Second-generation antipsychotics: A review of recently-approved agents and drugs in the pipeline

March 1, 2012

Second-generation antipsychotics are the mainstay of treatment in schizophrenia.

Key Points


Second-generation antipsychotics are the mainstay of treatment in schizophrenia. All of these agents, with the exception of aripiprazole, have the same basic mechanism of action. However, an additional range of binding activity at other receptor sites may account for the differences in adverse effects seen between each medication in this drug class. Iloperidone, lurasidone, and asenapine are the most recently approved second-generation antipsychotics in the United States. All 3 agents have been shown to be safe and effective in the treatment of acute schizophrenia, and asenapine has also been shown to be effective for the acute treatment of mixed or manic episodes of bipolar disorder, when compared to placebo. Several compounds are also in the research pipeline that may be approved in the future for the management of schizophrenia. Researchers have identified different pharmacologic targets for these agents, which may lead to improving treatment outcomes. (Formulary. 2012;47:106–112, 119–121.)


Iloperidone is a piperidinyl-benzisoxazole derivative.7 The exact mechanism of action of this medication is unknown, but therapeutic effects are speculated to be due to a combination of D2 and 5HT-2A blockade. In vitro studies have found that iloperidone has high binding affinity to 5HT2A, D2, and dopamine-3 (D3) receptors, moderate binding affinity to dopamine-4 (D4), serotonin-6 (5HT6), serotonin-7 (5HT7), and noradrenergic alpha1 receptors. Iloperidone possesses minimal binding affinity for serotonin-1A (5HT1A), dopamine-1 (D1), and histamine-1 (H1) receptors and has little to no affinity for cholinergic muscarinic receptors.11

Iloperidone is extensively absorbed when given orally with a relative bioavailability of 86%.7 Peak concentrations (Cmax) are reached within 2 to 4 hours of ingestion. When taken with food, the time to peak concentration of iloperidone is delayed, but overall exposure to the parent drug and metabolites is not significantly altered. Steady state is reached within 3 to 4 days after reaching stable doses. Iloperidone is metabolized in the liver by several different pathways including: carbonyl reduction, hydroxylation via cytochrome P450 2D6 (CYP2D6), and O-demethylation via cytochrome P450 3A4 (CYP3A4). The half-lives of the parent drug and the active metabolites, P88 and P95, range from 18, 26, and 23 hours in extensive metabolizers to 33, 37, and 31 hours in poor metabolizers, respectively.

Use of iloperidone is contraindicated in patients with a history of known hypersensitivity reaction to this agent or to any components in the formulation.7 Due to extensive metabolism by CYP2D6 and CYP3A4, inhibitors of these substrates may cause increased blood levels. Iloperidone should be used with caution when combined with other drugs that may increase QTc interval due to risk of further QT prolongation. The recommended starting dose of iloperidone is 1 mg twice daily, and it is recommended to titrate dose slowly to avoid orthostatic hypotension.7 Doses can be increased daily based on tolerability: 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg twice daily. The target therapeutic dose is 6 mg twice daily to 12 mg twice daily. Due to the titration, it must be noted that it may take 1 to 2 weeks to achieve adequate control of symptoms when compared to other antipsychotics that do not require the same titration. Iloperidone is not recommended for patients with hepatic impairment.

Costs estimates were not available from the manufacturer or from Per wholesaler Morris and Dickson, a 30-day supply of iloperidone (60 tablets) costs about $523.70, but it is noted that this price may vary slightly with other wholesalers.

The clinical efficacy of iloperidone was investigated in 4 short-term and 3 long-term clinical studies.12-15 Three initial phase 3 studies led to the approval of iloperidone by FDA.12 Each of the studies had a similar design with a single-blind, 3-day placebo run in and a 7-day fixed titration of active drug or placebo followed by 5 weeks of maintenance therapy. All trials included men and women aged 18 to 65 years with an acute or subacute exacerbation defined as a PANSS score of at least 60 at baseline and screening. The dosing differed among the studies, although treatment was administered twice daily for each medication. Study 1 randomized patients in a 1:1:1:1:1 ratio to iloperidone 4 mg daily, iloperidone 8 mg daily, iloperidone 12 mg daily, haloperidol 15 mg daily, or placebo. The primary efficacy variable for this study was the change from baseline to end point in PANSS total scores, with secondary efficacy variables of the change from baseline to each post-baseline assessment in PANSS positive subscale (PANSS-P), negative subscale (PANSS-N), general psychopathology subscale (PANSS-GP), and on the BPRS. Study 2 randomly assigned patients in a 1:1:1:1 ratio to iloperidone 4 mg to 8 mg daily, iloperidone 10 mg to 16 mg daily, and risperidone 4 mg to 8 mg daily, or placebo. The primary efficacy end point in this study was the change in baseline to end point score on the BPRS, the secondary end points noted previously, and the Clinical Global Impression of Severity (CGI-S) score. Study 3 randomly assigned patients in a 2:1:1:1 ratio to iloperidone 12 mg to 16 mg daily, iloperidone 20 mg to 24 mg daily, risperidone 6 mg to 8 mg daily, or placebo. Study 3 used the same primary and secondary end points that were seen in study 2.

A total of 1,943 patients were randomly assigned and received iloperidone, haloperidol, risperidone, or placebo.12 The studies were only powered to detect the differences between iloperidone versus placebo or active comparator versus placebo, not the differences between doses of iloperidone or iloperidone and the active comparator drug. In study 1, there was a significant improvement in PANSS score for the iloperidone 12-mg daily arm (P=.047) and the haloperidol arm (P<.001). The iloperidone 12-mg daily arm was noted to significantly improve BPRS scores from baseline to end point when compared to placebo (P=.042). In study 2, significant changes from baseline to end point in BPRS score were seen in the iloperidone 4-mg to 8-mg daily group (P=.012), the iloperidone 10-mg to 16-mg daily group (P=.001), and the risperidone group (P<.001) when compared to placebo. In this study, significant improvement was also seen in the PANSS (P=.017), PANSS-P (P=.002), PANSS-GP (P=.017), and the CGI-S scores (P=.003) in the iloperidone 4-mg to 8-mg daily group, whereas the iloperidone 10-mg to 16-mg daily group saw statistically significant improvement in all of these parameters plus the PANSS-N score (P=.021). The results of study 3 found a significant improvement in baseline to end point BPRS score for the iloperidone 20-mg to 24-mg daily group (P=.010) and the risperidone group (P<.001). The iloperidone 12-mg to 16-mg daily group did not reach statistical significance when compared to placebo (P=.090). For the secondary end points in study 3, the only statistically significant improvement for the 12-mg to 16-mg daily group was the change from baseline to end point on the CGI-S scale (P=.028). There was significant improvement in the PANSS (P=.005), PANSS-P (P=.008), PANSS-N (P=.023), PANSS-GP (P=.007), and the CGI-S scores (P=.037). A combined analysis was conducted of the 3 trials in an attempt to eliminate the impact of early discontinuation on results and to assess patients who had reached steady-state therapeutic doses of iloperidone for at least 1 week of treatment. This was also done to increased statistical power in detecting any differences between doses. Of the original 1,943 patients, 1,553 were included in this analysis; it was found that each iloperidone dose range and active comparator was significantly more effective than placebo.

Safety data from the 3 initial studies of iloperidone were pooled.13 A total of 1,912 patients who received at least 1 dose of study medication were included in the analysis. The most common treatment-related adverse events seen in the iloperidone groups were dizziness, dry mouth, somnolence, and dyspepsia. Treatment-related adverse events that led to discontinuation of medication in the iloperidone groups ranged from a rate of 3.9% to 5.6%, as compared to 7.6% in the haloperidol group and 6.2% in the risperidone group. The most common adverse events leading to discontinuation in the iloperidone group were dizziness (0.4%), psychiatric disorder (0.4%), and nausea (0.3%). Overall rating of EPS in the Extrapyramidal Symptom Rating Scale (ESRS) was noted to be improved with all iloperidone doses (P<.05). Significant improvement was observed from baseline to end point in the akathisia items on the ESRS and the Barnes Akathisia Rating Scale. Decreases in supine and standing blood pressures (both systolic and diastolic) were seen in all iloperidone dosing groups (P<.05), but it was noted that these changes were generally seen in the first week of treatment and were not sustained throughout the study. There was a significant increase in the least square mean QTc interval for all 3 iloperidone dosing groups: 2.9 msec for the 4-mg to 8-mg group, 3.9 msec for the 10-mg to 16-mg group, and 9.1 msec for the 20-mg to 24-mg group (P<.05 for all). No deaths or serious arrhythmias were noted in the trials. A small, but statistically significant change in weight was seen for all iloperidone groups (1.5 kg, 2.1 kg, and 1.7 kg in the 4-mg to 8-mg daily group, 10-mg to 16-mg group, and 20-mg to 24-mg group, respectively), which was similar to the weight gain seen in the risperidone group when compared to placebo. Clinically significant weight gain (>7%) was seen in 12.3% of iloperidone-treated patients, 11.9% of risperidone-treated patients, 5.1% of haloperidol-treated patients, and 5.1% of placebo patients. Similar increases were seen in blood glucose levels across all treatment groups (range 7.2-16.2 mg/dL in active treatment groups and -3.6 mg/dL in placebo group), and changes in total cholesterol were found to be negligible in all.

Patients who completed all 6 weeks of treatment in the initial efficacy studies were eligible to continue into a 46-week, long-term, double-blind, maintenance phase.14 These patients were evaluated using the PANSS and the 7-item Clinical Global Impressions of Change (CGI-C) scales and were randomized in a 3:1 ratio to either iloperidone or haloperidol. Antipsychotic response was defined as a 20% or greater reduction on the PANSS scale at weeks 4 and 6, and a CGI-C score of at least 4 at week 6. The primary efficacy variable was time to relapse during the long-term treatment phase. Relapse was defined as an increase in PANSS score of 25% or more from the start of the long-term treatment phase, including a 10-point or greater change, discontinuation because of lack of efficacy, aggravated psychosis with hospitalization, or a 2-point or greater increase on the CGI-C after week 6. During the maintenance phase, a similar dropout rate of 36.4% was seen in both the iloperidone and haloperidol groups. Rates of relapse were not found to be statistically significant between the groups (95% CI, 0.743-1.428, P=.8596). Mean time to relapse was 89.8 days for iloperidone and 101.8 days for haloperidol; this difference was not statistically significant (P=.8411). Adverse effects seen were similar to those from the acute trials.

The final efficacy and safety study for iloperidone was a 4-week, double-blind, placebo- and ziprasidone-controlled trial of iloperidone in patients with acute exacerbations of schizophrenia.15 There was a 1-week titration period and a 3-week maintenance phase during which patients were randomly assigned in a 2:1:1 ratio to iloperidone (titrated to 24 mg/d), ziprasidone (titrated to 160 mg/d), or placebo. All medications were dosed twice daily. The primary efficacy end point was change from baseline to end point on the PANSS-Total (PANSS-T) score. A total of 593 patients were randomized to the study, and approximately two-thirds of the patients completed the study. Patients in both the iloperidone group (P<.01) and the ziprasidone group (P<.05) significantly improved when compared to placebo on the PANSS-T score. Treatment-emergent adverse events were similar to those reported in the earlier trials.

Based on clinical trial data, iloperidone appears to be more effective than placebo in decreasing symptoms associated with schizophrenia as measured by standardized rating scales.12–15 Several limitations to use of this medication include the risk of orthostatic hypotension and QT prolongation. Due to the need for slow titration, it may take longer to achieve a therapeutic dose when attempting to stabilize a patient, which may limit use of this medication in the acute care setting. The need for twice-daily dosing to minimize the effects of orthostatic hypotension may also lead to decreased adherence. It is noted that iloperidone is associated with mild QT prolongation, which may limit utility in patients with underlying cardiovascular disease.


Lurasidone is an azapirone derivative.16 Similar to other agents within its class, the exact mechanism of lurasidone is not known.9 Lurasidone has been shown to exhibit high affinity for D2 and 5-HT2A receptors, in addition to other serotonergic receptors such as 5-HT7 and 5-HT1A. It also has high affinity for noradrenaline receptors (alpha2C).16 The pharmacologic activity of lurasidone is based primarily on the parent compound. It reaches peak serum concentrations approximately 1 to 3 hours after oral administration and is highly protein bound (~99%). Administration of lurasidone with more than 350 calories of food resulted in 3-fold and 2-fold increases with regard to Cmax and area under the curve (AUC), respectively. It is recommended that lurasidone be administered with at least 350 calories of food regardless of content. The elimination half-life of lurasidone is approximately 18 hours, and it is metabolized to 2 active and 2 inactive metabolites. Metabolism is mainly due to CYP3A4, and also undergoes biotransformation by N-dealkylation, hydroxylation of norbornane ring, and s-oxidation. As the metabolism of lurasidone is based on CYP3A4, strong inhibitors or inducers may adversely affect concentrations of lurasidone and should be avoided. Lurasidone is contraindicated with strong CYP3A4 inhibitors such as ketoconazole.9 Other drug-drug interactions are unlikely, and no dosage recommendations of other drugs when coadministered with lurasidone are recommended at this time. The starting dose of lurasidone is 40 mg orally once daily with food, and the maximum dose is 80 mg daily.9 No titration is required, and doses have been studied up to 120 mg daily.

The efficacy of lurasidone was established by the results of 6 short-term randomized, controlled trials involving adult patients experiencing acute episodes of schizophrenia, 4 of which were used to support its FDA approval and labeling.9 One trial was considered failed subsequent to no detection of difference in the active comparator or lurasidone from placebo.9,17-22

In the first study on which approval of lurasidone was based, adult patients (n=145) were randomly assigned (1:1:1) to receive lurasidone 40 mg, 120 mg, or placebo for 6 weeks. This phase 2 study included male and female patients aged 18 to 64 years with a diagnosis of schizophrenia for at least 1 year and the BPRS derived from PANSS (BPRSd) total score of greater than 42, score of at least 4 on 2 or more items of the positive symptom subcluster on the PANSS, and CGI-S greater than 4 at screening.18 The primary efficacy end point was the change in BPRSd score from baseline at week 6.9,18

The second study supporting the FDA approval of lurasidone was a phase 2, multicenter, parallel group trial comparing the efficacy of lurasidone 80 mg versus placebo in meeting the primary efficacy measure of total change in BPRSd score. Hospitalized patients in an acute episode of schizophrenia (n=180) were required to complete a screening period followed by a 3- to 7-day single-blind placebo washout period prior to receiving either intervention, which was double blinded. Patients were excluded from the trial if, among other criteria, they had failed to respond to 2 previous adequate trials of antipsychotic agents from 2 different classes, had a BPRSd score less than 42, and had no hospitalizations in the month prior to screening.9,18,21

In trial 3, adult patients (n=473) with an acute episode of schizophrenia were randomized (1:1:1:1) to receive 6 weeks of double-blinded treatment with lurasidone 40 mg, 120 mg, olanzapine 15 mg, or placebo. Patients were included in this multicenter, parallel group study if they were between 18 and 75 years of age, had a schizophrenia diagnosis for longer than 1 year, and have been hospitalized less than 2 weeks for the acute exacerbation. Patients were excluded if they were deemed to be a danger to themselves or others, had an organic disorder of the CNS other than schizophrenia, or had clinically significant alcohol or drug abuse/dependence within the prior 6 months. Olanzapine was used as an active comparator to establish assay sensitivity. The primary end point of this study was the change in PANSS total score.9,18-20 The final and fourth trial supporting lurasidone approval compared patients with randomization (1:1:1:1) to lurasidone 40 mg, 80 mg, 120 mg, or placebo. Patients in trial 4 (n=496) were evaluated using PANSS as the primary end point and CGI-S rating as a secondary end point.9,22

The results of study 1 show lurasidone to be more efficacious than placebo in both the 40-mg and 120-mg doses, although no added benefit was found and more adverse events were reported at the higher dosage.9,17,18 Additionally, there was a high dropout rate in this trial with only 51/149 participants completing the study.18 The dropout rates were 68%, 59%, and 70% in the 40-mg, 120-mg, and placebo groups, respectively. Almost half of participants had dropped out of the study by day 21. FDA medical review of this study notes that concomitant lorazepam use was much lower during the double-blind phase than the other 3 pivotal trials, which may contribute to the higher than expected dropout rates.18

Both doses of lurasidone did achieve the efficacy end point of mean change in BPRSd from baseline when compared to placebo. The mean change in BPRSd score in study participants was -4.6 at week 6 in the placebo group. The lurasidone-treated groups achieved significant reductions in BPRSd score when compared with placebo at the study end. The change in BPRSd scores was -9.4 (P=.024) in the 40-mg group and -10.3 (P=.008) in the 120-mg group.

Lurasidone 80 mg was significantly more effective than placebo in the primary efficacy end point of change in BPRSd at day 42 of treatment in study 2. In study 2, lurasidone (n=90) was shown to be more effective than placebo (n=90) in the primary efficacy end point; the mean change in BPRSd using the last observation carried forward (LOCF) was -8.9 and -4.2 for patients treated with lurasidone and placebo, respectively (P=.0118).21 The results of trial 3 showed a total PANSS score change of -25.7 in the lurasidone 40-mg group (P<.0001), -23.6 in the lurasidone 120-mg group (P<.011), -28.7 in the olanzapine 15-mg group (<0.001), and -16.0 in the placebo group.20 In the final trial, only lurasidone 80 mg was found to be more efficacious in the primary end point of PANSS total score (LOCF). There was no difference in lurasidone 40 mg or 120 mg in this trial.18,22

The safety of lurasidone has been evaluated in a pooled analysis comparing lurasidone-treated patients (n=1,004) to those treated with placebo (n=455). Adverse events occurring at a rate of greater than 10% and at least twice the rate of placebo include akathisia, nausea, sedation, and somnolence. Parkinsonism and agitation were also frequently reported; however parkinsonism does not include consistent definitions of events across studies.9 The proportion of EPS-related events was 14.7% versus 5.1% in patients treated with lurasidone compared with placebo. The mean increase in weight from baseline to week 6 was 0.75 kg in patients treated with lurasidone versus 0.26 kg in those treated with placebo in phase 2 and 3 studies (P<.001).9 Patients experiencing 7% or greater increase in body weight from baseline was 5.6% and 4.0% in those treated with lurasidone and placebo, respectively.9 There were a total of 34/192 patients treated with lurasidone who experienced a 7% or greater increase in body weight from baseline in a 52-week study.18 An open-label extension study of patients treated with lurasidone for 8 months did not show significant changes in weight, lipids, or glucose.17,18

Metabolic parameters such as changes in fasting glucose and evaluation of lipid abnormalities were not evaluated in phase 1 studies. In a pooled safety analysis of the phase 2 and 3 studies comparing lurasidone-treated patients (n=1,004) to placebo (n=455) and olanzapine (n=122), the mean increase in fasting blood glucose from baseline to LOCF end point was 1.4 mg/dL, 0.6 mg/dL, and 9.0 mg/dL, respectively (P<.05 for lurasidone compared to olanzapine).20 In the same analysis, mean change in fasting total cholesterol was -8.5 mg/dL, -9.3 mg/dL, and +9.0 mg/dL for the lurasidone, placebo, and olanzapine groups (P<.05 for lurasidone compared to olanzapine). Changes in low-density lipoprotein fasting cholesterol were -4.0 mg/dL, -3.0 mg/dL, and +3.0 mg/dL for the same groups, respectively (P<.05 for lurasidone compared to olanzapine). Changes in triglycerides and high-density lipoprotein cholesterol also favored lurasidone.

The proportion of patients with elevations in prolactin at least 5 times upper limit of normal (ULN) during short-term trials in patients treated with lurasidone and placebo was 3.6% and 0.7%, respectively. An increase in prolactin was observed in the third pivotal trial of lurasidone with a mean change of +10.9 ng/mL in the 120-mg group (P<.001 compared to placebo). Mean change in prolactin levels in uncontrolled open-label trials of longer duration was -1.9 ng/mL at week 24 (n=188), -5.4 ng/mL at week 36 (n=189), and -3.3 ng/mL at week 52 (n=243).9,18

Orthostatic hypotension reported in clinical trials was 0.4% with lurasidone-treated patients (n=1,004) and 0.2% in placebo-treated patients (n=455).9 The alpha-1-blocking action of lurasidone was much less than seen with risperidone, olanzapine, and haloperidol in animal studies.17 This difference may explain the tendency of lurasidone to cause minimal orthostatic hypotension relative to other agents. No significant changes in ECG developed and no patients had an increase in QTc interval greater than 500 ms during the studies.9

Lurasidone is pregnancy category B, making it the only atypical antipsychotic in this category. Lurasidone has not been adequately studied in human subjects, and the category B designation was granted solely based on data from pregnant rats and rabbits that were administered lurasidone.9 Caution should be used when interpreting this pregnancy category, as all antipsychotics carry a warning associated with EPS or withdrawal symptoms when used during the third trimester of pregnancy.

The efficacy and safety profiles of lurasidone support its use as a viable option in the realm of treatments for acute schizophrenia. The medication has been shown to cause a statistically significant decrease in symptoms; however, it is important to note that currently published trials have not addressed response and remission data, which would be better clinical markers of effectiveness. Although no currently published trials specifically support the use of lurasidone for maintenance of schizophrenia, longer-term extension trials have been completed and indicate efficacy at 8 weeks in flexible doses. A 12-month safety and tolerability study with efficacy as a secondary end point compared lurasidone with risperidone, finding efficacy in both drugs when used in patients with schizophrenia in the outpatient setting.17 Lurasidone is favorable in that it does not require titration, as with many agents within its class. It is noted that the manufacturer recommends taking this medication with food, so this may be a potential limitation in terms of prescribing. Although the manufacturer recommends a starting dose of 40 mg daily, this dose did not separate from placebo in all of the trials, so there is some question as to whether this should be the starting dose or if patients should be started at the 80-mg dose initially. A 30-day supply of lurasidone 80 mg tablets is $535.98 (, so cost may be prohibitive for patients who are uninsured or who have formulary restrictions that require trials of first-generation antipsychotics or generic second-generation antipsychotics such as risperidone and olanzapine.


Asenapine is an atypical antipsychotic classified as a tetracyclic of the dibenzo[2,3:6,7]oxepino[4,5-c]pyrrole class, proposed to have similar pharmacologic properties to the tetracyclic antidepressant mirtazepine.23,24 Asenapine has high affinity for serotonergic, noradrenergic, and dopaminergic receptors (5-HT2A, 5-HT2C, 5-HT6, 5HT-7, alpha2a, alpha2b, alpha2c, D3, D4). There is little muscarinic receptor activity of asenapine.23 Muscarinic activity can be attributed to anticholinergic side effects such as dry mouth and constipation in many patients.

Peak plasma concentrations of asenapine are achieved within 1 hour of administration. Bioavailability of asenapine is reduced from 35% with sublingual administration to less than 2% with oral administration. Food, water, and amount of saliva are also believed to reduce the bioavailability of asenapine; therefore it is recommend that patients do not eat or drink for 10 minutes following each dose.8

Asenapine is highly protein bound (>95%), including albumin and alpha-1-acid glycoprotein. Linear kinetics are not observed with asenapine, as the AUC is increased from 1.7-fold to 2-fold when a dose is doubled from 5 mg twice daily to 10 mg twice daily. The half-life is approximately 24 hours. The pharmacologic activity is based mostly on the parent compound of asenapine, which is metabolized through glucuronidation via UGT1A4 and oxidative metabolism through CYP1A2. Elimination of the parent compound and metabolites is both hepatic and renal, with 50% and 40% of a single dose found in urine and feces, respectively. Asenapine is not recommended in patients with severe hepatic impairment (Child-Pugh C).8,23,24

The information regarding drug-drug interactions with asenapine and other agents is limited, but caution should be used for patients requiring medications that may increase sedation or hypotension due to pharmacodynamic interaction potential. Caution is needed with concurrent use of asenapine and CYP2D6 substrates, as asenapine has been shown to cause weak CYP2D6 inhibition in vivo. Coadministration of paroxetine and asenapine 5 mg twice daily resulted in a 2-fold increase in paroxetine exposure in 15 healthy male subjects. Asenapine is pregnancy category C as are all other agents in its class with the exception of lurasidone.8

The approved dosages for asenapine in acute exacerbations of schizophrenia are 5 mg twice daily, with a maximum of 10 mg twice daily. For maintenance therapy, the 5-mg twice daily dose should be initiated for 1 week prior to increasing to the recommended and maximum dosage of 10 mg twice daily. When used as monotherapy for bipolar mania, 10 mg twice daily is the recommend starting dosage of asenapine; 5 to 10 mg twice daily are the recommended dosages thereafter. For the treatment of bipolar mania as adjunct medication to valproic acid or lithium, the starting dosage of asenapine is 5 mg twice daily; maximum dosage is 10 mg twice daily.8

The efficacy of asenapine in the treatment of adults with schizophrenia was established in a couple of 6-week duration trials and 1 maintenance trial.8 In the short-term trials, the primary efficacy end point was total change in PANSS score, with secondary measures of change in CGI-S and PANSS positive, negative, and general psychopathology subscale scores.8,23

The first short-term study of asenapine was a double-blind, double-dummy, 3-arm fixed-dose controlled trial of 6-week duration. Initial doses were titrated to the maintenance dose. Adult patients (n=182) were randomly assigned (1:1:1) to receive asenapine 5 mg twice daily, risperidone 3 mg twice daily, or placebo twice daily. Study participants were required to complete the standard placebo-washout period of 3 to 7 days on an inpatient basis and to be more than 75% adherent to medication. Patients were treated for at least 3 weeks as inpatients, and were eligible to receive treatment as an outpatient during the last 2 weeks if symptoms improved.23 For the primary end point of total change in PANSS score, asenapine achieved a greater change than placebo (-15.9 vs -5.3; P<.005, respectively), but no significant difference was detected between risperidone (-10.9) and placebo.8,25

The second trial supporting the efficacy of asenapine showed a significant difference in adult patients with schizophrenia (n=458) in change in total PANSS score, the primary end point, in the group receiving asenapine 5 mg twice daily when compared to placebo (-16.2; P<.05) using the LOCF method. Haloperidol was also included for an active control and successfully differentiated from placebo (-15.4; P<.05) Asenapine 10 mg twice daily did not successfully differentiate from placebo or the lower dosage in the primary efficacy end point measure, but was significant using the mixed-model repeated measures (MMRM) analysis (P<.05).8,26 Mean PANSS scores at baseline were 88-89. The proportion of patients discontinuing from the study were 37%, 33%, 41%, and 43% in the asenapine 5-mg, 10-mg, haloperidol, and placebo groups, respectively.

One longer term maintenance trial supported the approval of asenapine for adults with schizophrenia. This trial was a randomized, double-blind, placebo-controlled, multinational study. Two 26-week phases comprised the trial, of which phase 1 was open label, flexible dose, and phase 2 was randomized, double-blind, limited flexible dose, placebo controlled. Patients were started on 5 mg asenapine twice daily in the open-label phase. This dosage was increased to 10 mg twice daily after 1 week, and dose increases were allowed during the remainder of the open-label phase. Dose reductions during the double-blind phase were allowed for tolerability only.27 The primary efficacy measure was time to relapse or impending relapse. Criteria for relapse definition included 20% or greater change in total PANSS score or CGI-S score 4 or higher for designated time. A total of 386 patients met criteria for the long-term (phase 2) portion of the study. In the intent-to-treat population, the proportion of patients experiencing relapse or impending relapse was 12.1% and 47.7% with asenapine and placebo, respectively (P<.0001). A total dose of 10 mg twice daily was used by 77.8% of patients on the final day of the trial. The proportion of patients completing the double-blind phase of the study was 53.6% (n=386). Sixty-nine percent of the asenapine group and 37.5% of the placebo group completed the study.27

In short-term trials of patients with schizophrenia, the proportion of those experiencing weight gain of at least 7% of body weight at baseline was 4.9% versus 2% for asenapine-treated patients versus placebo. In a 52-week double-blind, comparator-controlled trial of patients with schizophrenia and schizoaffective disorder, the proportion of patients with at least a 7% increase in weight from baseline categorized by body mass index (BMI) was 22% (n=295), 13% (n=290), and 9% (n=302) in patients with BMI less than 23, 23 to 27, and more than 27, respectively.8

Overall, the incidence of weight gain was similar to other agents in its class in trials, but longer terms studies are needed. Pharmacologically, asenapine was initially predicted to cause weight gain based on its 5-HT2C activity. Asenapine may cause orthostatic hypotension due to its alpha-1-adrenergic antagonist activity, yet the rates observed in clinical trials were lower than expected. The proportion of patients experiencing orthostatic hypotension was 0.2% (n=572) in asenapine-treated patients compared with 0.3% (n=378) in placebo-treated patients.8

No indication of QT prolongation with asenapine use was seen in clinical trials.8 As postmarketing data have demonstrated a class wide effect of ECG changes, however, caution should be used in patients treated with asenapine or other antipsychotics. Prolactin decreased in patients treated with asenapine and placebo in trials, with a greater decrease in the placebo group (-6.5 ng/mL vs -10.7 ng/mL, respectively). This decrease in level may have occurred following cessation of a medication previously elevating prolactin in some patients.8,23 In a pooled analysis of four 6-week trials, the only adverse reaction deemed to be dose-related to asenapine was akathisia. The other most commonly reported adverse events were oral hypoesthesia, akathisia, and somnolence in clinical trials.8,23 It should be noted that asenapine has been associated with type 1 hypersensitivity reactions including angioedema and anaphylaxis, occurring after the first dose in several cases.8 The hypersensitivity reactions were identified during postmarketing reports.

Based on available clinical trial data, the efficacy of asenapine appears to be comparable to that of other agents within its class. The most common adverse effects observed in clinical trials also appear to be consistent with similar agents. The dosing and administration of asenapine may be disadvantageous for some patients due to its twice-daily dosing and required avoidance of food and water for 10 minutes following sublingual administration. Inadvertent oral ingestion of the sublingual tablet would be problematic, and bioavailability of asenapine is dramatically reduced. This agent may have a role in patients with impairment in swallowing, as it does have a unique route of administration when compared to other medications in the class. Clinical trial data are mixed regarding dose response curve for the use of asenapine in schizophrenia, and it is not currently clear based on the evidence whether or not some patients would benefit from a higher dose of 10 mg twice daily.25,26 The cost for a 30-day supply of asenapine is $676.02 (, so as noted with the other agents, cost may be prohibitive when compared to first-generation antipsychotic medications and generic second-generation antipsychotic agents, because there is no clear benefit in improving response and remission rates with use of this drug when compared to other agents in the class.


Several treatments for schizophrenia are currently being investigated, all at varying levels of development. It is difficult to ascertain the timeline to FDA submission of an agent, as new drug approval (NDA) information is usually confidential within the sponsor company.28 Nonetheless the pipeline of drugs and drug targets for schizophrenia does have several promising opportunities.

Partial dopamine agonists and multiple dopamine antagonists are an area of interest in schizophrenia drug development. Most currently available second-generation antipsychotics have an affinity preference for D2, but some drugs in development are aiming to have higher affinity for the D3 receptor. Most of the available antipsychotics have affinity for a number of dopamine receptors (D2, D3, D4) as well as serotonergic, adrenergic, and histamineric receptors, explaining many of the common side effects associated with their use.29 Currently in phase 3 studies, cariprazine is a unique antipsychotic candidate with antagonist–partial agonist properties at D3 and D2 receptors and high affinity to D3 receptors. It has been shown to be pharmacologically unique from aripiprazole, which is a partial D2 agonist.30

There has been interest in compounds with activity at D2/5-HT1A dual ligand receptors, with suggestions of use in concurrent anxiety, depression, and possibly improved side-effect profiles. Aripiprazole and lurasidone are now the only marketed agents known to have pharmacologic activity consistent with D2 antagonism with 5-HT1A agonism. Much of the development of agents within this class (PF-217830, F-15603) has stopped due to mixed results of effects seen in animal models.29

The 5-HT2C and 5-HT6 receptors have shown promise in the development of agents for schizophrenia. It is believed that 5-HT2C agonism has antipsychotic properties by linking to and ultimately lowering dopaminergic activity. It is suspected that weight gain is linked to 5-HT2C antagonism, as agents that have been shown to cause weight gain possess strong blockade at these receptors (olanzapine, clozapine).29 Vabicaserin is a selective 5-HT2C receptor agonist in this family.29,31 Currently phase 2 studies for this agent have been terminated, although reasons for discontinuation are unknown.

Glutamate has been another focus of interest in treatment for schizophrenia for several decades. Glutamate transmission, in particular N-methyl-D-aspartate (NMDA) activity, was implicated after the realization that phencyclidine and ketamine, NMDA antagonists, produced symptoms similar to those seen in patients with schizophrenia.32 The NMDA complex stimulates glutamate and glycine ligands, and glycine transport inhibitors such as RG1678 (phase 3).29,32 A number of other mechanisms are of interest in the development of treatments used for schizophrenia. These include GluR2/3 ligands, alpha7 nicotinic agonists, PDE10 alpha inhibitors, 5-HT6 antagonists, and H3 antagonists.29,33


Iloperidone, lurasidone, and asenapine are all newly approved second-generation antipsychotics with demonstrated efficacy in the treatment of schizophrenia. Although the mechanism of action is similar among these agents, differences in receptor binding affinities and safety profiles will guide therapy in individual patients. Each agent has different pharmacokinetic parameters, dosing, and administration, which may also help guide therapy selection of treatment. All of these medications have been shown to have some improvement in rating scales used to assess schizophrenia when compared to placebo and seem to have statistically similar effects when compared to active treatment with haloperidol, risperidone, olanzapine, or ziprasidone. To date, however, no head-to-head comparisons of these medications have been conducted with currently approved medications. The impact of these medications on the alteration of metabolic parameters is not entirely evident at this time due to lack of long-term clinical data, but incidence of weight gain, glucose abnormalities, and lipid changes seem to be similar to that of other commonly prescribed second-generation antipsychotic medications such as risperidone. Due to the relatively high cost of iloperidone, lurasidone, and asenapine, it would be reasonable to reserve these medications for patients who have failed multiple trials of previously approved antipsychotic medications, including clozapine, which has been shown to be the most effective antipsychotic for the management of treatment-resistant patients.33 Although there are now 10 second-generation antipsychotics available for use, patients with schizophrenia still suffer from severe manifestations of the illness. Dopamine-blocking agents seem to be relatively effective in the treatment of positive symptoms of schizophrenia, but these treatments do not robustly improve negative and cognitive symptoms, indicating the need for the discovery of agents that focus on different therapeutic targets in the brain. Several new agents are being investigated, but it remains to be seen if and when these agents will be available on the US market.

Dr Holmes is assistant professor of pharmacy practice, College of Pharmacy, Rosalind Frankin University of Medicine and Science, North Chicago, Ill. Dr Zacher is assistant division officer, Pharmacy Division, Captain James A. Lovell Federal Health Care Center, North Chicago

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.


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