Serotonin Reuptake Inhibitor Antidepressants Research Articles

Vilazodone,aNovel SSRI Antidepressant with 5-HT1A Partial Agonist Properties: Diminished Potentiation of Chronic Oral Methylphenidate-Induced Dynorphin Expression in the Striatum in Adolescent Male Rats.

Selective serotonin reuptake inhibitor (SSRI) antidepressants such as fluoxetine are used in combination with the medical psychostimulant methylphenidate (Ritalin) in a variety of treatments in children and adults. Unintended co-exposure to these psychotropic medications also occurs in patients on SSRIs who abuse methylphenidate as a "cognitive enhancer" or recreational drug. Preclinical research shows that SSRIs such as fluoxetine when given in conjunction with methylphenidate potentiate addiction-related gene regulation by methylphenidate in the striatum, consistent with the known facilitatory role for serotonin in psychostimulant-induced neuronal and behavioral changes. Moreover, fluoxetine combined with methylphenidate also facilitated subsequent acquisition of cocaine self-administration in adolescent rats, suggesting an increased addiction liability for methylphenidate. In the present study, we investigated the impact of a novel SSRI, vilazodone, on methylphenidate-induced gene regulation in adolescent male rats. In contrast to prototypical SSRIs such as fluoxetine, vilazodone also acts as a partial 5-HT1A serotonin receptor agonist and is thus proposed to temper serotonin input to the striatum. We compared the effects of chronic treatment (4 weeks) with vilazodone (10mg/kg, twice daily) with those of fluoxetine (5mg/kg, twice daily) on striatal dynorphin expression induced by oral methylphenidate treatment (30/60mg/kg/day in drinking water, 8h access daily). Our results demonstrate that, in contrast to fluoxetine, vilazodone had minimal or no potentiating effects on methylphenidate-induced dynorphin expression. This diminished impact on gene regulation was seen throughout the striatum, including the nucleus accumbens, where increased dynorphin expression has previously been associated with various aspects of addiction. Our findings suggest that vilazodone may serve as a better adjunct SSRI with reduced addiction-facilitating properties.

Serotonin reuptake inhibitors improve muscle stem cell function and muscle regeneration in male mice

Serotonin reuptake inhibitor antidepressants such as fluoxetine are widely used to treat mood disorders. The mechanisms of action include an increase in extracellular level of serotonin, neurogenesis, and growth of vessels in the brain. We investigated whether fluoxetine could have broader peripheral regenerative properties. Following prolonged administration of fluoxetine in male mice, we showed that fluoxetine increases the number of muscle stem cells and muscle angiogenesis, associated with positive changes in skeletal muscle function. Fluoxetine also improved skeletal muscle regeneration after single and multiples injuries with an increased muscle stem cells pool and vessel density associated with reduced fibrotic lesions and inflammation. Mice devoid of peripheral serotonin treated with fluoxetine did not exhibit beneficial effects during muscle regeneration. Specifically, pharmacological, and genetic inactivation of the 5-HT1B subtype serotonin receptor also abolished the enhanced regenerative process induced by fluoxetine. We highlight here a regenerative property of serotonin on skeletal muscle.

Fluoxetine, fluvoxamine, and hearing loss or tinnitus after cisplatin treatment: A retrospective cohort study.

Cisplatin use is often limited by its ototoxic side effects, which can lead to irreversible hearing loss. Preventing cisplatin-induced ototoxicity is crucial to improve patient outcomes. Fluoxetine and fluvoxamine, both selective serotonin reuptake inhibitors antidepressants, inhibit the NLR pyrin domain-containing protein 3 inflammasome, a potential therapeutic target for preventing ototoxicity. However, human studies have not evaluated if these antidepressants may protect against cisplatin-induced ototoxicity. The object of this study is to assess the association between fluoxetine or fluvoxamine use and incidence of hearing loss or tinnitus in a large cohort of patients receiving cisplatin chemotherapy. We use a retrospective cohort study within the U.S. Department of Veterans Affairs healthcare system. Adult patients with cancer who received cisplatin chemotherapy between 2000 and 2023 are included. Incidence of ototoxicity, defined by international classification of diseases revision 9-CM or international classification of diseases revision 10-CM diagnoses of hearing loss or tinnitus is compared between concurrent use of fluoxetine or fluvoxamine and cisplatin alone. A total of 20,552 patients were included. Of those, 489 received cisplatin and fluoxetine or fluvoxamine. After propensity score adjustment, the hazard of ototoxicity was lower in the group receiving fluoxetine or fluvoxamine compared to the group receiving cisplatin alone (HR = 0.62, 95% CI = (0.41-0.94)). Fluoxetine or fluvoxamine use may be associated with a reduced risk of cisplatin-induced ototoxicity. Randomized clinical trials are needed to confirm these findings and establish the efficacy of the medications in ototoxicity prevention. Further research is also warranted to investigate the potential mechanisms underlying this protective effect.

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.

Sex-Specific Transcriptomic Changes in the Villous Tissue of Placentas of Pregnant Women Using a Selective Serotonin Reuptake Inhibitor.

About 5% of pregnant women are treated with selective serotonin reuptake inhibitor (SSRI) antidepressants to treat their depression. SSRIs influence serotonin levels, a key factor in neural embryonic development, and their use during pregnancy has been associated with adverse effects on the developing embryo. However, the role of the placenta in transmitting these negative effects is not well understood. In this study, we aim to elucidate how disturbances in the maternal serotonergic system affect the villous tissue of the placenta by assessing whole transcriptomes in the placentas of women with healthy pregnancies and women with depression and treated with the SSRI fluoxetine during pregnancy. Twelve placentas of the Biology, Affect, Stress, Imaging and Cognition in Pregnancy and the Puerperium (BASIC) project were selected for RNA sequencing to examine differentially expressed genes: six male infants and six female infants, equally distributed over women treated with SSRI and without SSRI treatment. Our results show that more genes in the placenta of male infants show changed expression associated with fluoxetine treatment than in placentas of female infants, stressing the importance of sex-specific analyses. In addition, we identified genes related to extracellular matrix organization to be significantly enriched in placentas of male infants born to women treated with fluoxetine. It remains to be established whether the differentially expressed genes that we found to be associated with SSRI treatment are the result of the SSRI treatment itself, the underlying depression, or a combination of the two.

Prediction of treatment response in major depressive disorder using a hybrid of convolutional recurrent deep neural networks and effective connectivity based on EEG signal.

In this study, we have developed a novel method based on deep learning and brain effective connectivity to classify responders and non-responders to selective serotonin reuptake inhibitors (SSRIs) antidepressants in major depressive disorder (MDD) patients prior to the treatment using EEG signal. The effective connectivity of 30 MDD patients was determined by analyzing their pretreatment EEG signals, which were then concatenated into delta, theta, alpha, and beta bands and transformed into images. Using these images, we then fine tuned a hybrid Convolutional Neural Network that is enhanced with bidirectional Long Short-Term Memory cells based on transfer learning. The Inception-v3, ResNet18, DenseNet121, and EfficientNet-B0 models are implemented as base models. Finally, the models are followed by BiLSTM and dense layers in order to classify responders and non-responders to SSRI treatment. Results showed that the EfficiencyNet-B0 has the highest accuracy of 98.33, followed by DensNet121, ResNet18 and Inception-v3. Therefore, a new method was proposed in this study that uses deep learning models to extract both spatial and temporal features automatically, which will improve classification results. The proposed method provides accurate identification of MDD patients who are responding, thereby reducing the cost of medical facilities and patient care.

Neuroanatomical dimensions in medication-free individuals with major depressive disorder and treatment response to SSRI antidepressant medications or placebo

Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw MRI data were shared from international samples (N = 1,384) of medication-free individuals with first-episode and recurrent MDD (N = 685) in a current depressive episode of at least moderate severity, but not treatment-resistant depression, as well as healthy controls (N = 699). Prospective longitudinal data on treatment response were available for a subset of MDD individuals (N = 359). Treatments were either SSRI antidepressant medication (escitalopram, citalopram, sertraline) or placebo. Multi-center MRI data were harmonized, and HYDRA, a semi-supervised machine-learning clustering algorithm, was utilized to identify patterns in regional brain volumes that are associated with disease. MDD was optimally characterized by two neuroanatomical dimensions that exhibited distinct treatment responses to placebo and SSRI antidepressant medications. Dimension 1 was characterized by preserved gray and white matter (N = 290 MDD), whereas Dimension 2 was characterized by widespread subtle reductions in gray and white matter (N = 395 MDD) relative to healthy controls. Although there were no significant differences in age of onset, years of illness, number of episodes, or duration of current episode between dimensions, there was a significant interaction effect between dimensions and treatment response. Dimension 1 showed a significant improvement in depressive symptoms following treatment with SSRI medication (51.1%) but limited changes following placebo (28.6%). By contrast, Dimension 2 showed comparable improvements to either SSRI (46.9%) or placebo (42.2%) (β = –18.3, 95% CI (–34.3 to –2.3), P = 0.03). Findings from this case-control study indicate that neuroimaging-based markers can help identify the disease-based dimensions that constitute MDD and predict treatment response.

The lived experience of withdrawal from Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants: A qualitative interview study.

Our knowledge of the broader impacts of antidepressant withdrawal, beyond physical side effects, is limited. Further research is needed to investigate the lived experiences of withdrawal, to aid clinicians on how to guide patients through the process. To explore antidepressant users' experiences and views on the withdrawal process and how it affected their quality of life across multiple life domains. We conducted in-depth qualitative interviews with 20 individuals from the community who had attempted to withdraw from Serotonin Reuptake Inhibitor antidepressants in the past year. Semi-structured interviews were conducted online. A topic guide was used to ensure consistency across interviews. The interviews were audio-recorded and transcribed verbatim and analysed using inductive reflexive thematic analysis. Five themes were generated. The first highlighted the challenges of managing the release from emotional blunting and cognitive suppression following antidepressant discontinuation. The second related to the negative impact of withdrawal on close relationships and social interactions. The third showed that concurrent with negative physical symptoms, there was a positive impact on health (exercise was reported by some as a coping mechanism). The fourth theme focused on support from GPs and families, emphasising the importance of mental health literacy in others. The final theme underscored the importance of gradual and flexible tapering in enabling a manageable withdrawal experience,and the consideration of timing. The lived experience of withdrawal significantly impacts individuals' well-being. Participants emphasised that withdrawal is not just about physical side effects but also affects their emotional, cognitive, and social functioning. Eight people attended individual online meetings to share their experiences of antidepressant withdrawal to help inform the study design and recruitment strategy. Insights from these meetings informed the development of the topic guide. Questions about GP involvement, family relationships, and mood and thinking changes were included based on this PPI work. This ensured the inclusion of topics important to antidepressant users and facilitated the researcher's questioning during the interviews.

Cohort study finds prenatal SSRI exposure linked to reduced brain volume

A population‐based cohort study has found that prenatal exposure to selective serotonin reuptake inhibitor (SSRI) antidepressants was associated with reduced brain volume in children aged 7 to 15. The study did not examine whether any of the observed changes in the brain predisposed these young people to any impairments.

Trouble dysphorique prémenstruel : prises en charge médicamenteuses et psychothérapeutiques, une revue de littérature

IntroductionPremenstrual Dysphoric Disorder (PMDD) was first recognised in July 2013 in the DSM-5 after a long journey to identify its existence. It was not until 1983 that the US National Institute of Mental Health determined research criteria for the study of PMS. In 1994, the term “premenstrual dysphoric disorder” (PMDD) replaced this term in the 4th edition of the Diagnostic System Manual (DSM). It was listed in the section “Mood Disorder Not Otherwise Specified” and remained under consideration until the DSM-5, in which it appeared in the depressive disorders section. The legitimisation of the psychiatric diagnosis as well as the determination of clear symptomatology criteria in 2013 opened up possibilities for management, development of clinical, pathophysiological, therapeutic and psychotherapeutic studies. This disabling disorder can affect personal, social, family and professional life. In 2019, the ICD-11 in turn introduced the diagnosis of premenstrual dysphoric disorder, which solidifies the recognition of the disorder. Objective(I) to review the existing treatments, both medicinal and psychotherapeutic, and (II) to review their effectiveness. At the end of this work we will formulate recommendations for the management of these patients. MethodologyA bibliographic search was carried out from 7 June 2021 to 7 July2021 on the databases (bases de données) Psychinfo APA, Scopus, PubMed, as well as the bases de données of the Cochrane organisation and the recommendation documents of the Haute Autorité de la santé. After an initial selection based on keywords, the full text of all articles were read to arrive at the final selection of 32 articles. ResultsAntidepressants and Cognitive Behavioural Therapies (CBT) appear to be the most commonly recommended treatments for PMDD. Other research shows the effectiveness of oral contraceptives including drospirenone. Selective serotonin reuptake inhibitors (SSRIs) were identified as an effective treatment for PMDD. These data are consistent with the current etiological hypothesis of PMDD which has a negative impact of natural hormonal fluctuations on certain neurotransmitters. CBT showed positive results in reducing the functional impact of PMDD. DiscussionSelective serotonin reuptake inhibitor (SSRI) antidepressants were reported to be first-line treatments for PMDD (sertraline 50–150 mg/d, fluoxetine 10–20 mg/d, escitalopram 10–20 mg/d, paroxetine 12.5–25 mg/d). Drospirenone (EE 3 mg and EE 20 mg/d 24 days of hormonal pills, 4 days inactive) appears to have been a first or second line treatment depending on the articles. Current results clearly point to the effectiveness of CBT in helping to reduce: functional impairment, depressed mood, feelings of hopelessness, anxiety, mood swings, sensitivity, irritability, insomnia, conflict with others, impact of premenstrual symptoms on daily life, intensity of symptoms experienced, and symptom handicap. CBTs could also become a first-line treatment if there were to be more evidence of their effectiveness. In the future, it would seem useful to offer a psychotherapeutic treatment that can be reproduced and to multiply research with a high level of scientific comparability in order to clarify the place of CBT in the management of PMDD. Research on the etiopathology of the disorder and the optimal drug regimen is still ongoing. There is a need to develop appropriate psychotherapeutic techniques to support and accompany these patients. ConclusionIn order to better evaluate treatments for PMDD, there is a need to homogenise studies on the subject at several levels: design, treatment doses, psychotherapeutic techniques, and evaluation measures. At present, some studies include both premenstrual syndrome (PMS) and PMDD patients. PMS and PMDD do not include the same symptoms, nor the same severity and potentially the same aetiology in the patients studied. In order to propose rigorous research that evaluates the effectiveness of treatments for PMDD and to properly support people with both these disorders, it seems essential to distinguish the two conditions. The role of the health practitioner is to be able to identify PMDD by differentiating it from other clinically related disorders. The patient must then be accompanied to make a choice of treatment adapted to her symptoms, their severity, her history, her plans for procreation, contraindications and her preferences. In 2021, the French National Authority for Health did not offer any guidelines or recommendations for the management of premenstrual dysphoric disorder. There is a need to develop research in France.

Prenatal serotonin reuptake inhibitor antidepressant exposure, SLC6A4 genetic variations, and cortisol activity in 6-year-old children of depressed mothers: A cohort study.

Prenatal exposure to maternal depression and serotonin reuptake inhibitor (SRI) antidepressants both affect the development of the hypothalamic-pituitary-adrenal (HPA) system, possibly via the neurotransmitter serotonin (5HT). In a community cohort, we investigated the impact of two factors that shape prenatal 5HT signaling (prenatal SRI [pSRI] exposure and child SLC6A4 genotype) on HPA activity at age 6years. Generalized estimating equation (GEE) models were used to study associations between cortisol reactivity, pSRI exposure, and child SLC6A4 genotype, controlling for maternal depression, child age, and sex (48 pSRI exposed, 74 nonexposed). Salivary cortisol levels were obtained at five time points during a laboratory stress challenge: arrival at the laboratory, following two sequential developmental assessments, and then 20 and 40min following the onset of a stress-inducing cognitive/social task. Cortisol decreased from arrival across both developmental assessments, and then increased across both time points following the stress challenge in both groups. pSRI-exposed children had lower cortisol levels across all time points. In a separate GEE model, we observed a lower cortisol stress response among children with LG /S alleles compared with children with La/La alleles, and this was particularly evident among children of mothers reporting greater third trimester depressed mood. Our findings suggest that pSRI exposure and a genetic factor associated with modulating 5HT signaling shaped HPA reactivity to a laboratory stress challenge at school age.

Prediction of Treatment Outcome in Major Depressive Disorder Using Ensemble of Hybrid Transfer Learning and Long Short-Term Memory Based on EEG Signal

Major Depressive Disorder (MDD) is a widespread global mental disease. The Effectiveness of Selective Serotonin Reuptake Inhibitors (SSRIs) antidepressants prescribed for MDD patients is limited and pre-treatment assessment of treatment outcome is a vital task. In this study, a hybrid model based on Transfer Learning (TL) of powerful pre-trained deep Convolutional Neural Networks (CNNs) empowered with bidirectional Long Short-term Memory (BLSTM) cells and attention mechanism were developed to classify Responders (R) and Non-Responders (NR) to SSRI antidepressants, using raw data images of pre-treatment EEG signal obtained from 30 MDD patients. TL-LSTM-Attention models based on VGG16, Xception, and Densenet121 models were created for the classification of R/NR. Results show that the highest performance of hybrid TL-LSTM-Attention models was achieved by VGG16-LSTM-Attention with an accuracy of 98.21%, sensitivity of 96.22%, and specificity of 99.67%. An Ensemble model based on weighted majority voting among hybrid models is constructed to surpass the performance of each single hybrid model. Our proposed ensemble model gained accuracy, sensitivity, and specificity of 98.84%, 97.80%, and 99.60%, respectively. Hence, the proposed model which is an ensemble of TL-LSTM-Attention models fed by raw data images of EEG signal leads to high confidence in the prediction of antidepressants treatment outcome.

Combined Chronic Oral Methylphenidate and Fluoxetine Treatment During Adolescence: Effects on Behavior.

Attention Deficit Hyperactivity Disorder (ADHD) can be comorbid with depression, often leading to the prescription of both methylphenidate (MP) and selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (FLX). Moreover, these drugs are often misused as cognitive enhancers. This study examined the effects of chronic oral co-administration of MP and FLX on depressive- and anxiety-like behaviors. Adolescent rats received daily either water (control), MP, FLX, or the combination of MP plus FLX in their drinking water over the course of 4 weeks. Data analysis shows a decrease in food consumption and body weight for rats exposed to FLX or the combination of MP and FLX. Sucrose consumption was significantly greater in FLX or MP+FLX groups compared to controls. FLX-treated rats showed no effect in the elevated plus maze (EPM; open arm time) and forced swim test (FST; latency to immobility). However, rats treated with the combination (MP+FLX) showed significant anxiolytic-like and anti-depressive-like behaviors (as measured by EPM and FST), as well as significant increases in overall activity (distance traveled in open field test). Finally, the combined MP+FLX treatment induced a decrease in anxiety and depressive- like behaviors significantly greater than the response from either of these drugs alone. These behavioral results characterize the long-term effects of these drugs (orally administered) that are widely co-administered and co-misused and provide important insight into the potential neurobiological and neurochemical effects. Future research will determine the potential risks of the long-term use of MP and FLX together.

Effects of the immunoglobulin/histamine complex on panic disorder concurrent with chronic spontaneous urticaria: a case report

BackgroundPanic disorder and panic attacks are two of the most common problems in psychiatry. A psychoimmunological correlation between allergic diseases and panic disorder has been strongly suggested. Histamine H1 receptor antagonists have been suggested as alternative drugs for the treatment of panic disorder. Chronic spontaneous urticaria (CSU) and panic disorder improved simultaneously with selective serotonin reuptake inhibitor antidepressants. Panic disorder has also been treated with the antihistamine chlorpheniramine. The immunoglobulin/histamine complex is a histamine-fixed immunoglobulin preparation that was reported to be effective in treating CSU. This case report describes the successful treatment of a patient with concomitant panic disorder and CSU for 23 years using immunoglobulin/histamine complex therapy.Case presentationThis report describes a 52-year-old female Korean patient who suffered from CSU with panic disorder for 23 years. Basic allergy tests (blood tests and skin prick tests) were conducted before and after treatment for the evaluation of allergic conditions. A multiple allergosorbent test (MAST) for the detection of allergen-specific IgE levels was also performed. The clinical severity of CSU was evaluated using the urticaria severity score system. Diagnostic interviews systematically assessed the diagnostic criteria outlined by the DSM-V, and the patient was evaluated before, during and after treatment using the Beck Depression Inventory (BDI-2) for depression, the State-Trait Anxiety Inventory (STAI) for anxiety and the Beck Hopelessness Score (BHS) for hopelessness. The patient received 2 ml of Histobulin™ (12 mg human immunoglobulin/0.15 µg histamine complex) once a week by subcutaneous injection for the treatment of CSU. Initial improvement of CSU was achieved after the third injection. After the twenty-seventh injection of Histobulin™, she showed no symptoms or signs and ceased allergic medication use. With the remission of CSU, allergic rhinitis was also completely resolved. The frequency of the common cold was significantly decreased during and after treatment. The medication frequency and development of clinical manifestations of panic disorder changed in parallel with the clinical severity of CSU. Moreover, the patient exhibited no clinical manifestations and ceased medication for panic disorder and sleeping pills for insomnia simultaneously with the remission of CSU. In the psychological evaluation, the BDI, STAI and BHS scores improved accordingly.ConclusionsThe immunoglobulin/histamine complex was effective in treating CSU and concomitant panic disorder in this patient and could be effective in treating some types of panic disorder. Considering the mechanisms of action of histamine and the immunoglobulin/histamine complex together with the patient’s clinical progress, histamine seemed to be related to panic disorder in this case. The concept of histamine-mediated syndromes, including allergies and psychiatric disorders, shows that a wider disease identity may be needed. Further studies on the immunopathogenesis of panic disorder and the mechanisms of action of the immunoglobulin/histamine complex are necessary.

Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A Genotypes and Serotonin Reuptake Inhibitor Antidepressants.

Serotonin reuptake inhibitor antidepressants, including selective serotonin reuptake inhibitors (SSRIs; i.e., citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline), serotonin and norepinephrine reuptake inhibitors (i.e., desvenlafaxine, duloxetine, levomilnacipran, milnacipran, and venlafaxine), and serotonin modulators with SSRI-like properties (i.e., vilazodone and vortioxetine) are primary pharmacologic treatments for major depressive and anxiety disorders. Genetic variation in CYP2D6, CYP2C19, and CYP2B6 influences the metabolism of many of these antidepressants, which may potentially affect dosing, efficacy, and tolerability. In addition, the pharmacodynamic genes SLC6A4 (serotonin transporter) and HTR2A (serotonin-2A receptor) have been examined in relation to efficacy and side effect profiles of these drugs. This guideline updates and expands the 2015 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and SSRI dosing and summarizes the impact of CYP2D6, CYP2C19, CYP2B6, SLC6A4, and HTR2A genotypes on antidepressant dosing, efficacy, and tolerability. We provide recommendations for using CYP2D6, CYP2C19, and CYP2B6 genotype results to help inform prescribing these antidepressants and describe the existing data for SLC6A4 and HTR2A, which do not support their clinical use in antidepressant prescribing.

Establishing Core Symptoms of Acute Serotonin Reuptake Inhibitor Withdrawal: Results from an International Survey of Online Peer-Support Communities.

Serotonin reuptake inhibitor (SRI) antidepressants are commonly associated with withdrawal reactions. The Discontinuation Emergent Signs and Symptoms (DESS) checklist has been considered the gold standard research and screening tool for SRI withdrawal but has several limitations, including its length, lack of specificity, and omission of baseline symptom and symptom severity scores, making it impractical for use in clinical or research settings. We investigated the prevalence and severity of common SRI withdrawal symptoms to determine whether a very small subset of symptoms can capture most occurrences of SRI withdrawal. We surveyed 344 members of online peer-support communities aged 18-65, reporting withdrawal symptoms after chronic SRI treatment. The severity of nine common withdrawal symptoms was evaluated at baseline and during the withdrawal period. Dizziness, brain zaps, irritability/agitation, and anxiety/nervousness demonstrated the largest increase in severity during withdrawal relative to baseline. Nearly all (97.7%) of the 344 subjects and all (100%) 153 subjects with relatively low baseline symptom scores (total<5) reported a worsening of one of these four symptoms. The presence of a baseline anxiety disorder did not affect rates of withdrawal-emergent anxiety/nervousness. Nearly all surveyed subjects reported worsening either of dizziness, brain zaps, irritability/agitation, or anxiety/nervousness in acute withdrawal. A screening test incorporating these four core symptoms may be sufficiently sensitive to rule out SRI withdrawal and may be valuable in clinical and research settings. Incorporating withdrawal symptom severity may further enhance specificity.

Association analysis of gut microbiota and efficacy of SSRIs antidepressants in patients with major depressive disorder

BackgroundRelevant studies have shown that gut microbiome plays an important role in the occurrence, development and treatment of major depressive disorder (MDD). Many studies have also shown that, selective serotonin reuptake inhibitors (SSRIs) antidepressants can improve the symptoms of depression by changing the distribution of gut microbiome, Here we investigated whether a distinct gut microbiome was associated with Major depressive disorder (MDD), and how it was modulated by SSRIs antidepressants. MethodIn this study, we analyzed the gut microbiome composition of 62 patients with first-episode MDD and 41 matched healthy controls, before SSRIs antidepressants treatment, using 16S rRNA gene sequencing. MDD patients characterized as treatment-resistant (TR) or responders (R) to antidepressants by score reduction rate were ≥50 % after SSRIs antidepressants treatment for eight weeks. ResultsLDA effect size (LEfSe) analysis found that there were 50 different bacterial groups among the three groups, of which 19 genera were mainly at the genus level. The relative abundance of 12 genera increased in the HCs group, 5 genera in the R group increased in relative abundance, and 2 genera in the TR group increased in relative abundance. The correlation analysis of 19 bacterial genera and the score reduction rate showed that Blautia, Bifidobacterium and Coprococcus with higher relative abundance in the treatment effective group were related to the efficacy of SSRIs antidepressants. ConclusionsPatients with MDD have a distinct gut microbiome that changes after SSRIs antidepressants treatment. Dysbiosis could be a new therapeutic target and prognostic tool for the treatment of patients with MDD.

Serotonin Reuptake Inhibitor Increases Pseudarthrosis Rates in Anterior Cervical Discectomy and Fusions.

Retrospective cohort. To determine (1) the effects of serotonin reuptake inhibitors in pseudarthrosis rates after anterior cervical decompression and fusion (ACDF) and (2) to identify patient-reported outcome measures in patients taking serotonin reuptake inhibitors. Recent literature suggests that selective serotonin reuptake inhibitors (SSRIs) may inhibit fracture healing via downregulation of osteoblast differentiation. Spinal fusion supplementation with osteoblast-rich substances enhances spinal fusion, thus SSRIs may be detrimental. Patients with 1-year postoperative dynamic cervical spine radiographs following ACDF were grouped into serotonin reuptake inhibitor prescriptions (SSRI, serotonin-norepinephrine reuptake inhibitor [SNRI], or tricyclic antidepressant [TCA]) and no prescription (atypical antidepressant or no antidepressant). Pseudarthrosis was defined as ≥1 mm interspinous process motion on dynamic radiographs. Logistic regression models were controlled for confounding to analyze pseudarthrosis rates. Alpha was set at p - values of <0.05. Of the 523 patients who meet the inclusion criteria, 137 (26.2%) were prescribed an SSRI, SNRI, or TCA. Patients with these prescriptions were more likely to have pseudarthrosis (p =0.008) but not a revision surgery due to pseudarthrosis (p =0.219). Additionally, these patients had worse 1-year postoperative mental component summary (MCS)-12 (p =0.015) and Neck Disability Index (NDI) (p =0.006). The multivariate logistic regression analysis identified SSRI/SNRI/TCA use (odds ratio [OR], 1.82; 95% confidence interval [CI], 1.11-2.99; p =0.018) and construct length (OR, 1.91; 95% CI, 1.50-2.44; p <0.001) as pseudarthrosis predictors. A SSRI/SNRI/TCA prescription was a revision surgery predictor due to adjacent segment disease on univariate analysis (OR, 2.51; p =0.035) but not on multivariate logistic regression analysis (OR, 2.24; p =0.10). Patients taking serotonin reuptake-inhibiting antidepressants are at increased risk of worse postoperative outcome scores, including NDI and MCS-12, likely due to their underlying depression. This may contribute to their greater likelihood of having adjacent segment surgery. Additionally, preoperative use of serotonin reuptake inhibitors in patients undergoing an ACDF is a predictor of radiographic pseudarthrosis but not pseudarthrosis revision.

Methylone, a rapid acting entactogen with robust anxiolytic and antidepressant-like activity.

Selective serotonin reuptake inhibitor (SSRI) antidepressants represent first-line pharmacological treatment for a variety of neuropsychiatric illnesses, including major depressive disorder (MDD), anxiety, and post-traumatic stress disorder (PTSD), which show high rates of comorbidity. SSRIs have a delayed onset of action. Most patients do not show significant effects until 4-8 weeks of continuous treatment, have impairing side effects and as many as 40% of patients do not respond. Methylone (3,4-methylenedioxy-N-methylcathinone; MDMC, βk-MDMA, M1) is a rapid-acting entactogen that showed significant benefit in a clinical case series of PTSD patients and was well-tolerated in two Phase 1 studies of healthy volunteers. Based on these early observations in humans, in the current study we tested the hypothesis that methylone has antidepressant-like and anxiolytic effects in preclinical tests. For all studies, 6-8-week-old male Sprague Dawley rats (N = 6-16) were used. We employed the Forced Swim Test (FST), a classic and widely used screen for antidepressants, to explore the effects of methylone and to probe dose-response relationships, durability of effect, and potential interactions with combined SSRI treatment. We compared the effect of methylone with the prototypical SSRI fluoxetine. Three doses of fluoxetine (10 mg/kg) given within 24 h before FST testing caused a 50% reduction in immobility compared with controls that lasted less than 24 h. In contrast, a single dose of methylone (5-30 mg/kg) administered 30 min prior to testing produced a rapid, robust, and durable antidepressant-like response in the FST, greater in magnitude than fluoxetine. Immobility was reduced by nearly 95% vs. controls and effects persisted for at least 72 h after a single dose (15 mg/kg). Effects on swimming and climbing behavior in the FST, which reflect serotonergic and noradrenergic activity, respectively, were consistent with studies showing that methylone is less serotoninergic than MDMA. Fluoxetine pretreatment did not change methylone's antidepressant-like effect in the FST, suggesting the possibility that the two may be co-administered. In addition, methylone (5-30 mg/kg) exhibited anxiolytic effects measured as increased time spent in the center of an open field. Taken together, and consistent with initial clinical findings, our study suggests that methylone may have potential for treating depression and anxiety.

Epistemology of the side effect: anecdote and evidence in the digital age

Through the history of rxisk.org, this article explores some of the Web’s effects on the production and circulation of pharmaceutical knowledge. RxISK is an independent website that solicits reports from patients in order to uncover drug-induced harms which clinical trials and national pharmacovigilance schemes fail to identify. The first part of the article locates the origins of the project in the nearly 15-year struggle to obtain recognition and redress for one particular side effect of selective serotonin reuptake inhibitor (SSRI) antidepressants—their ability to trigger violent or suicidal behavior. That struggle, I show, brought to light the ways in which modern evidence-making practices obscure the harms of pharmacological treatment. The second part, based on interviews with the site’s creators, examines how RxISK’s data collection practices seek to convert the Web from a site for the circulation of misinformation into a usable source of new knowledge about drugs. The project’s originality, I argue, lies in its effort to reframe the relation between anecdote and evidence so as to liberate the patient’s voice from the burden of representativeness. Within this reframed epistemology, the project is also freed from the imperative of large-scale data extraction that increasingly dominates the economy of digital health.