Genetic factors and symptom dimensions associated with antidepressant treatment outcomes: clues for new potential therapeutic targets?

Treatment response and resistance in major depressive disorder (MDD) show a significant genetic component, but previous studies had limited power also due to MDD heterogeneity. This literature review focuses on the genetic factors associated with treatment outcomes in MDD, exploring their overlap with those associated with clinically relevant symptom dimensions. We searched PubMed for: (1) genome-wide association studies (GWASs) or whole exome sequencing studies (WESs) that investigated efficacy outcomes in MDD; (2) studies examining the association between MDD treatment outcomes and specific depressive symptom dimensions; and (3) GWASs of the identified symptom dimensions. We identified 13 GWASs and one WES of treatment outcomes in MDD, reporting several significant loci, genes, and gene sets involved in gene expression, immune system regulation, synaptic transmission and plasticity, neurogenesis and differentiation. Nine symptom dimensions were associated with poor treatment outcomes and studied by previous GWASs (anxiety, neuroticism, anhedonia, cognitive functioning, melancholia, suicide attempt, psychosis, sleep, sociability). Four genes were associated with both treatment outcomes and these symptom dimensions: CGREF1 (anxiety); MCHR1 (neuroticism); FTO and NRXN3 (sleep). Other overlapping signals were found when considering genes suggestively associated with treatment outcomes. Genetic studies of treatment outcomes showed convergence at the level of biological processes, despite no replication at gene or variant level. The genetic signals overlapping with symptom dimensions of interest may point to shared biological mechanisms and potential targets for new treatments tailored to the individual patient's clinical profile.

An interdisciplinary intervention for detection of sexual dysfunction associated with antidepressants: A pilot study.

Introduction: Treatment-emergent sexual dysfunction (TESD) is a commonly reported side effect of antidepressant medications in clinical trials. Limited literature exists exploring the role of routine use of the Arizona Sexual Experience Scale (ASEX) in identification of TESD in clinical practice. Therefore, we completed a retrospective study with the primary goal of capturing the rates of sexual dysfunction associated with antidepressant use among adult patients at an outpatient encounter with a psychiatric clinical pharmacist between June 2020 and March 2022. Methods: Rates of identification of sexual dysfunction were compared pre-ASEX survey (June 2020 to June 2021) to post-ASEX survey (July 2021 to March 2022). Results: There was a significant increase in the identification of sexual dysfunction following implementation of the ASEX scale (10% in the pre-ASEX group versus 59% meeting sexual dysfunction criteria with the ASEX scale). Approximately 70% of patients in the post-ASEX group shared they would not have reported symptoms unless directly asked. Discussion: In conclusion, a validated survey (ASEX) in an ambulatory psychiatry clinic improves identification of sexual dysfunction associated with antidepressants. Use of interdisciplinary care teams in the setting of medication follow-up can assist with identifying tolerability concerns between visits with patients' prescribing clinicians.

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

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Association between a selective 5-HT4 receptor agonist and incidence of major depressive disorder: emulated target trial.

BACKGROUND: The serotonin 4 receptor (5-HT4R) is a promising target for the treatment of depression. Highly selective 5-HT4R agonists, such as prucalopride, have antidepressant-like and procognitive effects in preclinical models, but their clinical effects are not yet established. AIMS: To determine whether prucalopride (a 5-HT4R agonist and licensed treatment for constipation) is associated with reduced incidence of depression in individuals with no past history of mental illness, compared with anti-constipation agents with no effect on the central nervous system. METHOD: Using anonymised routinely collected data from a large-scale USA electronic health records network, we conducted an emulated target trial comparing depression incidence over 1 year in individuals without prior diagnoses of major mental illness, who initiated treatment with prucalopride versus two alternative anti-constipation agents that act by different mechanisms (linaclotide and lubiprostone). Cohorts were matched for 121 covariates capturing sociodemographic factors, and historical and/or concurrent comorbidities and medications. The primary outcome was a first diagnosis of major depressive disorder (ICD-10 code F32) within 1 year of the index date. Robustness of the results to changes in model and population specification was tested. Secondary outcomes included a first diagnosis of six other neuropsychiatric disorders. RESULTS: Treatment with prucalopride was associated with significantly lower incidence of depression in the following year compared with linaclotide (hazard ratio 0.87, 95% CI 0.76-0.99; P = 0.038; n = 8572 in each matched cohort) and lubiprostone (hazard ratio 0.79, 95% CI 0.69-0.91; P < 0.001; n = 8281). Significantly lower risks of all mood disorders and psychosis were also observed. Results were similar across robustness analyses. CONCLUSIONS: These findings support preclinical data and suggest a role for 5-HT4R agonists as novel agents in the prevention of major depression. These findings should stimulate randomised controlled trials to confirm if these agents can serve as a novel class of antidepressant within a clinical setting.

Nanocarrier drug delivery system: promising platform for targeted depression therapy.

Depression is a chronic mental disorder characterized by persistent low mood and loss of interest. Treatments for depression are varied but may not be sufficient cure. Drug-based treatment regimens have drawbacks such as slow onset of action, low bioavailability, and drug side effects. Nanocarrier Drug Delivery Systems (NDDS) has received increasing attention for brain drug delivery since it assists the drug through the blood-brain barrier and improves bioavailability, which may be beneficial for treating depression. Due to the particle size and physicochemical properties of nanocarriers, it presents a promise to improve the stability and solubility of antidepressants, thereby enhancing the drug concentration. Moreover, ligand-modified nanocarriers can be taken as a target direct medicines release system and reduce drug side effects. The purpose of the present review is to provide an up-to-date understanding of the Nanocarrier drug delivery system and relevant antidepressants in different routes of ingestion, to lay a foundation for the treatment of patients with depression.

Serotoninergic antidepressants combination in psilocybin-assisted psychotherapy: a case report.

Psilocybin has reemerged as a promising treatment for difficult-to-treat depression (DTD). Although there is limited evidence regarding interactions between psilocybin and other psychotropic drugs, clinical trials require that patients discontinue their antidepressants before study entry to isolate the benefits of psilocybin and to minimize the risk of adverse events. We present the first case of an adult patient with DTD who received psilocybin-assisted psychotherapy (PAP) in combination with two serotoninergic antidepressants (duloxetine and vortioxetine). Since he displayed a partial response after the first PAP session, he agreed to discontinue duloxetine (but refused to stop vortioxetine) before the second PAP session to see if it could improve the therapeutic efficacy of psilocybin. However, his anxiety and depressive symptoms worsened. Psilocybin was well-tolerated in both PAP sessions; mild headaches were the main adverse effects experienced by the patient, and there were no cardiovascular safety concerns. This case report suggests that serotoninergic antidepressants combination with psilocybin appears to be safe and that antidepressant discontinuation prior to PAP may not be necessary. Since the continuation of antidepressants during PAP has the potential to improve treatment acceptability and accessibility, future research should assess whether psilocybin can be administered concurrently with antidepressants.

Diphenhydramine Intoxication With Blood Extended Half-Life and a False Positive Result for Tricyclic Antidepressants.

Diphenhydramine is a first-generation antihistamine medication. Acute intoxication with diphenhydramine can be severe and potentially fatal. The current case is of a 13-year-old girl who presented with central nervous system depression after voluntary intake of unknown drugs. Serum concentration analysis showed diphenhydramine intoxication, blood half-life extension, and a false positive result for tricyclic antidepressants (TCAs) in urine examination. To our knowledge, this is the first reported case of confirmed diphenhydramine overdose with a false positive result for TCAs and measurement of the serum level in a child. Considering the similarities between the clinical symptoms of diphenhydramine and TCA intoxication, this case illustrates that all physicians should consider the possibility of cross-reactivity during the diagnosis of patients with unknown acute drug intoxication who test positive for TCAs.

Hyponatremia in geriatric patients.

Hyponatremia is the most frequent electrolyte imbalance in geriatric medicine. Causes of hyponatremia were retrospectively analyzed in all in-patients treated in 2016 (N = 2267, 1564 women, 703 men, mean age ± standard deviation 81.9 ± 7.6 years). Any form of hyponatremia on admission, during the stay or on discharge was noted in 308 patients (13.6%, 231 women, 77 men; mean age ± standard deviation 83.1 ± 7.3 years, p = 0.009 vs. age of all patients). Women had a higher probability of developing hyponatremia compared to men (p = 0.019), 131 patients were hypovolemic, and dyspnea as an indicator of hypervolemia was noted in 71 patients.Only 12 patients suffering from hyponatremia (3.9%) did not receive any of the potentially sodium-lowering drugs assessed (diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, antidepressants, neuroleptics, nonsteroidal antirheumatics, carbamazepine, oxcarbazepine). The median number of drugs per patient potentially lowering the plasma sodium level was 3 and the maximum number was 7.Hypovolemic hyponatremia and the syndrome of inadequate antidiuretic hormone secretion were the most important causes of hyponatremia. Adverse drug effects were the main origins of both conditions. In patients with hyponatremia the drug load influencing plasma sodium level should be minimized, thiazide diuretics should be avoided and older individuals should receive a diet with sufficient salt content.

Effects of ketamine on GABAergic and glutamatergic activity in the mPFC: biphasic recruitment of GABA function in antidepressant-like responses.

Major depressive disorder (MDD) is associated with disruptions in glutamatergic and GABAergic activity in the medial prefrontal cortex (mPFC), leading to altered synaptic formation and function. Low doses of ketamine rapidly rescue these deficits, inducing fast and sustained antidepressant effects. While it is suggested that ketamine produces a rapid glutamatergic enhancement in the mPFC, the temporal dynamics and the involvement of GABA interneurons in its sustained effects remain unclear. Using simultaneous photometry recordings of calcium activity in mPFC pyramidal and GABA neurons, as well as chemogenetic approaches in Gad1-Cre mice, we explored the hypothesis that initial effects of ketamine on glutamate signaling trigger subsequent enhancement of GABAergic responses, contributing to its sustained antidepressant responses. Calcium recordings revealed a biphasic effect of ketamine on activity of mPFC GABA neurons, characterized by an initial transient decrease (phase 1, <30 min) followed by an increase (phase 2, >60 min), in parallel with a transient increase in excitation/inhibition levels (10 min) and lasting enhancement of glutamatergic activity (30-120 min). Previous administration of ketamine enhanced GABA neuron activity during the sucrose splash test (SUST) and novelty suppressed feeding test (NSFT), 24 h and 72 h post-treatment, respectively. Chemogenetic inhibition of GABA interneurons during the surge of GABAergic activity (phase 2), or immediately before the SUST or NSFT, occluded ketamine's behavioral actions. These results indicate that time-dependent modulation of GABAergic activity is required for the sustained antidepressant-like responses induced by ketamine, suggesting that approaches to enhance GABAergic plasticity and function are promising therapeutic targets for antidepressant development.

Exploring women's perception and attitude towards antidepressant use: a cross-sectional study.

BACKGROUND: The World Health Organization reports that depression affects more than 280 million people globally. Women are approximately 50% more likely to experience depression compared to men. Depression during pregnancy leads to deterioration of the mother's and the fetus's health. We aim to explore women's perceptions and attitudes toward using antidepressants and to identify the factors that influence decision-making regarding antidepressant use. METHOD: A cross-sectional survey, employing a convenience sampling method, was conducted on a university campus in Riyadh, Saudi Arabia. The survey was developed by the investigators and validated by health practitioners. Answers were reported using a 5-point Likert scale. The responses were summed up to give a total score for each respondent. Respondents who scored above or equal 75% of the total score was considered positive perception or favorable attitude. Binary logistic regression analysis was used to identify factors influencing participants' perception and attitude toward taking antidepressants. RESULTS: A total of 991 subjects were surveyed. The majority of women had negative perceptions and favorable attitudes towards using antidepressants during pregnancy reaching 64%. While women with positive perceptions and favorable attitudes represented about 20% of the study subjects. Participants reported that social stigma, religious beliefs, and fear of addiction significantly influenced their attitudes toward antidepressant use. CONCLUSIONS: This study explores women's perceptions of depression and antidepressant use, revealing that a significant proportion of Saudi women have a negative perception. The research emphasizes the need for tailored awareness programs to promote informed decision-making regarding antidepressant usage among Saudi women.

Patterns of antidepressant prescribing and health-related outcomes among older adults in Northern Ireland: an administrative data study.

OBJECTIVES: This study identifies patterns of antidepressant prescribing and subsequent hospital admissions from 2010 to 2018 amongst older adults in Northern Ireland (NI). METHOD: Participants comprised all General Practitioner (GP)-registered adults aged fifty-five years and above on 01/01/2010 (n = 386,119). Administrative data linkage included demographic information; antidepressant prescribing data from the NI Enhanced Prescribing Database (EPD); and hospital patient admissions. Repeated measures latent class analysis (RMLCA) identified patterns of antidepressant prescribing (from 2010 to 2018). RESULTS: RMLCA identified four latent classes: decreasing antidepressant prescribing (5.9%); increasing antidepressant prescribing (8.0%); no-antidepressant prescribing (68.7%); and long-term antidepressant prescribing (17.5%). Compared with those in no-antidepressant prescribing class, persons in the remaining classes were more likely to be female and younger, and less likely to live in either rural areas or less-deprived areas. Compared with no-antidepressant prescribing, those with increasing antidepressant prescribing were 60% and 52% more likely to be admitted to hospital in 2019 and 2020, respectively, and their admission rate per year was 11% and 8% higher in 2019 and 2020, respectively. Similarly, those with long-term prescriptions were 70% and 67% more likely to be admitted to hospital in 2019 and 2020, respectively, and their admission rate per year was 14% and 9% higher in 2019 and 2020, respectively. CONCLUSION: Findings show that approximately 26% of the NI hospital admissions population were impacted by sustained or increasing antidepressant prescribing. Because of their increased likelihood of hospitalization, these individuals may benefit from psychosocial support and social prescribing alternatives to psychopharmacological treatment.

Antidepressants for treating depression among older adults with dementia: A systematic review and meta-analysis.

BACKGROUND: Depression and dementia represent significant health challenges in older adults. Despite guidelines recommending antidepressants, their efficacy in depressed patients with dementia remains undetermined. OBJECTIVE: This review, in following a living systematic review approach, primarily aims to determine the effect of any-type antidepressant on the level of depressive symptoms in older adults with dementia and secondly if there is an effect of any-type antidepressants on cognitive state, quality of life, and functionality in the old-age population with dementia. METHODS: Systematic review and meta-analysis of RCTs from Medline, Embase, and Cochrane Register. Participants were ≥65 years, with both depression and any type of dementia. Certainty-of-Evidence was assessed through the Cochrane Risk-of-Bias tool and GRADE. Analysis involved standardized mean difference, with 95 % confidence-intervals (CIs). FINDINGS: Of the 27,771 screened articles, 8 studies (617 participants), treated with SSRI, SSNRI, atypical, and tricyclic antidepressants were retained for quantitative synthesis. No evidence for an effect was found (SMD -0.10 [-0.26, 0.07]), nor when subgrouped based on depression severity or dementia level, nor for secondary outcomes. INTERPRETATION: This review did not find evidence of a clinical effect of antidepressants for treating depression in older adults with dementia. Methodological challenges might contribute to this finding.

The emergence of antidepressant drugs targeting GABAA receptors: A concise review.

Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and the public health system. Treatment with classical antidepressants (e.g. tricyclic antidepressants and selective serotonine reuptake inhibitors), which primarily affect monoaminergic systems has several limitations, such as delayed onset of action and moderate efficacy in a relatively large proportion of depressed patients. Furthermore, depression is highly heterogeneus, and its different subtypes, including post-partum depression, involve distinct neurobiology, warranting a differential approach to pharmacotherapy. Given these shortcomings, the need for novel antidepressants that are superior in efficacy and faster in onset of action is fully justified. The development and market introduction of rapid-acting antidepressants has accelerated in recent years. Some of these new antidepressants act through the GABAergic system. In this review, we discuss the discovery, efficacy, and limitations of treatment with classic antidepressants. We provide a detailed discussion of GABAergic neurotransmission, with a special focus on GABAA receptors, and possible explanations for the mood-enhancing effects of GABAergic medications (in particular neurosteroids acting at GABAA receptors), and, ultimately, we present the most promising molecules belonging to this family which are currently used in clinical practice or are in late phases of clinical development.

Association between tricyclic antidepressants and health outcomes among older people: A systematic review and meta-analysis.

Tricyclic antidepressants are effective for managing depression and other disorders. However, they can cause adverse reactions due to their anticholinergic properties, with the risk of such events increasing with age. This study identifies and describes clinical studies that evaluate associations between the use of tricyclic antidepressants and adverse health outcomes (falls, fractures, and mortality) among older people. A systematic search of the literature in English, Spanish, and French was conducted using the electronic databases PubMed, ISI Web of Science, PsycINFO, and Cochrane. The systematic review included a total of 18 studies. The meta-analysis examined the 14 studies that investigated the association between the use of tricyclic antidepressants and the risk of falls and fractures (4 of the 18 studies focused on mortality and so were excluded from the meta-analysis). The odds ratio (OR) was 1.40 (95 % CI = 1.27-1.53, p < 0.001). The Cochran Q test was significant (X2 = 79.72, p < 0.001), indicating high heterogeneity (I2 = 84.9 %). An additional meta-analysis was conducted on studies reporting hazard ratios (HRs), yielding an HR of 1.21 (95 % CI = 0.93-1.58, p = 0.16). Meta-regression analysis indicated that the years of follow-up could have a significant effect on the association studied (p = 0.008). In conclusion, enhancing our understanding of the use of antidepressants and the associated risk of adverse events in older adults will enable the identification of the most appropriate type of antidepressant for each clinical situation.

Self-prescription with psychotropic medications by healthcare professionals working at mental health institutions in Saudi Arabia.

BACKGROUND: Healthcare professionals who work in mental health institutions are more exposed to psychotropic medications than those in other healthcare institutions and are, therefore, more likely to self-prescribe. Self-prescription is a concerning phenomenon because of the potential for medication misuse, drug interaction, addiction, and other social, physical, and psychological consequences. This study investigated the prevalence of self-prescription of psychotropic medications and the most common self-prescribed psychotropic medications by healthcare professionals in mental health institutions in Saudi Arabia. It also aimed to determine the possible side effects and factors associated with self-prescription of psychotropic medications. MATERIALS AND METHODS: This was a cross-sectional study using an electronic survey consisting of a researcher-designed checklist, targeting healthcare professionals in mental health institutions in Saudi Arabia. The independent variables were sex, nationality, occupation, place of residence, place of work, previous diagnosis of mental illness, marital, and living status. Data were analyzed, using SPSS, and frequency distribution and percentages were calculated. Chi-square test was employed to determine association between self-prescription and various independent variables. RESULTS: The final sample size was 588; 9.5% healthcare professionals working at mental health institutions in Saudi Arabia admitted to self-prescription with psychotropic medications. Almost half of those who admitted to self-prescription (48.2%) and about 1/4 (23.2%) self-prescribed selective serotonin reuptake inhibitors and benzodiazepines, respectively. The most commonly reported side effects of self-prescription were gastrointestinal symptoms and drowsiness. The study also suggested that males were significantly more prone to self-prescribing than females (P < 0.001). CONCLUSION: To our knowledge, this is the first study in Saudi Arabia to assess the self-prescription of psychotropic medications by healthcare professionals at mental health institutions. This study is important for decision-makers in their planning and updating of prescription policies. It is also equally important to spread awareness among healthcare professionals about the consequences of self-prescription.

Topical amitriptyline in burning mouth syndrome: A retrospective real-world evidence study.

OBJECTIVE: To evaluate the effectiveness, tolerability, and safety of topical amitriptyline as a potential route of administration for the management of burning mouth syndrome. BACKGROUND: Burning mouth syndrome is a complex, idiopathic, and debilitating orofacial pain disorder that impairs quality of life, with a prevalence of up to 18% in menopausal women. Available drugs to alleviate its burning sensation have inconsistent and limited efficacy. Given its physicochemical properties, excellent tolerability, and ability to target peripheral pathways, topical amitriptyline seems a promising mechanistically specific analgesic drug for burning mouth syndrome. METHODS: In this retrospective cross-sectional real-world evidence study, patients with burning mouth syndrome who were prescribed topical amitriptyline for 8 weeks were identified. Eligibility criteria stemmed from ICHD-3, ICOP, and consensus definitions. The primary outcome measure was mean daily pain intensity (on a 0-10 scale); secondary outcomes included adverse events and patient global impression of improvement. Data are given as the mean ± SD. RESULTS: A total of 15 patients fulfilling the eligibility criteria were included and analyzed. Mean daily pain was 6.7 ± 2.1 at baseline and 3.7 ± 2.3 after treatment, with a mean reduction of 3.1 ± 2.8 (p = 0.002). Half of the patients experienced a decrease in pain by at least 50% (p = 0.008). Several mild adverse events were reported, such as somnolence or dry mouth. CONCLUSIONS: Topical amitriptyline may be a safe and potent route of administration in the treatment of burning mouth syndrome, a hypothesis to be tested in further controlled trials.

Efficacy of antidepressants in functional dyspepsia: Systematic review and meta-analysis with trial sequential analysis of randomized controlled trials.

INTRODUCTION: The beneficial effects of using antidepressants in improving functional dyspepsia (FD) symptoms have been reported in previous meta-analyses; however, the results have not been conclusive. The aim was to perform an updated meta-analysis coupled with trial sequential analysis (TSA) to assess the efficacy of the use of any antidepressants in the treatment of FD in adults. METHODS: Electronic databases were searched up to March 2024 for randomized controlled trials (RCTs) recruiting adults with FD. Data of overall symptoms improved between the antidepressants and placebo groups was pooled to obtain risk ratio (RR) employing the random-effects model. The effect of random errors was evaluated with TSA. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence. Analyses were performed using STATA version 16.0. RESULTS: Nine RCTs with 924 patients met the eligible criteria. The RRs of FD symptoms improving with any antidepressants, tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors were (n = 9, RR = 1.30 [95% CI, 1.02-1.67]), (n = 5, RR = 1.41 [95% CI, 1.07-1.85]) and (n = 2, RR = 0.97 [95% CI, 0.72-1.29]), respectively. TSA demonstrated conclusive evidence for the beneficial effect of TCAs. The number needed to treat (NNT) with any depressants and TCAs were 11 (95% CI, 7-36) and 6 (95% CI, 4-15), respectively. The certainty of the evidence for an effect of TCAs was that of moderate GRADE quality. The benefit, however, was limited to the western population (n = 3, RR = 1.43 [95% CI, 1.04-1.96]) and did not extend to the Asian population (n = 2, RR = 1.32 [95% CI, 0.75-2.32]). Conversely, antidepressant-using patients experienced adverse events more frequently. However, no statistically significant association was found between TCAs and any adverse events (n = 3; RR = 1.36 [95% CI, 0.91-2.04]). CONCLUSION: Evidence was obtained suggesting TCAs can be an effective alternative in the treatment of FD, but more evidence from high-quality large trials is required to support their use, especially in the Asian population.

GluN2A: a promising target for developing novel antidepressants.

BACKGROUND: Depression is a heterogeneous disorder with high morbidity and disability rates that poses serious problems in regard to mental health care. It is now well established that N-methyl D-aspartate receptors (NMDARs) modulators are being increasingly explored as potential therapeutic options for treating depression, although relatively little is known about their mechanisms of action. NMDARs are glutamate-gated ion channels that are ubiquitously expressed in the central nervous system (CNS) and they have been shown to play key roles in excitatory synaptic transmission. GluN2A, the predominant Glu2N subunit of functional NMDARs in neurons, is involved in various physiological processes in the CNS and is associated with diseases such as anxiety, depression, and schizophrenia. However, the role of GluN2A in the pathophysiology of depression has not yet been elucidated. METHODS: We reviewed several past studies in order to better understand the function of GluN2A in depression. Additionally, we also summarized the pathogenesis of depression based on the regulation of GluN2A expression, particularly its interaction with neuroinflammation and neurogenesis, which has received considerable critical attention and is highly implicated in the onset of depression. RESULTS: These evidences suggest that GluN2A overexpression impairs structural and functional synaptic plasticity, which contributes to the development of depression. Consequently, this knowledge is vital for the development of selective antagonists targeting GluN2A subunits using pharmacological and molecular methods. CONCLUSIONS: Specific inhibition of GluN2A NMDAR subunit is resistant to chronic stress-induced depressive-like behaviors, making them promising targets for the development of novel antidepressants.

REM sleep in narcolepsy.

Narcolepsy is mainly associated with excessive daytime sleepiness, but the characteristic feature is abnormal rapid eye movement (REM) sleep phenomena. REM sleep disturbances can manifest as cataplexy (in narcolepsy type 1), sleep paralysis, sleep-related hallucinations, REM sleep behavior disorder, abnormal dreams, polysomnographic evidence of REM sleep disruption with sleep-onset REM periods, and fragmented REM sleep. Characterization of REM sleep and related symptoms facilitates the differentiation of narcolepsy from other central hypersomnolence disorders and aids in distinguishing between narcolepsy types 1 and 2. A circuit comprising regions within the brainstem, forebrain, and hypothalamus is involved in generating and regulating REM sleep, which is influenced by changes in monoamines, acetylcholine, and neuropeptides. REM sleep is associated with brainstem functions, including autonomic control, and REM sleep disturbances may be associated with increased cardiovascular risk. Medications used to treat narcolepsy (and REM-related symptoms of narcolepsy) include stimulants/wake-promoting agents, pitolisant, oxybates, and antidepressants; hypocretin agonists are a potential new class of therapeutics. The role of REM sleep disturbances in narcolepsy remains an area of active research in pathophysiology, symptom management, and treatment. This review summarizes the current understanding of the role of REM sleep and its dysfunction in narcolepsy.