Conventional Antidepressants Research Articles

Recent advances in the synthesis of antidepressant derivatives: pharmacologic insights for mood disorders.

Mood disorders, including depression, remain a significant global health concern, necessitating continuous efforts to develop novel and more effective antidepressant therapies. Although there have been significant advancements in comprehending the biology of Major Depressive Disorder (MDD), a considerable number of people suffering from depression do not exhibit positive responses to the pharmacologic treatments now available. This study specifically examines emerging targets and potential future approaches for pharmaceutical interventions in the treatment of MDD. The discussion revolves around novel therapeutic agents and their effectiveness in treating depression. The focus is on the specific pathophysiological pathways targeted by these agents and the amount of evidence supporting their use. While conventional antidepressants are anticipated to continue being the primary treatment for MDD in the foreseeable future, there is currently extensive research being conducted on numerous new compounds to determine their effectiveness in treating MDD. Many of these compounds have shown encouraging results. This review highlighted the recent advances in the synthesis of antidepressant derivatives and explores their pharmacologic insights for the treatment of mood disorders.

Pinocembrin alleviates LPS-induced depressive-like behavior in mice via the NLRP3/DCC signaling pathway

ObjectiveDepression, a prevalent and severe mental disorder, continues to be a significant area of research concerning its pathogenesis and therapeutic approaches. Conventional antidepressants are often limited by delayed therapeutic effects and notable adverse reactions, necessitating the development of innovative and efficacious treatment modalities. Multiple lines of evidence suggest that peripheral and central inflammation play a role in depression, and that anti-inflammatory drugs can ameliorate depressive symptoms in patients with inflammation-related depression. Pinocembrin (PB), a natural bioactive compound, is renowned for its anti-inflammatory and antioxidant properties, while the effect and mechanism of PB are still unclear. Consequently, this study employs PB as an intervention to investigate its effects on depression in mice model, with the objective of establishing a novel therapeutic strategy and foundational data for the treatment of depression. Methods(1) The acute inflammation model used lipopolysaccharide (LPS) to induce depression-like behavior in mice by injecting LPS intraperitoneally at a dose of 0.83mg/kg. The effects of PB (20 mg/kg, i.p.) and the NLRP3 inflammasome inhibitor MCC950 (10 mg/kg, i.p.) on improving depression behavior in mice were evaluated. (2) To explore the specific mechanism of PB in improving depression-like behavior in LPS mice by regulating NLRP3 and Netrin-1/DCC pathway. ResultsThe results showed that after intraperitoneal injection of LPS, the mice exhibited a significant decrease in body weight, sucrose preference score, and a significant increase in tail suspension immobility time. Treatment with PB and MCC950 increased the sucrose preference score and decreased the tail suspension immobility time. Besides, PB and MCC950 could inhibit the expression of NLRP3 related neuroinflammation, down-regulated the Netrin-1/DCC signaling pathway, and improved hippocampal neuroplasticity in mice. ConclusionIn conclusion, PB significantly improved LPS-induced depression-like behavior in mice by reducing the expression of hippocampal NLRP3 inflammasome and down-regulating the Netrin-1/DCC signaling pathway. Additionally, PB was found to regulate α-amino-3-hydroxy-5-methyl-4 isoxazole receptor (AMPAR) and postsynaptic density 95 (PSD95), protecting excitatory synaptic transmission and enhancing synaptic plasticity. This study demonstrates the effectiveness of PB in improving depressive symptoms induced by LPS and provides a new strategy for the clinical treatment of depression.

S-(+)-mecamylamine increases the firing rate of serotonin neurons and diminishes depressive-like behaviors in an animal model of stress

Mecamylamine, a noncompetitive blocker of nicotinic acetylcholine receptors (nAChRs), is the racemic mixture of two stereoisomers: S-(+)-mecamylamine (S-mec) and R-(−)-mecamylamine (R-mec), with distinct interactions with α4β2 nAChRs. It has been shown that mecamylamine increases glutamate release and excites serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN). In this study, we separately evaluated the effects of S-mec and R-mec on 5-HT neuron excitability. S-mec (3 μM) increased firing frequency by 40 %, while R-mec (3 μM) raised it by only 22 %. S-mec acts as a positive allosteric modulator on high-sensitivity (HS) α4β2 nAChRs at glutamate terminals, enhancing spontaneous excitatory postsynaptic currents (sEPSCs) in 5-HT neurons. Conversely, R-mec decreased sEPSCs by blocking HS α4β2 nAChRs and reduced GABA-mediated inhibitory currents (sIPSCs) by blocking α7 nAChRs at GABAergic terminals. These mechanisms make S-mec more effective than R-mec in enhancing 5-HT neuron firing. Moreover, combining S-mec with TC-2559, a selective agonist of HS α4β2 nAChRs, increased firing frequency by 65 %, exceeding the effect of S-mec alone. To validate these findings, we evaluated the antidepressant effects of S-mec (1 mg/kg) combined with TC-2559 or RJR-2403, another α4β2 nAChR agonist. This combination successfully reduced depression-like behaviors, suggesting a potential treatment strategy for patients resistant to conventional antidepressants.

Augmentation with prazosin for patients with depression and a history of trauma: A randomised, double-blind, placebo-controlled study.

Depression with a history of trauma often responds poorly to conventional antidepressants and has a poor prognosis. Prazosin, an α1-adrenoceptor blocker, has shown promise in treating post-traumatic stress disorder symptoms, particularly nightmares. Its potential in treating depression with trauma history warrants investigation. This randomised, double-blind, placebo-controlled study aimed to investigate the efficacy and tolerability of low-dose prazosin (0.5-1 mg/day) as an augmentation strategy in patients with depression and a history of trauma. We sought to determine if prazosin could provide rapid symptom improvement and enhance overall treatment response compared to placebo in this difficult-to-treat patient population. This randomised, double-blind, placebo-controlled clinical study included 59 patients with first-episode or recurrent unipolar or bipolar depression. After basic antidepressant treatment, they were randomly assigned to a prazosin (0.5-1 mg/day) or placebo group for a 6-week double-blind controlled study. The Montgomery-Åsberg Depression Rating Scale, 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) were used to evaluate efficacy. There were no significant differences in the results of the demographic and clinical symptom assessment between the two groups (p > 0.05). The difference between the HAMD-17 and HAMA scores was statistically significant after 3 days of treatment (p < 0.05). The difference in response rate between the two groups was statistically significant after week 4 of treatment (end of week 4, 56.7% vs. 24.1%, p = 0.011; end of week 6, 80.0% vs. 48.3%, p = 0.011). The incidence of adverse reactions in the prazosin and placebo groups was 20.0% and 24.1%, respectively, with no statistically significant differences (p > 0.05); however, the prazosin group had a lower incidence of sleeplessness or nightmares (3.3% vs. 20.7%, p = 0.039) but a higher incidence of orthostatic hypotension (16.7% vs. 0%, p = 0.007). The severity of orthostatic hypotension was mild to moderate. Low-dose prazosin can effectively improve the emotional symptoms of patients with depression and a history of trauma, and the common adverse reaction is mild-to-moderate orthostatic hypotension. ChiCTR2200063642.

The use of serotonin type 7 receptor antagonists as a pharmacological intervention in chronic stress. Insights from animal studies

This mini-review presents our current understanding of serotonin type 7 receptor research focusing on the possible network mechanisms underlying the behavioral action of receptor antagonists. The serotonin type 7 receptor is expressed widely throughout the nervous system and known to be involved in various cognitive and physiological mechanisms. It became a clinically significant target after the discovery that its selective antagonist SB 269970 can exert rapid-onset antidepressant effects either alone or in combination with lower doses of conventional antidepressant drugs. Further research has shown that administration of SB 269970 can effectively counteract negative neurobiological outcomes in various chronic stress paradigms. The authors hope they can introduce a wider scientific audience to this promising pharmacological target which, if successful, could in time lead to more discoveries and a better understanding of the underlying serotonin receptor biology as well as its clinical potential. Highlights•The 5-HT7 receptor is widely distributed throughout the nervous system.•5-HT7 receptor antagonist SB 269970 exerts rapid-onset antidepressant effects.•Antidepressant effects of SB 269970 occur via changes in dorsal raphe activity and subsequent cortical serotonin release.

Efficacy and safety of add-on sarcosine in patients with major depressive disorder: A randomized controlled trial

The main hurdles with current therapies for major depressive disorder (MDD) include lack of efficacy, therapeutic latency, and adverse drug reactions. Add-on therapy to conventional antidepressants may result in better therapeutic outcomes to overcome these obstacles. Sarcosine (N-methyl glycine), an endogenous amino acid that acts by modulating the NMDA receptor, is available as a dietary supplement. So, the present study was planned to evaluate the efficacy and safety of add-on sarcosine to SSRIs in MDD. In the present randomized, double-blind clinical trial (NCT04975100), 60 eligible participants with MDD were randomly assigned to either the test group (SSRI + sarcosine) or the control group (SSRI + placebo). Clinical and biochemical parameters like MADRS, CGI, serum BDNF, and serum glycine were assessed at baseline and eight weeks. The mean reduction in MADRS score was significant in both the control (−8.7, 95% CI: −11.0 to −6.4, p < 0.001) and the test group (−13.3, 95% CI: −14.9 to −11.7, p < 0.001), but the change in the test group was significantly greater (−4.6, 95% CI: −7.5 to −1.7, p = 0.003). The test group had a significantly higher response rate (p = 0.007) and remission rate (p = 0.038) compared to the control group. There was a significant increase in serum BDNF in both groups; however, the change in the test group was significantly higher than in the control group (p = 0.041). Similarly, the test group had a significantly higher increase in serum glycine than the control group (p < 0.001). Sarcosine may be considered an efficacious and safe add-on therapy to standard SSRIs in the management of MDD.ClinicalTrial.gov IdentifierNCT04975100.

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation

BackgroundThe cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns.MethodsRapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels.ResultsScopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC).ConclusionSubchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

Engaging Mood Brain Circuits with Psilocybin (EMBRACE): a study protocol for a randomized, placebo-controlled and delayed-start, neuroimaging trial in depression

BackgroundMajor depressive disorder (MDD) is a leading cause of disability worldwide across domains of health and cognition, affecting overall quality of life. Approximately one third of individuals with depression do not fully respond to treatments (e.g., conventional antidepressants, psychotherapy) and alternative strategies are needed. Recent early phase trials suggest psilocybin may be a safe and efficacious intervention with rapid-acting antidepressant properties. Psilocybin is thought to exert therapeutic benefits by altering brain network connectivity and inducing neuroplastic changes that endure for weeks post-treatment. Although early clinical results are encouraging, psilocybin’s acute neurobiological effects on neuroplasticity have not been fully investigated. We aim to examine for the first time how psilocybin acutely (intraday) and subacutely (weeks) alters functional brain networks implicated in depression.MethodsFifty participants diagnosed with MDD or persistent depressive disorder (PDD) will be recruited from a tertiary mood disorders clinic and undergo 1:1 randomization into either an experimental or control arm. Participants will be given either 25 mg psilocybin or 25 mg microcrystalline cellulose (MCC) placebo for the first treatment. Three weeks later, those in the control arm will transition to receiving 25 mg psilocybin. We will investigate whether treatments are associated with changes in arterial spin labelling and blood oxygenation level-dependent contrast neuroimaging assessments at acute and subacute timepoints. Primary outcomes include testing whether psilocybin demonstrates acute changes in (1) cerebral blood flow and (2) functional brain activity in networks associated with mood regulation and depression when compared to placebo, along with changes in MADRS score over time compared to placebo. Secondary outcomes include changes across complementary clinical psychiatric, cognitive, and functional scales from baseline to final follow-up. Serum peripheral neurotrophic and inflammatory biomarkers will be collected at baseline and follow-up to examine relationships with clinical response, and neuroimaging measures.DiscussionThis study will investigate the acute and additive subacute neuroplastic effects of psilocybin on brain networks affected by depression using advanced serial neuroimaging methods. Results will improve our understanding of psilocybin’s antidepressant mechanisms versus placebo response and whether biological measures of brain function can provide early predictors of treatment response.Trial registrationClinicalTrials.gov Identifier: NCT06072898. Registered on 6 October 2023.

Strategy for the development of small-molecule antidepressant targeting PAC1 receptor

Major depressive disorder (MDD) is a psychiatric disorder that affects more than 300 million people worldwide and has a serious impact on society. Conventional antidepressants targeting monoamines in the brain based on the monoamine hypothesis are known to take a prolonged time to be effective or less effective in 30% of MDD patients. Hence, there is a need to develop antidepressants that are effective against treatment-resistant depression and have a new mechanism different from the monoamine hypothesis. An increasing number of research groups including us have been establishing that pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1 receptor, are closely related to the etiology of stress-related diseases such as MDD. Therefore, it is strongly suggested that the PAC1 receptor is a promising target in the treatment of psychiatric disorders. We developed a novel, non-peptidic, small-molecule, high-affinity PAC1 receptor antagonists and conducted behavioral pharmacology experiments in mice to characterize a novel PAC1 receptor antagonist as a new option for MDD therapy. The results show that our novel PAC1 receptor antagonist has the potential to be a new antidepressant with a high safety profile. In this review, we would like to present the background of developing our novel PAC1 receptor antagonist and its effects on mouse models of acute stress.

Efficacy and safety of perioperative application of esketamine on postoperative depression: a meta-analysis of randomized controlled studies.

Postoperative depression has a profound impact on patients' postoperative rehabilitation and overall quality of life. Preventing postoperative depression is of significant value because conventional antidepressants have a slow onset of action. Esketamine showed prompt and sustained antidepressant efficacy. Nevertheless, the safety and effectiveness of perioperative esketamine in preventing postoperative depression are still unknown. The purpose of this meta-analysis was to assess the safety and effectiveness of perioperative intravenous esketamine in relation to its ability to prevent postoperative depression. Randomized controlled trials were searched in the following databases: Web of Science, Cochrane Central Registry of Controlled Trials, PubMed, and Embase. The primary outcome assessed is the postoperative depression scores. Postoperative pain ratings and adverse effects constituted secondary outcomes. Subgroup analyses were carried out on the basis of multiple variables, including the absence or presence of preoperative depression, the mode of esketamine administration, the dosage of esketamine, and the type of anesthesia. A total of 16 studies encompassed 1161 patients who received esketamine intervention, whereas 1106 patients served as controls. Esketamine was efficacious in reducing postoperative depression scores when administered perioperatively, and the esketamine group maintained a lower postoperative depression score than the control group more than four weeks after surgery. Esketamine effectively alleviated postoperative pain scores without increasing the occurrence of postoperative nausea and vomiting, dizziness, drowsiness, nightmares, and dissociation. The administration of esketamine during the perioperative has the potential to decrease postoperative depression and pain scores without increasing the incidence of adverse effects.

Baseline monocyte count predicts symptom improvement during intravenous ketamine therapy in treatment-resistant depression: a single-arm open-label observational study.

Neuroinflammatory processes in depression are associated with treatment resistance to conventional antidepressants. Ketamine is an effective new therapeutic option for treatment-resistant depression (TRD). Its well-established immunomodulatory properties are hypothesized to mediate its antidepressant effect. In this context, higher levels of inflammation may predict a better treatment response. However, conclusive evidence for this hypothesis is lacking. We thus investigated whether standard peripheral inflammatory cell markers and C-reactive protein (CRP) levels could predict symptom improvement during intravenous ketamine therapy in TRD patients. 27 participants with TRD were treated with six weight-adjusted intravenous ketamine infusions (0.5 mg/kg bodyweight) over three weeks. Baseline assessments included CRP, absolute monocyte count (AMC), and absolute neutrophil count (ANC). Depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline (D1), after the first (D3) and before the last ketamine infusion (D18). Raters were blinded for the baseline laboratory assessments. 13 participants responded to ketamine treatment, and 8 participants partially responded. Baseline AMC showed a strong negative correlation with MADRS change at D3 (r=-0.57, p=0.002) and at D18 (r =-0.48, p=0.010), indicating that a high baseline AMC was associated with greater symptom improvement. A generalized linear model confirmed the association of baseline AMC with symptom improvement during ketamine treatment when additionally accounting for age, sex, and body mass index. Specifically, baseline AMC demonstrated predictive value to discriminate responders and partial responders from non-responders, but lacked discriminative ability between partial responders and responders. Baseline ANC correlated with the MADRS changes at D3 (r=-0.39, p=0.046), while CRP values did not correlate at all. Our prospective single-arm open-label observational study demonstrated that baseline AMC reliably predicted symptom improvement during intravenous ketamine treatment in TRD patients. AMC could therefore serve as a simple and easily accessible marker for symptom improvement during ketamine therapy in daily clinical practice. Future studies with larger sample sizes and a more detailed longitudinal assessment of AMC subtypes are needed to better understand the specific relationship between monocytes and the neuromodulatory effects of ketamine.

Treatment-Resistant Depression and Medications

The management of treatment-resistant depression (TRD) is challenging. Researchers have identified novel targets, especially the glutamatergic system, in the pathogenesis of depressive disorder. N-methyl-D-aspartate (NMDA) receptor antagonists, like ketamine, have revolutionized the treatment of TRD due to their rapid antidepressant and antisuicidal effect. Various other receptor systems, including GABAergic, opioid receptors, the endogenous cannabinoid system, and cholinergic receptors, are novel targets to produce an antidepressant response. The US Food and Drug Administration (FDA) has approved intra-nasal ketamine as an add-on therapy to conventional antidepressants for TRD. Other compounds are in various stages of development. Identification and development of novel compounds by future research can help in overcoming the challenges of treating TRD. [ Psychiatr Ann . 2024;54(6):e177–e181.]

Beyond the serotonin deficit hypothesis: communicating a neuroplasticity framework of major depressive disorder.

The serotonin deficit hypothesis explanation for major depressive disorder (MDD) has persisted among clinicians and the general public alike despite insufficient supporting evidence. To combat rising mental health crises and eroding public trust in science and medicine, researchers and clinicians must be able to communicate to patients and the public an updated framework of MDD: one that is (1) accessible to a general audience, (2) accurately integrates current evidence about the efficacy of conventional serotonergic antidepressants with broader and deeper understandings of pathophysiology and treatment, and (3) capable of accommodating new evidence. In this article, we summarize a framework for the pathophysiology and treatment of MDD that is informed by clinical and preclinical research in psychiatry and neuroscience. First, we discuss how MDD can be understood as inflexibility in cognitive and emotional brain circuits that involves a persistent negativity bias. Second, we discuss how effective treatments for MDD enhance mechanisms of neuroplasticity-including via serotonergic interventions-to restore synaptic, network, and behavioral function in ways that facilitate adaptive cognitive and emotional processing. These treatments include typical monoaminergic antidepressants, novel antidepressants like ketamine and psychedelics, and psychotherapy and neuromodulation techniques. At the end of the article, we discuss this framework from the perspective of effective science communication and provide useful language and metaphors for researchers, clinicians, and other professionals discussing MDD with a general or patient audience.

Involvement of catecholaminergic and nitric oxide–cGMP pathways in the antidepressant-like effects of hydroethanolic leaf extract of Morinda Longiflora G. Don in Mice

Depression is a major world health issue. Though conventional antidepressants are employed for its management, they are fraught with inconsistent efficacy and untoward side effects. Therefore, finding alternative medicines for depression treatment is critical. The present study evaluated the possible antidepressant-like properties of hydroethanolic leaf extract of Morinda longiflora (MLE) in animal models. Acute animal models—Forced swim (FST) and tail suspension tests (TST)—as well as a chronic model, open space swim test, were used to establish antidepressant-like activity. The open field test was performed to exclude confounding psychostimulatory effects. Attempts were also made to investigate the possible underlying mechanism(s) of the antidepressant-like action of MLE. Oral treatment with MLE (30–300 mg/kg) significantly decreased the duration of immobility in the TST and FST. Also, treatment of mice with para-chlorophenylalanine (PCPA, 300 mg/kg, i.p.) failed to reverse the reduction in immobility duration induced by MLE. Furthermore, after treating mice with reserpine (1 mg/kg), α-methyl-p-tyrosine (AMPT, 100 mg/kg, i.p.), or both drugs combined, the reduction in immobility duration caused by MLE was reversed. Again, the anti-immobility actions produced by the extract were significantly reversed by l-arginine, sildenafil, haloperidol and prazosin but not propranolol, yohimbine or cyproheptadine. Pre-treatment of mice with l-NAME and methylene blue potentiated the anti-immobility action produced by the extract. The extract markedly reduced the duration of immobility in the OSST model. However, the extract (30–300 mg/kg) had no significant effect on the total distance travelled in the open field test. In conclusion, the current findings suggest that hydroethanolic leaf extract of Morinda longiflora has significant antidepressant-like activity and may involve catecholaminergic and nitric oxide-cyclic guanosine monophosphate pathways.

Investigation of Herb-Drug Interactions between Xylopia aethiopica, Its Principal Constituent Xylopic Acid, and Antidepressants.

Depression affects an estimated 350 million people worldwide and is implicated in up to 60% of suicides. Only about 60-70% of patients respond to antidepressant therapy. One of the factors causing patients to not attain therapeutic goals is herb-drug interactions. To investigate any potential herb-drug interaction that might exist between Xylopia aethiopica extract (XAE) or xylopic acid (XA) and selected conventional antidepressants (imipramine, fluoxetine, and venlafaxine) in mice. Dried, powdered fruits of Xylopia aethiopica were cold macerated in 70% ethanol to obtain XAE. XA was isolated by cold macerating dried fruits of Xylopia aethiopica in petroleum ether, crystallising impure XA with ethyl acetate, and purifying XA crystals with 96% ethanol. Pharmacodynamic interaction was assessed via isobolographic analysis of tail suspension tests of the agents individually and in their respective combinations. Pharmacokinetic interaction was assessed by monitoring the effect of coadministrations on the plasma concentration of antidepressants and xylopic acid via HPLC analysis. XAE and XA in mice showed significant antidepressant-like activity in the tail suspension test. With interaction indices less than one, synergism of antidepressant effect was observed in the Xylopia aethiopica extract/fluoxetine (γXAE/FL = 0.502), Xylopia aethiopica extract/imipramine (γXAE/IP = 0.322), Xylopia aethiopica extract/venlafaxine (γXAE/VL = 0.601), xylopic acid/imipramine (γXA/IP = 0.556), xylopic acid/venlafaxine (γXA/VL = 0.451), and xylopic acid/fluoxetine (γXA/FL = 0.298) combinations, which may be potentially due to elevation of serotonergic neurotransmission via varying mechanisms. The AUC of imipramine (AUCIP = 1966 ± 58.98 µg/ml.h) was significantly (P < 0.0001) reduced by Xylopia aethiopica extract (AUCIP = 1228 ± 67.40 µg/ml.h) and xylopic acid (AUCIP = 1250 ± 55.95 µg/ml.h), while the AUC of xylopic acid (AUCXA = 968.10 ± 61.22 µg/ml.h) was significantly (P < 0.0001) reduced by venlafaxine (AUCXA = 285.90 ± 51.92 µg/ml.h) and fluoxetine (AUCXA = 510.60 ± 44.74 µg/ml.h), possibly due to the effect of interfering agents on gastric emptying hence reducing oral absorption. Xylopia aethiopica extract and xylopic acid interacted synergistically with imipramine, fluoxetine, and venlafaxine and reduced the systemic circulation of imipramine.

Metabolic features of adolescent major depressive disorder: A comparative study between treatment-resistant depression and first-episode drug-naive depression

Major depressive disorder (MDD) is a psychiatric illness that can jeopardize the normal growth and development of adolescents. Approximately 40% of adolescent patients with MDD exhibit resistance to conventional antidepressants, leading to the development of Treatment-Resistant Depression (TRD). TRD is associated with severe impairments in social functioning and learning ability and an elevated risk of suicide, thereby imposing an additional societal burden. In this study, we conducted plasma metabolomic analysis on 53 adolescents diagnosed with first-episode drug-naïve MDD (FEDN-MDD), 53 adolescents with TRD, and 56 healthy controls (HCs) using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) and reversed-phase liquid chromatography-mass spectrometry (RPLC-MS). We established a diagnostic model by identifying differentially expressed metabolites and applying cluster analysis, metabolic pathway analysis, and multivariate linear support vector machine (SVM) algorithms. Our findings suggest that adolescent TRD shares similarities with FEDN-MDD in five amino acid metabolic pathways and exhibits distinct metabolic characteristics, particularly tyrosine and glycerophospholipid metabolism. Furthermore, through multivariate receiver operating characteristic (ROC) analysis, we optimized the area under the curve (AUC) and achieved the highest predictive accuracy, obtaining an AUC of 0.903 when comparing FEDN-MDD patients with HCs and an AUC of 0.968 when comparing TRD patients with HCs. This study provides new evidence for the identification of adolescent TRD and sheds light on different pathophysiologies by delineating the distinct plasma metabolic profiles of adolescent TRD and FEDN-MDD.

Efficacy of addition of the anti-inflammatory, IV glutathione to standard ketamine IV therapy in major depressive disorder

Ketamine, a N-methyl-D-aspartate (NMDA) antagonist, is used for treatment-resistant depression (TRD). Recent studies have shown that there are increased levels of pro-inflammatory cytokines in individuals with major depressive disorder (MDD) and those with higher levels of oxidative stress markers have a decreased or null response to conventional antidepressants. Glutathione (GSH) as an antioxidant adjuvant to ketamine has not been well studied. This double-blind study with 30 patients divided into 2 groups of 15 each, aimed to determine if GSH, added to standard ketamine infusion (GSH+K), rendered better outcomes in MDD patients versus patients receiving ketamine infusions with a normal saline placebo (K+NS). There were significant drops in BDI-II scores from day 1 to day 14, PHQ- scores from day 1 to day 14 and PHQ-9 scores day 14 to day 28, suggesting the overall treatment was effective. There were no statistically significant differences between the groups over time. However, a sustained improvement in depressive symptoms was observed for 14 days post-infusion in both groups.

Ketamine's mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine's antidepressant effects?

Over 300 million people worldwide suffer from major depressive disorder (MDD). Unfortunately, only 30-40% of patients with MDD achieve complete remission after conventional monoamine antidepressant therapy. In recent years, ketamine has revolutionized the treatment of MDD, with its rapid antidepressant effects manifesting within a few hours as opposed to weeks with conventional antidepressants. Many research endeavors have sought to identify ketamine's mechanism of action in mood disorders; while many studies have focused on ketamine's role in glutamatergic modulation, several studies have implicated its role in regulating neuroinflammation. The complement system is an important component of the innate immune response vital for synaptic plasticity. The complement system has been implicated in the pathophysiology of depression, and studies have shown increases in complement component 3 (C3) expression in the prefrontal cortex of suicidal individuals with depression. Given the role of the complement system in depression, ketamine and the complement system's abilities to modulate glutamatergic transmission, and our current understanding of ketamine's anti-inflammatory properties, there is reason to suspect a common link between the complement system and ketamine's mechanism of action. This review will summarize ketamine's anti- inflammatory roles in the periphery and central nervous system, with an emphasis on complement system regulation.

Assessment of Pharmacokinetic Effects of Herbal Medicines on Escitalopram.

Herbal medicines are occasionally used in combination with conventional antidepressants to mitigate various depression-associated symptoms. However, there is limited information on herb-antidepressant interactions. In this study, we investigated the pharmacokinetic (PK) effects of four herbal medicines (Gami-soyosan, Banhasasim-tang, Ojeok-san, and Bojungikgi-tang) on escitalopram, a commonly used antidepressant. In this open-label, fixed-sequence, three-period, crossover study, 18 participants were enrolled and divided into two groups. Each group received a 10 mg oral dose of escitalopram in period 1. Participants took escitalopram once daily and their assigned herbal medicines thrice a day for 7 d in periods 2 (group 1: Gami-soyosan, group 2: Ojeok-san) and 3 (group 1: Banhasasim-tang; group 2: Bojungikgi-tang). The primary endpoints were Cmax,ss and AUCtau,ss of escitalopram. Cmax,ss and AUCtau,ss in period 1 were obtained using nonparametric superposition from single-dose data. The PK endpoints were classified according to the CYP2C19 phenotype. Of 18 participants, 16 completed the study. Systemic exposure to escitalopram resulted in a minor increase in the presence of each herbal medicine. The geometric mean ratios (GMRs, combination with herbal medicines/escitalopram monotherapy) and their 90% confidence intervals (CIs) for Cmax,ss and AUCtau,ss were as follows: Gamisoyosan- 1.1454 (0.9201, 1.4258) and 1.0749 (0.8084, 1.4291), Banhasasim-tang-1.0470 (0.7779, 1.4092) and 1.0465 (0.7035, 1.5568), Ojeok-san-1.1204 (0.8744, 1.4357) and 1.1267 (0.8466, 1.4996), and Bojungikgi-tang-1.1264 (0.8594, 1.4762) and 1.1400 (0.8515, 1.5261), respectively. Furthermore, no significant differences in the GMRs of Cmax,ss and AUCtau,ss were observed across different CYP2C19 phenotypes in any of the groups. The co-administration of escitalopram with Gami-soyosan, Banhasasim-tang, Ojeok-san, or Bojungikgi-tang did not exert significant PK effects on escitalopram. These findings provide valuable insights into the safe use of herbal medicines along with escitalopram.

Converged avenues: depression and Alzheimer's disease- shared pathophysiology and novel therapeutics.

Depression, a highly prevalent disorder affecting over 280million people worldwide, is comorbid with many neurological disorders, particularly Alzheimer's disease (AD). Depression and AD share overlapping pathophysiology, and the search for accountable biological substrates made it an essential and intriguing field of research. The paper outlines the neurobiological pathways coinciding with depression and AD, including neurotrophin signalling, the hypothalamic-pituitary-adrenal axis (HPA), cellular apoptosis, neuroinflammation, and other aetiological factors. Understanding overlapping pathways is crucial in identifying common pathophysiological substrates that can be targeted for effective management of disease state. Antidepressants, particularly monoaminergic drugs (first-line therapy), are shown to have modest or no clinical benefits. Regardless of the ineffectiveness of conventional antidepressants, these drugs remain the mainstay for treating depressive symptoms in AD. To overcome the ineffectiveness of traditional pharmacological agents in treating comorbid conditions, a novel therapeutic class has been discussed in the paper. This includes neurotransmitter modulators, glutamatergic system modulators, mitochondrial modulators, antioxidant agents, HPA axis targeted therapy, inflammatory system targeted therapy, neurogenesis targeted therapy, repurposed anti-diabetic agents, and others. The primary clinical challenge is the development of therapeutic agents and the effective diagnosis of the comorbid condition for which no specific diagnosable scale is present. Hence, introducing Artificial Intelligence (AI) into the healthcare system is revolutionary. AI implemented with interdisciplinary strategies (neuroimaging, EEG, molecular biomarkers) bound to have accurate clinical interpretation of symptoms. Moreover, AI has the potential to forecast neurodegenerative and psychiatric illness much in advance before visible/observable clinical symptoms get precipitated.