Asenapine Transdermal Patch for the Management of Schizophrenia

Zhou, MD, Derakhshanian, MD, Rath, MD, Menard, MD, Louisiana State University Health Science Center Shreveport, Department of Psychiatry, and Behavioral Medicine. Bertrand, BS, DeGraw, BS, Barlow, BS, Louisiana State University Shreveport School of Medicine. Kaye, Pharm D, Thomas J. Long School of Pharmacy and Health Sciences, University of the Pacific, Department of Pharmacy Practice, Stockton, CA. Hasoon, MD, Beth Israel Deaconess Medical Center, Department of Anesthesiology, Critical Care, and Pain Medicine, Harvard Medical School, Boston, MA. Cornett, PhD, Kaye, MD, PhD, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA. Viswanath, MD, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, Creighton University School of Medicine, Department of Anesthesiology, Omaha, NE, Valley Anesthesiology and Pain Consultants – Envision Physician Services, Phoenix, AZ. Urits, MD, Beth Israel Deaconess Medical Center, Department of Anesthesiology, Critical Care, and Pain Medicine, Harvard Medical School, Boston, MA, Louisiana State University Shreveport, Department of Anesthesiology, Shreveport, LA.

To whom correspondence should be addressed: Maxine Zhou, Louisiana State University Health Shreveport Department of Psychiatry, Louisiana 71103. Phone: (318) 675-6619; E-mail: ude.cshusl@1uohzm

Copyright © 1964–2019 by MedWorks Media Inc, Los Angeles, CA All rights reserved. Printed in the United States.

Abstract

Purpose of Review

This is a comprehensive review of the literature regarding the use of asenapine for the treatment of schizophrenia (SZ) in adults. It covers an introduction, epidemiology, risk factors, pathophysiology, and current treatment modalities regarding SZ, provides a background on the mechanism of action of asenapine, and then reviews the existing evidence for use of asenapine in both its sublingual and transdermal formulation in the treatment of SZ.

Recent Findings

SZ is a complex and multifactorial mental disorder which is thought to combine several genetic, epigenetic, and environmental factors causing abnormalities in the dopaminergic system. Symptoms are categorized in delusions, hallucinations, disorganization, and negative presentations like affective flattening and apathy. Current treatment focuses on antipsychotic medications by means of oral administration or long-acting injection. Asenapine is a second-generation antipsychotic with 5HT-2A antagonist and 5HT-1A/1B partial agonist properties, which provides a favorable profile in targeting schizophrenic symptoms, while reducing motor side effects and improving mood and cognition. Asenapine in its sublingual formulation was FDA approved for treatment of SZ and bipolar I disorder in adults in August of 2009 and has been proven to be both effective and safe. Transdermal patch of asenapine (Secuado) was FDA approved in October of 2019, the first and only FDA approved patch for SZ in adults, which offers another strategy for treatment to improve compliance and ease of administration.

Summary

SZ is a chronic and debilitating disease which is still not well understood and comes at great cost with regards to the quality of life for patients. Medication side-effects and compliance are enormous issues which take a toll on health care systems in industrialized nations and keep patients from achieving stability with their disease. Transdermal asenapine is a new first-in-class dosage form and provides a novel modality of administration. It has been shown to be effective in reducing positive, as well as negative symptoms, while still maintaining a favorable side-effect profile.

Introduction

Schizophrenia (SZ) is a multi-faceted and heritable psychiatric disorder associated with positive, negative, and cognitive psychiatric symptoms. 1 The disease is characterized by delusions, disorganized behavior or speech, and hallucinations as well as negative symptoms, such as flat affect, anhedonia, avolition, and social withdrawal. 1 SZ is associated with comorbid conditions such as schizoaffective disorder, anxiety, and personality disorders. 2 While the positive symptoms are often the most noticeable hallmarks of the disorder, disability in schizophrenic patients often results from the negative and cognitive symptoms. 3 Current diagnosis of SZ is based upon psychiatric evaluations during which evaluators seek to identify two or more of the following symptoms, with at least one being one of the first three symptoms listed, for a significant period of time during a one-month period: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms. 4 Since the presentation of SZ is highly variable, and the pathophysiology of SZ is linked to several genetic elements, incidence and prevalence rates of SZ may be higher than reported related to misdiagnosis. 5 Current treatments include numerous antipsychotic drugs to mitigate symptoms. 6 However, these drugs have a low response rate and are linked to serious adverse side effects. 6 First-generation antipsychotics, such as chlorpromazine, can precipitate movement disorders or extrapyramidal symptoms. While second-generation antipsychotics (SGA’s) may decrease the risk for extrapyramidal symptoms (EPS) and tardive dyskinesia, these adverse effects still occur and drugs that treat the negative symptoms in SZ are still limited. 7 Pharmaceutical options for the treatment of SZ are limited to medications that focus on the attenuation of symptoms and the prevention of relapse. Additionally, current antipsychotics are recommended for long-term treatment that may cause compliance issues in various patient populations. 3 This review describes the use of asenapine, a SGA, and its efficacy in reducing both positive and negative symptoms of SZ, while improving compliance via transdermal administration and minimizing adverse side effects when compared to other SGAs. The transdermal form of asenapine, named Secuado, is a patch form of the drug. 8 Saphris is a sublingual tablet form of asenapine and was found to be efficacious in treating manic and mixed states in bipolar disorder. However, limitations remain at present since patients are required to adhere to twice daily dosing and are also recommended to not eat or drink for 10 minutes after taking the medication. Studies have shown that the drug has effects on catecholamine systems and neurotransmitter release in the prefrontal cortex and hippocampus. 9 The goal of pharmacologically treating SZ is to increase adaptive functioning and integrate schizophrenic patients back into the community with minimal risk of relapse. 3 In a meta-analysis of the efficacy of asenapine in acute SZ, Szegedi et al. concluded that asenapine is superior to placebo and comparable to other second-generation antipsychotics. 10 However, the extensive metabolism of the drug makes oral administration inconvenient and poses a problem for patient compliance. While the current standard of care suggests sublingual administration, a transdermal route of administration of asenapine may enhance drug efficacy due to improved compliance and allow for more successful reintegration within to society.

Presentation, Epidemiology, Risk Factors, and Pathophysiology

SZ is a chronic psychiatric disorder associated with a variety of clinical presentations, which include the disruption of patients’ thought and affect. 3 Symptoms are broadly categorized into three groups: positive, negative, and cognitive. Positive symptoms include hallucinations and delusions, which may be observed during periods of psychosis. 15 Psychotic episodes are patient-specific, and the symptoms reflect a false reality within the mind of affected patients. 3 Some patients may be asymptomatic at times, while others present with more negative symptoms such as social withdrawal, lack of motivation, anhedonia, alogia, and blunt affect. 3 , 15 Negative symptoms are linked to higher morbidity due to their interference with patients’ emotions and behaviors. 3 In order to document cognitive symptoms, such as disorganized speech and thought, learning impairments, and pathogenic executive functioning, the pathology must be evident and severe enough for others to realize it’s a deviation from the patient’s baseline functioning. Therefore, cognitive symptoms may often go unnoticed or under-documented, even when a patient’s communication and baseline functioning is impaired. 3 The diagnosis of SZ is most common in adolescents and young adults, and about 80% of patients diagnosed with SZ relapse within five years of their first psychotic episode. 2 , 3 Some schizophrenic patients have received various prior diagnoses, the most common being mood and anxiety disorders, and misdiagnosis of SZ is frequent. 2 SZ can ultimately result in disability attributed to the array of negative, positive, and cognitive symptoms. 3

The gap in mortality between schizophrenic patients and the average population has increased in recent decades, with schizophrenic patients having a two- to three-fold increased risk of dying. 5 Suicide contributes to the increased mortality rate as do comorbid conditions such as pre-existing psychiatric disorders like anxiety. 11 Several risk factors modulate the incidence, prevalence, and mortality of schizophrenic patients who die 12–15 years before the average population. 11 These risks include molecular, genetic, and environmental factors. 5 It is important to note that the diagnostic definition of SZ that is used can modulate the reported incidence and prevalence rates of the disease. Thus, broad definitions with less specific criteria may have higher reported incidence and prevalence than studies with more strict definitions. 11 In a systematic review, McGrath et al. reported the median incidence of SZ at 15.2/100,000 persons, while the median lifetime morbid risk is 7.2/1,000 persons. 5 The lifetime prevalence of SZ was reported as 4.0 per 1000 persons based on combined prevalence estimates. 5 These prevalence estimates showed no significant difference between sex; however, data suggest that SZ has an earlier onset in men and that the symptomatic expression is more severe. 5 A significant difference was also found between prevalence in native-born individuals and migrants, with that of migrants being higher. 5

SZ is not classified as a Mendelian disorder; the genetic contribution to its presentation is rather complex. There is no evidence to suggest a single gene with a deterministic effect on the incidence of SZ. 1 Studies suggest that several genetic and epigenetic variations contribute to the risk and development of symptomatic SZ. It is hypothesized that an accumulation of these small genetic variations such as single nucleotide polymorphisms (SNPs), insertions, deletions, copy number variations (CNVs), and single nucleotide variants (SNVs) may induce the onset of disease. 1 Potential genes involved in SZ include FAM63B, a gene involved in neuronal differentiation, the gene coding for the DRD2 dopamine receptor, and genes involved in dopamine synthesis regulation. 1 , 12 The hypothesis of dopamine involvement in the pathogenesis of SZ is based on the clinical observation that dopaminergic agonists can induce psychosis in healthy patients and worsen psychosis in schizophrenic patients, followed by the molecular observation of antipsychotic affinity or the D2 dopamine receptor. 12 Further research involving the Positron Emission Tomography (PET) scans of brains with radioactive labeled L-dopa, or D2/D3 receptors localized the dopaminergic abnormality in schizophrenic patients to the striatum. 12 These studies support the hypothesis that individuals with higher baseline synaptic dopamine levels at rest are at risk for the development of SZ. 12 In addition to functional brain pathways, the Fcg-mediated phagocytosis immune system pathway has been identified as a risk for SZ because of its impact on epigenetic bookmarking, thus supporting the hypothesis that environmental associations influence the onset of SZ. 1 Though no study has ever proven that a single gene accounts for most of the risk for SZ, such single genes may exist. This type of gene is hypothesized to be either a largely prevalent gene with low penetrance or a gene of low prevalence but high penetrance. 13

Aside from genetics, the effects of sex and environmental risk factors such as migrant status, urbanicity, economic status, and drug use have been implicated in the risk of developing SZ. Though the incidence of SZ in males is higher than that of females, reported prevalence and mortality have been largely the same for both sexes. 5 However, reviews of literature and research surrounding the epidemiology and pathogenesis of SZ seem to point toward a more severe and symptomatic disease course in men than women. 5 A higher incidence of SZ has also been reported in migrants as compared to native-born patients, as well as in urban patients as compared to rural or mixed-dwelling patients. The prevalence of SZ has been reported as higher in developed countries as compared to the less developed. 5 Regarding alcohol and recreational drug use disorders, there is evidence of psychoactive substances influencing the onset of SZ, particularly cannabis use. 2 In a German population cohort study, the effects of cannabis use on adolescents, and their development of psychosis were studied over a 10-year follow-up period. 14 The results showed that in individuals with no reported psychotic issues at baseline, incident cannabis use increased their risk of developing psychotic symptoms. 14 The incidence of psychotic symptoms of individuals exposed to cannabis over the time-course of the study was 30% and compared to those with no exposure (20%). 14 Thus, the study concluded cannabis use as a statistically significant risk for psychotic symptoms and possibly implicated in the development of psychotic disorders such as SZ. 14 Dopamine stimulants, such as amphetamines, induce psychotic effects in healthy individuals and those with SZ are more sensitive to these effects. 15 Another risk factor for developing SZ is stress, including maternal stress. 1 Obstetric complications have been associated with the development of SZ later in life and research suggests a seasonal correlation centering around stress and infectious disturbances in the second trimester. 3

The pathophysiology of SZ is hallmarked by key features: subcortical dopaminergic dysfunction and psychotic symptoms. 15 Clinical studies demonstrate that schizophrenic patients show increased presynaptic dopamine function in the associative striatum, and the same phenomena are observed in people at high risk for developing SZ. 15 Positive symptoms, such as suspiciousness, delusions, and hallucinations, and increased subcortical synaptic dopamine content, have been linked to positive treatment response. 15 In addition to dopamine, other neurotransmitters and neuromodulators such as gamma-aminobutyric acid (GABA), glycine, 5-hydroxytryptamine (5-HT), D-serine, and neuroactive steroids have been linked to the pathophysiology of SZ. 6 The nigrostriatal, mesolimbic, and mesocortical pathways are all thought to be linked to pathogenesis. 3 Low dopamine in the nigrostriatal pathway may affect the extrapyramidal system and precipitate motor symptoms. 3 Excess dopamine in the mesolimbic pathway may influence positive symptoms, while negative symptoms may be caused by low mesocortical dopamine levels. 3

Current Treatments of Schizophrenia

Multiple approaches to the treatment of SZ exist that aim to achieve the same goal. As the pathophysiology of SZ is not completely understood, the current treatment options mainly focus on the attenuation of symptoms and decreasing symptom relapse. A primary approach to achieving this decrease in symptoms is through pharmacological treatment. The medications conventionally used are termed antipsychotics or neuroleptics and were developed around the dopamine hypothesis of SZ, which links the occurrence of positive symptoms to overstimulation of the D2 receptor in the mesolimbic pathway in the brain. There are two generations of antipsychotics commonly used, and their mechanisms of action mainly target dopamine receptors. 16

The first medications developed to treat the symptoms of SZ are termed first-generation antipsychotics. They block dopamine D2 receptors but do not show any selectivity to specific pathways. This leads to a range of side effects, one of which is the development of extrapyramidal symptoms, a range of movement disorders that can develop along the course of the treatment with first-generation antipsychotics. 16 Chlorpromazine, the first of the first-generation antipsychotics to be introduced, is still used along with other first-generations in recommended clinical regimens. 17 In addition to first-generation antipsychotics, second-generation antipsychotics, such as clozapine, olanzapine, quetiapine, risperidone, ziprasidone, lurasidone, paliperidone, iloperidone, lumateperone, cariprazine, brexipiprazole and aripiprazole, are also available. SGA tend to block 5-HT2A receptors more than D2 receptors, leading to a proposed lower likelihood of developing EPS, however these symptoms along with tardive dyskinesia have still been reported with the use of SGA. 17 The SGAs have been more beneficial in the treatment of negative symptoms as compared to first-generation antipsychotics, but the pharmacological treatment options available for negative symptoms still remain limited. 18 SGAs have become more popular than first-generation antipsychotics as the first line in the SZ treatment regimen because of better tolerability; however, there are still unfavorable side effects. SGAs have been shown to cause severe metabolic adverse effects leading to weight gain, increased weight circumference, dyslipidemia, and high blood sugar. Clozapine specifically can cause agranulocytosis, so it is usually saved for forms of SZ that are resistant to treatment with other medications. 17

There are multiple clinical guidelines available regarding the duration, dosage, and preferred route of administration of antipsychotic medications. Most guidelines recommend continued maintenance treatment over intermittent treatment to prevent relapse in symptoms. 17 An intermittent treatment regimen is one in which a patient does not use medication continuously, but rather only uses medication during certain periods when experiencing relapse or exacerbation of symptoms. 19 A maintenance treatment is a continuous treatment with a constant dose of medication that is continued even after symptom remission (17). Only some guidelines give specifics regarding recommended dosing for long term treatment. In general, the different guidelines recommend different dosing for single-episode patients versus multi-episode patients. Regimens advise prescribing at the lowest dose possible to achieve efficacy and to minimize the side effect profile. With regards to duration of treatment, the guidelines recommend a 6–12 month period of maintenance therapy following the acute phase, and 2–5 years maintenance for patients who have experienced multiple episodes, and lifelong therapy for those diagnosed with severe cases. 17

Antipsychotics are considered the foundation for controlling symptoms of SZ, but incorporating the recommended long-term psychotherapy is often troublesome for patients. The poor adherence that is seen with oral antipsychotics makes it difficult to control the symptoms of SZ and lead to a higher rate of relapse. To overcome this, an alternative route of administration in the form of long-acting injectable antipsychotics has been developed. 20 These injections eliminate the daily dosing required with oral medications and replace daily dosing with biweekly, monthly, or trimonthly dosed injections. Many clinical guidelines specify that of the two available routes of administration, oral and long-acting injectable, long-acting injectable is an especially good alternative for patients with non-adherence. 17 Long-term injectables have been noted to reduce the risk of possible treatment failure. 20 In addition, they have been noted to help in maintaining longer periods of remission and improving the health-related quality of life in patients. 21 However, even with this proven efficacy, there are still obstacles to this administration option.

Administration of long-acting injectables provides less flexibility in available dosage, there are still not as many medications available currently as injections, and there can be a reaction to injection sites. In addition, patients are often reluctant to choose injection over oral. 20 When a survey was completed asking patients who had previously been on antipsychotic treatment regarding their preferred method of treatment, there was a significantly lower preference for long acting injectables. This may have been affected by the location of injections, deltoid versus gluteal and varying bioavailability and duration of action between the different sites of administration. However, the participants in the study noted this was mostly due to not being able to visit a healthcare facility as often as required to get the injections administered. Other reasons provided included a fear of the injection, considering the injections unnecessary, and preferring another type of medication in general. The study did find, however, that some of these patient opinions can be attributed to the lack of knowledge on injections and not to the injections themselves. 21

The current pharmacological treatment options for SZ include two classes of antipsychotic drugs, two forms of long-term care plans, and limited options for routes of administration. A study was completed that analyzed the treatment plan of almost 30,000 individuals to determine which antipsychotic treatments had the best treatment outcome with a low number of rehospitalizations and treatment failure. This study found that of all available options, the use of clozapine and long acting injectables are currently the pharmacological treatments with the best preventions of relapse. 22

The established foundation for the treatment of SZ is pharmacological; however other routes are being explored to include a more comprehensive treatment plan. Non-invasive brain stimulation, more specifically transcranial brain stimulation, is a treatment option currently being explored and utilized. It was found in one study to have a significant difference in control of symptoms when compared to a placebo, with favor for transcranial magnetic stimulation (TMS). However, the data was not strong enough to draw a definitive conclusion regarding the use of TMS as a singular therapy and rather, suggest that it would benefit patients when being used as an adjunct to pharmacological therapy. 23 No single currently available regimen has been shown to be completely successful in the elimination of symptoms for every patient diagnosed with SZ. Treatment options are being explored and developed every day with various non-pharmacologic possibilities being considered, as well as new routes of drug administration, favorable tolerability profile, and new receptor targets for drugs.

Asenapine Drug Information

Asenapine is a second-generation antipsychotic available for the treatment of acute SZ. It has shown evidence of reducing positive and negative symptoms while keeping the adverse effects to a minimum. It is currently being used via a sublingual route. 24 The use of this medication is approved in a transdermal form known as Secuado. Secuado is indicated specifically for the treatment of adults with SZ. It is a translucent, rounded, square patch that is applied once daily and worn for 24 hours at a time. Only one patch can be worn at a time, and it must be placed on a clean, dry and intact skin area. Recommended placement locations include upper arm, upper back, abdomen, or hip. It is safe to shower while wearing a Secuado patch; however, taking a bath or swimming while wearing a patch has not been evaluated. No heat can be applied to these patches, for instance, the use of a heating pad, as this can increase plasma concentrations. 25

There are three different dosages available, 3.8 mg, 5.7 mg, and a 7.6 mg patch. The recommended starting dose is one 3.8 mg patch every 24 hours and can be increased as needed using the other available patches. The safety of dosages higher than the available 7.6 mg asenapine patch has not been well investigated. 25 There are only two currently listed contraindications of this patch- patients who have severe hepatic impairment and patients who already have a previous history of hypersensitivity to asenapine or problems with transdermal administered medications. It has been noted that taking antipsychotics in the third trimester of pregnancy can cause withdrawal symptoms and extrapyramidal symptoms in the infant; however, no human studies have been conducted to study the safety of Secuado during pregnancy. In animal studies, there have been no reports of teratogenicity of intravenously administered asenapine. 25

The adverse effects associated with the use of Secuado patches are broadly similar to those of other antipsychotic given via alternate routes of administration. Particularly, most commonly reported adverse effects included somnolence (13%–24%), extrapyramidal symptoms (7%–12%), and dizziness (11%). In clinical trials, only a total of 4.9% of individuals ultimately discontinued the use of asenapine due to adverse effects. The most common adverse effect was akathisia. The other common adverse effects seen were extrapyramidal symptoms, reaction to the application site, and weight gain. Application site reactions included any reports of dermatitis, discoloration, discomfort, dryness, edema, erythema, exfoliation, induration, irritation, pain, papules, pruritus, and reaction at the site of patch placement. 25 In clinical trials, there were also adverse effects reported that did not lead to the discontinuation of Secuado such as gastrointestinal side effects including constipation, dyspepsia, and diarrhea, side effects of the nervous system including headache, somnolence, and dystonia, as well as hypertension, increased appetite, blood glucose increase, hepatic enzyme increase. There is also a black box warning associated with all antipsychotics, which state that elderly patients with dementia-related psychosis are at an increased risk of death when treated with antipsychotics, and Secuado is not currently approved for the treatment of elderly patient with dementia-related psychosis. 25

Mechanism of Action, Pharmacokinetics, and Pharmacodynamics

Asenapine has effects on several catecholamine systems that could be important in the treatment of SZ. It potently blocks 5HT-2A receptors and enhances 5-HT tone effects. 26 This particular study assessed monoamine system activities after two-day and 21-day asenapine administration (0.1mg/kg/day). In the ventral tegmental area, asenapine administration resulted in an increase in the number of spontaneously active dopamine neurons, while firing parameters remained unchanged. While asenapine partially prevented the D2 auto receptor-mediated inhibitory response to apomorphine after two days of the administration, this effect was not observed after 21 days of administration. In the locus coeruleus, asenapine increased the firing activity of noradrenergic neurons after 21 days, but no effect was seen at two days. Asenapine potently blocked 5-HT2A receptors, while α2-adrenergic receptors remained unaffected. In the hippocampus, 21-day asenapine administration increased serotonergic tone by partial agonist action on postsynaptic 5-HT1A and terminal 5-HT1B receptors. In the CA3 region of the hippocampus, both acute and long-term asenapine administration partially blocked α2-adrenergic receptors, and noradrenergic tone of α1- and α2-adrenoceptors remained unchanged.

Another study found that asenapine preferentially increased the efflux of dopamine, norepinephrine, acetylcholine in the medial prefrontal cortex, and the hippocampus compared to the nucleus accumbens. 27 Specifically, asenapine dosage of at 0.05, 0.1, and 0.5 mg/kg (s.c.), but not 0.01 mg/kg, significantly increased dopamine efflux in the rat’s medial prefrontal cortex and hippocampus. Only the 0.5mg/kg dose of asenapine enhanced dopamine efflux in the nucleus accumbens. A different study suggested the asenapine-induced dopamine release in the nucleus accumbens is dependent on the activation of dopaminergic neurons in the ventral tegmental area. 28 Intra-ventral tegmental area tetrodotoxin perfusion blocked asenapine-induced accumbal, but not cortical, dopamine outflow. The increase of cortical dopamine outflow involves a local action at nerve terminals. Norepinephrine efflux in the medial prefrontal cortex increased at 0.1mg/kg of asenapine. Acetylcholine efflux in the medial prefrontal cortex increased at 0.1 and 0.5 mg/kg doses of asenapine, but only 0.5mg/kg dose of asenapine caused an increase in the hippocampus. 27 Additionally, acetylcholine efflux in the nucleus accumbens did not increase at any dose tested. Taken all together, this suggested that similarly to clozapine and other atypical antipsychotic drugs, asenapine may improve the cognitive and negative symptoms in schizophrenic patients.

A different study, however, suggested that asenapine does not improve the cognitive functions associated with SZ. In fact, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone. 29 Tests for antipsychotic activity in rat models included amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted pre-pulse inhibition (Apo-PPI;0.5 mg/kg s.c.). To test short-term spatial memory and attention, delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks, respectively, were used. Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03–0.3 mg/kg; and risperidone, 0.01–0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05). According to these results, asenapine does not have the ability to improve cognitive deficits specifically, yet it still has potential as an antipsychotic agent.

A review analyzing the efficacy of asenapine determined that while asenapine is efficacious in the acute treatment of SZ, it is not without adverse effects such as metabolic and extrapyramidal symptoms. 30 In regard to pharmacokinetics, asenapine is metabolized by CYP1A2. Therefore, caution should be exercised when using either CYP1A2 inducers, such as carbamazepine or rifampin, as well as CYP1A2 inhibitors, including fluvoxamine and ciprofloxacin. 31 Asenapine has poor bioavailability and therefore has been developed as a sublingual formulation that is approved in the United States. In the sublingual asenapine 52-week, double-blind, comparator-controlled adult trial that included patients with SZ, the mean weight gain from baseline primarily was 0.9 kg. The proportion of patients with greater than a 7% increase in body weight (at endpoint) was 14.7%. 32 While sublingual caused weight gain, this is a common adverse effect associated with other second-generation antipsychotics.

Sublingual administration of asenapine may not be ideal for all patients. For instance, a patient who has previously had treatment success with sublingual asenapine but reported adverse effects such as dysgeusia would likely prefer another route of drug administration. Transdermal delivery of drugs may offer a solution to this problem. Advantages of transdermal treatment include ease of use, reduced dosing frequency, steady delivery of drug, the potential for similar efficacy with a lower dosage, increased tolerability, reduced drug-drug interactions, and avoidance of first-pass metabolism. 33 Transdermal patch, Secuado, has a different pharmacokinetic profile compared to sublingual asenapine. 32 This patch is applied once daily and should not be worn for longer than 24 hours. Maximum asenapine concentrations are typically reached between 12 and 24 hours. On average, approximately 60% of the asenapine was released from the transdermal system over these 24 hours. Following patch removal, the apparent elimination half-life is approximately 30 hours. If worn properly, patients with SZ may benefit from an asenapine patch and reap the benefits associated with transdermal delivery of medication.

Clinical Studies: Safety and Efficacy

There is some evidence that asenapine provides an improvement in positive, negative, and depressive symptoms while minimizing adverse effects. A review including randomized controlled trials compared asenapine to placebo in adults with SZ (34). Results showed a clinically significant change in global state (1 RCT, n = 336, RR 0.81, 95% CI 0.68 to 0.97, low-quality evidence) and mental state (1 RCT, n = 336, RR 0.72, 95% CI 0.59 to 0.86, very low-quality evidence) at short-term amongst people receiving asenapine. Individuals receiving asenapine also demonstrated significant reductions in negative symptoms (1 RCT, n = 336, MD –1.10, 95% CI –2.29 to 0.09, very low-quality evidence) at short-term. Additionally, people receiving asenapine demonstrated significantly fewer incidents of serious adverse effects compared to placebo (1 RCT, n = 386, RR 0.29, 95% CI 0.14 to 0.63, very low-quality evidence) at medium-term. Asenapine affected global state, mental state, reducing negative symptoms, and all while displaying fewer adverse effects relative to placebo.

Additional meta-analyses findings confirmed a similar decrease in PANSS total score after asenapine administration and indicated that the drug has the potential to improve symptoms associated with SZ. Asenapine was superior to placebo with regard to mean change in PANSS total score (last observation carried forward [LOCF]: –3.6, P = .002; mixed model for repeated measures [MMRM]: –4.1, P = .001), an effect comparable to active controls from the same trials (LOCF: –4.0, P = .002; MMRM: –4.8, P = .001). 36 Additionally, this study displayed that asenapine is comparable to other drugs currently used in the treatment of SZ. In regard to other second-generation antipsychotics, estimated differences between asenapine and these drugs ranged from 3.9 points (95% CI, 0.3 to 7.4) greater than ziprasidone to 2.9 points (95% CI, –0.1 to 5.9) less than olanzapine. Therefore, the estimated differences determined in these meta-analyses demonstrate the efficacy of asenapine.

An additional study also compared asenapine and olanzapine, specifically in their abilities to reduce the persistent negative symptoms (PNS) associated with SZ. 37 Two 26-week core studies with 26-week extensions (n = 502) showed no difference between asenapine and olanzapine at 26 weeks; however, at week 52, asenapine showed superiority over olanzapine in Negative Symptom Assessment-16 total score, NSA global, PANSS Marder negative and PANSS negative subscales, and four of five domains. This is consistent with a review of eight randomized clinical trials, encompassing 3765 patients, that compared asenapine with placebo (n = 5) and olanzapine (n = 3). No differences were found between asenapine and olanzapine in terms of changes to PANSS total or PANSS negative subscale scores. 38 While asenapine demonstrated fewer adverse metabolic outcomes than olanzapine, rates of extrapyramidal symptom-related adverse effects were higher.

An extension study, an initial 6-week double-blind, randomized trial that was extended for 52-weeks, compared the safety and efficacy of asenapine versus haloperidol (39). Of 272 patients who completed the 6-week trial, 187 entered the 52-week extension (placebo/asenapine, n = 51; asenapine, n = 93; haloperidol, n = 43) and 66 completed 58 weeks of treatment (placebo/asenapine, n = 20; asenapine, n = 30; haloperidol, n = 16). Incidence rates of treatment-emergent adverse events were 88%, 85%, and 86% for placebo/asenapine, asenapine, and haloperidol, respectively. These treatment-emergent adverse effects include insomnia (38%, 32%, 21%), parkinsonism (10%, 17%, 28%), akathisia (10%, 16%, 28%), and headache (26%, 16%,19%). Clinically significant weight gain, defined as greater than 7% increase from baseline, was recorded to be 13% in placebo/asenapine, 19% in asenapine, and 15% in haloperidol. Extrapyramidal symptom-related adverse effects were lower in placebo/asenapine (18%) and asenapine (35%) compared to haloperidol (54%). Overall, this study suggests that asenapine maintained its effect in schizophrenic patients throughout the 1-year extension and appeared to be well tolerated.

Extensive metabolism makes the oral route inconvenient for asenapine. While it is currently administered sublingually, transdermal asenapine administration has the potential to enhance the effects of the drug and make life easier for patients with SZ. Advantages of transdermal drug delivery systems (TDDS) include avoidance of the first-pass effect, the possibility of providing sustained release, and improving patient compliance. 40 Techniques for ensuring percutaneous delivery include the use of prodrugs, chemical penetration enhancers, transfersomes, and proniosomes.

In a phase 3 double-blind inpatient study of adults with SZ, 614 patients received either high dose medication (204 patients), low dose medication (204 patients), or placebo. 16 The medication was administered as in the form of a transdermal patch, HP-3070-low dose, and HP-3070-high dose, which is equivalent to sublingual asenapine 5mg and 10mg BID, respectively. At week 26, PANSS score change from baseline (CFB) was better for the treatment groups compared to the placebo group. Specifically, with least-squares mean (LSM) (standard error [SE]; 95% CI) estimates of PANSS score as –4.8 (1.634; –8.06, –1.64; p = 0.003) and –6.6 (1.630; –9.81, –3.40; p < 0.001) for high- and low-dose groups, respectively. Furthermore, the Clinical Global Impression-Severity of Illness Scale (CGI-S) at Week 6 LSM estimates were –0.4 (0.100; -0.55, –0.16; p < 0.001) and –0.4 (0.099; –0.64, –0.25; p < 0.001). With regard to the safety profile, HP-3070 was consistent with sublingual asenapine. Incidence of patch application site treatment-emergent adverse effects (TEAEs) was higher for HP-3070 (14.2% high-dose, 15.2% low-dose) vs placebo (4.4%). Discontinuations for application site reactions or skin disorders were less than 0.5% across all groups, indicating the benefit of asenapine administration outweighed the potential cutaneous side effects.

Conclusion

SZ is a lifelong disease that can be debilitating, particularly if left without treatment. Helping patients achieve a better quality of life is complicated by misdiagnoses, variable presenting symptomatology, and difficulty integrating back into society. Complex drug regimens can further confuse patients, leading to poor medication compliance. The foundation of currently recommended treatment plans is the use of antipsychotics; however, since the pathophysiology of the disease is not completely known, the available drugs are designed to target and reduce the symptoms of SZ. Treatment plans can be extensive, ranging from months to lifelong plans, which require complete compliance to have the lowest possible risk of relapse. It continues to be a challenging task to balance the remission of symptoms and achieve a better-quality life, given the complexity of currently recommended drug treatments. New routes of administration are being pursued to relieve some of the difficulties that lead to non-adherence. The asenapine transdermal system for the treatment of adults with SZ provides a promising option for pharmaceutical treatment of both positive and negative symptoms. The advantages of the transdermal delivery system include sustained release and avoidance of first-pass drug metabolism. Studies surrounding the use of asenapine in acute SZ confirms that the drug is comparable to the current standard of care treatments, indicated by a reduction in PANSS scores. Reduction of side effects like weight gain are another benefit of asenapine treatment. In comparison to olanzapine, asenapine has reported better treatment of negative symptoms in SZ, a group of symptoms that often prove particularly difficult to treat. Cutaneous side effects of the transdermal patch drug delivery system were minimal, which may allow for higher rates of patient compliance. More studies are needed to address the lack of understanding surrounding a diagnosis of SZ and time of onset in relation to the efficacy of asenapine in specific patients (i.e., those diagnosed in adolescence versus adulthood). Due to the complicated genetic heritability of the disease, more research surrounding potential contributory or single gene variants is necessary to answer the question of which patients would benefit most from the asenapine transdermal delivery system. It is possible that patients with specific epigenetic markers or mutations may respond differently to various therapies.

Table 1

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