Dispensing of Oral Antiviral Drugs for Treatment of COVID-19 by Zip Code-Level Social Vulnerability - United States, December 23, 2021-May 21, 2022.

The COVID-19 pandemic has highlighted and exacerbated long-standing inequities in the social determinants of health (1-3). Ensuring equitable access to effective COVID-19 therapies is essential to reducing health disparities. Molnupiravir (Lagevrio) and nirmatrelvir/ritonavir (Paxlovid) are oral antiviral agents effective at preventing hospitalization and death in patients with mild to moderate COVID-19 who are at high risk* for progression to severe COVID-19 when initiated within 5 days of symptom onset. These medications received Emergency Use Authorization from the Food and Drug Administration (FDA) in December 2021† and were made available at no cost to recipients through the U.S. Department of Health and Human Services (HHS) on December 23, 2021. Beginning March 7, 2022, a series of strategies was implemented to expand COVID-19 oral antiviral access, including the launch of the Test to Treat initiative.§ Data from December 23, 2021-May 21, 2022, were analyzed to describe oral antiviral prescription dispensing overall and by week, stratified by zip code social vulnerability. Zip codes represented areas classified as low, medium, or high social vulnerability; approximately 20% of U.S. residents live in low-, 31% in medium-, and 49% in high-social vulnerability zip codes.¶ During December 23, 2021-May 21, 2022, a total of 1,076,762 oral antiviral prescriptions were dispensed (Lagevrio = 248,838; Paxlovid = 827,924). Most (70.3%) oral antivirals were dispensed during March 7-May 21, 2022. During March 6, 2022-May 21, 2022, the number of oral antivirals dispensed per 100,000 population increased from 3.3 to 77.4 in low-, from 4.5 to 70.0 in medium-, and from 7.8 to 35.7 in high-vulnerability zip codes. The number of oral antivirals dispensed rose substantially during the overall study period, coincident with the onset of initiatives to increase access. However, by the end of the study period, dispensing rates in high-vulnerability zip codes were approximately one half the rates in medium- and low-vulnerability zip codes. Additional public health, regulatory, and policy efforts might help decrease barriers to oral antiviral access, particularly in communities with high social vulnerability.

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment.

The preferential dopamine D(3)-agonist pramipexole (4.25±0.38 mg/day) or placebo were added for up to 12 weeks to ongoing antipsychotic treatment for 24 adult patients with DSM-IV schizophrenia or schizoaffective disorder. Pramipexole was generally well-tolerated (82% trial-completion), and yielded greater decreases in PANSS-total scores (drug/placebo=2.1; p=0.04), with similar decreases in PANSS positive and negative scores and 6.7-fold greater reduction of serum prolactin concentrations compared to placebo. There were no differences in ratings of mood, cognition or extrapyramidal symptoms, all of which were low at intake.

A case of acute renal failure in a patient recently treated with clozapine and a review of previously reported cases.

Clozapine has been reported to cause acute renal failure due to acute interstitial nephritis. We discuss a case of clozapine-induced acute renal failure and compare it to 7 other cases reported in the literature. We review the signs and symptoms of the hypersensitivity response, such as fever and eosinophilia, caused by clozapine and make recommendations for early detection. Early detection and prompt discontinuation of clozapine can prevent renal damage, as can the avoidance of other nephrotoxic drugs like antibiotics.

Absence of the glucagon-like peptide-1 receptor does not affect the metabolic phenotype of mice with liver-specific G(s)α deficiency.

The stimulatory G protein α-subunit (G(s)α) couples hormone and other receptors to the generation of intracellular cAMP. We previously showed that mice with liver-specific G(s)α deficiency [liver-specific G(s)α knockout (LGsKO) mice] had reduced adiposity and improved glucose tolerance associated with increased glucose-stimulated insulin secretion, pancreatic islet hyperplasia, and very high serum glucagon and glucagon-like peptide 1 (GLP-1) levels. Because GLP-1 is known to stimulate insulin secretion and to have effects on energy balance, we mated LGsKO mice with germline GLP-1 receptor (GLP-1R) knockout mice (Glp1r(-/-)) and compared LGsKO to double-knockout (LGs/Glp1r(-/-)) mice to determine the contribution of excess GLP-1R signaling to the LGsKO phenotype. Loss of the GLP-1R failed to reverse most of the metabolic features of LGsKO mice, including reduced fat mass, increased glucose tolerance, and second-phase glucose-stimulated insulin secretion, islet cell hyperplasia, and very high glucagon and GLP-1 levels. However, loss of GLP-1R impaired first-phase insulin secretion in mice with or without liver-specific G(s)α deficiency. Thus, excess GLP-1 action (or at least through GLP-1R) does not contribute to the LGsKO metabolic phenotype, and other unknown factors involved in the cross talk between the liver G(s)α/cAMP pathway and pancreatic islet function need to be further elucidated.

Central nervous system imprinting of the G protein G(s)alpha and its role in metabolic regulation.

In Albright hereditary osteodystrophy, a monogenic obesity disorder linked to heterozygous mutations of G(s)alpha, the G protein that mediates receptor-stimulated cAMP generation, obesity develops only when the mutation is on the maternal allele. Likewise, mice with maternal (but not paternal) germline G(s)alpha mutation develop obesity, insulin resistance, and diabetes. These parent-of-origin effects are due to G(s)alpha imprinting, with preferential expression from the maternal allele in some tissues. As G(s)alpha is ubiquitously expressed, the tissue involved in this metabolic imprinting effect is unknown. Using brain-specific G(s)alpha knockout mice, we show that G(s)alpha imprinting within the central nervous system underlies these effects and that G(s)alpha is imprinted in the paraventricular nucleus of the hypothalamus. Maternal G(s)alpha mutation impaired melanocortin stimulation of energy expenditure but did not affect melanocortin's effect on food intake, suggesting that melanocortins may regulate energy balance in the central nervous system through both G(s)alpha-dependent and -independent pathways.

G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency.

The ubiquitously expressed G protein alpha-subunit G(s)alpha is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific G(s)alpha-knockout (KO) mice (MGsKO) by mating G(s)alpha-floxed mice with muscle creatine kinase-cre transgenic mice. MGsKO mice had normal body weight and composition, and their serum glucose, insulin, free fatty acid, and triglyceride levels were similar to that of controls. However, MGsKO mice were glucose intolerant despite the fact that insulin sensitivity and glucose-stimulated insulin secretion were normal, suggesting an insulin-independent mechanism. Isolated muscles from MGsKO mice had increased basal glucose uptake and normal responses to a stimulator of AMP-activated protein kinase (AMPK), which indicates that AMPK and its downstream pathways are intact. Compared with control mice, MGsKO mice had reduced muscle mass with decreased cross-sectional area and force production. In addition, adult MGsKO mice showed an increased proportion of type I (slow-twitch, oxidative) fibers based on kinetic properties and myosin heavy chain isoforms, despite the fact that these muscles had reduced expression of peroxisome proliferator-activated receptor coactivator protein-1alpha (PGC-1alpha) and reduced mitochondrial content and oxidative capacity. Therefore G(s)alpha deficiency led to fast-to-slow fiber-type switching, which appeared to be dissociated from the expected change in oxidative capacity. MGsKO mice are a valuable model for future studies of the role of G(s)alpha signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism.

Multiple versus single antipsychotic agents for hospitalized psychiatric patients: case-control study of risks versus benefits.

OBJECTIVE: Since use of multiple drugs to treat psychiatric patients is increasing, and research on this practice is rare, the authors carried out a retrospective case-control study of multiple versus single antipsychotic treatment in psychiatric inpatients. METHOD: Inpatient treatment groups receiving either antipsychotic monotherapy or polytherapy were matched in terms of age, sex, diagnostic category, and admission clinical ratings (Global Assessment of Functioning [GAF] and Clinical Global Impression [CGI]), which yielded 70 subject pairs. They were compared in terms of total chlorpromazine-equivalent daily dose, changes in total daily dose, length of hospitalization, incidence of adverse effects, and changes in clinical ratings (CGI, GAF, Positive and Negative Syndrome Scale score) between admission and discharge. RESULTS: Initial doses were closely similar at admission for both treatment groups, but the median total final antipsychotic dose was 78% higher for those receiving antipsychotic polytherapy versus monotherapy. Also, median length of stay in the hospital was 55% (8.5 days) longer, and risk of adverse effects was 56% higher with polytherapy, whereas clinical improvement scores were similar (within 11%) for both treatments. CONCLUSIONS: Short-term treatment with multiple antipsychotics was associated with major increases in drug exposure, adverse events, and time in the hospital but with no apparent gain in clinical benefit. These findings require further testing in controlled prospective studies.

Oxcarbazepine: clinical experience with hospitalized psychiatric patients.

BACKGROUND: Oxcarbazepine (10-keto-carbamazepine) appears to be better tolerated and simpler to use than carbamazepine. It has antimanic effects but, as its potential clinical usefulness and tolerability in broad samples of psychiatric patients remain to be tested, we reviewed both the pharmacology of oxcarbazepine and our early experience with this new agent among psychiatric inpatients. METHODS: We reviewed medical records of all inpatients given oxcarbazepine in the first 15 months of its use at McLean Hospital. Data analyzed included dosing, presenting illnesses, other medications, clinical changes, and adverse effects. RESULTS: Oxcarbazepine was given to 56 inpatients (1.3% of admissions; 31 women, 25 men) presenting with depression (n = 23), mania (n = 19), or psychosis (n = 14). The discharge daily dose for the 43 patients (76%) taking oxcarbazepine was 831 mg/day, 34% higher in men than women, and fell by 9 mg/year-of-age. Oxcarbazepine was the only putative mood-stabilizing agent given at discharge in 19 of 43 cases (44%). It was discontinued in 20% of patients for apparent inefficacy, and 4% for adverse effects. Changes in CGI and GAF scores were similarly high across illnesses, and unrelated to days of use of oxcarbazepine or its dose. CONCLUSIONS: Oxcarbazepine was well tolerated and simpler to use clinically than its precursor carbamazepine. This agent should be studied in controlled trials to test its efficacy in specific types of major psychiatric disorders, and particularly for long-term maintenance treatment in bipolar disorder.

Pilot comparison of extended-release and standard preparations of divalproex sodium in patients with bipolar and schizoaffective disorders.

OBJECTIVE: The authors compared the new extended-release and standard preparations of divalproex sodium. METHOD: Twelve patients with DSM-IV bipolar disorder or schizoaffective disorder who were clinically stable while taking the standard form of divalproex participated in the study. These patients were given a single daily dose of the extended-release preparation of divalproex in an open 6-week trial. Clinical symptoms and adverse effects were rated weekly. Doses were adjusted to maintain steady serum valproate concentrations. RESULTS: The medication change was associated with negligible changes in clinical status and tolerability. To maintain serum drug levels, however, 21% higher doses of the extended-release preparation were required. CONCLUSIONS: Use of extended-release divalproex once a day was as well tolerated as the standard preparation, with no change in efficacy within 6 weeks, but the daily dose needed to maintain stable serum valproic acid concentration was 21% higher.

Inpatient antipsychotic drug use in 1998, 1993, and 1989.

OBJECTIVE: Patterns of clinical use of antipsychotic agents have changed greatly in the past decade. The authors' goal was to examine these patterns. METHOD: They evaluated medication use in all McLean Hospital inpatients treated with antipsychotic drugs during 3 months in 1998 (N=349) and compared the results with McLean Hospital inpatients treated with antipsychotics in 1993 (N=299) and Boston area inpatients in 1989 (N=50). RESULTS: The most commonly prescribed antipsychotics in 1998 were atypical agents; olanzapine was prescribed more often than risperidone or quetiapine, which were prescribed more often than other antipsychotics. Two or more antipsychotics were prescribed at some time during their hospitalization for 150 (43%) of the patients in 1998. The total discharge dose in chlorpromazine equivalents for the 349 patients for whom antipsychotics were prescribed at discharge was 371 mg/day, 29% higher than the total discharge dose for patients in 1993 and 46% greater than the dose in 1989. The dose of antipsychotics was greater for patients with psychotic illnesses than for those with affective illnesses. Higher doses were associated with greater clinical improvement, polypharmacotherapy, and younger patient age. CONCLUSIONS: Emerging trends toward higher total antipsychotic doses and polypharmacotherapy require critical assessments of cost-benefit relationships.

Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents.

Innovation in atypical antipsychotic agents continues with new preparations of available drugs as well as novel agents. In this article, we provide an update on these novel products by reviewing information from a computerised literature search, recent abstracts and discussions with industry representatives. A generic formulation of clozapine is now available. It may be less well absorbed and/or less effective than Clozaril, although evidence is conflicting. A fatty acid amide derivative of clozapine is in early development. A liquid formulation of risperidone is currently available, which may be a useful treatment for psychotic agitation as well as a preferable alternative to tablets for some patients. A depot formulation is in development for the long-term management of psychosis. An orally disintegrating tablet formulation of olanzepine is a useful alternative to standard tablets. A short-acting injectable formulation of the drug is in development for psychotic agitation. Sachets and slow-release formulations of quetiapine are in development. Ziprasidone, a recently launched agent, is available in tablet form for schizophrenia/schizoaffective disorder, psychotic depression and mania. A short-acting injectable formulation is in development for psychotic agitation. Aripiprazole (tablets) and iloperidone (tablets and depot injection) are two antipsychotics in development for schizophrenia/schizoaffective disorder (available information regarding iloperidone is very limited). These new formulations and agents should broaden options for the treatment of psychosis.