New-generation Antidepressants Research Articles

Pharmaceutical Studies on Piperazine-Based Compounds Targeting Serotonin Receptors and Serotonin Reuptake Transporters.

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.

Adverse event profiles of drug-induced liver injury caused by antidepressant drugs: a disproportionality analysis.

Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to antidepressants. Therefore, drug-induced liver injury (DILI) caused by antidepressants deserves more attention. To investigate DILI adverse events reported due to antidepressant use in the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database. A disproportionality analysis of spontaneously reported adverse events was conducted to assess the association between antidepressant drugs and DILI. FAERS data from 1 January 2004 to 31 December 2021 were compiled and analyzed using the reporting odds ratio (ROR) and information component (IC). As per the FAERS database, of the 324,588 cases that were administered antidepressants, 10,355 were identified as cases with DILI. Among the identified 42 antidepressants, nefazodone (n = 47, ROR = 7.79, IC = 2.91), fluvoxamine (n = 29, ROR = 4.69, IC = 2.20), and clomipramine (n = 24, ROR = 3.97, IC = 1.96) had the highest ROR for cholestatic injury; mianserin (n = 3, ROR = 21.46, IC = 3.99), nefazodone (n = 264, ROR = 18.67, IC = 3.84), and maprotiline (n = 15, ROR = 5.65, IC = 2.39) for hepatocellular injury; and nefazodone (n = 187, ROR = 12.71, IC = 0.48), clomipramine (n = 35, ROR = 2.07, IC = 0.26), and mirtazapine (n = 483, ROR = 1.96, IC = 0.94) for severe drug-related hepatic disorders. Only nefazodone elicited hepatic failure signals (n = 48, ROR = 18.64, IC = 4.16). There are limited reports on the adverse reactions of relatively new antidepressant drugs, such as milnacipran, viloxazine, esketamine, and tianeptine, and those not approved by the Food and Drugs Administration, such as reboxetine and agomelatine. A significant association was observed between DILI and nefazodone. Duloxetine and clomipramine were associated with three DILI categories, except hepatic failure. The disproportionality analysis cannot conclude on a definite causal link between antidepressants and DILI. Additional research is required to assess new-generation antidepressants for their propensity to cause DILI.

Antidepressant Poisoning Trends in Pediatric Intensive Care: A Comparative Study of New- and Old-Generation Antidepressants.

This study aimed to compare the frequency, clinical findings, treatment practices, and outcomes of toxicity to old-generation (OG) and new-generation (NG) antidepressants in our pediatric intensive care unit (PICU) by year-to-year. The study included patients hospitalized for antidepressant poisoning during the 11-year period of January 2010 through December 2020. Antidepressants were classified as OG and NG. The groups were compared in terms of patient demographic characteristics, type of poisoning (accidental/suicidal), clinical findings, supportive and extracorporeal treatments received, and outcomes. The study included 58 patients (NG, n = 30; OG, n = 28). The median age of the patients was 178 months (range, 13.6-215 months) and 47 patients (81%) were female. Patients admitted for only antidepressant poisoning constituted 13.3% of all poisoning cases (58/436). Of these, 22 cases (37.9%) were accidental and 36 (62.3%) were suicidal. The most common cause of poisoning was amitriptyline (24/28) in the OG group and sertraline (13/30) in the NG group. Neurological symptoms were significantly more common in the OG group (76.2% vs 23.8%), while gastrointestinal involvement was more common in the NG group (82% vs 18%; P = 0.001 and P = 0.026, respectively). Old-generation antidepressant poisoning was associated with more frequent intubation (4 vs 0 patients, P = 0.048) and longer length of PICU stay (median, 1 day [range, 1-8] vs 1 day [range, 1-4], P = 0.019). Rates of therapeutic plasma exchange and intravenous lipid emulsion therapy did not differ ( P = 0.483 and P = 0.229, respectively). In poisoned patients, proper evaluation and management of patients requiring PICU admission are vital for favorable patient outcomes.

For children and adolescents with depression, how do new-generation antidepressants compare?

For children and adolescents with depression, how do new-generation antidepressants compare?

Prescribing Trends of Antidepressants and Psychotropic Coprescription for Youths in UK Primary Care, 2000-2018

BackgroundThere is lack of recent information on the prescribing trends of antidepressants and coprescription with other psychotropic medications in the United Kingdom (UK) pediatric population. MethodsUsing the Clinical Practice Research Datalink, we estimated the annual rates of patients newly prescribed an antidepressant (selective serotonin reuptake inhibitors (SSRIs), other newer generation antidepressants, and tricyclic antidepressants (TCAs)) and the percentage of new users of antidepressants with a same-day coprescription for other psychotropic medications. We also estimated the prevalence of patients with antidepressant prescriptions and percentage of coprescription for other psychotropic medications. ResultsAfter a 42% decline from 2000 to 2005, the rate of patients newly prescribed an antidepressant increased from 2006 onwards. From 2008 to 2018, the rate increased from 254.3 to 471.2 per 100,000 person-years (rate ratio 1.97, 95% confidence interval 1.96-1.99). The rate was higher in females and adolescents aged 15 to 17. SSRIs were most commonly prescribed (70% of all antidepressant prescriptions). Overall, 4.7% of patients newly prescribed an antidepressant had at least one same-day coprescription for another psychotropic medication. During the study period, coprescription rose from 2.6% to 6.4% and was more frequent in males. In 2018, most coprescriptions were anxiolytics and hypnotics (63%) and antipsychotics (26%). Trends in prevalent prescriptions corresponded to trends in new prescriptions. LimitationsBy using a primary care database, we did not have information on prescriptions from specialists or during hospitalizations. ConclusionsDuring the last decade, antidepressant prescriptions and psychotropic coprescription in primary care increased in UK children and adolescents.

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

BackgroundSelective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants.MethodsPrimary astrocytes were isolated and cultured using neurobasal-based serum-free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α, and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses, and the underlying mechanisms were analyzed.ResultsAll the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity.ConclusionsThe study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

The development of the conditions for vortioxetine isolation from biological fluids

The chemical-toxicological significance of antidepressant drugs is steadily increasing. The development of effective methods of the sample preparation of the biological material is an important analytical aspect in toxicology of the newgeneration antidepressants. Aim. To develop the conditions for the sample preparation of biological fluids in order use them in the chemicaltoxicological analysis of the new antidepressant vortioxetine. Materials and methods. The studies were performed with model blood and urine samples spiked with vortioxetine. When examining the blood the formed blood elements were pre-precipitated by adding 10 % solution of trichloroacetic acid. The extraction purification was performed with hexane at pH 1-2, and the drug was extracted from the biologicalfluids with methylene chloride at pH 8-9. The extracts obtained were further subjected to TLC purification. Vortioxetine in eluates from chromatograms was determined by the UV-spectrophotometric method. Results and discussion. The Rf value of vortioxetine in the mobile phase of ethyl acetate-methanol-25 % ammonium hydroxide solution (85 : 10 : 5) was 0.77 ± 0.05. The UV spectra of the eluates from the chromatograms had absorption maxima at the wavelengths of 229 ± 2 and 232 ± 2 nm and matched with the UV spectrum of the standard solution of vortioxetine in methanol. The quantitative determination was performed at λmax232 nm by the equation of the calibration curve y = (0.0172 ± 3 · 10-4)x + (0.027 ± 0.008). Under the conditions of the sample preparation developed 27 ± 1 % of vortioxetine from the blood and 62 ± 2 % of the drug from the urine were isolated. Conclusions. The efficiency of the sample preparation of biological fluids by the method of liquid-liquid extraction in relation to the new antidepressant vortioxetine has been determined. The methods developed are recommended for use in forensic and clinical toxicology.

Separation anxiety disorder among outpatients with major depressive disorder: Prevalence and clinical correlates

Prior studies have reported that separation anxiety disorder (SEPAD) can continue into or may begin in adulthood. Association of SEPAD with other psychiatric disorders has been frequently examined, and high rates of comorbidities have been found. The aim of this study was to investigate the prevalence and clinical correlation of SEPAD in adult patients undergoing treatment for major depressive disorder (MDD). The study sample was comprised of 100 outpatients. Participants underwent a DSM-5-based comprehensive assessment. Purposefully-designed semi-structured sociodemographic information and illness history forms were filled out by the researchers, and diagnoses of SEPAD were made using the Structured Clinical Interview for Separation Anxiety Symptoms, Separation Anxiety Symptom Inventory and Adult Separation Anxiety Survey. The frequency of SEPAD was 41% in patients with MDD, three-quarters of whom were adult onset. The use of new-generation antidepressants, adjunctive medications and comorbidity of other anxiety disorders were higher in patients with SEPAD (p < 0.05). SEPAD was highly prevalent, with a majority of cases starting in adulthood among patients with MDD, while SEPAD comorbidity was associated with high levels of anxiety and an increased likelihood of suboptimal response to usual depression treatment. Further studies are required to define the relevance and pathological basis for the comorbidity of SEPAD in people with MDD.

Risk of Intracranial Hemorrhage With Concomitant Use of Antidepressants and Nonsteroidal Anti-inflammatory Drugs: A Nested Case-Control Study.

Whereas previous studies found that concomitant antidepressant and nonsteroidal anti-inflammatory drug (NSAIDs) use may increase the risk of gastrointestinal bleeding, either drug alone increases the risk of intracranial hemorrhage (ICH). To assess the risk for ICH in patients on concomitant treatment with antidepressants and NSAIDs. This was a nested case-control study using national insurance claims data in Taiwan between 2005 and 2013. Drug exposure was measured and compared during 3 time windows: 1 to 30, 31 to 60, and 61 to 90 days before the index date, which is the date of the ICH event. Both traditional and newer-generation antidepressants were considered in this study. Patients exposed to both antidepressants and NSAIDs 1 to 30 days before the index date presented a 50% increased odds of developing ICH (OR: 1.53; 95% CI: 1.31-1.80) compared with patients receiving antidepressants alone. Specifically, the concomitant use of nonselective NSAIDs and antidepressants increased these odds compared with antidepressants alone (OR: 1.56; 95% CI: 1.31-1.84), but using a selective cyclooxygenase-2 inhibitor with antidepressant did not alter ICH risk. Regarding antidepressant class, newer-generation antidepressants generally increase the odds of developing ICH by 60% when used concomitantly with NSAIDs. Our results suggested that the concomitant use of antidepressants and NSAIDs was associated with an increased odds of developing ICH. NSAIDs, especially nonselective NSAIDs, and serotonergic antidepressants played an important role in this risk. Given the prevalent use of these 2 classes of drugs, this potential drug interaction deserves more attention.

Whole blood and oral fluid microsampling for the monitoring of patients under treatment with antidepressant drugs

Patients suffering from major depression and related pathologies (feeding and eating disorders, obsessive-compulsive disorder, post-traumatic stress disorder, anxiety disorders, etc.) are usually treated with antidepressant agents belonging to several pharmacological and chemical classes; the most recent of these agents are collectively known as “new-generation antidepressants”. In these patients, therapeutic drug monitoring (TDM) with the determination of drug and metabolite blood levels is one of the most useful procedures to optimise and personalise the treatment, enhancing both effectiveness and safety. A new approach is proposed in this study, based on microsampling of both blood and oral fluid by means of volumetric absorptive microsampling (VAMS). This approach makes sampling and storage much simpler and even self- and at-home-sampling possible, while retaining reliability, vastly increasing analyte stability and reducing overall expenses. The microsamples were pretreated by means of microextraction by packed sorbent (MEPS) on C2 sorbent and analysed by liquid chromatography with sequential spectrophotometric and spectrofluorimetric detection (HPLC-UV-FL). Method validation results were satisfactory (extraction yield >84%, precision RSD < 8.9%, stability>85.0% after 3 months). Application to blood and oral fluid VAMS from patients treated with four possible different antidepressants (sertraline, fluoxetine, citalopram and vortioxetine) provided results always in good agreement with those obtained from the corresponding fluid matrices, including the levels of drug metabolites.

New-generation, non-SSRI antidepressants: Drug-drug interactions and therapeutic drug monitoring. Part 2: NaSSAs, NRIs, SNDRIs, MASSAs, NDRIs, and others.

After the development of "classical" tricyclic antidepressants and monoamine oxidase inhibitors, numerous other classes of antidepressant drugs have been introduced onto the market. The selective serotonin reuptake inhibitor class is the best-known one, but many others exist, usually identified by their mechanism of activity. In this second part of the review, focused on new-generation antidepressants not included among selective serotonin reuptake inhibitors, the following classes are considered: noradrenergic and selective serotonergic antidepressants; norepinephrine reuptake inhibitors; serotonin, norepinephrine and dopamine reuptake inhibitors; melatonergic agonists and selective serotonergic antagonists; norepinephrine and dopamine reuptake inhibitors; and so forth. These different mechanisms underlie tolerability and safety profiles that can be very different among the classes, with each one providing significant advantages and disadvantages in comparison with others. The main characteristics of the following antidepressants are described: mianserin, mirtazapine, setiptiline, reboxetine, viloxazine, teniloxazine, atomoxetine, nefazodone, agomelatine, bupropion, esketamine, and tianeptine. The paper is focused on their metabolism and interactions, but also includes brief notes on analytical methods useful for their therapeutic drug monitoring.

Efficacy of new-generation antidepressants assessed with the Montgomery-Asberg Depression Rating Scale, the gold standard clinician rating scale: A meta-analysis of randomised placebo-controlled trials.

BackgroundIt has been claimed that efficacy estimates based on the Hamilton Depression Rating-Scale (HDRS) underestimate antidepressants true treatment effects due to the instrument’s poor psychometric properties. The aim of this study is to compare efficacy estimates based on the HDRS with the gold standard procedure, the Montgomery-Asberg Depression Rating-Scale (MADRS).Methods and findingsWe conducted a meta-analysis based on the comprehensive dataset of acute antidepressant trials provided by Cipriani et al. We included all placebo-controlled trials that reported continuous outcomes based on either the HDRS 17-item version or the MADRS. We computed standardised mean difference effect size estimates and raw score drug-placebo differences to evaluate thresholds for clinician-rated minimal improvements (clinical significance). We selected 109 trials (n = 32,399) that assessed the HDRS-17 and 28 trials (n = 11,705) that assessed the MADRS. The summary estimate (effect size) for the HDRS-17 was 0.27 (0.23 to 0.30) compared to 0.30 (0.22 to 0.38) for the MADRS. The effect size difference between HDRS-17 and MADRS was thus only 0.03 and not statistically significant according to both subgroup analysis (p = 0.47) and meta-regression (p = 0.44). Drug-placebo raw score difference was 2.07 (1.76 to 2.37) points on the HDRS-17 (threshold for minimal improvement: 7 points according to clinician-rating and 4 points according to patient-rating) and 2.99 (2.24 to 3.74) points on the MADRS (threshold for minimal improvement: 8 points according to clinician-rating and 5 points according to patient-rating).ConclusionsOverall there was no meaningful difference between the HDRS-17 and the MADRS. These findings suggest that previous meta-analyses that were mostly based on the HDRS did not underestimate the drugs’ true treatment effect as assessed with MADRS, the preferred outcome rating scale. Moreover, the drug-placebo differences in raw scores suggest that treatment effects are indeed marginally small and with questionable importance for the average patient.

Updates on Preclinical and Translational Neuroscience of Mood Disorders: A Brief Historical Focus on Ketamine for the Clinician.

The development of new-generation antidepressants comes at a time of great clinical need when the global burden of depression, suicide, and other psychiatric conditions continues to increase. Our current treatment armamentarium is limited by the time delay needed for antidepressant effects and the significant number of patients who do not show an adequate response to antidepressants. The past 2 decades of psychiatric research has revealed that ketamine, known to be used only as an anesthetic and drug of abuse and to produce experimental models of psychosis, is effective at subanesthetic doses to ameliorate clinical depression. We performed a systematic search of PubMed/MEDLINE indexed reports to identify clinical and translational research done with ketamine for purposes of treating depression. We will first present the rationale for investigating ketamine and other N-methyl-D-aspartate receptor antagonists as a novel class of glutamate system targeting antidepressants. We will summarize putative molecular pathways underlying mood disorders and outline a brief history of investigation into ketamine as a treatment for depression. Recent clinical/translational evidence of ketamine's rapid-acting antidepressant mechanism will be critically reviewed in detail. At the end of this review, we will opine on the role of ketamine and derivatives in clinical practice.

The Impact of Placebo Response Rates on Clinical Trial Outcome: A Systematic Review and Meta-Analysis of Antidepressants in Children and Adolescents with Major Depressive Disorder.

Objective: The high placebo response rate may hamper the discovery of antidepressants in children and adolescents with major depressive disorder (MDD). The aim of the study was to clarify the relationship between the placebo response rate and clinical trial outcomes of the use of antidepressants in children and adolescents, and distinguish main factors responsible to placebo response rate. Methods: The PubMed and Cochrane Library databases were searched for double-blind randomized placebo-controlled trials of the new-generation antidepressants for the acute treatment of MDD in children and adolescents. The response rate differences (RDs) between placebo group and treatment group under different level of placebo response rate were pooled by random-effects meta-analysis. The classification thresholds for low, medium, and high placebo response rate were set at <40%, 40%-50%, and ≥50%, respectively. Predictors of placebo response rate were explored using meta-regression. Results: The analysis included 18 trials with 4365 participants. This study found that the lower the placebo response rate, the greater the efficacy differences between antidepressants and placebo. In the high, moderate, and low placebo response rate subgroups, the response RDs (95% CI) between antidepressants and placebo were 8 (1-14)%, 10 (2-17)%, and 21 (9-32)%, respectively. The meta-regression showed that the number of study sites was the factor most associated with placebo response rate, and that response rate increased 3% with every additional 10 study sites. Conclusions: The clinical outcome was related to the placebo response rates in the clinical trials of antidepressants in children and adolescents with MDD. The efficacy differences between antidepressants and placebo will be maximized when placebo response rates are reduced. The number of study sites was the factor most associated with the placebo response rates.

Letter to the editor: newer-generation antidepressants and suicide risk in randomized controlled trials : a re-analysis of the FDA database

Letter to the editor: newer-generation antidepressants and suicide risk in randomized controlled trials : a re-analysis of the FDA database

Switching to Imipramine Versus Add-on Mirtazapine in Venlafaxine-Resistant Major Depression: A 10-Week Randomized Open Study.

Newer-generation antidepressants used in monotherapy or in combination with other newer-generation antidepressants or other psychotropic drugs are usually preferred as first- or second-step treatment options in resistant depression. According to our clinical experience, tricyclic antidepressants still are one of our preferred first choices in treatment-resistant moderate to severe unipolar major depressive episodes. This 10-week open-design randomized study assessed the effectiveness of switching to imipramine (adjusted to plasma levels) compared with add-on mirtazapine (30 mg/d) for treatment of moderate to severe unipolar major depressive episodes after a 10-week unsuccessful venlafaxine regimen (225-300 mg/d). Efficacy analyses examined the change in depressive symptoms severity from baseline visit to endpoint and the comparative remission rate between treatment subgroups. The randomized sample consisted of 112 venlafaxine-resistant moderate to severe unipolar major depressed patients. Both the percentage of remitters (71.43% vs 39.28%) and the mean reduction of the Hamilton Depression Rating Scale score (76.94% vs 50.72%) were significantly larger in the imipramine subgroup. Even though we should be cautious about generalizing these results to patients with a less severe unipolar major episodes, our study suggest that switching to imipramine is a very effective treatment option in unipolar major depressive episodes after an unsuccessful venlafaxine regimen.

Terapija peripartalnih psihičkih poremećaja

During the peripartum period, women are at a greater risk of developing a mental disorder or experiencing an exacerbation of the pre-existing mental disorders. Therapeutic interventions are based primarily on psychotherapy, but if the symptoms are severe and pose a risk to the mother and the child, then the use of drugs, hospitalization or electroconvulsive therapy is considered. Cognitive-behavioral psychotherapy is the first line of treatment in postpartum blues and postpartum depression, panic disorder, generalized anxiety disorder, and mild to moderate obsessive-compulsive disorder. More recent conceptions regarding the use of drugs during the postpartum period indicate that medications should be prescribed if the risk of using them is lower than the risk of complications caused by the symptoms of mental disorders. Nortriptyline or desipramine are recommended from the group of tricyclic antidepressants, but newer generation antidepressants are shown to be safer during pregnancy. Fluvoxamine, paroxetine and sertraline can be used in postpartum period during breastfeeding, while fluoxetine and citalopram should be avoided. The use of first-generation antipsychotics haloperidol and trifluoperazine is recommended in the antepartum period, during which some of second-generation antipsychotics such as quetiapine, olanzapine, risperidone and aripiprazole can also be used. Clozapine should be avoided during breast-feeding. The use of mood stabilizers during pregnancy requires a thorough knowledge of the recommendations, and it is not advised to use them during the postpartum if the patient is breastfeeding. From the group of benzodiazepines, it is recommended to uselorazepam. Every form of therapeutic approach has proven to be more effective in the presence of emotional support from partners and other family members.

Antidepressant Effect of an Orally Administered Dipeptide Mimetic of the Brain-Derived Neurotrophic Factor

Involvement of BDNF in the regulation of neuroplasticity and neurogenesis in the hippocampus, impairment of which underlies the pathophysiology of depression, makes this endogenous protein a promising object for the development of new-generation antidepressants with a neurophysiologically based mechanism of action. A low-molecular-weight BDNF mimetic, GSB-106 (a substituted dimeric dipeptide, bis-(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide), was designed and synthesized at the Zakusov Institute of Pharmacology. GSB-106 was found to activate BDNF-specific TrkB receptors and their main post-receptor signaling pathways MAPK/ERK and PI3K/AKT. GSB-106 exhibited pronounced antidepressant activity in a rodent test battery at a dose of 0.1 to 1.0 mg/kg administered intraperitoneally. Because oral administration is preferable in the treatment of depression, which is associated with a prolonged duration and outpatient character of pharmacotherapy, we examined the antidepressant properties of GSB-106 administered orally as a pharmaceutical substance (PS) and in tablet dosage form (TDF). In the study, we used the Porsolt forced swim test in rats; a conventional antidepressant, Amitriptyline, was used as a reference drug. The antidepressant activity of GSB-106 was found to retain upon oral administration and to manifest at doses of 0.5-5.0 mg/kg for PS and 0.01-5.0 mg/kg for TDF. The effective dose of TDF was 50-fold lower than that of PS, and the efficacy of tableted GSB-106 exceeded that of Amitriptyline, the "gold standard" in antidepression care. Therefore, GSB-106, both as a substance and as a tablet dosage form, exhibits antidepressant activity when administered orally, which makes it a promising antidepressant agent, the first in the class of BDNF mimetics.

Safety Limits of Antidepressant Use Plus Combinations: Focus on Cardiovascular Function.

Antidepressants have been widely prescribed for depression, anxiety, sleep disorders, and in the management of behavioural symptoms of adult-old patients. Although generally safe, newer generation antidepressants are not devoid of the risk of inducing clinically relevant adverse events. To investigate the association between newer generation antidepressants and the occurrence of cardiovascular adverse events and electrocardiogram (ECG) abnormalities. Studies were included in the review according to the following criteria: a) clinical trials (placebo-controlled or not) or case reports; b) short- or long-term interventions with antidepressants; c) prescription of newer generation antidepressants as first-line treatment; d) samples of adult or adult-old patients. From a total of 301 articles addressing the association between antidepressants and cardiovascular adverse events as primary or secondary outcomes, we selected 30 controlled clinical trials and 10 case reports. In most clinical studies, the effects of antidepressants on cardiac function are usually computed as secondary outcome variables, however with limited information. Conversely, case reports tend to present more comprehensive sets of clinical and laboratorial parameters, but the generalization of such data is limited by the small number of observations. The occurrence of QTc prolongation (with increased risk of torsade de pointes) has been reported. Aging, higher dosages of antidepressants, drug interaction, and pre-existing cardiovascular comorbidities were found as risk factors for the aforementioned cardiovascular and ECG abnormalities. Prescribing antidepressants requires caution given their potential impact on cardiac function, and the clinician should carefully monitor cardiovascular and ECG parameters particularly in cases with underlying heart disease.

Applying GRADE to a network meta-analysis of antidepressants led to more conservative conclusions

ObjectiveTo explore the impact of applying the Grading of Recommendations and Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of the evidence in a published network meta-analysis (NMA) of antidepressant therapies. Study design and settingsWe applied the GRADE approach to rate the certainty of the evidence for two outcomes, efficacy and acceptability, in each of the 66 paired comparisons within a previously published NMA assessing the relative efficacy and acceptability of 12 new-generation antidepressants. ResultsFor the outcome of efficacy, of the 25 comparisons in which the 95% CrI of OR excluded 1, 18 had certainty of evidence rated high or moderate. For the outcome of acceptability, of the 13 comparisons whose 95% CrI excluded 1, 10 had certainty of evidence rated high or moderate. Of the 11 comparisons involving sertraline, the antidepressants that the authors of the NMA suggested to be best, only 3 demonstrated it to be more effective and only 3 showed better tolerance, based on a 95% CrI excluding 1 and a high or moderate rating of certainty. ConclusionsIn this example, application of GRADE highlighted varying evidence certainty, led to more conservative conclusions, and potentially avoided unwarranted strong inferences based on low certainty evidence.