Effectiveness of Antidepressants in Combination with Psychotherapy.

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.

Interpersonal sensitivity and response to selective serotonin reuptake inhibitors in patients with acute major depressive disorder.

BACKGROUND: Patients with major depression often suffer from excessive interpersonal sensitivity, although it is not typically measured in antidepressant clinical trials. Preliminary evidence suggests selective serotonin reuptake inhibitors have the capacity to reduce interpersonal sensitivity. METHODS: This was a pooled analysis of data from 1709 patients in three randomized, double-blind, placebo-controlled trials of fluoxetine and paroxetine for acute major depressive disorder. Depressive symptoms were assessed with the Hamilton Depression Rating Scale. A factor from the Symptom Checklist was used to assess interpersonal sensitivity. Our outcome of interest was change from baseline scores at the last assessment (up to 8 or 12 weeks, depending on the trial). RESULTS: Both medications produced significantly greater reductions in interpersonal sensitivity relative to placebo. The effect of medication remained significant after controlling for depression improvement, which explained 18.5% of the variation in interpersonal sensitivity improvement among those treated with active medication. The effect of medication on depressive symptoms, relative to placebo, was not influenced by baseline interpersonal sensitivity. LIMITATIONS: The outcome measured interpersonal sensitivity over the last week, and the results do not necessarily reflect changes in long-standing, trait-like patterns of interpersonal sensitivity. Only two medications were studied. CONCLUSIONS: Selective serotonin reuptake inhibitors are effective at treating interpersonal sensitivity in acutely depressed patients. This appears to be a unique drug effect that is not only the result of depression improvement. Future clinical trials might benefit from assessing interpersonal sensitivity more routinely.

Intranasal delivery of paroxetine: A preclinical study on pharmacokinetics, depressive-like behaviour, and neurochemical sex differences.

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.

Current Understanding of Compulsive Sexual Behavior Disorder and Co-occurring Conditions: What Clinicians Should Know about Pharmacological Options.

Compulsive sexual behavior disorder (CSBD) has recently been recognized as a psychiatric disorder. Pharmacological treatments for CSBD have received little study and thus have limited empirical support. The main objective of the present work is to review existing literature on the efficacy of different drugs on the symptomatology of CSBD, including the subtype of problematic pornography use (PPU). The main pharmacological approaches to treating CSBD have included opioid antagonists (naltrexone and nalmefene), selective serotonin reuptake inhibitors (paroxetine, citalopram, fluoxetine, and sertraline), mood stabilizers (topiramate), tricyclic antidepressants (clomipramine), serotonin antagonist and reuptake inhibitors (nefazodone), and N-acetylcysteine. Since people with CSBD may experience different co-occurring disorders, these should be considered when choosing the best pharmacological treatment. Pharmacological therapy for CSBD/PPU has been suggested as an adjunct to psychological therapies, which, for the moment, have the most empirical evidence. However, to evaluate the efficacy of most of the drugs presented in this narrative review, data to date have only been available from case studies. Thus, empirical support is scant and generalizability of results is limited, highlighting the need for more research in this area.

Clinical side-effects based drug repositioning for anti-epileptic activity.

Several generations of anti-epileptic drugs (AEDs) are available but have several associated side effects apart from a limited success rate. Drug repositioning strategies have gained importance in the last two decades owing to lower failure rates and economic burden. Drugs with similar side effect profiles may share a common mechanism of action and thus can be linked to other disease treatments. The present study was carried out to identify the newly approved drug candidate(s) as AEDs using clinical side-effects drug repositioning strategy. The clinical side effect similarity of drugs available in the SIDER v4.1 database was estimated against common side effects of 5 major marketed AEDs, using the 'dplyr' package library in the R. Further drugs were filtered based on Blood Brain Barrier permeability prediction and FDA-approval status. Molecular docking studies were performed for selected 26 hits (drugs) against previously identified epilepsy target receptors: Voltage-gated sodium channel α2 (Nav1.2), GABA receptor α1-ß1 (GABAr α1-ß1), and Voltage-gated calcium channel α-1 G (Cav3.1). Only 2 drugs (Ziprasidone and Paroxetine) showed better binding affinities against studied epilepsy receptors Nav1.2, GABAr α1-ß1, and Cav3.1, than their corresponding standard AEDs, i.e. Carbamazepine, Clonazepam, and Pregabalin, respectively. Ziprasidone reportedly showed seizure-like symptoms in ∼3% of patients and was hence omitted from further study. The MDS study of docked complexes of Paroxetine with selected epilepsy target receptors showed stable RMSD values and better interaction energies. The study reveals Paroxetine as a potential candidate to be repurposed for 1st line epileptic seizure medication.Communicated by Ramaswamy H. Sarma.

Effect of the sEH inhibitor AUDA on arachidonic acid metabolism and NF-κB signaling of rats with postpartum depression-like behavior.

OBJECTIVE: To investigate whether sEH inhibitor AUDA can mitigate postpartum depression (PPD)-like symptoms in the rat model and regulate the AA/NF-κB pathway to suppress the inflammatory response in the prefrontal lobes of PPD rats. METHODS: Five groups of Sprague Dawley rats were used: normal, sham operated, PPD model, AUDA, and paroxetine hydrochloride. During the 21-day treatment period, animals in all groups underwent assessments (open field test, forced swimming test, and sucrose consumption) for depression-like behavior. At the conclusion of the treatment period, animals in all study groups were euthanized and various proteins in the prefrontal lobes were measured. RESULTS: Depression-like behavior in rats was attenuated by AUDA. In the prefrontal lobes of PPD rats, levels of 5-LOX, COX-2, sEH, IL-1ß, IL- 6, p65, p-p65, P-IκBα, NF-κB p65, and GFAP were increased while levels of epoxyeicosatrienoic acids and 5-HT were decreased. AUDA reversed these changes, thus having a similar effect as the classic antidepressant paroxetine hydrochloride. CONCLUSION: AUDA may constrain AA/NF-κB in the prefrontal cortex of PPD rats, thus inhibiting the inflammatory response and ultimately attenuating postpartum depression-like behavior.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Psychological status of patients with functional anorectal pain and treatment efficacy of paroxetine in alleviating the symptoms: a retrospective study.

The aim of this study was to investigate the clinical characteristics, psychological status, sleep quality, and quality of life of patients with functional anorectal pain (FAP). The study also assessed the treatment efficacy of paroxetine in alleviating FAP symptoms. A retrospective comparative study of forty-three patients with FAP who were first treated with an anal plug compound glycolate suppository versus paroxetine combined with anal plug compound glycolate suppository between November 2021 and August 2022. Pain, quality of life, depression, anxiety and sleep quality were assessed before and after treatment by the Chinese version of the Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), Health-related quality of life scale (The 12-Item Short-Form Health Survey, SF-12), 17-item Hamilton Depression Rating Scale (HDRS), 14-item Hamilton Anxiety Scale (HAMA), and Pittsburgh Sleep Quality Index (PSQI). A total of 46.5% of patients with FAP were found to have anxiety symptoms (HAMA ≥ 7), 37.2% of patients with FAP were found to have depressive symptoms (HDRS ≥ 8). A total of 32.6% of patients with FAP had sleep disorders (PSQI > 10). Within 1 week after drug withdrawal, the short-term efficacy rate of oral paroxetine was 95.5%. After treatment, the symptom pain score (VAS) and sleep score were lower than those before treatment (P < 0.01). In the areas of vitality (VT), Social Functioning (SF), and Mental Health (MH), the difference between the pre-treatment and 8 weeks posttreatment scores of the study group and the control group was statistically significant (P < 0.05). FAP patients have obvious symptoms of anxiety and depression, and the incidence of sleep disturbance is prevalent. Paroxetine, a typical serotonin reuptake inhibitor (SSRI), was able to alleviate depression, anxiety, and pain symptoms in FAP, which might have clinical application prospects.

Paroxetine protects against bleomycin-induced pulmonary fibrosis by blocking GRK2/Smad3 pathway.

G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-ß1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-ß1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-ß1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. In vitro experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-ß1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-ß1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-ß1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.

The effects of paroxetine therapy on depressive symptom and motor function in the treatment of depression with Parkinson's disease: A meta-analysis.

BACKGROUND: Paroxetine therapy has been used for treatment of patients with depression and Parkinson's disease (dPD) in many clinical studies, but, the effects of paroxetine in dPD patients are not completely understood. The aim of this study was to systematically evaluate the effects of paroxetine therapy on depressive symptom and motor function in the treatment of dPD, in order to confer a reference for clinical practice. METHODS: Randomized controlled trials (RCTs) of paroxetine for dPD published up to October, 2022 were retrieved. Standardised mean difference (SMD), odds ratio (OR), and 95% confidence interval (CI) were calculated and heterogeneity was measured with the I2 test. The outcomes of interest were as follows: the efficacy, Hamilton depression rating scale score, unified Parkinson's disease rating scale score, Hamilton anxiety rating scale score or adverse events. RESULTS: Thirty-four RCTs with 2819 participants were included. Compared with control group, the pooled effects of paroxetine therapy on depression were (22 trials; OR 3.62, 95% CI 2.63 to 4.98, P < .00001) for antidepressant response (25 trials; SMD -2.14, 95% CI -2.73 to -1.56, P < .00001) for Hamilton depression rating scale score, the pooled effects of paroxetine therapy on motor function were (10 trials; OR 4.63, 95% CI 3.15 to 6.79, P < .00001) for anti-PD efficacy (18 trials; SMD -2.02, 95% CI -2.48 to -1.55, P < .00001) for total unified Parkinson's disease rating scale score. The Hamilton anxiety rating scale score showed significant decrease in the paroxetine treatment group compared to control group (10 trials; SMD -1.93, 95% CI -2.65 to -1.22, P < .00001). In addition, paroxetine therapy reduced the number of any adverse events obviously in dPD patients (twenty trials; OR 0.42, 95% CI 0.31 to 0.57, P < .00001). CONCLUSIONS: Paroxetine therapy has clinical benefits for improvement of depressive symptom and motor function in dPD patients, moreover, it is of high drug safety. Further well-designed, multi-center RCTs needed to identify these findings.

Pharmacological approaches to the management of panic disorder in older patients: a systematic review.

INTRODUCTION: Recommendations for treating panic disorder (PD) in older patients are scarce. The authors have systematically reviewed whether several recommended medications are superior to others and their optimal doses in this age group. METHODS: A database search of studies involving patients with PD with/without agoraphobia aged ≥ 60 years was carried out using PubMed, PsycINFO, Embase, and Clinical Trials.gov, from their inception dates to 1 March 2023. Only four (published from 2002 to 2010) of the 1292 records screened were included. A risk of bias assessment was provided. This systematic review was performed using The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA). RESULTS: Two studies were randomized clinical trials, whereas two were open-label, including paroxetine, citalopram, escitalopram, and sertraline; three studies reported short-term evaluations, whereas one study included a 26-week follow-up. Medications provided benefits, with good tolerability. Preliminary results suggested greater benefits of paroxetine in reducing panic attacks vs. cognitive - behavioral therapy, and an earlier decrease in PAs with escitalopram vs. citalopram. Risk of bias was considerable. CONCLUSIONS: The pharmacological management of PD in older patients has received no attention. Findings are scant, dated, and affected by methodological flaws; thus, they do not provide significant advances.

A new method for analyzing clinical trials in depression based on individual propensity to respond to placebo estimated using artificial intelligence.

One of the major reasons for trial failures in major depressive disorders (MDD) is the presence of unpredictable levels of placebo response as the individual baseline propensity to respond to placebo is not adequately controlled by the current randomization and statistical methodologies. The individual propensity to respond to any treatment or intervention assessed at baseline was considered as a major non-specific prognostic and confounding effect. The objective of this paper was to apply the propensity score methodology to control for potential imbalance at baseline in the propensity to respond to placebo in clinical trials in MDD. Individual propensity was estimated using artificial intelligence (AI) applied to observations collected in two pre-randomization occasions. Cases study are presented using data from two randomized, placebo-controlled trials to evaluate the efficacy of paroxetine in MDD. AI models were used to estimate the individual propensity probability to show a treatment non-specific placebo effect. The inverse of the estimated probability was used as weight in the mixed-effects analysis to assess treatment effect. The comparison of the results obtained with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect size significantly larger than the conventional analysis.

Retrospective evaluation of the efficacy of daily paroxetine/tadalafil combination in patients with premature ejaculation and erectile dysfunction.

OBJECTIVE: Premature ejaculation (PE) and erectile dysfunction (ED) are sexual dysfunction diseases affecting males. The phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil are used to treat ED whereas selective serotonin reuptake inhibitors (SSRIs) are preferred for PE. Most of the patients with ED also suffer from PE simultaneously. The combined drug therapies are commonly preferred as they favor elevated intra-vaginal ejaculation latency time (IELT) scores and improved sexual function. The study aimed to evaluate the efficacy and safety of daily paroxetine and tadalafil combination therapy in patients with PE and ED. PATIENTS AND METHODS: A total of 81 PE patients with ED were enrolled in the study. Patients were treated with daily paroxetine 20 mg and tadalafil 5 mg for 4 weeks. Pre- and post-treatment IELT, premature ejaculation profile (PEP), and International Index of Erectile Function-Erectile Function (IIEF-EF) scores of the patients were analyzed. RESULTS: The mean IELT and PEP index scores, and mean IIEF-EF values improved after combination therapy (p<0.001 for each). When lifelong and acquired PE+ED patients were compared, significant improvements were observed in IELT, PEP, and IIEF-EF scores in both groups (p<0.001). CONCLUSIONS: Even though the treatment methods are different, combined therapies to treat simultaneous PE and ED presence are effective compared to monotherapies. However, there is still no definitive treatment that can cure all subtypes of PE or ED.

Artificial intelligence approach for the analysis of placebo-controlled clinical trials in major depressive disorders accounting for individual propensity to respond to placebo.

Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline individual propensity to respond non-specifically to any treatment or intervention can be considered as a major non-specific confounding effect. The greater is the baseline propensity, the lower will be the chance to detect any treatment-specific effect. The statistical methodologies currently applied for analyzing RCTs doesn't account for potential unbalance in the allocation of subjects to treatment arms due to heterogenous distributions of propensity. Hence, the groups to be compared may be imbalanced, and thus incomparable. Propensity weighting methodology was used to reduce baseline imbalances between arms. A randomized, double-blind, placebo controlled, three arms, parallel group, 8-week, fixed-dose study to evaluate efficacy of paroxetine CR 12.5 and 25 mg/day is presented as a cases study. An artificial intelligence model was developed to predict placebo response at week 8 in subjects assigned to placebo arm using changes from screening to baseline of individual Hamilton Depression Rating Scale items. This model was used to predict the probability to respond to placebo in each subject. The inverse of the probability was used as weight in the mixed-effects model applied to assess treatment effect. The analysis with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect-size about twice larger than the non-weighted analysis. Propensity weighting provides an unbiased strategy to account for heterogeneous and uncontrolled placebo effect making patients' data comparable across treatment arms.

Impact of CYP2D6 Genotype on Paroxetine Serum Concentration.

BACKGROUND: Paroxetine is a selective serotonin reuptake inhibitor metabolized by cytochrome P450 (CYP)2D6. Only small-scale studies have reported the impact of CYP2D6 genotype on paroxetine exposure, and international guidelines differ in their recommendations on whether paroxetine should be administered according to CYP2D6 genotype. To clarify this issue, the aim of the present study was to investigate the impact of CYP2D6 genotype on paroxetine serum concentration in a large population of patients after adjusting for CYP2C19 genotype, age, and sex. METHODS: Patients from a therapeutic drug monitoring database with records on their paroxetine serum concentrations and CYP2D6 and CYP2C19 genotyping between 2010 and 2021 were included in the study. The impact of CYP2D6 and CYP2C19 genotypes, age, and sex on the paroxetine concentration-to-dose (C/D) ratio was investigated by multiple linear regression analysis. Patients treated with relevant CYP inhibitors or inducers were excluded. RESULTS: In total, 304 patients were included in the study: 17 CYP2D6 poor metabolizers (PMs), 114 intermediate metabolizers (IMs), 168 extensive metabolizers (EMs), and 5 ultrarapid metabolizers. Multiple linear regression analysis showed that CYP2D6 IMs and PMs had 2.2-fold and 3.8-fold higher paroxetine C/D-ratios than extensive metabolizers, respectively ( P < 0.001). Patients who were CYP2C19 IMs (n = 70) or PMs (n = 13) had 1.6-fold higher paroxetine C/D ratio than extensive metabolizers ( P = 0.04). An age ≥65 years was associated with a 2.9-fold increased C/D ratio ( P < 0.001), whereas sex was not significantly associated with paroxetine exposure. CONCLUSIONS: The present study showed that CYP2D6 genotype is of significant importance for paroxetine dose adjustments. For CYP2D6 PMs, 25% of the regular paroxetine starting dose may be sufficient, whereas CYP2D6 IMs could receive 50% of the regular dosage. This well-powered study shows that the guidelines should consider the importance of CYP2D6 genotype for personalized dosing of paroxetine.

Identification and investigation of depression-related molecular subtypes in inflammatory bowel disease and the anti-inflammatory mechanisms of paroxetine.

Background: Up to 40 per cent of people with active inflammatory bowel disease (IBD) also suffer from mood disorders such as anxiety and depression. Notwithstanding, the fundamental biological pathways driving depression in IBD remain unknown. Methods: We identified 33 core genes that drive depression in IBD patients and performed consensus molecular subtyping with the NMF algorithm in IBD. The CIBERSORT were employed to quantify the immune cells. Metabolic signature was characterized using the "IOBR" R package. The scoring system (D. score) based on PCA. Pre-clinical models are constructed using DSS. Results: Using transcriptome data from the GEO database of 630 IBD patients, we performed a thorough analysis of the correlation between IBD and depression in this research. Firstly, the samples were separated into two different molecular subtypes (D. cluster1 and D. cluster2) based on their biological signatures. Moreover, the immunological and metabolic differences between them were evaluated, and we discovered that D. cluster2 most closely resembled IBD patients concomitant with depression. We also developed a scoring system to assess the IBD-related depression and predict clinical response to anti-TNF- therapy, with a higher D. score suggesting more inflammation and worse reaction to biological therapies. Ultimately, we also identified through animal experiments an antidepressant, paroxetine, has the added benefit of lowering intestinal inflammation by controlling microorganisms in the digestive tract. Conclusions: This study highlights that IBD patients with or without depression show significant variations and antidepressant paroxetine may help reduce intestinal inflammation.

Can the aberrant occipital-cerebellum network be a predictor of treatment in panic disorder?

BACKGROUND: This study aimed to detect altered brain activation pattern of patients with panic disorder (PD) and its changes after treatment. The possibilities of diagnosis and prediction of treatment response based on the aberrant brain activity were tested. METHODS: Fifty-four PD patients and 54 healthy controls (HCs) were recruited. Clinical assessment and resting-state functional magnetic resonance imaging scans were conducted. Then, patients received a 4-week paroxetine treatment and underwent a second clinical assessment and scan. The fractional amplitude of low-frequency fluctuations (fALFF) was measured. Support vector machine (SVM) and support vector regression (SVR) analyses were conducted. RESULTS: Lower fALFF values in the right calcarine/lingual gyrus and left lingual gyrus/cerebellum IV/V, whereas higher fALFF values in right cerebellum Crus II were observed in patients related to HCs at baseline. After treatment, patients with PD exhibited significant clinical improvement, and the abnormal lower fALFF values in the right lingual gyrus exhibited a great increase. The abnormal fALFF at pretreatment can distinguish patients from HCs with 80 % accuracy and predict treatment response which was reflected in the significant correlation between the predicted and actual treatment responses. LIMITATIONS: The impacts of ethnic, cultural, and other regional differences on PD were not considered for it was a single-center study. CONCLUSIONS: The occipital-cerebellum network played an important role in the pathophysiology of PD and should be a part of the fear network. The abnormal fALFF values in patients with PD at pretreatment could serve as biomarkers of PD and predict the early treatment response of paroxetine.

Design, synthesis and cytotoxic evaluation of a selective serotonin reuptake inhibitor (SSRI) by virtual screening.

Depression is one of the most common mental illnesses, affecting almost 300 million people. According to the WHO, depression is one of the world's leading causes of disability and morbidity. People with this illness require both psychological and pharmaceutical treatment because severe depressive episodes often result in suicide. Selective serotonin reuptake inhibitors (SSRI) are widely used antidepressants that target the human serotonin transporter (hSERT). The crystallization of hSERT and the experimental data available allows cost and time-efficient computational tools like virtual screening (VS) to be utilized in the development of therapeutic agents. Here, we synthesized, characterized, and evaluated the biological activity of a novel SSRI analog of paroxetine, rationally designed by applying an artificial neural network-based QSAR model and a molecular docking analysis on hSERT. The analog N-substituted 18a showed higher affinity for the transporter (-10.2 kcal/mol), lower Ki value (1.19 nM) and a safer toxicological profile than paroxetine and was synthesized with a 71% yield. The in vitro cytotoxicity of the analog was evaluated using human glioblastoma (U87 MG), human neuroblastoma (SH SY5Y) and murine fibroblast (L929) cell lines. Also, the hemolytic ability of the compound was assessed on human erythrocytes. Results showed that analog 18a did not exhibit cytotoxic activity on the cell lines used and has no hemolytic activity at any of the concentrations tested, whereas with paroxetine, hemolysis was observed at 2.3, 1.29 y 0.67 mM. Based on these results, it is possible to suggest that analog 18a could be a promising new SSRI candidate for the treatment of this illness.

Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial.

BACKGROUND: Patients with refractory erythema of rosacea have limited treatment options. OBJECTIVE: To evaluate the efficacy and safety of a 12-week course of paroxetine for moderate-to-severe erythema of rosacea. METHODS: In a multicenter, randomized, double-blinded, placebo-controlled trial, patients with refractory erythema of rosacea were randomly assigned (1:1) to receive paroxetine 25 mg daily or placebo for 12 weeks. RESULTS: Overall, 97 patients completed the study (paroxetine: 49; placebo: 48). The primary end point was the proportion of participants achieving Clinical Erythema Assessment success (defined as Clinical Erythema Assessment score of 0, 1, or ≥2-grade improvement from baseline) at week 12; this was significantly greater in the paroxetine group than in the placebo group (42.9% vs 20.8%, P = .02). Some secondary end points were met, such as flushing success with point reductions ≥2 (44.9% vs 25.0%, P = .04) and improvement in overall flushing (2.49 ± 3.03 vs 1.68 ± 2.27, P = .047), burning sensation (46.9% vs 18.8%, P = .003), and depression (P = .041). The most reported adverse events associated with paroxetine were dizziness, lethargy, nausea, dyspepsia, and muscle tremors. LIMITATIONS: Only a single-dosage regimen of paroxetine within a 12-week study was evaluated. CONCLUSIONS: Paroxetine is an effective and well-tolerated alternative treatment for moderate-to-severe erythema of rosacea.

Benefits and Risks of Antidepressant Drugs During Pregnancy: A Systematic Review of Meta-analyses.

BACKGROUND: The prescription of antidepressant drugs during pregnancy has been steadily increasing for several decades. Meta-analyses (MAs), which increase the statistical power and precision of results, have gained interest for assessing the safety of antidepressant drugs during pregnancy. OBJECTIVE: We aimed to provide a meta-review of MAs assessing the benefits and risks of antidepressant drug use during pregnancy. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature search on PubMed and Web of Science databases was conducted on 25 October, 2021, on MAs assessing the association between antidepressant drug use during pregnancy and health outcomes for the pregnant women, embryo, fetus, newborn, and developing child. Study selection and data extraction were carried out independently and in duplicate by two authors. The methodological quality of included studies was evaluated with the AMSTAR-2 tool. Overlap among MAs was assessed by calculating the corrected covered area. Data were presented in a narrative synthesis, using four levels of evidence. RESULTS: Fifty-one MAs were included, all but one assessing risks. These provided evidence for a significant increase in the risks for major congenital malformations (selective serotonin reuptake inhibitors, paroxetine, fluoxetine, no evidence for sertraline; eight MAs), congenital heart defects (paroxetine, fluoxetine, sertraline; 11 MAs), preterm birth (eight MAs), neonatal adaptation symptoms (eight MAs), and persistent pulmonary hypertension of the newborn (three MAs). There was limited evidence (only one MA for each outcome) for a significant increase in the risks for postpartum hemorrhage, and with a high risk of bias, for stillbirth, impaired motor development, and intellectual disability. There was inconclusive evidence, i.e., discrepant results, for an increase in the risks for spontaneous abortion, small for gestational age and low birthweight, respiratory distress, convulsions, feeding problems, and for a subsequent risk for autism with an early antidepressant drug exposure. Finally, MAs provided no evidence for an increase in the risks for gestational hypertension, preeclampsia, and for a subsequent risk for attention-deficit/hyperactivity disorder. Only one MA assessed benefits, providing limited evidence for preventing relapse in severe or recurrent depression. Effect sizes were small, except for neonatal symptoms (small to large). Results were based on MAs in which overall methodological quality was low (AMSTAR-2 score = 54.8% ± 12.9%, [19-81%]), with a high risk of bias, notably indication bias. The corrected covered area was 3.27%, which corresponds to a slight overlap. CONCLUSIONS: This meta-review has implications for clinical practice and future research. First, these results suggest that antidepressant drugs should be used as a second-line treatment during pregnancy (after first-line psychotherapy, according to the guidelines). The risk of major congenital malformations could be prevented by observing guidelines that discourage the use of paroxetine and fluoxetine. Second, to decrease heterogeneity and bias, future MAs should adjust for maternal psychiatric disorders and antidepressant drug dosage, and perform analyses by timing of exposure.