A study of elective genome sequencing and pharmacogenetic testing in an unselected population.

BACKGROUND: Genome sequencing (GS) of individuals without a medical indication, known as elective GS, is now available at a number of centers around the United States. Here we report the results of elective GS and pharmacogenetic panel testing in 52 individuals at a private genomics clinic in Alabama. METHODS: Individuals seeking elective genomic testing and pharmacogenetic testing were recruited through a private genomics clinic in Huntsville, AL. Individuals underwent clinical genome sequencing with a separate pharmacogenetic testing panel. RESULTS: Six participants (11.5%) had pathogenic or likely pathogenic variants that may explain one or more aspects of their medical history. Ten participants (19%) had variants that altered the risk of disease in the future, including two individuals with clonal hematopoiesis of indeterminate potential. Forty-four participants (85%) were carriers of a recessive or X-linked disorder. All individuals with pharmacogenetic testing had variants that affected current and/or future medications. CONCLUSION: Our study highlights the importance of collecting detailed phenotype information to interpret results in elective GS.

Multifocal Analysis of Acute Pain After Third Molar Removal.

Background: To analyze the pain modulation capacity profile in a Brazilian population, the relationship between opioid receptor (OPRM1) and Catechol-O-methyltransferase (COMT) 1polymorphisms and pain modulation capacity was determined through preoperative pain modulation tests and acute postoperative pain control evaluation, swelling, and trismus in 200 volunteers undergoing lower third molar removal. Methods: Psychologic and clinical parameters were measured. Patient DNA was sequenced for single nucleotide polymorphisms in OPRM1 and COMT, and the salivary concentration of interleukin (IL)-2 (IL)-6, interferon (IFN)-γ and tumor necrosis factor (TNF)-α was evaluated. Primary outcomes were the influence of all predictors on the fluctuation of pain intensity using a visual analogue scale (VAS), and swelling and trismus on the 2nd and 7th postoperative days. Preoperative pain modulation capacity (CPM), pain catastrophizing scale (PCS), body mass index (BMI), and surgery duration and difficulty were evaluated. Results: Salivary concentration of IFN-γ and IL-2 as well as the duration of surgery influenced the fluctuation of postoperative pain in the VAS, and in the sum of the differences in pain intensity test at 8, 48, and 96 h. BMI influenced swelling, while both BMI and COMT haplotype influenced trismus on the 2nd postoperative day. Conclusion: Polymorphisms in COMT, salivary concentrations of IL-2 and IFN-γ, BMI, and duration of surgery were predictors for pain fluctuation, swelling, and trismus on the 2nd day after lower third molar extraction. This therapy was effective in controlling inflammatory symptomatology after lower third molar extraction and ibuprofen was well tolerated by patients. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT03169127.

CYP450 polymorphisms and clinical pharmacogenetics of ibuprofen after lower third molar extraction.

PURPOSE: This study hypothesized that drugs accumulate in the bloodstream of poor-metabolizing patients and may have more adverse effects and different pain perceptions and aimed to investigate the influence of CYP450 polymorphisms on acute postoperative pain, swelling, and trismus controlled by ibuprofen (600 mg) in 200 volunteers after dental extraction. In addition, surgical outcomes can determine pain, edema, and trismus and indicate inflammatory reactions after oral surgeries. METHODS: Genetic sequencing was performed to identify CYP450 polymorphisms and the surgical parameters evaluated: pre and postoperative swelling, trismus, and temperature; self-reported postoperative pain with visual analog scale (VAS); rescue medication consumed; and severity of adverse reactions. RESULTS: A multiple linear regression model with independent variables [single nucleotide polymorphisms (SNPs), BMI (body mass index), duration, and difficulty of surgery] and dependent variables [postoperative pain by sum of pain intensity difference (SPID), trismus, and swelling] was used for analysis. The duration of surgery was a predictor for pain at 8 h and 96 h after surgery, and BMI was a predictor for both swelling and trismus on the 2nd postoperative day. When evaluating CYP2C8 and C9 genotyped SNPs, it was observed that normal metabolizers showed higher pain levels than the intermediate/poor metabolizers on the postoperative periods as compared with time 0 h. In another analysis, the poor metabolizers for CYP2C8 and C9 presented lower levels of postoperative pain after 8 h and used rescue medication earlier than normal metabolizers. CONCLUSION: Ibuprofen 600 mg was very effective in controlling inflammatory pain after lower third molar surgeries, without relevant adverse reactions; although in a very subtle way, patients with poor metabolism had higher levels of pain in the first hours, and no longer after 8 h, and used pain relief medication earlier. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov ID (NCT03169127), on March 16th, 2017.

Ambulatory detoxification in alcohol use disorder and opioid use disorder.

Ambulatory detoxification in alcohol use disorder and opioid use disorder is an important component in the management of patients experiencing withdrawal symptoms from alcohol or opioids. The goal of withdrawal management is ultimately to provide each patient with comfort and safety. Having the knowledge of the possible signs and symptoms of intoxication and withdrawal assists providers to institute the most appropriate treatment protocol and setting for the patient. Pharmacists play a vital role in choosing appropriate therapeutic management options for common or complex clinical situations involving ambulatory detoxification from alcohol and opioids. Ambulatory detoxification serves as an appealing option to many patients and helps save the limited inpatient resources that many institutions have for those patients with more severe withdrawal presentations.

Clozapine-induced myocarditis: Two case reports and review of clinical presentation and recognition.

Myocarditis is a potentially fatal cardiac disease marked by inflammation of the heart muscle. With a noted black-box warning, rates of clozapine-induced myocarditis are reportedly as high as 3%. Since the first case of clozapine-induced myocarditis was documented in 1994, more than 250 cases have been described in literature with an approximate 33% case-fatality rate. We report 2 cases of patients with primary psychotic disorders treated with clozapine, who developed signs and symptoms of myocarditis. The first was a 35-year-old white male patient with a primary diagnosis of schizoaffective disorder (bipolar type) who was initiated on clozapine after nonresponse to several therapies. On day 26, the patient was admitted to the emergency department for chest pain presenting with eosinophilia and notable elevations in several biomarkers, including troponin and C-reactive protein. The second patient was a 45-year-old black male who was initiated on clozapine for treatment-resistant schizophrenia. On day 13, the patient reported cardiac-related concerns (tachycardia) and flu-like symptoms resulting in hospitalization. Similarly, this patient demonstrated elevated biomarkers (troponin and creatine kinase). Both patients experienced resolution of symptoms after discontinuation of clozapine. Clozapine was not rechallenged for either patient. Review of literature further elucidates the relationship between clozapine and myocarditis, including potential risk factors, pathophysiology, and symptom presentation. Due to the potentially fatal nature of this condition, clinical vigilance and awareness is warranted upon initiation of clozapine through monitoring of symptoms along with cardiac and inflammatory biomarkers as indicated.

Integrating a mental health clinical pharmacy specialist into the Homeless Patient Aligned Care Teams.

INTRODUCTION: To address the complex needs of the homeless veteran population, the US Department of Veterans Affairs created the Homeless Patient Aligned Care Team (H-PACT) model. The South Texas Veterans Health Care System has an established H-PACT model, however it does not include a clinical pharmacy specialist in mental health (MH). METHODS: An H-PACT MH pharmacy resident clinic was created and managed by a postgraduate year-2 psychiatric pharmacy resident. Improvements in access to MH care, Veterans Health Administration performance metrics, and estimated cost savings associated with resident interventions were reviewed to evaluate clinic utility. RESULTS: Over the 6-month clinic time frame, there were a total of 40 patient encounters in which 21 veterans had MH medication evaluation on at least 1 occasion. The average wait time for Veterans previously followed by the H-PACT psychiatrist was approximately 8 weeks. The H-PACT MH pharmacy resident clinic enabled veterans to be evaluated every 4 to 6 weeks. Interventions made by the resident included identification of medication administration errors, medication adjustments, adherence education, reduction in polypharmacy, and referral to other services. Estimated cost savings from clinic interventions totaled $33 613.67. DISCUSSION: The H-PACT MH pharmacy resident clinic allowed for an improvement in wait time for psychiatric pharmacotherapy follow-up for homeless veterans, with interventions that were associated with significant estimated cost savings.

A review of medical marijuana for the treatment of posttraumatic stress disorder: Real symptom re-leaf or just high hopes?

INTRODUCTION: The incidence of posttraumatic stress disorder (PTSD) is common within the population and even more so among veterans. Current medication treatment is limited primarily to antidepressants. Such medicines have shown to produce low remission rates and may require 9 patients to be treated for 1 to have a response. Aside from the Veterans Affairs/Department of Defense guidelines, other guidelines do not recommend pharmacotherapy as a first-line option, particularly in the veteran population. Marijuana has been evaluated as an alternative and novel treatment option with 16 states legalizing its use for PTSD. METHODS: A systematic search was conducted to evaluate the evidence for the use of marijuana for PTSD. Studies for the review were included based on a literature search from Ovid MEDLINE and Google Scholar. RESULTS: Five studies were identified that evaluated the use of marijuana for PTSD. One trial was conducted in Israel and actively used marijuana. Three studies did not use marijuana in the treatment arm but instead evaluated the effects postuse. A retrospective chart review from New Mexico relied on patients to recall their change in PTSD symptoms when using marijuana. Three studies concluded there might be a benefit, but two discouraged its use. Although the two negative studies show a statistical difference in worse PTSD outcomes, clinical significance is unclear. DISCUSSION: Conflicting data exist for the use of marijuana for PTSD; however, current evidence is limited to anecdotal experiences, case reports, and observational studies, making it difficult to make clinical recommendations.

Evaluating psychiatric outcomes associated with direct-acting antiviral treatment in veterans with hepatitis C infection.

INTRODUCTION: Approximately 70% of veterans with hepatitis C virus infection have at least one psychiatric illness. The advent of direct-acting antiviral (DAA) therapy provided an alternative to interferon-alpha regimens and revolutionized treatment, however, the extent of psychiatric effects attributed to these agents are unclear. The primary objective of this pilot study was to prospectively analyze psychiatric outcomes, specifically depression, in veterans with hepatitis C virus infection who are initiated on DAA therapy. METHODS: In this single center, prospective cohort study, psychiatric outcomes were analyzed using Patient Health Questionnaire assessments at baseline and weeks 4, 8, and 12 of complete DAA treatment. Outcome analysis were stratified based on specific DAA therapy and preexisting mental illness (mental health [MH] subjects and non-MH subjects), with a sub-analysis of major depressive disorder patients. RESULTS: Analysis included 48 patients, majority males (96%), with a mean age of 59.4 years (±8.0). Twenty-four (50%) patients had a preexisting MH diagnosis, with major depressive disorder being the most common MH diagnosis (50%, n = 12). Despite a trend toward improvement, no significant changes in questionnaire scores after 12 weeks of DAA therapy were observed for all patient groups (P > .05). Neither MH subjects nor non-MH subjects displayed a significant change in questionnaire scores from baseline to end of treatment (P > .05). No patients required acute psychiatric interventions during DAA treatment. DISCUSSION: Treatment with DAA therapy was not associated with psychiatric decompensation. Data from this pilot study supports the safe utilization of DAA therapy in hepatitis C virus patients with preexisting MH illness as it appears to be devoid of depressive and psychiatric side effects.

Levocarnitine for valproate-induced hyperammonemia in the psychiatric setting: A case series and literature review.

INTRODUCTION: Hyperammonemia is a potential adverse effect of valproic acid (VPA) therapy, which is often asymptomatic but can lead to severe, life-threatening encephalopathy. Carnitine deficiency due to VPA is the proposed mechanism for hyperammonemia and the development of VPA-induced hyperammonemic encephalopathy (VHE). Levocarnitine, the active form of carnitine, has been suggested for treatment and prevention of VHE. METHODS: Data was collected by chart review of 3 patients who received oral levocarnitine supplementation in the psychiatric setting for VPA-induced hyperammonemia. Review of the literature was performed through June 2017 using the following PubMed search terms: valproate, valproic acid, hyperammonemia, altered mental status, encephalopathy, and levocarnitine. Articles were included if they described use of levocarnitine in VPA-treated patients with psychiatric disorders. RESULTS: One patient developed encephalopathy with resolution of symptoms after VPA discontinuation. Valproic acid was restarted with the addition of levocarnitine to prevent VHE reoccurrence. In the other 2 cases, levocarnitine was started prophylactically in patients who developed hyperammonemia without emergence of any clinical symptoms. Ammonia levels were reduced to normal in all cases, and no symptoms consistent with encephalopathy were reported. The literature search identified 6 additional cases with 5 of 6 reports supporting use of levocarnitine for decreased ammonia levels as well as an observational trial. DISCUSSION: This literature review and case series illustrates successful use of levocarnitine supplementation for reduction of ammonia levels in the setting of VPA-induced hyperammonemia among patients with psychiatric disorders. However, clinical significance of ammonia reduction in asymptomatic patients is difficult to determine.

Light Guided In-vivo Activation of Innate Immune Cells with Photocaged TLR 2/6 Agonist.

The complexity of the immune system creates challenges in exploring its importance and robustness. To date, there have been few techniques developed to manipulate individual components of the immune system in an in vivo environment. Here we show a light-based dendritic cell (DC) activation allowing spatial and temporal control of immune activation in vivo. Additionally, we show time dependent changes in RNA profiles of the draining lymph node, suggesting a change in cell profile following DC migration and indicating that the cells migrating have been activated towards antigen presentation.

Consumer satisfaction with National Alliance on Mental Illness written medicine information.

INTRODUCTION: Written medicine information (WMI) is a collection of facts for a specific medication, and it helps facilitate patient understanding of medication therapy. The primary objective of this study was to assess consumer satisfaction with National Alliance on Mental Illness (NAMI) WMI. A secondary objective was to assess health care professional satisfaction. METHODS: National Alliance on Mental Illness WMI and surveys were offered to consumers, health care professionals, and trainees at 3 treatment centers with psychiatric services. All adults who received medication counseling were eligible for inclusion. Survey responses were evaluated using descriptive statistics. RESULTS: Most consumers (82.4%) and providers (74.5%) reported overall satisfaction with NAMI WMI. Consumers were least satisfied with information on how to manage unwanted effects, drug-drug interactions, and readability (9.5%, 14.9%, 41.9% dissatisfaction). DISCUSSION: Evaluation and feedback from consumers and health care professionals may influence decisions to refine NAMI WMI to meet consumer needs.

Outcomes of mental health pharmacist-managed electronic consults at a Veterans Affairs health care system.

INTRODUCTION: The demand for mental health services has increased as more veterans have been diagnosed with-and sought care for-one or more mental health conditions. Within the South Texas Veterans Health Care System (STVHCS), providers may submit electronic consults (e-consults) to mental health clinical pharmacy specialists for medication review and recommendations. These consults aim to manage veterans with uncomplicated mental health conditions in primary care, making specialty mental health providers more available for those who need such services. Pharmacists have improved outcomes and access to care for conditions such as diabetes and hypertension, but currently, there is limited evidence demonstrating the impact of pharmacists in mental health. METHODS: This quality improvement project assessed the effectiveness of the e-consult service. Information was collected through a retrospective chart review of STVHCS veterans with the corresponding consult note placed in their chart from May 2014 through December 2015. Numbers of recommendations implemented and veterans maintained in primary care were analyzed as markers of effectiveness. Time and cost savings were secondarily explored. RESULTS: A total of 361 consults were submitted for 353 unique patients. Of the 322 patients included in analyses, a total of 301 unique patients (93.5%) were maintained in primary care for at least 3 months. Of the 21 not maintained in primary care, 15 recommendations were implemented; of those maintained in primary care, 271 recommendations were implemented. DISCUSSION: This service improves mental health care-and patient access-by promoting successful management and maintenance of less complicated patients in primary care.

Successful bystander-administered intranasal naloxone reversal of opioid overdose between two veterans: A case report.

Opioid overdose-related morbidity and mortality remain one of the most pressing public health crises. Overdose education and naloxone distribution have emerged as an effective initiative for mitigating overdose deaths. This case highlights areas of patient education essential to optimizing treatment outcome when using a naloxone reversal kit. The patient is a 46-year-old white male with a past medical history significant for opioid use disorder, alcohol use disorder, stimulant use disorder, sedative-hypnotic use disorder, and posttraumatic stress disorder. The patient received an intranasal naloxone kit during residential substance abuse treatment. Five months later, the patient requested a new kit and was asked about the disposition of his previous kit. The patient recounted how he was telephoned to pick up an unconscious friend (and fellow veteran) from a nonresidential location. Upon arrival, the patient recognized opioid products near his friend and took steps to reverse the suspected opioid overdose with his 2 mg/2 mL naloxone intranasal kit. The reversal was successful, but many critical rescue response steps were omitted. This case report may guide future changes to educating patients on appropriate responses to opioid overdoses with naloxone. A PubMed search located one other case report of successful naloxone reversal of opioid overdose in the veteran population, which involved fentanyl sold as heroin. In our case report, a veteran successfully used his naloxone kit to reverse a suspected opioid overdose in another veteran, but he incompletely provided the rescue response. This experience may influence content changes for future overdose education and naloxone distribution training.

Immune Response Modulation of Conjugated Agonists with Changing Linker Length.

We report immune response modulation with linked Toll-like receptor (TLR) agonists. Conjugating two agonists of synergistic TLRs induce an increase in immune activity compared to equal molarity of soluble agonists. Additionally, varying the distance between the agonists by changing the linker length alters the level of macrophage NF-κB activity as well as primary bone marrow derived dendritic cell IL-6 production. This modulation is effected by the size of the agonists and the pairing of the stimulated TLRs. The sensitivity of linker-length-dependent immune activity of conjugated agonists provides the potential for developing application specific therapeutics.

Hospitalizations and emergency room visits after initiation of long-acting injectable antipsychotics.

INTRODUCTION: Long-acting injectable antipsychotics (LAIs) serve as a means to ensure medication adherence with the intention of improving outcomes for psychiatric patients. Evidence remains inconclusive regarding the impact of LAIs on relapses and psychiatric hospitalizations rates. METHODS: The primary objective of this retrospective pre/post study was to determine whether initiating an LAI in a veteran population with schizophrenia, schizoaffective disorder, or bipolar disorder is associated with a decrease in the 1-year rate of psychiatric hospitalizations and emergency room (ER) visits. RESULTS: For the combined primary endpoint, the 1-year rate of psychiatric hospitalizations and ER visits for patients with schizophrenia, schizoaffective disorder, or bipolar disorder was not significantly reduced after initiation of LAIs (n = 50, median [interquartile range]: 1.5 [1, 3] to 1 [0, 3], P = .055). However, the secondary endpoint of the 1-year rate of psychiatric hospitalizations was reduced (1 [0, 3] to 0 [0, 2], P = .026). Additionally, for those who received injections on a regular basis, the 1-year rate of hospitalizations and ER visits was significantly reduced (2 [1, 3] to 0 [0, 1.5], P = .009). DISCUSSION: This retrospective study suggests that the initiation of LAIs is associated with a reduced rate of psychiatric hospitalizations as well as a reduced rate of psychiatric hospitalizations and ER visits for those patients who receive injections on a regular basis.

Modulation of Innate Immune Responses via Covalently Linked TLR Agonists.

We present the synthesis of novel adjuvants for vaccine development using multivalent scaffolds and bioconjugation chemistry to spatially manipulate Toll-like receptor (TLR) agonists. TLRs are primary receptors for activation of the innate immune system during vaccination. Vaccines that contain a combination of small and macromolecule TLR agonists elicit more directed immune responses and prolong responses against foreign pathogens. In addition, immune activation is enhanced upon stimulation of two distinct TLRs. Here, we synthesized combinations of TLR agonists as spatially defined tri- and di-agonists to understand how specific TLR agonist combinations contribute to the overall immune response. We covalently conjugated three TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NF-κB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same three agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity. To validate that the TLR4, 7, and 9 agonist combination would activate the immune response to a greater extent, we performed in vivo studies using a vaccinia vaccination model. Mice vaccinated with the linked TLR agonists showed an increase in antibody depth and breadth compared to mice vaccinated with the unconjugated mixture. These studies demonstrate how activation of multiple TLRs through chemically and spatially defined organization assists in guiding immune responses, providing the potential to use chemical tools to design and develop more effective vaccines.

Controlling the origins of inflammation with a photoactive lipopeptide immunopotentiator.

Inflammatory immune responses are mediated by signaling molecules that are both produced by and recognized across highly heterogeneous cell populations. As such, the study of inflammation using traditional immunostimulants is complicated by paracrine and autocrine signaling, which obscures the origin of a propagating response. To address this challenge, we developed a small-molecule probe that can photosensitize immune cells, thus allowing light-mediated inflammation. This probe was used to control the origin of inflammation using light. Following this motif, inflammation was initiated from fibroblasts or dendritic cells. The contributions of fibroblasts and dendritic cells in initiating inflammation in heterogeneous co-culture are reported, thus providing insights into the future development of vaccines and treatment of inflammation.

One-step site-specific modification of native proteins with 2-pyridinecarboxyaldehydes.

The chemical modification of proteins is an enabling technology for many scientific fields, including chemical biology, biophysics, bioengineering and materials science. These methods allow the attachment of strategically selected detection probes, polymers, drug molecules and analysis platforms. However, organic reactions that can proceed under conditions mild enough to maintain biomolecular function are limited. Even more rare are chemical strategies that can target a single site, leading to products with uniform properties and optimal function. We present a versatile method for the selective modification of protein N termini that does not require any genetic engineering of the protein target. This reaction is demonstrated for 12 different proteins, including the soluble domain of the human estrogen receptor. The function of this protein was confirmed through the binding of a fluorescent estrogen mimic, and the modified protein was explored as a prototype for the detection of endocrine-disrupting chemicals in water.

Assisting Social Security Disability Insurance beneficiaries with schizophrenia, bipolar disorder, or major depression in returning to work.

OBJECTIVE: People with psychiatric impairments (primarily schizophrenia or a mood disorder) are the largest and fastest-growing group of Social Security Disability Insurance (SSDI) beneficiaries. The authors investigated whether evidence-based supported employment and mental health treatments can improve vocational and mental health recovery for this population. METHOD: Using a randomized controlled trial design, the authors tested a multifaceted intervention: team-based supported employment, systematic medication management, and other behavioral health services, along with elimination of barriers by providing complete health insurance coverage (with no out-of-pocket expenses) and suspending disability reviews. The control group received usual services. Paid employment was the primary outcome measure, and overall mental health and quality of life were secondary outcome measures. RESULTS: Overall, 2,059 SSDI beneficiaries with schizophrenia, bipolar disorder, or depression in 23 cities participated in the 2-year intervention. The teams implemented the intervention package with acceptable fidelity. The intervention group experienced more paid employment (60.3% compared with 40.2%) and reported better mental health and quality of life than the control group. CONCLUSIONS: Implementation of the complex intervention in routine mental health treatment settings was feasible, and the intervention was effective in assisting individuals disabled by schizophrenia or depression to return to work and improve their mental health and quality of life.

Can medication management coordinators help improve continuity of care after psychiatric hospitalization?

OBJECTIVE: This demonstration project examined whether medication management coordinators enhanced continuity of care from inpatient facilities to an outpatient public mental health clinic. METHODS: From 2004 to 2008, patients (N=325) hospitalized with schizophrenia or schizoaffective or bipolar disorder enrolled in a medication management program before discharge or at their first clinic appointment. Medication management coordinators supplemented existing clinic practices by identifying recently hospitalized patients, providing inpatient and outpatient prescribing clinicians with patients' complete medication history, meeting with patients for six months postdischarge to assess clinical status and provide medication education, and advocating guideline-concordant prescribing. Recently discharged patients (N=345) assigned to a different outpatient clinic within the same agency served as the comparison group. Intent-to-treat, repeated-measures analyses for mixed models compared the groups' number of hospital admissions, hospital days, and medication appointments kept and use of nurse or case manager contact hours and emergency or crisis services during the 12 months before enrollment, the six-month intervention, and the six-month follow-up period. RESULTS: After discharge, individuals enrolled in medication management were more likely than comparison patients to attend outpatient appointments, and they had more medication visits and nurse or case manager treatment hours than the comparison group. Use of hospital and crisis or emergency services by all patients decreased. Almost one-third of patients never attended an outpatient appointment after hospital discharge. CONCLUSIONS: Although this program succeeded in improving continuity of care, additional interventions may be required to reduce rehospitalization and crisis care.