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Archives of Pharmacal Research May 2024Venlafaxine, a serotonin-norepinephrine reuptake inhibitor (SNRI), is indicated for the treatment of major depressive disorder, social anxiety disorder, generalized...
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 C 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 C 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.
Topics: Venlafaxine Hydrochloride; Clarithromycin; Humans; Cytochrome P-450 CYP2D6; Drug Interactions; Paroxetine; Genotype; Models, Biological; Adult; Male; Serotonin and Noradrenaline Reuptake Inhibitors; Female; Polymorphism, Genetic; Young Adult
PubMed: 38664354
DOI: 10.1007/s12272-024-01495-0 -
Psychiatry Research Jun 2024The relationship between the use of selective serotonin reuptake inhibitors (SSRIs) and suicide risk in patients with mental disorders remains controversial. We... (Meta-Analysis)
Meta-Analysis
The relationship between the use of selective serotonin reuptake inhibitors (SSRIs) and suicide risk in patients with mental disorders remains controversial. We conducted a network meta-analysis to examine the effects of SSRIs on suicide risk in patients with mental disorders. A comprehensive search was conducted across PubMed, Web of Science, PsycINFO, CENTRAL, Wanfang Database, and China National Knowledge Infrastructure for articles published until December 19, 2023. The main outcomes were suicidal ideation and instances of suicidal behavior. We included 29 double-blind randomized trials in our analysis. The findings suggest that SSRIs primarily offer short-term protection against suicidal ideation. By week 2, paroxetine, fluoxetine, escitalopram, and non-SSRI treatments were linked to a decreased suicide risk compared with a placebo, with the exception of sertraline. This protective effect was diminished by week 8. In contrast, studies on instances of suicidal behavior from weeks 1 to 10 found no significant difference in efficacy between SSRIs, non-SSRIs, and placebo. These results indicate that SSRIs may offer short-term protection against suicidal ideation. However, their long-term effectiveness in mitigating suicidal ideation and preventing suicidal behaviors is limited.
Topics: Selective Serotonin Reuptake Inhibitors; Humans; Randomized Controlled Trials as Topic; Suicidal Ideation; Network Meta-Analysis; Double-Blind Method; Suicide; Mental Disorders
PubMed: 38663222
DOI: 10.1016/j.psychres.2024.115917 -
Cureus Apr 2024Eating disorders (EDs) are among the most dangerous mental illnesses, that are characterized by high mortality rates, multisystem comorbidity, and an often chronic and...
Eating disorders (EDs) are among the most dangerous mental illnesses, that are characterized by high mortality rates, multisystem comorbidity, and an often chronic and relapsing disease course. EDs occur most commonly in the female gender, with a ratio of 10 females to 1 male for anorexia nervosa (AN). We present the case of a 15-year-old Saudi boy who presented with weight loss (BMI 11.6 kg/m) and began to have symptoms of obsessive-compulsive disorder (OCD) in prayer and ablution. His first treatment plan was psychoeducation. He then developed a fear of gaining weight and began to count calories; he was diagnosed with AN and started on olanzapine 2.5 mg. The patient had a history of multiple admissions due to electrolyte imbalance, hypokalemia, hypoglycemia, and anal fissure due to constipation, and was prescribed olanzapine 5 mg, fluoxetine 20. His last admission was the worst, as he became semi-comatose with a Glasgow Coma Scale (GCS) of 13, was diffused and disoriented to time and person, unable to walk or sit, and was uncooperative in answering questions. During admission, we changed the fluoxetine to paroxetine 25 mg and increased the olanzapine to 10 mg, and the patient showed a huge improvement physically and mentally. This case emphasizes the significance of including paroxetine in the treatment of diagnoses for AN to prevent unnecessary wasting of time and effort.
PubMed: 38654963
DOI: 10.7759/cureus.58765 -
Journal of Pharmaceutical and... Aug 2024Desvenlafaxine (O-desmethylvenlafaxine) and paroxetine are antidepressants that inhibit serotonin reuptake. Despite their relatively safe profiles, several serious side...
Desvenlafaxine (O-desmethylvenlafaxine) and paroxetine are antidepressants that inhibit serotonin reuptake. Despite their relatively safe profiles, several serious side effects, including serotonin syndrome, bleeding, mania, and high blood pressure, are observed. We report the confirmation of the death of a 41-year-old female, with an overdose of desvenlafaxine and paroxetine suspected as the main cause of death. To quantify the level of desvenlafaxine and paroxetine in whole blood and urine, solid phase extraction combined with liquid chromatography-tandem mass spectrometry was developed and validated. Calibration curves were linear with coefficients of determination (r) >0.999 for desvenlafaxine and paroxetine. The limits of detection and the limits of quantification for both desvenlafaxine and paroxetine were 0.001 µg/mL and 0.02 µg/mL, respectively. Desvenlafaxine and paroxetine were detected in the postmortem samples, along with various psychiatric drugs, and the blood alcohol content level was below 0.010%. The concentrations of desvenlafaxine and paroxetine in the heart blood were 11.0 µg/mL and 2.1 µg/mL, respectively, indicating lethal concentrations. In the urine, the concentrations of desvenlafaxine and paroxetine were 87.7 µg/mL and 3.5 µg/mL, respectively. This is the first report to determine the blood concentration of desvenlafaxine in a fatal intoxication caused by an overdose of desvenlafaxine single formulation.
Topics: Humans; Desvenlafaxine Succinate; Paroxetine; Female; Adult; Tandem Mass Spectrometry; Drug Overdose; Chromatography, Liquid; Solid Phase Extraction; Fatal Outcome; Antidepressive Agents; Limit of Detection; Selective Serotonin Reuptake Inhibitors
PubMed: 38652939
DOI: 10.1016/j.jpba.2024.116148 -
The Journal of Mental Health Policy and... Mar 2024Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no... (Observational Study)
Observational Study
BACKGROUND
Consensus-guidelines for prescribing antidepressants recommend that clinicians should be vigilant to match antidepressants to patient's medical history but provide no specific advice on which antidepressant is best for a given medical history.
AIMS OF THE STUDY
For patients with major depression who are in psychotherapy, this study provides an empirically derived guideline for prescribing antidepressant medications that fit patients' medical history.
METHODS
This retrospective, observational, cohort study analyzed a large insurance database of 3,678,082 patients. Data was obtained from healthcare providers in the U.S. between January 1, 2001, and December 31, 2018. These patients had 10,221,145 episodes of antidepressant treatments. This study reports the remission rates for the 14 most commonly prescribed single antidepressants (amitriptyline, bupropion, citalopram, desvenlafaxine, doxepin, duloxetine, escitalopram, fluoxetine, mirtazapine, nortriptyline, paroxetine, sertraline, trazodone, and venlafaxine) and a category named "Other" (other antidepressants/combination of antidepressants). The study used robust LASSO regressions to identify factors that affected remission rate and clinicians' selection of antidepressants. The selection bias in observational data was removed through stratification. We organized the data into 16,770 subgroups, of at least 100 cases, using the combination of the largest factors that affected remission and selection bias. This paper reports on 2,467 subgroups of patients who had received psychotherapy.
RESULTS
We found large, and statistically significant, differences in remission rates within subgroups of patients. Remission rates for sertraline ranged from 4.5% to 77.86%, for fluoxetine from 2.86% to 77.78%, for venlafaxine from 5.07% to 76.44%, for bupropion from 0.5% to 64.63%, for desvenlafaxine from 1.59% to 75%, for duloxetine from 3.77% to 75%, for paroxetine from 6.48% to 68.79%, for escitalopram from 1.85% to 65%, and for citalopram from 4.67% to 76.23%. Clearly these medications are ideal for patients in some subgroups but not others. If patients are matched to the subgroups, clinicians can prescribe the medication that works best in the subgroup. Some medications (amitriptyline, doxepin, nortriptyline, and trazodone) always had remission rates below 11% and therefore were not suitable as single antidepressant therapy for any of the subgroups.
DISCUSSIONS
This study provides an opportunity for clinicians to identify an optimal antidepressant for their patients, before they engage in repeated trials of antidepressants.
IMPLICATIONS FOR HEALTH CARE PROVISION AND USE
To facilitate the matching of patients to the most effective antidepressants, this study provides access to a free, non-commercial, decision aid at http://MeAgainMeds.com.
IMPLICATIONS FOR HEALTH POLICIES
Policymakers should evaluate how study findings can be made available through fragmented electronic health records at point-of-care. Alternatively, policymakers can put in place an AI system that recommends antidepressants to patients online, at home, and encourages them to bring the recommendation to their clinicians at their next visit.
IMPLICATIONS FOR FURTHER RESEARCH
Future research could investigate (i) the effectiveness of our recommendations in changing clinical practice, (ii) increasing remission of depression symptoms, and (iii) reducing cost of care. These studies need to be prospective but pragmatic. It is unlikely random clinical trials can address the large number of factors that affect remission.
Topics: Humans; Citalopram; Fluoxetine; Paroxetine; Sertraline; Bupropion; Nortriptyline; Amitriptyline; Duloxetine Hydrochloride; Venlafaxine Hydrochloride; Desvenlafaxine Succinate; Escitalopram; Trazodone; Doxepin; Prospective Studies; Cohort Studies; Retrospective Studies; Antidepressive Agents; Psychotherapy
PubMed: 38634393
DOI: No ID Found -
Journal of Clinical Medicine Apr 2024: The use of selective serotonin reuptake inhibitors (SSRIs) has been associated with potential effects on male fertility, although the exact mechanisms are not fully...
: The use of selective serotonin reuptake inhibitors (SSRIs) has been associated with potential effects on male fertility, although the exact mechanisms are not fully understood. The aim of this study was to understand the relationship between SSRIs and male infertility; : A retrospective chart review of Saudi males who were treated with SSRIs and attended an infertility clinic in KSMC was undertaken. The medical records of men from an infertility clinic were reviewed to screen the quality of the sperm parameters in patients taking SSRIs; : In total, 299 men were identified, of whom 29 (9.6%) were exposed to SSRIs, while 270 (90.4%) did not receive SSRIs, defined as the control infertile group. When comparing the mean ages, a notable disparity was observed between the control group of infertile men (34.2 ± 6.9 years) and the infertile group using SSRIs (41.5 ± 3.2 years) ( < 0.001). Regarding the sperm analysis and the use of SSRIs, the impact of SSRIs use showed no significant differences in sperm liquefaction ( = 0.1), motility ( = 0.17), viscosity ( = 0.16), or count ( = 0.069) with escitalopram, fluoxetine, or paroxetine use; : Our study showed no significant difference in the sperm analysis between the SSRI and non-SSRI cohorts. However, the relationship between SSRI use and sperm count warrants further investigation and consideration in clinical practice.
PubMed: 38610894
DOI: 10.3390/jcm13072129 -
Neuropsychopharmacology : Official... Apr 2024Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the...
Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.
PubMed: 38609530
DOI: 10.1038/s41386-024-01857-8 -
Inorganic Chemistry Apr 2024Advances in polyoxometalate (POM) self-assembly chemistry are always accompanied by new developments in molecular blocks. The exploration and discovery of uncommon...
Advances in polyoxometalate (POM) self-assembly chemistry are always accompanied by new developments in molecular blocks. The exploration and discovery of uncommon building blocks offer great possibilities for generating unprecedented POM clusters. An intriguing Sb-W-cotemplated antimonotungstate [HN(CH)]Na[SbWO]Er(HO)Sb[SbWWO]·22HO () was synthesized, which comprises a classical trivacant Keggin [SbWO] ({SbW}) fragment and an unclassical lacunary Dawson-like [SbWWO] ({SbWW}) subunit. Notably, the Dawson-like {SbWW} subunit is the first example of a [SbO] and [WO] mixed-heteroatom-directing POM segment. Hexacoordinated [WO] can not only serve as the heteroatom function but its additional oxygen sites can also link to lanthanide, main-group metal, and transition-metal centers to form the innovative structure. {SbWW} and {SbW} subunits are joined by the heterometallic [Er(HO)SbO] cluster to give rise to an asymmetric sandwich-type architecture. To further realize its potential application in electrochemical sensing, a conductive @rGO composite was obtained by the electrochemical deposition of with graphene oxide (GO). Using a @rGO-modified glassy carbon electrode as the working electrode, an electrochemical biosensor for detecting the antidepressant drug paroxetine (PRX) was successfully constructed. This work can provide a viable strategy for synthesizing mixed-heteroatom-directing POMs and demonstrates the application of POM-based materials for the electrochemical detection of drug molecules.
PubMed: 38591874
DOI: 10.1021/acs.inorgchem.3c03605 -
Journal of Affective Disorders Jun 2024Sleep disturbances are not only frequent symptoms, but also risk factors for major depressive disorder. We previously reported that depressed patients who experienced...
BACKGROUND
Sleep disturbances are not only frequent symptoms, but also risk factors for major depressive disorder. We previously reported that depressed patients who experienced "Hypersomnia" showed a higher and more rapid response rate under paroxetine treatment, but the underlying mechanism remains unclear. The present study was conducted to clarify the beneficial effects of sleep rebound through an experimental "Hypersomnia" rat model on glucocorticoid and hippocampal neuroplasticity associated with antidepressive potency.
METHODS
Thirty-four male Sprague-Dawley rats were subjected to sham treatment, 72-h sleep deprivation, or sleep deprivation and subsequent follow-up for one week. Approximately half of the animals were sacrificed to evaluate adrenal weight, plasma corticosterone level, hippocampal content of mRNA isoforms, and protein of the brain-derived neurotrophic factor (Bdnf) gene. In the other half of the rats, Ki-67- and doublecortin (DCX)-positive cells in the hippocampus were counted via immunostaining to quantify adult neurogenesis.
RESULTS
Prolonged sleep deprivation led to adrenal hypertrophy and an increase in the plasma corticosterone level, which had returned to normal after one week follow-up. Of note, sleep deprivation-induced decreases in hippocampal Bdnf transcripts containing exons II, IV, VI, and IX and BDNF protein levels, Ki-67-(+)-proliferating cells, and DCX-(+)-newly-born neurons were not merely reversed, but overshot their normal levels with sleep rebound.
LIMITATIONS
The present study did not record electroencephalogram or assess behavioral changes of the sleep-deprived rats.
CONCLUSIONS
The present study demonstrated that prolonged sleep deprivation-induced adversities are reversed or recovered by sleep rebound, which supports "Hypersomnia" in depressed patients as having a beneficial pharmacological effect.
Topics: Humans; Rats; Male; Animals; Sleep Deprivation; Rats, Sprague-Dawley; Brain-Derived Neurotrophic Factor; Depressive Disorder, Major; Corticosterone; Ki-67 Antigen; Hippocampus
PubMed: 38574868
DOI: 10.1016/j.jad.2024.04.008 -
Biochemical Pharmacology May 2024Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present...
Treatment of major depressive disorder remains a major unmet clinical need. Given the advantages of intranasal administration for targeted brain delivery, the present study aimed at investigating the pharmacokinetics of paroxetine, after its intranasal instillation and assessing its potential therapeutic effect on female and male mice subjected to unpredictable chronic mild stress (UCMS) protocol. IN administration revealed direct nose-to-brain paroxetine delivery but dose- and sex-dependent differences. Pharmacokinetics was nonlinear and paroxetine concentrations were consistently higher in plasma and brain of male mice. Additionally, UCMS decreased animal preference for sucrose in both male and female mice following acute (p < 0.01) and chronic stress (p < 0.05), suggesting anhedonia. Both male and female mice exhibited depressive-like behavior in the forced swimming test. UCMS females displayed a significantly longer immobility time and shorter climbing time than the control group (p < 0.05), while no differences were found between male mice. Two weeks of paroxetine intranasal administration reduced immobility time and lengthened climbing and swimming time, approaching values similar to those observed in the healthy control group. The therapeutic effect was stronger on female mice. Importantly, melatonin plasma levels were significantly decreased in female mice following UCMS (p < 0.05), while males exhibited heightened corticosterone levels. On the other hand, treatment with IN paroxetine significantly increased corticosterone and melatonin levels in both sexes compared to healthy mice (p < 0.05). Intranasal paroxetine delivery undoubtedly ameliorated the behavioral despair, characteristic of depressive-like animals. Despite its efficiency in male and female mice subjected to UCMS, females were more prone to this novel therapeutic strategy.
Topics: Female; Mice; Male; Animals; Paroxetine; Depressive Disorder, Major; Administration, Intranasal; Sex Characteristics; Corticosterone; Melatonin; Depression; Disease Models, Animal; Stress, Psychological
PubMed: 38556027
DOI: 10.1016/j.bcp.2024.116184