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Molecular Psychiatry Jan 2023A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to... (Meta-Analysis)
Meta-Analysis
A systematic review and random-effects model network meta-analysis were conducted to compare the efficacy, acceptability, tolerability, and safety of antidepressants to treat adults with major depressive disorder (MDD) in the maintenance phase. This study searched the PubMed, Cochrane Library, and Embase databases and included only double-blind, randomized, placebo-controlled trials with an enrichment design: patients were stabilized on the antidepressant of interest during the open-label study and then randomized to receive the same antidepressant or placebo. The outcomes were the 6-month relapse rate (primary outcome, efficacy), all-cause discontinuation (acceptability), discontinuation due to adverse events (tolerability), and the incidence of individual adverse events. The risk ratio with a 95% credible interval was calculated. The meta-analysis comprised 34 studies (n = 9384, mean age = 43.80 years, and %females = 68.10%) on 20 antidepressants (agomelatine, amitriptyline, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, vilazodone, and vortioxetine) and a placebo. In terms of the 6-month relapse rate, amitriptyline, citalopram, desvenlafaxine, duloxetine, fluoxetine, fluvoxamine, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, tianeptine, venlafaxine, and vortioxetine outperformed placebo. Compared to placebo, desvenlafaxine, paroxetine, sertraline, venlafaxine, and vortioxetine had lower all-cause discontinuation; however, sertraline had a higher discontinuation rate due to adverse events. Compared to placebo, venlafaxine was associated with a lower incidence of dizziness, while desvenlafaxine, sertraline, and vortioxetine were associated with a higher incidence of nausea/vomiting. In conclusion, desvenlafaxine, paroxetine, venlafaxine, and vortioxetine had reasonable efficacy, acceptability, and tolerability in the treatment of adults with stable MDD.
Topics: Female; Humans; Adult; Depressive Disorder, Major; Duloxetine Hydrochloride; Sertraline; Citalopram; Venlafaxine Hydrochloride; Vortioxetine; Fluoxetine; Paroxetine; Mirtazapine; Amitriptyline; Desvenlafaxine Succinate; Fluvoxamine; Reboxetine; Network Meta-Analysis; Antidepressive Agents; Randomized Controlled Trials as Topic
PubMed: 36253442
DOI: 10.1038/s41380-022-01824-z -
The Cochrane Database of Systematic... May 2021Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Major depressive disorders have a significant impact on children and adolescents, including on educational and vocational outcomes, interpersonal relationships, and physical and mental health and well-being. There is an association between major depressive disorder and suicidal ideation, suicide attempts, and suicide. Antidepressant medication is used in moderate to severe depression; there is now a range of newer generations of these medications.
OBJECTIVES
To investigate, via network meta-analysis (NMA), the comparative effectiveness and safety of different newer generation antidepressants in children and adolescents with a diagnosed major depressive disorder (MDD) in terms of depression, functioning, suicide-related outcomes and other adverse outcomes. The impact of age, treatment duration, baseline severity, and pharmaceutical industry funding was investigated on clinician-rated depression (CDRS-R) and suicide-related outcomes.
SEARCH METHODS
We searched the Cochrane Common Mental Disorders Specialised Register, the Cochrane Library (Central Register of Controlled Trials (CENTRAL) and Cochrane Database of Systematic Reviews (CDSR)), together with Ovid Embase, MEDLINE and PsycINFO till March 2020.
SELECTION CRITERIA
Randomised trials of six to 18 year olds of either sex and any ethnicity with clinically diagnosed major depressive disorder were included. Trials that compared the effectiveness of newer generation antidepressants with each other or with a placebo were included. Newer generation antidepressants included: selective serotonin reuptake inhibitors; selective norepinephrine reuptake inhibitors (SNRIs); norepinephrine reuptake inhibitors; norepinephrine dopamine reuptake inhibitors; norepinephrine dopamine disinhibitors (NDDIs); and tetracyclic antidepressants (TeCAs).
DATA COLLECTION AND ANALYSIS
Two reviewers independently screened titles/abstracts and full texts, extracted data, and assessed risk of bias. We analysed dichotomous data as Odds Ratios (ORs), and continuous data as Mean Difference (MD) for the following outcomes: depression symptom severity (clinician rated), response or remission of depression symptoms, depression symptom severity (self-rated), functioning, suicide related outcomes and overall adverse outcomes. Random-effects network meta-analyses were conducted in a frequentist framework using multivariate meta-analysis. Certainty of evidence was assessed using Confidence in Network Meta-analysis (CINeMA). We used "informative statements" to standardise the interpretation and description of the results.
MAIN RESULTS
Twenty-six studies were included. There were no data for the two primary outcomes (depressive disorder established via clinical diagnostic interview and suicide), therefore, the results comprise only secondary outcomes. Most antidepressants may be associated with a "small and unimportant" reduction in depression symptoms on the CDRS-R scale (range 17 to 113) compared with placebo (high certainty evidence: paroxetine: MD -1.43, 95% CI -3.90, 1.04; vilazodone: MD -0.84, 95% CI -3.03, 1.35; desvenlafaxine MD -0.07, 95% CI -3.51, 3.36; moderate certainty evidence: sertraline: MD -3.51, 95% CI -6.99, -0.04; fluoxetine: MD -2.84, 95% CI -4.12, -1.56; escitalopram: MD -2.62, 95% CI -5.29, 0.04; low certainty evidence: duloxetine: MD -2.70, 95% CI -5.03, -0.37; vortioxetine: MD 0.60, 95% CI -2.52, 3.72; very low certainty evidence for comparisons between other antidepressants and placebo). There were "small and unimportant" differences between most antidepressants in reduction of depression symptoms (high- or moderate-certainty evidence). Results were similar across other outcomes of benefit. In most studies risk of self-harm or suicide was an exclusion criterion for the study. Proportions of suicide-related outcomes were low for most included studies and 95% confidence intervals were wide for all comparisons. The evidence is very uncertain about the effects of mirtazapine (OR 0.50, 95% CI 0.03, 8.04), duloxetine (OR 1.15, 95% CI 0.72, 1.82), vilazodone (OR 1.01, 95% CI 0.68, 1.48), desvenlafaxine (OR 0.94, 95% CI 0.59, 1.52), citalopram (OR 1.72, 95% CI 0.76, 3.87) or vortioxetine (OR 1.58, 95% CI 0.29, 8.60) on suicide-related outcomes compared with placebo. There is low certainty evidence that escitalopram may "at least slightly" reduce odds of suicide-related outcomes compared with placebo (OR 0.89, 95% CI 0.43, 1.84). There is low certainty evidence that fluoxetine (OR 1.27, 95% CI 0.87, 1.86), paroxetine (OR 1.81, 95% CI 0.85, 3.86), sertraline (OR 3.03, 95% CI 0.60, 15.22), and venlafaxine (OR 13.84, 95% CI 1.79, 106.90) may "at least slightly" increase odds of suicide-related outcomes compared with placebo. There is moderate certainty evidence that venlafaxine probably results in an "at least slightly" increased odds of suicide-related outcomes compared with desvenlafaxine (OR 0.07, 95% CI 0.01, 0.56) and escitalopram (OR 0.06, 95% CI 0.01, 0.56). There was very low certainty evidence regarding other comparisons between antidepressants.
AUTHORS' CONCLUSIONS
Overall, methodological shortcomings of the randomised trials make it difficult to interpret the findings with regard to the efficacy and safety of newer antidepressant medications. Findings suggest that most newer antidepressants may reduce depression symptoms in a small and unimportant way compared with placebo. Furthermore, there are likely to be small and unimportant differences in the reduction of depression symptoms between the majority of antidepressants. However, our findings reflect the average effects of the antidepressants, and given depression is a heterogeneous condition, some individuals may experience a greater response. Guideline developers and others making recommendations might therefore consider whether a recommendation for the use of newer generation antidepressants is warranted for some individuals in some circumstances. Our findings suggest sertraline, escitalopram, duloxetine, as well as fluoxetine (which is currently the only treatment recommended for first-line prescribing) could be considered as a first option. Children and adolescents considered at risk of suicide were frequently excluded from trials, so that we cannot be confident about the effects of these medications for these individuals. If an antidepressant is being considered for an individual, this should be done in consultation with the child/adolescent and their family/caregivers and it remains critical to ensure close monitoring of treatment effects and suicide-related outcomes (combined suicidal ideation and suicide attempt) in those treated with newer generation antidepressants, given findings that some of these medications may be associated with greater odds of these events. Consideration of psychotherapy, particularly cognitive behavioural therapy, as per guideline recommendations, remains important.
Topics: Adolescent; Antidepressive Agents; Bias; Child; Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Duloxetine Hydrochloride; Female; Fluoxetine; Humans; Male; Mirtazapine; Network Meta-Analysis; Paroxetine; Selective Serotonin Reuptake Inhibitors; Sertraline; Suicidal Ideation; Venlafaxine Hydrochloride; Vilazodone Hydrochloride; Vortioxetine
PubMed: 34029378
DOI: 10.1002/14651858.CD013674.pub2 -
Journal of Affective Disorders May 2023Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses.... (Randomized Controlled Trial)
Randomized Controlled Trial
A multicenter, randomized, double-blind, duloxetine-controlled, non-inferiority trial of desvenlafaxine succinate extended-release in patients with major depressive disorder.
BACKGROUND
Desvenlafaxine and duloxetine are selective serotonin and norepinephrine reuptake inhibitors. Their efficacy has not been directly compared using statistical hypotheses. This study evaluated the non-inferiority of desvenlafaxine extended-release (XL) to duloxetine in patients with major depressive disorder (MDD).
METHODS
In this study, 420 adult patients with moderate-to-severe MDD were enrolled and randomly assigned (1:1) to receive 50 mg (once daily [QD]) of desvenlafaxine XL (n = 212) or 60 mg QD of duloxetine (n = 208). The primary endpoint was evaluated using a non-inferiority comparison based on the change from baseline to 8 weeks in the 17-item Hamilton Depression Rating Scale (HAMD) total score. Secondary endpoints and safety were evaluated.
RESULTS
Least-squares mean change in HAM-D total score from baseline to 8 weeks was -15.3 (95% confidence interval [CI]: -17.73, -12.89) in the desvenlafaxine XL group and - 15.9 (95% CI, -18.44, -13.39) in the duloxetine group. The least-squares mean difference was 0.6 (95% CI: -0.48, 1.69), and the upper boundary of 95% CI was less than the non-inferiority margin (2.2). No significant between-treatment differences were found in most secondary efficacy endpoints. The incidence of the most common treatment-emergent adverse events (TEAEs) was lower for desvenlafaxine XL than for duloxetine for nausea (27.2% versus 48.8%) and dizziness (18.0% versus 28.8%).
LIMITATIONS
A short-term non-inferiority study without a placebo arm.
CONCLUSIONS
This study demonstrated that desvenlafaxine XL 50 mg QD was non-inferior to duloxetine 60 mg QD in efficacy in patients with MDD. Desvenlafaxine had a lower incidence of TEAEs than duloxetine did.
Topics: Adult; Humans; Duloxetine Hydrochloride; Depressive Disorder, Major; Desvenlafaxine Succinate; Antidepressive Agents; Double-Blind Method; Treatment Outcome
PubMed: 36813043
DOI: 10.1016/j.jad.2023.02.067 -
Clinical Pharmacology and Therapeutics Jul 2020The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and... (Review)
Review
The US Food and Drug Administration (FDA) lists 22 medications as clinical inhibitors of cytochrome P450 2D6 isoenzyme, with classifications of strong, moderate, and weak. It is accepted that strong inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels for area under the plasma concentration-time curve (AUC) fold-changes caused by inhibitors in humans and identified 89 inhibitor-substrate pairs. Observed AUC fold-change of the substrate was used to create an observed inhibitor classification per FDA-defined AUC fold-change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.
Topics: Area Under Curve; Cimetidine; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Desvenlafaxine Succinate; Fluvoxamine; Humans
PubMed: 31910286
DOI: 10.1002/cpt.1768 -
Journal of Clinical PsychopharmacologyHeterogeneity has been documented in trajectories of symptom change during antidepressant treatment for major depressive disorder (MDD). It is unclear whether distinct... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE/BACKGROUND
Heterogeneity has been documented in trajectories of symptom change during antidepressant treatment for major depressive disorder (MDD). It is unclear whether distinct trajectories of change exist for functioning during antidepressant treatment.
METHODS/PROCEDURES
This analysis explored distinct trajectories of functioning in MDD and tested whether they corresponded to trajectories of symptom change. Data were from 4317 patients and were pooled from 9 randomized placebo-controlled trials. Growth mixture modeling was used to identify trajectories of Hamilton Rating Scale for Depression (HRSD) and Sheehan Disability Scale (SDS) for placebo- and desvenlafaxine-treated patients.
FINDINGS/RESULTS
Three trajectories were identified for symptoms (HRSD) in patients receiving placebo (mean reduction baseline to week 8, -18.4 [most favorable] to -2.6 points [least favorable]). Four HRSD trajectories were identified for patients receiving desvenlafaxine (mean reduction from baseline to week 8, -17.2 [most favorable] to -2.6 points [least favorable]). Four trajectories were identified for functioning (SDS) in patients receiving placebo (mean reduction baseline to week 8, -13.6 [most favorable] to -0.8 points [least favorable]), and 3 for desvenlafaxine (-12.8 to -1.4 points, respectively). Percentages of agreement between most favorable HRSD and SDS trajectories were 75% (placebo) and 85% (desvenlafaxine), and for least favorable trajectories were 88% (placebo) and 80% (desvenlafaxine).
IMPLICATIONS/CONCLUSIONS
Distinct trajectories of change based on symptoms and functioning were identified among patients with MDD receiving desvenlafaxine and among patients with MDD receiving placebo. Differentiating subpopulations of patients has the potential to provide a more personalized treatment of patients with MDD.ClinicalTrials.govIdentifiers: NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457.
Topics: Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Precision Medicine; Treatment Outcome
PubMed: 34183490
DOI: 10.1097/JCP.0000000000001435 -
The Mental Health Clinician May 2020Desvenlafaxine is a potent selective serotonin and norepinephrine reuptake inhibitor used to treat depression and anxiety. Several antidepressants have been associated...
Desvenlafaxine is a potent selective serotonin and norepinephrine reuptake inhibitor used to treat depression and anxiety. Several antidepressants have been associated with drug-induced hyperglycemia, but currently there are no reports for desvenlafaxine. A case of suspected desvenlafaxine-induced hyperglycemia is presented involving a 59-year-old female with type 2 diabetes whose average blood glucose increased by 30 mg/dL for fasting blood glucose and 75 mg/dL for postprandial blood glucose 1 month after switching from venlafaxine to desvenlafaxine. Prior to starting desvenlafaxine, she was stable on metformin 1000 mg twice daily, insulin glargine 8 units daily, and dulaglutide 1.5 mg once weekly. Over the course of 3 months after desvenlafaxine initiation, insulin glargine was increased and insulin lispro was initiated as the patient refused alternative antidepressant therapy due to favorable improvements in anxiety and depression. No other cause for elevated blood glucose could be elucidated. The Naranjo scale resulted in a score of 3, indicating a possible cause for the adverse drug reaction. Antidepressants have been associated with glucose dysregulation. However, literature also demonstrates improved glycemic control in treated versus untreated depression. If altered glucose levels are noted, all potential causative factors should be evaluated and risks and benefits weighed to guide therapy.
PubMed: 32420005
DOI: 10.9740/mhc.2020.05.085 -
International Journal of Molecular... Sep 2022Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time...
Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time is needed. In this study, we developed a novel radiopharmaceutical for quantitative imaging to estimate hepatic CYP3A4 and CYP2D6 activity. Iodine-123- and 125-labeled -desmethylvenlafaxine (I-ODV) was obtained with high labeling and purity, and its metabolism was found to strongly involve CYP3A4 and CYP2D6. SPECT imaging in normal mice showed that the administered I-ODV accumulated early in the liver and was excreted into the gallbladder, as evaluated by time activity curves. In its biological distribution, I-ODV administered to mice accumulated early in the liver, and only the metabolite of I-ODV was quickly excreted into the bile. In CYP3A4- and CYP2D6-inhibited model mice, the accumulation in bile decreased more than in normal mice, indicating inhibition of metabolite production. These results indicated that imaging and quantifying the accumulation of radioactive metabolites in excretory organs will aid in determining the dosages of various drugs metabolized by CYP3A4 and CYP2D6 for individualized medicine. Thus, I-ODV has the potential to direct, comprehensive detection and measurement of hepatic CYP3A4 and CYP2D6 activity by a simple and less invasive approach.
Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Desvenlafaxine Succinate; Iodine Radioisotopes; Liver; Mice; Radiopharmaceuticals; Venlafaxine Hydrochloride
PubMed: 36232758
DOI: 10.3390/ijms231911458 -
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 -
Brain, Behavior, and Immunity Jul 2020The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease...
INTRODUCTION
The response of patients with major depressive disorders (MDD) to antidepressant treatments have been shown to be affected by multiple factors, including disease severity and inflammation. Increasing evidence indicates that the kynurenine metabolic pathway is activated by inflammation in MDD patients and plays a role in the pathophysiology of depression. Antidepressant treatments have been reported to affect kynurenine pathway metabolite levels as well. This study investigates differential associations between the antidepressant treatment outcome to escitalopram versus desvenlafaxine with the pre-treatment and post-treatment-changes in serotonin and kynurenine pathway metabolite levels.
METHODS
The levels of serotonin and of kynurenine pathway metabolites were measured in plasma using liquid chromatography-mass spectrometry (LC-MS) in 161 currently depressed patients with MDD at baseline and after 8 weeks of treatment with either escitalopram or desvenlafaxine. Treatment response was defined conventionally by a reduction of at least 50% in the Hamilton Depression Rating Scale 21 item (HAMD-21) total score from baseline; remission was defined by reaching a post-treatment HAMD-21 score ≤7.
RESULTS
Response to escitalopram treatment was associated with higher baseline serotonin levels (p = 0.022), lower baseline kynurenine (Kyn)/tryptophan (Trp) ratio (p = 0.008) and lower baseline quinolinic acid (QuinA)/tryptophan (Trp) ratio (p = 0.047), suggesting a lower inflammation state. Greater improvement in depression symptoms as measured by percent change of HAMD-21 score from baseline was also associated with higher baseline serotonin levels (p = 0.033) in escitalopram treatment arm. Furthermore, remitters to escitalopram treatment showed significant increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio after treatment (p = 0.015). In contrast, response to desvenlafaxine treatment was not associated with any metabolite analyzed. We also confirmed a previous report that plasma serotonin levels are lower in MDD patients compared to healthy controls (p = 0.004) and that the kynurenine plasma level is negatively associated with depression symptom severity (p = 0.047).
CONCLUSIONS
In MDD patients the antidepressant response to escitalopram was positively associated with baseline serotonin levels and inversely associated with activation of the kynurenine pathway. These results appear consistent with previous literature showing that biomarker evidence of inflammation is associated with lower response to antidepressants from the selective serotonin reuptake inhibitor class. Moreover, increases in the kynurenic acid (KynA)/3-hydroxykynurenine (3HK) ratio, which previously has been characterized as a neuroprotective index, were associated with full remission under escitalopram treatment.
Topics: Citalopram; Depressive Disorder, Major; Desvenlafaxine Succinate; Humans; Kynurenic Acid; Kynurenine; Plasma; Serotonin
PubMed: 31978524
DOI: 10.1016/j.bbi.2020.01.011 -
Frontiers in Chemistry 2022We herein describe an optimal approach for the efficient synthesis of -desmethylvenlafaxine succinate monohydrate (DVS) with high yield and high purity through 5-step...
We herein describe an optimal approach for the efficient synthesis of -desmethylvenlafaxine succinate monohydrate (DVS) with high yield and high purity through 5-step reactions, including benzyl protection of the phenolic hydroxyl group, cyclohexanone condensation, deprotection, cyano reduction, dimethylation, and succinic acid salt formation from -hydroxybenzene acetonitrile as a starting material. 4-Benzyloxyphenylacetonitrile (Intermediate I) was prepared by the hydroxyl protection of the bromide benzyl--hydroxyphenylacetonitrile catalyzed by potassium carbonate with 99.83% purity and 98.92% yields. The 1, 2-nucleophilic addition of intermediate I to cyclohexanone promoted by sodium hydroxide with the homogeneous catalyst (n-Bu)NBr to the preparation of 1-[Cyano(4-benzyloxyphenyl)methyl]cyclohexanol (Intermediate II) was obtained by 99.13% purity and 99.71% yields. Cyclohexanone residues and benzyl bromide residues were trace, and tetrabutylammonium bromide residues were UNDER 0.7 ppm, which further improves the residual standards for genotoxic impurities (GIs). 1-[2-amino-1-(4-hydroxyphenyl)ethyl]cyclohexanol hydrochloride (Intermediate III) was prepared by 10% palladium-carbon under 2.0 MPa up to 98.32% purity and 94.20% yields. -desmethylvenlafaxine (ODV) was synthesized by dimethylation of intermediate III with 37% formaldehyde solution and 85% formic acid solution. The highest purity was up to 99.20% and the yield was up to 84.77%. -desmethylvenlafaxine succinate monohydrate (DVS) was formed from succinic acid and -desmethylvenlafaxine (ODV) and crystallized in a mixed solvent of acetone and water (3:1) to obtain 99.92% purity and 90.27% yields. The 5-step total yields of desvenlafaxine succinate monohydrate is 71.09%, and its crystal form has characteristic peaks at 5, 10, 21, and 26 min by XRD powder diffraction, which is consistent with the crystalline form I. Compared with conventional synthesis strategy, we revealed a novel and green process with a high total yield, high atomic economy, low environmental pollution, high operational safety, and high residual standards for genotoxic impurities (GIs), which improves drug safety.
PubMed: 36059880
DOI: 10.3389/fchem.2022.860292