Efficacy of HP-3070, A Once-Daily Asenapine Transdermal System, in the Treatment of Adults with Schizophrenia: A PANSS Five-Factor Analysis.

Introduction: HP-3070, a once-daily asenapine transdermal system, is the first antipsychotic "patch" formulation FDA approved for adults with schizophrenia. Positive and Negative Syndrome Scale (PANSS) score items can be grouped into a five-factor structure to describe specific schizophrenia symptom domains. This post hoc analysis of data from a pivotal study evaluated HP-3070's efficacy by examining these factors. Methods: In a phase 3 study, adults with an acute exacerbation of schizophrenia were randomized to six weeks of treatment with HP-3070 3.8mg/24h, 7.6mg/24h, or placebo. An analysis was performed using the five PANSS factor domains (negative symptoms, positive symptoms, disorganized thought, uncontrolled hostility/excitement, anxiety/depression). Mixed-model repeated-measures (MMRM) analysis included change from baseline (CFB) in PANSS factor score as the repeated dependent variable, with country, treatment, visit, treatment by visit interaction, and baseline PANSS score as covariates. Results: The analysis included 607 patients. Treatment with HP-3070 3.8mg/24h resulted in a statistically significant LS mean CFB (improvement) vs placebo at Weeks 4-6 for all domains except for anxiety/depression, where a numerical difference was observed in favor of active treatments. Among the domains, the positive symptom factor demonstrated the numerically greatest LS mean (SE) difference from placebo in CFB, which for HP-3070 7.6mg/24h was -2.0 [0.57] and for HP-3070 3.8mg/24h was -2.3 [0.57]; P<0.001 for both. Treatment effect size for the positive symptom factor using Cohen's d (95% confidence intervals) was 0.39 (0.17, 0.61) for HP-3070 7.6mg/24h and 0.45 (0.20, 0.64) for HP-3070 3.8mg/24h. Discussion: Post hoc analysis using a PANSS five-factor model suggests that HP-3070 may address a broad range of symptoms in people with schizophrenia.

A systematic review of clozapine for aggression and violence in patients with schizophrenia or schizoaffective disorder.

Although uncommon, the risk of aggression and violence is greater in people with schizophrenia than in the general population. Clozapine is the "gold standard" pharmacologic treatment for the management of persistent agitation and aggression in people with schizophrenia and is consistently recommended by guidelines and reviews for this purpose. Although clozapine is indicated for treatment-resistant schizophrenia based on its superior efficacy, studies have proposed that clozapine may have specific properties that ameliorate aggression and hostility that are distinct from its antipsychotic effects. A literature review was conducted on June 3, 2023, using the US National Library of Medicine's PubMed resource to identify articles focusing on clozapine for the treatment of aggression, violence, and/or hostility in patients with schizophrenia or schizoaffective disorder. The majority of evidence, including from randomized control trials, supports the utilization of clozapine as maintenance treatment for persistent aggressive behavior in patients with schizophrenia, and supports that its anti-aggressive effects may be independent from its antipsychotic properties (e.g. - treatment of hallucinations and delusions). Future randomized control studies evaluating clozapine and clozapine serum levels with aggression as the primary outcome would be of benefit.

Olanzapine Pharmacokinetics: A Clinical Review of Current Insights and Remaining Questions.

Olanzapine is one of the most widely used antipsychotics since its initial approval by the US Food and Drug Administration in 1996 and has undergone extensive pharmacokinetic study. Despite being utilized in clinical psychiatry for decades, there remain questions regarding the variety of available formulations, the utility of therapeutic drug monitoring, altered kinetic properties in special populations/medical illnesses, the use of high-dose olanzapine, and drug interactions, among many others. We performed a narrative literature review of olanzapine pharmacokinetics in June 2023 using the US National Library of Medicine's PubMed.gov resource (https://www.ncbi.nlm.nih.gov/pubmed) and Google Scholar. Herein, we review clinically relevant aspects of olanzapine pharmacokinetic data while highlighting knowledge gaps and potential areas of future study.

Improving the pharmacotherapeutic treatment of agitation associated with bipolar disorder.

INTRODUCTION: Agitation is commonly encountered in people with bipolar disorder, particularly when experiencing a manic episode. The number of approved pharmacological agents to manage acute episodes of agitation in this population is limited. AREAS COVERED: A search was conducted using the US National Library of Medicine PubMed.gov resource for English-language papers of clinical trials and reviews/meta-analyses, using the text words 'bipolar disorder' AND 'agitation,' as well as any papers with both two text words in the title, without any date restrictions. EXPERT OPINION: Existing pharmacologic options approved by regulatory authorities for the treatment of acute episodes of agitation associated with bipolar disorder have similar degrees of efficacy but differ in their tolerability profiles and ease of use, giving clinicians an opportunity to individualize treatment. The goal is to treat mild-moderate agitation before it evolves into severe agitation, encouraging noninvasive pharmacologic treatment options. Inhaled loxapine and sublingual dexmedetomidine are newer options with rapid onset of action and may be preferable for patients willing to cooperate with treatment.

Potassium channel modulators and schizophrenia: an overview of investigational drugs.

INTRODUCTION: Schizophrenia is a severe mental illness comprising positive, negative, and cognitive symptoms. Existing pharmacologic options exert their actions on the dopamine receptor but are largely ineffective at treating negative and cognitive symptoms. Alternative pharmacologic options that do not act directly on the dopamine receptor are being investigated, including potassium channel modulators. It has been hypothesized that dysfunctional fast-spiking parvalbumin-positive GABA interneurons, regulated by Kv3.1 and Kv3.2 potassium channels, contribute to the symptoms of schizophrenia, making potassium channels an area of clinical interest. AREAS COVERED: This review will highlight potassium channel modulators for the treatment of schizophrenia, with a focus on AUT00206. Background on Kv3.1 and Kv3.2 potassium channels will be explored. Our search strategy included a literature review utilizing PubMed, Clinicaltrials.gov, and sources available on the manufacturer's website. EXPERT OPINION: Initial data on potassium channel modulators is promising; however, further study is needed, and existing evidence is limited. Early data suggests that dysfunctional GABA interneurons can be ameliorated through modulators of Kv3.1 and Kv3.2 channels. AUT00206 has been shown to improve dopaminergic dysfunction induced by ketamine and PCP, improve resting gamma power in patients with schizophrenia, impact dopamine synthesis capacity in a subgroup of individuals with schizophrenia, and affect reward anticipation-related neural activation.

Sublingual dexmedetomidine: repurposing an anesthetic as an anti-agitation agent.

INTRODUCTION: Especially when acutely ill, individuals with schizophrenia and bipolar disorder can present with agitated behavior. The initial approach to agitation management are non-pharmacologic strategies such as verbal de-escalation techniques; however, pharmacologic interventions may be needed. Dexmedetomidine is a selective alpha-2 adrenergic receptor agonist, and a sublingual formulation has been approved in the US for the treatment of agitation associated with schizophrenia and bipolar disorder in adults. AREAS COVERED: The authors review the published literature on sublingual dexmedetomidine using the US National Library of Medicine's PubMed.gov resource. Pharmacodynamics, pharmacokinetics, and efficacy and tolerability findings are summarized. The authors also provide a discussion to its potential place in the treatment armamentarium. EXPERT OPINION: Sublingual dexmedetomidine is an effective and well-tolerated pharmacologic option for the treatment of agitation associated with schizophrenia and bipolar disorder. The sublingual method of administration allows for a rapid onset of action with treatment effects beginning as early as 20 minutes after administration. Adverse effects include somnolence, hypotension, oral paresthesia, hypoesthesia, and dry mouth. Further study will be needed to evaluate sublingual dexmedetomidine in real-world patients receiving concomitant psychotropic medications.

Schizophrenia: One Name, Many Different Manifestations.

Schizophrenia is a disabling condition impacting approximately 1% of the worldwide population. Symptoms include positive symptoms (eg, hallucinations, delusions), negative symptoms (eg, avolition, anhedonia), and cognitive impairment. There are likely many different environmental and pathophysiologic etiologies involving distinct neurotransmitters and neurocircuits. Pharmacologic treatment at present consists of dopamine receptor antagonists, which are reasonably effective at treating positive symptoms, but less effective at treating cognitive and negative symptoms. Nondopaminergic medications targeting alternative receptors are under investigation. Supportive psychosocial treatments can work in tandem with antipsychotic medications and optimize patient care.

Olanzapine-samidorphan combination tablets for the treatment of schizophrenia and bipolar I disorder - what is it, and will it be used?

INTRODUCTION: Although olanzapine remains one of the most efficacious antipsychotic medications for the treatment of schizophrenia, there are significant tolerability concerns related to its weight and metabolic profile. Olanzapine-samidorphan combination tablets (OLZ/SAM), branded as Lybalvi, is a newly FDA approved formulation aimed at attenuating antipsychotic induced weight gain via modulation of the endogenous opioid system with samidorphan, while retaining the robust antipsychotic efficacy of olanzapine. AREAS COVERED: We reviewed the published literature of OLZ/SAM for the management of schizophrenia using the US National Library of Medicine's PubMed.gov resource. Topics covered in this narrative review include the pharmacokinetics, pharmacodynamics, efficacy, and tolerability of OLZ/SAM. EXPERT OPINION: OLZ/SAM is an effective and well-tolerated pharmacologic option in mitigating olanzapine induced weight gain while retaining olanzapine's efficacy. OLZ/SAM cumulatively tends to attenuate weight gain rather than promote weight loss. Effect on metabolic laboratory variables appears limited. Additional research will be needed to determine its effectiveness compared to alternative strategies to attenuate antipsychotic induced weight gain.

Asenapine: an atypical antipsychotic with atypical formulations.

Asenapine is a second-generation (atypical) antipsychotic medication not available in a pill that can be swallowed; rather, it is commercialized in sublingual and transdermal formulations. This is a consequence of extensive first-pass metabolism if ingested. The sublingual formulation is approved in many jurisdictions for the treatment of schizophrenia and manic or mixed episodes associated with bipolar I disorder and is available generically. The efficacy profile is well characterized in a number of clinical trials, including an off-label use for the management of agitation. Obstacles to its use include food and drink restrictions, twice-daily dosing and adverse effects such as dysgeusia (distorted, altered, or unpleasant taste) and oral hypoesthesia (numbness). Transdermal asenapine was approved by the US Food and Drug Administration in 2019 for the treatment of schizophrenia in adults. Efficacy was established in a registrational study examining acutely ill inpatients with schizophrenia. The patch needs to changed once daily. Obstacles to its use include the potential for skin reactions such as erythema and pruritis, and being a branded product, it is more costly than other options. This is a narrative review of the chemistry and pharmacokinetics/pharmacodynamics of asenapine, as well as summarizing the efficacy and tolerability of both sublingual and transdermal asenapine, and its possible place in treatment.

Does antipsychotic combination therapy reduce the risk of hospitalization in schizophrenia?

INTRODUCTION: : Despite treatment with antipsychotic medication, approximately 1/3 of individuals with schizophrenia will fail to have an adequate response. To treat these patients, a commonly utilized approach is antipsychotic combination therapy. Antipsychotic combination therapy is controversial with mixed efficacy and tolerability results. It is also unclear if antipsychotic combination therapy reduces or increases the risk of psychiatric hospitalization. AREAS COVERED: : The authors review the prevalence, efficacy and tolerability concerns, and rationale behind antipsychotic combination therapy. Evidence comparing antipsychotic monotherapy vs polypharmacy using hospitalization as an outcome measure is summarized. EXPERT OPINION: : Psychiatric rehospitalization is a useful measure of treatment effectiveness, incorporating aspects of treatment efficacy and tolerability. The evidence comparing the impact of antipsychotic monotherapy vs combination therapy on rehospitalization is mixed. Evidence is primarily retrospective in nature, and there is high heterogeneity between studies, which could partially explain the mixed results. There is likely a subset of patients for whom antipsychotic combination therapy reduces the risk of hospitalization greater than antipsychotic monotherapy. Patients should be treated individually taking into account their specific pattern of response.

Intravenous brexanolone for postpartum depression: what it is, how well does it work, and will it be used?

Postpartum depression is considered to be a subtype of major depressive disorder that occurs in approximately 10-20% of mothers worldwide. However, in actuality, these numbers are likely underreported due to minimization and the stigma of mental illness. Until recently, there were no approved medications for the treatment of postpartum depression. Allopregnanolone is a naturally occurring neuroactive steroid whose serum levels decline precipitously following childbirth. This hormonal fluctuation has been postulated as playing a role in the pathophysiology of postpartum depression. Brexanolone is the first medication approved by the US Food and Drug Administration for the treatment of postpartum depression. Brexanolone is an intravenous proprietary formulation of allopregnanolone that can be administered to produce stable serum levels comparable with third-trimester concentrations in postpartum mothers. It is hypothesized to modulate neuronal excitability by functioning as an allosteric modulator of γ-aminobutyric acid-A receptors and is administered under monitoring as a 60 h continuous infusion. In this review, we will highlight the results of the clinical trial program, including efficacy and tolerability data. Practical and logistical considerations of brexanolone will be reviewed, as will its potential place in therapy for the treatment of postpartum depression.

Examining the safety, efficacy, and patient acceptability of inhaled loxapine for the acute treatment of agitation associated with schizophrenia or bipolar I disorder in adults.

Agitation is a common and serious symptom of bipolar mania and schizophrenia, and can be defined as excessive motor and verbal activity. If left unrecognized and untreated, agitation can evolve into aggression, resulting in potential patient and staff injury. An ideal treatment for agitation would have a rapid onset, cause calmness without sedation, and be tolerable, efficacious, and non-coercive, while managing the underlying condition. A novel approach for the treatment of agitation is inhaled loxapine. Inhaled loxapine is rapidly absorbed into the systemic circulation through the alveoli, resulting in a near immediate onset of action. The efficacy of inhaled loxapine was established in an extensive clinical development program that included persons with schizophrenia and bipolar mania. Additionally, inhaled loxapine has comparable efficacy to intramuscular ziprasidone, olanzapine, haloperidol, aripiprazole, and lorazepam, with the added benefit of being non-painful and non-traumatizing. Inhaled loxapine carries a bolded black box warning for bronchospasm, and as a result, in the US, requires enrollment in a Risk Evaluation and Mitigation Strategy program, and is contraindicated in those with pulmonary disease. Additionally, the use of inhaled loxapine can be associated with dysgeusia and throat irritation. Inhaled loxapine requires some degree of patient cooperation, and therefore may not be appropriate for all agitated patients.

A review and update on the diagnosis and treatment of neuropsychiatric Wilson disease.

Introduction: This paper reviews the presenting signs and symptoms of Wilson's disease, with an emphasis on the recognition and treatment of neuropsychiatric symptoms. Areas covered: A literature search was conducted using PubMed.gov utilizing the following keywords: Wilson disease, neuropsychiatric, psychiatric symptoms, treatment, antipsychotics, mood stabilizer, psychotherapy, antidepressant, ATP7B. The diagnosis of Wilson's disease and the treatment of hepatic and neuropsychiatric symptoms are reviewed. Expert opinion: Wilson's disease is a rare autosomal recessive disorder with a heterogeneous presentation. Prominent neuropsychiatric symptoms can cloud the initial diagnosis, delaying treatment. Early disease recognition and prompt treatment to restore copper balance is critical in mitigating neuropsychiatric symptoms. Lifetime adherence to maintenance treatment with a chelating agent or zinc is vital for prevention or recurrence of symptoms. Education and supportive psychotherapy have been shown to improve medication adherence. If a psychotropic medication is needed, preference should be given to one with a low risk for extrapyramidal symptoms and hepatotoxicity.

Resistance is not futile: treatment-refractory schizophrenia - overview, evaluation and treatment.

INTRODUCTION: Schizophrenia is a debilitating condition with three main symptom domains: positive, negative, and cognitive. Approximately one-third of persons with schizophrenia will fail to respond to treatment. Growing evidence suggests that treatment-resistant (refractory) schizophrenia (TRS) may be a distinct condition from treatment-respondent schizophrenia. There is limited evidence on effective treatments for TRS, and a lack of standardized diagnostic criteria for TRS has hampered research. Areas covered: A literature search was conducted using Pubmed.gov and the EMBASE literature database. The authors discuss the pragmatic definitions of TRS and review treatments consisting of antipsychotic monotherapy and augmentation strategies. Expert opinion: Currently available first-line antipsychotic medications are generally effective at treating the positive symptoms of schizophrenia, leaving residual negative and cognitive symptoms. Before diagnosing TRS, rule out any pharmacodynamic or pharmacokinetic failures. Most evidence supports clozapine as having the most efficacy for TRS. If clozapine is used, it should be optimized, and serum levels should be at least 350-420 ng/ml. If clozapine is unable to be tolerated, some evidence suggests olanzapine at dosages up to 40mg/day can be useful. Augmentation strategies have weak evidence. Tailoring treatment to the specific domain is the preferred approach, and the use of a structured assessment/outcome measure is encouraged.