Major depressive disorder (MDD) is a chronic, highly prevalent, and debilitating mental disorder associated with significant illness and economic burden globally. Exposure to trauma (eg, physical, sexual, emotional abuse, and/or physical, and emotional neglect) is common among individuals with MDD. Persons with MDD and a history of trauma often exhibit an attenuated response to conventional serotonergic antidepressants compared to those with non-traumatized depression. Emerging evidence indicates that exposure to trauma is associated with increased inflammatory markers [eg, C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)] as well as glutamatergic dysregulation in the central nervous system (CNS). It is hypothesized that individuals with MDD and a history of trauma may be conceptualized as a distinct bio-phenotype compared to non-traumatized depression. Furthermore, preliminary evidence positions select glutamatergic modulators as potential, novel, mechanistically-informed therapeutic strategies that may provide benefit to persons with elevated inflammation and glutamatergic dysregulation.

G protein-coupled receptors (GPCRs) are involved in many physiological and pathophysiological processes. Conventional pharmacological models categorize the typology of pharmacologic ligands as agonists or antagonists. Biased agonism is a relatively newer pharmacodynamic characteristic that has potential to optimize therapeutic efficacy while minimizing adverse effects in psychiatric and neurological treatments. We conducted a narrative literature review of articles obtained from PubMed, Embase, and MEDLINE from inception to April 2025, focusing on pharmacologic antagonism (i.e., competitive, noncompetitive, uncompetitive) and agonism (i.e., full, partial, inverse, superagonism, biased). Primary and secondary articles defining these concepts were included, provided they addressed pharmacologic (rather than chemical) antagonism and agonism. Distinct mechanisms of antagonism and agonism were identified, each contributing nuanced receptor modulation beyond the conventional models. Notably, biased agonism facilitates targeted intracellular signaling (e.g., G protein- versus β-arrestin–mediated). Use cases demonstrate relatively greater efficacy (e.g., incretin receptor agonist, tirzepatide) and improved safety (e.g., serotonergic psychedelics, opioids). Biased agonism provides a potential avenue for future drug development, with emerging preclinical evidence suggesting potential to differentially activate intracellular pathways and thereby improve efficacy and safety profiles of psychopharmacologic agents—pending clinical validation. Future research vistas should aim to rigorously assess the long-term outcomes of biased agonism, explicitly addressing individual variability in receptor signaling and therapeutic response.

Schizophrenia is a severe mental disorder with heterogeneous outcomes that depend heavily on symptom stability as a prerequisite for psychosocial rehabilitation and reintegration. Long-acting injectable antipsychotics (LAIs) are a relevant treatment tools that can help advance meaningful outcomes through improved antipsychotic adherence and relapse prevention, deliver pharmacokinetic advantages less achievable with oral formulations, improve patient autonomy, increase functioning, and reduce the risk of premature mortality even more than oral antipsychotics. However, LAIs remain largely underutilized. Non-modifiable and modifiable risk factors for relapse are summarized, potential advantages and disadvantages of LAIs are reviewed, and myths and misconceptions regarding LAIs are outlined and contrasted with evidence. This information is crucial when engaging in shared decision-making and motivational interviewing to educate patients and caregivers about the treatment option of LAIs, including in early illness stages. Since the first episode and early phases of schizophrenia are a defining time, choosing treatments with the greatest potential for improved outcomes is key. In adults with multi-episode schizophrenia, LAIs have shown superiority over oral antipsychotics for relapse/hospitalization and a variety of multiple other efficacy, effectiveness, functionality, and survival metrics. Additionally, LAIs have shown superiority over oral antipsychotics in patients with first-episode/ or early-phase illness, at least in meaningful subgroups of studies and patients that point toward superiority in settings, individuals, and treatment paradigms that more closely match clinical care. Based on this evidence, hesitancies to discuss and offer LAIs in clinical care need to be overcome, framing LAIs not as a last resort but a viable first-line/earlyphase treatment option that can meaningfully transform the long-term course of schizophrenia.

It was found that a significant number of patients with major depressive disorder (MDD) did not respond to the treatment, leading to high ongoing costs and disease burden. The main objective of this study was to find neurobiological indicators that can predict the effectiveness of antidepressant treatment using diffusion tensor imaging (DTI). A group of 103 patients who were experiencing their first episode of MDD were included in the study. After 2 weeks of SSRI treatment, the group of patients was split into two categories: ineffectiveand effective. The FMRIB Software Library (FSL) was used for diffusion data preprocessing to obtain tensor-based parameters such as FA, MD, AD, and RD. Tract-Based Spatial Statistical (TBSS) voxel-wise statistical analysis of the tensor-based parameters was carried out using the TBSS procedure in FSL. We conducted an investigation to determine if there were notable variations in neuroimaging attributes among the three groups. Compared to HC, the effective group showed significantly higher AD and MD values in the left CgH. Correlating neuroimaging characteristics and clinical manifestations revealed a significant positive correlation between CgH-l FA and clinical 2-week HAMD-17 total scores and a significant positive correlation between CgH-r FA and clinical 2-week HAMD-17 total scores. Functional damage to the cingulum bundle in the hippocampal region may predispose patients to MDD and predict antidepressant treatment outcomes. More extensive multicenter investigations are necessary to validate these MRI findings that indicate treatment effectiveness and assess their potential significance in practical therapeutic decision-making.

Roger was a 60-year-old man living with both HIV and schizophrenia who was admitted to the hospital for treatment of a chronic obstructive pulmonary disease exacerbation. He was referred to the psychiatry consultation-liaison team due to persistent psychotic symptoms that had not responded to multiple antipsychotic trials. Roger’s psychiatric history revealed a diagnosis of schizophrenia in early adulthood, marked by hallucinations and delusions of grandeur. Over the next 4 decades, he cycled through jails, prisons, shelters, and periods of homelessness. Though intermittently connected with outpatient care, his illness remained poorly controlled.

Schizophrenia is known to be a disabling psychiatric condition with wide reaching impact on everyday functioning and outcomes. These functional outcomes include increases in all-cause mortality (especially suicide and injury), cognitive and functional capacity deficits, lower reported levels of quality of life (QoL), increased incarceration, higher risk for violence and victimization, and homelessness. Studies have shown that medications and outpatient services can improve each of these functional outcomes in individuals with schizophrenia. However, most studies of pharmacological treatment utilize rating scales that do not reflect these real-world outcomes. This review looks at available studies focused on real-world outcomes and argues for an expansion of this body of research.

In this review, the aim is to differentiate between the 3 second-generation antipsychotics available as long-acting injectables (risperidone/paliperidone, aripiprazole, and olanzapine) and their varied formulations. Differences and similarities among the available products are discussed, including the amenities of care: route of administration (intramuscular or subcutaneous), injection frequency, needle gauge and length, injection volume, injection site, reconstitution procedures, initiation with oral medication or multiple injections, refrigeration requirements, post-injection observation requirements, drug–drug interactions preventing use or requiring dosing adjustments, adjustments requirements for late or missed doses, availability of patient assistance programs, and access barriers for off-label use. Effectiveness in acute and maintenance treatment are reviewed using the metrics of number needed to treat and number needed to harm.

Clozapine is the gold standard for treatment-resistant schizophrenia. In the setting of malignancy with concurrent anti-cancer agent use, clozapine use may be of increased concern. Clozapine cessation holds its own risks. This study aims to systematically review all cases of concurrent pharmacotherapy with clozapine and anti-cancer agents and analyze the psychiatric and physical health outcomes. PubMed, EMBASE, CINAHL, and PsycINFO databases were searched from inception to February 2025. Descriptive statistics and narrative analysis of the included cases occurred. There were 53 cases of clozapine use with anti-cancer agents, with a male to female ratio of 1.7:1 and a mean age of 45.0 years. In 30 cases, clozapine was continued without interruption, and in additional 16 cases, clozapine was recommenced after a period of interruption. In cases with clozapine interruption or discontinuation, 90% noted significant deterioration in mental state despite alternative antipsychotic treatments. There were 34 cases of neutropenia, mostly (94%) in the setting of cytotoxic chemotherapy, with low rates of neutropenic complications. The successful continuation of clozapine with anti-cancer agents can occur, although risk-benefit analysis taking into account individual, clozapine, psychiatric, and physical health factors is required. Consideration of prophylactic neutropenia protective measures should form part of the discussion with the individual and their family.