- Email: [email protected]
Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism
Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213 – 1219 www.elsevier.com/locate/pnpbp
Review article
Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism Dieter Naber*, Martin Lambert Department of Psychiatry and Psychotherapy, Universita¨tsklinikum Hamburg-Eppendorf, Martinistrage 52, Hamburg 20246, Germany Accepted 29 June 2004 Available online 26 August 2004
Abstract Aripiprazole is a new atypical antipsychotic with a mode of action that is distinct from currently available antipsychotic drugs. In phase III comparative clinical studies, aripiprazole 15–30 mg/day was at least as effective as haloperidol and risperidone in short term treatment of acute exacerbation of schizophrenia but superior to haloperidol in long term maintenance therapy. Consistent with an atypical profile, aripiprazole is effective against positive, negative and cognitive symptoms of schizophrenia and has a favourable side effect profile with the incidence of extrapyramidal symptoms (EPS) comparable to placebo. It is also devoid of side effects such as clinically significant hyperprolactinaemia, hypercholesterolaemia and cardiotoxicity, and has a low propensity for weight gain. Symptom relief is achieved without significant sedation. These clinical data suggest its usefulness in psychosocial rehabilitation, as well as in long-term prevention of schizophrenic relapse. Recent results from a multicentre, open-label study in a general psychiatric setting provide the first evidence that aripiprazole is also effective under naturalistic conditions. However, only post-marketing experience will show whether the positive results of these controlled trials can be replicated in everyday practice. D 2004 Elsevier Inc. All rights reserved. Keywords: Aripiprazole; Atypical antipsychotics; Schizophrenia
Contents 1. 2.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical efficacy and safety versus haloperidol and risperidone 2.1. Short-term studies . . . . . . . . . . . . . . . . . . . . 2.2. Long-term studies . . . . . . . . . . . . . . . . . . . . 3. Meta-analyses safety data . . . . . . . . . . . . . . . . . . . 4. Conclusions: aripiprazole’s potential for improved patient care References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
1213 1214 1214 1216 1217 1218 1218
1. Introduction
Abbreviations: CGI, Clinical Global Impressions; EPS, extrapyramidal symptoms; BPRS, PANSS-derived Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; QoL, quality of life; TD, tardive dyskinesia. * Corresponding author. Tel.: +49 40 42803 2201; fax: +49 40 42803 2999. E-mail address: [email protected] (D. Naber). 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.06.020
Schizophrenia is a serious, chronic and debilitating mental illness for which most patients require long-term treatment with antipsychotic medication. Until recently, this has centred almost exclusively on the use of conventional or typical antipsychotic agents. However, these agents have limited efficacy, with 40% of medicationtreated patients continuing to exhibit moderate-to-severe
1214
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
psychotic symptoms (American Psychiatric Association, 2003). Furthermore, typical antipsychotics possess limited effectiveness against the negative symptoms and cognitive deficits of schizophrenia as well as causing severe and pervasive side effects (Jibson and Tandon, 1998). Extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) are recognized as being among the most troublesome side effects of typical antipsychotics and there is now a growing awareness that they also have adverse effects on drive, emotion and cognition, all of which impact adversely on the patient’s quality of life (QoL) (Naber and Karow, 2001). Not surprisingly, among other factors poor tolerability leads to poor treatment compliance, a greater risk of relapse and poorer long-term outcome (Fenton et al., 1997). The introduction of the atypical antipsychotics into clinical practice in the mid-to-late 1990s has had a major impact on the treatment of schizophrenia. Success criteria of antipsychotic treatment have become much more ambitious and the patient’s perspective is now also of scientific interest. Atypical agents, which in addition to the prototype clozapine now include zotepine, risperidone, olanzapine, amisulpride, quetiapine and ziprasidone, combine broader efficacy with improved tolerability especially with regard to motor and affective symptoms. Importantly, atypical antipsychotics have enabled treatment to progress beyond simply symptom relief to improvements in QoL and a more thorough consideration of the patient’s perspective (Naber et al., 2001, 2002). However, these new atypical antipsychotics also have side effects which, due to the markedly different pharmacological profiles, range from weight gain, impaired glucose tolerance, hyperprolactinaemia with potential associated sexual dysfunction, to cardiotoxicity (Collaborative Working Group on Clinical Trial Evaluations, 1998; Allison et al., 1999). In a considerable number of patients, these adverse effects are of clinical relevance, leading to poor compliance and an increased risk of relapse. Despite the progress in antipsychotic treatment, there is certainly room for further improvement regarding efficacy as well as tolerability. Aripiprazole is a new atypical antipsychotic with a pharmacological mechanism that distinguishes it from currently available antipsychotic agents (Burris et al., 2002; Kikuchi et al., 2002). It acts as a potent partial dopamine D2 receptor agonist, a partial serotonin 5-HT1A agonist, and 5-HT2A receptor antagonist. Partial D2 receptor agonism is believed to help stabilize dopaminergic neurotransmission in schizophrenia in the mesocortical and mesolimbic pathways (Stahl, 2001). Partial agonist activity at the 5-HT1A receptor may confer efficacy against negative and affective symptoms of schizophrenia, while antagonism at the 5-HT2A receptor may contribute to efficacy against negative symptoms as well as reducing EPS liability (Jordan et al., 2002; Leysen et al., 1998). Thus, aripiprazole has a receptor binding
profile which might predict efficacy against both positive and negative symptoms of schizophrenia as well as a low risk of side effects. The hypothesis of treating schizophrenia with partial D2 receptor agonist activity is not new; the experimental compound SDZ HDC 912 for example was shown to act in this manner in a double-blind controlled comparison with haloperidol (Naber et al., 1992). Objectively, there were no differences regarding efficacy or tolerability. Subjectively, however, 52% of patients treated with the experimental drug said that their experience was better than that with their previous antipsychotic medication compared with 32% of patients receiving haloperidol ( Pb0.05). A series of randomized, controlled clinical studies have been carried out to investigate whether aripiprazole’s action as a dopamine system stabilizer translates into quantifiable clinical benefits in patients with schizophrenia. The studies reviewed are all key published clinical trials on aripiprazole that concerned both short-term and long-term clinical data in schizophrenia with aripiprazole versus typical and atypical antipsychotics.
2. Clinical efficacy and safety versus haloperidol and risperidone In phase III comparative clinical studies, aripiprazole was compared to haloperidol and risperidone in short-term treatment of acute exacerbation of schizophrenia and to haloperidol in long-term maintenance therapy. Both comparators were given in the recommended dosages, the dose equivalent to 100 mg/day of chlorpromazine is 7.5 mg/day of aripiprazole (Woods, 2003). 2.1. Short-term studies In a 4-week short-term study, in which over 400 patients were randomized to 4 weeks’ treatment with either aripiprazole (15 and 30 mg/day), haloperidol (10 mg/day) or placebo, both active treatments produced statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale (BPRS) core and Clinical Global Impressions (CGI)Severity scores compared with placebo ( PV0.05) (Kane et al., 2002). A significantly greater improvement was seen in PANSS negative subscale score with aripiprazole (15 mg) than with placebo ( P=0.006) (Table 1). Acute administration of aripiprazole was well tolerated (Kane et al., 2002). Indeed, the number of patients discontinuing therapy due to adverse events in the aripiprazole treatment arm was lower than under placebo or haloperidol. EPS-related adverse events occurred with similar frequency in the aripiprazole and placebo groups and were higher in the haloperidol group. The percentage
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
1215
Table 1 Short-term studies and meta-analyses in patients with schizophrenia or schizoaffective disorder Reference
Duration (weeks)
n
Treatment
Efficacy
Safety
Kane et al., 2002
4
414
aripiprazole (15, 30 mg/day), haloperidol (10 mg/day) placebo
active treatment induced significant improvement in efficacy measures compared to placebo
404
aripiprazole (20, 30 mg/day), risperidone (6 mg/day) placebo
active treatments were significantly superior to placebo
1545
aripiprazole (2–30 mg/day), haloperidol (10 mg/day), risperidone (6 mg/day) placebo
aripiprazole showed superior antipsychotic efficacy to placebo and comparable efficacy to active controls switching to aripiprazole resulted in improvements for patients in all three groups not measured in this meta-analysis
aripiprazole was well-tolerated, number of discontinuations lower in aripiprazole group than in placebo or haloperidol groups aripiprazole was well tolerated, most common side effects with aripiprazole were headache, nausea, vomiting and somnolence not measured in this meta-analysis
Potkin et al., 2003
4
Lieberman et al., 2002
4–6
Casey et al., 2003
8
Marder et al., 2003
4–6
1549
Carson et al., 2002
4–6
1648
aripiprazole (range of doses), haloperidol (10 mg/day), risperidone (6 mg/day)
not measured in this meta-analysis
Stock et al., 2002
4–6
1648
aripiprazole (range of doses), haloperidol (10 mg/day), risperidone (6 mg/day) placebo
not measured in this meta-analysis
311
three different strategies for switching patients to aripiprazole (30 mg/day) aripiprazole (2–30 mg/day), haloperidol (5–20 mg/day) placebo
of patients in the haloperidol group who needed at least one administration of benztropine was almost three times higher than the placebo group, whereas the percentage of aripiprazole-treated patients who required benztropine was comparable to placebo. The incidence of hyperprolactinaemia with aripiprazole was not significantly different from placebo, whereas haloperidol produced a significant increase in mean serum prolactin level compared with placebo ( Pb0.001). Clinically significant weight gain (defined as z7% increase from baseline) occurred in 6% of patients receiving aripiprazole and in 10% of those receiving haloperidol. Three patients in the haloperidol group and one patient in the placebo group experienced a clinically significant increase in QTc interval (defined as a QTcz450 ms and a z10% increase from baseline), whereas in the aripiprazole group there was no evidence of significant QTc prolongation. Another short-term study (4 weeks’ duration) compared the efficacy of aripiprazole (20 and 30 mg/day) with risperidone (6 mg/day) and placebo in 404 patients with acute exacerbation of schizophrenia or schizoaffective disorder (Potkin et al., 2003). Both doses of aripiprazole produced significant improvements in the three primary efficacy measures (PANSS-total score, PANSS-positive score and CGI-S score) compared with placebo. The
aripiprazole treatment was well tolerated in all three groups akathisia, somnolence and EPS more common in haloperidol group than either the aripiprazole or placebo groups haloperidol and risperidone produced clinically significant increases in plasma prolactin levels, aripiprazole produced a decrease in plasma prolactin levels aripiprazole comparable to placebo in mean changes in QTc
risperidone group also showed significantly greater improvement in all primary efficacy measures. Overall, both doses of aripiprazole were well tolerated with most adverse events being mild-to-moderate in intensity. The number of subjects with treatment-related side effects was similar in all four groups. In the aripiprazole groups headache, nausea, vomiting and somnolence mainly occurred in the first week of treatment. EPS-related adverse events were comparable in the aripiprazole and risperidone groups. The incidence of clinically relevant weight gain (defined as z7% increase from baseline) was significantly higher than with placebo for both active treatments (placebo 2%, aripiprazole 20 mg 13%, aripiprazole 30 mg 9%, risperidone 6 mg 11%). Mean prolactin levels decreased with aripiprazole but significantly increased with risperidone. Mean change in QTc interval did not differ significantly from placebo with either active treatment. Results from individual prospective clinical trials suggest that aripiprazole is at least as effective as current antipsychotic agents in the short-term management of acute exacerbation of schizophrenia, with an equally rapid onset of action. These findings are supported by a meta-analysis of pooled efficacy data from the short-term placebocontrolled trials involving 1545 patients hospitalized with
1216
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
2.2. Long-term studies
Fig. 1. Percentage of patients on treatment and still responding following 8, 26 and 52 weeks’ treatment with aripiprazole or haloperidol (Reprinted with permission from Fig. 2 of Kasper et al., 2003. Copyright 2003. International Journal of Neuropsychopharmacology.).
acute schizophrenic relapse (Lieberman et al., 2002). The data confirm that aripiprazole shows statistically superior antipsychotic efficacy to placebo. Significant improvements in positive and negative symptoms are seen 1 week after starting treatment with aripiprazole, without concomitant sedation. An 8-week, open-label, randomised study investigated the efficacy, safety and tolerability of three different strategies for switching stable outpatients from prior antipsychotic monotherapy to 30 mg/day aripiprazole (Casey et al., 2003). Patients in all three treatment groups showed consistent, progressive improvement in PANSS total, positive and negative score assessments following the switch to aripiprazole. Comparably, CGI-S and CGI-I scores showed a similar improvement in scores following the switch to aripiprazole in all three groups over the duration of the study.
A study of the long-term efficacy and safety of aripiprazole for maintenance treatment in patients experiencing acute schizophrenic relapse suggests that the benefits seen with acute administration are sustained over the long term (Kujawa et al., 2002). Involving 1294 patients with acute schizophrenic relapse, this trial compared the efficacy and safety of aripiprazole (30 mg/day) with haloperidol (10 mg/day) over a 52-week treatment period. Significantly more patients (40% vs. 27%, Pb0.001) met the response criteria (30% improvement in PANSS) when treated with aripiprazole than with haloperidol and importantly remained on therapy for the duration of the study (Fig. 1). Compared with haloperidol, aripiprazole was also significantly more effective in treatment of negative and depressive symptoms (Table 2). Consistent with the short-term studies, long-term administration of aripiprazole was much better tolerated than haloperidol, with a significantly lower incidence of EPSrelated adverse effects and hyperprolactinaemia. This was reflected in a lower rate of discontinuations due to adverse effects and contributed to greater compliance with long-term treatment (Fig. 2). A 26-week placebo-controlled trial in which aripiprazole 15 mg/day was administered to patients with stable chronic disease has shown that while aripiprazole was significantly more effective in preventing relapse (34% vs. 57%), there was no difference between treatments with respect to the overall incidence of adverse events (Pigott et al., 2003). The frequency of EPS-related adverse effects (including akathisia) and weight change were similar for aripiprazole and placebo and neither caused hyperprolactinaemia or QTc prolongation. These data indicate that aripiprazole is markedly superior to haloperidol during long-term maintenance therapy, due to an improved safety and tolerability profile. The neuropsychological effects of aripiprazole and olanzapine were compared in an open-label trial in 255
Table 2 Long-term studies and meta-analyses in patients with schizophrenia or schizoaffective disorder Reference
Duration (weeks)
n
Treatment
Efficacy
Safety
Kujawa et al., 2002
52
1294
aripiprazole (30 mg/day), haloperidol (10 mg/day)
Pigott et al., 2003
26
310
aripiprazole (15 mg/day) placebo
more patients responded successfully when treated with aripiprazole than with haloperidol aripiprazole more effective in preventing relapse
Kern et al., 2002
26
255
aripiprazole (30 mg/day), olanzapine (15 mg/day)
significant improvement in secondary verbal memory with aripiprazole but not with olanzapine
Jody et al., 2002
26–52
1549
aripiprazole (range of doses), haloperidol, olanzapine
not measured in this meta-analysis
Stock et al., 2002
26–52
1549
aripiprazole (range of doses), haloperidol, olanzapine
not measured in this meta-analysis
haloperidol was not tolerated as well as aripiprazole (higher incidence of EPS and hyperprolactinaemia) aripiprazole comparable to placebo with respect to overall incidence of adverse events aripiprazole associated with reduction in cholesterol levels and with lower incidence of weight gain than olanzapine aripiprazole associated with minimal weight gain comparable to haloperidol but less than olanzapine no evidence of QTc prolongation with aripiprazole treatment
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
1217
Fig. 2. Rates of premature discontinuation due to adverse effects following long-term treatment with aripiprazole or haloperidol (Reprinted with permission from Fig. 4 of Kasper et al., 2003. Copyright 2003. International Journal of Neuropsychopharmacology.).
patients with chronic stable schizophrenia (Kern et al., 2002). Cognitive data were reduced to three factors: general cognitive functioning, secondary verbal memory and executive functioning. At 8 weeks, the general cognitive factor improved significantly in patients in both treatment arms. Significant within-group improvements in secondary verbal memory were seen with aripiprazole at weeks 8 and 26 ( Pb0.001), but not with olanzapine. No psychopathological data were reported in this study. Regarding tolerability, aripiprazole was associated with a lower incidence of significant weight gain (i.e. a greater than 7% increase from baseline) than olanzapine (7% vs. 27%). A significant reduction in cholesterol levels was seen with aripiprazole compared with olanzapine.
3. Meta-analyses safety data Individual studies suggest aripiprazole has a favourable side effect profile. In common with other atypical agents it has a low propensity to induce EPS but also appears devoid of the metabolic and cardiac side effects seen with other atypical agents. Meta-analyses of pooled safety data from patients with schizophrenia or schizoaffective disorder have looked specifically at its effects on weight, plasma prolactin levels and cardiac function (Table 2). Pooled data from the five short-term studies showed that headache, insomnia, agitation and anxiety were the most commonly reported events in all three treatment groups (2– 30 mg/day aripiprazole [n=932], placebo [n=416] or 5–20 mg/day haloperidol [n=201]). The majority of adverse events occurred with similar frequency in the three treatments groups, with the exception of akathisia, somnolence
and EPS, which were more common in the haloperidol group than either the aripiprazole or placebo groups (Marder et al., 2003). The short-term effects of aripiprazole on weight gain were assessed in five 4–6-week double-blind studies in 1648 patients randomized to aripiprazole, placebo or active control (haloperidol 10 mg/day or risperidone 6 mg/day). Long-term effects on weight gain were evaluated in a 52-week haloperidol-controlled study (n=1294) and a 26-week open-label olanzapine-controlled study (n=255) (Jody et al., 2002). Aripiprazole was associated with minimal weight gain comparable to haloperidol but less than olanzapine. In the olanzapine-controlled study, patients treated with aripiprazole experienced weight loss over time, whereas patients treated with olanzapine showed significant increases in weight. Several antipsychotic agents cause elevations in prolactin which can lead to troublesome side effects such as amenorrhea, impotence and gynaecomastia. Pooled safety data from short-term studies on 1648 patients showed that both haloperidol and risperidone produced clinically significant increases in plasma prolactin (125% and 607% above baseline, respectively) (Carson et al., 2002). As expected based on its partial agonist profile aripiprazole produced a 50% decrease from baseline in plasma prolactin levels. Adverse cardiac effects, reflected by prolongation of the QT interval, are known to occur with several antipsychotic agents. Based on pooled safety data from 1648 patients, short-term treatment with aripiprazole across all doses was found comparable to placebo in mean changes in QTc, irrespective of gender or race (Stock et al., 2002). Similarly, pooled safety data on 1549 patients receiving long-term antipsychotic therapy showed no evidence of QTc prolongation following treatment with aripiprazole for 52 weeks.
1218
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
4. Conclusions: aripiprazole’s potential for improved patient care Treatment of schizophrenia today is designed not only to reduce the disabling psychotic symptoms of the illness but also to help patients lead fulfilling lives. As discussed in a previous review, QoL is of great importance to patients with schizophrenia, and with the availability of newer atypical agents, is becoming an important criterion on which to judge the success of treatment (Naber and Karow, 2001). The advent of atypical antipsychotic agents has certainly helped to bridge treatment gaps, especially with respect to the amelioration of negative symptoms of schizophrenia and reducing the frequency of adverse motor symptoms. However, as the burden of EPS has been reduced, the focus has shifted to other side effects and especially to metabolic complications such as weight gain, heart disease and hyperprolactinaemia. It is therefore apparent that, despite the recent advances, further improvements in tolerability and compliance are still needed. While the aripiprazole studies carried out to date have not specifically evaluated QoL issues in patients with schizophrenia, they suggest that its favourable side effect profile will result in better compliance with treatment, a reduced likelihood of relapse and a better overall prognosis. Results from a recent US multicentre study, in which 1599 patients with schizophrenia were treated in a general psychiatric practice setting in naturalistic conditions, showed that over 50% of patients and 41% of caregivers rated aripiprazole as much better than prior antipsychotic treatment (Tandon et al., 2003). Expectations for aripiprazole are high based on currently available clinical data (some of which are published as abstracts only). It remains to be seen whether the positive results observed with aripiprazole in selected patients involved in clinical trials will be replicated in everyday practice. Only time will tell as to what extent the promising results will translate into benefits for patients.
References Allison, D.B., Mentore, J.L., Moonseong, H., Chandler, L.P., Cappelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry 156, 1686 – 1696. American Psychiatric Association, 2003. Practice guideline for the treatment of patients with schizophrenia: III. Treatment principles and alternatives (http://www.psych.org/clin_res/pg_schizo_3.cfm). Burris, K.D., Molski, T.F., Xu, C., Ryan, E., Tottori, K., Kikuchi, T., Yocca, F.D., Molinoff, P.B., 2002. Aripiprazole, a novel antipsychotic, is a highaffinity partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther. 302, 381 – 389. Carson, W.H., Saha, A.R., Iwamoto, T., Lin, C., Kujawa, M.J., 2002. Metaanalysis of prolactin effects with aripiprazole. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186.
Casey, D.E., et al.on behalf of the Aripiprazole Study Group, 2003. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology 166, 391 – 399. Collaborative Working Group on Clinical Trial Evaluations, 1998. Adverse effects of the atypical antipsychotics. J. Clin. Psychiatry 59 (Suppl. 12), 17 – 22. Fenton, W.S., Blyler, C.R., Heinssen, R.K., 1997. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr. Bull. 23, 637 – 651. Jibson, M.D., Tandon, R., 1998. New atypical antipsychotic medications. J. Psychiatr. Res. 32, 215 – 228. Jody, D., Saha, A.R., Iwamoto, T., Biswas, D., Lin, C., Marcus, R., McQuade, R.D., 2002. Meta-analysis of weight effects with aripiprazole. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186. Jordan, S., Koprivica, V., Chen, R., Tottori, K., Kikuchi, T., Altar, C.A., 2002. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur. J. Pharmacol. 441, 137 – 140. Kane, J.M., Carson, W.H., Saha, A.R., McQuade, R.D., Ingenito, G.G., Zimbroff, D.L., Ali, M.W., 2002. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J. Clin. Psychiatry 63, 763 – 771. Kasper, S., Lerman, M.N., McQuade, R.D., Saha, A., Carson, W.H., Ali, M., Archibald, D., Ingenito, G., Marcus, R., Pigott, T., 2003. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int. J. Neuropsychopharmacol. 6, 325 – 337. Kern, R.S., Cornblatt, B., Carson, W.H., Stock, E., Saha, A.R., Ali, M.W., Ingenito, G., Green, M.F., 2002. Neurocognitive effects: aripiprazole vs olanzapine in stable psychosis. Eur. Psychiatr. 17 (Suppl. 1), 104s. Kikuchi, T., Burris, K.D., Jordan, S., McQuade, R.D., 2002. Aripiprazole: a dopamine–serotonin system stabilizer. Eur. Psychiatr. 17 (Suppl. 1), 103s. Kujawa, M., Saha, A., Ingenito, G.G., Ali, M., Luo, X., Archibald, D.G., Carson, W.H., 2002. Aripiprazole for long-term maintenance treatment of schizophrenia. Poster presented at American Psychiatric Association 155th annual meeting, May 2002, Philadelphia, PA, USA, . Leysen, J.E., Janssen, P.M.F., Heylen, L., Gommeren, W., Gompel, P.V., Lesage, A.S., Megens, A.A.H.P., Schotte, Alain, 1998. Receptor interactions of new antipsychotics: relation to pharmacodynamic and clinical effects. Int. J. Psychiatry Clin. Pract. 2 (Suppl. 1), S3 – S17. Lieberman, J., Carson, W.H., Saha, A.R., Stringfellow, J.C., Archibald, D.G., Kujawa, M.J., Iwamoto, T., 2002. Meta-analysis of the efficacy of aripiprazole in schizophrenia. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186. Marder, S.R., McQuade, R.D., Stock, E., Kaplita, S., Marcus, R., Safferman, A.Z., Saha, A., Ali, M., Iwamoto, T., 2003. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr. Res. 61, 123 – 126. Naber, D., Karow, A., 2001. Good tolerability equals good results: the patient’s perspective. Eur. Neuropsychopharmacol. 11 (Suppl. 4), S391 – S396. Naber, D., Gaussares, C., Moeglen, J.M., Tremmel, L., P.E., Bailey, SDZ HDC 912 Collaborative Study Group, 1992. Efficacy and tolerability of SDZ HDC 912, a partial dopamine D2 agonist, in the treatment of schizophrenia. In: Meltzer, H.Y. (Ed.), Novel Antipsychotic Drugs. Raven Press, New York, pp. 99 – 107. Naber, D., Moritz, S., Lambert, M., Pajonk, F., Holzbach, R., Mass, R., Andresen, B., 2001. Improvement of schizophrenic patients’ subjective well-being under atypical antipsychotic drugs. Schizophr. Res. 50, 79 – 88. Naber, D., Karow, A., Lambert, M., 2002. Psychosocial outcomes in patients with schizophrenia: quality of life and reintegration. Curr. Opin. Psychiatry 15, 31 – 36. Pigott, T.A., et al.for the Aripiprazole Study Group, 2003. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizo-
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219 phrenia: a placebo-controlled 26-week study. J. Clin. Psychiatry 64, 1048 – 1056. Potkin, S.G., Saha, A.R., Kujawa, M.J., Carson, W.H., Ali, M., Stock, E., Stringfellow, J., Ingenito, G., Marder, S.R., 2003. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch. Gen. Psychiatry 60, 681 – 690. Stahl, S.M., 2001. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics: Part 1. dGoldilocksT actions at dopamine receptors. J. Clin. Psychiatry 62, 841 – 842.
1219
Stock, E., Saha, A., Brunell, R., Archibald, D.G., Iwamoto, T., McQuade, R.D., 2002. Meta-analysis of cardiac safety with aripiprazole. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186. Tandon, R., Stock, E.G., Kujawa, M.J., Torbeyns, A.F., Borian, F.B., Reira, L., McQuade, R.D., 2003. Broad effectiveness trial with aripiprazole. Poster presented at the 55th Institute on Psychiatric Services, October– November 2003, Boston, MA, USA. Woods, S.W., 2003. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J. Clin. Psychiatry 64, 663 – 667.
Review article
Aripiprazole: a new atypical antipsychotic with a different pharmacological mechanism Dieter Naber*, Martin Lambert Department of Psychiatry and Psychotherapy, Universita¨tsklinikum Hamburg-Eppendorf, Martinistrage 52, Hamburg 20246, Germany Accepted 29 June 2004 Available online 26 August 2004
Abstract Aripiprazole is a new atypical antipsychotic with a mode of action that is distinct from currently available antipsychotic drugs. In phase III comparative clinical studies, aripiprazole 15–30 mg/day was at least as effective as haloperidol and risperidone in short term treatment of acute exacerbation of schizophrenia but superior to haloperidol in long term maintenance therapy. Consistent with an atypical profile, aripiprazole is effective against positive, negative and cognitive symptoms of schizophrenia and has a favourable side effect profile with the incidence of extrapyramidal symptoms (EPS) comparable to placebo. It is also devoid of side effects such as clinically significant hyperprolactinaemia, hypercholesterolaemia and cardiotoxicity, and has a low propensity for weight gain. Symptom relief is achieved without significant sedation. These clinical data suggest its usefulness in psychosocial rehabilitation, as well as in long-term prevention of schizophrenic relapse. Recent results from a multicentre, open-label study in a general psychiatric setting provide the first evidence that aripiprazole is also effective under naturalistic conditions. However, only post-marketing experience will show whether the positive results of these controlled trials can be replicated in everyday practice. D 2004 Elsevier Inc. All rights reserved. Keywords: Aripiprazole; Atypical antipsychotics; Schizophrenia
Contents 1. 2.
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical efficacy and safety versus haloperidol and risperidone 2.1. Short-term studies . . . . . . . . . . . . . . . . . . . . 2.2. Long-term studies . . . . . . . . . . . . . . . . . . . . 3. Meta-analyses safety data . . . . . . . . . . . . . . . . . . . 4. Conclusions: aripiprazole’s potential for improved patient care References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
. . . . . . .
1213 1214 1214 1216 1217 1218 1218
1. Introduction
Abbreviations: CGI, Clinical Global Impressions; EPS, extrapyramidal symptoms; BPRS, PANSS-derived Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; QoL, quality of life; TD, tardive dyskinesia. * Corresponding author. Tel.: +49 40 42803 2201; fax: +49 40 42803 2999. E-mail address: [email protected] (D. Naber). 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.06.020
Schizophrenia is a serious, chronic and debilitating mental illness for which most patients require long-term treatment with antipsychotic medication. Until recently, this has centred almost exclusively on the use of conventional or typical antipsychotic agents. However, these agents have limited efficacy, with 40% of medicationtreated patients continuing to exhibit moderate-to-severe
1214
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
psychotic symptoms (American Psychiatric Association, 2003). Furthermore, typical antipsychotics possess limited effectiveness against the negative symptoms and cognitive deficits of schizophrenia as well as causing severe and pervasive side effects (Jibson and Tandon, 1998). Extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) are recognized as being among the most troublesome side effects of typical antipsychotics and there is now a growing awareness that they also have adverse effects on drive, emotion and cognition, all of which impact adversely on the patient’s quality of life (QoL) (Naber and Karow, 2001). Not surprisingly, among other factors poor tolerability leads to poor treatment compliance, a greater risk of relapse and poorer long-term outcome (Fenton et al., 1997). The introduction of the atypical antipsychotics into clinical practice in the mid-to-late 1990s has had a major impact on the treatment of schizophrenia. Success criteria of antipsychotic treatment have become much more ambitious and the patient’s perspective is now also of scientific interest. Atypical agents, which in addition to the prototype clozapine now include zotepine, risperidone, olanzapine, amisulpride, quetiapine and ziprasidone, combine broader efficacy with improved tolerability especially with regard to motor and affective symptoms. Importantly, atypical antipsychotics have enabled treatment to progress beyond simply symptom relief to improvements in QoL and a more thorough consideration of the patient’s perspective (Naber et al., 2001, 2002). However, these new atypical antipsychotics also have side effects which, due to the markedly different pharmacological profiles, range from weight gain, impaired glucose tolerance, hyperprolactinaemia with potential associated sexual dysfunction, to cardiotoxicity (Collaborative Working Group on Clinical Trial Evaluations, 1998; Allison et al., 1999). In a considerable number of patients, these adverse effects are of clinical relevance, leading to poor compliance and an increased risk of relapse. Despite the progress in antipsychotic treatment, there is certainly room for further improvement regarding efficacy as well as tolerability. Aripiprazole is a new atypical antipsychotic with a pharmacological mechanism that distinguishes it from currently available antipsychotic agents (Burris et al., 2002; Kikuchi et al., 2002). It acts as a potent partial dopamine D2 receptor agonist, a partial serotonin 5-HT1A agonist, and 5-HT2A receptor antagonist. Partial D2 receptor agonism is believed to help stabilize dopaminergic neurotransmission in schizophrenia in the mesocortical and mesolimbic pathways (Stahl, 2001). Partial agonist activity at the 5-HT1A receptor may confer efficacy against negative and affective symptoms of schizophrenia, while antagonism at the 5-HT2A receptor may contribute to efficacy against negative symptoms as well as reducing EPS liability (Jordan et al., 2002; Leysen et al., 1998). Thus, aripiprazole has a receptor binding
profile which might predict efficacy against both positive and negative symptoms of schizophrenia as well as a low risk of side effects. The hypothesis of treating schizophrenia with partial D2 receptor agonist activity is not new; the experimental compound SDZ HDC 912 for example was shown to act in this manner in a double-blind controlled comparison with haloperidol (Naber et al., 1992). Objectively, there were no differences regarding efficacy or tolerability. Subjectively, however, 52% of patients treated with the experimental drug said that their experience was better than that with their previous antipsychotic medication compared with 32% of patients receiving haloperidol ( Pb0.05). A series of randomized, controlled clinical studies have been carried out to investigate whether aripiprazole’s action as a dopamine system stabilizer translates into quantifiable clinical benefits in patients with schizophrenia. The studies reviewed are all key published clinical trials on aripiprazole that concerned both short-term and long-term clinical data in schizophrenia with aripiprazole versus typical and atypical antipsychotics.
2. Clinical efficacy and safety versus haloperidol and risperidone In phase III comparative clinical studies, aripiprazole was compared to haloperidol and risperidone in short-term treatment of acute exacerbation of schizophrenia and to haloperidol in long-term maintenance therapy. Both comparators were given in the recommended dosages, the dose equivalent to 100 mg/day of chlorpromazine is 7.5 mg/day of aripiprazole (Woods, 2003). 2.1. Short-term studies In a 4-week short-term study, in which over 400 patients were randomized to 4 weeks’ treatment with either aripiprazole (15 and 30 mg/day), haloperidol (10 mg/day) or placebo, both active treatments produced statistically significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total, PANSS positive, PANSS-derived Brief Psychiatric Rating Scale (BPRS) core and Clinical Global Impressions (CGI)Severity scores compared with placebo ( PV0.05) (Kane et al., 2002). A significantly greater improvement was seen in PANSS negative subscale score with aripiprazole (15 mg) than with placebo ( P=0.006) (Table 1). Acute administration of aripiprazole was well tolerated (Kane et al., 2002). Indeed, the number of patients discontinuing therapy due to adverse events in the aripiprazole treatment arm was lower than under placebo or haloperidol. EPS-related adverse events occurred with similar frequency in the aripiprazole and placebo groups and were higher in the haloperidol group. The percentage
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
1215
Table 1 Short-term studies and meta-analyses in patients with schizophrenia or schizoaffective disorder Reference
Duration (weeks)
n
Treatment
Efficacy
Safety
Kane et al., 2002
4
414
aripiprazole (15, 30 mg/day), haloperidol (10 mg/day) placebo
active treatment induced significant improvement in efficacy measures compared to placebo
404
aripiprazole (20, 30 mg/day), risperidone (6 mg/day) placebo
active treatments were significantly superior to placebo
1545
aripiprazole (2–30 mg/day), haloperidol (10 mg/day), risperidone (6 mg/day) placebo
aripiprazole showed superior antipsychotic efficacy to placebo and comparable efficacy to active controls switching to aripiprazole resulted in improvements for patients in all three groups not measured in this meta-analysis
aripiprazole was well-tolerated, number of discontinuations lower in aripiprazole group than in placebo or haloperidol groups aripiprazole was well tolerated, most common side effects with aripiprazole were headache, nausea, vomiting and somnolence not measured in this meta-analysis
Potkin et al., 2003
4
Lieberman et al., 2002
4–6
Casey et al., 2003
8
Marder et al., 2003
4–6
1549
Carson et al., 2002
4–6
1648
aripiprazole (range of doses), haloperidol (10 mg/day), risperidone (6 mg/day)
not measured in this meta-analysis
Stock et al., 2002
4–6
1648
aripiprazole (range of doses), haloperidol (10 mg/day), risperidone (6 mg/day) placebo
not measured in this meta-analysis
311
three different strategies for switching patients to aripiprazole (30 mg/day) aripiprazole (2–30 mg/day), haloperidol (5–20 mg/day) placebo
of patients in the haloperidol group who needed at least one administration of benztropine was almost three times higher than the placebo group, whereas the percentage of aripiprazole-treated patients who required benztropine was comparable to placebo. The incidence of hyperprolactinaemia with aripiprazole was not significantly different from placebo, whereas haloperidol produced a significant increase in mean serum prolactin level compared with placebo ( Pb0.001). Clinically significant weight gain (defined as z7% increase from baseline) occurred in 6% of patients receiving aripiprazole and in 10% of those receiving haloperidol. Three patients in the haloperidol group and one patient in the placebo group experienced a clinically significant increase in QTc interval (defined as a QTcz450 ms and a z10% increase from baseline), whereas in the aripiprazole group there was no evidence of significant QTc prolongation. Another short-term study (4 weeks’ duration) compared the efficacy of aripiprazole (20 and 30 mg/day) with risperidone (6 mg/day) and placebo in 404 patients with acute exacerbation of schizophrenia or schizoaffective disorder (Potkin et al., 2003). Both doses of aripiprazole produced significant improvements in the three primary efficacy measures (PANSS-total score, PANSS-positive score and CGI-S score) compared with placebo. The
aripiprazole treatment was well tolerated in all three groups akathisia, somnolence and EPS more common in haloperidol group than either the aripiprazole or placebo groups haloperidol and risperidone produced clinically significant increases in plasma prolactin levels, aripiprazole produced a decrease in plasma prolactin levels aripiprazole comparable to placebo in mean changes in QTc
risperidone group also showed significantly greater improvement in all primary efficacy measures. Overall, both doses of aripiprazole were well tolerated with most adverse events being mild-to-moderate in intensity. The number of subjects with treatment-related side effects was similar in all four groups. In the aripiprazole groups headache, nausea, vomiting and somnolence mainly occurred in the first week of treatment. EPS-related adverse events were comparable in the aripiprazole and risperidone groups. The incidence of clinically relevant weight gain (defined as z7% increase from baseline) was significantly higher than with placebo for both active treatments (placebo 2%, aripiprazole 20 mg 13%, aripiprazole 30 mg 9%, risperidone 6 mg 11%). Mean prolactin levels decreased with aripiprazole but significantly increased with risperidone. Mean change in QTc interval did not differ significantly from placebo with either active treatment. Results from individual prospective clinical trials suggest that aripiprazole is at least as effective as current antipsychotic agents in the short-term management of acute exacerbation of schizophrenia, with an equally rapid onset of action. These findings are supported by a meta-analysis of pooled efficacy data from the short-term placebocontrolled trials involving 1545 patients hospitalized with
1216
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
2.2. Long-term studies
Fig. 1. Percentage of patients on treatment and still responding following 8, 26 and 52 weeks’ treatment with aripiprazole or haloperidol (Reprinted with permission from Fig. 2 of Kasper et al., 2003. Copyright 2003. International Journal of Neuropsychopharmacology.).
acute schizophrenic relapse (Lieberman et al., 2002). The data confirm that aripiprazole shows statistically superior antipsychotic efficacy to placebo. Significant improvements in positive and negative symptoms are seen 1 week after starting treatment with aripiprazole, without concomitant sedation. An 8-week, open-label, randomised study investigated the efficacy, safety and tolerability of three different strategies for switching stable outpatients from prior antipsychotic monotherapy to 30 mg/day aripiprazole (Casey et al., 2003). Patients in all three treatment groups showed consistent, progressive improvement in PANSS total, positive and negative score assessments following the switch to aripiprazole. Comparably, CGI-S and CGI-I scores showed a similar improvement in scores following the switch to aripiprazole in all three groups over the duration of the study.
A study of the long-term efficacy and safety of aripiprazole for maintenance treatment in patients experiencing acute schizophrenic relapse suggests that the benefits seen with acute administration are sustained over the long term (Kujawa et al., 2002). Involving 1294 patients with acute schizophrenic relapse, this trial compared the efficacy and safety of aripiprazole (30 mg/day) with haloperidol (10 mg/day) over a 52-week treatment period. Significantly more patients (40% vs. 27%, Pb0.001) met the response criteria (30% improvement in PANSS) when treated with aripiprazole than with haloperidol and importantly remained on therapy for the duration of the study (Fig. 1). Compared with haloperidol, aripiprazole was also significantly more effective in treatment of negative and depressive symptoms (Table 2). Consistent with the short-term studies, long-term administration of aripiprazole was much better tolerated than haloperidol, with a significantly lower incidence of EPSrelated adverse effects and hyperprolactinaemia. This was reflected in a lower rate of discontinuations due to adverse effects and contributed to greater compliance with long-term treatment (Fig. 2). A 26-week placebo-controlled trial in which aripiprazole 15 mg/day was administered to patients with stable chronic disease has shown that while aripiprazole was significantly more effective in preventing relapse (34% vs. 57%), there was no difference between treatments with respect to the overall incidence of adverse events (Pigott et al., 2003). The frequency of EPS-related adverse effects (including akathisia) and weight change were similar for aripiprazole and placebo and neither caused hyperprolactinaemia or QTc prolongation. These data indicate that aripiprazole is markedly superior to haloperidol during long-term maintenance therapy, due to an improved safety and tolerability profile. The neuropsychological effects of aripiprazole and olanzapine were compared in an open-label trial in 255
Table 2 Long-term studies and meta-analyses in patients with schizophrenia or schizoaffective disorder Reference
Duration (weeks)
n
Treatment
Efficacy
Safety
Kujawa et al., 2002
52
1294
aripiprazole (30 mg/day), haloperidol (10 mg/day)
Pigott et al., 2003
26
310
aripiprazole (15 mg/day) placebo
more patients responded successfully when treated with aripiprazole than with haloperidol aripiprazole more effective in preventing relapse
Kern et al., 2002
26
255
aripiprazole (30 mg/day), olanzapine (15 mg/day)
significant improvement in secondary verbal memory with aripiprazole but not with olanzapine
Jody et al., 2002
26–52
1549
aripiprazole (range of doses), haloperidol, olanzapine
not measured in this meta-analysis
Stock et al., 2002
26–52
1549
aripiprazole (range of doses), haloperidol, olanzapine
not measured in this meta-analysis
haloperidol was not tolerated as well as aripiprazole (higher incidence of EPS and hyperprolactinaemia) aripiprazole comparable to placebo with respect to overall incidence of adverse events aripiprazole associated with reduction in cholesterol levels and with lower incidence of weight gain than olanzapine aripiprazole associated with minimal weight gain comparable to haloperidol but less than olanzapine no evidence of QTc prolongation with aripiprazole treatment
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
1217
Fig. 2. Rates of premature discontinuation due to adverse effects following long-term treatment with aripiprazole or haloperidol (Reprinted with permission from Fig. 4 of Kasper et al., 2003. Copyright 2003. International Journal of Neuropsychopharmacology.).
patients with chronic stable schizophrenia (Kern et al., 2002). Cognitive data were reduced to three factors: general cognitive functioning, secondary verbal memory and executive functioning. At 8 weeks, the general cognitive factor improved significantly in patients in both treatment arms. Significant within-group improvements in secondary verbal memory were seen with aripiprazole at weeks 8 and 26 ( Pb0.001), but not with olanzapine. No psychopathological data were reported in this study. Regarding tolerability, aripiprazole was associated with a lower incidence of significant weight gain (i.e. a greater than 7% increase from baseline) than olanzapine (7% vs. 27%). A significant reduction in cholesterol levels was seen with aripiprazole compared with olanzapine.
3. Meta-analyses safety data Individual studies suggest aripiprazole has a favourable side effect profile. In common with other atypical agents it has a low propensity to induce EPS but also appears devoid of the metabolic and cardiac side effects seen with other atypical agents. Meta-analyses of pooled safety data from patients with schizophrenia or schizoaffective disorder have looked specifically at its effects on weight, plasma prolactin levels and cardiac function (Table 2). Pooled data from the five short-term studies showed that headache, insomnia, agitation and anxiety were the most commonly reported events in all three treatment groups (2– 30 mg/day aripiprazole [n=932], placebo [n=416] or 5–20 mg/day haloperidol [n=201]). The majority of adverse events occurred with similar frequency in the three treatments groups, with the exception of akathisia, somnolence
and EPS, which were more common in the haloperidol group than either the aripiprazole or placebo groups (Marder et al., 2003). The short-term effects of aripiprazole on weight gain were assessed in five 4–6-week double-blind studies in 1648 patients randomized to aripiprazole, placebo or active control (haloperidol 10 mg/day or risperidone 6 mg/day). Long-term effects on weight gain were evaluated in a 52-week haloperidol-controlled study (n=1294) and a 26-week open-label olanzapine-controlled study (n=255) (Jody et al., 2002). Aripiprazole was associated with minimal weight gain comparable to haloperidol but less than olanzapine. In the olanzapine-controlled study, patients treated with aripiprazole experienced weight loss over time, whereas patients treated with olanzapine showed significant increases in weight. Several antipsychotic agents cause elevations in prolactin which can lead to troublesome side effects such as amenorrhea, impotence and gynaecomastia. Pooled safety data from short-term studies on 1648 patients showed that both haloperidol and risperidone produced clinically significant increases in plasma prolactin (125% and 607% above baseline, respectively) (Carson et al., 2002). As expected based on its partial agonist profile aripiprazole produced a 50% decrease from baseline in plasma prolactin levels. Adverse cardiac effects, reflected by prolongation of the QT interval, are known to occur with several antipsychotic agents. Based on pooled safety data from 1648 patients, short-term treatment with aripiprazole across all doses was found comparable to placebo in mean changes in QTc, irrespective of gender or race (Stock et al., 2002). Similarly, pooled safety data on 1549 patients receiving long-term antipsychotic therapy showed no evidence of QTc prolongation following treatment with aripiprazole for 52 weeks.
1218
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219
4. Conclusions: aripiprazole’s potential for improved patient care Treatment of schizophrenia today is designed not only to reduce the disabling psychotic symptoms of the illness but also to help patients lead fulfilling lives. As discussed in a previous review, QoL is of great importance to patients with schizophrenia, and with the availability of newer atypical agents, is becoming an important criterion on which to judge the success of treatment (Naber and Karow, 2001). The advent of atypical antipsychotic agents has certainly helped to bridge treatment gaps, especially with respect to the amelioration of negative symptoms of schizophrenia and reducing the frequency of adverse motor symptoms. However, as the burden of EPS has been reduced, the focus has shifted to other side effects and especially to metabolic complications such as weight gain, heart disease and hyperprolactinaemia. It is therefore apparent that, despite the recent advances, further improvements in tolerability and compliance are still needed. While the aripiprazole studies carried out to date have not specifically evaluated QoL issues in patients with schizophrenia, they suggest that its favourable side effect profile will result in better compliance with treatment, a reduced likelihood of relapse and a better overall prognosis. Results from a recent US multicentre study, in which 1599 patients with schizophrenia were treated in a general psychiatric practice setting in naturalistic conditions, showed that over 50% of patients and 41% of caregivers rated aripiprazole as much better than prior antipsychotic treatment (Tandon et al., 2003). Expectations for aripiprazole are high based on currently available clinical data (some of which are published as abstracts only). It remains to be seen whether the positive results observed with aripiprazole in selected patients involved in clinical trials will be replicated in everyday practice. Only time will tell as to what extent the promising results will translate into benefits for patients.
References Allison, D.B., Mentore, J.L., Moonseong, H., Chandler, L.P., Cappelleri, J.C., Infante, M.C., Weiden, P.J., 1999. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am. J. Psychiatry 156, 1686 – 1696. American Psychiatric Association, 2003. Practice guideline for the treatment of patients with schizophrenia: III. Treatment principles and alternatives (http://www.psych.org/clin_res/pg_schizo_3.cfm). Burris, K.D., Molski, T.F., Xu, C., Ryan, E., Tottori, K., Kikuchi, T., Yocca, F.D., Molinoff, P.B., 2002. Aripiprazole, a novel antipsychotic, is a highaffinity partial agonist at human dopamine D2 receptors. J. Pharmacol. Exp. Ther. 302, 381 – 389. Carson, W.H., Saha, A.R., Iwamoto, T., Lin, C., Kujawa, M.J., 2002. Metaanalysis of prolactin effects with aripiprazole. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186.
Casey, D.E., et al.on behalf of the Aripiprazole Study Group, 2003. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology 166, 391 – 399. Collaborative Working Group on Clinical Trial Evaluations, 1998. Adverse effects of the atypical antipsychotics. J. Clin. Psychiatry 59 (Suppl. 12), 17 – 22. Fenton, W.S., Blyler, C.R., Heinssen, R.K., 1997. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr. Bull. 23, 637 – 651. Jibson, M.D., Tandon, R., 1998. New atypical antipsychotic medications. J. Psychiatr. Res. 32, 215 – 228. Jody, D., Saha, A.R., Iwamoto, T., Biswas, D., Lin, C., Marcus, R., McQuade, R.D., 2002. Meta-analysis of weight effects with aripiprazole. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186. Jordan, S., Koprivica, V., Chen, R., Tottori, K., Kikuchi, T., Altar, C.A., 2002. The antipsychotic aripiprazole is a potent, partial agonist at the human 5-HT1A receptor. Eur. J. Pharmacol. 441, 137 – 140. Kane, J.M., Carson, W.H., Saha, A.R., McQuade, R.D., Ingenito, G.G., Zimbroff, D.L., Ali, M.W., 2002. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J. Clin. Psychiatry 63, 763 – 771. Kasper, S., Lerman, M.N., McQuade, R.D., Saha, A., Carson, W.H., Ali, M., Archibald, D., Ingenito, G., Marcus, R., Pigott, T., 2003. Efficacy and safety of aripiprazole vs. haloperidol for long-term maintenance treatment following acute relapse of schizophrenia. Int. J. Neuropsychopharmacol. 6, 325 – 337. Kern, R.S., Cornblatt, B., Carson, W.H., Stock, E., Saha, A.R., Ali, M.W., Ingenito, G., Green, M.F., 2002. Neurocognitive effects: aripiprazole vs olanzapine in stable psychosis. Eur. Psychiatr. 17 (Suppl. 1), 104s. Kikuchi, T., Burris, K.D., Jordan, S., McQuade, R.D., 2002. Aripiprazole: a dopamine–serotonin system stabilizer. Eur. Psychiatr. 17 (Suppl. 1), 103s. Kujawa, M., Saha, A., Ingenito, G.G., Ali, M., Luo, X., Archibald, D.G., Carson, W.H., 2002. Aripiprazole for long-term maintenance treatment of schizophrenia. Poster presented at American Psychiatric Association 155th annual meeting, May 2002, Philadelphia, PA, USA, . Leysen, J.E., Janssen, P.M.F., Heylen, L., Gommeren, W., Gompel, P.V., Lesage, A.S., Megens, A.A.H.P., Schotte, Alain, 1998. Receptor interactions of new antipsychotics: relation to pharmacodynamic and clinical effects. Int. J. Psychiatry Clin. Pract. 2 (Suppl. 1), S3 – S17. Lieberman, J., Carson, W.H., Saha, A.R., Stringfellow, J.C., Archibald, D.G., Kujawa, M.J., Iwamoto, T., 2002. Meta-analysis of the efficacy of aripiprazole in schizophrenia. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186. Marder, S.R., McQuade, R.D., Stock, E., Kaplita, S., Marcus, R., Safferman, A.Z., Saha, A., Ali, M., Iwamoto, T., 2003. Aripiprazole in the treatment of schizophrenia: safety and tolerability in short-term, placebo-controlled trials. Schizophr. Res. 61, 123 – 126. Naber, D., Karow, A., 2001. Good tolerability equals good results: the patient’s perspective. Eur. Neuropsychopharmacol. 11 (Suppl. 4), S391 – S396. Naber, D., Gaussares, C., Moeglen, J.M., Tremmel, L., P.E., Bailey, SDZ HDC 912 Collaborative Study Group, 1992. Efficacy and tolerability of SDZ HDC 912, a partial dopamine D2 agonist, in the treatment of schizophrenia. In: Meltzer, H.Y. (Ed.), Novel Antipsychotic Drugs. Raven Press, New York, pp. 99 – 107. Naber, D., Moritz, S., Lambert, M., Pajonk, F., Holzbach, R., Mass, R., Andresen, B., 2001. Improvement of schizophrenic patients’ subjective well-being under atypical antipsychotic drugs. Schizophr. Res. 50, 79 – 88. Naber, D., Karow, A., Lambert, M., 2002. Psychosocial outcomes in patients with schizophrenia: quality of life and reintegration. Curr. Opin. Psychiatry 15, 31 – 36. Pigott, T.A., et al.for the Aripiprazole Study Group, 2003. Aripiprazole for the prevention of relapse in stabilized patients with chronic schizo-
D. Naber, M. Lambert / Progress in Neuro-Psychopharmacology & Biological Psychiatry 28 (2004) 1213–1219 phrenia: a placebo-controlled 26-week study. J. Clin. Psychiatry 64, 1048 – 1056. Potkin, S.G., Saha, A.R., Kujawa, M.J., Carson, W.H., Ali, M., Stock, E., Stringfellow, J., Ingenito, G., Marder, S.R., 2003. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch. Gen. Psychiatry 60, 681 – 690. Stahl, S.M., 2001. Dopamine system stabilizers, aripiprazole, and the next generation of antipsychotics: Part 1. dGoldilocksT actions at dopamine receptors. J. Clin. Psychiatry 62, 841 – 842.
1219
Stock, E., Saha, A., Brunell, R., Archibald, D.G., Iwamoto, T., McQuade, R.D., 2002. Meta-analysis of cardiac safety with aripiprazole. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), S186. Tandon, R., Stock, E.G., Kujawa, M.J., Torbeyns, A.F., Borian, F.B., Reira, L., McQuade, R.D., 2003. Broad effectiveness trial with aripiprazole. Poster presented at the 55th Institute on Psychiatric Services, October– November 2003, Boston, MA, USA. Woods, S.W., 2003. Chlorpromazine equivalent doses for the newer atypical antipsychotics. J. Clin. Psychiatry 64, 663 – 667.