Dose Of Venlafaxine Research Articles

Effects of age, sex, daily dose, comorbidity and co-medication on venlafaxine-associated cardiovascular adverse events: A pharmacovigilance analysis of the FDA Adverse Event Reporting System database.

This study aimed to provide a comprehensive view of cardiovascular adverse events (AEs) associated with venlafaxine (VEN) therapy. Cardiovascular AE reports for patients receiving VEN therapy were retrieved from January 2004 to December 2023 from the FDA Adverse Event Reporting System database. Effects of age, sex and daily VEN dose on the occurrence of different types of cardiovascular AEs and the influence of demographics, VEN dose, comorbidity and co-medication on death in patients with cardiovascular AEs were analysed by multivariate logistic regression analysis. The study included 16 110 AE reports following VEN treatment (median age: 51 years, females: 69.78%, median VEN daily dose: 100 mg/day). VEN daily dose was associated with increased risks of cardiac arrhythmias, embolic and thrombotic events, torsade de pointes/QT prolongation, ischaemic heart disease, cardiac failure, cardiomyopathy and overall cardiovascular events. The elderly (≥ 75 years), male sex, comorbidity (infections and infestations, cardiac disorders, nervous system disorders) and co-medication (quetiapine and clozapine) were related to death following VEN-associated cardiovascular AEs; however, the risk of cardiovascular death did not increase with regular VEN doses. Our study confirmed the association of cardiovascular AEs with VEN therapy and revealed the influencing factors for the risk of VEN-related cardiovascular AEs and death due to these events. Based on the obtained evidence, the cardiovascular health of late-elderly patients with complex comorbidity and polytherapy should be closely monitored when they receive VEN therapy. As an exploratory study, prospective studies are needed to validate our findings in the future.

A - 146 Psychiatric Drugs Can Precipitate Neuropsychological Predicates of Homicide

Abstract Objective A man inexplicably killed his beloved wife. He had no history of violence, was a prominent member of the community, and gave no indications of the impending horrific act. He had been recently commenced treatment with psychiatric drugs, and his condition deteriorated, culminating in homicide. After his incarceration, he stopped taking psychiatric drugs and his mental health improved. Many practitioners are not aware that psychiatric drugs can create a risk for violence - or precursors of violence - such as anger, hostility, and agitation. This risk is often described on the product label. Method The subject was an intensive care nurse who became exhausted and despondent serving long hours during the Covid epidemic, when many of his patients were put on ventilators and died. He had suffered panic attacks from his difficulty breathing through the respiratory masks. He temporarily left employment and sought psychiatric assistance for his professional “burn-out” condition. After three doses of venlafaxine, he reported side effects including increased anxiety, blood pressure and heart rate. He was then prescribed escitalopram without tapering of the venlafaxine. As his anxiety progressed, he was prescribed escitalopram once daily and buspirone three times daily, yet he continued to deteriorate until the homicide. Results Expert genetic analysis found susceptibility to the psychiatric drugs prescribed. The neuropsychological evaluation, months post-homicide, found excellent neuropsychological function, although psychomotor and processing speed was deficit. Personality testing found no disorders, with a profile inconsistent with violent behavior. Conclusions Prescribers need to monitor patients carefully for potentially adverse and violent outcomes of treatment.

Combination of low doses of mirtazapine plus venlafaxine produces antidepressant-like effects in rats, without affecting male or female sexual behavior.

Pharmacological treatments for depression are not always effective and produce unwanted side effects. Male and female sexual dysfunction is one of these side effects, which can lead to treatment withdrawal. Combination of two antidepressants with different mechanisms of action, like mirtazapine (MTZ) and venlafaxine (VLF) have been shown to be effective for treatment-resistant depression in humans. Combination of low doses of these drugs may still exert antidepressant-like effects without altering sexual behavior. To investigate the potential antidepressant-like effect of the chronic administration of low doses of MTZ plus VLF combined, as well as its impact on male and female sexual behavior in rats. The antidepressant-like effect of a 14-day treatment with combinations of MTZ plus VLF (0/0, 2.5/3.75 or 5/7.5mg/kg) was assessed in young adult male and female rats in the forced swim test (FST). The 5/7.5mg/kg MTZ/VLF combination was also tested in the chronic mild stress (CMS) test, in both males and females treated for 21days. The sexual effects of this last treatment were assessed in sexually experienced males and in gonadally-intact females during proestrus. The 5/7.5mg/kg MTZ/VLF combination produced an antidepressant-like effect in the FST and reversed the CMS-induced anhedonia in both male and female rats. This combination did not alter male sexual behavior, female proceptive and receptive behaviors or the regularity of the estrous cycle. The combination of low doses of MTZ and VLF might be a promising therapeutic alternative to treat depression without affecting the sexual response.

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

Venlafaxine dose regimens vary considerably between individuals, requiring personalized dosing. 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. 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. 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 75mg, 150mg, and 225mg were 0.90, 0.85, and 0.90, respectively. 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.

The protective effect of venlafaxine on hydrogen peroxide-induced cytotoxicity in C6 glioma cells

Aim: Neurodegeneration is the progressive loss and structural deterioration of neuronal cells. Hydrogen peroxide (H2O2) is formed by dismutation and causes oxidative stress in neuronal cells. Venlafaxine is a drug that increases both serotonin and noradrenaline in the synaptic gap.In this study, the effect of venlafaxine on H2O2-induced cytotoxicity in C6 cells was investigated. Methods: First of all, different doses of venlafaxine (25, 50, and 100 µM) were tried to find the appropriate dose in C6 glioma cells. Then, the effect of venlafaxine on H2O2-induced cytotoxicity in the cells was investigated. For this purpose, cell viability rate, proinflammatory markers IL-1β and TNF-α, and NO and iNOS levels were examined by ELISA kits. Results: H2O2-treated caused cytotoxicity in the C6 glioma cells; when venlafaxine 25, 50, and 100 μM doses were evaluated in terms of cell viability, it was observed that the 100 μM venlafaxine applied group significantly increased cell viability compared to the other groups. When we look at the levels of IL-1β and TNF-α, it is observed that there is an increase in the H2O2 applied group and a significant decrease in the venlafaxine (100 μM) applied group. It was observed that NO and iNOS levels increased in the H2O2 applied group compared to the other groups. It was observed that Venlafaxine treatment reduced the increased NO and iNOS levels caused by H2O2. Conclusion: The study results showed that venlafaxine may have a protective effect on H2O2-induced cytotoxicity in C6 glioma cells.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

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.

Treatment of Persistent Idiopathic Dentoalveolar Pain with Venlafaxine: A Multicentric Retrospective Study on Its Effectiveness and Safety.

To determine the effectiveness and safety of venlafaxine in treating persistent idiopathic dentoalveolar pain (PIDP). A retrospective analysis was conducted on a cohort comprising 129 patients with a definite diagnosis of PIDP, who were treated with venlafaxine between May 2020 and December 2022 at three different institutions. Baseline characteristics were statistically described, and visual analog scale (VAS) scores before and during treatment were collected. The percentage of pain relief was calculated. Differences in baseline characteristics between responsive and unresponsive patients were evaluated. Additionally, side effects experienced during treatment were also summarized. Among the included patients, 4 suffered immediate side effects following the initial dose of venlafaxine and the treatment was discontinued. 104 (80.6%) patients achieved pain relief. VAS scores of responsive patients at weeks 2, and months 1, 2, and 3 were significantly lower than baseline (p<0.001). Duration of pain was the only factor related to responsiveness (Wilcoxon rank sum test p<0.001, logistic regression p=0.001). 64 patients (49.6%) suffered from mild side effects. No serious side effects were observed during the study. Venlafaxine is potentially effective and safe in the management of PIDP. Early application of venlafaxine following the diagnoses of PIDP can result in a higher possibility of pain relief.

Investigation of the DNA Damage and Oxidative Effect Induced by Venlafaxine in Mouse Brain and Liver Cells.

Venlafaxine is an antidepressant used worldwide. Therefore, studies to confirm its safe use are mandatory. This report evaluated the drug DNA damage capacity in the brain and liver of ICR mice, and its oxidative effect on DNA, lipids, and proteins, as well as the amount of nitrites, also in the brain and liver. Determinations were made at 2, 6, 12, and 24 h post-treatment, excluding DNA oxidation that was observed at 2 h. The tested doses of venlafaxine were 5, 50, and 250 mg/kg. The results showed DNA damage in the brain with the two more elevated doses of venlafaxine at 2 and 6 h post-treatment and also at 12 h in the liver. The comet assay plus the FPG enzyme showed DNA damage in both organs with all doses. The two high doses increased lipoperoxidation in the two tissues from 6 to 12 h post-administration. Protein oxidation increased with the three doses, mainly from 2 to 12 h, and nitrite content was elevated only with the high dose in the liver. The drug was found to affect both tissues, although it was more pronounced in the liver. Interestingly, DNA oxidative damage was observed even with a dose that corresponds to the therapeutic range. The clinical relevance of these findings awaits further investigations.

Psychopharmacological properties and therapeutic profile of the antidepressant venlafaxine.

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.

Venlafaxine-induced spontaneous ejaculation: Case report and literature review

IntroductionVenlafaxine is a serotonin-norepinephrine reuptake inhibitor and its extensive use for major depressive disorder and anxiety disorders. Although it has been reported that venlafaxine may have various side effects, as far as we know, spontaneous ejaculation(SE) has not been reported yet.ObjectivesWe aim to describe this clinical case with venlafaxine-induced SE and to discuss the possible etiological factors.MethodsCase report and literature review.ResultsA 53-year-old male with generalized anxiety disorder was initiated venlafaxine treatment with 75 mg/day. After two months patient’s complaints partially regressed and the dose of venlafaxine treatment was increased to 150 mg/day. 10 days after the dose increase, the patient applied with the complaint of SE 2-3 times a day. No urological etiology was found. During outpatient follow-ups, after the 5 days from reducing the daily dose to 75 mg/day, SE complaint completely regressed. After following couple of months, the patient by himself, increased the dose of venlafaxine to 150 mg/day without consulting a psychiatrist. Then SE recurred approximately 15 days later. Venlafaxine treatment dose was reduced again to 75 mg/day and urological complaints spontaneously regressed.ConclusionsSE, a rare sexual side effect, represents ejaculation that occurs involuntarily and in the absence of any sexual stimuli. The possible mechanism of SE, detected as a side effect in our case, may be that increased adrenergic activity reduces ejaculatory latency and triggers spontaneous ejaculation. Antidepressant-associated sexual dysfunction could be a dose-dependent adverse event. Therefore, reducing the dosage of the treatment to a minimum effective dose could be an option.DisclosureNo significant relationships.

Painful ejaculation induced by venlafaxine: a case report

IntroductionSexual dysfunction is a quite common side effect of antidepressant treatment. Sexual side effects may affect the person’s adherence to treatment, quality of life, and relations. Premature ejaculation is rarely seen as an adverse effect of antidepressant drugs.ObjectivesWe aimed to present a clinical case of a 53-year-old man who developed painful ejaculation with the use of venlafaxine.MethodsWe made a narrative literature search in Pubmed and Google scholar with the terms of painful ejaculation induced by venlafaxine and antidepressant treatment.Results A 53-year-old man was admitted to the psychiatric outpatient unit with symptoms of anhedonia, decreased sleep, decreased self-esteem for the last month. The patient was diagnosed with depression and he started to take 37,5 mg venlafaxine per day. After one month, when venlafaxine dose was increased to 75mg and the patient started to complain of painful ejaculation. The pain continued from the beginning to the end of the ejaculation. The pain increased more when the venlafaxine dose increased to 150mg per day. The patient was consulted at the urology clinic. The urological examination, laboratory tests (direct microscopic examination of the urethral discharge and urethral culture), and serum prostate-specific antigen levels were normal. No pathology was found in uroflowmetry and ultrasonography of the urinary system. The dose of venlafaxine decreased and the patient started to take 20 mg of fluoxetine per day. His symptoms disappeared after venlafaxine was discontinued.ConclusionsTo literature, this is the second presentation of painful ejaculation observed during the use of venlafaxine.DisclosureNo significant relationships.

Atrial fibrillation debut following first electroconvulsive therapy combined with venlafaxine: a case report and a literature review

IntroductionCardiovascular events (CVE) are infrequent adverse effects in patients receiving electroconvulsive therapy (ECT). Nonetheless, it constitutes a threat for patient’s life and may compromise continuing ECT.ObjectivesTo describe a case of acute-onset atrial fibrillation under combined therapy with ECT and venlafaxine.MethodsWe present a 76-year-old man diagnosed of delusional disorder and without any previous CVE, who was hospitalized in our acute psychiatric unit by major depressive episode with psychotic symptoms resistant to pharmacological treatment (valproic-acid 100mg/d, haloperidol 6mg/d, venlafaxine 300mg/d). ECT was initiated presenting atrial fibrillation after first session of ECT, requiring amiodarone and anticoagulant treatment for stabilization. Second session of ECT was delayed for three-weeks, worsening the psychiatric symptoms. Haloperidol was discontinued initiating lurasidone with better cardiovascular profile.Results CVE occur in 2% of the patients receiving ECT, being acute arrhythmia the most frequent one. Among them, few cases of atrial fibrillation (AF) under ECT have been reported. It has been hypothesised that initial vagal response followed by catecholamine surge secondary to ECT could facilitate the development of AF. In addition venlafaxine, an antidepressant drug, may also predispose to arrhythmia in high-risk individuals. High doses of venlafaxine (&gt;300mg/d) combined with ECT have been related with an increment of CVE.ConclusionsAlthough clinically effective for the treatment of major depression disorder, combined therapy of ECT and venlafaxine could precipitate the start of a CVE in genetically susceptible individuals. Therefore, identify and clarify potential risk factors other than previous history of CVE is critical to reduce morbidity and mortality in these patients.DisclosureNo significant relationships.

A Case of Ruminative Hypomania Induced by High Dose Venlafaxine

IntroductionObsessive phenomena, when present, are usually seen in the depressive phase of bipolar disorder.ObjectivesThe peculiar case with aggravation in ruminative and obsessive thinking with simultaneous hypomania may widen our understanding of the phenomenology of antidepressant induced hypomanic symptoms.MethodsWe present a case of ruminative hypomania induced by high dose venlafaxine. Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D) and Yale Brown Obsessive Compulsive Scale (YBOCS) were used for symptom ratings.ResultsThe patient was 30 years old and she had treatment history of depression for 3 months. She had two consecutive suicide attempts with drugs in the week before she was hospitalized for suicidal risk. She was using venlafaxine 300 mg/day and olanzapin 2,5 mg/day; continuous ruminative thinking about the past and imaginary sexual affairs with former friends were apparent with an unremitting pattern, leading to intense psychomotor agitation and suicide attempts. Irritable mood, and increased energy was observed with continuous ruminations. She was diagnosed with bipolar-II-disorder, with mixed features and anxious distress (YMRS:17, HAM-D:22, YBOCS:34). After discontinuing venlafaxine and starting anti-manic treatment with haloperidol 10 mg/day in the first week, both affective symptoms and ruminations were improved (YMRS:2, HAM-D:4, YBOCS:8). Aripiprazol 20 mg/day and quetiapine 100 mg/day which were given for continuation treatment were also effective for preserving full remission.ConclusionsWhen prescribing high dose venlafaxine for treatment resistant depression, it should be remembered that this may induce hypomanic symptoms and prominent ruminative thinking which can be ameliorated with anti-manic treatment.DisclosureNo significant relationships.

Analysis of Genetic Polymorphism for CYP2D6 &amp; CYP2C19 on a Forensic Autopsy Case Involving Venlafaxine Poisoning

Venlafaxine (VEN) is a type of serotonin-norepinephrine reuptake inhibitor. It is known that the pharmacogenetics of VEN is mainly affected by metabolizer status of the Cytochrome P450 (CYP) 2D6 and CYP2C19 enzymes. We investigate a fatal overdose case of VEN in relation to CYP2D6 and CYP2C19 genetic polymorphisms. Qualitative and quantitative analyses for VEN were performed using gas chromatography-mass spectrometry and it is subsequently confirmed using ultra-high-performance liquid chromatography-tandem mass spectrometry. Genetic analysis for CYP2D6 and CYP2C19 polymorphism was performed using polymerase chain reaction (PCR) followed by DNA sequencing. The result was determined to be a fatal overdose of VEN in a Korean man with CYP2D6 heterozygous genotype *1/*2 that did not affect enzyme activity and wild allele of CYP2C19. The use of genotyping of CYP2D6 and CYP2C19 may assist interpretation for a considerable fatal dose of VEN in individuals with different CYP2D6 genotypes.

Effects of Zuojin Pill (Rhizoma Coptidis and Fructus Evodiae preparation) on the pharmacokinetics and side effects of venlafaxine in humans.

Venlafaxine (VEN), a first-line antidepressant, and Zuojin Pill (ZJP), a common herbal medicine consisting of Rhizoma Coptidis and Fructus Evodiae, are high likely co-administered in China. ZJP could significantly inhibit VEN pharmacokinetics in vitro and in rats through suppression of CYP2D6 activity. To date, however, no clinical study has demonstrated the clinical relevance. Here, the VEN pharmacokinetics at a single dose of VEN with or without co-administration of ZJP was compared. ZJP had a weak herb-drug interactions (HDI) on the pharmacokinetics of VEN. The geometric means of Cmax and AUC0-∞ of VEN increased by 36.7% and 34.6%, respectively, and the corresponding 90% confidence intervals (CIs) of geometric mean ratios (GMRs) exceed outside bioequivalent range of 0.80-1.25. However, the corresponding 90% CIs of GMRs of these parameters for ODV were within the range. Since ODV exposure (AUC), approximately 3.4-fold higher than that of VEN, hardly changed, the systemic exposure of VEN active moiety (VEN + ODV) with ZJP increased slightly (≤8.5%) compared with that of VEN alone. In addition, the incidence of VEN-related side effects, especially gastrointestinal relevance, was significantly reduced with ZJP. Therefore, rational concomitant use of VEN and ZJP might have low risk of HDI and be promising in clinical practice.

Successful use of extended cardiopulmonary resuscitation followed by extracorporeal oxygenation after venlafaxine-induced takotsubo cardiomyopathy and cardiac arrest: a case report

BackgroundSevere venlafaxine intoxication may cause arrhythmias, cardiac failure, and even cardiac arrest.Case presentationA 48-year-old caucasian male with an extensive psychiatric history ingested a high dose of venlafaxine causing a serum venlafaxine concentration of 12.6 mg/L 24 hours after ingestion. Seven hours post-ingestion, he experienced tonic–clonic seizures, and 8 hours later, takotsubo cardiomyopathy was recognized followed by cardiac arrest. The patient was resuscitated with prolonged cardiopulmonary resuscitation including ongoing automatic external compressions during helicopter transportation to a tertiary hospital for extracorporeal membrane oxygenation treatment. Despite a cardiopulmonary resuscitation duration of 2 hours, 36 hours of extracorporeal membrane oxygenation, and a total of 30 days of intensive care, the patient made a full recovery.ConclusionIn cases of intoxication-induced cardiac arrests among otherwise young and healthy patients, prolonged cardiopulmonary resuscitation and extracorporeal circulation can be a life-saving bridge to recovery.

Serotonin Syndrome Associated with Antidepressant Discontinuation in a Neonate Following Drug Exposure During Pregnancy

Sudden withdrawal of some drugs leads to withdrawal issues. We describe a baby girl who was indirectly exposed to venlafaxine as her mother was administered this drug during pregnancy for treatment of depression. The subject presented with involuntary movement of the limbs. The mother had also encountered similar scenario along with some other symptoms after she suddenly discontinued her medication. The symptoms of the mother completely resolved a few hours after the she took another dose of venlafaxine. The baby was kept under observation and recovered completely without any intervention. We suggest that healthcare professionals should be aware that patients may require tapering of anti-depressants before discontinuation.

Lack of an Effect of Supratherapeutic Dose of Venlafaxine on Cardiac Repolarization in Healthy Subjects.

This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.

Serotonin Syndrome Induced by a Single Dose of Venlafaxine and Magnesium Valproate.

Serotonin Syndrome Induced by a Single Dose of Venlafaxine and Magnesium Valproate.

Effects of CYP2D6 Genotypes on Venlafaxine Metabolism in Japanese Psychiatric Patients With Depression.

Venlafaxine (VEN) is primarily metabolized by CYP2D6. Although several studies have reported the significant effects of CYP2D6 on VEN and O-desmethylvenlafaxine (ODV) pharmacokinetics in Whites, limited data are available regarding the effects of the Asian-specific CYP2D6 genotype on VEN metabolism. This study evaluated the effects of the CYP2D6*10 and CYP2D6*5 genotypes on the steady-state plasma concentrations of VEN and ODV in Japanese patients. This study included 75 Japanese patients with depression who were treated with VEN. Steady-state plasma concentrations of VEN and ODV were measured using liquid chromatography. Polymerase chain reaction was used to determine CYP2D6 genotypes. A stepwise multiple regression analysis was performed to analyze the relationship between independent variables (sex, age, smoking habit, and number of mutated alleles, CYP2D6*10 and CYP2D6*5), subject-dependent variables (plasma concentrations of VEN and ODV [all corrected for dose and body weight]), and the ODV/VEN ratio. Significant correlations were observed between the daily dose of VEN (corrected for body weight) and plasma concentrations of VEN (r = 0.498, P < 0.001) and ODV (r = 0.380, P = 0.001); ODV plasma concentrations were approximately 3.2 times higher than VEN plasma concentrations (VEN versus ODV = 18.60 ng/mL versus 59.10 ng/mL). VEN plasma concentrations (corrected for dose and body weight) did not differ with differing numbers of CYP2D6-mutated alleles. However, the ODV/VEN ratio decreased as the number of mutated CYP2D6 alleles increased (P = 0.001). This is the first study to examine the effects of CYP2D6*10 in a clinical setting. Although no effects on the plasma concentrations of VEN or ODV were observed, CYP2D6 polymorphism affects the ODV/VEN ratio. Further studies are needed to confirm the clinical relevance of these findings.