Antidepressant Treatment Research Articles

Ethyl acetate extract of Nymphaea candida Presl: A potential anti-depressant and neuroprotective treatment strategy

Nymphaea candida Presl (NC), traditionally used in medicine for heat syndrome-related ailments, possesses antioxidative, anti-inflammatory, hepatoprotective, and neuroprotective properties. This research investigates the antidepressant and neuroprotective effects and mechanisms of Nymphaea candida Presl ethyl acetate (NCEA). Primary components of NCEA were identified as phenolic acids and flavonoids through UPLC-MS/MS analysis. The depression mouse model was induced via intracerebroventricular injection of Lipopolysaccharide (LPS), followed by oral administration of fluoxetine and NCEA for one week. Biochemical assays and HE staining confirmed NCEA's non-toxicity and protective effects on the liver and lungs. NCEA administration mitigated LPS-induced depressive behaviors, decreased IL-1β, TNF-α levels in the hippocampus, suppressed microglial activation, reduced Iba-1 expression, and increased NA, brain-derived neurotrophic factor (BDNF), and dendritic spine density in the hippocampus. Furthermore, NCEA enhanced cell viability in a CORT-induced PC12 cell model, decreased lactate dehydrogenase (LDH) release rate, total superoxide dismutase (SOD) inhibition rate, intracellular nitric oxide (NO) release, and reduced reactive oxygen species (ROS) production. Our research findings suggest that NCEA exhibits significant antidepressant effects, which may be attributed to its reduction of neuroinflammation, improvement in neurotransmitter levels, neuronal protection, and antioxidative stress properties.

Repurposing Duloxetine as a Potent Butyrylcholinesterase Inhibitor: Potential Cholinergic Enhancing Benefits for Elderly Individuals with Depression and Cognitive Impairment.

Despite the advent of new treatment strategies, cholinesterase inhibitors (ChEIs) are still the go-to treatment for dementia disorders. ChEIs act by inhibiting the main acetylcholine-degrading enzyme, acetylcholinesterase (AChE). Nonetheless, accumulating evidence indicates that the impact of inhibition of the sister enzyme, butyrylcholinesterase (BChE), could be even broader in older adults due to the multifaceted role of BChE in several biological functional pathways. Therefore, we employed an in silico modeling-based drug repurposing strategy to identify novel potent BChE inhibitors from the FDA drug database. This was followed by in vitro screening and ex vivo enzyme kinetic validation using human plasma samples as the source of BChE. The analysis revealed that the antidepressant drug, duloxetine, inhibited BChE with high selectivity in comparison to AChE. In contrast, two other antidepressants, namely, citalopram and escitalopram exhibited a weak to moderate activity. Ex vivo enzyme inhibition kinetic analyses indicated that duloxetine acted as a competitive inhibitor of BChE with an inhibition constant (K i) of 210 nM. This K i value is comparable with 100-400 nM concentration of duloxetine following normal dosages in humans, thereby indicating that duloxetine should be able to induce a pharmacologically and biologically relevant in vivo inhibition of BChE. Additionally, we performed the enzyme inhibition kinetic assessment in parallel for ethopropazine, a known potent selective BChE inhibitor, and physostigmine, a dual inhibitor of AChE and BChE. These analyses indicated that duloxetine should be considered a potent BChE inhibitor since its K i was comparable with ethopropazine (K i = 150 nM) but was 4 times smaller than that of physostigmine (K i = 840 nM). In conclusion, this study reports the discovery of duloxetine being a highly potent selective competitive BChE inhibitor. This, in turn, indicates that duloxetine could be the choice of antidepressive treatment in older adults with both depressive and dementia symptoms since it may offer additional clinically beneficial effects via this secondary mode of cholinergic enhancing action.

Interaction Effect of Childhood Abuse History and Suicidality on 12-Month Antidepressant Response in Patients With Depressive Disorder.

We aimed to identify the individual and interactive effects of childhood abuse and suicidal ideation on antidepressant treatment response in 12 months. In this prospective research, 1,262 depressive patients were asked about their childhood abuse history, suicidal ideation, and other clinical characteristics and socio-demographic features at baseline, and 1,015 of them were followed during 1 year of stepwise pharmacotherapy. The individual and interactive relationships of the childhood abuse history and suicidal ideation on 12-month antidepressant non-remission were explored by logistic regression with relevant covariates. Having a childhood abuse history and higher suicidal ideation significantly predicted a non-remission state in 12 months respectively. The interaction term of childhood abuse and suicidal ideation was also significantly related to a non-remission state at 12 months. To be specific, in the low suicidal ideation group, depressive patients with a childhood abuse history were more likely to be in a non-remission state after 12 months of medication. In the high suicidal ideation group, however, childhood abuse history was not significantly associated with the non-remission state at 12 months. The childhood abuse history and the level of suicidal ideation are informative factors predicting the long-term results of antidepressant treatment, especially when they are combined. Clinicians may consider antidepressants with a higher affinity for patients with childhood abuse history even if they don't have suicidal ideation. The cognitive intervention for suicidal ideation might be helpful in addition to pharmacological treatment.

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.

Evaluating the Efficacy of a Digital Therapeutic (CT-152) as an Adjunct to Antidepressant Treatment in Adults With Major Depressive Disorder: Protocol for the MIRAI Remote Study.

Major depressive disorder (MDD) is common worldwide and can be highly disabling. People with MDD face many barriers to treatment and may not experience full symptom relief even when treated. Therefore, new treatment modalities are needed for MDD. Digital therapeutics (DTx) may provide people with MDD an additional treatment option. This study aimed to describe a phase 3 remote, multicenter, randomized, masked, sham-controlled trial evaluating the efficacy of a smartphone app-based DTx (CT-152) in adult participants diagnosed with MDD, used as an adjunct to antidepressant therapy (ADT). Participants aged 22-64 years with a current primary diagnosis of MDD and an inadequate response to ADT were included. Participants were randomized 1:1 to CT-152 or a sham DTx. CT-152 is a smartphone app-based DTx that delivers a cognitive-emotional and behavioral therapeutic intervention. The core components of CT-152 are the Emotional Faces Memory Task exercises, brief lessons to learn and apply key therapeutic skills, and SMS text messaging to reinforce lessons and encourage engagement with the app. The sham DTx is a digital working memory exercise with emotionally neutral stimuli designed to match CT-152 for time and attention. Participants took part in the trial for up to 13 weeks. The trial included a screening period of up to 3 weeks, a treatment period of 6 weeks, and an extension period of 4 weeks to assess the durability of the effect. Sites and participants had the option of an in-person or remote screening visit; the remaining trial visits were remote. Efficacy was evaluated using the Montgomery-Åsberg Depression Rating Scale, the Generalized Anxiety Disorder-7, Clinical Global Impression-Severity scale, the Patient Health Questionnaire-9, and the World Health Organization Disability Assessment Schedule 2.0. The durability of the effect was evaluated with the Montgomery-Åsberg Depression Rating Scale and Generalized Anxiety Disorder-7 scale. Adverse events were also assessed. Satisfaction, measured by the Participant and Healthcare Professional Satisfaction Scales, and health status, measured by the EQ-5D-5L, were summarized using descriptive statistics. This study was initiated in February 2021 and had a primary completion date in October 2022. This represents the methodological design for the first evaluation of CT-152 as an adjunct to ADT. This study protocol is methodologically robust and incorporates many aspects of conventional pivotal pharmaceutical phase 3 trial design, such as randomization and safety end points. Novel considerations included the use of a sham comparator, masking considerations for visible app content, and outcome measures relevant to DTx. The rigor of this methodology will provide a more comprehensive understanding of the effectiveness of CT-152. ClinicalTrials.gov NCT04770285; https://clinicaltrials.gov/study/NCT04770285. RR1-10.2196/56960.

Research progress on intestinal flora and depression

In recent years, the prevalence of depression and suicide rates have continued to increase, especially among adolescents, and existing treatment methods are still incomplete and have certain limitations. Although some progress has been made in studying the relationship between gut microbiota and depression, a clear explanation of the physiological mechanisms of the "Microbiota-Gut-Brain Axis" (MGBA) and a review of treatments for depression based on MGBA regulation are still lacking. This article examines the traits of the gut microbiota in patients with depression, highlighting that their richness and diversity are significantly lower compared to healthy controls. The neurological, endocrine and immune mechanisms of MGBA and its role in the pathogenesis of depression were further explored. This article also reviews MGBA-based treatments, such as Fecal Microbiota Transplantation (FMT) and probiotic therapy, noting their potential efficacy in alleviating depressive symptoms. This article unveils the pivotal role of gut microbiota in the development of depression, offering a new avenue for researching the pathological mechanisms of the disorder and laying a scientific foundation for creating novel antidepressant treatments. At present, there is no consistent conclusion about the changes in the composition of the intestinal flora in depression. Future studies can expand the sample size and conduct experiments on different groups to deeply reveal the changes in the intestinal flora of patients with depression.

Glycolytic metabolism: Food for immune cells, fuel for depression?

Inflammation is one biological pathway thought to impact the brain to contribute to major depressive disorder (MDD) and is reliably associated with resistance to standard antidepressant treatments. While peripheral immune cells, particularly monocytes, have been associated with aspects of increased inflammation in MDD and symptom severity, significant gaps in knowledge exist regarding the mechanisms by which these cells are activated to contribute to behavioral symptoms in MDD. One concept that has gained recent appreciation is that metabolic rewiring to glycolysis in activated myeloid cells plays a crucial role in facilitating these cells’ pro-inflammatory functions, which may underlie myeloid contribution to systemic inflammation and its effects on the brain. Given emerging evidence from translational studies of depression that peripheral monocytes exhibit signs of glycolytic activation, better understanding the immunometabolic phenotypes of monocytes which are known to be elevated in MDD with high inflammation is a critical step toward comprehending and treating the impact of inflammation on the brain. This narrative review examines the extant literature on glycolytic metabolism of circulating monocytes in depression and discusses the functional implications of immunometabolic shifts at both cellular and systemic levels. Additionally, it proposes potential therapeutic applications of existing immunomodulators that target glycolysis and related metabolic pathways in order to reverse the impact of elevated inflammation on the brain and depressive symptoms.

Charles Bonnet Syndrome asssociated with glaucoma in a 95-year old female: A case report

Vision problems increase with age and evaluation of visual perception is important in geriatric practice. Visual hallucinations may occur in elderly individuals for various reasons. Hallucinations secondary to loss of severe visual acuity or visual field, also known as Charles Bonnet Syndrome(CBS), may be rarely seen. We reported a case of CBS secondary to glaucoma in a 95-year-old female patient. It is stated that this patient's visual hallucination has been developing for the last 3 years. The patient had simple hallucinations that were not related to dementia or psychotic disorder. The patient had accompanying depressive mood and fear of being alone. Visual hallucinations decreased after antidepressant treatment. The oldest known case of CBS is presented.

The effect of vortioxetine on faecal microbiota in high-fat diet-exposed mice-A link to weight protection.

Weight gain is a common side effect of antidepressive treatment, causing distress among patients and caretakers as it can lead to treatment discontinuation and complications such as diabetes type II and cardiovascular disease. Vortioxetine is one of the newer antidepressants and the pharmacodynamics differ from the selective serotonin reuptake inhibitors. It is marketed as being weight neutral; however, there is little evidence as to why. In recent years, there has been an increased focus on the faecal microbiota and its impact on body weight and mental and physical health. In the current work, we examine the effect of vortioxetine on weight gain and faecal microbiota composition. Forty male C57BL/6NTac mice were primed for 8 weeks with a high-fat diet (Hfd) or control diet (Cd), followed by a 4-week period on the same diet and additional +/- vortioxetine 10 mg/kg/daily. Vortioxetine reduced Hfd-induced weight gain (Hfd + V: 8.2%, Hfd - V: 12.7%; p=0.0374) but did not affect weight gain of the control group (Cd + V: 7.54%, Cd - V: 7.56%; p=0.4944). Significant differences in faecal microbiota were observed in mice who received vortioxetine. Vortioxetine caused significant changes to the faecal microbiota composition and appeared to limit Hfd-induced weight gain.

Hypocretin-1/Hypocretin Receptor 1 Regulates Neuroplasticity and Cognitive Function through Hippocampal Lactate Homeostasis in Depressed Model.

Cognitive dysfunction is not only a common symptom of major depressive disorder, but also a more common residual symptom after antidepressant treatment and a risk factor for chronic and recurrent disease. The disruption of hypocretin regulation is known to be associated with depression, however, their exact correlation is remains to be elucidated. Hypocretin-1 levels are increased in the plasma and hypothalamus from chronic unpredictable mild stress (CUMS) model mice. Excessive hypocretin-1 conducted with hypocretin receptor 1 (HCRTR1) reduced lactate production and brain-derived neurotrophic factor (BDNF) expression by hypoxia-inducible factor-1α (HIF-1α), thus impairing adult hippocampal neuroplasticity, and cognitive impairment in CUMS model. Subsequently, it is found that HCRTR1 antagonists can reverse these changes. The direct effect of hypocretin-1 on hippocampal lactate production and cognitive behavior is further confirmed by intraventricular injection of hypocretin-1 and microPET-CT in rats. In addition, these mechanisms are further validated in astrocytes and neurons in vitro. Moreover, these phenotypes and changes in molecules of lactate transport pathway can be duplicated by specifically knockdown of HCRTR1 in hippocampal astrocytes. In summary, the results provide molecular and functional insights for involvement of hypocretin-1-HCRTR1 in altered cognitive function in depression.

Brain region-specific action of ketamine as a rapid antidepressant.

Ketamine has been found to have rapid and potent antidepressant activity. However, despite the ubiquitous brain expression of its molecular target, the N-methyl-d-aspartate receptor (NMDAR), it was not clear whether there is a selective, primary site for ketamine's antidepressant action. We found that ketamine injection in depressive-like mice specifically blocks NMDARs in lateral habenular (LHb) neurons, but not in hippocampal pyramidal neurons. This regional specificity depended on the use-dependent nature of ketamine as a channel blocker, local neural activity, and the extrasynaptic reservoir pool size of NMDARs. Activating hippocampal or inactivating LHb neurons swapped their ketamine sensitivity. Conditional knockout of NMDARs in the LHb occluded ketamine's antidepressant effects and blocked the systemic ketamine-induced elevation of serotonin and brain-derived neurotrophic factor in the hippocampus. This distinction of the primary versus secondary brain target(s) of ketamine should help with the design of more precise and efficient antidepressant treatments.

Omega-3 Polyunsaturated Fatty Acids in Depression.

Omega-3 polyunsaturated fatty acids have received considerable attention in the field of mental health, in particular regarding the treatment of depression. This review presents an overview of current research on the role of omega-3 fatty acids in the prevention and treatment of depressive disorders. The existing body of evidence demonstrates that omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have antidepressant effects that can be attributed to their modulation of neuroinflammation, neurotransmitter function, and neuroplasticity. Nevertheless, clinical trials of omega-3 supplementation have yielded inconsistent results. Some studies have demonstrated significant reductions in depressive symptoms following omega-3 treatment, whereas others have shown minimal to no beneficial impact. A range of factors, encompassing dosage, the ratio of EPA to DHA, and baseline nutritional status, have been identified as having a potential impact on the noted results. Furthermore, it has been suggested that omega-3 fatty acids may act as an adjunctive treatment for those undergoing antidepressant treatment. Notwithstanding these encouraging findings, discrepancies in study designs and variability in individual responses underscore the necessity of further research in order to establish uniform, standardized guidelines for the use of omega-3 fatty acids in the management of depressive disorders.

RTMS as a Next Step in Antidepressant Nonresponders: A Randomized Comparison With Current Antidepressant Treatment Approaches.

Although repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, little is known about the comparative effectiveness of rTMS and other treatment options, such as antidepressants. In this multicenter randomized controlled trial, rTMS was compared with the next pharmacological treatment step in patients with treatment-resistant depression. Patients with unipolar nonpsychotic depression (N=89) with an inadequate response to at least two treatment trials were randomized to treatment with rTMS or to a switch of antidepressants, both in combination with psychotherapy. Treatment duration was 8 weeks and consisted of either 25 high-frequency rTMS sessions to the left dorsolateral prefrontal cortex or a switch of antidepressant medication following the Dutch treatment algorithm. The primary outcome was change in depression severity based on the Hamilton Depression Rating Scale (HAM-D). Secondary outcomes were response and remission rates as well as change in symptom dimensions (anhedonia, anxiety, sleep, rumination, and cognitive reactivity). Finally, expectations regarding treatment were assessed. rTMS resulted in a significantly larger reduction in depressive symptoms than medication, which was also reflected in higher response (37.5% vs. 14.6%) and remission (27.1% vs. 4.9%) rates. A larger decrease in symptoms of anxiety and anhedonia was observed after rTMS compared with a switch in antidepressants, and no difference from the medication group was seen for symptom reductions in rumination, cognitive reactivity, and sleep disorders. Expectations regarding treatment correlated with changes in HAM-D scores. In a sample of patients with moderately treatment-resistant depression, rTMS was more effective in reducing depressive symptoms than a switch of antidepressant medication. In addition, the findings suggest that the choice of treatment may be guided by specific symptom dimensions.

Effect of Antidepressant Treatment on 5-HT4 Receptor Binding and Associations With Clinical Outcomes and Verbal Memory in Major Depressive Disorder

BackgroundBrain serotonin 4 receptor (5-HT4R) levels are lower in untreated patients with major depressive disorder (MDD) and are linked to verbal memory. Here, we investigated the relationship between 5-HT4R levels, clinical outcomes, and cognitive function in patients with MDD who initiated selective serotonin reuptake inhibitor drug treatment. MethodsNinety patients with moderate to severe depression underwent molecular brain imaging to measure 5-HT4R binding prior to antidepressant treatment with escitalopram. Pretreatment 5-HT4R binding was assessed for its ability to predict treatment outcome at weeks 4, 8, or 12. In 40 patients who were rescanned 8 weeks posttreatment, change in cerebral 5-HT4R binding was correlated with change in verbal memory and with change in depressive symptoms, as evaluated by the 6-item Hamilton Depression Rating Scale. ResultsAfter 8 weeks of serotonergic intervention, neostriatal 5-HT4R binding was reduced by 9%. Global change in 5-HT4R binding from baseline was associated with verbal memory outcomes, but not with overall clinical depressive symptom outcomes. Pretreatment 5-HT4R binding did not predict clinical recovery status at week 8 and was not associated with change in the 6-item Hamilton Depression Rating Scale scores. ConclusionsIn patients with moderate to severe MDD, treatment with selective serotonin reuptake inhibitors downregulated neostriatal 5-HT4R levels, which is consistent with the notion that the drugs increase cerebral extracellular serotonin. The less global brain 5-HT4R levels were downregulated after selective serotonin reuptake inhibitors, the more verbal memory improved, highlighting the potential importance of 5-HT4R as a treatment target in MDD. The findings offer insights into mechanisms that underlie antidepressant effects and point to new directions for precision medicine treatments for MDD.

Antidepressant treatment initiation among children and adolescents with acute versus long COVID: a large retrospective cohort study

BackgroundChild and adolescent antidepressant use increased post-pandemic, but it is unknown if this disproportionally affected those who develop post-acute sequelae of coronavirus disease 2019 (COVID) or long COVID. This study compared the risk of antidepressant initiation among children and adolescents with long COVID with those who had COVID but did not have evidence of long COVID.MethodsOur retrospective cohort study of children and adolescents aged 3–17 years at the first evidence of COVID or long COVID from October 1, 2021 through April 4, 2022 was conducted within Komodo’s Healthcare Map™ database. The index date was the earliest date of a medical claim associated with a COVID (COVID comparators) or long COVID diagnosis (long COVID cases). The baseline period was six months before the index date. The outcome was antidepressant initiation within twelve months after the index date. Due to the large number of COVID relative to long COVID cases, COVID comparators were randomly selected with a ratio of 2 COVID to 1 long COVID. We used propensity score matching to control for confounding due to imbalances in the baseline covariates. Log-binomial models estimated the relative risk (RR) of antidepressant initiation in the propensity score matched sample. We conducted several sensitivity analyses to test the robustness of our findings to several assumptions.ResultsOur child and adolescent sample included 18 274 with COVID and 9137 with long COVID. Compared with those with COVID, a larger proportion of long COVID children and adolescents had psychiatric disorders, psychotropic use, medical comorbidities, were previously hospitalized, or visited the emergency department. In the propensity score-adjusted analysis, the long COVID group had a statistically significant higher risk of antidepressant initiation relative to the COVID comparator (adjusted-RR: 1.40, 95% CI = 1.20, 1.62). Our findings were robust across sensitivity analyses.ConclusionsThe increased risk of antidepressant initiation following long COVID warrants further study to better understand the underlying reasons for this higher risk. Emerging evidence of long COVID’s impact on child mental health has important implications for prevention and early interventions.

INVESTIGATION OF THE EFFECT OF THE ONSET OF BRUXISM AS A RESULT OF EARLY ANTIDEPRESSANT USE

Among antidepressants, selective serotonin and noradrenaline reuptake inhibitors (SSRIs and SNRIs) have been widely used in the treatment of major depression and may induce sleep disorders and bruxism. In the present study, the effects of SSRIs and SNRIs on awake and sleep bruxism have been evaluated. A total of 125 patients who had been prescribed SSRIs or SNRIs for the treatment of major depression have been evaluated for bruxism. For the purpose of the study, data from the first week (T1) and the fourth week (T2) of antidepressant treatment have been considered. In conclusion, in the early period, the presence of bruxism has not been observed to be significantly influenced by the use of antidepressants. It has been determined that sleep bruxism increased in the fourth week only in males who were using antidepressants (p = 0.015; p < 0.05). An increase in the presence of sleep bruxism due to specific SSRIs and SNRIs has been determined in the fourth week of drug use. Paroxetine in the SSRI group and duloxetine in the SNRI group have been found to cause an increase in sleep bruxism (p = 0.013; p < 0.05). Other active substances have not been found to affect sleep or awake bruxism significantly. The present study has shown that although some antidepressants increase bruxism in the early period of drug use, the effects of similar drugs on sleep or awake bruxism need to be evaluated in detail in long-term studies.

An Updated Review on Possible Therapeutic Role of Vincamine Via 5-HT Receptors in the Treatment of Depression

Background: Serotonin is a neurotransmitter that regulates neuronal activity and a variety of cognitive functions, and medicines that target serotonin receptors are frequently utilized in psychiatry and neurology. Clinical and preclinical research on the role of serotonin in major depressive disorder is growing. These findings demonstrate the intricacy of serotonin transmission across multiple receptors, in a variety of brain areas, and across the lifespan. The serotonin transporter's significance in major depressive disorder has been highlighted in geneenvironment association studies, as well as its participation in the mechanism of the most successful antidepressant medications, selective serotonin reuptake inhibitors. While most of the 15 known serotonin receptors have been linked to depression or depressive-like behaviour, the serotonin 1A (5-HT) and 1B (5-HT) receptors have received the most attention. Objectives: The primary goal of this study is to review the antidepressant effect of herbal medications by modifying serotonin receptors in the future. Result: Human brain imaging and genetic studies suggest that 5-HT and 5-HT receptors play a role in major depressive disorder and antidepressant treatment response. The availability of tissue-specific and inducible knockout mice lines in rodents has allowed for the detection of 5- HT and 5-HT receptor involvement throughout development and in cell-type specific ways. It may be found that herbal drugs will be effective as the serotonin reuptake inhibitors. Conclusion: This and other future preclinical pharmacology studies show that these receptors' autoreceptor and heteroreceptor populations play different roles in modulating depressionrelated behaviour and antidepressant responses, as well as having different functions during early postnatal development versus adulthood. According to analysis of our research findings, alkaloids may have some therapeutic promise as natural antidepressants. Given their widespread distribution in nature, alkaloids might be a cheap way to treat depression.

The Antidepressant Action of Fluoxetine Involves the Inhibition of Dlx5/6 in Cortical GABAergic Neurons through a TrkB-Dependent Pathway.

Major depressive disorder (MDD) is a complex and devastating illness that affects people of all ages. Despite the large use of antidepressants in current medical practice, neither their mechanisms of action nor the aetiology of MDD are completely understood. Experimental evidence supports the involvement of Parvalbumin-positive GABAergic neurons (PV-neurons) in the pathogenesis of MDD. DLX5 and DLX6 (DLX5/6) encode two homeodomain transcription factors involved in cortical GABAergic differentiation and function. In the mouse, the level of expression of these genes is correlated with the cortical density of PV-neurons and with anxiety-like behaviours. The same genomic region generates the lncRNA DLX6-AS1, which, in humans, participates in the GABAergic regulatory module downregulated in schizophrenia and ASD. Here, we show that the expression levels of Dlx5/6 in the adult mouse brain are correlated with the immobility time in the forced swim test, which is used to measure depressive-like behaviours. We show that the administration of the antidepressant fluoxetine (Flx) to normal mice induces, within 24 h, a rapid and stable reduction in Dlx5, Dlx6 and Dlx6-AS1 expression in the cerebral cortex through the activation of the TrkB-CREB pathway. Experimental Dlx5 overexpression counteracts the antidepressant effects induced by Flx treatment. Our findings show that one of the short-term effects of Flx administration is the reduction in Dlx5/6 expression in GABAergic neurons, which, in turn, has direct consequences on PV expression and on behavioural profiles. Variants in the DLX5/6 regulatory network could be implicated in the predisposition to depression and in the variability of patients' response to antidepressant treatment.

An online evidence-based dictionary of common adverse events of antidepressants: a new tool to empower patients and clinicians in their shared decision-making process

BackgroundAdverse events (AEs) are commonly reported in clinical studies using the Medical Dictionary for Regulatory Activities (MedDRA), an international standard for drug safety monitoring. However, the technical language of MedDRA makes it challenging for patients and clinicians to share understanding and therefore to make shared decisions about medical interventions. In this project, people with lived experience of depression and antidepressant treatment worked with clinicians and researchers to co-design an online dictionary of AEs associated with antidepressants, taking into account its ease of use and applicability to real-world settings.MethodsThrough a pre-defined literature search, we identified MedDRA-coded AEs from randomised controlled trials of antidepressants used in the treatment of depression. In collaboration with the McPin Foundation, four co-design workshops with a lived experience advisory panel (LEAP) and one independent focus group (FG) were conducted to produce user-friendly translations of AE terms. Guiding principles for translation were co-designed with McPin/LEAP members and defined before the finalisation of Clinical Codes (CCs, or non-technical terms to represent specific AE concepts). FG results were thematically analysed using the Framework Method.ResultsStarting from 522 trials identified by the search, 736 MedDRA-coded AE terms were translated into 187 CCs, which balanced key factors identified as important to the LEAP and FG (namely, breadth, specificity, generalisability, patient-understandability and acceptability). Work with the LEAP showed that a user-friendly language of AEs should aim to mitigate stigma, acknowledge the multiple levels of comprehension in ‘lay’ language and balance the need for semantic accuracy with user-friendliness. Guided by these principles, an online dictionary of AEs was co-designed and made freely available (https://thesymptomglossary.com). The digital tool was perceived by the LEAP and FG as a resource which could feasibly improve antidepressant treatment by facilitating the accurate, meaningful expression of preferences about potential harms through a shared decision-making process.ConclusionsThis dictionary was developed in English around AEs from antidepressants in depression but it can be adapted to different languages and cultural contexts, and can also become a model for other interventions and disorders (i.e., antipsychotics in schizophrenia). Co-designed digital resources may improve the patient experience by helping to deliver personalised information on potential benefits and harms in an evidence-based, preference-sensitive way.

Understanding profiles of patients with treatment-resistant depression by stringency of health plan prior authorization criteria for approval of esketamine nasal spray

Objectives In the United States (US), prescription drug coverage is subject to prior authorization (PA) criteria, which may vary between health plans and may exceed drug label requirements. This study aimed to characterize profiles and treatment history of patients with treatment-resistant depression (TRD) who initiated esketamine nasal spray, by stringency of their health plans’ PA criteria relative to the esketamine label. Methods Adults with evidence of TRD (≥2 antidepressant courses of adequate dose and duration) prior to initiating esketamine were identified using US insurance claims data (03/2016–02/2022). Based on health plan PA criteria for esketamine obtained from Managed Markets Insight & Technology data (05/2020–02/2022), patients were grouped into stringent (PA criteria exceeds label) and non-stringent (PA criteria less stringent or equal to label) cohorts. Patient treatment history before esketamine initiation was compared using Wilcoxon rank sum and Fisher’s exact tests. Results The stringent cohort included 168 patients (mean age: 45 years, 63% female) and the non-stringent cohort included 400 patients (mean age: 45 years, 70% female). During the ongoing major depressive episode before esketamine initiation, the stringent versus non-stringent cohort completed 3.9 versus 3.8 antidepressant treatment courses, on average (p = 0.217); 94.6% versus 96.8% used augmentation therapy (p = 0.240), including 59.3% versus 58.1% with an antipsychotic (p = 0.844), respectively. Conclusions Regardless of health plan stringency, on average, patients exceeded US label-mandated number of antidepressant trials before esketamine initiation, which questions the need for health insurance plans PA criteria above label.