Serotonin syndrome presenting as acute dizziness with supine hypertension and orthostatic hypotension.

Serotonin syndrome (SS) is a drug-induced clinical syndrome characterised by a combination of cognitive, neuromuscular and autonomic dysfunctions. The symptoms may include mild non-specific symptoms such as tremors and diarrhoea to coma and sudden death. Herein, we describe a case of SS in which acute dizziness was associated with supine hypertension and orthostatic hypotension. A man in his mid-30s had a 10-month history of anxiety, depression and chronic tension-type headache. He had been on amitriptyline (25 mg daily) and sertraline (50 mg daily). Increment of sertraline (75 mg daily) and amitriptyline (75 mg daily) and the addition of tramadol led to the development of acute severe dizziness. Physical examinations demonstrate supine hypertension and orthostatic hypotension. He also met the diagnostic criteria of SS. The administration of cyproheptadine provided a complete response to dizziness, supine hypertension, orthostatic hypotension and other clinical features of SS.

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.

Inhibition of Kv2.1 potassium channels by the antidepressant drug sertraline.

Sertraline is a commonly used antidepressant of the selective serotonin reuptake inhibitors (SSRIs) class. In this study, we have used the patch-clamp technique to assess the effects of sertraline on Kv2.1 channels heterologously expressed in HEK-293 cells and on the voltage-gated potassium currents (IKv) of Neuro 2a cells, which are predominantly mediated by Kv2.1 channels. Our results reveal that sertraline inhibits Kv2.1 channels in a concentration-dependent manner. The sertraline-induced inhibition was not voltage-dependent and did not require the channels to be open. The kinetics of activation and deactivation were accelerated and decelerated, respectively, by sertraline. Moreover, the inhibition by this drug was use-dependent. Notably, sertraline significantly modified the inactivation mechanism of Kv2.1 channels; the steady-state inactivation was shifted to hyperpolarized potentials, the closed-state inactivation was enhanced and accelerated, and the recovery from inactivation was slowed, suggesting that this is the main mechanism by which sertraline inhibits Kv2.1 channels. Overall, this study provides novel insights into the pharmacological actions of sertraline on Kv2.1 channels, shedding light on the intricate interaction between SSRIs and ion channel function.

Research Report: A Link between Sertraline Treatment and Susceptibility to (Mis)information.

Recent research revealed that several psycho-cognitive processes, such as insensitivity to positive and negative feedback, cognitive rigidity, pessimistic judgment bias, and anxiety, are involved in susceptibility to fake news. All of these processes have been previously associated with depressive disorder and are sensitive to serotoninergic manipulations. In the current study, a link between chronic treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline and susceptibility to true and fake news was examined. Herein, a sample of 1162 participants was recruited via Prolific Academic for an online study. Half of the sample reported taking sertraline (Zoloft) for at least 8 weeks (sertraline group), and the other half confirmed not taking any psychiatric medication (control group). The sertraline group was further divided according to their daily dosage (50, 100, 150, and 200 mg/day). All participants completed a susceptibility to misinformation scale, wherein they were asked to determine the veracity of the presented true and fake news and their willingness to behaviorally engage with the news. The results were compared between those of the sertraline groups and the control group. The results showed that sertraline groups did not differ significantly in the assessment of the truthfulness of information or their ability to discern the truth. However, those taking sertraline appeared to have a significantly increased likelihood of behavioral engagement with the information, and this effect was observed for both true and fake news. The research presented here represents the initial endeavor to comprehend the neurochemical foundation of the susceptibility to misinformation. The association between sertraline treatment and increased behavioral engagement with information observed in this study can be explained in light of previous studies showing positive correlations between serotonin (5-HT) system activity and the inclination to engage in social behaviors. It can also be attributed to the anxiolytic effects of sertraline treatment, which mitigate the fear of social judgment. The heightened behavioral engagement with information in people taking sertraline may, as part of a general phenomenon, also shape their interactions with fake news. Future longitudinal studies should reveal the specificity and exact causality of these interactions.

The risk of acute infections in new users of antidepressants: An observational cohort study.

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.

Effects of Transcranial Magnetic Stimulation Combined with Sertraline on Cognitive Level, Inflammatory Response and Neurological Function in Depressive Disorder Patients with Non-suicidal Self-injury Behavior.

BACKGROUND: Depressive disorder is a chronic mental illness characterized by persistent low mood as its primary clinical symptom. Currently, psychotherapy and drug therapy stand as the primary treatment modalities in clinical practice, offering a certain degree of relief from negative emotions for patients. Nevertheless, sole reliance on drug therapy exhibits a delayed impact on neurotransmitters, and long-term usage often results in adverse side effects such as nausea, drowsiness, and constipation, significantly impeding medication adherence. This study aims to investigate the impact of combining transcranial magnetic stimulation with sertraline on the cognitive level, inflammatory response, and neurological function in patients with depressive disorder who engage in non-suicidal self-injury (NSSI) behavior. METHODS: A total of 130 depressive patients NSSI behavior, who were admitted to our hospital from December 2020 to February 2023, were selected as the subjects for this research. The single-group (65 cases) received treatment with oral sertraline hydrochloride tablets, while the combination group (65 cases) underwent repetitive transcranial magnetic stimulation (rTMS) in conjunction with sertraline. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was utilized to assess the depression status and cognitive function levels of both groups. Additionally, the enzyme-linked immunosorbent assay (ELISA) was employed to measure serum levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Furthermore, serum levels of neurotransmitters (norepinephrine (NE), dopamine (DA), 5-hydroxytryptamine (5-HT)) and neuro-cytokines (brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), glial fibrillary acidic protein (GFAP)) were assessed. The clinical effects of the interventions on both groups were then evaluated. RESULTS: Following the treatment, the combination group exhibited significantly higher levels of immediate memory, delayed memory, attention, visual function, and language function compared to the single group, with statistically significant differences (p < 0.05). Additionally, the serum levels of TNF-α, IL-1ß, IL-6, and GFAP in the combination group were lower than those in the single group, while the levels of BDNF and NGF were higher in the combination group compared to the single group. These differences were also statistically significant (p < 0.05). Simultaneously, the total clinical effective rate in the combination group reached 95.38%, surpassing the 84.61% observed in the single group, and the disparity between the two groups was statistically significant (p < 0.05). CONCLUSIONS: The combined use of rTMS and sertraline in treating patients with depressive disorder exhibiting NSSI behavior has proven to be effective in enhancing cognitive function, mitigating inflammatory responses, and elevating levels of neurotransmitters and nerve cytokines in the patients.

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.

Impact of PTSD treatment on postconcussive symptoms in veterans: A comparison of sertraline, prolonged exposure, and their combination.

Many Veterans who served in Iraq and Afghanistan struggle with posttraumatic stress disorder (PTSD) and the effects of traumatic brain injuries (TBI). Some people with a history of TBI report a constellation of somatic, cognitive, and emotional complaints that are often referred to as postconcussive symptoms (PCS). Research suggests these symptoms may not be specific to TBI. This study examined the impact of PTSD treatment on PCS in combat Veterans seeking treatment for PTSD. As part of a larger randomized control trial, 198 Operation Iraqi Freedom, Operation Enduring Freedom, Operation New Dawn (OIF/OEF/OND) Veterans with PTSD received Prolonged Exposure Therapy, sertraline, or the combination. Potential deployment related TBI, PCS, PTSD and depression symptoms were assessed throughout treatment. Linear mixed models were used to predict PCS change over time across the full sample and treatment arms, and the association of change in PTSD and depression symptoms on PCS was also examined. Patterns of change for the full sample and the subsample of those who reported a head injury were examined. Results showed that PCS decreased with treatment. There were no significant differences across treatments. No significant differences were found in the pattern of symptom change based on TBI screening status. Shifts in PCS were predicted by change PTSD and depression. Results suggest that PCS reduced with PTSD treatment in this population and are related to shift in depression and PTSD severity, further supporting that reported PCS symptoms may be better understood as non-specific symptoms.

Integrated physio-biochemical and transcriptomic analysis reveals the joint toxicity mechanisms of two typical antidepressants fluoxetine and sertraline on Microcystis aeruginosa.

Selective serotonin reuptake inhibitor (SSRI) antidepressants are of increasing concern worldwide due to their ubiquitous occurrence and detrimental effects on aquatic organisms. However, little is known regarding their effects on the dominant bloom-forming cyanobacterium, Microcystis aeruginosa. Here, we investigated the individual and joint effects of two typical SSRIs fluoxetine (FLX) and sertraline (SER) on M. aeruginosa at physio-biochemical and molecular levels. Results showed that FLX and SER had strong growth inhibitory effects on M. aeruginosa with the 96-h median effect concentrations (EC50s) of 362 and 225 µg/L, respectively. Besides, the mixtures showed an additive effect on microalgal growth. Meanwhile, both individual SSRIs and their mixtures can inhibit photosynthetic pigment synthesis, cause oxidative damage, destroy cell membrane, and promote microcystin-leucine-arginine (MC-LR) synthesis and release. Moreover, the mixtures enhanced the damage to photosynthesis, antioxidant system, and cell membrane and facilitated MC-LR synthesis and release compared to individuals. Furthermore, transcriptomic analysis revealed that the dysregulation of the key genes related to transport, photosystem, protein synthesis, and non-ribosomal peptide structures was the fundamental molecular mechanism underlying the physio-biochemical responses of M. aeruginosa. These findings provide a better understanding of the toxicity mechanisms of SSRIs to microalgae and their risks to aquatic ecosystems.

An assessment and characterization of pharmaceuticals and personal care products (PPCPs) within the Great Lakes Basin: Mussel Watch Program (2013-2018).

Defining the environmental occurrence and distribution of chemicals of emerging concern (CECs), including pharmaceuticals and personal care products (PPCPs) in coastal aquatic systems, is often difficult and complex. In this study, 70 compounds representing several classes of pharmaceuticals, including antibiotics, anti-inflammatories, insect repellant, antibacterial, antidepressants, chemotherapy drugs, and X-ray contrast media compounds, were found in dreissenid mussel (zebra/quagga; Dreissena spp.) tissue samples. Overall concentration and detection frequencies varied significantly among sampling locations, site land-use categories, and sites sampled proximate and downstream of point source discharge. Verapamil, triclocarban, etoposide, citalopram, diphenhydramine, sertraline, amitriptyline, and DEET (N,N-diethyl-meta-toluamide) comprised the most ubiquitous PPCPs (> 50%) detected in dreissenid mussels. Among those compounds quantified in mussel tissue, sertraline, metformin, methylprednisolone, hydrocortisone, 1,7-dimethylxanthine, theophylline, zidovudine, prednisone, clonidine, 2-hydroxy-ibuprofen, iopamidol, and melphalan were detected at concentrations up to 475 ng/g (wet weight). Antihypertensives, antibiotics, and antidepressants accounted for the majority of the compounds quantified in mussel tissue. The results showed that PPCPs quantified in dreissenid mussels are occurring as complex mixtures, with 4 to 28 compounds detected at one or more sampling locations. The magnitude and composition of PPCPs detected were highest for sites not influenced by either WWTP or CSO discharge (i.e., non-WWTPs), strongly supporting non-point sources as important drivers and pathways for PPCPs detected in this study. As these compounds are detected at inshore and offshore locations, the findings of this study indicate that their persistence and potential risks are largely unknown, thus warranting further assessment and prioritization of these emerging contaminants in the Great Lakes Basin.

Treatment Response Prediction in Major Depressive Disorder Using Multimodal MRI and Clinical Data: Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVE: Response to antidepressant treatment in major depressive disorder varies substantially between individuals, which lengthens the process of finding effective treatment. The authors sought to determine whether a multimodal machine learning approach could predict early sertraline response in patients with major depressive disorder. They assessed the predictive contribution of MR neuroimaging and clinical assessments at baseline and after 1 week of treatment. METHODS: This was a preregistered secondary analysis of data from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a multisite double-blind, placebo-controlled randomized clinical trial that included 296 adult outpatients with unmedicated recurrent or chronic major depressive disorder. MR neuroimaging and clinical data were collected before and after 1 week of treatment. Performance in predicting response and remission, collected after 8 weeks, was quantified using balanced accuracy (bAcc) and area under the receiver operating characteristic curve (AUROC) scores. RESULTS: A total of 229 patients were included in the analyses (mean age, 38 years [SD=13]; 66% female). Internal cross-validation performance in predicting response to sertraline (bAcc=68% [SD=10], AUROC=0.73 [SD=0.03]) was significantly better than chance. External cross-validation on data from placebo nonresponders (bAcc=62%, AUROC=0.66) and placebo nonresponders who were switched to sertraline (bAcc=65%, AUROC=0.68) resulted in differences that suggest specificity for sertraline treatment compared with placebo treatment. Finally, multimodal models outperformed unimodal models. CONCLUSIONS: The study results confirm that early sertraline treatment response can be predicted; that the models are sertraline specific compared with placebo; that prediction benefits from integrating multimodal MRI data with clinical data; and that perfusion imaging contributes most to these predictions. Using this approach, a lean and effective protocol could individualize sertraline treatment planning to improve psychiatric care.

Post-Stroke Depression in Older Adults: An Overview.

Detailed data on post-stroke depression (PSD) in older adults are limited in spite of the high vulnerability of this population to stroke. In fact, PSD prevalence in older adults ranges from 16.0 to 43.9%; however, timing and instruments of evaluation often differ significantly across all available studies. The etiology, genetic and inflammatory factors, as well as structural brain alterations, are claimed as part of a multifaceted mechanism of action in PSD onset. Thus, the aim of this narrative review was to further elaborate on the prevalence, etiology, diagnosis, consequences and treatment of PSD in older adults. The consequences of PSD in older adults may be devastating, including a poor functional outcome after rehabilitation and lower medication adherence. In addition, lower quality of life and reduced social participation, higher risk of new stroke, rehospitalization, and mortality have been reported. In this scenario, treating PSD represents a crucial step to prevent these complications. Both pharmacological and non-pharmacological therapies are currently available. The pharmacological treatment utilizes antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TAs) and new multimodal antidepressants (NMAs). Non-pharmacological therapies include psychological interventions and non-invasive brain stimulation techniques, while excluding drug administration. In the general population experiencing PSD, SSRIs (sertraline in particular) are the most prescribed, whereas the combination of antidepressants and psychotherapy is underused. Furthermore, about one-third of patients do not receive treatment for PSD. In regard to older adults with PSD, the possibility of more adverse effects or contraindications to antidepressant prescription due to comorbidities may limit the therapeutic window. Although drugs such as citalopram, escitalopram, sertraline, venlafaxine, and vortioxetine are usually well tolerated by older patients with PSD, the few randomized controlled trials (RCTs) specifically considering older adults with PSD have been conducted with fluoxetine, fluvoxamine, reboxetine, citalopram and nortriptyline, often with very small patient samples. Furthermore, data regarding the results of non-pharmacological therapies are scarce. High-quality RCTs recruiting large samples of older adults are needed in order to better manage PSD in this population. In addition, adequate screening and diagnosis instruments, with reliable timing of evaluation, should be applied.

Machine Learning-Based Prediction of Escitalopram and Sertraline Side Effects With Pharmacokinetic Data in Children and Adolescents.

Selective serotonin reuptake inhibitors (SSRI) are the first-line pharmacologic treatment for anxiety and depressive disorders in children and adolescents. Many patients experience side effects that are difficult to predict, are associated with significant morbidity, and can lead to treatment discontinuation. Variation in SSRI pharmacokinetics could explain differences in treatment outcomes, but this is often overlooked as a contributing factor to SSRI tolerability. This study evaluated data from 288 escitalopram-treated and 255 sertraline-treated patients ≤ 18 years old to develop machine learning models to predict side effects using electronic health record data and Bayesian estimated pharmacokinetic parameters. Trained on a combined cohort of escitalopram- and sertraline-treated patients, a penalized logistic regression model achieved an area under the receiver operating characteristic curve (AUROC) of 0.77 (95% confidence interval (CI): 0.66-0.88), with 0.69 sensitivity (95% CI: 0.54-0.86), and 0.82 specificity (95% CI: 0.72-0.87). Medication exposure, clearance, and time since the last dose increase were among the top features. Individual escitalopram and sertraline models yielded an AUROC of 0.73 (95% CI: 0.65-0.81) and 0.64 (95% CI: 0.55-0.73), respectively. Post hoc analysis showed sertraline-treated patients with activation side effects had slower clearance (P = 0.01), which attenuated after accounting for age (P = 0.055). These findings raise the possibility that a machine learning approach leveraging pharmacokinetic data can predict escitalopram- and sertraline-related side effects. Clinicians may consider differences in medication pharmacokinetics, especially during dose titration and as opposed to relying on dose, when managing side effects. With further validation, application of this model to predict side effects may enhance SSRI precision dosing strategies in youth.

Comparative effectiveness of selective serotonin reuptake inhibitors (SSRIs) for depression in 43,061 older adults with chronic somatic diseases: A Danish target trial emulation study.

OBJECTIVE: To investigate the comparative effectiveness of commonly used selective serotonin reuptake inhibitors (SSRIs) for comorbid depression in older adults with chronic somatic diseases by applying a target-trial-emulation framework. METHODS: Danish target-trial-emulation study including 43,061 individuals aged ≥65 years (54.1% females, mean age 77.8 years) with a first redeemed prescription for depression with sertraline (n = 6673), escitalopram (n = 7104) or citalopram (n = 29,284) in 2006-2017. Individuals had cancer, cardiovascular diseases (CVD), chronic-obstructive-pulmonary-disease (COPD)/asthma, diabetes, neurodegenerative disorders, or osteoporosis. Outcomes were treatment switching, combination/augmentation, psychiatric hospital contact for depression, and any psychiatric in-patient care. Follow-up was one year and adjusted Cox regression analyses calculated hazard rate ratios (HRR) within each somatic disease. RESULTS: Across all six disease groups and four outcomes, we found that citalopram use, compared with sertraline, was associated with lower risks in several analyses, with statistically significant results in cancer, CVD, COPD/asthma, and diabetes (e.g., HRRs for psychiatric hospital contacts for depression/any psychiatric in-patient care ranging between 0.47 and 0.61). For escitalopram, compared with sertraline, some analyses indicated poorer outcomes with significantly higher risks for combination/augmentation treatment (HRRs ranging between 1.15 and 1.40). CONCLUSIONS: Although observational studies are prone to confounding, these findings indicate clinically relevant differences between the SSRIs, with better outcomes in citalopram users and poorer outcomes in escitalopram users than sertraline, urging the need for clinical studies in this vulnerable patient population.

The Relevance of Integrating CYP2C19 Phenoconversion Effects into Clinical Pharmacogenetics.

INTRODUCTION: CYP2D6 and CYP2C19 functional status as defined by genotype is modulated by phenoconversion (PC) due to pharmacokinetic interactions. As of today, there is no data on the effect size of PC for CYP2C19 functional status. The primary aim of this study was to investigate the impact of PC on CYP2C19 functional status. METHODS: Two patient cohorts (total n=316; 44.2±15.4 years) were investigated for the functional enzyme status of CYP2C19 applying two different correction methods (PCBousman, PCHahn&Roll) as well as serum concentration and metabolite-to-parent ratio of venlafaxine, amitriptyline, mirtazapine, sertraline, escitalopram, risperidone, and quetiapine. RESULTS: There was a decrease in the number of normal metabolizers of CYP2C19 and an increase in the number of poor metabolizers. When controlled for age, sex, and, in the case of amitriptyline, venlafaxine, and risperidone, CYP2D6 functional enzyme status, an association was observed between the CYP2C19 phenotype/functional enzyme status and serum concentration of amitriptyline, sertraline, and escitalopram. DISCUSSION: PC of CYP2C19 changes phenotypes but does not improve correlations with serum concentrations. However, only a limited number of patients received perturbators of CYP2C19. Studies with large numbers of patients are still lacking, and thus, it cannot be decided if there are minor differences and which method of correction to use. For the time being, PC is relevant in individual patients treated with CYP2C19-affecting drugs, for example, esomeprazole. To ensure adequate serum concentrations in these patients, this study suggests the use of therapeutic drug monitoring.

The efficacy and safety of sertraline in maintenance hemodialysis patients with depression: A randomized controlled study.

OBJECTIVE: To determine the efficacy and safety of sertraline in maintenance hemodialysis (MHD) patients with depression. METHODS: A randomized controlled trial was conducted involving 125 MHD patients with depression. The treatment group received sertraline, while the control group did not receive any antidepressant treatment. After 12 weeks, we compared the changes in the Hamilton Depression Rating Scale (HAMD), the Medication Adherence Report Scale-5 (MARS-5), the Mini Nutritional Assessment short-form (MNA-SF), the Kidney Disease Quality of Life-36 (KDQOL-36) scores, selected clinical and laboratory indicators, and the incidence of drug-related adverse reactions between the two groups. RESULTS: After 12 weeks of treatment, the HAMD scores of patients in the treatment group significantly decreased compared to before treatment and were lower than those in the control group. The KDQOL-36, MARS-5, and MNA-SF scores in the treatment group also significantly improved compared to before treatment and were superior to those in the control group. Albumin and hemoglobin levels in the treatment group significantly increased, while C-reactive protein significantly decreased. The incidence of nausea was slightly higher in the treatment group, and was mostly relieved after reducing the dosage of sertraline. LIMITATIONS: This study is a single-center, small-sample study with a relatively short duration of treatment and follow-up. CONCLUSIONS: Sertraline can alleviate depressive symptoms, and improve the quality of life and treatment compliance of MHD patients, while improving chronic inflammation, malnutrition, and anemia. However, starting with a low dose and reducing the maintenance dose is recommended when administering sertraline.

Comparative responses to 17 different antidepressants in major depressive disorder: Results from a 2-year long-term nation-wide population-based study emulating a randomized trial.

BACKGROUND: Long-term studies comparing nonresponse to antidepressants for major depressive disorder (MDD) are lacking. AIMS: To present systematic population-based nation-wide register data on comparative 2-year non-response within six antidepressant drug classes and 17 different antidepressants in patients with MDD. METHOD: The study included all 106,920 patients in Denmark with a first main index diagnosis of MDD at a psychiatric hospital inpatient or outpatient contact and who subsequently had a purchase of an antidepressant in the period from 1995 to 2018. Non-response to first antidepressant within a 2-year study period was defined as switch to or add-on of another antidepressant, antipsychotic medication, lithium, or hospitalization. Analyses emulated a targeted trial in populations standardized according to age, sex, socioeconomic status, and comorbidity with psychiatric and physical disorders. RESULTS: Compared with sertraline, there was no difference for citalopram (RR: 1.00 [95% CI: 0.98-1.02]) but fluoxetine (1.13 [95% CI: 1.10-1.17]), paroxetine (1.06 [95% CI: 1.01-1.10]) and escitalopram (1.22 [95% CI: 1.18-1.25]) were associated with higher risk ratio of non-responses. Within selective noradrenaline reuptake inhibitors, sertraline outperformed reboxetine; within serotonin-norepinephrine reuptake inhibitors, venlafaxine outperformed duloxetine; within noradrenergic and specific serotonergic antidepressants, mirtazapine outperformed mianserin and within the class of other antidepressants, sertraline outperformed agomelatine and vortioxetine. Within tricyclic antidepressants, compared to amitriptyline, nortriptyline, dosulepin, and clomipramine had higher non-response, whereas there was no difference for imipramine. CONCLUSIONS: These analyses emulating a randomized trial of "real world" observational register-based data show that 2-year long-term non-responses to some antidepressants within six different drug classes are increased over others.

Sertraline Promotes Health and Longevity in Caenorhabditis elegans.

INTRODUCTION: While several antidepressants have been identified as potential geroprotectors, the effect and mechanism of sertraline on healthspan remain to be elucidated. Here, we explored the role of sertraline in the lifespan and healthspan of Caenorhabditis elegans. METHODS: The optimal effect concentration of sertraline was first screened in wild-type N2 worms under heat stress conditions. Then, we examined the effects of sertraline on lifespan, reproduction, lipofuscin accumulation, mobility, and stress resistance. Finally, the expression of serotonin signaling and aging-related genes was investigated to explore the underlying mechanism, and the lifespan assays were performed in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. RESULTS: Sertraline extended the lifespan in C. elegans with concomitant extension of healthspan as indicated by increasing mobility and reducing fertility and lipofuscin accumulation, as well as enhanced resistance to different abiotic stresses. Mechanistically, ser-7 orchestrated sertraline-induced longevity via the regulation of insulin and AMPK pathways, and sertraline-induced lifespan extension in nematodes was abolished in ser-7 RNAi strain, daf-2, daf-16, and aak-2 mutants. CONCLUSION: Sertraline promotes health and longevity in C. elegans through ser-7-insulin/AMPK pathways.