Adiponectin blood levels and autism spectrum disorders: a systematic review.

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.

Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.

Surge of Midazolam Use in the Midst of Lorazepam Shortage.

BACKGROUND: Lorazepam is a widely prescribed benzodiazepine that is used to manage anxiety, insomnia, and status epilepticus and is used for pre-anesthetic care as well as several off-label indications including aggression, alcohol withdrawal, panic disorder, chemotherapy-associated anticipatory nausea, and catatonia. Recent increases in demand, manufacturing changes, and quality control issues have resulted in a shortage of injectable and oral lorazepam, prompting clinicians to use alternatives. One such alternative is midazolam, a drug that has been used primarily in the intensive care unit and anesthesia settings. PROCEDURES: This article examines the significant pharmacologic differences between lorazepam and midazolam. In addition, this article provides dosage guidelines based on the current scientific knowledge and recommendations for conversion equivalencies. RESULTS: The clinical preference for lorazepam can be attributed to its simpler metabolism with no active metabolites, better suitability for patients with less severe hepatic and renal impairment, less risk of adverse reactions, fewer drug-drug interactions, and greater desirability for special populations. In periods of shortages, midazolam has been shown to be effective for a number of off-label uses. To manage conditions that have not been extensively studied, clinicians may opt to use conversion equivalencies, with the caveat that guidelines may vary greatly between institutions and online sources; therefore, it would be best to start low and titrate slowly. CONCLUSIONS: Our goal is to aid clinicians in safely and effectively prescribing midazolam during the shortage of injectable lorazepam so that patients are provided the same effects and benefits.

Can antidepressant use be associated with emotional blunting in a subset of patients with depression? A scoping review of available literature.

INTRODUCTION: Despite frequent recognition of emotional blunting in the published literature, either as a primary symptom of depression or as an adverse effect of antidepressants, there is no systematic synthesis on this topic to our knowledge. We undertook this scoping review to assess the prevalence, clinical features, implicated causes and management of emotional blunting, outlining the phenomenological and clinical gaps in research. METHOD: A systematic search was done until March 15, 2022, to include all original studies (i.e., interventional trials, cohort & cross-sectional studies, case reports, and case series). All reviewed data were delineated to answer pertinent clinical, phenomenological, and management questions related to the phenomenon of emotional blunting. RESULTS: A total of 25 original studies were included in our scoping review. Emotional blunting was described as a persistent diminution in both positive and negative feelings in depressed patients, who could subjectively differentiate it from their acute symptoms. However, the literature lacked the distinction between emotional blunting as a primary symptom of depression or an adverse effect of antidepressants. Common clinical strategies to manage antidepressant-induced emotional blunting included dose reduction or switching to a different antidepressant. CONCLUSION: Emotional blunting was a significant patient-reported concern with antidepressants. Future research should clarify phenomenological and neurobiological constructs underlying emotional blunting to improve diagnostic and management skills.

Insight and neurocognitive functioning in bipolar subjects.

BACKGROUND: Insight concerning having a mental illness has been found to influence outcome and effectiveness of treatment. It has been studied mainly in the area of schizophrenia with few studies addressing other disorders. This study evaluates insight in individuals with bipolar disorder using the Scale to Assess Unawareness of Mental Disorder (SUMD), a comprehensive interview for evaluation of awareness of illness and attribution of symptoms. The hypothesis was that in bipolar disorder level of awareness may be associated with numerous factors including neurocognitive function, structural changes in the frontal lobes and hippocampus evaluated by MRI, neurocognitive status, severity of mania and other psychiatric symptoms and comorbid alcoholism. METHOD: In order to evaluate this hypothesis 33 individuals with DSM-IV diagnosed bipolar disorder, some with and some without comorbid alcoholism, were administered the SUMD and a number of other procedures including a quantitative MRI measuring volume of the frontal lobes and hippocampus, a brief battery of neurocognitive tests, the Brief Psychiatric Rating Scale, and the Young Mania Rating Scale. The data were analyzed by comparing participants with and without alcoholism on these procedures using t tests and by linear multiple regression, with SUMD ratings of awareness and attribution as the dependent variables and variable sets from the other procedures administered as multivariate independent variables. RESULTS: The median score obtained from the SUMD for current awareness was in a range between full awareness and uncertainty concerning presence of a mental disorder. For attribution, the median score indicated that attribution was usually made to the illness itself. None of the differences between participants with and without comorbid alcoholism were significant for the SUMD awareness and attribution scores, neurocognitive or MRI variables. The multiple regression analyses only showed a significant degree of association between the SUMD awareness score and the Young Mania Rating Scale (r(2)=.632, p<.05). A stepwise analysis indicated that items assessing degree of insight, irritability, and sleep disturbance met criteria for entry into the regression equation. None of the regression analyses for the SUMD attribution item were significant. CONCLUSIONS: Apparently unlike the case for schizophrenia, most of the participants, all of whom had bipolar disorder, were aware of their symptoms and correctly related them to a mental disorder. Hypotheses concerning the relationships between degree of unawareness and possible contributors to its development including comorbid alcoholism, cognitive dysfunction and structural reduction of gray matter in the frontal region and hippocampus, were not associated with degree of unawareness but symptoms of mania were significantly associated. The apparent reason for this result is that the sample obtained a SUMD modal awareness score of 1 or 2, reflecting the area between full awareness and uncertainty about having a mental disorder. None of the participants were rated as having a 5 response reflecting the belief that s/he does not have a mental disorder.

Recent Developments in Pharmacotherapy of Depression: Bench to Bedside.

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.

Seventy Years of Antipsychotic Development: A Critical Review.

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.

Effect of transcranial magnetic stimulation on postural control of individuals with major depressive disorder: A case report.

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.

Neurobiological Correlates of Psilocybin Response in Depression.

Objective: To synthesize the neurobiological basis of brain-resetting effects of psilocybin and identify neuroimaging correlates of psilocybin response in depressed patients.Data Sources: MEDLINE(R), Embase, APA PsycINFO, Cochrane, and CINAHL were systematically searched on June 3, 2022, with no date restrictions using the following string: (psilocybin) AND (psychedelics) AND (MRI) OR (fMRI)) OR (PET)) OR (SPECT)) OR (imaging)) OR (neuroimaging)).Study Selection: After duplicates were removed from 946 studies, 391 studies remained, of which 8 qualified for full-text analysis, but only 5 fulfilled the eligibility criteria of randomized, double-blind, or open-label neuroimaging study with psilocybin treatment in depressed patients.Data Extraction: The Covidence platform was used for deduplication and bias assessment. The a priori data points included concomitant psychological intervention, modality of neuroimaging technique, changes in depression scores, brain functional changes, and association between functional and psilocybin response. Assessment bias was assessed with the standard risk of bias tool for randomized controlled trials and the tool for risk of bias in nonrandomized studies of interventions.Results: Four studies were open-label, and one was a combined open-label and randomized controlled trial using functional magnetic resonance imaging. Psilocybin-assisted psychotherapy was administered in 3 studies, 1 in refractory and 2 in nonrefractory patients. The remaining 2 studies were in refractory patients. The transient increase in psilocybin-induced global connectivity in major neural tracts and specific areas of brain activation was associated with antidepressant response.Conclusions: Transient functional brain changes with psilocybin therapy resemble the "brain reset" phenomenon and may serve as the putative predictors of psilocybin antidepressant response.

High-Dose Therapy in Treatment-Refractory Psychosis: A Retrospective Study.

Objective: To examine the impact of antipsychotic dose adjustments (mainly reduction) on the efficacy and tolerability of antipsychotic medications (APMs) to facilitate hospital discharge in long-term hospitalized forensic patients with treatment-refractory psychosis.Methods: This was a retrospective review of the medical charts of 22 patients with psychosis who were discharged from January 2020 to August 2020 from a long-term state psychiatric facility after restoration of their competency to stand trial. Due to the lack of specific guidelines, the high-dose therapy was defined as a dose ≥ 50% above the average package insert dose. The primary outcome was discharge time after the antipsychotic dosing adjustments.Results: Sixty-eight percent of subjects, who were hospitalized for a mean ± SD total of 11.6 ± 5.3 months, were discharged after 2.3 ± 0.78 months of 44.4% antipsychotic dose reduction. Two patients, who were hospitalized for 14.5 ± 6.7 months, were discharged after 4 months of optimizing their subtherapeutic doses. Five patients, who were already receiving effective dosages, were discharged after a total hospital duration of 6.8 ± 2.17 months.Conclusions: The results from this study extend the finding of beneficial effects of antipsychotic dose reduction from prior reports to the forensic population.

Dispensing practices for psychotropic medications amongst pharmacists in Karachi, Pakistan.

Background & Objective: Uninformed use of medications can be dangerous especially those medications that require some level of monitoring to ensure safety and tolerability and prevent misuse, such as benzodiazepines and other psychotropic medications. In most developed countries, medications (except over-the-counter medications) are not dispensed without a physician's script. This may not be true for developing countries, like Pakistan, where nearly all medications are dispensed without a script. However, the extent and nature of script-less dispensing has never been studied. This study was designed to investigate the extent and prevalence of dispensing psychotropic medications without physicians' prescriptions, and the pharmacy practices, including the staff qualifications, to not only dispense but also recommend psychotropic medications, in Karachi, Pakistan. Method: A Cross-sectional study was conducted in Karachi over three months (September 2021 to November 2021) with 200 pharmacists in various pharmacies, using a structured questionnaire in a convenient study sample. Pharmacists from registered pharmacies were included in the study. Statistical analysis was done using the Chi-Square test of association. Results: Out of 200 pharmacists working at various locations, 89.0% did not required prescriptions to dispense medications, with benzodiazepines being the most frequently dispensed medication. Surprisingly, only 9.0% had a bachelor's in pharmacy and were qualified enough to legally dispense medications. 76.0% admitted to recommending medications to the patients. Since many of the pharmacists were not qualified enough to dispense medications, 78.5% mentioned that they did not had awareness regarding the abuse potential of psychotropic medications. Conclusion: Dispensing of psychotropic medications without prescriptions and recommending such medications has been a significant issue in the past. Our study reveals this practice to be prevalent in this part of the world, posing a serious threat to the patients. Steps should be taken by the government to ensure proper dispensing of these medications having an abuse potential to prevent harm.

Different Modalities of Transcranial Magnetic Stimulation to Manage Schizophrenia.

Objective: To analyze all current literature related to different transcranial magnetic stimulation (TMS) modalities in the management of schizophrenia symptoms and compare the main controversies in the outcome measures.Data Sources: A comprehensive search in Ovid MEDLINE, APA PsycINFO, and PubMed was conducted (1996 to present) to identify all articles using the search terms schizophrenia and single pulse TMS, schizophrenia and paired pulse TMS, schizophrenia and repetitive TMS, schizophrenia and deep TMS, and schizophrenia and TBS.Data Selection: Search results were limited to the English language and human subjects. Unrelated articles were excluded after the initial review. Nineteen studies fulfilled the eligibility criteria. These studies included 531 schizophrenia patients and 283 healthy controls.Results: While some adverse effects of TMS are reported, the process is generally considered safe. However, discrepancies exist regarding the length of the cortical silent period. The cortical silent period is thought to be mediated by γ-aminobutyric acid (GABA) receptors and is considered a useful probe to assess motor cortical inhibition. It is generally believed that patients with schizophrenia present changes in the cortical silent period due to GABA abnormalities. A few physiologic studies utilized TMS to study motor cortical excitability in schizophrenia and reported longer, and some shorter, cortical silent periods compared with healthy controls. Also, some studies reported a shorter cortical silent period for unmedicated versus medicated patients, while others reported no differences.Conclusion: TMS treatment is commonly reported to improve auditory hallucination in schizophrenia. Advantage of use of deep TMS over repetitive TMS, however, is controversial.

Novel combination strategy to optimize treatment for PTSD.

Post-traumatic stress disorder (PTSD) is increasingly recognized as a serious and potentially debilitating condition in combat veterans returning from Iraq and Afghanistan. Exposure to a potentially life-threatening event such as military combat may be followed by PTSD. Despite recent advances in pharmacotherapy for PTSD, monotherapy with the currently available medications is only partially effective, as demonstrated in large clinical trials of combat veterans with PTSD. This underscores the need to investigate novel combination strategies to enhance treatment response in PTSD. The α-1 adrenergic receptor (AR) antagonist, prazosin, appears promising in recent studies for its capacity to reduce trauma-related nightmares (a group B night-time intrusion symptom) and insomnia (a group D night-time arousal symptom), while recent evidence supports using the ß-AR antagonist, propranolol, to dampen the emotional content of traumatic memories (daytime intrusion symptoms including flashbacks, intrusive recollections of traumatic event, and heightened physiological reactivity/ responsivity to trauma reminders). In this review, we present data supporting the potential utility of combined drug regimen (prazosin and propranolol) acting through different noradrenergic mechanisms, with the potential to target more than one set of PTSD symptoms to optimize PTSD treatment.

Genetic Testing for Antipsychotic Pharmacotherapy: Bench to Bedside.

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.

Valproic acid autoinduction: a case-based review.

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.

COVID-Related Psychosis in Adolescents: A Case-Based Review.

Despite several reports of the neuropsychiatric effects of coronavirus disease 2019 (COVID-19) in older adults, only a few cases of COVID-related psychosis have been reported in young patients. This case-based review compares the clinical presentations of 2 previously published cases of adolescent patients who developed psychosis in the context of COVID-related complications with a new case of a male adolescent who developed post-COVID psychosis. A discussion to raise clinicians' awareness of COVID-related psychosis in young patients as well as the need for cautious use of antipsychotic medications in this highly vulnerable age group is also provided.

Relationship Between Clozapine Levels and Acute Inflammatory Stress.

Stress-induced changes in pharmacokinetics can significantly alter the plasma levels of some drugs such as clozapine. This report describes the case of a middle-aged man with schizoaffective disorder, bipolar type who showed sustained elevation in clozapine levels 3 days after discontinuation. Before the clozapine levels were drawn, he had developed acute bacterial pneumonia and signs of acute bacterial meningitis followed by neuroleptic malignant syndrome after he received multiple doses of intravenous haloperidol for worsening psychosis and aggressive behavior. Existing literature on this topic is also reviewed to investigate potential reasons for sustained clozapine levels during acute inflammatory stress and neuroleptic malignant syndrome.