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.

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.

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.

This chapter discusses the Dutch Law on Compulsory Mental Healthcare (Wvggz), which aims to strengthen the autonomy of patients with severe mental disorders by recognizing that coercive measures can be used not only to prevent harm, but also to restore autonomy. This approach challenges the traditional notion that coercive measures inherently undermine autonomy. The chapter also explores the unintended consequences of the law, such as increased bureaucracy. We argue that while the Wvggz introduces valuable ideas, its practical implementation has highlighted the challenges of translating legislative goals into effective practices.

Anosognosia, a term that denotes a lack of insight into one’s own condition, is a defining characteristic of many psychotic illnesses. As a result, generations of psychiatrists have pursued a paternalistic approach to care. Yet in the past century, the overall trend in patient care has been toward autonomy. What does it mean to respect the autonomy of patients whose lack of insight may bring them harm? This chapter will explore these questions through each of the four principles generally employed in bioethical analysis: beneficence, nonmaleficence, justice, and autonomy. Each will have an illustrative case study and explore how anosognosia can further complicate already perplexing ethical scenarios.

Parkinson’s disease, the second most prevalent neurological disorder, is a multisystem neurodegenerative disease characterized by both motor and non-motor symptoms. Transcranial direct current stimulation (tDCS) is a non-invasive brain neuromodulation technique that has been shown to be effective in some neurological conditions and for some clinical outcomes. To evaluate the efficacy of tDCS combined with gait training in Parkinson’s disease, compared to placebo, absence of treatment, conventional therapy, or other therapies. A systematic review and meta-analysis were performed in accordance with the PRISMA guidelines and registered in PROSPERO CRD42024542552. The literature search was conducted in PubMed, CINAHL, SPORT Discus, Web of Science, Scopus, MEDLINE, and Academic Search Ultimate (EBSCO) databases up to May 2024, limited to trials from the last 10 years. A total of 600 articles were identified; 9 were included in the systematic review and 8 in the meta-analysis. Significant intra-group changes were observed, but in the meta-analysis, no significant differences were seen between tDCS + gait training and tDCS placebo + gait training, although variables such as motor function slightly favored the combination (MD = −0.49; 95% CI [−1.55; 0.57], I2 = 0%). The combination of tDCS and gait training could provide significant motor benefits in terms of gait speed, functional mobility, cadence, motor function, quality of life, 6MWT, coordination and dynamic balance, flexibility, and stretch resistance in patients with Parkinson’s disease, but not in a more effective way than the same training without stimulation.

Continuous glucose monitoring (CGM) has revolutionized diabetes management by providing real-time data on blood glucose fluctuations. Unlike traditional methods, CGM systems offer continuous feedback, enabling individuals to better regulate glucose levels in response to lifestyle factors such as diet, exercise, and stress. This technology has been shown to improve glycemic control and stabilize HbA1c levels. Beyond its primary role in diabetes management, emerging research highlights the relationship between metabolic health and mental wellbeing. Glucose dysregulation has been implicated in mood instability, and fluctuations in blood glucose levels may directly influence emotional states. Notably, some researchers have proposed reclassifying major depressive disorder (MDD) as “Metabolic Syndrome Type II” due to shared pathophysiological mechanisms involving glucose homeostasis and inflammation. Given these connections, CGM technology may offer mental health benefits by promoting glucose stability. For individuals with diabetes who also experience psychiatric conditions such as MDD or generalized anxiety disorder (GAD), CGM use may contribute to improved mood regulation and reduced psychiatric symptoms. By addressing both metabolic and mental health concerns, CGM holds promise as a valuable tool in enhancing overall wellbeing. Further research is warranted to explore the full potential of CGM in supporting mental health outcomes in individuals with metabolic disorders.

Schizophrenia is a severe and disabling psychiatric illness that profoundly affects a person’s ability to think clearly, perceive reality, manage emotions, and engage in daily activities. While antipsychotic medications have long been the cornerstone of treatment, debates persist around their long-term use and potential impacts on brain structure and function. In our review, we examine whether antipsychotic medications improve or worsen long-term outcomes in schizophrenia, particularly when treatment is refused or discontinued. Drawing from randomized controlled trials, large-scale observational studies, forensic outcome data, international guidelines, and neuroimaging research, the findings demonstrate that sustained antipsychotic treatment significantly reduces relapse, improves functional outcomes, and may protect against neurobiological deterioration. In contrast, untreated or inconsistently treated psychosis is associated with higher relapse rates, treatment resistance, cognitive decline, and progressive brain changes. While treatment must be personalized and compassionate, the cumulative evidence supports the critical role of early and continuous antipsychotic use in preserving health, autonomy, and long-term recovery for individuals living with schizophrenia.