Sertraline Treatment Research Articles

Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas.

The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPHV116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/glyhigh glioblastoma models. Interestingly, ser/glyhigh glioblastomas, including PSPHamp and PSPHV116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/glyhigh glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/glyhigh cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/glyhigh glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.

Understanding serine and glycine metabolism in cancer: a path towards precision medicine to improve patient's outcomes.

In this perspective, we highlight and reflect on the current knowledge with respect to serine/glycine metabolism in cancer, therapeutic resistance, and precision medicine opportunities for therapeutic targeting and treatment follow-up. Cancer subtypes with high mortality rates include lung cancer and glioblastomas. In order to improve future therapeutic opportunities, patient stratification need to be performed to select patients that might benefit from adjuvant serine/glycine targeting compounds. In an effort to identify the group of patients for stratification purposes, we analyzed publicly available TCGA patient datasets to test associations between serine/glycine metabolism enzyme expression and important cancer drivers in lung cancer and glioblastoma. These patients presenting serine/glycine pathway overexpression might benefit from adjuvant sertraline treatment in the future.

Changes in P300 amplitude to negative emotional stimuli correlate with treatment responsiveness to sertraline in adolescents with depression

ObjectiveAdolescents with depression is characterized by high rates of recurrence and functional impairment, with a significant association with suicide risk. Antidepressants are commonly prescribed to treat depression, yet few reproducible neurobiological markers for depression and antidepressant treatment response have been identified. Therefore, discovering a stable and reliable neurobiological marker holds significant value for both the clinical diagnosis and treatment of depression in adolescents. MethodsOne hundred and seven patients with major depressive disorder (MDD group, 30 males, 77 females, mean age: 14.80 years), and 25 healthy subjects (HC group, 13 males, 12 females, mean age: 15.72 years) were recruited to perform a two-choice oddball task related to negative emotional cues. All participants completed a self-administered questionnaire to gather demographic information. A trained psychiatrist administered the Hamilton Depression Scale (HAMD-17) to assess depression severity. Of the 107 adolescents with depression, 61 received antidepressant medication for 8 weeks, and 61 of these patients were followed up. Multichannel EEG was recorded continuously from 64 scalp electrodes using the Curry 8 system. EEG signal preprocessing and analysis was performed offline using the EEGLAB toolbox in MATLAB. The ERP component characteristics associated with emotional processing were extracted from the difference waves and statistically analyzed. ResultsAdolescents with depression exhibited significantly larger P300 amplitudes than healthy controls in response to both neutral and negative emotional cues. Following sertraline treatment, both depression scores and P300 amplitudes decreased significantly in adolescents with depression. Moreover, a strong positive correlation was observed between changes in depression scores and changes in P300 amplitude in response to negative emotional cues before and after treatment. ConclusionsChanges in neural reactivity to negative emotional stimuli among adolescents with depression can be selectively modulated by sertraline and are significantly associated with improvements in depressive symptoms. SignificanceChanges in P300 amplitude to negative emotional stimuli significantly correlate with treatment responsiveness to sertraline in adolescents with depression.

Combined mindfulness-based stress reduction and physical activity improved psychological factors and sleep quality in patients with MDD: A randomized controlled trial study

Non-pharmacological interventions are available to improve sleep quality including mindfulness-based stress reduction (MBSR) and physical activity (PA). The present study aimed to evaluate the effectiveness of the combination of MBSR and PA interventions as an augmentation to treatment as usual with sertraline to improve sleep and psychological factors among patients with MDD. Sixty-seven patients in outpatient care diagnosed with MDD for a minimum of 2 months (mean age: 35.32 ± 7.8; 65 % female) and currently on sertraline treatments were randomized into four groups including: 1) Physical activity, 2) MBSR, 3) Combination MBSR and physical activity (MBSRPA), and 4) Control. All participants completed self-reported questionnaires on sleep quality, depression, anxiety, and perceived stress from baseline to 8 weeks later at post-test and four weeks later at follow-up. Over time, sleep disturbance and psychological problems were reduced in all conditions when compared to the control. Moreover, MBSRPA had a more positive impacts on perceived stress, anxiety, depressive symptoms and sleep quality. The results of the present study confirmed the effectiveness of MBSRPA as an augmentation to standard therapy to help reduce symptoms of depression, anxiety, perceived stress, and sleep problems in patients with MDD.

Prefrontal cortex-nucleus reuniens-hippocampus network exhibits sex-differentiated responses to stress and antidepressant treatment in rats.

Depression is a serious psychiatric disease, which is diagnosed twice as frequently in women than men. We have recently shown that lesioning or inactivation of the nucleus reuniens (RE), which interconnects the prefrontal cortex (PFC) and hippocampus, promoted resilience to stress in males, exerts an antidepressant effect in the Forced Swim Test (FST) and prevents the development of behavioral and neurobiological alterations induced by the chronic mild stress model of depression. In this study, we expand our findings on the FST in female rats and we investigate whether RE lesion presents sex differences following treatment with two distinct antidepressants, a selective serotonin reuptake inhibitor, i.e. sertraline and a tricyclic antidepressant, i.e. clomipramine. Male and female rats received either a surgical lesion of the RE or sham operation, then treated with vehicle, sertraline (10mg/kg) or clomipramine (10mg/kg) and were subjected to the FST. Activation of key brain areas of interest (PFC, Hippocampus and RE) were measured by c-Fos immunoreactivity. RE lesion induced an antidepressant-like phenotype in both female and male rats, confirming its crucial role in the stress response. Similarly to RE lesion, sertraline treatment resulted in increased swimming and decreased immobility duration, as well as enhanced head shake frequency, in both sexes. Notably, climbing behavior was increased only following clomipramine treatment. RE area was less active in females compared to male rats and in clomipramine-treated males compared to their corresponding vehicle-group. Activation of the PFC and the CA1 hippocampal area was reduced in clomipramine-treated females, in comparison to vehicle-treated female rats. This effect was not evident in males, which exhibited less activation in the PFC and the hippocampus than females. Re lesion proves equally effective in female and male rats, but sex is highlighted as a pivotal factor in behavioral and treatment response in FST, as well as in related circuit connectivity and activation.

Luteal phase sertraline treatment of premenstrual dysphoric disorder (PMDD): Effects on markers of hypothalamic pituitary adrenal (HPA) axis activation and inflammation

RationalePremenstrual dysphoric disorder (PMDD) is characterized by severe affective symptoms during the luteal phase of the menstrual cycle. There is some evidence of altered interactions between the hypothalamic pituitary gonadal (HPG) and hypothalamic pituitary adrenal (HPA) axes in PMDD. There is also evidence that similar affective disorders such as major depression and perinatal depression are associated with dysregulation in immune factors, but this has not been characterized in PMDD. AimsThe goals of this exploratory study were to identify 1) whether HPA-HPG axis interactions and immune markers differ between PMDD patients and controls across the menstrual cycle; 2) how luteal phase sertraline treatment impacts stress and inflammatory markers. MethodsParticipants were females age 18–50 with regular menstrual cycles, not using psychotropic or hormonal medications, and were assigned to a control group or PMDD group based on prospective daily symptom ratings and clinical interview. Blood was drawn in the follicular and luteal phases, during laboratory sessions involving a mildly stressful task. In a second luteal phase, PMDD participants received open-label sertraline (50 mg/d) from ovulation to menses. Serum cortisol and ACTH were measured via ELISA and operationalized as area under the curve with respect to ground (AUCg), and peak level following laboratory task. Serum TNF-α, IL-6, CXCL-8, and IL-1β were measured using multiplex kits. Serum allopregnanolone (ALLO) was measured by gas chromatography/mass spectroscopy. To characterize HPA-HPG axis interactions across the menstrual cycle in PMDD participants and controls, multilevel linear models predicted cortisol and ACTH from the interaction of cycle phase (controlling for sertraline treatment), ALLO, and group. To determine the effects of sertraline treatment on inflammatory markers and how groups might differ in cyclical change on each marker, multilevel linear models predicted inflammatory markers from cycle phase (controlling for sertraline treatment) and group. A final set of exploratory models tested whether inflammatory markers predict premenstrual symptom score severity. ResultsThe sample included n=77 participants (41 controls, 36 PMDD); 28 participants with PMDD completed sertraline treatment. Group x phase x ALLO interactions showed that higher ALLO levels predicted lower cortisol peak in the treated luteal phase (interaction between phase and ALLO, p=0.042), and there was a higher cortisol peak in the treated luteal phase than the untreated luteal phase (p=0.038). CXCL-8 was significantly associated with premenstrual symptom severity after controlling for group and cycle phase (p=0.011). There were no main effects of group, phase, or ALLO on cortisol AUCg, ACTH AUCg, IL-6, CXCL-8, IL-1β, nor TNF-α (p’s>0.05). ConclusionSerum markers of HPA axis and immune function did not vary by menstrual cycle phase nor PMDD status. However, sertraline treatment in the luteal phase was associated with higher ALLO levels predicting lower cortisol peak in response to mild laboratory stress, suggesting that sertraline treatment may normalize HPG-HPA axis interactions among individuals with PMDD. Greater premenstrual symptomatology was associated with higher levels of the inflammatory marker CXCL-8, but further research is needed into the potential role of inflammation in PMDD.

Characteristics of depression treatment in men with testosterone deficiency

BACKGROUND: Treatment of depression in men with testosterone deficiency is particularly challenging because of the overlap between the symptoms of depression itself and those associated with testosterone deficiency, which requires the development of additional diagnostic and therapeutic approaches. AIM: To enhance the effectiveness of comprehensive treatment of depression in men with testosterone deficiency. MATERIALS AND METHODS: The study involved 140 male participants (aged 18–65 years) diagnosed with depressive episodes and recurrent depressive disorder according to the International Classification of Diseases, 10th revision. Patients were divided into the main group (testosterone levels below 12.1 nmol/l) and the control group (normal testosterone levels). The main group (n=90) was further divided into three therapeutic subgroups of 30 patients each: receiving sertraline monotherapy, testosterone monotherapy, and combined sertraline and testosterone treatment. The control group included men with depression and normal testosterone levels (n=50), who received sertraline only. RESULTS: Depression in men in the context of testosterone deficiency has distinct clinical features, both phenomenologically and syndromally. The severity of the depressive syndrome in men with testosterone deficiency is lower (17.0 [16.0; 18.75] points on the HDRS scale) than in patients with normal testosterone levels (19.0 [18.0; 22.0] points on the HDRS scale), and the depressive episode tends to occur later in life (47.0 [42.0; 55.0] years) compared to those with normal levels of testosterone (29.5 [24.25; 40.0] years) and is less likely to be recurrent than in those with normal testosterone levels (29.5 [24.25; 40.0] years). The study of the efficacy and safety of depression therapy in the context of testosterone deficiency shows that a combined approach to the treatment of depression in men with testosterone deficiency has both advantages (considering the specifics of patients by normalizing testosterone levels and erectile function) and disadvantages (relatively higher risk of adverse events) compared to sertraline monotherapy. CONCLUSION: The identified characteristics of the course and treatment of depression in the context of reduced testosterone levels allowed for the development of a more effective therapeutic and diagnostic algorithm.

Sertraline Alleviates Chronic Prostatitis by Regulating the TRPV1 Channel.

Although sertraline has been widely used for chronic prostatitis (CP), the mechanisms are unclear. Herein, we explored the mechanisms of sertraline in treating CP. Network pharmacology methods were used to explore the potential targets and molecular mechanisms. LPS was used to stimulate RWPE-1 cells to construct an in vitro model of CP. An experimental autoimmune prostatitis (EAP) mice model was built. CCK-8 assay, EdU assay, BrdU detection, and Tunel assay were performed to evaluate the proliferation and apoptosis process of cells or tissues, respectively. DCFH-DA and Fluo-4 fluorescence probes were used to detect intracellular ROS and calcium concentrations. Von Frey filaments and open-field tests were utilized to evaluate pain response and depressive-like behavior of mice. Histopathology was evaluated through hematoxylin and eosin staining. RT-qPCR, Western blot, immunofluorescence, and immunohistochemistry were utilized to evaluate the transcription, expression, and location of related proteins. Molecular dynamics (MD) simulation and surface plasmon resonance (SPR) assay were performed to measure the binding capacity of sertraline and related proteins. Through a network pharmacology analysis, 27 potential targets of sertraline for CP were obtained, and 5 key targets (CHRM1, ADRA1B, HTR2B, HTR2A, and TRPV1) were finally identified. Functional experiments suggested that TRPV1 was involved in the proliferation, apoptosis inhibition, and ROS production of LPS-induced RWPE-1 cells. In vitro experiments showed that sertraline significantly inhibited cell proliferation, ROS generation, and transcription of inflammation cytokines of LPS-induced RWPE-1 cells. Additionally, sertraline markedly promoted the apoptosis level of LPS-stimulated RWPE-1 cells and elevated the expression level of BAX while reducing the expression levels of Bcl2 and Caspase-3. MD simulation and SPR assay confirmed the direct binding of sertraline to TRPV1. Moreover, sertraline significantly down-regulated the expression level of TRPV1 and inhibited calcium influx of LPS-induced RWPE-1 cells. TRPV1 agonist (Capsaicin) significantly restored the effects on proliferation, apoptosis, ROS production, and calcium influx of sertraline on LPS-induced RWPE-1 cells. Mice experiments demonstrated that sertraline treatment could reduce pain response, improve depression-like symptoms, and relieve local prostate inflammation of EAP mice, as well as down-regulated the expression level of TRPV1, inhibit the proliferation, and promote apoptosis of prostate tissues in EAP mice. The results revealed the anti-inflammatory effect of sertraline for RWPE-1 cells and EAP mice, and the potential mechanism was regulating the TRPV1 channel. It indicated that sertraline might serve as a complementary anti-inflammatory agent for CP.

Selective Serotonin Reuptake Inhibitors for the Treatment of Depression in Parkinson's Disease: A Systematic Review and Meta-Analysis.

Although selective serotonin reuptake inhibitors (SSRIs)are usually considered safe to use in patients with Parkinson's disease (PD), there are mixed data about their effectiveness, and only a few investigations have led to a total improvement of depressive symptoms in patients with PD. We aimed to conduct a comprehensive systematic review and meta-analysis of all studies that investigated the effectiveness of SSRIs in treating depression in the context of PD. From its commencement to June 2024, the databases of MEDLINE via PubMed, Scopus, Embase, and Google Scholar were electronically searched for the relevant papers. All full-text journal articles assessing the effectiveness of SSRIs in treating depression in patients with PD were included. The tool developed by the Cochrane Collaboration was utilized to evaluate the bias risk. Data were analyzed utilizing a pair-wise comparison meta-analysis using the standardized mean difference. A total of 19 articles and 22 separate interventions were included. We found that SSRI treatment attenuated depression in patients with PD (1.242 standardized mean difference, 95% confidence interval 0.956, 1.529, p < 0.001). The general heterogeneity of the studies was medium (ϰ2 = 72.818, T2 = 0.317, df = 21, I2 = 71.15%, p < 0.001). The funnel plot was reasonably symmetrical. However, three studies were trimmed to the left of the mean. Begg's test (p = 0.080), Egger's test (p = 0.121), and funnel plot showed no significant risk of publication bias. The meta-regression showed that the treatment effect increased as a function of paroxetine treatment duration (slope p = 0.001) but decreased as a function of sertraline treatment duration (slope p = 0.019). There are few controlled antidepressant trials on the PD population, even though patients with PD frequently experience depression and use antidepressants. Clinical studies that are larger and better structured are needed in the future to determine if antidepressants are useful for treating patients with PD with depression.

Sertraline-Induced Stuttering in an Adolescent with Autism Spectrum Disorder

There is also evidence that stuttering is caused by an adverse reaction to various medications. Antiepileptic drugs, antidepressants, antipsychotics, and methylphenidate have all been linked to drug-induced stuttering. The patient was 13 years old (male) and was diagnosed with autism spectrum disorder, attention deficit hyperactivity disorder, and mild mental retardation. The patient had language development and was able to form sentences of 4-5 words. Atomoxetine 50 mg/day and aripiprazole 15 mg/day treatment was used. Sertraline 50 mg/day treatment was initiated because of repeated questioning, order-symmetry compulsions and repetitive behaviors. Approximately one month after the initiation of sertraline treatment, the patient came for a follow-up visit and it was found that the compulsions of the patient had decreased, but one week after sertraline treatment, it was learned that the patient started to have word blocks, prolongation of words and repetitions during speech. No pathology was found in the examination, hemogram and biochemistry tests, brain MRI and EEG tests. After sertraline treatment was discontinued, the stuttering of the patient gradually decreased and improved within 2 weeks. Both serotonergic and dopaminergic effects of sertraline as well as autism spectrum disorder (white matter anomalies) are thought to contribute to sertraline-induced stuttering.

Proton Pump Inhibitors Induced Hyponatremia in a Liver Transplanted Patient—The Role of Deprescribing: A Case Report and Literature Review

Liver transplant patients are frail subjects due to lifelong therapy with immunosuppressants. In these patients, comorbidity and polytherapy increase the risk of adverse drug reactions. In this study, we report the development of hyponatremia, probably related to pantoprazole in a liver transplant patient. Sertraline dismission and treatment with sodium chloride did not improve clinical symptoms and laboratory levels. Pantoprazole dismission induced an improvement in clinical symptoms and the normalization of sodium levels. A five-month follow-up revealed the absence of clinical symptoms and normal serum sodium levels.

Combining MRI, clinical data has predictive value in sertraline treatment

A secondary analysis of results from a clinical trial of predictors of response to sertraline treatment for major depressive disorder (MDD) has found that a combination of magnetic resonance imaging (MRI) and clinical data can predict treatment response. These results were specific for sertraline treatment compared with placebo treatment.

Sex-controlled differences in sertraline and citalopram efficacies in major depressive disorder: a randomized, double-blind trial.

To investigate the response to antidepressants while controlling for sex, which has been controversial, 92 outpatient males and females with major depressive disorder were assigned to sertraline (100 mg/day) or citalopram (40 mg/day) in two strata and were assessed using Hamilton depression rating scale (HDRS) scores and brain-derived neurotrophic factor (BDNF), interleukin (IL)-6 and cortisol serum levels in this 8-week, randomized, parallel-group, double-blind clinical trial. Data of 40 sertraline and 40 citalopram recipients with equal representation of males and females assigned to each medication were analyzed, while their baseline characteristics were not statistically different (P > 0.05). There were no significant differences between sertraline and citalopram recipients in outcome changes (P > 0.05), all of which indicated improvement, but a significant time-treatment-sex interaction effect in BDNF levels was observed (P = 0.035). Regarding this, subgroup analyses illustrated a significantly greater increase in male BDNF levels following sertraline treatment (P = 0.020) with a moderate to large effect size (Cohen's d = 0.76 and ). Significant associations were observed between percentage changes in IL-6 levels and BDNF levels in sertraline recipients (P = 0.033) and HDRS scores in citalopram recipients (P < 0.001). Sex was an effect modifier in BDNF alterations following sertraline and citalopram administration. Further large-scale, high-quality, long-term studies are recommended.

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.

Retracted: Fetal Congenital Cardiac and Vascular Disorders Associated with Sertraline Treatment during Pregnancy: Analysis of FAERS Data.

[This retracts the article DOI: 10.1155/2022/9914931.].

Targeting serine/glycine metabolism improves radiotherapy response in non-small cell lung cancer

BackgroundLung cancer is the most lethal cancer, and 85% of cases are classified as non-small cell lung cancer (NSCLC). Metabolic rewiring is a cancer hallmark that causes treatment resistance, and lacks insights into serine/glycine pathway adaptations upon radiotherapy.MethodsWe analyzed radiotherapy responses using mass-spectrometry-based metabolomics in NSCLC patient’s plasma and cell lines. Efficacy of serine/glycine conversion inhibitor sertraline with radiotherapy was investigated by proliferation, clonogenic and spheroid assays, and in vivo using a serine/glycine dependent NSCLC mouse model by assessment of tumor growth, metabolite and cytokine levels, and immune signatures.ResultsSerine/glycine pathway metabolites were significantly consumed in response to radiotherapy in NSCLC patients and cell models. Combining sertraline with radiotherapy impaired NSCLC proliferation, clonogenicity and stem cell self-renewal capacity. In vivo, NSCLC tumor growth was reduced solely in the sertraline plus radiotherapy combination treatment group. Tumor weights linked to systemic serine/glycine pathway metabolite levels, and were inhibited in the combination therapy group. Interestingly, combination therapy reshaped the tumor microenvironment via cytokines associated with natural killer cells, supported by eradication of immune checkpoint galectin-1 and elevated granzyme B levels.ConclusionOur findings highlight that targeting serine/glycine metabolism using sertraline restricts cancer cell recovery from radiotherapy and provides tumor control through immunomodulation in NSCLC.

Personality traits as predictors for treatment response to sertraline among unmedicated obsessive-compulsive Disorder: A 12-weeks retrospective longitudinal study

The effectiveness of selective serotonin reuptake inhibitors (SSRIs) as a primary treatment for obsessive-compulsive disorder (OCD) remains uncertain. Even after undergoing standard SSRIs treatment, 40%–60% of individuals with OCD persistently endure symptoms. Recent studies proposed that personality traits may influence the diversity of OCD treatment results. Thus, in this retrospective study, we evaluated the Eysenck Personality Questionnaire (EPQ) scores of 51 untreated patients with OCD and 35 healthy controls. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was employed to assess OCD symptom severity at weeks 0, 2, 4, 8, and 12 of sertraline treatment. The primary outcome focused on the reduction rate of Y-BOCS scores (response: ≥25%; marked response: ≥50%). Our findings revealed that individuals with OCD demonstrated a significantly higher neuroticism score compared to healthy controls. Correlation analyses exposed a positive link between psychoticism and the duration of the disease. Moreover, family history strongly correlated with both obsessive thoughts and the total Y-BOCS score. Subsequent univariate Cox proportional analyses indicated that both low neuroticism and high extraversion traits could forecast the response to sertraline. Furthermore, only a high extraversion trait was linked to a marked response. Our results support the idea that personality traits may contribute to OCD vulnerability and predict sertraline treatment outcomes.

Intranasal administration of sertraline ensures sustained brain delivery and antidepressant effect in a mouse model of depression

The pursuit of more potent and efficacious antidepressant therapies is of utmost significance. Herein, the intranasal (IN) route was investigated for sertraline brain delivery, encompassing a comparative pharmacokinetic study after a single-dose administration to mice by IN, intravenous (IV) (4.87 mg/kg) and oral (10 mg/kg) routes, and an efficacy/toxicity study to explore the therapeutic effect in mice subjected to the unpredictable chronic mild stress (UCMS) protocol. Neurotransmitters and melatonin were quantified in prefrontal cortex and plasma, respectively. A different drug biodistribution behavior was unveiled for a CNS-acting drug administered by means of the IN route. For the first time, IN administration of sertraline exhibited heightened systemic exposure (bioavailability = 166 %), and a sustained drug release into the brain, in opposition to IV and oral routes, avoiding drug fluctuation. The lower lung exposition (given by normalized area under the curve) observed after IN instillation envisions the reduction of sertraline pulmonary side effects and similarly other peripheral side effects. IN sertraline treatment displayed significant efficacy in ameliorating anhedonia after one week of administration while the 14-day IN treatment regimen translated into decreased immobility time and increased swimming time in the forced swimming test, suggesting an improvement of the depressive-like behavior displayed by the animal depressive-model. Remarkably, these effects were absent with oral sertraline, despite the higher used dose. Noteworthy neurotransmitter alterations were observed, with IN sertraline markedly reducing adrenaline in the prefrontal cortex, while serotonin and melatonin increased following both administration routes. With its sustained brain delivery and serotonin- and melatonin-enhancing potential, the innovative strategy of IN sertraline holds the potential not only to effectively address depressive symptoms but also to mitigate challenges inherent to classic treatments.

GABAergic neuroactive steroid response to sertraline in premenstrual dysphoric disorder

RationalePremenstrual dysphoric disorder (PMDD) affects approximately 5% of menstruating individuals, with significant negative mood symptoms in the luteal phase of the menstrual cycle. PMDD’s pathophysiology and treatment mechanisms are poorly characterized, but may involve altered neuroactive steroid function in the brain. Selective serotonin reuptake inhibitors (SSRIs), a first-line PMDD treatment, reportedly alter gamma-aminobutyric acid (GABA)ergic neuroactive steroid levels in PMDD. AimsThe aims of this study were to determine whether the SSRI sertraline increased serum levels of neuroactive steroids that modulate the effect of GABA at GABA-A receptors (GABAAR) and if so, whether an increase was associated with improvement in PMDD symptoms. MethodsParticipants included controls and individuals with PMDD. Serum levels of 9 neuroactive steroids were measured (3α,5α-THP; 3α5β-THP; pregnenolone; 3α,5α-androsterone; 3α,5β-androsterone; 3α,5α-A-diol; 3α5β-A-diol; 3α,5α-THDOC; 3α5β-THDOC) in the follicular and luteal phases. In the subsequent luteal phase, neuroactive steroids were measured during sertraline treatment (50 mg sertraline from approximate ovulation to menses onset) in the PMDD group. Mixed models assessed associations among diagnostic group, menstrual cycle phase, and sertraline treatment. ResultsParticipants included 38 controls and 32 women with PMDD. There were no significant differences in neuroactive steroid levels between controls and participants with PMDD in the luteal phase (p > 0.05). Within the PMDD group, sertraline treatment significantly increased serum pregnanolone levels and the pregnanolone:progesterone ratio, and decreased 3α,5α-androsterone. ConclusionsThis was the first study to assess the impact of SSRI treatment on peripheral levels of GABAergic neuroactive steroids in PMDD. Within the PMDD group, sertraline treatment was associated with a significant increase in luteal phase serum pregnanolone levels and a significantly increased pregnanolone:progesterone ratio, a novel finding. Future research should examine alterations in the metabolic pathways among GABAergic neuroactive steroids in individuals with PMDD, in a placebo-controlled design.

Developing an Electroencephalography-Based Model for Predicting Response to Antidepressant Medication

Untreated depression is a growing public health concern, with patients often facing a prolonged trial-and-error process in search of effective treatment. Developing a predictive model for treatment response in clinical practice remains challenging. To establish a model based on electroencephalography (EEG) to predict response to 2 distinct selective serotonin reuptake inhibitor (SSRI) medications. This prognostic study developed a predictive model using EEG data collected between 2011 and 2017 from 2 independent cohorts of participants with depression: 1 from the first Canadian Biomarker Integration Network in Depression (CAN-BIND) group and the other from the Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) consortium. Eligible participants included those aged 18 to 65 years who had a diagnosis of major depressive disorder. Data were analyzed from January to December 2022. In an open-label trial, CAN-BIND participants received an 8-week treatment regimen of escitalopram treatment (10-20 mg), and EMBARC participants were randomized in a double-blind trial to receive an 8-week sertraline (50-200 mg) treatment or placebo treatment. The model's performance was estimated using balanced accuracy, specificity, and sensitivity metrics. The model used data from the CAN-BIND cohort for internal validation, and data from the treatment group of the EMBARC cohort for external validation. At week 8, response to treatment was defined as a 50% or greater reduction in the primary, clinician-rated scale of depression severity. The CAN-BIND cohort included 125 participants (mean [SD] age, 36.4 [13.0] years; 78 [62.4%] women), and the EMBARC sertraline treatment group included 105 participants (mean [SD] age, 38.4 [13.8] years; 72 [68.6%] women). The model achieved a balanced accuracy of 64.2% (95% CI, 55.8%-72.6%), sensitivity of 66.1% (95% CI, 53.7%-78.5%), and specificity of 62.3% (95% CI, 50.1%-73.8%) during internal validation with CAN-BIND. During external validation with EMBARC, the model achieved a balanced accuracy of 63.7% (95% CI, 54.5%-72.8%), sensitivity of 58.8% (95% CI, 45.3%-72.3%), and specificity of 68.5% (95% CI, 56.1%-80.9%). Additionally, the balanced accuracy for the EMBARC placebo group (118 participants) was 48.7% (95% CI, 39.3%-58.0%), the sensitivity was 50.0% (95% CI, 35.2%-64.8%), and the specificity was 47.3% (95% CI, 35.9%-58.7%), suggesting the model's specificity in predicting SSRIs treatment response. In this prognostic study, an EEG-based model was developed and validated in 2 independent cohorts. The model showed promising accuracy in predicting treatment response to 2 distinct SSRIs, suggesting potential applications for personalized depression treatment.