A Review of its Use in the Management of Schizophrenia in Adults

ADIS DRUG EVALUATION CNS Drugs 2012; 26 (2): 155-183 1172-7047/12/0002-0155/$49.95/0 ª 2012 Adis Data Information BV. All rights reserved. Aripiprazole A Review of its Use in the Management of Schizophrenia in Adults Jamie D. Croxtall Adis, Auckland, New Zealand Various sections of the manuscript reviewed by: R. Andrezina, Department of Psychiatry, Riga Mental Health Centre, Riga, Latvia; S. Kasper, Department of General Psychiatry, Medical University of Vienna, Vienna, Austria; P. Mohr, Department of Pyschiatry 3rd Faculty of Medicine, Charles Univserity, Prague, Czech Republic; A. Paktar, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA; R. Tandon, Department of Psychiatry, University of Florida College of Medicine, Gainesville, FL, USA. Data Selection Sources: Medical literature (including published and unpublished data) on aripiprazole was identified by searching databases (including MEDLINE and EMBASE and in-house AdisBase) for articles published since 1996, bibliographies from published literature, clinical trial registries/databases and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug. Search strategy: MEDLINE, EMBASE and AdisBase search terms were aripiprazole and schizophrenia. Searches were last updated on 12 December 2011. Selection: Studies in patients with schizophrenia who received aripiprazole. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Aripiprazole, schizophrenia, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability. Contents Abstract................................................................................. 156 1. Introduction.......................................................................... 156 2. Pharmacodynamic Properties........................................................... 157 2.1 Mechanism of Action.............................................................. 157 2.2 In Vivo Studies.................................................................... 158 2.3 Neurocognitive Studies in Patients with Schizophrenia.................................. 158 3. Pharmacokinetic Properties............................................................. 158 3.1 Absorption and Distribution......................................................... 158 3.2 Metabolism and Elimination......................................................... 159 3.3 Drug Interactions.................................................................. 159 3.4 Special Populations................................................................ 159 4. Therapeutic Efficacy................................................................... 160 4.1 Placebo-Controlled Trials........................................................... 160 4.2 Active-Comparator Trials........................................................... 161 4.3 Open-Label Switching Trials......................................................... 165 4.4 In Patients with Acute Agitation Associated with Schizophrenia.......................... 168 5. Tolerability............................................................................ 169 5.1 General Profile.................................................................... 169 5.2 Class Adverse Events............................................................... 171 5.3 Other Adverse Effects.............................................................. 172

156 Croxtall 6. Pharmacoeconomic Considerations..................................................... 174 7. Dosage and Administration............................................................. 176 8. Place of Aripiprazole in the Management of Schizophrenia in Adults.......................... 176 Abstract Oral aripiprazole (Abilify Ò ) is an atypical antipsychotic agent that is approved worldwide for use in adult patients with schizophrenia. It is a quinolinone derivative that has a unique receptor binding profile as it exhibits both partial agonist activity at dopamine D 2 receptors and serotonin 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. In several well designed, randomized, clinical trials of 4 6 weeks duration, aripiprazole provided symptomatic control for patients with acute, relapsing schizophrenia or schizoaffective disorder. Furthermore, following 26 weeks treatment, the time to relapse was significantly longer for patients with chronic, stabilized schizophrenia receiving aripiprazole compared with those receiving placebo. Using a variety of efficacy outcomes, aripiprazole showed a mixed response when evaluated against other antipsychotic agents in randomized clinical trials. Longer-term data showed that improvements in remission rates and response rates favoured aripiprazole over haloperidol, although, the time to failure to maintain a response was not significantly different between the treatment arms. On the other hand, improvements in positive and negative symptom scores mostly favoured olanzapine over aripiprazole, although, the time to all-cause treatment discontinuation was not significantly different between the two treatments. Several open-label, switching trials showed that aripiprazole provided continued control of symptoms in patients with schizophrenia or schizoaffective disorder. Using a variety of efficacy outcomes or quality-of-life scores, longerterm treatment generally favoured patients switched to receive aripiprazole compared with standard-of-care oral antipsychotics. Aripiprazole was generally well tolerated in patients with schizophrenia. In particular, its use seems to be associated with a lower incidence of extrapyramidal symptoms than haloperidol and fewer weight-gain issues than olanzapine. Aripiprazole also showed a favourable cardiovascular tolerability profile and its use was associated with a reduced risk of metabolic syndrome than placebo or olanzapine. As a consequence, aripiprazole may provide a more cost-effective treatment option compared with other atypical antipsychotics. In conclusion, oral aripiprazole provides an effective and well tolerated treatment alternative for the acute and long-term management of patients with schizophrenia. 1. Introduction Schizophrenia is generally a chronic debilitating psychiatric disorder that is characterized by positive symptoms such as delusions, hallucinations and grossly disorganized or catatonic behaviour, and negative symptoms such as blunted affect, alogia and apathy. [1,2] The condition is also often associated with depression and cognitive deficits such as impaired executive functioning, attention and short- and long-term memory. [3,4] Schizophrenia generally onsets in late adolescence or early adulthood. [5] The usual clinical picture is one of acute exacerbations of positive and negative symptoms (requiring hospitalization) followed by a remission and stabilization. [6] However, the recovery from each exacerbation may be incomplete and the patients functional ability often

Aripiprazole: A Review 157 declines with each successive relapse. [7] Schizophrenia affects approximately 1% of the world s population. [6] In most cases it impacts upon all aspects of life and requires long-term therapy with antipsychotic medication. [6] Consequently, the condition imposes considerable socioeconomic costs. [8] Increasingly, treatment with second-generation (or atypical) antipsychotic agents (SGAs) has taken a key role in managing patients with schizophrenia. [9] In general, meta-analyses have shown that SGAs (such as amisulpride, clozapine, olanzapine and risperidone) appear to achieve a broader symptomatic control of schizophrenia than the older, first-generation or typical agents (such as haloperidol). [10] Furthermore, atypical agents also appear to be less likely to induce extrapyramidal symptoms (EPS; e.g. akathisia, dystonia, parkinsonism and tardive dyskinesia) than typical agents. [10] However, although they do not represent a homogenous class of compounds, atypical agents are themselves associated with adverse effects such as metabolic disturbances, including weight gain and impaired glucose and lipid metabolism, and cardiovascular effects, such as prolongation of the corrected QT interval (QT c ). [9,11] Consequently, there remains a need for more effective and better tolerated antipsychotic agents. Aripiprazole (Abilify Ò ) is an atypical antipsychotic that, as a consequence of its unique receptor binding profile, has a proposed mechanism of action that is distinct from that of other antipsychotic drugs (reviewed previously in Drugs). [12] It is currently approved worldwide for the acute and long-term management of schizophrenia. [13-15] This review focuses on the pharmacological properties, clinical efficacy and tolerability of oral aripiprazole in adult patients with schizophrenia or schizoaffective disorder. Data regarding the efficacy of oral and intramuscular aripiprazole for the management of agitation associated with schizophrenia are also discussed in this review. 2. Pharmacodynamic Properties The pharmacodynamic properties of aripiprazole have been extensively reviewed elsewhere. [12,16] Therefore, this section provides a brief, updated overview of relevant properties. Aripiprazole is a quinolinone derivative, 7-{4-(2,3-dichlorophenyl)- 1-piperazinyl]butyloxy}-3,4-dihydro-2(1H)-quinolinone, [17] with a unique receptor binding profile. [16] 2.1 Mechanism of Action Unlike other classes of antipsychotics, which are dopamine receptor antagonists, aripiprazole exhibits partial agonist activity at dopamine D 2 and D 3 receptors and serotonin 5-HT 1A receptors and antagonist activity at 5-HT 2A receptors. [17-19] The receptor affinity profile of aripiprazole is shown in table I; the affinity profile for dehydroaripiprazole, the major metabolite of aripiprazole, is similar to that of the parent compound. [13] Combined D 2 and D 3 receptor occupancy was high (50 100%) throughout the brain in patients with schizophrenia, with complete receptor saturation achieved once serum levels of aripiprazole exceeded 100 150 ng/ml. [20] As with all antipsychotic agents, the precise mechanism of action of aripiprazole is unknown. However, as a result of its receptor binding profile, aripiprazole will reduce dopamine activity in dopaminergic and serotonergic systems where neurotransmitter levels are high, and where levels are low, it will function as an agonist. [21,22] It is hypothesized that these properties of aripiprazole as both a dopamine and serotonin stabilizer Table I. Affinity of aripiprazole for G-protein-coupled receptors [12,13] Receptor K i (nmol/l) Dopamine D 2 0.34 3.3 D 3 0.8 D 4 44 Serotonin 5-HT 1A 1.7 5.6 5-HT 2A 3.4 8.7 5-HT 2B 0.36 5-HT 2C 15 180 5-HT 7 10.3 39 Other a 1A -Adrenergic 25.7 a 1B -Adrenergic 34.8 Histamine H 1 25.1 61 K i = mean inhibitory constant.

158 Croxtall underlie its antipsychotic effects. [13,14,23] Modulation of serotonergic activity in cortical pyramidal cells and the prefrontal cortex may also contribute to the antipsychotic effects of aripiprazole. [21,23] Although, whether this is achieved with therapeutic dosages has been questioned. [16] 2.2 In Vivo Studies In animal studies, aripiprazole was shown to decrease firing of dopamine neurons in the ventral tegmental area and the substantia nigra. [24-26] Furthermore, aripiprazole reversed prepulse inhibition deficits induced by dopamine agonists and NMDA antagonists. [27,28] In contrast, typical antipsychotics, such as haloperidol, generally act only against prepulse inhibition deficits induced by dopamine agonists. [28] Aripiprazole may also have neuroprotective effects. Kainic acid-induced neuronal degeneration in the striatum was reversed by aripiprazole, clozapine and ziprasidone but not haloperidol. [29] Data from in vivo [30] and in vitro [31] studies also showed that aripiprazole blocked enhanced glutamate release in the medial prefrontal cortex, which may prevent progression to schizophrenialike behavioural abnormalities. Furthermore, the duration of catalepsy in mice was reduced following chronic treatment with aripiprazole but persisted following chronic treatment with haloperidol, which may be relevant to its more favourable profile with regard to EPS (see section 5.2). [32] 2.3 Neurocognitive Studies in Patients with Schizophrenia High levels of D 2 receptor occupancy may be negatively correlated with some neurocognitive functions. [33,34] The effect of aripiprazole on neurocognitive functions was evaluated in a randomized, open-label comparison with olanzapine (a potent D 2 receptor antagonist) in patients with schizophrenia or schizoaffective disorder (n = 169). [35] In addition, pooled data from two double-blind and one open-label trial in patients with acute schizophrenia (n = 129) evaluated the effect of aripiprazole, quetiapine, risperidone and olanzapine on a range of neurocognition scores. [36] Significant improvements from baseline in general cognitive functioning were evident at week 8 of the open-label trial for recipients of both aripiprazole and olanzapine (p = 0.023 and 0.015) and the effect remained stable until week 26. [35] Neither group showed a significant improvement from baseline in executive functioning. [35] However, recipients of aripiprazole showed significant improvements from baseline in verbal learning at weeks 8 and 26 (p < 0.0001 for both), whereas recipients of olanzapine did not. [35] The pooled data showed that all evaluable cognitive scores were improved from baseline at week 8 following treatment with an atypical antipsychotic; however, between-group differences were not reported. [36] 3. Pharmacokinetic Properties Data regarding the pharmacokinetics of approved dosages of oral aripiprazole in patients with schizophrenia are limited. Therefore, this section focuses on the pharmacokinetics of multiple doses of orally administered aripiprazole 10 or 15 mg once daily (the approved initial and target dose) derived from a randomized, doubleblind, placebo-controlled study in healthy male volunteers. [37] An open-label study evaluated the pharmacokinetics of escalating doses (1 45 mg once daily for 4 days) of intramuscular aripiprazole in patients with schizophrenia and compared the pharmacokinetics of single-dose aripiprazole administered orally (5 mg), intramuscularly (5 mg) or intravenously (2 mg) in healthy volunteers; [38] these data are also briefly discussed. Additional data are derived from the manufacturer s prescribing information [13] and the European Medicine Agency s (EMA s) summary of product characteristics. [14] 3.1 Absorption and Distribution Aripiprazole is readily absorbed following oral administration, with peak plasma concentrations (C max ) achieved within a time (t max )ofapproximately 3 hours. [37] The noncompartmental, steady-state mean values for the 10 and 15 mg/day dosages for C max were 163 and 242 ng/ml and for the area under the plasma concentration-time curve from 0 to 24 hours (AUC 24 ) were 2947 and

Aripiprazole: A Review 159 4430 ng h/ml on day 14.[37] The pharmacokinetics of aripiprazole were dose proportional over the range of 5 30 mg/day, and exposure to aripiprazole accumulates with multiple-dose administration with steady-state achieved within 14 days. [37] The absolute bioavailability of aripiprazole was 87%. [13,14] Administration of oral aripiprazole 15 mg with a standard high-fat meal did not affect appreciably the pharmacokinetic profile of the drug. [13,14] Consequently, oral aripiprazole may be administered without regard to food. [13,14] The pharmacokinetics of intramuscular aripiprazole were also linear following once-daily administration of 1 45 mg doses. [38] Amorerapid absorption was observed following intramuscular injection compared with oral administration; plasma concentrations of aripiprazole were 78% and 5% of C max, respectively, 0.5 hours postdose. [38] Furthermore, the AUC 2 was 90% higher following intramuscular injection than with oral administration. [38] Following intravenous administration, the steady state volume of distribution of aripiprazole (dose not reported) was 404 L (or 4.9 L/kg) indicating extensive extravascular distribution, even though at therapeutic concentrations 99% of the drug and its major active metabolite is bound to plasma protein. [13,14] 3.2 Metabolism and Elimination Aripiprazole is extensively metabolized via N- dealkylation, hydroxylation or dehydrogenation in the liver by the cytochrome P450 (CYP) 3A4 and 2D6 enzyme pathways. [13,14] The major metabolite is dehydro-aripiprazole of which steadystatesystemicexposureis40% of that of the parent drug. [13,14] Approximately 3 8% of Black/African Americans, 8% of Caucasians and 50% of Asians have reduced CYP2D6 activity and are classified as poor metabolizers of aripiprazole. [13,39] In general, poor metabolizers of aripiprazole have approximately a 60% higher exposure to total active moieties of the drug compared with extensive metabolizers. [13,39] Following multiple doses, the mean terminal elimination half-life (t ½ ) of aripiprazole 10 or 15 mg/day was approximately 50 hours. [37] However, the t ½ for a single dose of aripiprazole (dosage not reported) was approximately 74 hours for extensive metabolizers and 146 hours for poor metabolizers. [13,14] Consequently, the initial dosage of aripiprazole should be reduced by one-half in poor metabolizers. [13] Following oral administration of a single dose of radiolabelled aripiprazole, approximately 25% and 55% of radioactivity was recovered in the urine and the faeces with less than 1% and»18%, respectively, in unchanged form. [13] 3.3 Drug Interactions There are relatively limited data regarding pharmacokinetic drug-drug interactions between aripiprazole and other agents. A small (n = 81) study in patients with schizophrenia indicated that the pharmacokinetics of aripiprazole may be affected by a range of commonly coadministered drugs, although the clinical relevance of the changes was not clear. [40] Coadministration of aripiprazole with inhibitors of CYP2D6 (such as quinidine, paroxetine or fluoxetine) or CYP3A4 (such as ketoconazole, itraconazole or protease inhibitors) results in an increase in aripiprazole exposure. [13,14] Whereas, coadministration with inducers of CYP3A4 (such as carbamazepine, rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine or St. John s Wort) reduces aripiprazole exposure. [13,14,41] Consequently, dosage adjustments of aripiprazole may be necessary when coadministered with these drugs. [13,14] On the other hand, the pharmacokinetics of aripiprazole are not affected to any clinically relevant degree following coadministration with lithium or valproate. [42] Aripiprazole is not expected to affect to any clinically significant degree the pharmacokinetics of other drugs metabolized via CYP pathways. [13,14] In vivo studies showed that the pharmacokinetics of omeprazole, warfarin or dextromethorphan were not significantly affected by aripiprazole. [13,14] 3.4 Special Populations There are no dosage adjustments generally required based on patients age, gender, race, smoking

160 Croxtall status, hepatic function or renal function. [13,14] Aripiprazole is secreted in breast milk of lactating rats and it is recommended that nursing mothers receiving aripiprazole do not breast feed. [13,14] There are no adequate studies regarding the use of aripiprazole in pregnant women. Consequently, aripiprazole should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus. [13,14] 4. Therapeutic Efficacy The efficacy of oral aripiprazole in adults was evaluated in several fully published, placebocontrolled trials of 4 [43,44] and 6 [45,46] weeks duration in hospitalized patients with an acute relapse of schizophrenia [43-46] or schizoaffective disorder [43,44] and their pooled analysis. [47] In addition, the efficacy of aripiprazole in terms of preventing relapse was evaluated in a placebo-controlled 26-week trial in stabilized adult patients with chronic schizophrenia. [48] These data are discussed in section 4.1. The efficacy of oral aripiprazole versus other antipsychotic agents was evaluated in shorterterm trials of 4 [49,50] and 6 [51] weeks duration and in longer-term trials of 28 [52] and 52 [53,54] weeks duration in patients with schizophrenia [49-54] or schizoaffective disorder. [49,50] These data are discussed in section 4.2. The efficacy of switching to oral aripiprazole was evaluated in outpatients with schizophrenia [55-65] or schizoaffective disorder [55,57-59,63,65] in several open-label shorter-term trials of 8 12 weeks duration [55-59] and in longer-term trials of 24 weeks to 2 years duration, [60-65] some of which also reported data regarding quality-of-life (QOL) outcomes. [55,56,61,62,65] In addition, the efficacy of switching to aripiprazole versus olanzapine was evaluated in patients with acutely relapsing or stabilized, chronic schizophrenia in an open-label 52-week extension [66] of a 26-week, placebo-controlled trial. [48] These data are discussed in section 4.3. The immediate effects of aripiprazole in controlling agitation associated with schizophrenia or schizoaffective disorder in hospitalized adults was evaluated versus other antipsychotic agents in trials of up to 5 days duration; [67,68] these data are discussed in section 4.4. The efficacy of oral aripiprazole as adjunctive therapy with other antipyschotic agents [69-72] and in treatment-resistant schizophrenia [73] has also been evaluated. However, aripiprazole is not currently approved for these indications and, for this reason, these data are not reviewed here. The approved dosage of oral aripiprazole in the management of schizophrenia is 10 or 15 mg once daily (section 7). [13,14] Several trials investigated the efficacy of lower (2 or 5 mg/day) [45] or higher (20 or 30 mg/day) [43,44,46,53,54,67] dosages, and many trials used a flexible dose strategy of 5 30, [64,65] 10 30, [50,55-63] or 15 30 mg/day. [51,52,66,67] In one of the trials investigating agitation associated with schizophrenia, [68] aripiprazole was initially administered intramuscularly (up to three injections of 9.75 mg within the first 24 hours) before switching to oral treatment (10 or 15 mg/day for 4 days). Data are included from all of these trials for completeness. Where defined, eligible patients were aged 18 years and had a baseline Positive and Negative Syndrome (PANSS) total score of 60 and a score of 4 on any two items of the PANSS psychotic subscale [43-46,48-54] or a PANSS Excited Component (PEC) score 15. [67,68] In several trials, [43-46,49-51,53,54,67] patients were required to have evidence of treatment responsiveness. Most trials excluded patients with any other psychiatric disorder and female patients who were pregnant or nursing. Patients receiving other medications were also excluded, although the concomitant use of benzodiazepines and anticholinergics was, in general, permitted if necessary. The majority of patients were male and had a mean age of 35 43 years; [43-46,48-68] where reported, approximately 4 58% of patients had schizoaffective disorder. [43,44,50,55,57,58,63,67] 4.1 Placebo-Controlled Trials All trials were of randomized, double-blind, multicentre design. [43-46,48] Active controls were used in the two 4-week trials (an atypical antipsychotic, risperidone [44] or a conventional antipsychotic, haloperidol [43] ), although, direct comparisons were made only between active comparators and placebo and not between comparator drugs. A placebo

Aripiprazole: A Review 161 washout period of 2 5 days preceded all the trials. [43-46,48] Primary efficacy endpoints included the mean change from baseline in PANSS total score, [43-46] PANSS positive symptom score [43,44] and Clinical Global Impression-Global Severity of Illness (CGI-S) score. [43,44] In the 26-week trial, the primary efficacy endpoint was the time to relapse following randomization with relapse defined as a CGI-Global Improvement (CGI-I) score of 5, a PANSS score of 5 on the hostility or uncooperativeness subscales on 2 successive days or a 20% increase in PANSS total score. [48] Patients were defined as responders if they had a CGI-I score of 1 or 2 or a 30% decrease from baseline in their PANSS total score. [43,44,46] Oral aripiprazole was effective in controlling the symptoms of schizophrenia or schizoaffective disorder over 4- and 6-week treatment periods. [43-46] At study endpoint, significantly greater improvements from baseline in mean PANSS total [43,45,46] and positive symptom scores [43,45,46] and mean CGI-S scores [43,46] (primary endpoints) were achieved for recipients of aripiprazole 10 or 15 mg/day compared with recipients of placebo (table II). Moreover, symptomatic improvements were evident from weeks 1 2 of the trials. [43-46] Higher dosages of aripiprazole (20 or 30 mg/day) were also associated with significantly greater improvements in primary efficacy endpoints compared with placebo, but did not appear to offer any further benefit over the recommended dosages. [43,44] Secondary endpoints were also improved following treatment with aripiprazole 10 or 15 mg/day (table II). [43,46] Two trials showed generally significantly greater improvements from baseline in mean PANSS negative symptom and PANSSderived Brief Psychiatric Rating scale (BPRS) scores and mean CGI-I scores and response rates at study endpoint for recipients of aripiprazole 10 or 15 mg/day than for recipients of placebo. [43,46] One trial showed significantly greater improvements from baseline in CGI-S scores with aripiprazole 10 mg/day than with placebo; improvements in the other secondary endpoints were not significant. [45] Haloperidol [43] and risperidone [44] were also effective in terms of improving primary and secondary efficacy outcomes. A post hoc pooled analysis evaluated the efficacy of aripiprazole (10 30 mg/day; n = 790) versus placebo (n = 397) in patients divided according to baseline agitation scores. [47] Patients with PEC scores of 14 and a score of 4 onat least one PEC item (excitement, hostility, tension, uncooperativeness or poor impulse control) were assigned to the higher agitation group. [47] In both the higher (n = 389) and lower (n = 798) agitation groups, recipients of aripiprazole achieved significantly (all p < 0.05) lower PANSS total, CGI-I and PEC scores at weeks 2 and 6 than recipients of placebo. [47] Aripiprazole was also effective in preventing relapse over the longer-term in stabilized patients with chronic schizophrenia. [48] The time to relapse following randomization (primary endpoint) was significantly (p < 0.001) longer for recipients of aripiprazole 15 mg/day than recipients of placebo; at week 26, the estimated Kaplan- Meier survival rate was 62.6% in the aripiprazole group versus 39.4% in the placebo group. [48] The relative risk of relapse with aripiprazole versus placebo was 0.5 (95% CI 0.35, 0.71). In addition, significantly more patients in the aripiprazole group than the placebo group had not discontinued treatment because of a lack of efficacy, relapse or adverse event (58.8% vs 38.1%;p< 0.001) at study endpoint. 4.2 Active-Comparator Trials All comparative trials were of randomized, double-blind, multicentre design. [49-54] The 52-week trial comprised two separate, identical studies that were prospectively designed for combined analysis. [53,54] Trials used fixed- [49,53,54] or flexibledose [50-52] aripiprazole and active controls included risperidone, [49] olanzapine, [51,52] haloperidol [53,54] or ziprasidone, [50] according to treatment strategies described in tables III and IV. The trials were preceded by a 2- to 9-day washout or screening period. [49-54] One trial was conducted in Asian patients. [49] Primary endpoints included the mean change from baseline in PANSS total score, [49,51] CGI-S score, [50] Brief Psychiatric Rating Scale derived from PANSS (BPRSd), [50] time to all-cause

162 Croxtall Table II. Efficacy of oral aripiprazole in adults (aged 18 years) hospitalized for an acute relapse of schizophrenia [43-46] or schizoaffective disorder. [43,44] Results of primary and secondary endpoints of randomized, double-blind, placebo-controlled, multicentre, 4- [43,44] or 6-week [45,46] phase III trials are summarized. All trials were preceded by a 2- to 5-day washout period. Analyses were based on last observation carried forward and results are presented as mean change from baseline at study endpoint Trial Regimen No. of pts PANSS score CGI-S CGI-I Response rate b (mg/day) a total positive symptoms negative symptoms score score (% pts) b/line mean b/line mean b/line mean change d change e change b/line mean change e Cutler et al. [45] ARI 2 93 90.8-8.2 24.3-2.4 f 21.6-2.0 f 4.6 NR NR NR NR PANSS-derived BPRS score c mean change ARI 5 92 92.2-10.6 24.5-3.4 f 22.9-2.9 *f 4.7-0.6 * NR 37 NR ARI 10 94 90.0-11.3 * 24.3-4.2 * 21.7-2.7 f 4.7-0.6 * 3.2 43 NR PL 88 90.9-5.3 24.6-2.3 22.1-1.3 f 4.7-0.3 3.6 33 NR Kane et al. [43] ARI 15 102 98.5-15.5 *** 24.8-4.2 *** 25.1-3.6 * 4.9-0.6 *** 3.5 *** 35 * -3.1 * ARI 30 102 99.0-11.4 * 24.5-3.8 * 25.5-2.3 4.8-0.4 * 3.8 * 28-3.0 * HAL 10 104 99.3-13.8 * 25.2-4.4 *** 25.6-2.9 * 4.8-0.5 * 3.7 * 26-3.5 *** PL 106 100.2-2.9 25.0-0.6 25.8-1.2 4.9-0.1 4.3 17-1.1 McEvoy et al. [46] ARI 10 106 92.7-15.0 *** 24.5-5.0 *** 23.4-3.5 *** 4.8-0.6 ** 3.3 ** 41 * -3.9 *** ARI 15 106 93.2-11.7 *** 24.6-3.8 ** 23.3-2.6 ** 4.8-0.5 * 3.4 ** 35-2.9 * ARI 20 100 92.5-14.4 *** 24.3-4.5 *** 23.5-3.3 *** 4.7-0.6 ** 3.3 ** 45 ** -3.6 *** PL 108 92.3-2.3 24.3-1.1 22.6 0.1 4.6-0.2 4.0 26-1.4 Potkin et al. [44] ARI 20 101 94.4-14.5 * 24.7-4.9 * 23.6-3.4 * 4.8-0.5 * 3.4 * 36 * -3.5 * ARI 30 101 92.6-13.9 * 24.1-3.9 * 23.2-3.4 * 4.8-0.6 * 3.3 * 41 * -3.3 * RIS 6 99 94.9-15.7 *** 24.2-5.2 *** 24.8-3.1 * 4.8-0.7 *** 3.3 *** 40 * -3.9 *** PL 103 95.7-5.0 24.8-1.8 23.6-0.8 4.8-0.2 4.0 23-1.7 a The recommended dosage of oral ARI is 10 or 15 mg/day. [13,14] All dosages were fixed (except RIS, which was titrated on the first 2 days) [44] and all drugs were administered orally, either once (ARI and HAL) [43,45,46] or twice daily (RIS). [44] b Responders were defined as pts with a CGI-I score of 1 or 2 or a 30% decrease from baseline in their PANSS total score. c Baseline values were reported only for the McEvoy et al. study and ranged from 16.7 to 16.9 between the treatment groups. [46] d Primary endpoint in all trials. [43-46] e Primary endpoint in both 4-week trials. [43,44] f Value read from graph. ARI = aripiprazole; b/line = baseline; BPRS = Brief Psychiatric Rating Scale; CGI-I = Clinical Global Impression-Global Improvement scale; CGI-S = CGI-Severity of Illness scale; HAL = haloperidol; NR = not reported; PANSS = Positive and Negative Syndrome Scale; PL = placebo; pts = patients; RIS = risperidone; * p < 0.05, ** p 0.01, *** p 0.001 vs PL.

Aripiprazole: A Review 163 Table III. Shorter-term efficacy of oral aripiprazole versus risperidone, olanzapine or ziprasidone in adults (aged 18 years) with schizophrenia [50,51] or schizoaffective disorder. [49,50] Results of primary and secondary endpoints of randomized, double-blind, multicentre trials are summarized. [49-51] Trials were preceded by a 2- to 5-day washout/screening period. One trial included Asian patients only. [49] Analyses were based on last observation carried forward [49,50] or post hoc longitudinal random regression [51] and results are presented as mean [49,51] or least squares mean [50] change from baseline at wk 4 [49,50] or wk 6 [51] in the intent-to-treat population. One trial [51] evaluated the noninferiority of aripiprazole with olanzaoine and one trial [50] evaluated the noninferiority of ziprasidone with aripiprazole Trial Treatment groups (mg/day) a Main endpoints Baseline value Response [no. of pts] Chan et al. [49] ARI 15 [48] vs RIS 6 [34] PANSS total score b 85.1 vs 84.6-19.6 vs -21.1 CGI-S score 5.0 vs 5.1-1.2 vs -1.6 CGI-I score 3.0 vs 2.6 Response rate c (%) 51 vs 68 Fleischhacker et al. [51] ARI 15 30 [347] vs OLA 10 20 [344] PANSS total score b NR -24.6 vs -29.5 d CGI-S score NR -1.25 vs -1.42 e CGI-I score 2.50 vs 2.23 e Response rate f (%) 73 vs 78 Zimbroff et al. [50] ARI 10 30 [128] vs ZIP 80 160 [125] g CGI-S b 4.8 vs 4.8-1.15 vs -1.12 h BPRSd total score b 57.4 vs 57.4-15.2 vs -13.0 i BPRSd core score 16.1 vs 16.2-5.2 vs -4.3 * PANSS total score 98.1 vs 98.7-24.6 vs -21.6 PEC score 13.7 vs 14.4-3.4 vs -2.9 Hospital discharge rate on day 28 j (%) 59.8 vs 61.2 a The recommended dosage of oral ARI is 10 or 15 mg/day. [13,14] b Primary endpoint. c Responders were defined as pts with a CGI-I score 2 ora 30% increase from baseline in PANSS total score. d Noninferiority of ARI with OLA was not established as the between-group difference was less than the prespecified margin of 6 points; the Hedge s G effect size favoured OLA (0.39). e Statistically significant difference in favour of OLA, significance not reported. f Criteria for response not defined. g Pts initially received fixed-dose ARI 15 mg/day on days 1 14 or fixed-dose ZIP 40 mg bid on day 1, 60 mg bid on day 2 and 80 mg bid on days 3 14 with flexible dosing of both agents permitted on days 15 28. h Noninferiority of ZIP with ARI was established as the upper limit of the 95% CI was less than the prespecified margin of 0.35. i Noninferiority of ZIP with ARI was not established as the upper limit of the 95% CI was more than the prespecified margin of 3.5. j Based on investigators assessment of clinical criteria. ARI = aripiprazole; bid = twice daily; BPRSd = Brief Psychiatric Rating Scale derived from Positive and Negative Syndrome Scale; CGI-I = Clinical Global Impression-Global Improvement scale; CGI-S = CGI-Severity of Illness scale; NR = not reported; OLA = olanzapine; PANSS = Positive and Negative Syndrome Scale; pts = patients; PEC = PANSS Excited Component; RIS = risperidone; ZIP = ziprasidone; * p < 0.05 vs ZIP. treatment discontinuation, [52] time to failure to maintain a response [53] and remission rate. [54] One of the shorter-term trials was followed by a 46-week extension phase that evaluated weight gain as a co-primary endpoint, and these data are discussed in section 5. [51] Where defined, [49,53] patients were described as responders if they had a CGI-I score 2 or a 30% decrease from baseline in PANSS total score maintained for at least 28 days. Patients were described as in remission if they achieved PANSS subscale item (delusions, unusual thought content, hallucinatory behaviour, conceptual disorganization, mannerisms/posturing, blunted affect, social withdrawal and lack of spontaneity) scores of 3for 6 consecutive months. [54] Two trials were designed to evaluate noninferiority, one of aripiprazole versus olanzapine [51] and the other of ziprasidone versus aripiprazole. [50] Overall, aripiprazole had generally similar efficacy to risperidone and ziprasidone but was less

164 Croxtall effective than olanzapine in controlling the symptoms of schizophrenia or schizoaffective disorder over a 4- to 6-week treatment period (table III). [49-51] With regard to primary endpoints, improvements from baseline in PANSS total scores were significantly greater for recipients of olanzapine than aripiprazole (Hedge s G effect size 0.39) and noninferiority of aripiprazole with olanzapine was not achieved. [51] On the other hand, improvements in CGI-S and BPRSd total scores were not significantly different between the aripiprazole and ziprasidone treatment arms. [50] Ziprasidone achieved noninferiority with aripiprazole in terms of improvements in CGI-S scores but not BPRSd total scores. [50] Furthermore, in the trial in Asian patients, [49] improvements in PANSS total scores from baseline were not significantly different between the aripiprazole and risperidone treatment arms. With regard to secondary endpoints, recipients of aripiprazole also showed a mixed response in several efficacy outcomes in the shorter-term trials, when compared with recipients of other antipsychotic agents (table III). For example, improvements in CGI-S and CGI-I scores were significantly greater for recipients of olanzapine than recipients of aripiprazole, although response rates were not significantly different between the two treatment arms. [51] Whereas, improvements in BPRSd core scores were significantly greater for recipients of aripiprazole than recipients of ziprasidone, although improvements in PANSS total and PEC scores and the hospital discharge rate were not significantly different between the two treatment arms. [50] Improvements in CGI-S and CGI-I scores and response rates were also not significantly different between recipients of aripiprazole and risperidone. [49] Table IV. Longer-term efficacy of oral aripiprazole versus olanzapine or haloperidol in adults (aged 18 years) with schizophrenia. [52-54] Results of primary and secondary endpoints of randomized, double-blind, multicentre, 28- [52] or 52-week [53,54] trials are sumarized. Trials were preceded by a 2- to 9-day washout/screening period. Analyses were based on last observation carried forward [52,54] or analysis of covariance [53] and results are presented as mean [53] or least squares mean [52] change from baseline at study endpoint in the intent-to-treat population Trial Treatment groups (mg/day) a Main endpoints Baseline value Response [no. of pts] Kane et al. [52] ARI 15 30 [285] vs OLA 15 20 [281] b Time to all-cause discontinuation c (%) 50.2 vs 42.7 PANSS total score 95.0 vs 95.7-25.9 vs -30.2 * PANSS positive score 16.8 vs 16.8-5.0 vs -5.9 * PANSS negative score 30.0 vs 30.9-7.6 vs -8.8 CGI-S score 4.8 vs 4.7-1.1 vs -1.2 CGI-I score 4.1 vs 4.1 2.8 vs 2.7 Kasper et al. [53] ARI 30 [853] vs HAL 10 d [430] Time to failure to maintain a response c,e (%) 85 vs 79 Kane et al. [54] Remission rate c,f (%) 32 vs 22 *** Response rate e (%) 52 vs 44 ** PANSS negative score 24.7 vs 24.7-5.4 vs -4.4 *g MADRS total score 12.5 vs 12.8-2.6 vs -1.7 *g a The recommended dosage of oral ARI is 10 or 15 mg/day. [13,14] b Pts initially received fixed-dose ARI 15 mg/day or OLA 15 mg/day with dose increases permitted from week 2. c Primary endpoint. d Pts initially received HAL 5 mg/day on days 1 3 then HAL 10 mg/day on day 4 onwards. e Responders were defined as pts with a 30% decrease (maintained for 28 days) from baseline in their PANSS total score. [53] f Pts in remission achieved PANSS subscale item (delusions, unusual thought content, hallucinatory behaviour, conceptual disorganization, mannerisms/posturing, blunted affect, social withdrawal and lack of spontaneity) scores of 3 for 6 consecutive months. [54] g Value read from graph. ARI = aripiprazole; CGI-I = Clinical Global Impression-Global Improvement scale; CGI-S = CGI-Severity of Illness scale; HAL = haloperidol; MADRS = Montgomery-Åsberg Depression Rating Scale; OLA = olanzapine; PANSS = Positive and Negative Syndrome Scale; pts = patients; * p < 0.05, ** p < 0.01, *** p < 0.001 vs comparator.

Aripiprazole: A Review 165 Aripiprazole demonstrated longer-term efficacy that was, in general, comparable to both olanzapine and haloperidol treatment (table IV). [52-54] With regard to primary endpoints, the time to allcause treatment discontinuation was not significantly different between recipients of aripiprazole and recipients of olanzapine, following 28 weeks treatment. [52] The time required for 50% of patients to discontinue treatment for any reason was 204 days for recipients of aripiprazole and could not be calculated for recipients of olanzapine; treatment discontinuation rates were also not significantly different between the treatment arms (table IV). [52] In addition, the time to failure to maintain a response (primary endpoint) was not significantly different between recipients of aripiprazole and recipients of haloperidol, following 52 weeks treatment (risk ratio 0.70; 95% CI 0.45, 1.07; p = 0.098). [53] However, remission rates (also a primary endpoint) were significantly higher for recipients of aripiprazole than recipients of haloperidol (table IV). [54] Moreover, of those patients in remission, recipients of aripiprazole achieved the PANSS subscale item threshold in a significantly (log rank p = 0.0024) shorter period of time compared with recipients of haloperidol. Patient response rates and improvements from baseline in PANSS negative scores and Montgomery-A sberg Depression Rating Scale scores were also significantly greater for recipients of aripiprazole than recipients of haloperidol, following 52 weeks treatment (table IV). [53] On the other hand, improvements in both PANSS total scores and PANSS positive scores were significantly greater for recipients of olanzapine than recipients of aripiprazole, following 28 weeks treatment; although improvements in PANSS negative scores, CGI-S and CGI-I scores were not significantly different between the treatment arms. [52] 4.3 Open-Label Switching Trials All switching studies were randomized, openlabel multicentre trials in outpatients with clinically stable schizophrenia or schizoaffective disorder who, in the opinion of the study investigator, would benefit from a change of antipsychotic medication. [55-65] Data from patients with acutely relapsing or stabilized, chronic schizophrenia who completed a double-blind treatment phase of a 26-week placebocontrolled trial (discussed in section 4.1 [48] ) and were then randomized to receive either aripiprazole (n = 104) or olanzapine (n = 110) in an open-label 52-week extension phase are also discussed briefly. [66] Two trials also included untreated patients who required initiation of antipsychotic medication. [55,56] Two trials were based in an Asian patient population. [58,63] One trial only included patients with a body mass index (BMI) 27 and non-highdensity lipoprotein (non-hdl) cholesterol levels 130 mg/dl. [65] Active controls included standard-of-care oral antipsychotics (SOC) [55,56,58,60-63,65] or long-acting risperidone 25 50 mg injected intramuscularly once every 2 weeks. [64] Direct comparisons between active comparators were made in three trials. [58,60-62,65] Two shorter-term trials used immediate, titrated or tapered switching regimens. [57,59] Dosage regimens, switching strategies, baseline scores and statistical analyses are reported in tables V and VI. The mean CGI-I score at study endpoint, [55,56,58,63] discontinuation rate due to an adverse event, [59] Investigator s Assessment Questionnaire (IAQ) score, [60] time in remission, [64] time to relapse [64] and the change from baseline in non-hdl cholesterol levels [65] (reported in section 5.3) were defined as a primary efficacy endpoints. Switching to oral aripiprazole following prior antipsychotic treatment provided continued control of the symptoms of schizophrenia or schizoaffective disorder in trials of 8 12 weeks duration (table V). [55-59] Where evaluated, [55,56,58,59] CGI-I scores were significantly improved at study endpoint, with 19 54% of recipients of aripiprazole classified as much or very much improved compared with 16 38% of recipients of SOC. Improvements in CGI-I scores were evident as early as week 1 in the aripiprazole and SOC treatment arms of two trials. [55,56] Where statistical analyses were performed, [58] there was no significant difference in CGI-I scores between aripiprazole and SOC following 12 weeks of treatment. Although the trials were not specifically designed to evaluate the comparative efficacy of

166 Croxtall Table V. Shorter-term efficacy of switching to oral aripiprazole in stable adults ( 18 years) with schizophrenia [55-59] or schizoaffective disorder. [55,57,58] Two trials, [55,56] also included previously untreated pts who required initiation of antipsychotic medication. One trial was based on an Asian population. [58] Results of primary and other efficacy endpoints of randomized, open-label, multicentre 8- [55-57] or 12-week [58,59] trials are summarized. Three trials, [55,56,58] evaluated the efficacy of aripiprazole versus non-aripiprazole, standard-of-care oral antipsychotic. a Switching to aripiprazole was immediate [57,59] or preceded by a 1- to 14-day screening and washout period. [55,56,58] Analyses were based on last observation carried forward and are presented as mean change from baseline at study endpoint Trial Regimen (mg/day) b No. of pts CGI-I score Response rate d (%) PANSS total score (acronym) study endpoint 95% CI c b/line mean change Casey et al. [57] ARI 30 e 104 3.17 70.2-7.6 ARI 30 taper e 104 3.31 68.0-8.2 ARI 30 titrate e 103 3.16 70.9-10.1 Kim et al. [58] ARI 10 30 245 3.56 f 3.39, 3.73 19 63.0-5.4 *g SOC 47 3.45 f 3.14, 3.77 16 59.7-6.2 *g Ryckmans et al. [59] ARI 10 30 fixed h 200 2.8 76.6-17.2 ARI 10 30 titrate h 200 2.9 75.0-14.8 Tandon et al. [55] ARI 10 30 1295 2.77 f 2.68, 2.86 54 (BETA) SOC 304 3.59 f 3.39, 3.79 31 Wolf et al. [56] ARI 10 30 680 3.16 f 3.04, 3.28 43 (EU-BETA) SOC 153 3.37 f 3.14, 3.60 28 a Pts were switched to a specifically selected antipsychotic that was different from previous medication, which included, where described, [55] ziprasidone, risperidone, quetiapine, olanzapine, clozapine, a typical antipsychotic or a combination of antipsychotics, with dosages based on local prescribing information. b The recommended dosage of oral ARI is 10 or 15 mg/day. [13,14] c An upper 95% CI limit of <4 indicates a significant improvement from b/line. d Responders were defined as pts with a CGI-I score of 1 or 2. e Pts received immediate initiation of ARI and discontinuation of prior therapy (ARI 30), immediate initiation of ARI 30 while tapering off prior therapy over 14 days (ARI 30 taper) or titration of ARI from 10 to 30 mg/day over 3 weeks while tapering off prior therapy over 2 weeks (ARI 30 titrate). f Primary endpoint. g Value read from graph. h Pts were previously treated with risperidone with dosages maintained for the first 2 weeks, then halved at weeks 3 and 4 and discontinued at week 5. They were switched to receive ARI 5 mg/day for week 1, 10 mg/day for weeks 2 and 3 and 15 mg/day for weeks 4 and 5 (ARI 10 30 titrate) or ARI 15 mg/day for weeks 1 5 (ARI 10 30 fixed), with flexible dosing of ARI 10 30 in both treatment arms for the remainder of the trial. ARI = aripiprazole; BETA = Broad Effectiveness Trial with Aripiprazole; b/line = baseline; CGI-I = Clinical Global Impression-Global Improvement scale; EU-BETA = a substudy of BETA in Europe; PANSS = Positive and Negative Syndrome Scale; SOC = standard-of-care oral antipyschotics; * p < 0.01 vs b/line. switching strategies, the improvements in CGI-I outcomes were maintained in recipients of aripiprazole whether they received tapered, titrated or immediate treatment (table V). [57] Furthermore, following prior therapy with risperidone, there was no significant difference between recipients switched to aripiprazole using either a titrated or fixed-dose strategy in discontinuation rate (3.5% vs 5.0%) or CGI-I score at study endpoint. [59] The mean change from baseline to study endpoint in PANSS total scores ranged from -5.4 to -17.2 in the aripiprazole treatment arms (table V). [57-59] The improvement from baseline in PANSS total score was significant for both recipients of aripiprazole and SOC treatment, but not significantly different between the treatment arms in the one trial where the between-group difference was evaluated. [58] Using the Preference of Medicine (POM) questionnaire in the BETA (Broad Effectiveness Trial with Aripiprazole) trials, [55,56] approximately 70% of patients preferred aripiprazole to their previous therapy, following 8 weeks treatment. Approximately half of the patients rated aripiprazole

Aripiprazole: A Review 167 treatment as much better whether switched via a titrated- or fixed-dose strategy, following 12 weeks treatment. [59] Using the IAQ (a 10-item questionnaire used to evaluate the relative effectiveness of antipyschotics in patients with schizophrenia or schizoaffective disorder), [74] two-thirds or more of investigators rated energy levels, negative symptoms and somnolence as better for recipients of aripiprazole, whereas, approximately half of investigators rated the same items as better for recipients of SOC. [56] The mean IAQ score in the titrated- or fixed-dose treatment arms was not significantly different (24.6 and 24.5). [59] The longer-term efficacy of switching to oral aripiprazole was demonstrated in the STAR (Schizophrenia Trial of Aripiprazole) [60-62] and other studies [63-65] using a variety of efficacy endpoints, which are summarized in table VI. In the STAR studies, IAQ scores were significantly lower (i.e. improved) for recipients of aripiprazole than recipients of SOC, following 26 weeks treatment. [60] In addition, the mean change from baseline in QOL total or Arizona Sexual Experience (ASEX) score and the proportion of patients who rated the switched study medication as much better was also significantly greater in the aripiprazole Table VI. Longer-term efficacy of switching to oral aripiprazole, non-aripiprazole standard-of-care oral antipyschotic a or long-acting injectable risperidone in stable adults ( 18 years) with schizophrenia [60-65] or schizoaffective disorder. [63,65] One trial, [63] was based in an Asian population, and one trial only included patients with a BMI 27 and non-hdl cholesterol levels 130 mg/dl. [65] Results of primary and other efficacy endpoints of randomized, open-label, multicentre trials are summarized. [60-65] Treatments were switched over a period of 2 12 weeks [60-62,64,65] or following a washout/screening period of 1 14 days. [63] Analyses were based on last observation carried forward, [60,63] observed cases, [61,62] repeated measures mixed effects linear model [65] or Kaplan-Meier plots [64] and are presented as mean change from baseline at study endpoint Trial (efficacy timepoint) STAR study Treatment groups (mg/day) b [no. of pts] Main endpoints Baseline value Response Kerwin et al. [60] ARI 10 30 [284] vs SOC [271] IAQ score c 25.7 vs 27.7 *** Hanssens et al. [61] CGI-I score 3.34 vs 3.45 Taylor et al. [62] ASEX score 19.27 vs 19.70-1.88 vs -0.92 * (week 26) POM item much better (%) 59 vs 35 ***d QOL total score 61.66 vs 60.01 16.21 vs 10.01 *** EQ-5D Utility score 0.716 vs 0.667 0.117 vs 0.100 Other studies Lee et al. [63] ARI 10 30 [135] vs SOC [31] CGI-I score c 2.92 vs 2.81 (week 26) MacFadden et al. [64] ARI 5 30 [172] vs RIS 25 50 e [177] Time to relapse c (%) 43.6 vs 45.8 (week 104) Time in remission c (days) 357 vs 373 Stroup et al. [65] ARI 5 30 [109] vs SOC [106] PANSS total score 65 vs 67-5.0 vs -3.9 (week 24) CGI-S score 4 vs 4-0.2 vs -0.2 IWQOL total score 65 vs 66-14.2 vs -4.7 ** a In most trials, pts were switched to a specifically selected antipsychotic, that was different from previous medication, and included OLA, QUE or RIS; dosages were not reported. In one trial, [65] pts were switched to ARI or remained on their current antipsychotic of OLA 5 20 mg/day, QUE 200 1200 mg/day or RIS 1 16 mg/day. b The recommended dosage of oral ARI is 10 or 15 mg/day. [13,14] c Primary endpoint. d Assessed by pts. e Injected intramuscularly every 2 weeks. ARI = aripiprazole; ASEX = Arizona Sexual Experience scale; BMI = body mass index; CGI-I = Clinical Global Impression-Global Improvement scale; CGI-S= CGI-Severity of Illness scale; EQ-5D = EuroQOL-5D; IAQ= Investigator Assessment Questionnaire; IWQOL= Impact of Weight on QOL; non-hdl= non-high-density liporotein; OLA = olanzapine; PANSS= Positive and Negative Syndrome Scale; POM= Preference of Medicine; pts= patients; QOL= quality of life; QUE = quetiapine; RIS= risperidone; SOC = standard-of-care oral antipsychotic; STAR = Schizophrenia Trial of Aripiprazole; * p < 0.5, ** p < 0.01, *** p < 0.001 vs SOC.