Developing an innovative 3D printing platform for production of personalised medicines in a hospital for the OPERA clinical trial.

Breast cancer is the most frequently diagnosed cancer in women worldwide, and non-adherence to adjuvant hormonotherapy can negatively impact cancer recurrence and relapse. Non-adherence is associated with side effects of hormonotherapy. Pharmacological strategies to mitigate the side effects include coadministration of antidepressants, however patients remain non-adherent. The aim of this work was to develop medicines containing both hormonotherapy, tamoxifen (20 mg), along with anti-depressants, either venlafaxine (37.5 or 75 mg) or duloxetine (30 or 60 mg), to assess the acceptability and efficacy of this personalised approach for mitigating tamoxifen side effects in a clinical trial. A major criterion for the developed medicines was the production rate, specified at minimum 200 dosage units per hour to produce more than 40,000 units required for the clinical trial. A novel capsule filling approach enabled by the pharmaceutical 3D printer M3DIMAKER 2 was developed for this purpose. Firstly, semi-solid extrusion 3D printing enabled the filling of tamoxifen pharma-ink prepared according to French compounding regulation, followed by filling of commercial venlafaxine or duloxetine pellets enabled by the development of an innovative pellet dispensing printhead. The medicines were successfully developed and produced in the clinical pharmacy department of the cancer hospital Gustave Roussy, located in Paris, France. The developed medicines satisfied quality and production rate requirements and were stable for storage up to one year to cover the duration of the trial. This work demonstrates the feasibility of developing and producing combined tamoxifen medicines in a hospital setting through a pharmaceutical 3D printer to enable a clinical trial with a high medicines production rate requirement.

Personalized venlafaxine dose prediction using artificial intelligence technology: a retrospective analysis based on real-world data.

BACKGROUND: Venlafaxine dose regimens vary considerably between individuals, requiring personalized dosing. AIM: This study aimed to identify dose-related influencing factors of venlafaxine through real-world data analysis and to construct a personalized dose model using advanced artificial intelligence techniques. METHOD: We conducted a retrospective study on patients with depression treated with venlafaxine. Significant variables were selected through a univariate analysis. Subsequently, the predictive performance of seven models (XGBoost, LightGBM, CatBoost, GBDT, ANN, TabNet, and DT) was compared. The algorithm that demonstrated optimal performance was chosen to establish the dose prediction model. Model validation used confusion matrices and ROC analysis. Additionally, a dose subgroup analysis was conducted. RESULTS: A total of 298 patients were included. TabNet was selected to establish the venlafaxine dose prediction model, which exhibited the highest performance with an accuracy of 0.80. The analysis identified seven crucial variables correlated with venlafaxine daily dose, including blood venlafaxine concentration, total protein, lymphocytes, age, globulin, cholinesterase, and blood platelet count. The area under the curve (AUC) for predicting venlafaxine doses of 75 mg, 150 mg, and 225 mg were 0.90, 0.85, and 0.90, respectively. CONCLUSION: We successfully developed a TabNet model to predict venlafaxine doses using real-world data. This model demonstrated substantial predictive accuracy, offering a personalized dosing regimen for venlafaxine. These findings provide valuable guidance for the clinical use of the drug.

Developing a machine learning model for predicting venlafaxine active moiety concentration: a retrospective study using real-world evidence.

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 (R2 = 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.

Effect of venlafaxine on anhedonia and amotivation in patients with major depressive disorder.

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.

PBPK modeling to predict the pharmacokinetics of venlafaxine and its active metabolite in different CYP2D6 genotypes and drug-drug interactions with clarithromycin and paroxetine.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized anxiety disorder, and panic disorder. Venlafaxine is metabolized to the active metabolite desvenlafaxine mainly by CYP2D6. Genetic polymorphism of CYP2D6 and coadministration with other medications can significantly affect the pharmacokinetics and/or pharmacodynamics of venlafaxine and its active metabolite. This study aimed to establish the PBPK models of venlafaxine and its active metabolite related to CYP2D6 genetic polymorphism and to predict drug-drug interactions (DDIs) with clarithromycin and paroxetine in different CYP2D6 genotypes. Clinical pharmacogenomic data for venlafaxine and desvenlafaxine were collected to build the PBPK model. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) characteristics of respective compounds were obtained from previously reported data, predicted by the PK-Sim® software, or optimized to capture the plasma concentration-time profiles. Model evaluation was performed by comparing the predicted pharmacokinetic parameters and plasma concentration-time profiles to the observed data. Predicted plasma concentration-time profiles of venlafaxine and its active metabolite were visually similar to the observed profiles and all predicted AUC and Cmax values for respective compounds were included in the twofold error range of observed values in non-genotyped populations and different CYP2D6 genotypes. When clarithromycin or clarithromycin plus paroxetine was concomitantly administered, predicted plasma concentration-time profiles of venlafaxine properly captured the observed profiles in two different CYP2D6 genotypes and all predicted DDI ratios for AUC and Cmax were included within the acceptance range. Consequently, the present model successfully captured the pharmacokinetic alterations of venlafaxine and its active metabolite according to CYP2D6 genetic polymorphism as well as the DDIs between venlafaxine and two CYP inhibitors. The present model can be used to predict the pharmacokinetics of venlafaxine and its active metabolite considering different races, ages, coadministered drugs, and CYP2D6 activity of individuals and it can contribute to individualized pharmacotherapy of venlafaxine.

Suicide ideation and male-female differences in major depressive disorder.

OBJECTIVE: This study aimed to explore male-female differences in suicide ideation (SI) and suicide risk factors in major depressive disorder (MDD). METHODS: We analysed 482 adults (sample 1) and 438 elderly outpatients (sample 2) with MDD. Sample 1 was treated with different antidepressant combinations (escitalopram; bupropion plus escitalopram; venlafaxine plus mirtazapine) and assessed by means of the Concise Health Risk Tracking (SI), Quick Inventory of Depressive Symptomatology, Altman Mania Rating Scale and Psychiatric Diagnostic Screening Questionnaire. Sample 2 was treated with venlafaxine and assessed using the Hamilton scale for depression, Anxiety Sensitivity Index and Penn State Worry Questionnaire for anxiety, Beck Scale for Suicide Ideation and Repeatable Battery for the Assessment of Neuropsychological Status. RESULTS: In sample 1, females had greater depression severity (O.R 0.961 99%CI: 0.929 - 0.995), males reported more alcohol abuse (O.R 1.299 99%CI: 1.118 - 1.509) and active SI (O.R 1.109 99%CI: 1.005 - 1.255). In sample 2 men showed more severe SI (O.R 1.067; 99%CI: 1.014 - 1.122) and weight loss (OR = 5.89 99%CI: 1.01 - 34.19), women more gastrointestinal symptoms. CONCLUSIONS: In these selected samples, although women had more severe depression, men had more suicide risk factors. Such differences might contribute to men's increased suicide risk.

In major depressive disorder sex differences affect the clinical expression of depressive episodes. In comparison to men, women endorse higher levels of overall depression in adult MDD and more somatic anxiety and gastrointestinal symptoms in late-life MDD.After controlling for confounding variables, males have more severe SI and a larger number of suicide risk factors (eg. alcohol abuse; weight loss). The association between male sex and SI is detectable in both adults and elderly patients with MDD.Further studies are necessary to elucidate how sex differences in suicide ideation and suicide risk factors are related to men's increased suicide risk.

Sertraline versus venlafaxine combined with psychotherapy in trauma-affected refugees - a follow-up study on a pragmatic randomised trial.

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.

Venlafaxine-Associated Rhabdomyolysis: A Literature Review.

PURPOSE: This systematic review aimed to investigate the clinical manifestations and characteristics of venlafaxine-associated rhabdomyolysis. METHODS: A systematic search was conducted in PubMed, Elsevier, Science Direct, Embase, Springer Link, Wiley Online Library, CNKI, and Wanfang databases from the date of database inception to January 2023. Previously reported cases of venlafaxine-associated rhabdomyolysis were identified, and relevant data from these cases were collected for descriptive statistical analysis. Cases that met the inclusion criteria were evaluated to determine the correlation between adverse reactions and venlafaxine. RESULTS: A total of 12 patients with venlafaxine-associated rhabdomyolysis were included. None of these patients had a history of muscle pain or discomfort. Of the 12 patients, 5 patients received venlafaxine at doses of ≤225 mg/d, whereas the remaining 7 patients received doses exceeding 225 mg/d. The main clinical symptoms included myalgia, muscle weakness, and renal injury. All 12 patients discontinued venlafaxine and received symptomatic care. CONCLUSIONS: Venlafaxine, used either as a monotherapy or in combination with other drugs, may be associated with rhabdomyolysis. Creatine kinase levels may normalize or significantly decrease after discontinuation of venlafaxine and symptomatic treatment.

Pindolol potentiates the antidepressant effect of venlafaxine by inhibiting 5-HT1A receptor in DRN neurons of mice.

INTRODUCTION: Antidepressants increase the level of 5-HT in the somatodendritic region of the serotonergic dorsal raphe nucleus (DRN) neurons in the first few days of their usage, which, in turn, inhibits the serotonergic neurons locally. Pindolol may eliminate this inhibition when used in combination with antidepressants. MATERIAL AND METHODS: We aimed to determine the effect of pindolol on 5-HT1A receptor response in the DRN neurons, using voltage clamp recordings and prove the potentiation of antidepressant effect of venlafaxine by pindolol through behavior experiments. Balb/c mice, 28-35 days-old were used. RESULTS: 5-HT application (25 µM) induced an outward current by 23.36 ± 3.79 pA at the neurons in the dorsal subnucleus of DRN. This effect was inhibited by pre-administration of WAY-100135 (21 µM) and pindolol (10 µM) separately. The current induced by 5-HT and 8-OHDPAT have no statistically significance. 8-OHDPAT (30 µM) induced a 5-HT-like outward current, which was inhibited by pre-administration of pindolol (10 µM). Combination of venlafaxine (20 mg/kg/day) and pindolol (15 mg/kg/day) significantly reduced immobilization time when compared to the control group in tail suspension test and forced swim test without any significant change in locomotor activity. Administration of venlafaxine (20 mg/kg/day) alone or pindolol (15 mg/kg/day) alone did not significantly reduce immobilization time. CONCLUSION: Pindolol has the potential to prevent the inhibition of serotonergic neurons after antidepressant use. Hence, we, for the first time, demonstrated that pindolol can potentiate antidepressant effect of venlafaxine. In the mood disorders, pindolol is likely to increase the effectiveness of antidepressant drugs when given in combination.

Venlafaxine demonstrated anti-arthritic activity possibly through down regulation of TNF-α, IL-6, IL-1ß, and COX-2.

Venlafaxine is a serotonin-norepinephrine reuptake inhibitor used to treat depression. Previous studies demonstrated its anti-nociceptive and anti-inflammatory activities through the suppression of pro-inflammatory cytokines. Present research aimed to explore its anti-arthritic potential. Different in-vitro assays including egg albumin, bovine serum albumin denaturation and human red blood cell (RBC) membrane stabilization assays along with in-vivo models of formaldehyde and complete Freund's adjuvant-induced arthritis were used to study its anti-arthritic effect. Venlafaxine inhibited egg albumin and bovine serum albumin denaturation and preserve the integrity of red blood cells membrane in concentration-dependent manner. In formaldehyde-induced arthritis venlafaxine significantly (p < 0.001) reduced the paw edema on treatment for 10 days. Chronic administration of venlafaxine for 28 days in Freund's adjuvant-induced arthritis model decreased the paw volume (p < 0.001), arthritic index (p < 0.01), flexion pain score (p < 0.05), mobility score (p < 0.05), and improved the stance score (p < 0.05). Venlafaxine also significantly declined the rheumatoid factor (p < 0.01) and C-reactive protein (p < 0.05) levels and increased the RBC count (p < 0.01) and Hb value (p < 0.001). Upon PCR analysis venlafaxine remarkably turndown the mRNA expression of TNF-α, IL-6, IL-1ß, and COX-2. Taken together it is inferred from current findings that venlafaxine possesses the significant anti-arthritic activity and could be a potential therapeutic option for the treatment of rheumatoid arthritis.

Dose-Dependent Inhibition of CYP2D6 by Bupropion in Patients With Depression.

PURPOSE: The aim of this study was to investigate the potential dose-dependent CYP2D6 inhibition by bupropion (BUP) in patients with depression. METHODS: Patients combining BUP with venlafaxine were included from a therapeutic drug monitoring (TDM) database at the Diakonhjemmet Hospital (Oslo, Norway). The O/N-desmethylvenlafaxine metabolic ratio measured in TDM samples was used as a biomarker for CYP2D6 phenotype and was compared between patients treated with BUP 150 mg/d and 300 mg/d or greater. In addition, reference groups of venlafaxine-treated patients genotyped as CYP2D6 poor metabolizers (PMs, no CYP2D6 activity) and normal metabolizers (NMs, fully functional CYP2D6 activity) were included. FINDINGS: A total of 221 patients were included in the study. The median O/N-desmethylvenlafaxine metabolic ratio was significantly higher in patients treated with BUP 150 mg/d (n = 59) versus 300 mg/d or greater (n = 34, 1.77 vs 0.96, P < 0.001). In CYP2D6 NMs (n = 62) and PMs (n = 66), the median metabolic ratios were 40.55 and 0.48, respectively. For patients treated with BUP 150 mg/d, 11 (19%) of the 59 patients were phenoconverted to PMs, whereas this was the case for 17 (50%) of the 34 patients treated with BUP 300 mg/d or greater. CONCLUSIONS: Bupropion exhibits a clear dose-dependent CYP2D6 inhibitory effect during treatment of patients with depression. This finding is of clinical relevance when adjusting dosing of CYP2D6 substrates during comedication with BUP. Half of the patients treated with high-dose BUP are converted to CYP2D6 PM phenotype. Because of the variability in CYP2D6 inhibition, TDM of CYP2D6 substrates should be considered to provide individualized dose adjustments during comedication with BUP.

Alleviating neuropathy of diabetic foot ulcer by co-delivery of venlafaxine and matrix metalloproteinase drug-loaded cellulose nanofiber sheets: production, in vitro characterization and clinical trial.

BACKGROUND: The objective of the present study was co-delivery of venlafaxin (VEN) and doxycycline (DOX), a matrix metalloproteinase inhibitor drug, for alleviating inflammation and neuropathy in diabetic foot ulcer (DFU). METHODS: Bacterial cellulose nanofiber sheets (BCNS) were loaded with DOX and VEN and categorized by their loading efficiency, release profiles and ex vivo permeation throughrat skin. The optimized nanofibers were used in patients with DFU to compare with the standard wound care regimen during a 12-week trial. Wound area was measured every 2 weeks. Biochemical parameters and microscopic studies of the skin were examined prior and at the end of the treatment. The Michigan Neuropathy Screening Instrument (MNSI) questionnaire was utilized to assess diabetic neuropathy. RESULTS: The optimum formulation showed loading efficiency of 37.8 ± 1.6% for DOX and 48 ± 1.9% for VEN. Rat skin permeation was 40% for DOX after 7-29 h and 83% for VEN during 105 h. Patients treated with BCNS showed no significant difference in their biochemical parameters before and after intervention. The ulcer size showed faster reduction after 12 weeks in the treatment group compared to the control group. The abnormal responses in the MNSI questionnaire decreased and pain-free walking distance increased significantly in the treatment group compared with the control group (p < 0.001). Microscopic studies of the skin after using nanofibers showed a large number of polymorphonuclear chronic inflammatory cells and formation of new capillary beds. CONCLUSIONS: The BCNS loaded with DOX and VEN may expedite healing and reduce neuropathy in the DFU of diabetic patients.

CYP2D6*10 polymorphism and the enantioselective O-desmethylation of S-(+)- and R-(-)-venlafaxine in Japanese psychiatric patients.

According to previous studies, R-(-)-venlafaxine (VEN) has higher enantioselectivity than S-(+)-VEN, and the plasma concentration of R-(-)-VEN varies depending on CYP2D6 activity. Therefore, we examined the pharmacokinetic effects of CYP2D6*10 genotypes on the steady-state concentrations of the enantiomers of VEN. The individuals were 71 Japanese depressed patients treated with racemic VEN. The concentrations of the enantiomers of VEN and O-desmethylvenlafaxine (ODV) were measured. Polymerase chain reaction (PCR) was used to determine the CYP2D6*10 genotypes. The plasma concentrations of S-(+)-VEN were approximately 1.9-fold higher than those of R-(-)-VEN. The plasma concentrations of S-(+)-VEN and R-(-)-VEN seemed to be higher in individuals with two mutant alleles of CYP2D6*10, although no significant differences were found in the plasma levels of S-(+)-VEN and R-(-)-VEN between CYP2D6*10 genotypes. The number of mutant alleles of CYP2D6*10 was a significant factor associated with the R-(-)-ODV/R-(-)-VEN ratio (P = .004) in multiple regression analysis. This suggests that CYP2D6*10 mutations affect the metabolism of R-(-)-VEN and S-(+)-VEN. Further studies are needed to examine how these findings affect clinical practice.

Long-term effects of pre-gestational stress and perinatal venlafaxine treatment on neurobehavioral development of female offspring.

Preclinical studies suggest that stress-related disorders even prior gestation can cause long-term changes at the level of neurobehavioral adaptations. Therefore, it is critical to consider undergoing antidepressant therapy which could reverse the negative consequences in the offspring. Venlafaxine is widely used in clinical practice; however insufficient amount of well-controlled studies verified the safety of venlafaxine therapy during gestation and lactation. The aim of this work was to investigate the effects of perinatal venlafaxine therapy on selected neurobehavioral variables in mothers and their female offspring using a model of maternal adversity. Pre-gestational stressed and non-stressed Wistar rat dams were treated with either venlafaxine (10 mg/kg/day) or vehicle during pregnancy and lactation. We have shown that pre-gestational stress decreased the number of pups with a significant reduction in the number of males but not females. Furthermore, we found that offspring of stressed and treated mothers exhibited anxiogenic behavior in juvenile and adolescent age. However, during adulthood pre-gestational stress significantly increased anxiety-like behavior of female, with venlafaxine treatment normalizing the state to control levels. Additionally, we found that even maternal stress prior gestation can have long-term impact on adult number of hippocampal immature neurons of the female offspring. A number of questions related to the best treatment options for maternal depression still remains, however present data may provide greater insight into the possible outcomes associated with perinatal venlafaxine therapy.

Environmental level of the antidepressant venlafaxine induces behavioral disorders through cortisol in zebrafish larvae (Danio rerio).

Psychoactive drugs discharged into the environment have different effects on the behavior of vertebrates. The objective of this study was to evaluate the effect of venlafaxine on the behavior of zebrafish, and whether melatonin could reverse the induction of venlafaxine. In this study, a series of venlafaxine concentrations (1 µg/L, 10 µg/L, 100 µg/L) was used to treat zebrafish embryos from 2 hours post-fertilization (hpf) to 5dpf. We found that venlafaxine (1 µg/L) can stimulate the growth of the head area, eye area, and body length of zebrafish. The light-dark test showed that venlafaxine (1 µg/L) could increase the activity of zebrafish larvae. What's more, venlafaxine (1 µg/L) upregulated the expression of steroid regulatory factors including steroidogenic acute regulatory protein (star), cytochrome P450 family member 11A1 (cyp11a1) and 11 ß hydroxylase (cyp11b1) by cAMP-pCREB pathway, affecting the function of the steroidogenic cells, which might be involved in the increased cortisol levels in zebrafish larvae. Whereas, melatonin (230 µg/L) restored the altered locomotion behavior induced by venlafaxine and recovered the altered gene expression. Our results demonstrate that venlafaxine at levels detected in the aquatic environment impacts behavior and may compromise the adaptive responses to the environment in zebrafish larvae.

Cortical inhibition, facilitation and plasticity in late-life depression: effects of venlafaxine pharmacotherapy.

BACKGROUND: Late-life depression is often associated with non-response or relapse following conventional antidepressant treatment. The pathophysiology of late-life depression likely involves a complex interplay between aging and depression, and may include abnormalities in cortical inhibition and plasticity. However, the extent to which these cortical processes are modifiable by antidepressant pharmacotherapy is unknown. METHODS: Sixty-eight patients with late-life depression received 12 weeks of treatment with open-label venlafaxine, a serotonin-norepinephrine reuptake inhibitor (≤ 300 mg/d). We combined transcranial magnetic stimulation of the left motor cortex with electromyography recordings from the right hand to measure cortical inhibition using contralateral cortical silent period and paired-pulse short-interval intracortical inhibition paradigms; cortical facilitation using a paired-pulse intracortical facilitation paradigm; and short-term cortical plasticity using a paired associative stimulation paradigm. All measures were collected at baseline, 1 week into treatment (n = 23) and after approximately 12 weeks of treatment. RESULTS: Venlafaxine did not significantly alter cortical inhibition, facilitation or plasticity after 1 or 12 weeks of treatment. Improvements in depressive symptoms during treatment were not associated with changes in cortical physiology. LIMITATIONS: The results presented here are specific to the motor cortex. Future work should investigate whether these findings extend to cortical areas more closely associated with depression, such as the dorsolateral prefrontal cortex. CONCLUSION: These findings suggest that antidepressant treatment with venlafaxine does not exert meaningful changes in motor cortical inhibition or plasticity in late-life depression. The absence of changes in motor cortical physiology, alongside improvements in depressive symptoms, suggests that age-related changes may play a role in previously identified abnormalities in motor cortical processes in latelife depression, and that venlafaxine treatment does not target these abnormalities.

AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar-Kyoto rats.

BACKGROUND: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar-Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. METHODS: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. RESULTS: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. CONCLUSIONS: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

Comparing Medications for DSM-5 PTSD in Routine VA Practice.

OBJECTIVE: Fluoxetine, paroxetine, sertraline, topiramate, and venlafaxine have previously shown efficacy for posttraumatic stress disorder (PTSD). One prior study using US Department of Veterans Affairs (VA) medical records data to compare these agents found no differences in symptom reduction in clinical practice. The current study addresses several weaknesses in that study, including limited standardization of treatment duration, inability to account for prior treatment receipt, use of an outdated symptomatic assessment for PTSD, and lack of functional outcome. METHODS: A total of 834 VA outpatients were identified with DSM-5 clinical diagnoses of PTSD between October 2016 and March 2018 who initiated one of the medications and met prespecified criteria for treatment duration and dose, combined with baseline and endpoint DSM-5 PTSD Checklist (PCL-5) measurements. Twelve-week acute-phase changes in PCL-5 score and remission of PTSD symptoms were compared among patients receiving the different medications, as was use of acute psychiatric services in the subsequent 6-month continuation phase. RESULTS: In the acute phase, patients improved by a mean of 6.8-10.1 points on the PCL-5 and 0.0%-10.9% achieved remission of PTSD symptoms. Those taking venlafaxine were significantly more likely to achieve remission (P = .008 vs fluoxetine and P < .0001 vs paroxetine, sertraline, and topiramate). In the continuation phase, there were no differences in acute psychiatric care use between medications. Those who continued their medication were less likely to use acute psychiatric services (HR = 0.55; P = .03). CONCLUSIONS: There may be an advantage to venlafaxine over other agents in achieving acute-phase remission for DSM-5 PTSD in routine clinical practice, but this finding requires further study. Regardless of the agent chosen, medication cessation during the continuation phase is associated with a higher risk of acute psychiatric care use.

Coprescribed Benzodiazepines in Older Adults Receiving Antidepressants for Anxiety and Depressive Disorders: Association With Treatment Outcomes.

OBJECTIVE: There is a paucity of data on the effects of coprescribed benzodiazepines on treatment response variability and adherence to antidepressant pharmacotherapy for depression and anxiety in late life. The objective of this transdiagnostic analysis was to examine the effect of benzodiazepines on treatment outcomes in older patients with generalized anxiety disorder (GAD) or major depressive disorder (MDD). METHODS: Secondary analyses of data from 2 clinical trials of antidepressant pharmacotherapy for GAD (escitalopram vs placebo, 2006-2009) or MDD (open treatment with venlafaxine, 2009-2014) were conducted. Participants included 640 adults aged 60+ years with DSM-IV-defined GAD (n = 177) or MDD (n = 463). Benzodiazepine data were collected at baseline. Adherence and treatment response were assessed over 12 weeks. The analysis addressed whether coprescribed benzodiazepines are associated with treatment response, antidepressant medication adherence, dropout, final dose of antidepressant medication, and report of antidepressant-related adverse effects. RESULTS: Participants with GAD and coprescribed benzodiazepines were treated with a lower mean dosage of escitalopram and were less likely to complete the trial; there was no difference in adherence or treatment response. Participants with MDD and coprescribed benzodiazepines were less likely to tolerate a therapeutic dose of venlafaxine and reported more medication-related adverse effects; there was no difference in adherence, dropout, or treatment response. CONCLUSIONS: Coprescription of benzodiazepines was associated with increased dropout in older patients with GAD and more medication-related adverse effects in older patients with MDD. However, with the systematic clinical attention offered in a clinical trial, they do not impede treatment response. Clinicians should be aware that a coprescribed benzodiazepine may be a marker of a more challenging treatment course. Trial Registration: Data analyzed were from studies with ClinicalTrials.gov identifiers NCT00892047 and NCT00105586.