-
International Journal of Clinical... Oct 2023Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result...
BACKGROUND
Pharmacogenetics (PGx), especially in regard to CYP2D6, is gaining more importance in routine clinical settings. Including phenoconversion effects (PC) in result interpretation could maximize its potential benefits. However, studies on genetics of pharmacokinetic genes including the functional enzyme status are lacking.
AIM
The retrospective analyses of clinical routine data aimed to investigating how the CYP2D6 functional enzyme status affects serum concentrations and metabolite-to-parent ratios of seven common psychotropic drugs and allows an evaluation of the relevance of this information for patient care.
METHOD
Two patient cohorts (total n = 316; 44.2 ± 15.4 years) were investigated for the CYP2D6 functional enzyme status and its associations with drug exposure and metabolism of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone and quetiapine.
RESULTS
We found an increase in intermediate and poor metabolizers, as well as a decrease in normal metabolizers of CYP2D6 when including PC. Moreover, we found associations between amitriptyline exposure with the phenoconversion-corrected activity score of CYP2D6 (Spearman correlation; p = 0.03), and risperidone exposure with CYP2D6 functional enzyme status (Kruskal-Wallis test; p = 0.01), as well as between metabolite-to-parent ratio of venlafaxine and risperidone with CYP2D6 functional enzyme status (Kruskal-Wallis test; p < 0.001; p = 0.05).
CONCLUSION
The data stress the relevance of PC-informed PGx in psychopharmacological treatment and suggest that PC should be included in PGx result interpretation when PGx is implemented in routine clinical care, especially before initiating amitriptyline- or risperidone-treatment, to start with a dose adequate to the respective CYP2D6 functional enzyme status. Moreover, PGx and therapeutic drug monitoring should be used complementary but not alternatively.
Topics: Humans; Antipsychotic Agents; Cytochrome P-450 CYP2D6; Retrospective Studies; Risperidone; Pharmacogenetics; Venlafaxine Hydrochloride; Amitriptyline; Genotype; Phenotype; Antidepressive Agents
PubMed: 37166747
DOI: 10.1007/s11096-023-01588-8 -
The Science of the Total Environment Nov 2022Ozonation has been used to effectively remove micropollutants from the secondary effluent in several wastewater treatment plants. It is known that ozonation transforms...
Ozonation has been used to effectively remove micropollutants from the secondary effluent in several wastewater treatment plants. It is known that ozonation transforms tertiary amine compounds into their respective N-oxides, however in an earlier study a mass balance could not be closed at elevated ozone concentrations, leading to the assumption that more ozonation products are possible. This study was conducted to elucidate which (hitherto unknown) ozonation products can be formed from venlafaxine and tramadol when ozonating wastewater. Ozonation experiments were performed with tramadol and venlafaxine N-oxide in two different set-ups. Both tramadol- and venlafaxine N-oxide degraded during ozonation in pure (deionized) water in both semi-continuous and batch mode ozonation set-ups. 13 and 17 new transformation products were detected from tramadol- and venlafaxine N-oxide respectively, using high resolution mass spectrometry with ESI(+) ionization. Empirical chemical formulas were proposed based on the determination of the exact masses and interpretation of the product ion spectra. These transformation products result from the addition of one to three oxygen atoms and removal of C, -CH, CH, CH, etc., from the parent molecule, respectively. Quenching experiments suggested that most of the transformation products originated from the direct reaction with ozone (eight for tramadol N-oxide and ten for venlafaxine N-oxide), whereas fewer products originated from the reaction with OH radicals (three for tramadol N-oxide and three for venlafaxine N-oxide). Reaction mechanisms and chemical structures of products are proposed, based on the available active sites and past literature on ozone reaction mechanisms. The experimental results are compared to theory and literature on ozone reactive sites and ozone reaction mechanisms. All in all this shows that there can be multiple ozonation products, and ozonation pathways can be complex, even if initially only one ozonation product is formed.
Topics: Organic Chemicals; Oxides; Ozone; Tramadol; Venlafaxine Hydrochloride; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Water Purification
PubMed: 35817117
DOI: 10.1016/j.scitotenv.2022.157259 -
Molecules (Basel, Switzerland) Oct 2020Widespread presence of pharmaceuticals and their metabolites in the environment of industrialized countries is an emerging global concern. Potential contamination of the...
Widespread presence of pharmaceuticals and their metabolites in the environment of industrialized countries is an emerging global concern. Potential contamination of the soil and water by such pharmacologically active substances poses serious ecotoxicological implications. Several studies assessing the long-term ecological risks of pharmaceutical contaminants mainly focus on the risk assessment of the parent drug, while the potential contributions of their metabolites is often neglected. Presence of selective serotonin and norepinephrine reuptake inhibitor venlafaxine, an antidepressant drug, and its metabolites is a matter of serious concern for aquatic systems, since they are difficult to remove by traditional wastewater treatment processes. The concentration of VEN present in water is reportedly one of the highest among pharmaceuticals; however, the long-term effects of its metabolites have not yet been systematically studied. Given the consideration to complex and time-consuming effluent treatment, and realizing the importance of levels of venlafaxine and its metabolites, a simple and accurate analytical method for quick determination is needed. We designed a selective colorimetric method by using oxidative coupling of drug molecules with 3-methyl-2-benzothiazolinone hydrazone hydrochloride (MBTH) reagent, to quantify the presence of venlafaxine and its metabolites in aquatic samples, with special emphasis on effluent. The method was validated for selectivity, specificity and robustness as per the ICH Q2 guidelines to assess its suitability in pharmaceutical samples, as well. Highly sensitive and green economical analytical method was successfully established for estimation of venlafaxine and its metabolites in aquatic samples. The method was quick, as it involved minimum processing steps. The method was accurate and linear in the range of 0.5 to 80 ppm and could successfully detect lowest concentration of 1.3 ppm, thus qualifying its applicability for the desired purpose to check the presence of trace levels of VEN or its metabolites in aquatic samples or in pharmaceutical formulations.
Topics: Environmental Monitoring; Humans; Venlafaxine Hydrochloride; Waste Disposal, Fluid; Wastewater; Water Pollutants, Chemical; Water Purification
PubMed: 33086601
DOI: 10.3390/molecules25204793 -
Journal of Clinical PsychopharmacologySince insomnia and depression are interrelated, improved sleep early in antidepressant pharmacotherapy may predict a positive treatment outcome. We investigated whether... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
Topics: Humans; Antidepressive Agents; Depression; Depressive Disorder, Major; Psychotic Disorders; Sleep; Sleep Initiation and Maintenance Disorders; Treatment Outcome; Venlafaxine Hydrochloride
PubMed: 37930199
DOI: 10.1097/JCP.0000000000001756 -
The International Journal of... Apr 2022Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter...
BACKGROUND
Venlafaxine is a dual serotonin (5-HT) and norepinephrine reuptake inhibitor. The specific dose at which it begins to efficiently engage the norepinephrine transporter (NET) remained to be determined. Paroxetine is generally considered as a selective 5-HT reuptake inhibitor but exhibits some affinity for NET. Atomoxetine is a NET inhibitor but also has some affinity for the 5-HT reuptake transporter (SERT).
METHODS
This study examined the effects of forced titration of venlafaxine from 75 to 300 mg/d, paroxetine from 20 to 50 mg/d, or atomoxetine from 25 to 80 mg/d in 32 patients with major depressive disorder. Inhibition of SERT was estimated using the depletion of whole-blood 5-HT. Inhibition of NET was assessed using the attenuation of the systolic blood pressure produced by i.v. injections of tyramine.
RESULTS
All 3 medications significantly reduced 5-HT levels at the initiating regimens: venlafaxine and paroxetine by approximately 60% and atomoxetine by 16%. The 3 subsequent regimens of venlafaxine and paroxetine reduced 5-HT levels by over 90%, but the highest dose of atomoxetine only reached a 40% inhibition. Atomoxetine dose dependently inhibited the tyramine pressor response from the lowest dose, venlafaxine from 225 mg/d, and paroxetine left it unaltered throughout.
CONCLUSION
These results confirm that venlafaxine and paroxetine are potent SERT inhibitors over their usual therapeutic range but that venlafaxine starts inhibiting NET only at 225 mg/d, whereas paroxetine remains selective for SERT up to 50 mg/d. Atomoxetine dose dependently inhibits NET from a low dose but does not inhibit SERT to a clinically relevant degree.
Topics: Antidepressive Agents, Second-Generation; Atomoxetine Hydrochloride; Cyclohexanols; Depressive Disorder, Major; Humans; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Paroxetine; Serotonin; Selective Serotonin Reuptake Inhibitors; Tyramine; Venlafaxine Hydrochloride
PubMed: 34958348
DOI: 10.1093/ijnp/pyab086 -
Journal of Psychopharmacology (Oxford,... Apr 2023Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and...
BACKGROUND
Dyslipidaemia is an important cardiovascular risk factor for people with severe mental illness, contributing to premature mortality. The link between antipsychotics and dyslipidaemia is well established, while evidence on antidepressants is mixed.
AIMS
To investigate if antidepressant/antipsychotic use was associated with lipid parameters in UK Biobank participants and if and genetic variation plays a role.
METHODS
Review of self-reported prescription medications identified participants taking antidepressants/antipsychotics. Total, low-, and high-density lipoprotein cholesterol (L/HDL-C) and triglycerides derived from blood samples. and metabolic phenotypes were assigned from genetic data. Linear regression investigated aims, adjusted for key covariates.
RESULTS
Of 469,739 participants, 36,043 took antidepressants (53% female, median age 58, 17% taking cholesterol-lowering medications) and 3255 took antipsychotics (58% female, median age 57, 27% taking cholesterol-lowering medications). Significant associations were found between use of each amitriptyline, fluoxetine, citalopram/escitalopram, sertraline, paroxetine and venlafaxine with higher total cholesterol, LDL-C, and triglycerides and lower HDL-C, compared to participants not taking each medication. Venlafaxine was associated with the worst lipid profile (total cholesterol, adjusted mean difference: 0.21 mmol/L, 95% confidence interval (CI): 0.17 to 0.26, < 0.001). Antipsychotic use was significantly associated with lower HDL-C and higher triglycerides. In participants taking sertraline, intermediate metabolisers had higher HDL-C (0.05 mmol/L, 95% CI: 0.01 to 0.09, = 0.007) and lower triglycerides (-0.17 mmol/L, 95% CI: -0.29 to -0.05, = 0.007), compared to normal metabolisers.
CONCLUSIONS
Antidepressants were significantly associated with adverse lipid profiles, potentially warranting baseline and regular monitoring. Further research should investigate the mechanistic pathways underlying the protective effects of the intermediate metaboliser phenotype on HDL-C and triglycerides in people taking sertraline.
Topics: Female; Male; Animals; Cytochrome P-450 CYP2D6; Sertraline; Antipsychotic Agents; Venlafaxine Hydrochloride; Cytochrome P-450 CYP2C19; Antidepressive Agents; Triglycerides; Cholesterol; United Kingdom
PubMed: 36772859
DOI: 10.1177/02698811231152748 -
Journal of Feline Medicine and Surgery Jun 2022Venlafaxine, a specific inhibitor of both noradrenaline and serotonin, is commonly used in human medicine to treat depression, anxiety and social phobia. Its formulation...
OBJECTIVES
Venlafaxine, a specific inhibitor of both noradrenaline and serotonin, is commonly used in human medicine to treat depression, anxiety and social phobia. Its formulation in small granules renders it interesting to test on cats, which are usually reluctant to take medication. Venlafaxine was administered at 1 mg/kg for 60 days, using a double-blind, placebo-controlled protocol, to cats aged ⩾6 months exhibiting aggressiveness, fear or house-soiling.
METHODS
After one cat's withdrawal, 21 cats were included in the study: 11 in the venlafaxine group and 10 in the placebo group. Three consultations were conducted, on day 0, day 30 and day 60. Each visit consisted of (1) veterinarian- and owner-based scoring of the cat's behavioural improvement; (2) scoring of the cat's compliance with removal from its carrier and compliance with manipulation; and (3) owner scoring of the ease of administration and recording of the potential adverse effects of the treatment.
RESULTS
Improvement was significantly higher in the venlafaxine group; as early as day 30, according to the veterinarian scoring, and at day 60, according to both the veterinarian and owner scoring. In contrast, neither the removal nor the manipulation scores were significantly different between the two treatment groups. Venlafaxine seemed to improve all three studied signs, as early as day 30 for fear and aggressiveness, and at day 60 for house-soiling. The adverse effects of venlafaxine were limited to drowsiness in one cat. All cats tolerated the treatment well during the 60-day period.
CONCLUSIONS AND RELEVANCE
These results suggest that venlafaxine is efficient in treating several behavioural problems and is easy to administer. More studies should be conducted to explore its effects at different dosages on specific diagnoses.
Topics: Animals; Anxiety; Cats; Double-Blind Method; Fear; Pilot Projects; Treatment Outcome; Venlafaxine Hydrochloride
PubMed: 34420375
DOI: 10.1177/1098612X211036792 -
Journal of Chromatography. B,... Aug 2022The majority of women have health problems that require medication after giving birth. Complications such as allergies, postpartum depression, and diabetes are often...
The majority of women have health problems that require medication after giving birth. Complications such as allergies, postpartum depression, and diabetes are often treated with drugs such as cetirizine, venlafaxine, and metformin, respectively. These treatments are considered safe during lactation, but information of the transfer of drugs to breast milk and possible effects on the infant is scarce. Therefore, this needs to be systematically investigated in larger populations. To enable the determination of drug transfer, we here describe the validation of two rapid, sensitive, and high-throughput analysis methods for 1) simultaneous quantification of cetirizine, venlafaxine, and O-desmethylvenlafaxine in human breast milk, and 2) metformin in human breast milk and plasma. In both methods, a simple protein precipitation protocol with acetonitrile and benchtop-centrifugation was used prior to compound analysis with liquid-chromatography tandem mass spectrometry. The methods had linear ranges between 0.39 - 194.5 ng/mL for cetirizine, 0.28 - 138.7 ng/mL for venlafaxine, 0.26 - 131.7 ng/mL for O-desmethylvenlafaxine, in milk, and 0.65 - 193.7 ng/mL for metformin in both milk and plasma. Intra-run and inter-run precision and accuracy were ≤ 9% for cetirizine, venlafaxine, and O-desmethylvenlafaxine in milk, and ≤ 7% for metformin in milk and plasma. Cetirizine was measured to median milk concentrations of 13 ng/mL (range: 0.65 - 65 ng/mL) in 228 donor samples from breast-feeding women.
Topics: Cetirizine; Chromatography, High Pressure Liquid; Desvenlafaxine Succinate; Female; Humans; Infant; Metformin; Milk, Human; Pregnancy; Reproducibility of Results; Tandem Mass Spectrometry; Venlafaxine Hydrochloride
PubMed: 35732105
DOI: 10.1016/j.jchromb.2022.123340 -
International Journal of Molecular... May 2024Depression is emerging as the predominant psychiatric disorder globally. Despite the wide availability of antidepressants, up to 30% of patients exhibit poor response to...
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 ( < 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 ( < 0.05 central zone; ≤ 0.05 periphery zone) and SMe1EC2M3 ( < 0.05 central zone; < 0.05 periphery zone) groups compared to the venlafaxine + zoletil group. SMe1EC2M3 was able to significantly increase the time of climbing in FST ( < 0.05) in comparison with the venlafaxine and control groups. The NOR test revealed a significantly higher discrimination ratio in the SMe1EC2M3 group ( < 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 ( < 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.
Topics: Animals; Rats; Male; Disease Models, Animal; Antidepressive Agents; Venlafaxine Hydrochloride; Depression; Behavior, Animal; Depressive Disorder, Treatment-Resistant; Rats, Inbred WKY; Stress, Psychological; Anxiety; Indoles; Anhedonia
PubMed: 38791304
DOI: 10.3390/ijms25105265 -
Journal of Clinical Psychopharmacology 2020Venlafaxine is a commonly used antidepressant with both serotonergic and noradrenergic activity. There are concerns that it may prolong the corrected QT interval (QTc),... (Clinical Trial)
Clinical Trial
PURPOSE/BACKGROUND
Venlafaxine is a commonly used antidepressant with both serotonergic and noradrenergic activity. There are concerns that it may prolong the corrected QT interval (QTc), and older adults may be at higher risk for this adverse effect, especially at higher dosages of the medication.
METHODS/PROCEDURES
In this secondary analysis of a prospective clinical trial, we measured changes in QTc and other electrocardiogram (ECG) parameters in 169 adults 60 years or older with a major depressive disorder treated acutely with venlafaxine extended release up to 300 mg daily. We examined the relationship of venlafaxine dosage and ECG parameters, as well as the relationship between serum levels of venlafaxine and ECG parameters.
FINDINGS/RESULTS
Venlafaxine exposure was not associated with an increase in QTc. Heart rate increased with venlafaxine treatment, whereas the PR interval shortened, and QRS width did not change significantly. The QTc change from baseline was not associated with venlafaxine dosages or serum concentrations. Age, sex, cardiovascular comorbidities, and depression remission status did not predict changes in QTc with venlafaxine.
IMPLICATIONS/CONCLUSIONS
Venlafaxine treatment did not prolong QTc or other ECG parameters, even in high dosages in older depressed adults. These findings indicate that venlafaxine does not significantly affect cardiac conduction in most older patients.
Topics: Action Potentials; Age Factors; Aged; Aged, 80 and over; Depressive Disorder, Major; Electrocardiography; Female; Heart Conduction System; Heart Rate; Humans; Long QT Syndrome; Male; Middle Aged; North America; Predictive Value of Tests; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome; Venlafaxine Hydrochloride
PubMed: 33044352
DOI: 10.1097/JCP.0000000000001287