Bipolar disorder (BD) has been associated with impaired cellular resilience. Recent studies have shown abnormalities in the unfolded protein response (UPR) in BD. The UPR is the cellular response to endoplasmic reticulum (ER) stress. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a trophic factor, decreases ER stress by modulating the UPR. The objective of this study is to investigate the MANF-ER stress pathway in BD and major depressive disorder (MDD) compared to healthy controls (HC).

Opioid use disorder (OUD) affects over 40 million people worldwide, creating significant social and economic burdens. Medication for opioid use disorder (MOUD) is often considered the primary treatment approach for OUD. MOUD, including methadone, buprenorphine, and naltrexone is effective for some, but its benefits may be limited by poor adherence to treatment recommendations. Immunopharmacotherapy offers an innovative approach by using vaccines to generate antibodies that neutralize opioids, blocking them from crossing the blood-brain barrier and reducing their psychoactive effects. To date, only three clinical trials for opioid vaccines have been published. While these studies demonstrated the potential of opioid vaccines for relapse prevention, there is currently no standardized protocol for evaluating their effectiveness. We have reviewed recent preclinical studies that demonstrated the efficacy of vaccines targeting opioids, including heroin, morphine, oxycodone, hydrocodone, and fentanyl. These studies showed that vaccines against opioids reduced drug reinforcement, decreased opioid-induced antinociception, and increased survival rates against lethal opioid doses. These studies also demonstrated the importance of vaccine formulation and the use of adjuvants in enhancing antibody production and specificity. Finally, we highlighted the strengths and concerns associated with the opioid vaccine treatment, including ethical considerations.

Suicide is among the severe outcomes of mental illness and has been reported to be associated with neurodegeneration and cognitive impairment. The blood neurofilament light chain (NfL) level is a biomarker of neuronal damage in neuropsychiatric disorders. This study investigated whether the NfL levels are associated with lifetime suicidal behaviors and whether this level is higher in patients with major depressive disorder (MDD) compared with healthy controls.

This study aims to quantitatively evaluate the efficacy and safety of various treatment regimens for treatment-resistant depression (TRD) across oral, intravenous, and intranasal routes to inform clinical guidelines.

Esketamine nasal spray (ESK) is approved, in conjunction with an oral antidepressant, for the treatment of treatment-resistant depression in adults and for the treatment of depressive symptoms in adults with major depressive disorder with acute suicidal ideation or behavior. No adverse events (AEs) of respiratory depression were reported in ESK phase 3 clinical trials; however, postmarketing incidents of respiratory depression associated with ESK use have been observed.

Glutamatergic system dysfunction contributes to a full spectrum of schizophrenia-like symptoms, including the cognitive and negative symptoms that are resistant to treatment with antipsychotic drugs (APDs). Aripiprazole, an atypical APD, acts as a dopamine partial agonist, and its combination with haloperidol (a typical APD) has been suggested as a potential strategy to improve schizophrenia. Recently, an analog of aripiprazole, UNC9994, was developed. UNC9994 does not affect dopamine 2 receptor (D2R)-mediated Gi/o protein signaling but acts as a partial agonist for D2R/β-arrestin interactions. Hence, one of our objectives was to probe the behavioral effects of co-administrating haloperidol with UNC9994 in the N-methyl-D-aspartate receptor (NMDAR) mouse models of schizophrenia. The biochemical mechanisms underlying the neurobiological effects of dual haloperidol × UNC9994 action are currently missing. Hence, we aimed to explore D2R- and NMDAR-dependent signaling mechanisms that could underlie the effects of dual drug treatments.

The regulatory neuropeptide Y (NPY) is implicated in anxiety and post-traumatic stress disorder (PTSD)-related behaviors. NPY exerts its effects through 5 receptor subtypes, with Y1 and Y2 receptors being predominantly expressed in the rat brain. Activation of Y1 by full-length NPY1-36 induces anxiolytic effects, whereas Y2 binds truncated peptides, eliciting region-specific anxiogenic responses. Dipeptidyl peptidase-IV (DPP-IV) cleaves NPY, thereby modulating its functionality. Sitagliptin, a DPP-IV inhibitor (DPP-IV-I), inhibits the degradation of various vasoactive peptides, including cerebral NPY. As such, the therapeutic potential of DPP-IV-I following a traumatic event remains inconclusive. We assessed the effects of a highly selective DPP-IV-I, administered either shortly after the stressor or intermittently over 3 days, on behavioral outcomes using the predator scent stress (PSS) model of PTSD.

Oxytocin is being evaluated as a potential treatment for psychostimulant use disorders. It is unknown what effect oxytocin has on dopamine signaling in response to psychostimulants in brain regions such as the striatum where oxytocin and dopamine interact to process natural rewards. We investigated the effect of oxytocin on striatal dopamine release stimulated by methylphenidate whose mechanism of action is analogous to that of cocaine.

The results from a pilot, 1-year, randomized, open-label, add-on treatment study in treatment-resistant schizophrenia (TRS) with evenamide, a glutamate modulator, were not associated with any safety abnormalities at all doses (7.5-30 mg bid), with a high retention rate even at 6-month (~85%), and 1-year (~75%), and the absence of psychotic relapses during the 1-year treatment period. Overall, treatment with evenamide showed a gradual, sustained, and clinically important improvement up to 1 year in all efficacy measures (eg, PANSS mean change ~ -20%; CGI-S mean change ~ -1.0). In addition, compared to the results at Week 6, the responder rates generally more than doubled at 1-year (PANSS "≥20% improvement from baseline" = ~45%; CGI-S "2-category of improvement" = ~25%; CGI-C "much improved" = ~40%). These results, rarely replicated in other trials in TRS, support the use of evenamide as an add-on treatment in patients who are not benefiting from their current first- or second-generation antipsychotic medication.

Postoperative cognitive dysfunction (POCD) is a common neurological complication in older patients and correlated with adverse outcomes. 17β-estradiol treatment was reported to provide neuroprotective protection in various neurologic disorders, but whether it attenuated POCD was unknown. The purpose of this study was to explore the effects of 17β-estradiol treatment on POCD and its mechanisms.

Understanding drug addiction as a disorder of maladaptive learning, where drug-associated or environmental cues trigger drug cravings and seeking, is crucial for developing effective treatments. Actin polymerization, a biochemical process, plays a crucial role in drug-related memory formation, particularly evident in conditioned place preference paradigms involving drugs like morphine and methamphetamine. However, the role of actin polymerization in the reconsolidation of heroin-associated memories remains understudied.

Negative symptoms of schizophrenia represent an unmet therapeutic need for many patients in whom pentoxifylline may be effective in terms of its dopaminergic, anti-inflammatory, and cerebral blood flow-increasing properties. This study aimed to evaluate pentoxifylline as a therapeutic agent for improving negative symptoms of schizophrenia.

Hypofunction of the N-methyl-D-aspartate receptor (NMDAR) has been proposed to underlie the pathophysiology of schizophrenia, suggesting that promoting NMDAR activity may alleviate the negative or cognitive symptoms associated with schizophrenia. To circumvent excitotoxicity that may accompany direct agonism of the glutamate binding site on the NMDAR, therapeutic trials have focused on targeting the glycine binding site on the NMDAR. Direct administration of either glycine or D-serine, both of which are endogenous coagonists at the NMDAR glycine site, has yielded mixed outcomes across an array of clinical trials investigating different doses or patient populations. Furthermore, directly administering D-serine and glycine is challenging, and thus attention has turned to alternative, indirect methods that increase endogenous D-serine and glycine levels in the brain, such as D-amino acid oxidase (DAAO) inhibitors and glycine transporter 1 inhibitors, respectively. In this review, we provide an overview of the evidence supporting the potential of NMDAR modulators in general, and DAAO inhibitors in particular, as potential adjunctive treatments for schizophrenia. We also discuss the preclinical and clinical data related to luvadaxistat, an investigational highly selective and potent DAAO inhibitor that was under development for the treatment of the cognitive impairment associated with schizophrenia.

Recent interest in the clinical use of psychedelics has highlighted plant-derived medicines like ayahuasca showing rapid-acting and sustainable therapeutic effects in various psychiatric conditions. This traditional Amazonian plant decoction contains N,N-dimethyltryptamine (DMT) and β-carboline alkaloids such as harmine. However, its use is often accompanied by distressing effects like nausea, vomiting, and intense hallucinations, possibly due to complex pharmacokinetic/pharmacodynamic (PK-PD) interactions and lack of dose standardization.

The tachykinin substance P (SP) facilitates learning and memory processes after its central administration. Activation of its different receptive sites, neurokinin-1 receptors (NK1Rs), as well as NK2Rs and NK3Rs, was shown to influence learning and memory. The basal ganglia have been confirmed to play an important role in the control of memory processes and spatial learning mechanisms, and as part of the basal ganglia, the globus pallidus (GP) may also be involved in this regulation. SP-immunoreactive fibers and terminals, as well as NK1Rs and NK3Rs, were shown to be present in the GP.

Psychedelics are emerging as potential treatments for a range of mental health conditions, including anxiety and depression, treatment-resistant depression, and substance use disorders. Recent studies have also suggested that the psychedelic psilocybin may be able to treat obsessive-compulsive disorder (OCD). Since the 1960s, case studies have reported improvements to obsessive and compulsive behaviors in patients taking psychedelics recreationally. The effects of psilocybin were then systematically assessed in a small, open-label trial in 2006, which found that psilocybin significantly reduced the symptoms of OCD. Reduced compulsive behaviors have also been seen in rodent models of OCD after administration of psilocybin. Nonetheless, the mechanisms underlying the effects of psychedelics for OCD are unclear, with hypotheses including their acute pharmacological effects, changes in neuroplasticity and resting state neural networks, and their psychological effects. This review will evaluate the evidence supporting the theory that psychedelics can be used for the treatment of OCD, as well as the data regarding claims about their mechanisms. It will also discuss issues with the current evidence and the ongoing trials of psilocybin that aim to address these knowledge gaps.

Anhedonic features within major depressive disorder (MDD) have been associated with worse course and outcome and may predict nonresponse to treatment. However, a detailed clinical profile of anhedonia in MDD is still lacking.

Depression is a prevalent and disabling disorder that poses serious problems in mental health care, and rapid antidepressants are novel treatments for this disorder. Cannabidiol (CBD), a non-intoxicating phytocannabinoid, is thought to have therapeutic potential due to its important neurological and anti-inflammatory properties. Despite major advances in pharmacotherapy in experimental animals, the exact mechanism of antidepressant-like effects remains to be elucidated.

Gonadal hormones have been reported to be involved in the molecular mechanisms of schizophrenia (SCH). However, only a few studies have examined the gonadal hormone dysfunctions in first-episode schizophrenia (FES) patients, in particular in young patients with SCH. This study was designed to investigate the sex differences in gonadal hormones in young and antipsychotic-naïve FES patients.

While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (3 double-blind [DB] studies: DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared with a placebo (PBO) combined with active-comparator, on cognition in patients with TRD.