Iloperidone

Approved by the US Food and Drug Administration (FDA) in 2009, iloperidone is indicated for the treatment of schizophrenia in adults. At present iloperidone is only available in the US. The efficacy of iloperidone was assessed in one 4-week and three 6-week randomized, double-blind, placebo- and active comparator-controlled multicenter studies in which two studies were accepted by the FDA as positive.Reference Potkin, Litman, Torres and Wolfgang^4–Reference Citrome⁷ Post hoc analyses of pooled patient data from all four trials demonstrated superiority of iloperidone over placebo on the Positive and Negative Syndrome Scale (PANSS) total, PANSS positive subscale, PANSS negative subscale and Brief Psychiatric Rating Scale-derived (BPRSd) total scores,Reference Citrome, Meng, Hochfeld and Stahl⁸ and on the PANSS factor scores.Reference Citrome, Meng and Hochfeld⁹

Data are also available from three long-term (52-week), prospective, randomized, multicenter, double-blind, flexible-dose, parallel group trials that compared the efficacy and safety of iloperidone and haloperidol in patients with schizophrenia, using a non-inferiority design.Reference Kane, Lauriello, Laska, Di Marino and Wolfgang¹⁰ Rates of relapse and reasons for relapse were similar between iloperidone and haloperidol.

According to the recommendations in the product label,¹¹ iloperidone must be titrated slowly from a low starting dose (1 mg BID) to a target of 6 mg BID over a 4-day period to avoid orthostatic hypotension. This requirement can be explained by iloperidone's strong alpha adrenergic receptor blocking properties (Table 1). Consequently, control of symptoms may be delayed compared with some other antipsychotic drugs that do not require similar titration.¹¹ BID dosing was used in the clinical trials in order to decrease the likelihood of adverse events; however, the half-life of iloperidone and its active metabolite supports the notion that once daily dosing may be feasible once the patient is stabilized at a therapeutic dose.

Commonly observed adverse reactions in short-term trials (incidence ≥5% and two-fold greater than placebo) were dizziness, dry mouth, fatigue, nasal congestion, orthostatic hypotension, somnolence, tachycardia and weight increase.¹¹ Dizziness and tachycardia were more common with iloperidone 20–24 vs. 10–16 mg/day in the clinical trials however this may not necessarily translate to what can be expected in clinical practice as patients in the clinic would not be routinely force-titrated to a high dose. Increases in QTc were observed with all dose ranges of iloperidone however there were no deaths or serious arrhythmias attributable to QT prolongation in these studies.

Mean weight change from baseline to end-point in the 4–6 week short-term studies was 2.0 kg for patients receiving iloperidone 10–16 mg/day, 2.7 kg with iloperidone 20–24 mg/day, and −0.1 kg with placebo.¹¹ Based on the 4–6 week studies, the proportions of patients having a weight gain of at least 7% from baseline were 4% for placebo, 12% for iloperidone 10–16 mg/day, and 18% for iloperidone 20–24 mg/day.¹¹ However, no medically important differences were observed between iloperidone and placebo in mean change from baseline to end-point in routine hematology, urinalysis or serum chemistry, including glucose, triglycerides and total cholesterol measurements.¹¹ Product labeling notes that in the short-term trials, iloperidone was associated with modest levels of prolactin elevation compared to greater prolactin elevations observed with some other antipsychotic agents.¹¹

In the 52-week trials the most common adverse events were insomnia, anxiety, and aggravated schizophrenia with iloperidone, and insomnia, akathisia, tremor, and muscle rigidity with haloperidol.Reference Kane, Lauriello, Laska, Di Marino and Wolfgang¹⁰ Metabolic changes were minimal for both groups. Mean changes in the ECG QTc interval were 10.3 msec (iloperidone) and 9.4 msec (haloperidol) at end point.

Remarkably, there was no significant association with extrapyramidal disorder, akathisia, or tremor noted for iloperidone at any dose and this low potential for extrapyramidal side effects is akin to what is observed with quetiapine.^{12, 13} It is speculated that iloperidone's low risk for EPS or akathisia may be related to alpha 1 adrenergic blockade; there is preclinical evidence that alpha 1 receptors are localized on the same pyramidal neurons that have 5HT2A receptors.Reference Marek and Aghajanian^14, Reference Stahl¹⁵

Iloperidone is unique among antipsychotics in terms of being relatively metabolically “friendly” and free of liability for EPS or akathisia. The principal practical obstacle in using iloperidone is the need for initial titration to a therapeutic dose in order to manage the risk for orthostatic hypotension.

Asenapine

Asenapine was approved by the FDA in 2009 and has regulatory approval for the indications of schizophrenia and bipolar mania/mixed episodes, the latter either as a monotherapy or in combination with lithium or valproate.¹⁶ Asenapine is also available in other countries. Efficacy in schizophrenia was demonstrated in two of the four 6-week randomized, double-blind, placebo- and active comparator-controlled multicenter studies and in a placebo-controlled, double-blind, multicenter, maintenance treatment trial.Reference Kane, Cohen, Zhao, Alphs and Panagides^17–Reference Citrome²⁰ Efficacy in the treatment of manic or mixed episodes of bipolar I disorder is supported by two of two completed phase III randomized, placebo and active-controlled 3-week trialsReference Citrome^20–Reference McIntyre, Cohen, Zhao, Alphs, Macek and Panagides²² and in a placebo-controlled trial of asenapine combined with lithium or valproate vs. lithium or valproate monotherapy.Reference Szegedi, Calabrese, Stet, Mackle, Zhao and Panagides²³

Long-term data are available from a 1-year double-blind study in patients with schizophrenia or schizoaffective disorder randomized to asenapine or olanzapine.Reference Schoemaker, Naber, Vrijland, Panagides and Emsley²⁴ Rates of discontinuation because of insufficient therapeutic effect were 25.1% for asenapine and 14.5% for olanzapine. Changes from baseline in PANSS total score were similar for asenapine and olanzapine at week 6 but showed a statistically significant difference in favor of olanzapine at endpoint (Last Observation Carried Forward). Among the patients who completed the entire year-long trial, changes in PANSS total score were similar for asenapine and olanzapine at week 6 and also at week 52. Additional long-term data are available from two randomized, double-blind, 26-week studies and their respective 26-week extensions that tested the hypothesis that asenapine is superior to olanzapine for persistent negative symptoms of schizophrenia and that also assessed the comparative long-term efficacy and safety of these agents.Reference Buchanan, Panagides and Zhao²⁵ Asenapine was not superior to olanzapine in change in the Negative Symptom Assessment Scale total score in either core study, but asenapine was superior to olanzapine at week 52 in one of the extension studies. Asenapine's longer-term efficacy in patients with manic or mixed episodes of bipolar disorder was assessed and supported in a 9-week extensionReference McIntyre, Cohen, Zhao, Alphs, Macek and Panagides²⁶ to the 3-week studies,Reference McIntyre, Cohen, Zhao, Alphs, Macek and Panagides^21, Reference McIntyre, Cohen, Zhao, Alphs, Macek and Panagides²² followed by an additional 40-week extension.Reference McIntyre, Cohen, Zhao, Alphs, Macek and Panagides²⁷

Because bioavailability is less than 2% if ingested but 35% when taken sublingually, asenapine must be administered in the form of an orally-disintegrating tablet so that the medication is absorbed in the oral mucosa. No initial dose titration is required but the product label recommends specific doses depending on the disease state and other circumstances for treatment: acute schizophrenia 5 mg BID, maintenance 10 mg BID, bipolar mania/mixed as a monotherapy 10 mg BID, bipolar mania/mixed with lithium or valproate 5 mg BID.¹⁶ These doses are based on the design of the clinical trials used to obtain regulatory approval. Product labeling further recommends that food or drink should be avoided for 10 minutes after administration of asenapine in order to maximize bioavailability; however, 2 minutes may be sufficient in that only a 19% reduction in bioavailability was observed when this was tested at that time point.Reference Citrome²⁸ Although the product label recommends BID dosing (used in the clinical trials to decrease the likelihood of adverse events), the half-life is about 24 hours, thus once daily dosing may be possible in stabilized patients where tolerability has been established.

Commonly observed adverse reactions in short-term trials (incidence ≥5% and two-fold greater than placebo) were akathisia, oral hypoesthesia and somnolence for patients with schizophrenia, and somnolence, dizziness, extrapyramidal symptoms other than akathisia, and increased weight for patients with bipolar disorder.¹⁶ Somnolence is the single most common adverse event associated with asenapine treatment and the product label describes this event as usually transient with the highest incidence reported during the first week of treatment. Somnolence led to discontinuation in only a small proportion (0.6%) of patients treated with asenapine.¹⁶ Although rates of spontaneously reported oral hypoesthesia (numbness) and dysgeusia (altered or unpleasant taste) were not particularly alarming in the clinical trials, patients in clinical practice may more readily complain about these potential effects and should be forewarned in order to avoid patients becoming nonadherent. A black cherry flavored formulation is now available as well. The packaging is also different from ordinary tablets or capsules and from what the patient may be used to – asenapine orally disintegrating tablets are easily damaged by moisture or rough handling so they are housed in a hard plastic case that can be challenging for some people to open.

Overall, asenapine treatment had no significant effect on clinical laboratory parameters.¹⁶ Asenapine has a mild effect on QTc similar to that seen with quetiapine.^16, Reference Citrome²⁸ In addition to a favorable weight gain profile, asenapine has shown limited effects on glucose-related laboratory parameters, such as fasting glucose and fasting insulin.^16, Reference Citrome²⁰

The mucosal absorption of asenapine renders it as the only antipsychotic in which in order to “cheek it” you have to swallow it (and swallowing asenapine orally disintegrating tablets is difficult to do since this formulation disintegrates within seconds once placed in the mouth). This is different from other orally disintegrating tablets of antipsychotics such as olanzapine, risperidone and aripiprazole where swallowing is necessary because absorption occurs further down the GI tract. With asenapine administration a rapid rise is plasma levels occurs, with peak plasma levels in as early as 30 minutes (Table 1); this may be helpful in situations where agitation is a presenting problem, and is being tested for this purpose in a clinical trial (see http://clinicaltrials.gov/ct2/show/NCT01400113).

Lurasidone

Lurasidone was approved by the FDA in 2010 for the indication of schizophrenia. Lurasidone is also available in Canada. Initial approval was based on a clinical trial program that included five 6-week randomized, double-blind, placebo- and active comparator-controlled multicenter studies of which four were positive.Reference Nakamura, Ogasa and Guarino^29–Reference Citrome³² After the product was launched, results from a fifth positive 6-week study became available and were subsequently integrated into product labeling.³³ An analysis of pooled data from the six 6-week pivotal trials demonstrated superiority of lurasidone over placebo on categorical definitions of antipsychotic response.Reference Citrome³⁴

Long-term data have been published and include a 12-month double-blind safety and tolerability study, where clinically stable adult outpatients with schizophrenia were randomized to lurasidone or risperidone.Reference Citrome, Cucchiaro and Sarma³⁵ A higher proportion of patients receiving risperidone had at least a 7% endpoint increase in weight and the median endpoint change in prolactin was significantly higher for risperidone. A comparable improvement in efficacy measures was observed with both agents and the rates of relapse were similar, however all-cause discontinuation rates were higher for lurasidone vs. risperidone. Preliminary findings from 12-month double-blind extension to a short-term study that included quetiapine extended-release as an active control have been presented.Reference Loebel, Cucchiaro, Xu, Sarma, Pikalov and Kane³⁶ Lurasidone was non-inferior to quetiapine in risk for relapse over the 12-month treatment period and moreover, the probability of relapse at 12 months was lower for lurasidone vs. quetiapine.

The recommended starting dose is 40 mg/day administered once daily. No initial dose titration is required. The current maximum recommended dose is 160 mg/day. There is no information available on the potential utility of dosing in excess of 160 mg/day, although a clinical trial is underway of lurasidone doses of up to 240 mg/day in patients with treatment resistant schizophrenia (see http://clinicaltrials.gov/ct2/show/NCT01569659). Similar to ziprasidone, lurasidone should be administered with food and the current recommendation is that lurasidone be given when consuming a meal of at least 350 calories, regardless of fat content.³³ In a food effect study, lurasidone maximum plasma concentration and total plasma exposure (i.e. area under the curve) were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions.³³ Whether administering 40 mg without food would be equivalent to 20 mg with food is not known, and although the pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 20 mg to 160 mg,³³ it is not known if this would be the case when fasting.

From the short-term registration studies, the commonly observed adverse reactions (incidence ≥5% and at least twice the rate for placebo) included somnolence, akathisia, nausea and parkinsonism.³³ A key issue may be time of administration – evening may be preferable.Reference Citrome^34, Reference Citrome³⁷ Lurasidone is associated with minimal weight gain and no clinically meaningful alterations in glucose, lipids, prolactin, or the ECG QT interval.

Positive preliminary findings are available from two 6-week placebo-controlled trials in major depressive episodes in patients with bipolar I disorder without psychotic features.Reference Loebel, Cucchiaro and Silva^38, Reference Loebel, Cucchiaro and Silva³⁹

Lurasidone differs from iloperidone and asenapine in terms of the recommended dosing frequency (once daily vs. BID). Lurasidone also appears best-in-class in terms of minimizing untoward alterations in body weight and metabolic variables.^33, Reference Citrome^34, Reference Citrome and Nasrallah⁴⁰ Potential obstacles to use include sedation, extrapyramidal side effects, akathisia and nausea.

Differentiating features

As noted, iloperidone, asenapine and lurasidone have different receptor binding and pharmacokinetic profiles (Table 1) and thus different tolerability “personalities.” However all three are relatively less likely to be associated with metabolic abnormalities than some other first-line second-generation antipsychotics. It would be logical to compare iloperidone, asenapine and lurasidone with ziprasidone and aripiprazole, as these second-generation antipsychotics also have a lower propensity for alterations in body weight, glucose and lipid metabolism than risperidone, olanzapine, or quetiapine. Table 2 illustrates some differences and similarities among these agents. These differences are not always clinically relevant and would depend on the individual patient's history at baseline; for example, key questions include a patient's past experiences with EPS, akathisia or sedation. Prolongation of the ECG QT interval is largely irrelevant in routine practice with reasonably healthy patients; initial concerns regarding the risk for QT prolongation with ziprasidone have not materialized in clinically significant arrhythmias.Reference Citrome⁴¹

Table 2

Highlights of differences and similarities among iloperidone, asenapine, lurasidone, ziprasidone and aripiprazole

From US product labeling [11,16,33] and [40].

IM – intramuscular

ODT – orally disintegrating tablet

Cariprazine (RGH-188)

Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist under development for the treatment of schizophrenia and bipolar disorder. Available are preliminary results from a 6-week randomized controlled study that enrolled acutely ill patients with schizophrenia.Reference Bose, Li and Migliore⁴² Subjects were randomized to receive cariprazine 1.5, 3.0, or 4.5 mg/day, risperidone 4.0 mg/day, or placebo. Improvement in the PANSS total score at week 6 was greater for cariprazine 1.5, 3.0 and 4.5 mg/day versus placebo as well as for risperidone versus placebo. The most common adverse events in the cariprazine groups were insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness and constipation. There were no clinically meaningful metabolic parameter changes for cariprazine; no prolactin elevation or QTc prolongation were observed. Results from the 48-week open-label extension study have also been presented;Reference Cutler, Bose and Durgam⁴³ treatment-emergent adverse events reported in at least 10% of patients were akathisia, insomnia, and increased weight.

Randomized controlled trials of cariprazine in acute mania have also been conducted and the results of a Phase IIReference Knesevich, Papadakis and Bose⁴⁴ and a Phase III studyReference Starace, Bose and Wang⁴⁵ have been presented. In the Phase III trial, subjects were randomized to cariprazine 3–12 mg/day or placebo for 3-weeks of double-blind treatment. Statistically significant improvement was demonstrated with cariprazine vs. placebo on the Young Mania Rating Scale. The most common adverse events were akathisia, extrapyramidal disorder, tremor, dyspepsia, and vomiting.

Brexpiprazole (OPC-34712)

Brexpiprazole is a dopamine D2 receptor partial agonist currently in clinical trials for schizophrenia. Presented were the preliminary results of a 6-week double-blind, placebo- and aripiprazole-controlled Phase II study that explored the dose-response relationship of brexpiprazole in acutely ill patients with schizophrenia.Reference McQuade, Hobart and Forbes⁴⁶ Mean improvement in PANSS scores was clinically meaningful for all dose groups, including placebo. Improvements in the brexpiprazole (1.0 mg, 2.5 mg and 5.0 mg) and aripiprazole treatment groups were numerically greater, but not significantly different, compared with placebo. Also available are the preliminary results of a study examining brexpiprazole as an adjunct to antidepressants in the treatment of major depressive disorder.Reference Thase, Fava and Hobart⁴⁷ Statistically significant improvements in depression rating scores were observed for adjunctive brexpiprazole 1.5 mg/day vs. adjunctive placebo.

Potential “antipsychotics” that act on glutamate receptors

Current FDA-approved pharmacological options for the treatment of schizophrenia involve antagonism (or partial agonism) at the dopamine D2 receptor, and additionally, in the case of second-generation antipsychotics, antagonism at the serotonin 5-HT2A receptor. This may still be insufficient for symptom relief. There is substantial research activity in the area of schizophrenia and the glutamate neurotransmitter system.Reference Kantrowitz and Javitt⁴⁸ The interplay between glutamate and dopamine may provide a way to identify therapeutic targets that could treat the negative and cognitive symptoms of schizophrenia. One model of schizophrenia is that of hypofunction of the NMDA receptor complex. The NMDA receptor is a glutamate receptor. Under normal circumstances tonic inhibition occurs in the NMDA receptor regulation of the mesolimbic dopamine pathway but in the presence of NMDA receptor hypofunction in cortical brainstem projections of patients with schizophrenia, hyperactivity of the mesolimbic dopamine pathway would take place. Moreover, under normal conditions, NMDA receptor regulation of mesocortical dopamine pathways is that of tonic excitation. With NMDA receptor hypofunction, the direct result would be hypoactivity of mesocortical dopamine pathways, with insufficient dopamine release in the pre-frontal cortex, resulting in the cognitive, negative, and affective symptoms of schizophrenia.

Glycine is needed in addition to glutamate for the NMDA receptor to function. NMDA receptor functioning can thus be enhanced by making available more glycine at the synapse. This can be accomplished by action at the glycine reuptake pumps, the major route of inactivation of synaptic glycine. Glycine transport inhibitors are analogous to the drugs that are used for the treatment of major depressive disorder (ie, serotonin-specific reuptake inhibitors), although instead of inhibiting serotonin reuptake, these agents inhibit glycine transport, increasing the synaptic availability of glycine, and presumably enhancing NMDA-mediated neurotransmission.