: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low., Authors' Conclusions: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Background: Since insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether early insomnia improvement (EII) predicted treatment outcome in psychotic depression (PD) and examined if there was an interaction effect between EII and treatment type to assess if findings were treatment-specific., Methods: This study is a secondary analysis of a randomized trial comparing 7 weeks treatment with the antidepressants venlafaxine, imipramine and venlafaxine plus the antipsychotic quetiapine in PD ( n = 114). Early insomnia improvement, defined as ≥20% reduced insomnia after 2 weeks, was assessed by the Hamilton Rating Scale for Depression (HAM-D-17). Associations between EII and treatment outcome were examined using logistic regressions. Subsequently, we added interaction terms between EII and treatment type to assess interaction effects. The predictive value of EII was compared with early response on overall depression (≥20% reduced HAM-D-17 score after 2 weeks)., Results: EII was associated with response (odds ratio [OR], 7.9; 95% confidence interval [CI], 2.7-23.4; P = <0.001), remission of depression (OR, 6.1; 95% CI, 1.6-22.3; P = 0.009), and remission of psychosis (OR, 4.1; 95% CI, 1.6-10.9; P = 0.004). We found no interaction effects between EII and treatment type on depression outcome. Early insomnia improvement and early response on overall depression had a comparable predictive ability for treatment outcome., Conclusions: Early insomnia improvement was associated with a positive outcome in pharmacotherapy of PD, regardless of the medication type. Future studies are needed to confirm our findings and to examine the generalizability of EII as predictor in treatment of depression., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: Guidance on Major Depressive Disorder (MDD) treatment in those with comorbid Alcohol Use Disorder (AUD) is limited. We performed a secondary analysis on the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, examining the association between comorbid AUD and depression outcomes., Methods: STAR*D was a real-world effectiveness trial starting with citalopram in level 1. Non-responding participants progressed through 3 other sequential treatment levels with different switch or augmentation options. Antidepressant outcomes were compared between MDD (n = 2826) and comorbid MDD and AUD (n = 864). Logistic regressions were performed to evaluate remission and response predictors in the total STAR*D sample and the AUD-comorbidity interaction., Results: Chi-squared tests showed no significant difference in response or remission rates from depression between groups across treatment levels. Higher Hamilton Rating Scale for Depression (HRSD) score was associated with overall lower odds of remission in treatment level 1 (OR = 0.93, p < 0.001) and 2 (OR = 0.95, p < 0.001), with no significant interaction with comorbid AUD. Higher baseline suicidality had overall lower odds of remission in level 1 (OR = 0.82, p < 0.001) and 2 (OR = 0.1, p < 0.001), but with comorbid AUD compared to no AUD, suicidality increased odds of level 1 remission (OR = 1.30, p = 0.012). In comorbid AUD in level 2, venlafaxine was associated with lower odds of remission (OR = 0.13, p = 0.013) and response (OR = 0.12, p = 0.006); bupropion with lower odds of response (OR = 0.22, p = 0.024)., Limitations: Open label study design and lack of alcohol use data., Conclusions: Comorbid AUD may interact with predictors of antidepressant response in MDD and using venlafaxine or bupropion may be less effective. Addressing this comorbidity requires unique assessment and treatment approaches., Competing Interests: Declaration of competing interest VMT has received research support from the Physicians' Services Incorporated Foundation, the Labatt Family Network for Research on the Biology of Depression, and the CAMH Discovery Fund. DY has received research grants from the University of Texas at Arlington. CRW has received research funding from the Brain and Behavior Research Foundation and consulting fees from GoodCap Pharmaceuticals Inc. BDMJ, GW, and BLF have none declared. MES receives research funding through the Canadian Institutes of Health Research, the Ontario Ministry of Health and Long-Term Care, the Centre for Addiction and Mental Health, and the Canadian Cancer Society. DMB has received grants or contracts from Brainsway and MagVenture and payment or honoraria from Welcony Inc. ZJD has received grants from the National Institutes of Mental Health, the Canadian Institutes of Health Research, and Brainsaway Inc. He is on the scientific advisory board of Brainsway Inc. and Gazebo Health Inc. He has received equipment and materials from Brainsway Inc. and MagVenture Inc. DV received research support from CIHR, the Temerty Centre and through the Centre for Addiction and Mental Health, and holds the Labatt Family Professorship in Depression Biology, a University Named Professorship at the University of Toronto., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Mental health disorders, especially depressive and anxiety disorders, are associated with substantial health-related burden. While the second-generation antidepressants are widely accepted as first-line pharmacological treatment for major depressive disorder (MDD), patient response to such treatment is variable, with more than half failing to achieve complete remission, and residual symptoms are frequently present., Areas Covered: Here, the pharmacodynamics of venlafaxine XR are reviewed in relation to its role as both a selective serotonin reuptake inhibitor (SSRI) and a serotonin-norepinephrine-reuptake inhibitor (SNRI), and we look at how these pharmacodynamic properties can be harnessed to guide clinical practice, asking the question 'is it possible to develop a symptom-cluster-based approach to the treatment of MDD with comorbid anxiety utilizing venlafaxine XR?.' Additionally, three illustrative clinical cases provide practical examples of the utility of venlafaxine-XR in real-world clinical practice. The place of venlafaxine XR in managing fatigue/low energy, a frequent residual symptom in MDD, is explored using pooled data from clinical trials of venlafaxine XR., Expert Opinion: Venlafaxine XR should be considered as a first-line treatment for MDD with or without comorbid anxiety, and there are clear pharmacodynamic signals supporting a symptom cluster-based treatment paradigm for venlafaxine XR.

Objective: Vestibular migraine is in the process of recognition as an individual clinical entity. At present, no guidelines exist for its management. This study aimed to conduct a systematic review and meta-analysis to determine the effectiveness of available prophylactic medication., Method: A literature search was performed using PubMed, Ovid and Embase databases. Qualitative and quantitative analysis were performed as well as risk of bias analysis. Meta-analysis for the mean differences for pre- and post-treatment impact based on Dizziness Handicap Inventory and Vertigo Symptom Scale were performed. Proportionate transformation meta-analysis for the successful event rate based on complete symptoms control was explored., Results: Thirteen publications were identified: 3 were randomised, controlled trials and 10 were non-randomised, controlled trials. Propranolol and venlafaxine improved the Vertigo Symptom Scale score by -13.31 points and -4.16 points, respectively, and the Dizziness Handicap Inventory score by -32.24 and -21.24, respectively. Only propranolol achieved statistically significant impact with 60 per cent of patients achieving complete symptom control., Conclusion: Propranolol should be offered as the first-line treatment for vestibular migraine followed by venlafaxine. Amitriptyline, flunarizine and cinnarizine showed a trend for symptom improvement, but this was not statistically significant.

Objectives: Depression in persons with epilepsy (PWE) goes undiagnosed and untreated. Despite being common, there are no direct efficacy comparisons of available antidepressants in PWE. Our aim was to compare the effectiveness of Venlafaxine (VEN) and Escitalopram (ESCIT) in comorbid depression in PWE., Methods: In a single-center, prospective, double-blinded randomized controlled trial (RCT) 90 PWE (age ≥18 years) with mild to moderate depression, were randomized in a 1:1 ratio to receive ESCIT (5-20 mg/day) or VEN (37.5-150 mg/day) for 8 weeks. The primary outcome was to study differences in the efficacy, based on the change in scores of the Hamilton depression rating scale (HAM-D) at 8 weeks. Seizure frequency, QOLIE-31, adverse event profile, and medication adherence were secondary outcome measures., Results: Using the NDDI-E scale, we screened 350 PWE, 90 were enrolled. ITT analysis included all participants and the PP analysis included 40 participants to VEN group and 42 to ESCIT group. Baseline mean (±SD) HAM-D scores for both groups were similar (13.53 ± 3.27; 13.02 ± 3.57). The mean difference (95%CI) on HAM-D scores at 8 weeks was found to be significant within both groups (ITT/PP- VEN: 7.75(6.75, 8.79)/7.92 (7.06, 8.78); p < 0.001, ESCIT: 8.21 (7.39, 9.03)/8.23(7.43, 9.04); p < 0.001). However, there was no significant difference in the efficacy of VEN versus ESCIT at 8 weeks. A significant improvement in QOLIE-31 index and seizure frequency was observed from baseline in both the groups. 90% of those on VEN and 92.9% of those using ESCITadhered to the treatment at week 8. Adverse events were more in VEN group than the ESCIT group., Conclusions: This study found that HAMD scores improved significantly in the ESCIT and VEN groups, despite the fact that there was no clinically meaningful difference observed between the two groups. Trials with a larger sample size and longer duration are required to establish whether ESCIT or VEN is superior., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Post-traumatic stress disorder (PTSD) is a mental disorder that can emerge after an individual experiences a traumatic event such as physical abuse, sexual/relationship violence, combat exposure, witnessing death, or serious injury. This study aimed to identify the most suitable drugs for the management of PTSD based on a network meta-analysis (NMA)., Methods: Six databases (Ovid Medline, EMBase, CENTRAL, PsycINFO, Ovid Health and Psychosocial Instruments, and Web of Science) were searched from inception to September 6, 2022., Results: Thirty articles with a total of 5170 participants were included. Compared with placebo, active drugs including olanzapine (SMD = -0.66, 95% CI: -1.19 to -0.13), risperidone (SMD = -0.23, 95% CI: -0.42 to -0.03), quetiapine (SMD = -0.49, 95% CI: -0.93 to -0.04), venlafaxine (SMD = -0.29, 95% CI: -0.42 to -0.16), sertraline (SMD = -0.23, 95% CI: -0.34 to -0.11), paroxetine (SMD = -0.48, 95% CI: -0.60 to -0.36) and fluoxetine (SMD = -0.27, 95% CI: -0.42 to -0.12), significantly reduced the total clinician-administered PTSD scale score., Conclusion: The results of this study support the use of paroxetine, venlafaxine, and quetiapine as first-line treatment for PTSD. In addition, quetiapine is recommended for patients with PTSD affected by symptoms of hyperarousal and re-experience disorder. Clinicians should prescribe medications based on the severity of PTSD symptoms and other conditions to develop the best treatment strategy for this patient population., Competing Interests: Declaration of Competing Interest All other authors declare that they have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Depression is associated with intestinal dysbiosis. Venlafaxine is a commonly used antidepressant in clinical practice as a serotonin and noradrenaline reuptake inhibitor. However, its effects on gut bacteria in depression remain unclear. Here, we established a mouse model of depression induced by chronic unpredictable mild stress (CUMS), and investigated the alterations of venlafaxine on the gut microbiota and potential key bacteria. Our data show that venlafaxine exerts antidepressant effects by restoring the serotonin (5-HT) system and glutamate (Glu) levels in CUMS mice. Moreover, we revealed that venlafaxine altered the diversity of gut bacteria in CUMS mice, and at genus level, Blautia, Oscillibacter, Tyzzerella, Butyricicoccus, and Enterorhabdus are the key bacteria responsible for venlafaxine-ameliorated depression in mice. Among these potential key bacteria, Blautia, Oscillibacter, and Butyricicoccus are correlated significantly with the 5-HT and 5-hydroxyindoleacetic acid levels; while Tyzzerella is correlated markedly with Glu levels. We further show that venlafaxine affected multiple functional metabolic pathways of gut bacteria in mice with CUMS-induced depression. Our results suggest that venlafaxine possibly ameliorates depression via modulating gut bacteria, and found the potential targets of its antidepressant effects., Competing Interests: Conflicts of interest The authors declare that there is no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Studies explicitly reporting data concerning the evaluation of the effect of antidepressants on the periodic leg movements during sleep (PLMS) index obtained by polysomnography were reviewed and selected. A random-effects model meta-analysis was carried out. The level of evidence was also assessed for each paper. Twelve studies were included in the final meta-analysis, seven interventional and five observational. Most studies were characterized by Level III evidence (non-randomized controlled trials), with the exception of four studies, which were classified as Level IV (case series, case-control, or historically controlled studies). Selective serotonin reuptake inhibitors (SSRIs) were used in seven studies. The analysis of the assessments involving SSRIs or venlafaxine showed an overall large effect size, clearly much larger than that obtained with studies using other antidepressants. Heterogeneity was substantial. This meta-analysis confirms the previous reports on the increase in PLMS often associated with the use of SSRIs (and venlafaxine); however, the absent or smaller effect of the other categories of antidepressants needs to be confirmed by more numerous and better controlled studies., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Despite several antidepressant treatments being available in clinics, they are not effective in all patients. In recent years, N-acetylcysteine (NAC) has been explored as adjunctive therapy for many psychiatric disorders, including depression, for its antioxidant properties. Given the promising efficacy of this compound for the treatment of such pathologies, it is fundamental to investigate, at the preclinical level, the ability of the drug to act in the modulation of neuroplastic mechanisms in basal conditions and during challenging events in order to highlight the potential features of the drug useful for clinical efficacy. To this aim, adult male Wistar rats were treated with the antidepressant venlafaxine (VLX) (10 mg/kg) or NAC (300 mg/kg) for 21 days and then subjected to 1 h of acute restraint stress (ARS). We found that NAC enhanced the expression of several immediate early genes, markers of neuronal plasticity in the ventral and dorsal hippocampus, prefrontal cortex and amygdala, and in particular it mediated the acute-stress-induced upregulation of Nr4a1 expression more than VLX. These data suggested the ability of NAC to induce coping strategies to face external challenges, highlighting its potential for the improvement of neuroplastic mechanisms for the promotion of resilience, in particular via the modulation of Nr4a1 .

Purpose: Patient-Reported Outcomes are essential to properly assess treatment effectiveness in randomized clinical trial (RCT) for Major Depressive Disorder (MDD). MDD self-assessment may vary over time depending on change in the meaning of patients' self-evaluation of depression, i.e. Response Shift (RS). Our aim was to investigate RS and its impact on different depression domains in a clinical trial comparing rTMS versus Venlafaxine., Methods: The occurrence and type of RS was determined using Structural Equation Modeling applied to change over time in 3 domains (Sad Mood, Performance Impairment, Negative Self-Reference) of the short-form Beck Depression Inventory (BDI-13) in a secondary analysis of a RCT on 170 patients with MDD treated by rTMS, venlafaxine or both., Results: RS was evidenced in the venlafaxine group in the Negative Self-Reference and Sad Mood domains., Conclusion: RS effects differed between treatment arms in self-reported depression domains in patients with MDD. Ignoring RS would have led to a slight underestimation of depression improvement, depending on treatment group. Further investigations of RS and advancing new methods are needed to better inform decision making based on Patient-Reported Outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Ltd.)

Posttraumatic stress disorder (PTSD) is common, with a lifetime prevalence of approximately 6%. PTSD may develop at least one month after a traumatic event involving the threat of death or harm to physical integrity, although earlier symptoms may represent an acute stress disorder. Symptoms typically involve trauma-related intrusive thoughts, avoidant behaviors, negative alterations of cognition or mood, and changes in arousal and reactivity. Assessing for past trauma in patients with anxiety or other psychiatric illnesses may aid in diagnosing and treating PTSD. The Diagnostic and Statistical Manual of Mental Disorders, 5th ed., text revision provides diagnostic criteria, and the PTSD Checklist for DSM-5 uses these diagnostic criteria to help physicians diagnose PTSD and determine severity. First-line treatment of PTSD involves psychotherapy, such as trauma-focused cognitive behavior therapy. Pharmacotherapy is useful for patients who have residual symptoms after psychotherapy or are unable or unwilling to access psychotherapy. Selective serotonin reuptake inhibitors (i.e., fluoxetine, paroxetine, and sertraline) and the serotonin-norepinephrine reuptake inhibitor venlafaxine effectively treat primary PTSD symptoms. The addition of other pharmacotherapy, such as atypical antipsychotics or topiramate, may be helpful for residual symptoms. Patients with PTSD often have sleep disturbance related to hyperarousal or nightmares. Prazosin is effective for the treatment of PTSD-related sleep disturbance. Clinicians should consider testing patients with PTSD for obstructive sleep apnea because many patients with PTSD-related sleep disturbance have this condition. Psychiatric comorbidities, particularly mood disorders and substance use, are common in PTSD and are best treated concurrently.

Importance: Menopause, due to loss of ovarian follicular activity without another pathological or physiological cause, typically occurs between the ages of 45 years and 56 years. During the menopausal transition, approximately 50% to 75% of women have hot flashes, night sweats, or both (vasomotor symptoms) and more than 50% have genitourinary symptoms (genitourinary syndrome of menopause [GSM])., Observations: Vasomotor symptoms typically last more than 7 years and GSM is often chronic. Efficacious treatments for women with bothersome vasomotor symptoms or GSM symptoms include hormonal and nonhormonal options. Systemic estrogen alone or combined with a progestogen reduces the frequency of vasomotor symptoms by approximately 75%. Oral and transdermal estrogen have similar efficacy. Conjugated equine estrogens (CEE) with or without medroxyprogesterone acetate (MPA) were the only hormonal treatments for which clinical trials were designed to examine cardiovascular events, venous thromboembolism, and breast cancer risk. Compared with placebo, the increased risk of stroke and venous thromboembolism associated with CEE (with or without MPA) and breast cancer (with use of CEE plus MPA) is approximately 1 excess event/1000 person-years. Low-dose CEE plus bazedoxifene is not associated with increased risk of breast cancer (0.25%/year vs 0.23%/year with placebo). Bioidentical estrogens approved by the US Food and Drug Administration (with identical chemical structure to naturally produced estrogens, and often administered transdermally) also are available to treat vasomotor symptoms. For women who are not candidates for hormonal treatments, nonhormonal approaches such as citalopram, desvenlafaxine, escitalopram, gabapentin, paroxetine, and venlafaxine are available and are associated with a reduction in frequency of vasomotor symptoms by approximately 40% to 65%. Low-dose vaginal estrogen is associated with subjective improvement in GSM symptom severity by approximately 60% to 80%, with improvement in severity by 40% to 80% for vaginal prasterone, and with improvement in severity by 30% to 50% for oral ospemifene., Conclusions and Relevance: During the menopausal transition, approximately 50% to 75% of women have vasomotor symptoms and GSM symptoms. Hormonal therapy with estrogen is the first-line therapy for bothersome vasomotor symptoms and GSM symptoms, but nonhormonal medications (such as paroxetine and venlafaxine) also can be effective. Hormone therapy is not indicated for the prevention of cardiovascular disease.

Introduction: Currently, major depressive disorder (MDD) treatment plans are based on trial-and-error, and remission rates remain low. A strategy to replace trial-and-error and increase remission rates could be treatment stratification. We explored the heartbeat-evoked potential (HEP) as a biomarker for treatment stratification to either antidepressant medication or rTMS treatment., Methods: Two datasets were analyzed: (1) the International Study to Predict Optimized Treatment in Depression (iSPOT-D; n = 1,008 MDD patients, randomized to escitalopram, sertraline, or venlafaxine, and n = 336 healthy controls) and (2) a multi-site, open-label rTMS study (n = 196). The primary outcome measure was remission. Cardiac field artifacts were removed from the baseline EEG using independent component analysis (ICA). The HEP-peak was detected in a bandwidth of 20 ms around 8 ms and 270 ms (N8, N270) after the R-peak of the electrocardiogram signal. Differences between remitters and non-remitters were statistically assessed by repeated-measures ANOVAs for electrodes Fp1, Cz, and Oz., Results: In the venlafaxine subgroup, remitters showed a lower HEP around the N8 peak than non-remitters on electrode site Cz (p = 0.004; d = 0.497). The rTMS group showed a non-significant difference in the opposite direction (d = -0.051). Retrospective stratification to one of the treatments based on the HEP resulted in enhanced treatment outcome prediction for venlafaxine (+22.98%) and rTMS (+10.66%)., Conclusion: These data suggest that the HEP could be used as a stratification biomarker between venlafaxine and rTMS; however, future out-of-sample replication is warranted., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Major depressive disorders represent a significant burden to society, and it is recommended that antidepressant therapy should last at least 6 months. In Italy, antidepressant use in clinical practice was reported to increase by 1.7% in 2020 compared to 2019, but only 40% of new prescriptions are characterized by a treatment duration longer than 3 months., Objective: The study aims to describe adherence and persistence to therapy in a subset of antidepressants (citalopram, duloxetine, escitalopram, paroxetine, sertraline, venlafaxine) vs. vortioxetine in Italy during a 2-year period from 2017 to 2019., Methods: A retrospective analysis of the longitudinal patient database reporting data from general practitioners on drug prescriptions in Italy was carried out in a cohort of 8,235 adult patients who were prescribed antidepressants., Results: Overall, 32.4% of the patients adhered to treatment for ≥6 months over a 1-year period. Vortioxetine had a lower risk of low adherence compared to duloxetine, paroxetine, and venlafaxine and a higher risk compared to citalopram, escitalopram, and sertraline. 68.7% of patients discontinued treatment during follow-up. The greatest percentage of patients continuing therapy was seen with duloxetine, while citalopram was associated with the highest proportion of patients discontinuing therapy. No significant differences in discontinuation were observed when comparing vortioxetine to the other antidepressants., Conclusion: Adherence results were considerably less than the 6-month recommendation in this real- world analysis of antidepressant therapies. Also, persistence to therapy was low, with most patients discontinuing treatment. Thus, there is a need for interventions to help patients adhere to their planned therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: SARS-CoV-2 main protease (M pro or 3CL pro ) and papain-like protease (PL pro ) are common viral targets for repurposed drugs to combat COVID-19 disease. Recently, several antidepressants (such as fluoxetine, venlafaxine and citalopram) belonging to the Selective Serotonin Reuptake Inhibitors (SSRIs) and the Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) classes have been shown to in vitro inhibit viral replication., Aim: Investigate a possible action of fluoxetine and derivatives on SARS-CoV-2 protease sites., Methods: Molecular docking was performed using AutoDock Vina. Both protease structures and different drug conformations were used to explore the possibility of SARS-CoV-2 inhibition on a M pro or PL pro related pathway. Drug structures were obtained by optimization with the Avogadro software and MOPAC using the PM6 method. Results were analysed on Discovery Studio Visualizer., Results: The results indicated that M pro interacted in a thermodynamically favorable way with fluoxetine, venlafaxine, citalopram, atomoxetine, nisoxetine and norfluoxetine in the region of the active site, whether PL pro conformers did not come close to the active site., Conclusion: In an in silico perspective, it is likely that the SSRIs and other anti-depressants could interact with M pro and cause the enzyme to malfunction. Unfortunately, the same drugs did not present similar results on PLpro crystal, therefore, no inhibition is expected in an in vitro trial. Anyway, in vitro tests are necessary for a better understanding of the links between SARS-CoV-2 proteases and antidepressants., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: The prevalence of major depressive disorder in patients with schizophrenia (SZ-MDD) has been reported to be about 32.6 %, but it varies considerably depending on the stage (early or chronic) and state (acute or post-psychotic) of schizophrenia. The exploration of ideal strategies for the treatment of major depressive disorder in the context of schizophrenia is urgently needed. Thus, the present study was conducted to investigate the treatment effects of clozapine, electrical stimulation (ECS; the mouse model equivalent of electroconvulsive therapy for humans), venlafaxine, and mirtazapine for SZ-MDD., Methods: A mouse model of SZ-MDD was established with MK801 administration and chronic unpredictable mild stress exposure. Clozapine and ECS, alone and with mirtazapine and/or venlafaxine, were used as treatment strategies. In-vivo two-photon imaging was performed to visualize Ca 2+ neural activity in the prefrontal cortex (PFC). Mouse performance on behavioral assays was taken to reflect acute treatment effects., Results: ECS + venlafaxine + mirtazapine performed significantly better than other treatments in alleviating major depressive disorder, as reflected by PFC Ca 2+ activity and behavioral assay performance. Clozapine + venlafaxine + mirtazapine did not have an ideal treatment effect. Brain Ca 2+ activity alterations did not correlate with behavioral expression in any treatment group., Conclusions: In this mouse model of SZ-MDD, ECS + venlafaxine + mirtazapine improved brain Ca2+ activity, pre-pulse inhibition, and immobility time. These findings provide useful information for the further exploration of treatment methods for patients with SZ-MDD, although the mechanisms underlying this comorbidity needed to be investigated further., Competing Interests: Conflict of interest None., (Copyright © 2022. Published by Elsevier B.V.)

Background: Emotional blunting is theorized to be an adverse effect of antidepressants, particularly serotonin reuptake inhibitors, but this has not been firmly established. Another possibility is that emotional blunting represents a residual depressive symptom., Methods: We analyzed data from adult outpatients with acute major depressive disorder who participated in three 8-week randomized controlled trials. Trials 1 and 2 were pooled (venlafaxine, n = 378; bupropion, n = 389; placebo, n = 383) and Trial 3 (escitalopram, n = 254; bupropion, n = 260) was analyzed separately. Emotional blunting was measured with the "inability to feel" item from the Montgomery-Åsberg Depression Rating Scale., Results: Emotional responsiveness improved, on average, in all treatment groups. Only a minority of participants (≤6 %) experienced more emotional blunting post-treatment, compared to baseline, with no significant differences between treatment groups, although roughly 20-25 % continued to report an inability to feel normal emotions at the final assessment. In Trials 1 and 2, emotional blunting was associated with poorer outcomes in terms of depressive symptoms, suicidal ideation, and sexual function, but these correlations were nearly identical in the placebo group., Limitations: The trials were short and cannot speak to the possibility of emotional blunting from long-term treatment. Emotional blunting was measured with a single item., Conclusions: The study medications did not significantly decrease emotional responsiveness, and there was no evidence that emotional blunting mediated treatment response. In acute treatment, emotional blunting may be better conceptualized as a residual symptom than as an adverse drug effect., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Studies report an increased risk of self-harm or suicide in people prescribed mirtazapine compared with other antidepressants., Objectives: To compare the risk of serious self-harm in people prescribed mirtazapine versus other antidepressants as second-line treatments., Design and Setting: Cohort study using anonymised English primary care electronic health records, hospital admission data and mortality data with study window 1 January 2005 to 30 November 2018., Participants: 24 516 people diagnosed with depression, aged 18-99 years, initially prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine, a different SSRI, amitriptyline or venlafaxine., Main Outcome Measures: Hospitalisation or death due to deliberate self-harm. Age-sex standardised rates were calculated and survival analyses were performed using inverse probability of treatment weighting to account for baseline covariates., Results: Standardised rates of serious self-harm ranged from 3.8/1000 person-years (amitriptyline) to 14.1/1000 person-years (mirtazapine). After weighting, the risk of serious self-harm did not differ significantly between the mirtazapine group and the SSRI or venlafaxine groups (HRs (95% CI) 1.18 (0.84 to 1.65) and 0.85 (0.51 to 1.41) respectively). The risk was significantly higher in the mirtazapine than the amitriptyline group (3.04 (1.36 to 6.79)) but was attenuated after adjusting for dose., Conclusions: There was no evidence for a difference in risk between mirtazapine and SSRIs or venlafaxine after accounting for baseline characteristics. The higher risk in the mirtazapine versus the amitriptyline group might reflect residual confounding if amitriptyline is avoided in people considered at risk of self-harm., Clinical Implications: Addressing baseline risk factors and careful monitoring might improve outcomes for people at risk of serious self-harm., Competing Interests: Competing interests: All authors have completed the ICMJE declaration of interest form and declare support from the National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, NIHR School for Primary Care Research, and NIHR MindTech MedTech Co-operative. JHC is a shareholder and former director of ClinRisk Ltd, outside of the submitted work. JHC is an unpaid director of QResearch which is an alternative database to CPRD run as a partnership between the University of Oxford and EMIS (commercial supplier of GP computer systems) outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Predictors of antidepressant response in older patients with major depressive disorder (MDD) need to be confirmed before they can guide treatment., Objective: To create decision trees for early identification of older patients with MDD who are unlikely to respond to 12 weeks of antidepressant treatment, we analysed data from 454 older participants treated with venlafaxine XR (150-300 mg/day) for up to 12 weeks in the Incomplete Response in Late-Life Depression: Getting to Remission study., Methods: We selected the earliest decision point when we could detect participants who had not yet responded (defined as >50% symptom improvement) but would do so after 12 weeks of treatment. Using receiver operating characteristic models, we created two decision trees to minimise either false identification of future responders (false positives) or false identification of future non-responders (false negatives). These decision trees integrated baseline characteristics and treatment response at the early decision point as predictors., Finding: We selected week 4 as the optimal early decision point. Both decision trees shared minimal symptom reduction at week 4, longer episode duration and not having responded to an antidepressant previously as predictors of non-response. Test negative predictive values of the leftmost terminal node of the two trees were 77.4% and 76.6%, respectively., Conclusion: Our decision trees have the potential to guide treatment in older patients with MDD but they require to be validated in other larger samples., Clinical Implications: Once confirmed, our findings may be used to guide changes in antidepressant treatment in older patients with poor early response., Competing Interests: Competing interests: HKK has no competing interests to disclose. DMB has received research support from Canadian Institutes of Health Research (CIHR), US National Institute of Health (NIH), Brain Canada, and the Temerty Family through the CAMH Foundation and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway. He is the site principal investigator for three sponsor-initiated studies for Brainsway. He also receives in-kind equipment support from Magventure for two investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. JFK received medication supplies from Pfizer and Indivor for investigator-initiated studies. He is also on the scientific advisory board of Aifred Health. EL has received funding from Takeda, Lundbeck, Janssen, Alkermes, Aptynx, and Patient-Centered Outcomes Research Institute (PCORI). He is also a consultant for Janssen and Jazz Pharmaceuticals. CFR received research support from NIH, PCORI, American foundation for suicide prevention, center for Medicare and Medicaid services, commonwealth of Pennsylvania, and the Brain and behavior research foundation. His work is also sponsored by pharmaceutical supplies from Bristol Meyers Squib and Pfizer. BHM receives support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto. He receives research support from Brain Canada, CIHR, the CAMH Foundation, PCORI, NIH, Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada). He has been an unpaid consultant to Myriad Neuroscience., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Dementia is a group of symptoms that largely affects older people. The majority of patients face behavioural and psychological symptoms (BPSD) during the course of their illness. Alzheimer's disease (AD) and vascular dementia (VaD) are two of the most prevalent types of dementia. Available medications provide symptomatic benefits and provide relief from BPSD and associated health issues. However, it is unclear how specific dementia, antidepressant, antipsychotic, antianxiety, and mood stabiliser drugs, used in the treatment of depression and dementia subtypes are prescribed in hospital admission, during hospital stay, and at the time of discharge. To address this, we apply multi-dimensional data analytical approaches to understand drug prescribing practices within hospitals in England and Wales., Methods: We made use of the UK National Audit of Dementia (NAD) dataset and pre-processed the dataset. We evaluated the pairwise Pearson correlation of the dataset and selected key data features which are highly correlated with dementia subtypes. After that, we selected drug prescribing behaviours (e.g. specific medications at the time of admission, during the hospital stay, and upon discharge), drugs and disorders. Then to shed light on the relations across multiple features or dimensions, we carried out multiple regression analyses, considering the number of dementia, antidepressant, antipsychotic, antianxiety, mood stabiliser, and antiepileptic/anticonvulsant drug prescriptions as dependent variables, and the prescription of other drugs, number of patients with dementia subtypes (AD/VaD), and depression as independent variables., Results: In terms of antidepressant drugs prescribed in hospital admission, during stay and discharge, the number of sertraline and venlafaxine prescriptions were associated with the number of VaD patients whilst the number of mirtazapine prescriptions was associated with frontotemporal dementia patients. During admission, the number of lamotrigine prescriptions was associated with frontotemporal dementia patients, and with the number of valproate and dosulepin prescriptions. During discharge, the number of mirtazapine prescriptions was associated with the number of donepezil prescriptions in conjunction with frontotemporal dementia patients. Finally, the number of prescriptions of donepezil/memantine at admission, during hospital stay and at discharge exhibited positive association with AD patients., Conclusion: Our analyses reveal a complex, multifaceted set of interactions among prescribed drug types, dementia subtypes, and depression., (© 2022. The Author(s).)

Objective:  To evaluate the effect of neuromodulatory drugs on the intensity of chronic pelvic pain (CPP) in women., Data Sources:  Searches were carried out in the PubMed, Cochrane Central, Embase, Lilacs, OpenGrey, and Clinical Trials databases., Selection of Studies:  The searches were carried out by two of the authors, not delimiting publication date or original language. The following descriptors were used: chronic pelvic pain in women OR endometriosis , associated with MESH/ENTREE/DeCS: gabapentinoids , gabapentin , amitriptyline , antidepressant , pregabalin , anticonvulsant , sertraline , duloxetine , nortriptyline , citalopram , imipramine , venlafaxine , neuromodulation drugs , acyclic pelvic pain , serotonin , noradrenaline reuptake inhibitors , and tricyclic antidepressants , with the Boolean operator OR . Case reports and systematic reviews were excluded., Data Collection:  The following data were extracted: author, year of publication, setting, type of study, sample size, intervention details, follow-up time, and results., Data Synthesis:  A total of 218 articles were found, with 79 being excluded because they were repeated, leaving 139 articles for analysis: 90 were excluded in the analysis of the titles, 37 after reading the abstract, and 4 after reading the articles in full, and 1 could not be found, therefore, leaving 7 articles that were included in the review., Conclusion:  Most of the studies analyzed have shown pain improvement with the help of neuromodulators for chronic pain. However, no improvement was found in the study with the highest statistical power. There is still not enough evidence that neuromodulatory drugs reduce the intensity of pain in women with CPP., Competing Interests: None to declare., (Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).)

Background: Migraine affects 1 billion people worldwide and > 30 million Brazilians; besides, it is an underdiagnosed and undertreated disorder., Objective: The need to disseminate knowledge about the prophylactic treatment of migraine is known, so the Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee of authors with the objective of establishing a consensus with recommendations on the prophylactic treatment of episodic migraine based on articles from the world literature as well as from personal experience., Methods: Meetings were held entirely online, with the participation of 12 groups that reviewed and wrote about the pharmacological categories of drugs and, at the end, met to read and finish the document. The drug classes studied in part II of this Consensus were: antihypertensives, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, calcium channel blockers, other drugs, and rational polytherapy., Results: From this list of drugs, only candesartan has been established as effective in controlling episodic migraine. Flunarizine, venlafaxine, duloxetine, and pizotifen were defined as likely to be effective, while lisinopril, enalapril, escitalopram, fluvoxamine, quetiapine, atorvastatin, simvastatin, cyproheptadine, and melatonin were possibly effective in prophylaxis of the disease., Conclusions: Despite an effort by the scientific community to find really effective drugs in the treatment of migraine, given the large number of drugs tested for this purpose, we still have few therapeutic options., Competing Interests: AOK: Speaker for Allergan, Ipsen Pharma, Merz, and Onyxcann Cantera; AT: Lilly, Teva, Ache, Supera, Allergan, and Novartis; CAPR: Teva, Novartis, Eli Lilly, Lundbeck, Aché, Apsen, and EJPC: Speaker for Novartis, Allergan, Libbs, and Lilly; EMS: Speaker for Libbs, Allergan, Novartis, Lilly, Lundbeck, and Teva. Advisory board: Allergan, Libbs, Teva, and Lundbeck; EMM: Speaker for Teva, Novartis, Eli Lilly, and Allergan; Advisory board: Libbs and Eli Lilly; GOMT: Speaker for Eli Lilly; HCC: Speaker for Allergan and Eli Lilly; ID, JAMJ, BAJS, MRCFF, MEJ, PFMMF, RPSN, YDF: No conflict of interests to declare; AJS: Speaker for Eli Lilly, Novartis, and Teva; JJC: Speaker for Eli Lilly, Novartis, Teva, and Libbs; Advisory board: Teva, Novartis, and Eli Lilly; JCS: Speaker for Teva, Novartis, and Allergan, Lilly; LCC: Speaker for Allergan, Novartis, and Sanofi; Advisory board: Allergan; LMB: Speaker for Novartis; LPQ: Speaker for Eli Lilly and Allergan; Advisory board: Eli Lilly and Teva; MNPS: Speaker for Eli Lilly, Novartis, Teva, Allergan, and Libbs; Advisory board: Sanofi, Eli Lilly, and Libbs; MENMC: Speaker for Eli Lilly, Novartis, Teva, and Allergan; Advisory board: Eli Lilly; MFPP: Grants from Fapesp and CNPq; personal fees from Allergan, Eurofarma, Eli Lilly, Libbs, Novartis, Pfizer, and Teva, during studies; PMP: Speaker for Novartis, Teva, Eli Lilly, and Libbs; Advisory board: Libbs; PSFS: Speaker for Teva, Novartis, Allergan, EMS, and Politec; Advisory board: Libbs and Eli Lilly; PAK: Fees for services from Libbs, Novartis, Allergan, Livanova, and Teva; PASRF: Speaker for Eli Lilly, Novartis, Allergan, and Libbs; Advisory board: Novartis, and Eli Lilly., (Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Painful post-traumatic trigeminal neuropathy (PPTTN) can result from iatrogenic injury to one or more branches of the trigeminal nerve during oral surgical procedures such as tooth extractions. Like other chronic neuropathic pain conditions, PPTTN can significantly alter the patient's quality of life, especially when pharmacological treatment is ineffective or not tolerated. As such, new treatment options have been investigated, including local injections of botulinum toxin type A (BTX-A). A 29-year-old woman presented to our tertiary orofacial pain clinic for evaluation of chronic electric shock-like pain attacks and severe allodynia in the territory of the right inferior alveolar nerve and buccal nerve following right mandibular third molar extraction 3 years prior. Following several failed attempts at classic pharmacological management (including carbamazepine, venlafaxine, duloxetine, pregabalin, clonazepam, and amitriptyline), BTX-A injections were administered in the vicinity of the right mental nerve. This treatment provided significant improvement in the patient's condition and overall quality of life with no significant adverse effects. Because both neuropathies were significantly improved by remote BTX-A injections, this case report provides preliminary clinical evidence supporting spinopetal transport of BTX-A, as shown in animal models, as an underlying pathophysiological mechanism of BTX-A-mediated analgesia.

Major depression (MD) is one of the most common psychiatric disorders worldwide. Currently, the first-line treatment for MD targets the serotonin system but these drugs, notably the selective serotonin reuptake inhibitors, usually need 4 to 6 weeks before the benefit is felt and a significant proportion of patients shows an unsatisfactory response. Numerous treatments have been developed to circumvent these issues as venlafaxine, a mixed serotonin-norepinephrine reuptake inhibitor that binds and blocks both the SERT and NET transporters. Despite this pharmacological profile, it is difficult to have a valuable insight into its ability to produce more robust efficacy than single-acting agents. In this review, we provide an in-depth characterization of the pharmacological properties of venlafaxine from in vitro data to preclinical and clinical efficacy in depressed patients and animal models of depression to propose an indirect comparison with the most common antidepressants. Preclinical studies show that the antidepressant effect of venlafaxine is often associated with an enhancement of serotonergic neurotransmission at low doses. High doses of venlafaxine, which elicit a concomitant increase in 5-HT and NE tone, is associated with changes in different forms of plasticity in discrete brain areas. In particular, the hippocampus appears to play a crucial role in venlafaxine-mediated antidepressant effects notably by regulating processes such as adult hippocampal neurogenesis or the excitatory/inhibitory balance. Overall, depending on the dose used, venlafaxine shows a high efficacy on depressive-like symptoms in relevant animal models but to the same extent as common antidepressants. However, these data are counterbalanced by a lower tolerance. In conclusion, venlafaxine appears to be one of the most effective treatments for treatment of major depression. Still, direct comparative studies are warranted to provide definitive conclusions about its superiority., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)