Premenopausal Singaporean Women Suffering from Major Depressive Disorder Treated with Selective Serotonin Reuptake Inhibitors Had Similar Bone Mineral Density as Compared with Healthy Controls

The association between selective serotonin reuptake inhibitor (SSRI) treatment and lower bone mineral density (BMD) remains controversial, and further research is required. This study aimed to compare the BMD, levels of bone formation and bone metabolism markers in medicated premenopausal Singaporean women with major depressive disorder (MDD) and matched healthy controls. We examined 45 women with MDD who received SSRI treatment (mean age: 37.64 ± 7) and 45 healthy controls (mean age: 38.1 ± 9.2). BMD at the lumbar spine, total hip and femoral neck were measured using dual-energy X-ray absorptiometry. We also measured bone formation markers, procollagen type 1 N-terminal propeptide (P1NP) and bone metabolism markers, osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa-Β ligand (RANKL). There were no significant differences in the mean BMD in the lumbar spine (healthy controls: 1.04 ± 0.173 vs. MDD patients: 1.024 ± 0.145, p = 0.617, left hip (healthy controls: 0.823 ± 0.117 vs. MDD patients: 0.861 ± 0.146, p = 0.181) and right hip (healthy controls: 0.843 ± 0.117 vs. MDD patients: 0.85 ± 0.135, p = 0.784) between healthy controls and medicated patients with MDD. There were no significant differences in median P1NP (healthy controls: 35.9 vs. MDD patients: 37.3, p = 0.635), OPG (healthy controls: 2.6 vs. MDD patients: 2.7, p = 0.545), RANKL (healthy controls: 23.4 vs. MDD patients: 2178.93, p = 0.279) and RANKL/OPG ratio (healthy controls: 4.1 vs. MDD patients: 741.4, p = 0.279) between healthy controls and medicated patients with MDD. Chronic SSRI treatment might not be associated with low BMD in premenopausal Singaporean women who suffered from MDD. This finding may help female patients with MDD make an informed decision when considering the risks and benefits of SSRI treatment.

Ongoing Use of SSRIs Does Not Alter Outcome in Hospitalized COVID-19 Patients: A Retrospective Analysis

SARS-CoV-2 continues to have devastating consequences worldwide. Though vaccinations have helped reduce spread, new strains still pose a threat. Therefore, it is imperative to identify treatments that prevent severe COVID-19 infection. Recently, acute use of SSRI antidepressants in COVID+ patients was shown to reduce symptom severity. The aim of this retrospective observational study was to determine whether COVID+ patients already on SSRIs upon hospital admission had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Electronic medical records of 9044 patients with laboratory-confirmed COVID-19 from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. In this sample, no patients admitted on SSRIs had them discontinued. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs. those not taking SSRIs, after controlling for age category, gender, and race. This study shows the utility of large clinical databases in determining what commonly prescribed drugs might be useful in treating COVID-19. During pandemics due to novel infectious agents, it is critical to evaluate safety and efficacy of drugs that might be repurposed for treatment.

Serotonin Transporter Genetic Variation and Antidepressant Response and Tolerability: A Systematic Review and Meta-Analysis

Antidepressants are used to treat several psychiatric disorders; however, a large proportion of patients do not respond to their first antidepressant therapy and often experience adverse drug reactions (ADR). A common insertion–deletion polymorphism in the promoter region (5-HTTLPR) of the serotonin transporter (SLC6A4) gene has been frequently investigated for its association with antidepressant outcomes. Here, we performed a systematic review and meta-analysis to assess 5-HTTLPR associations with antidepressants: (1) response in psychiatric disorders other than major depressive disorder (MDD) and (2) tolerability across all psychiatric disorders. Literature searches were performed up to January 2021, yielding 82 studies that met inclusion criteria, and 16 of these studies were included in the meta-analyses. Carriers of the 5-HTTLPR LL or LS genotypes were more likely to respond to antidepressant therapy, compared to the SS carriers in the total and European ancestry-only study populations. Long (L) allele carriers taking selective serotonin reuptake inhibitors (SSRIs) reported fewer ADRs relative to short/short (SS) carriers. European L carriers taking SSRIs had lower ADR rates than S carriers. These results suggest the 5-HTTLPR polymorphism may serve as a marker for antidepressant outcomes in psychiatric disorders and may be particularly relevant to SSRI treatment among individuals of European descent.

Tianeptine, but not fluoxetine, decreases avoidant behavior in a mouse model of early developmental exposure to fluoxetine

Depression and anxiety, two of the most common mental health disorders, share common symptoms and treatments. Most pharmacological agents available to treat these disorders target monoamine systems. Currently, finding the most effective treatment for an individual is a process of trial and error. To better understand how disease etiology may predict treatment response, we studied mice exposed developmentally to the selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX). These mice show the murine equivalent of anxiety- and depression-like symptoms in adulthood and here we report that these mice are also behaviorally resistant to the antidepressant-like effects of adult SSRI administration. We investigated whether tianeptine (TIA), which exerts its therapeutic effects through agonism of the mu-opioid receptor instead of targeting monoaminergic systems, would be more effective in this model. We found that C57BL/6J pups exposed to FLX from postnatal day 2 to 11 (PNFLX, the mouse equivalent in terms of brain development to the human third trimester) showed increased avoidant behaviors as adults that failed to improve, or were even exacerbated, by chronic SSRI treatment. By contrast, avoidant behaviors in these same mice were drastically improved following chronic treatment with TIA. Overall, this demonstrates that TIA may be a promising alternative treatment for patients that fail to respond to typical antidepressants, especially in patients whose serotonergic system has been altered by in utero exposure to SSRIs.

Biological and Pharmacogenomics Bases of Gastrointestinal and Some Long-Term Selective Serotonin Reuptake Inhibitors-Induced Adverse Effects

Background: Patients being treated with SSRIs who experience intolerable Adverse Effects (AEs) have a penchant for discontinuing treatment, inevitably jeopardizing any probability for treatment response. Aim: This study aims to identify the Single Nucleotide Polymorphisms (SNPs) that are associated with certain AEs of SSRI treatment in Major Depression Disorder (MDD). Results: Patients with the short (SS) genotype (44 base pair deletion) and those with the long along with guanine substitution (LgLg - 44 base pair insertion with rs25531- guanine substitution variant) of the serotonin transporter gene (STG) have substantially been reported with a higher incidence of AEs to SSRI. While variants of glutamate receptor ionotropic genes have been found to be linked with different domains of sexual dysfunction, polymorphisms of 5-HT2A gene - rs6311 (G > A), the long allele (L) of STG, rs6295 (C > G) polymorphism of HTR1A and polymorphism rs1160351 (A > C) of MAM domain-containing glycosyl-phosphatidyl inositol anchor 2 (MDGA2) gene have also been found to be associated with sexual dysfunction. The rs4680 (G>A; Val > Met) polymorphism of catechol-O-methyltransferase (COMT), AA genotype of rs18532 polymorphism of tryptophan hydroxylase, the rs6318 (C > G) polymorphism of the serotonin receptor 2C (HTR2C), and S allele of STG were found to be associated with weight gain following SSRI treatment. The sanctity of these results is limited by the inability of some researchers to replicate these association findings. Conclusion: This review highlights a number of polymorphisms associated with some of the key AEs encountered in SSRI treatments. Standardized study designs in pharmacogenomic evaluations hold great promise for replication of association findings.

Expectancy effects on serotonin and dopamine transporters during SSRI treatment of social anxiety disorder: a randomized clinical trial

It has been extensively debated whether selective serotonin reuptake inhibitors (SSRIs) are more efficacious than placebo in affective disorders, and it is not fully understood how SSRIs exert their beneficial effects. Along with serotonin transporter blockade, altered dopamine signaling and psychological factors may contribute. In this randomized clinical trial of participants with social anxiety disorder (SAD) we investigated how manipulation of verbally-induced expectancies, vital for placebo response, affect brain monoamine transporters and symptom improvement during SSRI treatment. Twenty-seven participants with SAD (17 men, 10 women), were randomized, to 9 weeks of overt or covert treatment with escitalopram 20 mg. The overt group received correct treatment information whereas the covert group was treated deceptively with escitalopram, described as an active placebo in a cover story. Before and after treatment, patients underwent positron emission tomography (PET) assessments with the [11C]DASB and [11C]PE2I radiotracers, probing brain serotonin (SERT) and dopamine (DAT) transporters. SAD symptoms were measured by the Liebowitz Social Anxiety Scale. Overt was superior to covert SSRI treatment, resulting in almost a fourfold higher rate of responders. PET results showed that SERT occupancy after treatment was unrelated to anxiety reduction and equally high in both groups. In contrast, DAT binding decreased in the right putamen, pallidum, and the left thalamus with overt SSRI treatment, and increased with covert treatment, resulting in significant group differences. DAT binding potential changes in these regions correlated negatively with symptom improvement. Findings support that the anxiolytic effects of SSRIs involve psychological factors contingent on dopaminergic neurotransmission while serotonin transporter blockade alone is insufficient for clinical response.

Ongoing use of SSRIs and the hospital course of COVID-19 patients: a retrospective outcome analysis

Background: The SARS-CoV2 virus continues to have devastating consequences worldwide. Though vaccinations have helped to reduce the impact of the virus, new strains still pose a threat to unvaccinated, and to a lesser extent vaccinated, individuals. Therefore, it is imperative to identify treatments that can prevent the development of severe COVID-19. Recently, acute use of SSRI antidepressants in COVID+ patients has been shown to reduce the severity of symptoms compared to placebo. Since SSRIs are a widely used anti-depressant, the aim of this study was to determine if COVID+ patients already on SSRI treatment upon admission to the hospital had reduced mortality compared to COVID+ patients not on chronic SSRI treatment. Methods: A retrospective observational study design was used. Electronic medical records of 9,043 patients with a laboratory-confirmed diagnosis of Covid-19 from 03/2020 to 03/2021from six hospitals were queried for demographic and clinical information. Using R, a logistic regression model was run with mortality as the outcome and SSRI status as the exposure. An adjusted logistic regression model was run to account for age category, gender, and race. All tests were considered significant at p of 0.05 or less. Results: In this sample, no patients admitted on SSRIs had them discontinued. This is consistent with current recommendations. There was no significant difference in the odds of dying between COVID+ patients on chronic SSRIs vs COVID+ patients not taking SSRIs, after controlling for age category, gender, and race. The odds of COVID+ patients on SSRIs dying was 0.98 (95%CI: 0.81, 1.18) compared to COVID+ patients not on SSRIs (p=0.83). Conclusion: In times of pandemics due to novel infectious agents it is difficult, but critical to evaluate safety and efficacy of drugs that might be repurposed for treatment. This large sample size of 9,043 patients suggests that there will be no significant benefit to use of SSRIs to decrease mortality rates for hospitalized patients with Covid-19 who are not currently on SSRI medications. This study shows the utility of large clinical databases in addressing the urgent issue of determining what commonly prescribed drugs might be useful in treating COVID-19.

Selective serotonin reuptake inhibitors and suicidal behaviour: a population-based cohort study

There is concern that selective serotonin reuptake inhibitor (SSRI) treatment may increase the risk of suicide attempts or deaths, particularly among children and adolescents. However, debate remains regarding the nature of the relationship. Using nationwide Swedish registers, we identified all individuals aged 6–59 years with an incident SSRI dispensation (N = 538,577) from 2006 to 2013. To account for selection into treatment, we used a within-individual design to compare the risk of suicide attempts or deaths (suicidal behaviour) in time periods before and after SSRI-treatment initiation. Within-individual incidence rate ratios (IRRs) of suicidal behaviour were estimated. The 30 days before SSRI-treatment initiation was associated with the highest risk of suicidal behaviour compared with the 30 days 1 year before SSRI initiation (IRR = 7.35, 95% CI 6.60–8.18). Compared with the 30 days before SSRI initiation, treatment periods after initiation had a reduced risk—the IRR in the 30 days after initiation was 0.62 (95% CI 0.58–0.65). The risk then declined over treatment time. These patterns were similar across age strata, and when stratifying on history of suicide attempts. Initiation with escitalopram was associated with the greatest risk reduction, though CIs for the IRRs of the different SSRI types were overlapping. The results do not suggest that SSRI-treatment increases the risk for suicidal behaviour in either youths or adults; rather, it may reduce the risk. Further research with different study designs and in different populations is warranted.