Search

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.

Background: Schizophrenia-like presentations of frontotemporal dementia (FTD) are well documented in medical literature, especially during the initial stage of the illness. We present an interesting case of middle-aged white male, who was initially misdiagnosed with major depression at age 50 and then with schizophrenia due to florid psychosis typically seen in Mild Behavioral Impairment (MBI). It was not until over 4-years that a detailed clinical history along with specific investigations confirmed the diagnosis of right temporal variant frontotemporal dementia (rtv-FTD). Methods: The unusual presentation of this case warranted 2-deoxy-2-[fluorine-18]fluoro- D-glucose integrated with computed tomography (FDG-PET) and comprehensive neuropsychological testing to estblish a final diagnosis. Results: The results from neuroimaging and neuropsychological testing supported a diagnosis of rtv-FTD without any evidence for Alzheimer’s dementia. Conclusion: This case illustrates that late-onset atypical psychiatric symptoms should be evaluated for neurocognitive disorders, and the evaluation should include neuroimaging. It is preferable that the neuroimaging findings be personally interpreted by the provider, who therefore needs to be skilled in interpreting neuroimaging studies.

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.

Objective To demonstrate how effectively aripiprazole can be utilized to manage antipsychotic-induced hyperprolactinemia. Methods The files of 3 female patients with a history of psychotic illness and hyperprolactinemia who were treated at a state hospital between February 2018 and May 2019 were retrospectively analyzed. All were found to have elevated prolactin levels and underwent treatment with aripiprazole in addition to their concomitant medications. Results In general, the addition of aripiprazole to the treatment regimen of each of the patients corresponded to a decline in their serum prolactin levels. Conclusions Hyperprolactinemia is frequently observed in patients treated with antipsychotic medications. Low-dose treatment with aripiprazole may offer a relatively rapid relief from sustained hyperprolactinemia and associated adverse effects even after a long-acting injectable is discontinued.

Clozapine is the only approved treatment for Treatment-Refractory Schizophrenia. Here we describe a case series of three hospitalized patients with clozapine nonresponse. One of them responded to clozapine after dose adjustments were made for an interaction between clozapine and ciprofloxacin. The other two cases remained clozapine nonresponders despite optimizing clozapine treatment. However, both these patients responded to other antipsychotic medications (APMs) with better tolerability than observed with clozapine treatment. This case series focuses on diagnosing a genuine from a pseudo-nonresponse to clozapine and to consider other APMs in genuine nonresponse before switching to invasive interventions, such as ECT.

Background Treatment-resistant aggressive behavior is a complex psychoneurological phenomenon with high health care and societal costs commonly observed in mental illnesses involving psychosis. Here, we report a preliminary evaluation of treatment with dextromethorphan/quinidine in 4 adult patients with significant history of psychosis-related aggression and impulsive behaviors. Methods The files of 4 inpatients with DSM-5-defined psychotic disorder and treatment-resistant aggression treated at the Oregon State Hospital (Salem, Oregon) between June and November of 2017 were retrospectively analyzed. The patients (age: mean ± SD = 59.8 ± 7.6) received open-label treatment with dextromethorphan/quinidine (final dose 20 mg/10 mg twice daily) for at least 12 weeks. Outcome was measured on the basis of patient self-report, treatment team evaluation, and physical examination by psychiatrists and primary care physicians. Results Three of the 4 patients were considered responders to dextromethorphan/quinidine based on clinical impressions of reduction in aggression and impulsive behavior. The nonresponder, who had a history of multiple traumatic brain injuries, showed mild improvement in agitation but continued to display impulsive self-harm behavior despite treatment. Dextromethorphan/quinidine was generally well-tolerated. No metabolic, gastrointestinal, or cardiovascular side effects were observed. Conclusions These preliminary findings support dextromethorphan/quinidine as a potential alternative to conventional regimens for treating aggression and impulsive behavior in patients with psychotic disorder. These results should be interpreted cautiously, as extended, double-blinded, placebo-controlled studies with a larger sample size are needed to validate findings from this retrospective case series.

Accurate and noninvasive quantification of regional cerebral blood perfusion (CBF) of the human brain tissue would advance the study of the complex interplay between human brain structure and function, in both health and disease. Despite the plethora of works on CBF in gray matter, a detailed quantitative white matter perfusion atlas has not been presented on healthy adults using the International Consortium for Brain Mapping atlases. In this study, we present a host of assurance measures such as temporal stability, spatial heterogeneity and age effects of regional and global CBF in selected deep, cortical gray matter and white matter tracts identified and quantified using diffusion tensor imaging (DTI). We utilized whole brain high-resolution DTI combined with arterial spin labeling to quantify regional CBF on 15 healthy adults aged 23.2-57.1years. We present total brain and regional CBF, corresponding volume, mean diffusivity and fractional anisotropy spatial heterogeneity, and dependence on age as additional quality assurance measures to compare with published trends using both MRI and nuclear medicine methods. Total CBF showed a steady decrease with age in gray matter (r=-0.58; P=.03), whereas total CBF of white matter did not significantly change with age (r=0.11; P=.7). This quantitative report offers a preliminary baseline of CBF, volume and DTI measurements for the design of future multicenter and clinical studies utilizing noninvasive perfusion and DT-MRI.

Despite advances in pharmacotherapy, schizophrenia continues to carry a high societal disease burden related to positive and negative symptoms, and neurocognitive deficits and severe functional impairment. Findings from epigenetics have yet to translate the epigenetics targets to efficacious drug therapy. We review the repertoire of CNS pharmacology of curcumin derived from Curcuma Longa, commonly known as “turmeric”: the well-known curry extract. We highlight the body of evidence in support of the emerging role of curcumin as a panhistone deacetylase (HDAC) inhibitor regulating the expression of genes involved in inflammation and NMDA N-methyl-aspartic acid (NMDA)-glutamate systems, as related to schizophrenia. Based on the findings from translational studies of curcumin extracts, curcumin C-3 complex formulation (Supercurcumin™) and patented liposome-based curcumin (Lipocurc™), we propose that intravenous infusion of Lipocurc™ holds promise as the novel drug lead and preferred targeted brain delivery mode in reprogramming faculty epigenetics network and in remodeling restrictive chromatin configuration in schizophrenia. Phase II/Phase III epigenetics-biomarker-based randomized placebo-controlled trials in treatment resistant schizophrenia are warranted. Our approach of intravenous infusion of Lipocurc™ behaving as pan HDAC inhibitor represents a new paradigm of drug development in combining targeting epigenetics footprints with brain-specific drug delivery system in schizophrenia. Lipocurc™ can open the Pandora box in unexplored therapeutics vistas in modifying the phenotype of treatment resistant schizophrenia.

The authors examined whether African Americans, compared with whites, received guideline-concordant care for bipolar I disorder.A retrospective analysis was conducted of data for patients who received a diagnosis of bipolar I disorder in fiscal year 2001 and received care in facilities in the Department of Veterans Affairs (VA) mid-Atlantic region. Indicators of guideline-concordant care were based on prescription data and data on utilization of inpatient and outpatient services from VA databases.A total of 2,316 patients with a diagnosis of bipolar I disorder were identified. Their mean age was 52 years; 9.4 percent (N=218) were women, and 13.1 percent (N=303) were African American. Overall, mood stabilizers were prescribed for 74.6 percent (N=1,728) of the patients; 67.1 percent (N=1,554) had an outpatient mental health visit within 90 days after the index diagnosis, and 54.3 percent (N=1,258) had an outpatient visit within 30 days after discharge from a psychiatric hospitalization. Multivariate logistic regression analyses with adjustment for sociodemographic and facility factors revealed that African Americans were less likely than whites to have an outpatient follow-up visit within 90 days after the index diagnosis. Race was not associated with receipt of mood stabilizers or use of outpatient services after a hospital discharge.Although a majority of patients received guideline-concordant care for bipolar disorder, potential gaps in continuity of outpatient care may exist for African-American patients.

Objective: Treatment of coexisting medical comorbidities may reduce the risk of adverse outcomes among patients with bipolar disorder. We determined the prevalence of general medical conditions in a population-based sample of patients diagnosed with bipolar disorder in the Veterans Administration (VA). Methods: We conducted a cross-sectional study of patients (n = 4310) diagnosed with bipolar disorder in fiscal year 2001 receiving care at VA facilities located within the mid-Atlantic region. General medical conditions were assessed using ICD-9 codes, and we compared the prevalence of each condition in our bipolar sample with national data on the VA patient population. Results: The mean age was 53 (SD = 13), 10% were women, and 12% African-American. The mean age of the VA national patient population was higher (58 years). The most prevalent conditions among patients with bipolar disorder included cardiovascular (e.g. hypertension, 35%), endocrine (e.g. hyperlipidemia, 23%; diabetes, 17%), and alcohol use disorder (25%). When compared with national data, the prevalence of diabetes was higher in the bipolar cohort than in the national cohort (17.2% versus 15.6%; p = 0.0035). Hepatitis C was more common in the bipolar group than the national cohort (5.9% versus 1.1%; p

Recently with the changing landscape of the aging population and the increase in incidence of Alzheimer’s disease (AD), there has been marked interest to develop strategies to prevent, delay and modify AD. We review the diverse lines of evidence in support of the emerging role of cAMP-mediated Phosphodiesterase (PDE) signalling with respect to aging, inflammation and depression. In view of the link of PDE to Epigenetic complex, targeting PDE through designing modulators and inhibitors of PDE may represent a novel approach in AD therapeutics. We review critically the translational studies of the proprietary Zembrin extract harvested and processed from the South African plant, Sceletium tortuosum, highlighting the dual property of Zembrin in targeting coupling of PDE and serotonin signaling mechanisms in vitro and in vivo models of AD and cognition. The promising clinical findings of Zembrin in cognition suggest that Zembrin extract may merit randomized controlled trials in AD to establish the efficacy and safety in AD.

Converging evidence identifies stress-related disorders as putative risk factors for Alzheimer Disease (AD). This article reviews evidence on the complex interplay of stress, aging, and genes-epigenetics interactions. The recent classification of AD into preclinical, mild cognitive impairment, and AD offers a window for intervention to prevent, delay, or modify the course of AD. Evidence in support of the cognitive effects of epigenetics-diet, and nutraceuticals is reviewed. A proactive epigenetics diet and nutraceuticals program holds promise as potential buffer against the negative impact of aging and stress responses on cognition, and can optimize vascular, metabolic, and brain health in the community.

This report seeks to analyze and discuss different pharmacokinetic factors that might be responsible for a case of clozapine toxicity on a conventional clozapine dose. A 41-year-old Caucasian male with schizoaffective disorder was cross-titrated to 400 mg/day of clozapine to manage inadequate response on 6 mg/day of risperidone. A week later the patient became gradually confused and disoriented and eventually lost consciousness. The combined clozapine and norclozapine levels were elevated at 2500 ng/mL. Patient's symptoms resolved after clozapine was reduced to 75 mg/day with a reduction in clozapine and norclozapine levels to 420 ng/mL. Toxic clozapine levels may result from abnormal drug absorption, distribution, metabolism or elimination. Changes in absorption and/or distribution are unlikely to explain the toxic levels as clozapine has relatively high oral bioavailability at steady state and a large volume of distribution. In terms of metabolism, clozapine is primarily metabolized by CYP1A2, which biotransforms clozapine to norclozapine. However, it is unlikely that CYP1A2 was responsible, as any reduction in CYP1A2 activity would have likely altered clozapine and norclozapine ratio, which was not observed in this patient. Involvement of other CYP enzymes in the development of clozapine toxicity was ruled out through genotyping. Since liver and renal function tests were also within normal limit, it is difficult to pinpoint a single pharmacokinetic factor responsible for unusually high clozapine and norclozapine levels in this patient. However, a combination of various pharmacokinetic factors may provide an explanation for clozapine toxicity in this patient. Conclusion Some patients can develop unusually high levels of clozapine and/or its metabolites on routine clozapine dosages resulting in clinically serious adverse effects as observed in our patient.

Objective: As of July 9, 2004, to report the first case of potential pharmacodynamic and pharmacokinetic interactions between clozapine and phenytoin occurring simultaneously in a patient. Case Summary: A 60-year-old African American female treated with clozapine and phenytoin developed neutropenia after the clozapine dose was increased from 650 to 900 mg/day. The neutropenia resolved after phenytoin was discontinued, and the clozapine dose was decreased from 900 to 300 mg/day without any significant change in clozapine levels. Discussion: Neutropenia can be explained on the basis of a potential pharmacodynamic interaction between clozapine and phenytoin. However, neutropenia did not occur until the clozapine dose was increased from 650 to 900 mg/day, corresponding to an increase in clozapine levels from 90 to 114 ng/mL. Neutropenia resolved after phenytoin was discontinued, even though the clozapine concentrations achieved after phenytoin discontinuation (137 ng/mL) were almost the same as those when phenytoin was coadministered (114 ng/mL). This finding suggests that neutropenia was precipitated not only by an increase in the clozapine dose, but also by the concomitant use of phenytoin. On the other hand, the decrease in clozapine concentrations can be explained on the basis of a pharmacokinetic interaction between clozapine and phenytoin. Phenytoin has the potential to decrease clozapine concentrations by inducing the activity of CYP1A2, which provides a primary metabolic pathway for clozapine. Conclusions: Concomitant use of phenytoin may not only decrease clozapine concentrations and compromise its efficacy, but can also precipitate neutropenia. Although based on a single case report, these findings warrant caution when coadministering clozapine and phenytoin.