Asenapine, Iloperidone and Lurasidone

Critical Appraisal of the Most Recently Approved Pharmacotherapies for Schizophrenia in Adults

William V Bobo


Expert Rev Clin Pharmacol. 2013;6(1):61-91. 

In This Article

Expert Commentary

Schizophrenia is a severe, chronic, impairing and costly mental disorder. In spite of remarkable advances in terms of pharmacotherapeutic options for treating the disorder, many unmet therapeutic needs remain. Positive signs and symptoms such as hallucinations, delusions, and disorganized thinking and behavior, long considered the defining psychopathological features of schizophrenia, have continued to be the symptom domain most responsive to antipsychotic drug treatment. However, the clinical significance of other psychopathological domains, such as negative (or deficit) signs and symptoms, depression and cognitive impairment are now widely recognized. In particular, negative signs and symptoms, and cognitive dysfunction may be more directly related to the profound levels of functional incapacity observed in many patients with schizophrenia than positive signs and symptoms. Thus far, available antipsychotic drugs, appear to be far less effective for reducing primary negative signs and symptoms and improving cognitive performance than they are for treating positive signs and symptoms.[68–70] Improvement in cognition with atypical antipsychotic drugs is typically modest in comparison with the total degree of impairment wrought by the underlying disorder.[71]

Many patients with schizophrenia and related psychotic disorders, such as schizoaffective disorder, still respond poorly to a given antipsychotic agent in spite of adequate treatment adherence. For patients that do have a positive antipsychotic response, many continue to experience residual, persisting symptoms that are associated with poor clinical outcomes and low functioning. With the exception of clozapine for treatment-resistant schizophrenia,[14,15,72] recent evidence suggests that, on the one hand, there is considerable overlap in the effectiveness of most antipsychotics.[73,74] On the other hand, the interindividual variability in therapeutic response to antipsychotic treatment is considerable. To optimize pharmacotherapeutic benefit for patients with schizophrenia, the wide array of antipsychotic drugs available to practitioners may be considered beneficial. At the same time, this presents a formidable challenge – each drug must be evaluated by clinicians, patients and caregivers on their individual merits and limitations within, ideally, a shared decision making framework.[75]

Iloperidone, asenapine and lurasidone are the newest agents from a very large therapeutic class of atypical antipsychotic drugs. In broad terms, they appear to share a lot in common. First, like most other atypical antipsychotic drugs, iloperidone and asenapine display more potent antagonist activity at 5-HT2A receptors than D2 receptors, while lurasidone displays relatively equivalent binding at both sites. Second, all three are approved for the treatment of acute schizophrenia in adults, while asenapine is additionally approved for maintenance treatment of schizophrenia, and manic or mixed episodes in adults with bipolar I disorder (with or without psychotic features, as a single agent or as a pharmacological adjunct or lithium or valproic acid). There is currently no evidence of differential efficacy in acute- or maintenance-phase treatment of schizophrenia in adults for any of these agents. Finally, prior to the release of these medications and paliperidone, another relatively new atypical antipsychotic, there were only two antipsychotic drugs (ziprasidone and aripiprazole) that were classified widely as having low risk of clinically significant treatment-emergent weight gain, glycemic dysregulation, hyperglycemia and atherogenic dyslipidemia. Thus far, iloperidone, asenapine, and lurasidone have been associated with only limited changes in body weight, and nonclinically significant changes in glycemic and lipid indices. Available evidence therefore suggests that these agents may eventually be classified as also having low metabolic risk as additional data accumulates, and will be reasonable therapeutic options in patients for whom metabolic concerns are treatment-limiting.

While iloperidone, asenapine and lurasidone are similar in many ways, there are some practical and theoretical differences between these drugs based on their individual pharmacological properties,[76] which may translate clinically to particular advantages and disadvantages. These are summarized in Table 8 and discussed in greater detail below.

For example, iloperidone has been associated with strikingly low rates of treatment-emergent akathisia in short-term trials[202] and has the lowest rates of treatment-emergent akathisia of the three newest antipsychotics, and lower rates of incident akathisia than two other atypical antipsychotics, ziprasidone and risperidone, in short-term trials.[64] Even within the atypical class, the risk of EPS is not absent.[77] Thus, limiting EPS liability remains an important therapeutic objective. This is especially true for patients who are highly EPS-sensitive (e.g., patients with first-episode psychosis, clinically significant parkinsonism, history of neuroleptic malignant syndrome or a history of severe or difficult-to-control akathisia or parkinsonism) or EPS-intolerant (i.e., patients with histories of poor adherence because of EPS, regardless of severity). Clozapine and quetiapine have long been considered to have the lowest EPS risk among the available antipsychotics;[78] however, wider use of both agents may be limited by adverse metabolic risk and potentially severe (even life-threatening) side-effects in the case of clozapine. Based on this, iloperidone may be preferred for treating patients with who are highly EPS-sensitive or -intolerant. These advantages may be offset, however, by a number of factors, the first one being risk of orthostatic hypotension and dizziness. Although slow titration can reliably limit the incidence of orthostatic hypotension, it can also limit the clinical utility of iloperidone in acute settings, where limited lengths of stay often make even brief delays in achieving therapeutic doses and adequate symptom control unacceptable. Given the need for titration to limit side effects, it is not likely that oral iloperidone will be useful for spot-management of agitation. An even slower titration may be required for individuals who are particularly sensitive to dizziness or orthostasis, including elderly patients, patients with heart disease, and persons taking antihypertensive drugs and other medications associated with orthostatic blood pressure changes. Second, although no cases of iloperidone-associated torsades de pointes or sudden death due to ventricular arrhythmias have been reported, prolongation of the QTc interval has been observed across all iloperidone doses. Avoidance of iloperidone may be prudent for patients who are medically susceptible to ventricular arrythmias because of underlying heart disease, or for patients taking medically necessary concomitant medications that lengthen the QT interval (e.g., anti-arrhythmics, or certain antibiotics, antihistamines, antidepressants, and so on), or who have other known risk factors for ventricular arrhythmias.[79] These precautions are similar to those for ziprasidone. When the balance between clinical benefit and cardiac safety is uncertain, consultation with a cardiologist may be warranted. Fourth, monitoring for emergence of orthostatic blood pressure changes and QTc interval prolongation may be especially important during a switch from another antipsychotic to iloperidone and vice-versa, since some other antipsychotics also carry significant risk of orthostasis and QTc lengthening. This clearly applies when cross-tapering from one drug to another (resulting in a short period of time when both drugs are ingested), a reasonable switch method in ambulatory settings given the slow titration required to achieve therapeutic doses of iloperidone. However, due caution would also apply when abrupt switching is performed, since several days may be required to clear most preswitch antipsychotics. Finally, concomitant medications must be closely monitored – the dose of iloperidone needs to be reduced in the presence of concomitant drugs that are strong CYP450 2D6 and 3A4 inhibitors, and increased if these agents are discontinued.

Asenapine is the only antipsychotic drug available exclusively in a rapidly dissolvable sublingual form, with reliable buccal absorption. This can have a number of advantages – first, rapidly dissolvable formulations may be preferred by some patients to swallowing solid oral tablets, including those with impaired swallowing mechanisms or gastrointestinal malabsorption problems. Second, rapidly dissolving asenapine is more difficult to cheek than solid oral tablets, making adherence easier to monitor, especially in inpatient or other controlled settings. Third, because it is rapidly absorbed and associated with mild to moderate somnolence, oral asenapine may be appropriate for spot-management of acute agitation and is being clinically investigated for this purpose (NCT 01400113). Of the three newest antipsychotics, asenapine appears to have the lowest propensity for elevating prolactin levels, although increases in prolactin concentrations were modest with iloperidone and lurasidone, and clinically significant prolactin-related adverse effects occurred only rarely. Still, for patients in whom these effects could be especially bothersome (including young people) or patients with a history of treatment-emergent galactorrhea, menstrual changes, gynecomastia or sexual dysfunction clearly correlated with elevations in prolactin concentration, asenapine may be an especially attractive option. Asenapine's approval for treating acute mixed or manic episodes in patients with bipolar I disorder may also be considered an advantage, at least, for the time being, as most other atypical antipsychotics were first approved for treating acute schizophrenia, with subsequent approval for the treatment of acute bipolar manic or mixed episodes. Finally, because asenapine undergoes direct glucuronidation and is dependent on the CYP450 system to a relatively limited degree, there may also be low potential for clinically significant drug–drug interactions. For example, lack of CYP3A4 metabolism may make asenapine the best choice of the three newest agents to combine with carbamazepine, where clinically indicated. There are some potential disadvantages with asenapine. First, patients and caregivers must be carefully educated regarding the proper handling (with dry hands) and administration of asenapine. Critical details must include avoidance of swallowing the medication; most patients with extensive prior treatment histories will be used to swallowing their medication. Allowing a tablet to dissolve orally and avoiding food or drink to allow full absorption may represent a considerable break from routine that can be surprisingly hard to accomplish for many patients. Patients may also be tempted to chew the tablets, which must also be avoided. Second, because of its negligible bioavailability if ingested, swallowing asenapine can lead to covert or unintended problems with adherence, thus threatening clinical stability outside of supervised settings. Finally, some patients will experience dysgeusia or oral hypoesthesia, which can occasionally prove bothersome enough to threaten adherence. Switching to the black cherry-flavored formulation may be helpful in such cases. Use of gum, candy, breath mints, or related measures to overcome these effects must be strictly avoided; at least, in the 10 min following asenapine administration.

Lurasidone has the lowest short-term risk of clinically significant weight increases and the most favorable glycemic and lipid profile among the newest atypical antipsychotic drugs based on indirect comparisons. That said, the overall metabolic profiles of each of these new agents appears favorable in comparison with several older atypical antipsychotics (excluding aripiprazole and ziprasidone) and low-potency typical neuroleptics, and the metabolic profiles of each have not been directly compared. Still, the available data indicate that lurasidone will be considered a low-risk agent in terms of metabolic adverse effect burden alongside ziprasidone and aripiprazole. This would be advantageous for any patient with schizophrenia, given the high long-term cardiovascular morbidity and early mortality associated with the disorder.[6,80] This may be especially true for patient subgroups who are particularly vulnerable to the dysmetabolic effects of antipsychotic drugs (i.e., young people, first-episode patients and patients who have already begun to show substantial weight gain or adverse changes in glycemic or lipid indices).[81–84] For these individuals, even small differences between agents in terms of weight gain or metabolic profile can be clinically meaningful and drive patient or caregiver preferences. Pragmatic advantages of lurasidone include once-daily dosing, which may improve adherence, and the ability to initiate treatment at a clinically effective dose, which may result in more rapid symptom control during acute-phase treatment. On the other hand, there are some potential disadvantages. First, lurasidone may be associated with higher rates of akathisia than iloperidone or asenapine, although direct comparisons are needed to confirm this observation. Should treatment-emergent akathisia become problematic, administering lurasidone at bedtime may be helpful and even preferable, at least initially, to dose reduction (which risks symptomatic worsening) or pharmacological augmentation (which may increase overall adverse effect burden). Night time administration of lurasidone to reduce daytime somnolence is practicable if evening meals can be timed accordingly and onset of akathisia does not adversely impact sleep. Second, lurasidone, like ziprasidone, must be taken with food (at least 350 kilocalories). Otherwise, drug absorption will likely be substantially reduced. While this will not present a pragmatic challenge for most patients, the requirement that lurasidone be taken in a fed state may be a limitation for low-functioning or very resource-poor patients with inconsistent access to regular meals, hypocaloric diets or highly irregular mealtimes. Finally, of the three newest antipsychotics, lurasidone appears to be associated with the highest rate of treatment-emergent somnolence, an often under-appreciated adverse effect that can profoundly impact daytime functioning and prove inconvenient or embarrassing for patients. To reduce daytime somnolence, dosing lurasidone at night may be helpful, provided that the medication can still be taken with (or in close proximity to) evening meals and that akathisia, if present, does not interfere with sleep initiation.