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Background: Selective Serotonin Reuptake Inhibitors (SSRIs) represent a diverse class of medications widely prescribed for depression and anxiety. Despite their common use, there is an absence of large-scale, real-world evidence capturing the heterogeneity in their effects on individuals. This study addresses this gap by utilizing naturalistic search data to explore the varied impact of six different SSRIs on user behavior., Methods: The study sample included ∼508 thousand Bing users with searches for one of six SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) from April-December 2022, comprising 510 million queries. Cox proportional hazard models were employed to examine 30 topics (e.g., shopping, tourism, health) and 195 health symptoms (e.g., anxiety, weight gain, impotence), using each SSRI as a reference. We assessed the relative hazard ratios between drugs and, where feasible, ranked the SSRIs based on their observed effects. We used Cox proportional hazard models in order to account for both the likelihood of users searching for a particular topic or symptom and the associated time to that search. The temporal aspect aided in distinguishing between potential symptoms of the disorder, short-term medication side effects, and later appearing side effects., Results: Differences were found in search behaviors associated with each SSRI. E.g., fluvoxamine was associated with a significantly higher likelihood of searching weight gain compared to all other SSRIs (HRs 1.85-2.93). Searches following citalopram were associated with significantly higher rates of later impotence queries compared to all other SSRIs (HRs 5.11-7.76), except fluvoxamine. Fluvoxamine was associated with a significantly higher rate of health related searches than all other SSRIs (HRs 2.11-2.36)., Conclusions: Our study reveals new insights into the varying SSRI impacts, suggesting distinct symptom profiles. This novel use of large-scale, naturalistic search data contributes to pharmacovigilance efforts, enhancing our understanding of intra-class variation among SSRIs, potentially uncovering previously unidentified drug effects., Competing Interests: Declaration of competing Interest NCJ has a received grant from Boehringer-Ingelheim. NCJ has edited a book through Academic Press and receives book royalties, and NCJ also receives speaking fees related to his research. MVH has worked as a paid consultant for Artisight and ChatNexus. EYT was previously employed by Microsoft Research., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Previous studies have examined the correlation between paroxetine concentrations and therapeutic efficacy in patients diagnosed with major depressive disorder (MDD), but findings have been contradictory., Aims: This study aimed to investigate the relationships among plasma concentrations, severity of symptoms, and adverse drug reactions (ADRs) to optimize individual dosing., Methods: Eighty-seven MDD patients, after completing treatment with paroxetine, were divided into low-concentration (LC, n  = 38), medium-concentration (MC, n  = 27), and high-concentration (HC, n  = 22) groups, based on cutoff value concentrations with the 50% response rate and the laboratory alert level from the 2017 consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology. The severity of depression and anxiety was evaluated using a 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), respectively. Dosage, plasma concentrations, scale scores, and ADRs were recorded across the three groups at different treatment stages to define the therapeutic reference range., Results: The 4-week plasma concentration of paroxetine (65.00 ng/mL) could predict the clinical response in MDD patients at 8 weeks. Symptom relief in patients with 4-week paroxetine concentrations ranging from 65.00 to 120.00 ng/mL at 8 weeks was greater than in those with concentrations below 65.00 ng/mL, with no significant difference observed above this range. In addition, more cases of liver injury and weight gain were observed in patients with high paroxetine concentrations., Conclusion: Our results support that early paroxetine concentration may predict clinical efficacy and the incidence of ADRs, thus improving individual dosing regimens for MDD patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Among antidepressants, selective serotonin and noradrenaline reuptake inhibitors (SSRIs and SNRIs) have been widely used in the treatment of major depression and may induce sleep disorders and bruxism. In the present study, the effects of SSRIs and SNRIs on awake and sleep bruxism have been evaluated. A total of 125 patients who had been prescribed SSRIs or SNRIs for the treatment of major depression have been evaluated for bruxism. For the purpose of the study, data from the first week (T1) and the fourth week (T2) of antidepressant treatment have been considered. In conclusion, in the early period, the presence of bruxism has not been observed to be significantly influenced by the use of antidepressants. It has been determined that sleep bruxism increased in the fourth week only in males who were using antidepressants (p = 0.015; p < 0.05). An increase in the presence of sleep bruxism due to specific SSRIs and SNRIs has been determined in the fourth week of drug use. Paroxetine in the SSRI group and duloxetine in the SNRI group have been found to cause an increase in sleep bruxism (p = 0.013; p < 0.05). Other active substances have not been found to affect sleep or awake bruxism significantly. The present study has shown that although some antidepressants increase bruxism in the early period of drug use, the effects of similar drugs on sleep or awake bruxism need to be evaluated in detail in long-term studies.

American Urological Association (AUA) guidelines recommend selective serotonin reuptake inhibitors (SSRI) as first-line pharmacotherapy for premature ejaculation (PE). While previous studies have described sexual adverse events (AE) associated with each medication, there is limited data directly comparing rates of specific sexual AEs across SSRIs. This study investigates the Food and Drug Administration Adverse Event Reporting System (FAERS) database for reports of monotherapy use of fluoxetine 20 mg, paroxetine 20 mg, sertraline 50 mg, and sertraline 100 mg in males from January 2004-June 2021. We examined 2608 reports from patients using SSRIs for PE or other psychiatric conditions. The average number of AEs was significantly different (p < 0.01) with paroxetine 20 mg having the highest (5.1 AEs/case report). Changes in libido was the most common sexual AE for fluoxetine 20 mg (6.7% of reports), paroxetine 20 mg (4.2%), and sertraline 50 mg (7.2%) while orgasm disorder was the most reported for sertraline 100 mg (3.9%). The SSRIs had different rates of changes in libido, erection disorder, orgasm disorder, and other sexual dysfunction (outside those listed). The SSRIs also differed in the rates of fatigue, ear/hearing changes, headache, and psychological AEs. The differences in specific AEs warrant future studies to determine true differences that would affect patient counseling., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Serotonin syndrome is an iatrogenic disorder induced by serotonergic drug. It is characterised by a symptomatic polymorphism that may create confusion with other clinical conditions, delaying diagnosis and putting the vital prognosis at risk. In light of a case report and a literature review, we here report the clinical case of a patient presenting with confusion, psychomotor agitation, hyperreflexia and spontaneous myoclonus following simultaneous use of paroxetine and amitriptyline. The diagnosis of serotonin syndrome was made after ruling out other possible diagnoses. The patient was admitted to the intensive care unit. This clinical case highlights the importance of thoroughly understanding the clinical manifestations of serotonin syndrome to ensure early and appropriate therapeutic management., Competing Interests: Les auteurs ne déclarent aucun conflit d´intérêts., (Copyright: Kaouthar El Mir et al.)

Background: Preclinical studies suggested that drugs that functionally inhibit acid sphingomyelinase (FIASMA)may enhance immune cell longevity and potentially offer protection against infections. Many antidepressants have shown FIASMA activity., Methods: We conducted a cohort study using primary-care data from the UK-based Clinical Practice Research Datalink (2000-2021). We assessed the association of composite diagnosed acute infections in new users of fluoxetine, sertraline, paroxetine, or venlafaxine aged 18-80 years compared to citalopram. We compared SARS-CoV-2 infections between groups in a secondary analysis. We estimated incidence rates (IR) and IR ratios (IRR) of acute infections in four pairwise comparisons using negative binomial regression. We applied propensity score (PS) fine stratification to control for confounding., Results: In the PS-weighted cohorts, we included 353,138 fluoxetine, 222,463 sertraline, 69,963 paroxetine, 32,608 venlafaxine, and between 515,996 and 516,583 new citalopram users. PS-weighted IRs ranged between 76.8 acute infections /1000 person-years (py) (sertraline) and 98.9 infections/1000 py (citalopram). We observed PS-weighted IRRs around unity for paroxetine (0.97, 95 % CI, 0.95-1.00), fluoxetine (0.94, 95 % CI, 0.92-0.95), and venlafaxine (0.90, 95 % CI, 0.87-0.94) vs citalopram. Reduced IRR for sertraline vs citalopram (0.84, 95 % CI, 0.82-0.85), became null within subgroups by cohort entry date. In the analysis of SARS-CoV-2 infection, no statistically relevant risk reduction was seen., Limitations: Analysis not limited to patients with diagnosed depression, possible underestimation of infection incidence, and unclear FIASMA activity of citalopram., Conclusions: Fluoxetine, sertraline, paroxetine, and venlafaxine were not associated with a reduced risk of acute infection when compared with the presumably weak FIASMA citalopram., Competing Interests: Declaration of competing interest The authors have no relevant personal or financial conflicts of interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Existing guidelines for primary care clinicians (PCCs) on the detection and management of perinatal depression (PD) contain important gaps. This review aims to provide PCCs with a summary of clinically relevant evidence in the field., Methods: A narrative literature review was conducted by searching PubMed and PsycINFO for articles published between 2010 to 2023. Guidelines, systematic reviews, clinical trials, and/or observational studies were all examined., Results: Screening with the Edinburgh Postnatal Depression Scale or Patient Health Questionnaire-9 followed by a diagnostic evaluation for major depressive disorder in probable cases can enhance PD detection. At-risk individuals and mild to moderate PD should be referred for cognitive behavioral therapy or interpersonal psychotherapy when available. Selective serotonin reuptake inhibitors should be used for moderate to severe PD, with sertraline, escitalopram, or citalopram being preferred first. Using paroxetine or clomipramine in pregnancy, and fluoxetine or doxepin during lactation is generally not preferred. Gestational antidepressant use is associated with a small increase in risk of reduced gestational age at birth, low birth weight, and lower APGAR scores, though whether these links are causal is unclear. Sertraline and paroxetine have the lowest rate of adverse events during lactation. Consequences of untreated PD can include maternal and offspring mortality, perinatal complications, poor maternal-infant attachment, child morbidity and maltreatment, less breastfeeding, and offspring developmental problems., Conclusions: These clinically relevant data can support the delivery of high-quality care by PCCs. Risks and benefits of PD treatments and the consequences of untreated PD should be discussed with patients to support informed decision making., Competing Interests: Conflict of interest: The authors have no conflicts of interest to declare., (© Copyright by the American Board of Family Medicine.)

Antidepressants are a commonly used, easily accessible, and overall safe treatment option for post-traumatic stress disorder (PTSD). The present review aims to evaluate the efficacy and safety of antidepressants in treating sleep disturbances in patients with PTSD. PubMed and the Cochrane Library were searched (July 2022) for systematic reviews and meta-analyses on the treatment of PTSD. Moreover, PubMed and ClinicalTrials.gov were searched for individual trials investigating the antidepressant treatment of PTSD (up to September 2022), and reference lists of all possibly relevant identified studies were screened. Sleep-related outcomes, i.e., total sleep time, sleep quality, dreams/ nightmares, insomnia, and somnolence, were extracted independently by at least two reviewers. Metaanalytic evaluations were performed wherever possible. 39 randomised controlled trials (RCTs) were identified; data from pooled analyses, reviews, and observational studies were used for antidepressants with a weak evidence base or when their findings were deemed important. Overall, scarce data exist on the effects of antidepressants on sleep outcomes among patients with PTSD. Some evidence may support the use of amitriptyline, nefazodone, paroxetine, and sertraline for improving sleep in patients with PTSD. Τhere was a meta-analytical trend indicating improvement of nightmares with fluoxetine, less insomnia with amitriptyline and more with brofaromine, as well as more somnolence with paroxetine vs. placebo, respectively. However, data from more than 1 RCT with a considerable number of patients were only available for paroxetine. Evidence is insufficient to draw safe conclusions. More and better-designed RCTs, with consistent reporting of sleep-related outcomes, are needed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: Investigate risk for falls, fractures and syncope in older adult patients treated with nortriptyline compared with paroxetine and alternative medications., Design: Retrospective cohort study., Setting: The electronic medical record and prescription drug database of a large integrated healthcare system in Southern California., Participants: Ambulatory patients, age ≥65 years diagnosed with depression, anxiety disorder or peripheral neuropathy, dispensed one or more of ten study medications between 1 January 2008 and 31 December 2018., Main Outcome Measures: HR for falls, fractures and syncope with exposure to study medications adjusted for patient demographic variables and comorbidities., Results: Among 195 207 subjects, 19 305 falls, 15 088 fractures and 11 313 episodes of syncope were observed during the study period. Compared with the reference medication, nortriptyline, the adjusted HRs (aHRs) for falls were statistically significantly greater for: paroxetine (aHR 1.48, 95% CI 1.39 to 1.57), amitriptyline (1.20, 95% CI 1.08 to 1.33), venlafaxine (1.44, 95% CI 1.34 to 1.56), duloxetine (1.25, 95% CI 1.12 to 1.40), fluoxetine (1.51, 95% CI 1.44 to 1.59), sertraline (1.53, 95% CI 1.44 to 1.62), citalopram (1.61, 95% CI 1.52 to 1.71) and escitalopram (1.37, 95% CI 1.21 to 1.54), but not gabapentin (0.95, 95% CI 0.89 to 1.02). For fractures, compared with nortriptyline, aHRs were significantly greater for: paroxetine, venlafaxine, duloxetine, fluoxetine, sertraline, citalopram, escitalopram and gabapentin, with aHRs ranging from 1.30 for gabapentin to 1.82 for escitalopram; risk was statistically similar for amitriptyline. For syncope, the aHRs were significantly greater for: paroxetine, venlafaxine, fluoxetine, sertraline and citalopram, with aHRs ranging from 1.19 for fluoxetine and paroxetine up to 1.30 for citalopram and sertraline; risk was similar for amitriptyline, duloxetine, escitalopram and gabapentin., Conclusions: Compared with therapeutic alternatives, nortriptyline was found to represent a lower risk for falls, fractures and syncope, versus comparator medications, except for a few instances that had equivalent risk. The risk for these adverse events from paroxetine was comparable to the alternative medications., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Ulotaront is a novel psychotropic agent with agonist activity at trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT 1A ) receptors in phase III clinical development for the treatment of schizophrenia., Objective: This study aimed to investigate the effect of paroxetine, a strong cytochrome P450 (CYP) 2D6 inhibitor, on ulotaront pharmacokinetics (PK) in healthy volunteers., Methods: Subjects received a single oral dose of 25 mg ulotaront on Day 1 and an oral dose of 20 mg paroxetine once daily from Days 5 to 10 to achieve steady-state plasma paroxetine levels. On Day 11, subjects received another single oral dose of 25 mg ulotaront, with continued daily oral dosing of 20 mg paroxetine from Days 11 to 14. All 24 subjects were CYP2D6 normal metabolizers., Results: Coadministration of paroxetine increased ulotaront maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time zero to infinity (AUC ∞ ) by 31% and 72%, respectively, and decreased ulotaront apparent clearance (CL/F) by approximately 42%. While coadministration of paroxetine increased AUC ∞ of active but minor metabolite SEP-363854 by 32%, it had no effect on SEP-363854 C max , or on SEP-363854 to the ulotaront AUC from time zero to the last quantifiable concentration (AUC last ) ratio. Based on the acceptable adverse event profile of ulotaront across previous phase II studies, the increase in ulotaront exposure is unlikely to be clinically meaningful., Conclusions: Weak drug-drug interactions were observed between ulotaront and the strong CYP2D6 inhibitor paroxetine; however, dose adjustment as a precondition when ulotaront is coadministered with strong CYP2D6 inhibitors or administered to CYP2D6 poor metabolizers should not be necessary., (© 2023. The Author(s).)

Objective: To evaluate the efficacy and safety of Jianpi Jieyu Decoction (JJD) for treating patients with mild-to-moderate depression of Xin (Heart)-Pi (Spleen) deficiency (XPD) syndrome., Methods: In this multi-center, randomized, controlled study, 140 patients with mild-to-moderate depression of XPD syndrome were included from Xiyuan Hospital of China Academy of Chinese Medical Sciences and Botou Hospital of Traditional Chinese Medicine from December 2017 to December 2019. They were randomly divided into JJD group and paroxetine group by using a random number table, with 70 cases in each group. The patients in the JJD group were given JJD one dose per day (twice daily at morning and evening, 100 mL each time), and the patients in the paroxetine group were given paroxetine (10 mg/d in week 1; 20 mg/d in weeks 2-6), both orally administration for a total of 6 weeks. The primary outcome was the change of 17-item Hamilton Depression Rating Scale (HAMD-17) score at week 6 from baseline. The secondary outcomes included the Hamilton Anxiety Scale (HAMA) score, Traditional Chinese Medicine Symptom Scale (TCMSS), and Clinlcal Global Impression (CGI) scores at the 2nd, 4th, and 6th weekends of treatment, HAMD-17 response (defined as a reduction in score of >50%) and HAMD-17 remission (defined as a score of ⩽7) at the end of the 6th week of treatment. Adverse events (AEs) were also recorded., Results: From baseline to week 6, the HAMD-17 scores decreased 10.2 ± 4.0 and 9.1 ± 4.9 points in the JJD and paroxetine groups, respectively (P=0.689). The HAMD-17 response occurred in 60% of patients in the JJD group and in 50% of those in the paroxetine group (P=0.292); HAMD-17 remission occurred in 45.7% and 30% of patients, respectively (P=0.128). The differences of CGI scores at the 6th week were not statistically significant (P>0.05). There were significant differences in HAMD-17 scores between the two groups at 2nd and 4th week (P=0.001 and P=0.014). The HAMA scores declined 8.1 ± 3.0 and 6.9 ± 4.3 points from baseline to week 6 in the JJD and paroxetine groups, respectively (P=0.905 between groups). At 4th week of treatment, there was a significant difference in HAMA between the two groups (P=0.037). TCMSS decreased 11.4 ± 5.1, and 10.1 ± 6.8 points in the JJD and paroxetine groups, respectively (P=0.080 between groups). At the 6th week, the incidence of AEs in the JJD group was significantly lower than that in the paroxetine group (7.14% vs. 22.86%, P<0.05)., Conclusion: Compared with paroxetine, JJD was associated with a significantly lower incidence of AEs in patients with mild-to-moderate depression of XPD syndrome, with no difference in efficacy at 6 weeks. (Trial registration No. ChiCTR2000040922)., (© 2022. The Chinese Journal of Integrated Traditional and Western Medicine Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Antidepressant drugs are prescribed to patients with depressive, anxiety disorders, and other conditions. Evidence about antidepressant discontinuation syndrome (ADS) and related outcomes is sparse, although potentially burdensome in some patients. The present state-of-the-art review aims to appraise the most current evidence about ADS critically. ADS has been documented for most antidepressant drugs, although most literature focuses on selective serotonin reuptake inhibitors prescribed for depression. While down-titration cannot exclude the chance of ADS, it is nonetheless warranted in the clinical setting, especially for short half-life and sedative compounds such as paroxetine. Integrative management with concurrent pharmacotherapy and psychotherapy may minimize the eventual unpleasant effects arising within the discontinuation process. In addition, patient-tailored interventions and education should be part of the discontinuation strategy. Future research must rely on broadly accepted definitions for ADS and related phenomena such as antidepressant withdrawal and shed further light on the underpinning neurobiology. Discriminating between ADS-related phenomena and relapse of depression is likewise warranted, along with a neuroscience-based nomenclature instead of a class one., Competing Interests: Declaration of Competing Interest EV has received grants and served as consultant, advisor, or CME speaker for the following entities (unrelated to the present work): AB-Biotics, Abbvie, Aimentia, Angelini, Biogen, Boehringer -Ingelheim, Casen-Recordati, Celon, Dainippon Sumitomo Pharma, Ferrer, Gedeon Richter, GH Research, Glaxo Smith-Kline, Janssen, Lundbeck, Organon, Otsuka, Sage, Sanofi-Aventis, Sunovion, Takeda, and Viatris. All outside of the present work. MF received consulting fees & fees for non-CME/CE services from: Angelini, AstraZeneca, Boehringer Ingelheim, Bristol Meyers Squibb, Eli Lilly, GlaxoSmithKline, Innova Pharma, Lundbeck, Pfizer, Sanofi, Servier. All outside of the present work. GM has been a consultant and/or a speaker and/or has received research grants from Angelini, Doc Generici, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Servier, and Recordati. All outside of the present work. CIC received consulting fees from Lundbeck and Johnson and Johnson. All outside of the present work. FVR and DDB have no conflict of interest to disclose in conjunction with the present work., (Copyright © 2022 Elsevier B.V. and ECNP. All rights reserved.)

BACKGROUND Serotonin toxicity, often referred to as 'serotonin syndrome,' is a drug-induced condition due to excess serotonin released from brain synapses, resulting in symptoms that may be autonomic, neuromuscular, and/or cognitive in nature. Most cases involve more than 1 of the following drug regimens: monoamine oxidase inhibitors (MAOIs), serotonin releasers, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs). This report is of a 70-year-old woman who presented with confusion and muscle spasms due to serotonin toxicity associated with paroxetine and quetiapine treatment. CASE REPORT An elderly woman with dementia presented to the Emergency Department with fever, altered mental status, labile blood pressures, and inducible clonus. No known medication dosage increases had been made, nor had any new serotonergic agents been added to the patient's drug regimen. She underwent a thorough workup in the Emergency Department and later during her hospitalization. A presumptive diagnosis of serotonin toxicity was made early on during her stay, with the etiology attributed to use of paroxetine and quetiapine. Clinical improvement was observed after benzodiazepine administration, discontinuation of offending agents, and a brief cyproheptadine course. The patient survived her hospital stay and was ultimately discharged to hospice care with a return to her baseline level of functioning. CONCLUSIONS Diagnosing serotonin toxicity requires a high degree of clinical suspicion and can occur in the absence of increased dosage of existing, or initiation of new, serotonergic agents.

This study focused on the effect of unripe (UPP) and ripe (RPP) plantain peels' extracts (200 and 400 mg/kg) on sexual behavior, hormonal profiles [testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH)], and enzymes [acetylcholinesterase (AChE), phosphodiesterase-5' (PDE-5), arginase, angiotensin-I converting enzyme (ACE), ecto-5'neucleotidase, and adenosine deaminase (ADA)] in paroxetine (PAR)-induced penile dysfunction rats. From the result, arginase, PDE-5', ACE, ecto-5'-nucleotidase ADA, and AChE activities, sexual activities, hormonal profile, and NO level were reduced, while thiobarbituric acid reactive species (TBARS) level increased (p < .05) relative to normal control rats. However, treatment with UPP and URP reduced the activities of these enzymes, decreased TBARS levels, and increased hormones, and penile NO levels in PAR-induced rats. Thus, the use of UPP and RPP could be channeled towards the improvement of sexual performance in erectile dysfunction (ED) disorder. PRACTICAL APPLICATIONS: Plantain fruits are a tropical staple food crop commonly consumed at various stages of ripeness and cooking methods. However, its peels are regarded as a waste product with reported cases of environmental menace. Interestingly, plantain peel is being used as a major raw material for industrial applications in the agro-based industries and in folklore for the treatment of many human ailments due to its rich phytochemicals such as polyphenols, carotenoids, alkaloids, etc., which have been reported. A prelude study has also indicated its usefulness in ED management, but further pharmacological investigations are needed to proffer information on its effect in ED management and its anti-androgenic activity in male Wistar rats. The information from this study could be of pharmaceutical importance in designing natural remedies capable of improving penile rigidity, hormone profiles, and alteration of enzymes linked with ED., (© 2022 Wiley Periodicals LLC.)

Despite the antidepressant potency of paroxetine, its side effect of erectile dysfunction is burdensome. Grapefruit peels (GFPs) are underutilized cultivar wastes with wide range of therapeutic potentials which have been attributed to their antioxidant behavior and phenolic contents' abilities to effectively inhibit enzymatic activities and manage endothelial dysfunction in cardiovascular disorders. This study aims to investigate the erectogenic potentials of GFP extract in a rat model of paroxetine-induced ED. Experimental rats were sectioned into five groups: [1: control; 2: paroxetine (10 mg/kg); 3: paroxetine + sildenafil (5 mg/kg); 4: paroxetine + GFP (50 mg/kg); 5: paroxetine + GFP (100 mg/kg)] and treated for 28 days. Sexual behavior of rats was assessed and effect of GFP on ecto-5' nucleotidases, phosphodiesterase-5, and adenosine deaminase (ADA) activities was determined in rats' penile tissues. The levels of malondialdehyde, nitric oxide (NO) as well as superoxide dismutase (SOD) and catalase activities were also determined. HPLC-DAD analysis showed the presence of naringin, rutin, caffeic acid, quercitrin, quercetin, and kaempferol glycoside. Oral administration of paroxetine reduced erectile response as revealed by their low intromission and mounting numbers as well as high intromission and mounting latencies. Paroxetine caused a significant elevation of ADA and phosphodiesterase-5 activities and malondialdehyde levels with drastic reduction in levels of NO, SOD, and catalase activities in rats' penile tissues. However, GFP extract reversed PDE-5, ADA, and antioxidant activities to normal levels, raised the concentration of NO. These results suggest the erectogenic effects and protective potentials of GFP extract against paroxetine-induced erectile dysfunction. PRACTICAL APPLICATION: Grapefruit peels are an environmental menace in many countries and this study showed that the peels can be used in the prevention / management of erectile dysfunction. The therapeutic potentials of the peels are due to the presence of bioactive compounds such as flavonoids and phenolic acids. Therefore, exploring the erectogenic potentials of the peels will translate to conversion of the wastes to therapeutic products., (© 2022 Wiley Periodicals LLC.)

Since exploding rates of modern mental diseases, application of antidepressants has increased. Worryingly, the antidepressant-induced liver injury has gradually become a serious health burden. Furthermore, since most of the knowledge about antidepressant hepatotoxicity are from pharmacovigilance and clinical case reports and lack of observational studies, the underlying mechanisms are poorly understood and there is a lack of efficient treatment strategies. In this study, antidepressant paroxetine directly triggered inflammasome activation evidenced by caspase-1 activation and downstream effector cytokines interleukin(IL)-1β secretion. The pretreatment of echinatin, a bioactive component of licorice, completely blocked the activation. This study also found that echinatin effectively inhibited the production of inflammasome-independent tumor necrosis factor α(TNF)-α induced by paroxetine. Mechanistically, the accumulation of mitochondrial reactive oxygen species(mtROS) was a key upstream event of paroxetine-induced inflammasome activation, which was dramatically inhibited by echinatin. In the lipopolysaccharide(LPS)-mediated idiosyncratic drug-induced liver injury(IDILI) model, the combination of LPS and paroxetine triggered aberrant activation of the inflammasome to induce idiosyncratic hepatotoxicity, which was reversed by echinatin pretreatment. Notably, this study also found that various bioactive components of licorice had an inhibitory effect on paroxetine-triggered inflammasome activation. Meanwhile, multiple antidepressant-induced aberrant activation of the inflammasome could be completely blocked by echinatin pretreatment. In conclusion, this study provides a novel insight for mechanism of antidepressant-induced liver injury and a new strategy for the treatment of antidepressant-induced hepatotoxicity.

Importance: Opioids can cause severe respiratory depression by suppressing feedback mechanisms that increase ventilation in response to hypercapnia. Following the addition of boxed warnings to benzodiazepine and opioid products about increased respiratory depression risk with simultaneous use, the US Food and Drug Administration evaluated whether other drugs that might be used in place of benzodiazepines may cause similar effects., Objective: To study whether combining paroxetine or quetiapine with oxycodone, compared with oxycodone alone, decreases the ventilatory response to hypercapnia., Design, Setting, and Participants: Randomized, double-blind, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) with 25 healthy participants from January 2021 through May 25, 2021., Interventions: Oxycodone 10 mg on days 1 and 5 and the following in a randomized order for 5 days: paroxetine 40 mg daily, quetiapine twice daily (increasing daily doses from 100 mg to 400 mg), or placebo., Main Outcomes and Measures: Ventilation at end-tidal carbon dioxide of 55 mm Hg (hypercapnic ventilation) using rebreathing methodology assessed for paroxetine or quetiapine with oxycodone, compared with placebo and oxycodone, on days 1 and 5 (primary) and for paroxetine or quetiapine alone compared with placebo on day 4 (secondary)., Results: Among 25 participants (median age, 35 years [IQR, 30-40 years]; 11 female [44%]), 19 (76%) completed the trial. The mean hypercapnic ventilation was significantly decreased with paroxetine plus oxycodone vs placebo plus oxycodone on day 1 (29.2 vs 34.1 L/min; mean difference [MD], -4.9 L/min [1-sided 97.5% CI, -∞ to -0.6]; P = .01) and day 5 (25.1 vs 35.3 L/min; MD, -10.2 L/min [1-sided 97.5% CI, -∞ to -6.3]; P < .001) but was not significantly decreased with quetiapine plus oxycodone vs placebo plus oxycodone on day 1 (33.0 vs 34.1 L/min; MD, -1.2 L/min [1-sided 97.5% CI, -∞ to 2.8]; P = .28) or on day 5 (34.7 vs 35.3 L/min; MD, -0.6 L/min [1-sided 97.5% CI, -∞ to 3.2]; P = .37). As a secondary outcome, mean hypercapnic ventilation was significantly decreased on day 4 with paroxetine alone vs placebo (32.4 vs 41.7 L/min; MD, -9.3 L/min [1-sided 97.5% CI, -∞ to -3.9]; P < .001), but not with quetiapine alone vs placebo (42.8 vs 41.7 L/min; MD, 1.1 L/min [1-sided 97.5% CI, -∞ to 6.4]; P = .67). No drug-related serious adverse events were reported., Conclusions and Relevance: In this preliminary study involving healthy participants, paroxetine combined with oxycodone, compared with oxycodone alone, significantly decreased the ventilatory response to hypercapnia on days 1 and 5, whereas quetiapine combined with oxycodone did not cause such an effect. Additional investigation is needed to characterize the effects after longer-term treatment and to determine the clinical relevance of these findings., Trial Registration: ClinicalTrials.gov Identifier: NCT04310579.

This network meta-analysis aimed to assess the efficacy and safety of "on-demand" and "daily" use of paroxetine for patients with premature ejaculation (PE). We searched PubMed, Embase and Cochrane Library from inception to October 2021 to collect randomized controlled trials, and 24 articles including 2, 308 patients were finally involved. The results indicated that paroxetine (daily or on-demand) was superior to placebo at increasing intravaginal ejaculatory latency time (IELT), and 20 mg paroxetine daily was significantly better than fluoxetine and tramadol in improving IELT. Besides, 20 mg paroxetine on-demand was less effective than 20 mg paroxetine on-demand plus phosphodiesterase-5 inhibitors (PDEI5) and tramadol monotherapy in increasing IELT. Tramadol monotherapy was more effective than paroxetine monotherapy in improving sexual satisfaction score. Although patients treated with paroxetine had more coitus/week than patients treated with placebo, it was less than patients treated with PDEI5. These findings were robust to sensitivity analyses. The common adverse events related with paroxetine were fatigue, yawning and abnormal sleep (10.96%), gastrointestinal upset (10.80%). The "on-demand" and "daily" use of paroxetine can significantly improve the clinical symptoms of patients with PE and were well tolerated. Combination therapy and tramadol monotherapy can also be used as alternative treatments., (© 2022 Wiley-VCH GmbH.)

Treatment with SSRI have a high frequency of treatment of emergent sexual dysfunction. The mechanism is thought to be through serotoninergic inhibition of the sexual response. More than 70% of patients treated with sertraline, citalopram or paroxetine experience sexual side effects, while escitalopram and fluvoxamine yield the lowest degree of sexual dysfunction within the group. This review suggests management strategies including dose reduction, change of medication and add-on treatment. A small group of patients experience post-SSRI dysfunction, in which sexual dysfunction persists after treatment termination.

Adverse drug reactions (ADRs) of targeted therapy drugs (TTDs) are frequently unexpected and long-term toxicities detract from exceptional efficacy of new TTDs. In this proof-of-concept study, we explored how molecular causation involved in trastuzumab-induced cardiotoxicity changes when trastuzumab was given in combination with doxorubicin, tamoxifen, paroxetine, or lapatinib. The data analytical platform Molecular Health Effect was utilized to map population ADR data from the US Food and Drug Administration (FDA) Adverse Event Reporting System to chemical and biological databases (such as UniProt and Reactome), for hypothesis generation regarding the underlying molecular mechanisms causing cardiotoxicity. Disproportionality analysis was used to assess the statistical relevance between adverse events of interest and molecular causation. Literature search was performed to compare the established hypotheses to published experimental findings. We found that the combination therapy of trastuzumab and doxorubicin may affect mitochondrial dysfunction in cardiomyocytes through different molecular pathways such as BCL-X and PGC-1α proteins, leading to a synergistic effect of cardiotoxicity. We found, on the other hand, that trastuzumab-induced cardiotoxicity would be diminished by concomitant use of tamoxifen, paroxetine, and/or lapatinib. Tamoxifen and paroxetine may cause less cardiotoxicity through an increase in antioxidant activities, such as glutathione conjugation. Lapatinib may decrease the apoptotic effects in cardiomyocytes by altering the effects of trastuzumab on BCL-X proteins. This patient-centered systems-based approach provides, based on the trastuzumab-induced ADR cardiotoxicity, an example of how to apply reverse translation to investigate ADRs at the molecular pathway and target level to understand the causality and prevalence during drug development of novel therapeutics., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Objective: The aim of this review was to determine whether selective serotonin reuptake inhibitors (SSRIs) affect the ability to conceive in men and women of reproductive age, as well as to find out whether there are certain differencies between them in terms of effects on fertility. Methods: Our review was based on systematic search of literature in four online databases: Medline (PubMed), Scopus, Web of Science and SCIndex (Serbian Citation Index). Results: Several clinical studies reported that SSRIs can decrease the number and viability of sperm, and cause a disruption of their morphological structure. Regarding the effect of these antidepressants on female fertility, some experimental findings suggest that paroxetine and escitalopram may have a negative effect on the ability to conceive due to their stimulatory effect on fallopian tube motility. However, several observational studies favor the use of SSRIs in women with depression/anxiety undergoing in vitro fertilization (IVF) given their efficiency in suppressing these unpleasant symptoms without a relevant negative impact on IVF outcomes. Conclusions: SSRIs should be avoided male patients of reproductive age who wish to conceive, while the use of these antidepressants seems to be justified in women with depression or anxiety who have undergone IVF.Key pointsSSRIs could cause dose and duration-dependent reversible adverse effects on male fertility parameters.In depressed or anxious male patients of reproductive age who wish to conceive mirtazapine or bupropion should be used because of their lower potential to cause sexual side effects.The results of certain experimental studies indicate that paroxetine and escitalopram may have a negative effect on the fertility of female patients.The use of SSRIs in women with depression or anxiety who have undergone IVF seems to be justified, because these psychiatric disorders reduce the likelihood of becoming pregnant.

Importance: Some selective serotonin reuptake inhibitors (SSRIs) inhibit the enzymes responsible for the metabolism of oxycodone, a potent prescription opioid. The clinical consequences of this interaction on the risk of opioid overdose have not been elucidated., Objective: To compare opioid overdose rates in patients initiating oxycodone while taking SSRIs that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) vs SSRIs that are not., Design, Setting, and Participants: This cohort study included adults who initiated oxycodone while receiving SSRI therapy between 2000 and 2020 whose data were included in 3 US health insurance databases., Exposures: Use of SSRIs that strongly inhibit CYP2D6 enzyme (fluoxetine or paroxetine) vs use of other SSRIs at the time of oxycodone initiation., Main Outcomes and Measures: Opioid overdose hospitalization or emergency department visit. Outcomes were assessed within 365 days of oxycodone initiation; in primary analyses, patients were followed up until the discontinuation of either oxycodone or their index SSRI group. Propensity score matching weights were used to adjust for confounding. Crude and weighted (adjusted) incidence rates and hazard ratios were estimated using Cox regression models, separately within each database and overall, stratifying on database., Results: A total of 2 037 490 initiated oxycodone while taking SSRIs (1 475 114 [72.4%] women; mean [SD] age, 50.1 [15.3] years). Most (1 418 712 [69.6%]) were receiving other SSRIs at the time of oxycodone initiation. In the primary analysis, we observed 1035 overdose events (0.05% of the study cohort). The adjusted incidence rate of opioid overdose in those using inhibiting SSRIs at the time of oxycodone initiation (9.47 per 1000 person-years) was higher than in those using other SSRIs (7.66 per 1000 person-years), indicating a greater risk of overdose among patients using CYP2D6-inhibiting SSRIs (adjusted hazard ratio, 1.23; 95% CI, 1.06-1.31). Results were consistent across multiple subgroup and sensitivity analyses., Conclusions and Relevance: In this cohort study of US adults, initiating oxycodone in patients treated with paroxetine or fluoxetine was associated with a small increased risk of opioid overdose.

Selective serotonin reuptake inhibitors (SSRI) show high efficacy in treating depression, however during treatment side effects, like for instance sexual dysfunction, may appear, decreasing compliance. In some cases, this condition will last after drug discontinuation, leading to the so-called post-SSRI sexual dysfunction (PSSD). The etiology of PSSD is still unknown, however a role for neuroactive steroids may be hypothesized. Indeed, these molecules are key physiological regulators of the nervous system, and their alteration has been associated with several neuropathological conditions, including depression. Additionally, neuroactive steroids are also involved in the control of sexual function. Interestingly, sexual dysfunction induced by SSRI treatment has been also observed in animal models. On this basis, we have here evaluated whether a subchronic treatment with paroxetine for two weeks and/or its withdrawal (i.e., a month) may affect the levels of neuroactive steroids in brain areas (i.e., hippocampus, hypothalamus, and cerebral cortex) and/or in plasma and cerebrospinal fluid of male rats. Data obtained indicate that the SSRI treatment alters neuroactive steroid levels and the expression of key enzymes of the steroidogenesis in a brain tissue- and time-dependent manner. Indeed, these observations with the finding that plasma levels of neuroactive steroids are not affected suggest that the effect of paroxetine treatment is directly on neurosteroidogenesis. In particular, a negative impact on the expression of steroidogenic enzymes was observed at the withdrawal. Therefore, it is possible to hypothesize that altered neurosteroidogenesis may also occur in PSSD and consequently it may represent a possible pharmacological target for this disorder., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50-150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges., (© 2020 The British Pharmacological Society.)

Diverse dermatological side effects in relation to using psychotropic agents, include the serious outcomes as hypersensitivity and StevensJohnson syndrome as well as milder forms as ecchymosis and hair loss. Whereas hair loss is frequently associated with mood stabilizers, rarely ,it is also attributed to antidepressants. Selective serotonin reuptake inhibitors (SSRIs) which are the first choice treatment for depression, anxiety disorders and obsessive-compulsive spectrum disorders, are the most commonly used antidepressant drugs. Psychiatric comorbidities have been known in many dermatological diseases and their treatment have positive effects on the course and outcome as well as on the adaptation process to the disease. Due to their favorable side effect profile, for comorbid cases SSRIs are frequently used. Here we present a case of hair loss during paroxetine in a 24-year-old male with social anxiety disorder. In this case the hair loss improved after discontinuing and recurred after resuming paroxetine. After replacing paroxetine with sertraline, another SSRI, alopecia did not recur.

BACKGROUND A musical hallucination (MH) is a type of auditory hallucination, and is defined as hearing music, sounds, or songs in the absence of external auditory stimuli. There are several case reports of conventional doses of tri- or tetracyclic antidepressants inducing MHs, but no such report for selective serotonin reuptake inhibitors. Here we report a case of a patient with MHs induced by conventional doses of paroxetine. CASE REPORT The patient was a 22-year-old woman with panic disorder (PD) and major depressive disorder (MDD). On the 10th day of treatment with paroxetine 20 mg/d, olanzapine 5 mg/d, and lorazepam 1.5 mg/d, she developed MHs such as "an opera song sung by a female singer." The MHs occurred several times a day, and once continued for 5 to 10 min. Because of a suspicion of paroxetine-induced MHs and poor clinical improvement, paroxetine was reduced and discontinued on the 31st day, whereas venlafaxine was started and increased to 75 mg/d. Two days after the discontinuation of paroxetine, the MHs disappeared and symptoms of PD and MDD were much improved. Several weeks later, in response to a negative life event, her symptoms of PD and MDD returned to the original levels, but MHs were not observed. CONCLUSIONS The present report suggests that conventional doses of paroxetine can induce MHs, which are most likely ascribable to the anticholinergic effects of the drug. This adverse effect should be differentially diagnosed from psychotic symptoms arising from psychiatric disorders, especially MDD.

Antidepressant drugs are globally used to treat several psychiatric disorders in pediatric patients and their prescription has continued to increase in recent years, especially among girls. In addition to its well-known metabolic and gastrointestinal side effects, antidepressants can cause sexual dysfunction in adults. However, the effects of the antidepressants on puberty onset and reproductive system remain unclear in children and adolescents. Therefore, the goal of this study is to examine the effects of chronic postnatal antidepressant drugs, paroxetine or bupropion, treatments on puberty onset and reproductive system components in female rats weaned at postnatal day (PND) 21. Female rats (n = 10 for each group) were exposed to vehicle (0.2 mL of saline), paroxetine (3.6 mg/kg in 0.2 mL of saline) or bupropion (17 mg/kg in 0.2 mL of saline) daily by oral gavage from the PND 21 to PND 90-93. Chronic paroxetine or bupropion treatments advanced the puberty onset, but the difference was statistically significant in only the paroxetine group. The exposure to bupropion significantly decreased the serum anti-Müllerian hormone (AMH) levels and luteinizing hormone (LH) levels. There were increases in serum estradiol levels by both antidepressant treatments and the significance was found in only the paroxetine group. Consistent with these results, histopathologic changes were observed in the ovary and uterus tissues taken from both antidepressant-treated rats. The obtained results of chronic postnatal exposure to paroxetine or bupropion may change the timing of puberty onset and lead to disruption of reproductive functions in females., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

The aim of the study was to examine possible impacts of paroxetine and agomelatine on the levels of some components that constitute the seminal vesicle fluid. As a second purpose, it was also aimed to examine how possible negative effects induced by paroxetine on seminal vesicle fluid components were affected by kisspeptin and RF9 (an RFamide-related peptide antagonist, RFRP). Forty-two male rats, aged 21 days, divided into six groups; control, sham, paroxetine, agomelatine, paroxetine + kisspeptin and paroxetine + RF9. Paroxetine (3.6 mg/kg) and agomelatine (10 mg/kg) were administrated by oral gavage. Kisspeptin (1 nmol) and RF9 (20 nmol) were administered intracerebroventricular (i.c.v). The experiments were ended on post-natal 120 days; fructose, vitamin E, sodium, potassium and magnesium levels were measured in seminal vesicle fluid. Fructose, vitamin E, magnesium and potassium levels were significantly decreased in seminal vesicle fluid from the rats treated with paroxetine but did not show significant differences following agomelatine administration. The co-administration of kisspeptin or RF9 with paroxetine prevented the paroxetine-induced negative effects on seminal vesicle fluid components. These results suggest that reduction in sperm fertilising ability caused by changes in seminal vesicle fluid can be seen in long-term antidepressant use. RF-9 and kisspeptin might have positive effects on long-term antidepressant use-induced infertility., (© 2020 Blackwell Verlag GmbH.)

Many factors can cause depression including genes (DNA), brain chemistry or stress. Antidepressant drugs affect the brain, heart, liver and kidney. We investigated the effects of the antidepressant drugs, amitriptyline (AMI) and paroxetine (PARO) on kidney. We used 24 adult female rats that were ovariectomized bilaterally 7 days before the experiment. The ovariectomized (OVX) animals and healthy control rats were divided into four equal groups for 4 weeks: control group, OVX control group (sham), AMI group and PARO group. Following the experimental period, the Cavalieri method was applied to sections of the kidney. PARO produced adverse effects on distal and proximal tubule volume, but AMI had no effect on the volume of distal and proximal tubules. Both PARO and AMI decreased the volume of Bowman spaces. PARO also damaged the kidney tubules and cells.

Objective: The purpose of our study is to evaluate the efficacy of paroxetine in poststroke depression (PSD) patients by conducting a meta-analysis., Methods: We searched Web of Science (science and social science citation index), PubMed, the Cochrane Central Register of Controlled Trials, Embase up to August 2019. Randomized controlled trials that paroxetine compared to other antidepressants or control treatments as monotherapy for patients with PSD., Results: This review identified a total of 4 studies including 212 patients. This meta-analysis presented that paroxetine exhibits beneficial efficacy than routine treatment in PSD patients in terms of the reducing score of Hamilton Depression Scale (HAMD). Control treatment is more effective than paroxetine. No significant advantage was found with paroxetine., Conclusions: The efficacy of paroxetine maybe not very significant compared to other pharmacological and nonpharmacological interventions. Further high quality and large sample size studies are needed to evaluate the efficacy and safety of paroxetine in treating PSD in future., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Paroxetine is a selective serotonin reuptake inhibitor (SSRI) with several indications, one of which is for depression. We present a case of probable paroxetine-induced serotonin syndrome., Case Summary: A 21-year-old female with a history of generalized anxiety disorder and major depression presented with increased depressive symptoms over several months while taking fluoxetine 20 mg daily. Fluoxetine was discontinued without taper and replaced with paroxetine 10 mg daily, along with hydroxyzine 50 mg twice daily as needed for anxiety. Within a week of starting the paroxetine, the patient reported increased anxiety, insomnia, and constant shaking. The paroxetine continued to be uptitrated over a 3-week period to a dose 30 mg due to unremitting depressive symptoms. One month later, the patient presented with tachycardia, generalized body aches, extreme fatigue, weakness, uncontrollable twitching, tremor, and hyperreflexia. A widespread burning sensation accompanied by random hot flashes without diaphoresis was also noted. Serotonin syndrome was diagnosed using the Hunters criteria. Paroxetine was discontinued, and the patient's physical symptoms resolved within a week., Discussion: To date, only 5 cases of serotonin syndrome have been reported in patients receiving SSRI monotherapy at recommended therapeutic doses.

We currently have a wide range of antidepressants available. However, the mechanisms of action are different, giving a theoretical justification for their combination in the failure of monotherapy. However, the combination of drugs entails, in addition to benefits, an increase in the risk of, for example, drug interactions. Many drug interactions in psychiatry are due to the pharmacokinetic interactions between drugs, where their plasma concentrations are altered by inhibiting or inducing cytochrome P450 isoenzymes, especially CYP2D6 and CYP3A4 and P-glycoprotein. When treating depression, we should consider the risks and benefits of combination therapy in individual patients and take measures to minimize the side effects of medicines. The case report describes a case of a patient who reported significant depression after adding paroxetine and mirtazapine to psychiatric medication. As a theoretical cause, it discusses the possible clinically demonstrated interaction between paroxetine and mirtazapine, which has been clinically manifested by fatigue and pronounced daytime sleepiness.

Long-term use of selective serotonin reuptake inhibitors (SSRIs) targeting the serotonin transporter (SERT) has been suggested to be associated with an increased risk for obesity and type 2 diabetes. Previously, using a murine knockout model of SERT, we showed that estrogen suppression is involved in SERT deficiency-induced obesity and glucose intolerance in nonpregnant mice. The present study investigated the effects of chronic paroxetine treatment on adiposity and glucose tolerance in mice before and during pregnancy. Chronic paroxetine treatment in nonpregnant mice resulted in visceral adiposity and glucose intolerance accompanied by reduced circulating 17 β -estradiol levels and ovarian expression of the aromatase (CYP19a1). Remarkably, pregnancy significantly reduced adiposity and improved glucose tolerance in paroxetine-treated mice by rebooting ovarian CYP19a1 expression and 17 β -estradiol production. These effects appear to be reversible as ovarian CYP19a1 expression and circulating 17 β -estradiol returned to prepregnancy levels soon after parturition. As in pregnant mice, 17 β -estradiol replacement treatment in nonpregnant mice reduced paroxetine-induced adiposity. Our findings further suggested that modulation of estrogen synthesis underlies the observed metabolic adverse effects of SSRIs. Although our data revealed a transient reversal effect of pregnancy on SSRI-induced metabolic abnormalities, these observations are experimental and limited to mice. The use of SSRIs during human pregnancy should be cautioned because of potential adverse effects to the fetuses., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Introduction: Sexual dysfunction is prevalent among patients with depression, but assessment of treatment-emergent sexual dysfunction (TESD), a common side effect of antidepressants, can be confounded by the treatment of depressive symptoms in some patients., Aim: To evaluate sexual functioning in healthy volunteers administered vortioxetine compared with paroxetine, an antidepressant known to cause sexual dysfunction, and placebo., Methods: This phase 4, multicenter, randomized, double-blind, placebo-controlled, 4-arm, fixed-dose, head-to-head study compared sexual functioning in healthy volunteers administered vortioxetine (10 and 20 mg once daily [QD]), paroxetine (20 mg QD), or placebo for 5 weeks. Approximately equal numbers of men and women ages 18-40 years with normal sexual functioning (self-reported Changes in Sexual Functioning Questionnaire Short-Form [CSFQ-14] score > 47 for men; > 41 for women) were enrolled. Two modified full analysis sets adjusting for treatment non-compliance were prespecified., Main Outcome Measure: The primary endpoint was change in CSFQ-14 total score for vortioxetine (10 and 20 mg) vs paroxetine after 5 weeks. Additional endpoints included CSFQ-14 change scores vs placebo, CSFQ-14 subscales, and patient global impression., Results: Of the 361 subjects enrolled (mean age, 28.4 years), approximately 57% were white, 34% black/African American, and 4% Asian. Vortioxetine 10 mg was associated with significantly less TESD than paroxetine (mean difference, +2.74 points; P = .009). Although vortioxetine 20 mg was associated with numerically less TESD than paroxetine (mean difference, +1.05 points), this difference did not reach statistical significance. Non-compliance appeared to influence results, particularly the paroxetine and vortioxetine 20 mg arms. Paroxetine, but not vortioxetine, was associated with statistically significantly more TESD vs placebo. Vortioxetine also had better outcomes than paroxetine in the 3 phases and 5 dimensions of sexual functioning measured by CSFQ-14., Clinical Implications: These data establish that vortioxetine is associated with less TESD than paroxetine in healthy individuals, suggesting that vortioxetine may be a drug of choice in managing depressive disorders when sexual functioning is a concern., Strengths & Limitations: Conducting the study in healthy adults mitigated the risk of an underlying condition (eg, depression) confounding the results. Assay sensitivity was demonstrated by statistically significant TESD with paroxetine vs placebo. The single comparator, paroxetine, and short study duration limit the generalizability of these results., Conclusion: Vortioxetine is associated with less TESD than paroxetine in healthy adults across all phases and dimensions of the sexual response cycle. Vortioxetine was not significantly different from placebo on sexual functioning; however, the difference was significant between paroxetine and placebo, validating study results. Jacobsen P, Zhong W, Nomikos G, et al. Paroxetine, but not Vortioxetine, Impairs Sexual Functioning Compared With Placebo in Healthy Adults: A Randomized, Controlled Trial. J Sex Med 2019; 16:1638-1649., (Copyright © 2019. Published by Elsevier Inc.)

A female neonate with in utero selective serotonin reuptake inhibitor exposure presented with bradycardia shortly after birth. Electrocardiography showed severe QT prolongation and second-degree atrioventricular block. Over time QT-times spontaneously normalised and genetic testing did not show mutations associated with long QT syndrome making maternal selective serotonin reuptake inhibitor usage the most likely explanation for the observed severe transient neonatal QT prolongation.

Antidepressant use in adolescents has become more common in recent years. We have found several studies stating that prenatal antidepressant exposure can lead to delayed or earlier puberty onset but there was no study on postnatal paroxetine or bupropion. The main aim of this study was to investigate the effect of postnatal exposure to bupropion or paroxetine on puberty onset, reproductive and feeding results. The male rats (n = 8/group) aged 21 days were exposed to paroxetine (3.6 mg/kg) or bupropion (17 mg/kg) orally by gastric gavage every day from postnatal day 21-90. Also, control group received only saline orally as a vehicle. Postnatal exposure to bupropion or paroxetine delayed puberty onset compared to control group, but it was not significant. Sperm counts were significantly lower in the paroxetine and bupropion groups compared to control group. Sperm motility was significantly lower in only bupropion group. In addition, sperm motility was lower in paroxetine group, but it was not significant. In the histopathological examination, there was damage to the testicular structure in both treatments. Taken together, our result indicates that postnatal paroxetine or bupropion exposure may affect puberty onset and contribute to the impairment in fertility in male rats., (© 2019 Blackwell Verlag GmbH.)

Objective: Antidepressants are frequently prescribed and are the first-line pharmacological treatments for psychiatric disorders in children and adolescents. Although antidepressants are generally effective and well-tolerated by children, between 31% to 48% will not respond and up to 25% will experience an adverse drug reaction. Evidence from adult populations suggests pharmacogenetic information can assist with identifying individuals at greatest risk for poor response or adverse drug reactions but the evidence base in pediatric populations is less clear., Method: We systematically identified, reviewed, and critically evaluated the antidepressant pharmacogenetics literature among children and adolescents using standardized tools and consensus criteria., Results: We identified 24 studies, most of which were of fair to moderate quality. Collectively, the studies identified 25 significant gene-antidepressant associations involving 10 genes (ABCB1, BDNF, CYP2C19, CYP2D6, FKBP5, GNB3, HTR1B, HTR2A, SLC6A4, TPH2) and nine antidepressants (amitriptyline, citalopram, escitalopram, fluoxetine, fluvoxamine, nortriptyline, paroxetine, sertraline, and venlafaxine). None of the identified associations have been independently replicated in children., Limitations: Included studies were heterogenous in terms of study design, genes and drugs assessed, and outcomes measured., Conclusion: The antidepressant pharmacogenetics knowledge base in pediatric populations is still emerging, but results to date echo many of the gene-antidepressant associations identified in adult populations. Given ubiquitous prescribing of antidepressants in the care of children and adolescents with psychiatric disorders, further research on identifying new and confirming current gene-antidepressant associations are warranted., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Evidence in humans and rodents suggests that perinatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants can have serious long-term consequences in offspring exposed in utero or infancy via breast milk. In spite of this, there is limited knowledge of how perinatal SSRI exposure impacts brain development and adult behaviour. Children exposed to SSRIs in utero exhibit increased internalizing behaviour and abnormal social behaviour between the ages of 3 and 6, and increased risk of depression in adolescence; however, the neurobiological changes underlying this behaviour are poorly understood. In rodents, perinatal SSRI exposure perturbs hippocampal gene expression and alters adult emotional behaviour (including increased depression-like behaviour). The present study demonstrates that perinatal exposure to the SSRI paroxetine leads to DNA hypomethylation and reduces DNA methyltransferase 3a (Dnmt3a) mRNA expression in the hippocampus during the second and third weeks of life. Next-generation sequencing identified numerous differentially methylated genomic regions, including altered methylation and transcription of several dendritogenesis-related genes. We then tested the hypothesis that transiently decreasing Dnmt3a expression in the early postnatal hippocampus would mimic the behavioural effects of perinatal SSRI exposure. We found that siRNA-mediated knockdown of Dnmt3a in the dentate gyrus during the second to third week of life produced greater depression-like behaviour in adult female (but not male) offspring, akin to the behavioural consequences of perinatal SSRI exposure. Overall, these data suggest that perinatal SSRI exposure may increase depression-like behaviours, at least in part, through reduced Dnmt3a expression in the developing hippocampus., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Senile depression patients in China usually present with a higher risk of coronary heart disease that may trigger cardiac death. Selective serotonin reuptake inhibitors (SSRIs) were the most prescribed antidepressants in China; the cardiovascular safety of SSRIs when used in Chinese senile depression patients has not been evaluated., Methods: A network of meta-analysis was conducted to fill the objectives. PubMed, Embase databases, and 2 Chinese language electronic databases WANFANG and CNKI were searched for the related articles. The primary outcome of the present study was the number of cardiovascular reactions when each SSRI drug was used among senile depression patients in China. Odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were calculated within pairwise and network meta-analysis., Results: Fifteen trials were identified, including 1432 patients; the network meta-analysis showed that Chinese senile depression patients treated by Escitalopram were associated with a lower risk of cardiovascular reaction (CDR) than Paroxetine (ORs 0.37, 95% CI 0.14-0.37). Escitalopram also exhibited distinct advantages compared with other SSRIs. The rank of SSRIs with respect to cardiovascular safety was Escitalopram > Sertraline > Citalopram > Paroxetine > Fluoxetine, respectively., Conclusion: Escitalopram exhibited distinct advantages compared with other SSRIs, while Fluoxetine had the biggest cardiovascular reaction probability.

Objective: To guide clinicians in selecting the "next line" selective serotonin reuptake inhibitor (SSRI) for adolescents with treatment-resistant major depressive disorder, we sought to compare response rates among SSRIs in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study and to jointly model tolerability and efficacy for the specific SSRI comparisons. Methods: Efficacy and tolerability data for paroxetine, citalopram, and fluoxetine were extracted from the TORDIA study. Using a joint bivariate normal likelihood for response and tolerability (based on the maximum implied variance from the 95% credible intervals previously reported for the three SSRIs), a Monte Carlo pseudorandom sample (100,000 draws) was obtained, from which credible intervals, means, posterior tail probabilities, etc. were determined. Joint null hypotheses of no difference in efficacy and tolerability were then evaluated with regard to superiority of each SSRI over the others. Results: No significant differences in response were observed for citalopram compared with fluoxetine ( p  = 0.247) or for fluoxetine compared with paroxetine ( p  = 0.110), although citalopram trended toward being superior to paroxetine (mean difference: 0.2, p  = 0.055). For efficacy-tolerability models, citalopram and fluoxetine were superior to paroxetine ( p  = 0.029 and p  = 0.022, respectively) but did not differ between each other ( p  = 0.146). Conclusions: Joint efficacy-tolerability models suggest that citalopram and fluoxetine were statistically significantly superior to paroxetine while citalopram trended toward superiority over paroxetine in the efficacy model. These findings provide a more granular and practical evidence base for clinicians faced with treatment sequencing decisions in adolescents with SSRI-resistant depression.

Selective serotonin reuptake inhibitors (SSRIs), especially sertraline and paroxetine, are first-line antidepressants in the treatment of postpartum depression in breastfeeding women as these drugs are well tolerated by most breastfed infants. Although some women with these diagnoses require additional antidepressants to SSRIs, the safety of combined usage of SSRIs and mirtazapine is currently unknown. This report includes short-term safety data of breastfed infants exposed to paroxetine plus low-dose mirtazapine.

Purpose: Our study aimed to evaluate the side effects of selective serotonin reuptake inhibitors (SSRIs) on the ocular surface., Methods: Twenty patients with depression and dry eye disease (DED) were randomly picked to receive SSRI treatment, whereas another 20 patients received placebo treatment. The serotonin, inflammatory cytokine, and proapoptotic protein levels were determined by using protein chip, qRT-PCR, and ELISA analyses. A rat depression model was established, and SSRIs were applied for 3 or 6 weeks. Tear production and corneal epithelial barrier function were evaluated. The serotonin and inflammatory cytokine levels were analyzed by qRT-PCR, immunohistochemical staining, and ELISA. Human corneal epithelial cells were subjected to serotonin, a HTR antagonist, and/or an NF-κB signaling inhibitor. The inflammatory cytokine and proapoptotic protein levels were determined by qRT-PCR, Western blot analysis, and ELISA. The cell apoptosis rate was assessed by using flow cytometry., Results: The SSRI group had higher tear serotonin levels and more serious inflammation and cell apoptosis on the ocular surface. In the rat depression model, depression decreased tear secretion and increased IL-1β and TNF-α production, whereas the serotonin, TLR2, and TLR4 levels were not increased. SSRI aggravated DED, disrupted the corneal epithelial barrier, and promoted an inflammatory response on the ocular surface by increasing the tear serotonin levels. In addition, serotonin induced an inflammatory response and cell apoptosis in corneal epithelial cells by activating NF-κB signaling., Conclusions: SSRIs aggravate depression-associated DED via activating the NF-κB pathway. The antagonist of HTRs or the inhibitor of NF-κB signaling presents a potential therapeutic strategy for depression-associated DED. (Trial registration number, ChiCTR1800015592).

Background: Studies report that up to 80% of individuals with chronic obstructive pulmonary disease (COPD) may struggle with symptoms of depression. However, this major comorbidity in COPD is rarely managed effectively. A number of recent studies indicate that left untreated, COPD-related depression is associated with worse quality of life, worse compliance with COPD treatment plan, increased exacerbations, hospital admissions, and healthcare costs when compared to individuals with COPD without depression. Regrettably, COPD practice guidelines do not provide conclusive treatment recommendations for the use of antidepressants in patients with COPD, and base their guidelines on findings from trials in the general population. This may be problematic, as there is an elevated risk of respiratory issues associated with antidepressant treatment and COPD. Evaluating effectiveness and safety of pharmacological interventions specifically for patients with COPD and depression was therefore paramount., Objectives: To assess the effectiveness and safety of pharmacological interventions for the treatment of depression in patients with COPD., Search Methods: The last search was performed on 26 November 2018. We initially searched the following databases via the Specialised Trials Registers of the Cochrane Airways and Common Mental Disorders Groups (to June 2016): MEDLINE, Embase, PsycINFO, CINAHL, AMED, and the Cochrane Library trials register (CENTRAL). Searches from June 2016 to November 2018 were performed directly on Ovid MEDLINE, Embase, PsycINFO and the Cochrane Library (Issue 11, 2018). We searched ClinicalTrials.gov, the ISRCTN registry, and the World Health Organization International Clinical Trials Registry Platform to 26 November 2018. We searched the grey literature databases to identify studies not indexed in major databases and the reference lists of studies initially identified for full-text screening., Selection Criteria: All published and unpublished randomised controlled trials (RCTs) comparing the efficacy of pharmacological interventions with no intervention, placebo or co-intervention in adults with diagnosed COPD and depression were eligible for inclusion., Data Collection and Analysis: Two review authors independently assessed articles identified by the search for eligibility. Our primary outcomes were change in depressive symptoms and adverse events. The secondary outcomes were: change in quality of life, change in dyspnoea, change in forced expiratory volume in one second (FEV 1 ), change in exercise tolerance, change in hospital utilisation (length of stay and readmission rates), and cost-effectiveness. For continuous outcomes, we calculated the pooled mean difference (MD) or standardised mean difference (SMD) with 95% confidence interval (CI) as appropriate. For dichotomous outcomes, we calculated the pooled odds ratio (OR) and corresponding 95% CI using a random-effects model. We assessed the quality of evidence using the GRADE framework., Main Results: Of the 1125 records screened for eligibility, four RCTs (N = 201 participants), and one on-going study, met the inclusion criteria. Two classes of antidepressants were investigated in two separate comparisons with placebo: a tricyclic antidepressant (TCA) and selective serotonin reuptake inhibitors (SSRIs).TCA versus placeboOnly one RCT (N = 30 participants) provided results for this comparison.Primary outcomesThe TCA (nortriptyline) reduced depressive symptoms post-treatment compared to placebo (MD -10.20, 95% CI -16.75 to -3.65; P = 0.007; very low-quality evidence), as measured by the Hamilton Depression Rating Scale (HAM-D). Three participants withdrew from the trial due to adverse events related to the tested antidepressant (dry mouth, sedation, orthostatic hypotension).Secondary outcomesThe overall results post-treatment indicated that nortriptyline was not effective in improving the quality of life of individuals with COPD, as measured by the Sickness Impact Profile (MD -2.80, 95% CI -11.02 to 5.42; P = 0.50; very low-quality evidence).The results for the change in dyspnoea for the domains examined (e.g. dyspnoea scores for 'most day-to-day activities') post-treatment showed no improvement in the intervention group (MD 9.80, 95% CI -6.20 to 25.80; P = 0.23; very low-quality evidence).No data were reported for change in FEV 1 , change in exercise tolerance, change in hospital utilisation, or cost-effectiveness. The TCA study provided short-term results, with the last follow-up data collection at 12 weeks.The quality of the evidence for all the outcomes evaluated was very low due to a small sample size, imprecision, attrition, and selection and reporting bias.SSRIs versus placeboThree RCTs (N = 171 participants) provided results for this comparison.Primary outcomesThe pooled results for two studies showed no difference for the change in depressive symptoms post-intervention (SMD 0.75, 95% CI -1.14 to 2.64; 148 participants; 2 studies; P = 0.44; very low-quality evidence). High heterogeneity was observed (I² = 95%), limiting the reliability of these findings.While it was not possible to meta-analyse the total adverse events rates across the studies, it was possible to combine the results for two medication-specific adverse effects: nausea and dizziness. There were no significant post-treatment group differences for nausea (OR 2.32, 95% CI 0.66 to 8.12; 171 participants; 3 studies; P = 0.19; very low-quality evidence) or dizziness (OR 0.61, 95% CI 0.09 to 4.06; 143 participants; 2 studies; P = 0.61; very low-quality evidence).Secondary outcomesThe pooled analysis of two trials reporting data for the change in quality of life did not show improvement post-treatment in the intervention group compared to placebo (SMD 1.17, 95% CI -0.80 to 3.15; 148 participants; 2 studies; P = 0.25; very low-quality evidence).There was no difference between groups in change in FEV 1 post-treatment (MD 0.01, 95% CI -0.03 to 0.05; 148 participants; 2 studies; P = 0.60; low-quality evidence). However, two trials reported improvement in exercise tolerance in the SSRI group versus the placebo group (MD 13.88, 95% CI 11.73 to 16.03; 148 participants; 2 studies; P < 0.001; very low-quality evidence).The trials included in this comparison did not report data related to the change in dyspnoea, hospital utilisation rates, or cost-effectiveness., Authors' Conclusions: There is insufficient evidence to make definitive statements about the efficacy or safety of antidepressants for treating COPD-related depression. New RCTs are needed; with better methodological quality and more accurate reporting of the methods used. Moreover, longer-term follow-up data collection is needed, including outcomes such as adverse events, hospital utilisation and cost-effectiveness.

Objectives: To determine whether antidepressant use is associated with dementia risk., Design: Prospective cohort study., Setting: Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system., Participants: Community-dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059)., Measurements: Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10-year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models., Results: During a mean follow-up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0-90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18-2.42; 91-365 TSDDs: HR=1.40, 95% CI=0.88-2.23; 366-1095 TSDDs: HR=2.13, 95% CI=1.32-3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82-2.46)., Conclusion: Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations., (© 2018, Copyright the Author Journal compilation © 2018, The American Geriatrics Society.)

It has been suggested that the superiority of antidepressants over placebo in controlled trials is merely a consequence of side effects enhancing the expectation of improvement by making the patient realize that he/she is not on placebo. We explored this hypothesis in a patient-level post hoc-analysis including all industry-sponsored, Food and Drug Administration-registered placebo-controlled trials of citalopram or paroxetine in adult major depression that used the Hamilton Depression Rating Scale (HDRS) and included a week 6 symptom assessment (n=15). The primary analyses, which compared completers on active treatment without early adverse events to completers on placebo (with or without adverse events) with respect to reduction in the HDRS depressed mood item showed larger symptom reduction in patients given active treatment, the effect sizes being 0.48 for citalopram and 0.33 for paroxetine. In actively treated subjects reporting early adverse events, who also outperformed those given placebo, the severity of the adverse events did not predict response. Several sensitivity analyses, for example, including (i) those using change of the sum of all HDRS-17 items as effect parameter, (ii) those excluding all subjects with adverse events (that is, also those on placebo) and (iii) those based on the intention-to-treat population, were all in line with the primary analyses. The finding that both paroxetine and citalopram are clearly superior to placebo also when not producing adverse events, as well as the lack of association between adverse event severity and response, argue against the theory that antidepressants outperform placebo solely or largely because of their side effects.