Explore the vast range of titles available.

Since the mid-1950s discovery of the first effective antipsychotic medications (APM), we have only been able to improve the tolerability but not the overall efficacy of currently available APMs, as reflected by effectiveness trials in Europe and the United States. This inability to develop more effective APMs is attributable to multiple factors, including failure to create and use assessment tools to assess core symptom domains in schizophrenia, move beyond the dopaminergic hypothesis and to develop “me too” drugs, imposing ill-defined research domain criteria, and lacking federal funding for clinical trials. The classification of APMs is also confusing, including second-generation, partial agonists, and multimodal APMs in the same class of APMs, despite significant differences in their mechanisms of action. Other factors stagnating drug development include inadequate sample sizes to address heterogeneity, lack of statistical measures correlating with clinical significance, using the atheoretical basis of psychiatric diagnoses, failure to control placebo response, and high cost of newer and perhaps more tolerable APMs. Furthermore, there has been a failure to develop early predictors of antipsychotic response and various tools to optimize an APM response. Finally, some mental health providers are also responsible for the suboptimal use of APMs, by using excessive maintenance doses, often with irrational polypharmacy, further compromising effectiveness and medication adherence. However, some bright spots in antipsychotic development include improved tolerability of APMs and long-acting injectables to address the high prevalence of medication nonadherence. This review critically reviews 70 years of antipsychotic development, the reasons behind the failure to develop more effective APMs, and suggestions for future direction.

For the last 70 years, we did not move beyond the monoamine hypothesis of depression until the approval of the S-enantiomer of ketamine, an N-methyl-D-aspartate (NMDA) receptor blocker and the first non-monoaminergic antidepressant characterized by rapid antidepressant and antisuicidal effects. A similar profile has been reported with another NMDA receptor antagonist, dextromethorphan, which has also been approved to manage depression in combination with bupropion. More recently, the approval of a positive allosteric modulator of GABA-A receptors, brexanolone, has added to the list of recent breakthroughs with the relatively rapid onset of antidepressant efficacy. However, multiple factors have compromised the clinical utility of these exciting discoveries in the general population, including high drug acquisition costs, mandatory monitoring requirements, parenteral drug administration, lack of insurance coverage, indirect COVID-19 effects on healthcare systems, and training gaps in psychopharmacology. This narrative review aims to analyze the clinical pharmacology of recently approved antidepressants and discuss potential barriers to the bench-to-bedside transfer of knowledge and clinical application of exciting recent discoveries. Overall, clinically meaningful advances in the treatment of depression have not reached a large proportion of depressed patients, including those with treatment-resistant depression, who might benefit the most from the novel antidepressants.

[...]every effort should be made to optimize clozapine treatment in patients who remain unresponsive despite adequate clozapine dose and duration. [...]the clozapine dose was gradually lowered from 800 to 400 mg/day over the course of 2 months, followed by the gradual discontinuation of quetiapine over the course of 4 months. [...]higher-than-conventional doses of clozapine are more likely to increase the adverse effects mediated by these receptors than the clozapine response. A good example is genetically mediated rapid inducibility of CYP1A2 with smoking13 and omeprazole,14 which may be diagnosed by a low ratio between clozapine and norclozapine levels, suggesting ultra-rapid conversion of clozapine into norclozapine.15 Although this patient did not show any decrease in the clozapine to norclozapine ratio, higher norclozapine levels may increase the risk for neutrophil toxicity,16 other adverse effects (eg, sedation, weight gain, and metabolic disturbances), and a decrease in efficacy.17 However, norclozapine is a muscarinic agonist, and higher norclozapine levels may benefit cognitive function and help counter clozapine's anticholinergic effects.18 Clozapine TDM may help diagnose genetic differences in clozapine's metabolism and help detect drug interactions when a concomitantly administered drug alters the clozapine to norclozapine ratio by changing CYP1A2 activity.

Objective To review the relationship between adiponectin levels and autism spectrum disorders (ASDs) in children. Background ASDs are associated with pervasive social interaction and communication abnormalities. Researchers have studied various pathophysiological mechanisms underlying ASDs to identify predictors for an early diagnosis to optimize treatment outcomes. Immune dysfunction, perhaps mediated by a decrease in anti-inflammatory adipokine, adiponectin, along with changes in other adipokines, may play a central role in increasing the risk for ASDs. However, other factors, such as low maternal vitamin D levels, atherosclerosis, diabetes, obesity, cardio-metabolic diseases, preterm delivery, and oxytocin gene polymorphism may also contribute to increased risk for ASDs. Methods Searches on the database; PubMed, Google Scholar, and Cochrane using keywords; adiponectin, adipokines, ASD, autism, autistic disorder, included English-language studies published till September 2022. Data were extracted on mean differences between adiponectin levels in children with and without ASDs. Results The search yielded six studies providing data on adiponectin levels in young patients with ASDs. As can be seen from Table 1, four of the six studies were positive for an inverse correlation between ASD and adiponectin levels. In addition, two of the four positive and one negative studies found low adiponectin levels associated with and the severity of autistic symptoms. However, results from one reviewed study were insignificant. Conclusion Most studies reviewed yielded lower adiponectin levels in children with ASDs as well as the severity of autistic symptoms.

There is growing research interest in learning the genetic basis of response and adverse effects with psychotropic medications, including antipsychotic drugs. However, the clinical utility of information from genetic studies is compromised by their controversial results, primarily due to relatively small effect and sample sizes. Clinical, demographic, and environmental differences in patient cohorts further explain the lack of consistent results from these genetic studies. Furthermore, the availability of psychopharmacological expertise in interpreting clinically meaningful results from genetic assays has been a challenge, one that often results in suboptimal use of genetic testing in clinical practice. These limitations explain the difficulties in the translation of psychopharmacological research in pharmacogenetics and pharmacogenomics from bench to bedside to manage increasingly treatment-refractory psychiatric disorders, especially schizophrenia. Although these shortcomings question the utility of genetic testing in the general population, the commercially available genetic assays are being increasingly utilized to optimize the effectiveness of psychotropic medications in the treatment-refractory patient population, including schizophrenia. In this context, patients with treatment-refractory schizophrenia are among of the most vulnerable patients to be exposed to the debilitating adverse effects from often irrational and high-dose antipsychotic polypharmacy without clinically meaningful benefits. The primary objective of this comprehensive review is to analyze and interpret replicated findings from the genetic studies to identify specific genetic biomarkers that could be utilized to enhance antipsychotic efficacy and tolerability in the treatment-refractory schizophrenia population.

Background: Major depressive disorder (MDD) frequently begins during adolescence and is associated with significant morbidity and mortality. However, little is known about the neurobiology of adolescent depression. A better understanding of the neurobiology will be helpful in developing more effective preventive and treatment interventions for this highly disabling illness. Methods: Using a voxel-based morphometric method, the study compared gray matter and white matter volumes in 22 adolescents with MDD and 22 age- and gender-matched normal controls. Results: Compared with controls, depressed adolescents had smaller gray matter volume in the frontal lobe and caudate nucleus bilaterally and right superior and middle temporal gyri. However, the groups did not differ significantly on white matter volume. Conclusions: These findings in depressed adolescents are consistent with the previous findings of gray matter abnormalities in frontolimbic areas and the striatum in depressed adults and suggest the presence of these structural changes at the onset of depressive illness.

Although valproic acid (VPA) induces the metabolism of multiple other drugs, the clinical reports of VPA autoinduction are rare. A comprehensive literature search yielded only one published case series, which provided the rationale to conduct a review of the published cases along with a new case of VPA autoinduction. Although there may be myriad of reasons for lack of published cases of VPA autoinduction, potential underreporting may be one of the core reasons. Lack of understanding into the highly complex metabolism of VPA may also make it difficult to recognize and report VPA autoinduction. However, it is important to mention that in addition to autoinduction increased elimination of VPA may be mediated by several pharmacokinetic (PK) factors, such as drug interactions, genetic polymorphisms of metabolic enzymes, and protein displacement reactions. As VPA is metabolized by multiple metabolic pathways, the risk for drug interactions is relatively high. There is also a growing evidence for high genetic inducibility of some enzymes involved in VPA metabolism. Protein displacement reactions with VPA increase the biologically active and readily metabolizable free fraction and pose a diagnostic challenge as they are usually not requested by most clinicians. Thus, monitoring of free fraction with total VPA levels may prevent clinically serious outcomes and optimize VPA treatment in clinically challenging patients. This case-based review compares the clinical data from three published cases and a new case of VPA autoinduction to enhance clinicians' awareness of this relatively rare but clinically relevant phenomenon along with a discussion of potential underlying mechanisms.

A review of the learning objectives followed each case presentation to ensure that each resident achieved the presentation’s goals, followed by multiple-choice questions to test residents’ learning. [...]a 3-item paper survey was administered, without any personally identifiable information, to receive feedback from the participating residents and were collected unanimously by the instructor. Educational technologies in problem-based learning in health sciences education: a systematic review.

Accidental falls and major depressive disorder (MDD) are two common conditions associated with aging. Initial treatment of MDD often starts with administering antidepressants, followed by transcranial magnetic stimulation (TMS) for treatment-resistant individuals. The purpose of this case study was to determine the effect of repetitive TMS (rTMS) on postural control of an individual with MDD. A 44-year-old male with recurrent severe MDD was assessed for postural balance during eyes closed and eyes open conditions, pre and post three consecutive sessions receiving high-frequency rTMS (NeuroStar). Total excursion and velocity of sway significantly decreased following rTMS treatment when eyes were closed (p < 0.05). Power of the sway changed, but the changes were not statistically significant. The fractal dimension confidence circle area decreased significantly in eyes closed trials (p < 0.05). It appears that rTMS application can potentially impact postural steadiness in individuals with MDD. Our results warrant further studies with larger study samples.