A Review of Asenapine in the Treatment of Bipolar Disorder

Clin Drug Investig (2018) 38:87–99 https://doi.org/10.1007/s40261-017-0592-2 REVIEW ARTICLE A Review of Asenapine in the Treatment of Bipolar Disorder 1 2 Eduard Vieta • Jose´ Manuel Montes Published online: 24 October 2017 Ó The Author(s) 2017. This article is an open access publication Abstract Bipolar disorder places a significant burden on the affected individuals, their family, healthcare systems and the Key Points overall economy. More treatment options are needed, espe- cially those with better efficacy and tolerability. Asenapine is a Asenapine is a second-generation atypical second-generation antipsychotic approved in Europe (brand antipsychotic drug with demonstrated efficacy in the Ò name Sycrest ) for the treatment of moderate-to-severe manic treatment of mania associated with bipolar I disorder. episodes associated with bipolar I disorder in adults, and in the US (brand name SaphrisÒ) for the treatment of manic or mixed Asenapine was also effective in the treatment of episodes of bipolar I disorder in adults and children aged mixed states in patients with bipolar I disorder, as defined by the Diagnostic and Statistical Manual of 10–17 years. It is the antagonistic activity at the D2 receptor that is likely responsible for the antimanic properties of ase- Mental Disorders (DSM), 4th Edition, Text napine. Clinical trials have demonstrated that asenapine mono- Revision, or major depressive disorder with mixed and add-on therapy is effective in the short- and long-term features, as defined by DSM-5. treatment of mania associated with bipolar I disorder in adult Several pharmacoeconomic studies have shown that and paediatric patients. In addition, post hoc and pooled data asenapine is likely to be associated with lower analyses have shown that asenapine is effective in reducing healthcare costs and higher quality of life. clinically significant depressive symptoms in patients with bipolar I disorder. The most common adverse events associated with asenapine are somnolence, dizziness, extrapyramidal symptoms, increased bodyweight and oral hypoesthesia. 1 Introduction However, the incidence of these events, particularly weight gain, is generally lower than with olanzapine. In one study, Bipolar disorder is a chronic affective condition charac- asenapine has been shown to improve health-related quality of terised by episodes of mania and depression [1]. Two major life. Economic analyses indicate that the use of asenapine can, types of bipolar disorder have been defined: bipolar I and over time, lead to a reduction in the costs of treatment. bipolar II [2]. Manic episodes are the dominant feature of bipolar I; however, depressive episodes are also common. & Eduard Vieta In bipolar II, manic symptoms have lower intensity and [email protected] duration (hypomania), while depression is more pro- nounced. In addition, patients with bipolar disorder may 1 Psychiatry and Psychology Department of the Hospital Clıńic, Institute of Neuroscience, University of Barcelona, experience episodes that combine the features of both IDIBAPS, CIBERSAM, 170 Villarroel St, 08036 Barcelona, mania and depression. The criteria for diagnosing these Catalonia, Spain episodes vary. In the Diagnostic and Statistical Manual of 2 Psychiatry Section of the Ramoń y Cajal University Hospital, Mental Disorders (DSM)-IV, co-occurrence of full mania IRYCIS, CIBERSAM, University of Alcala´, Ctra. Colmenar and depression for more than 1 week is defined as a mixed Viejo, km. 9,100, 28034 Madrid, Spain 88 E. Vieta, J. M. Montes state (episode), whereas in the DSM-5 it has been replaced approximately 35% [13]. Exposure increases non-linearly with a ‘mixed features’ specifier [3]. and approximately 1.7-fold when the dose is doubled [13]. In the general population, lifetime prevalence of bipolar It is recommended that eating and drinking is avoided for spectrum disorders has been estimated at 2.4%, while the 10 min following administration [13]. Drinking water 2 prevalence of bipolar I and II is approximately 0.6 and and 5 min after administration has been shown to decrease 0.4%, respectively [4]. Bipolar disorder is associated with exposure by approximately 20 and 10%, respectively. decreased cognitive function [5] and professional ability, These variations are within the range of intraindividual and increased risk of suicide and substance abuse [4]. It is variability and may not be clinically significant [14]. characterised by a high degree of comorbidity with other Taking asenapine within 30 min of consuming a high-fat psychiatric conditions [4] and places a significant burden meal has been shown to reduce exposure by approximately on healthcare systems [6]. In 2010, bipolar disorder was 20%, while consuming a high-fat meal 4 h after taking responsible for 0.5% of the total number of disability-ad- asenapine reduced exposure by approximately 13% [15]. justed life-years (DALYs) worldwide, or 5.0% of DALYs Supralingual administration has been shown to be essen- attributable to mental illness, surpassing Alzheimer’s dis- tially bioequivalent to sublingual administration based on ease, Parkinson’s disease and multiple sclerosis [6]. area under the concentration-time curve values [16]. If Recommended treatments for bipolar disorder include swallowed, the bioavailability of asenapine is approxi- lithium, antipsychotics, anxiolytics, antidepressants, anti- mately 2% [17]. With sublingual administration, peak convulsants, electroconvulsive therapy and their various plasma concentration is reached within 0.5–1.5 h [13]. combinations [7]. Atypical, or second-generation, Half-life is approximately 20 h [16], and steady-state antipsychotics are a class of drugs most commonly used in plasma levels are reached within 3 days of twice-daily the treatment of bipolar disorder [8]. Asenapine is an administration [13]. Asenapine is extensively metabolised, atypical antipsychotic drug used for the treatment of mania mostly by uridine diphosphate-glucuronosyltransferase 1-4 in bipolar disorder and schizophrenia. Its active ingredient, and cytochrome P450 (CYP) 1A2 [13, 18]; however, none asenapine maleate, is a synthetic tetracyclic compound that of the metabolites can cross the blood–brain barrier [17]. is chemically distinct from other drugs in this class. In Approximately 90% of asenapine is excreted in faeces 2009, asenapine, under the brand name SaphrisÒ, received (50%) and urine (40%) within 96 h of administration marketing authorisation in the US for the treatment of [13, 18]. manic or mixed episodes in adult patients with bipolar I Fluvoxamine, a CYP1A2 inhibitor, has been shown to disorder, as monotherapy or adjunctive treatment to lithium increase asenapine exposure, and coadministration should or valproate [9]. Then, in 2010, it was approved in the EU be avoided [13]. In patients with severe hepatic impair- for the treatment of moderate-to-severe manic episodes in ment, asenapine exposure has been shown to be approxi- adult patients with bipolar I disorder [10]. In 2015, the US mately seven times higher than in those with normal liver FDA also approved asenapine for the acute treatment of function, and commensurate dose titration is advised in this manic or mixed episodes of bipolar I disorder in paediatric population. Renal impairment does not have any substan- patients (ages 10–17 years) [11]. Asenapine has been tial effect on asenapine exposure [13]. approved for the treatment of mania associated with bipolar Asenapine increases blood concentrations of paroxetine I disorder in multiple countries in North and South [13], and should be administered with caution in combi- America, Europe, Asia and Oceania [12]. Furthermore, nation with drugs that are both substrates and inhibitors of asenapine is approved for the treatment of schizophrenia in CYP2D6 [13]. the US, Canada, Australia, New Zealand and Argentina. In Europe, asenapine (brand name SycrestÒ) is available as 5 and 10 mg rapidly dissolving tablets for sublingual 3 Pharmacodynamics administration. The aim of this narrative review was to summarise the The exact mechanism of action of asenapine is unknown pharmacology, efficacy and safety of asenapine, and dis- [19]. Asenapine has been shown to interact with a wide cuss its place in the treatment of bipolar disorder. range of receptors, including serotonin receptor subtypes 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6 and 5-HT7; adrenoceptor subtypes a1A, a2A, a2B and a2C; 2 Pharmacokinetics dopamine receptor subtypes D1,D2L,D2S,D3 and D4; and histamine receptor subtypes H1 and H2. At most of these, Asenapine is available in 5 and 10 mg sublingual tablets asenapine acts as an antagonist [20], while it is likely a for twice-daily administration. If administered sublin- partial agonist at the 5-HT1A receptor [21]. Asenapine has a gually, the bioavailability of a 5 mg dose of asenapine is low affinity for muscarinic receptors (negative logarithm of Asenapine in the Treatment of Bipolar Disorder 89 the binding affinity [pKi] B 5) [20]. Occupancy at the D2 doses were associated with significant reductions in mean dopamine receptor is believed to be responsible for the total CGI-BP scores at day 4 and at the end of the treatment antimanic activity of asenapine [19]. Compared with other period (Table 1)[24]. Furthermore, mean MADRS scores atypical antipsychotic drugs, the affinity of asenapine for were significantly reduced with both doses of asenapine at this receptor subtype is second only to that of aripiprazole day 7 and at the end of the study [24]. [20]. In addition,

Load more