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

Five-year View

Iloperidone, asenapine and lurasidone are the latest agents to enter the very competitive atypical antipsychotic market. Over 50 antipsychotic drugs are available worldwide, including 14 atypical agents, of which ten are now available in the USA. The broad availability of such a large number of antipsychotics raises the question of what additional benefit these three new antipsychotics may bring. On the one hand, the availability of three new atypical antipsychotics with low impact on body weight and metabolic indices is highly desirable. Indeed, most recent antipsychotic drug development efforts have focused on improving metabolic safety and overall tolerability, an important consideration given the high prevalence of cardiovascular risk factors and premature mortality from cardiovascular causes among persons with chronic and severe mental disorders who are most likely to require long-term antipsychotic treatment,[6,85] and notoriously high rates of treatment nonadherence to which poor antipsychotic tolerability is a known contributor.[86,87] Concerns about long-term metabolic safety with some atypical antipsychotics have already begun to influence recommendations in published clinical practice guidelines. Owing to metabolic safety concerns, olanzapine is no longer recommended as a first-line treatment for patients with first-episode schizophrenia in the 2009 Schizophrenia Patient Outcomes Research Team (PORT) treatment recommendations,[88] or patients with bipolar disorder in the 2005 update of Texas Medication Algorithm Project (TMAP) guideline.[89] Based in part on their advantageous metabolic profiles, iloperidone, asenapine and lurasidone will likely be considered first-line therapeutic options in future practice guidelines for treating schizophrenia, particularly for patients with first-episode psychosis.

On the other hand, clinicians, patients and caregivers will be looking for specific advantages for each of these compounds in addition to their favorable metabolic profiles and the bar will be set very high in terms of distinguishing themselves among the other atypical antipsychotic drugs. Nearly all of the older atypical antipsychotics (with the exception of paliperidone) have been around for more than 10 years; thus, each has an established place within the therapeutic armamentarium based on years of clinical experience and research efforts. Although iloperidone, asenapine, and lurasidone are not new, they have been available to clinicians for only a brief period of time. Because practice experience is so limited with these agents, direct head-to-head comparative effectiveness studies are needed. Currently, there is no evidence of clinical superiority for iloperidone, asenapine, or lurasidone over other antipsychotics, and any potential tolerability advantages discussed in this review would also need to be confirmed by direct comparison trials.

Although many acute-phase, placebo-controlled studies reviewed herein also included an active control group consisting of treatment with older and more established antipsychotics, they were not sufficiently powered to provide valid comparisons, other than with placebo. Even if they were adequately powered, results of short-term, registration-type clinical trials would generalize poorly to real-world care.[90] Long-term efficacy and safety data are also limited, and consist chiefly of extension or responder-enriched studies. Until data from real-world comparative effectiveness studies of iloperidone, asenapine and lurasidone become available, clinical impressions will be based solely on indirect comparisons with other antipsychotics.

Of course, for such studies to be conducted with sufficient validity to guide clinical practice, very large sample sizes and long-term follow-up will be required. The expense and logistical challenges involved make it unlikely that such data will be available any time soon. Future research endeavors involving iloperidone, asenapine and lurasidone will instead focus on broadening the therapeutic range of these compounds. Indeed, the number of approved indications for several atypical antipsychotics has expanded well beyond schizophrenia and acute manic/mixed bipolar mood episodes to now include acute bipolar depression (olanzapine combined with fluoxetine, and quetiapine) and treatment-resistant major depression (aripiprazole, olanzapine, and quetiapine as adjuncts to antidepressants).[91–95] Several large-scale research efforts in this regard are underway or have been recently completed for asenapine, iloperidone, and lurasidone (Table 9), particularly for treating mood disorders. Asenapine is already approved for treating manic or mixed bipolar mood episodes; however, the efficacy of all reviewed agents for the treatment of major depression or the depressive phase of bipolar I disorder is being actively investigated. Significantly greater reduction in depressive symptoms with lurasidone, as both a monotherapy and an adjunct with lithium or divalproex, has been recently demonstrated in two randomized, placebo-controlled, Phase III studies, resulting in submission of two supplemental New Drug Applications to the US FDA.[96,97] Given the limited number of well-established options for managing the depressed phase of bipolar disorder,[98] considerable therapeutic potential exists for lurasidone to address a critical unmet need in managing patients with bipolar disorder.

The clinical effects of iloperidone, asenapine and lurasidone are also being investigated in clinically important patient subgroups, including treatment-resistant patients, elderly patients and youth (Table 9). The need is especially great for persons with treatment-resistant schizophrenia. Up to 30% of patients with schizophrenia are considered treatment resistant.[99–101] Clozapine continues to be the sole evidence-based pharmacotherapy for treatment-resistant illness;[102] thus, no credible evidence-supported alternatives to clozapine exist. Broader use of clozapine is limited, even for patients who require such treatment, by well-characterized but severe adverse effects, including dose-dependent seizure risk, idiosyncratic risk of bone marrow suppression and agranulocytosis, cardiac effects (cardiomyopathy, myocarditis), clinically significant weight gain, hyperglycemia and new-onset Type 2 diabetes, and atherogenic hyperlipidoses.[103] The efficacy of lurasidone (at higher than usual doses – up to 240 mg/day) for treatment-resistant schizophrenia or schizoaffective disorder is being investigated (Table 9) and similar research efforts may be pursued in the future for iloperidone and asenapine.

The development of reliable biological predictors of clinical benefit and adverse effects under antipsychotic treatment will be an additional research focus. Currently, no genetic or biological response predictors are yet sufficiently valid for routine clinical use. Whole-genome association studies have been conducted using data from the randomized, double-blind, placebo- and ziprasidone-controlled Phase III study by Cutler et al. to identify genetic predictors of efficacy response and risk markers for QT interval prolongation.[35,104,105] These analyses uncovered several DNA polymorphisms that were significantly associated with clinical response and QT prolongation in iloperidone-treated patients.[104–106] While these results are promising, further study is needed and routine genetic testing of patients who require antipsychotic treatment is not likely to become adopted outside of the clinical research setting in the immediate future.

Finally, development of new formulations for expanded clinical use will be also be given high priority. An injectable depot formulation of iloperidone has already been developed and is in Phase II testing (NCT 1348100). If further developed, depot iloperidone would be only the second long-acting injectable atypical antipsychotic (other than paliperidone palmitate) formulated for administration every 4 weeks. However, a long-acting injectable form of aripiprazole, also formulated for administration once monthly, is nearing the end of Phase III testing (NCT 00705783, 01432444) and may be available for clinical use relatively soon.

In conclusion, iloperidone, asenapine and lurasidone are the newest agents from a long line of atypical antipsychotic drugs. While none of these agents appear to be more clinically effective than other antipsychotics for treating adults with schizophrenia, they may have advantages over some available antipsychotics in terms of metabolic safety. Comparative effectiveness studies with older and more established antipsychotics are lacking, and long-term pragmatic trials are needed in order to assess the effectiveness of the newer agents in patients under usual-care conditions. Until such data are available, the exact place of iloperidone, asenapine or lurasidone within a broader clinical context will be based on indirect comparisons of available outcome data, and consideration of pharmacological differences between agents that may confer putative advantages and disadvantages for each drug. Wider testing of these newer agents will be needed to determine the extent to which these differences are clinically meaningful, and to explore the therapeutic potential of each for indications outside of schizophrenia (and acute manic or mixed bipolar mood episodes in the case of asenapine) and in clinically important patient populations that were not included in Phase III testing. Ultimately, newer agents with novel mechanisms are likely to be required.[107]