Aripiprazole in the Treatment of Schizophrenia

Giovan B. Cassano; Andrea Fagiolini; Lorenzo Lattanzi; Palmiero Monteleone; Cinzia Niolu; Emilio Sacchetti; Alberto Siracusano; Antonio Vita

Disclosures

Clin Drug Invest. 2007;27(1):1-13.

Clinical Profile of Aripiprazole as Reflected by Clinical Trial Data

Aripiprazole, which is administered once daily, has a linear pharmacokinetic profile at all doses between 5 and 30 mg/day.^[28] Rapid absorption (maximum plasma concentrations occurring within 3-5 hours of dosing) and a relatively long half-life (47-68 hours) mean that aripiprazole accumulates with multiple-dose administration, with steady-state plasma concentrations occurring by day 14.^[28]

In clinical trials involving patients with acute relapse of chronic schizophrenia, significant reductions from baseline in the mean Positive and Negative Syndrome Scale (PANSS) total score, which were comparable to those seen with haloperidol or risperidone, were observed with aripiprazole,^[29,30] and efficacy was maintained long term.^[31] Aripiprazole was also associated with improvements in PANSS positive and negative symptom subscale scores in patients experiencing acute psychotic relapse.^[29,30] In addition to prevention of relapse,^[31] cognitive benefits have been observed with aripiprazole in stable patients.^[32] Consistent with published trial results, a recent Cochrane review of clinical data noted that aripiprazole has comparable antipsychotic efficacy to conventional and other atypical antipsychotics for the treatment of schizophrenia.^[33]

Aripiprazole was safe and well tolerated in short- and long-term clinical trials,^{[29,30,31,32,34,35]} and it has been accepted that, in comparison with conventional antipsychotics, aripiprazole is associated with a relatively low risk of akathisia, and that, unlike some other atypical antipsychotics, aripiprazole does not stimulate excessive production of prolactin.^[33] Minimal weight gain with aripiprazole compared with olanzapine has also been commented upon, as has the absence of any QTc prolongation associated with aripiprazole.^[33]

The efficacy of aripiprazole has been evaluated in patients with acute exacerbation of schizophrenia in a series of short and longer term trials.^{[29,30,31,32,34,36]}

Short-Term Trials. Short-term studies in patients with acute exacerbation of schizophrenia have shown that, compared with placebo, aripiprazole 10-30 mg/day is effective for the treatment of both positive and negative symptoms.^[29,30,36] Fixed doses of aripiprazole were administered throughout the 4- to 6-week studies. Compared with placebo, improvements in symptoms of schizophrenia were evident as early as 1 week of treatment with aripiprazole. By the end of the trials, treatment with aripiprazole resulted in improvements on the PANSS positive subscale score (p < 0.001 vs placebo), and there was a significant improvement on the negative subscale score (p < 0.01 vs placebo). Although formal comparisons between aripiprazole and risperidone 6 mg/day^[30] or haloperidol 10 mg/day^[29] treatment groups were not performed in these trials, efficacy findings appeared to be comparable between treatment groups. Additional analyses using pooled data from 4- or 6-week trials revealed that, relative to placebo, patients receiving aripiprazole experienced significant reductions in symptoms of depression and anxiety,^[37] and in symptoms of hostility and excitability.^[38]

Unlike haloperidol, there were no significant differences between aripiprazole and placebo in mean change from baseline in EPS rating scales.^[29,30] Mean prolactin levels increased with haloperidol and risperidone, but not with aripiprazole. Mean change in QTc interval did not differ significantly from placebo with any active treatment group, and there were similarly low incidences of clinically significant weight gain.

The most frequently reported adverse events collected in a pooled analysis of safety and tolerability data from short-term placebo-controlled trials of aripiprazole included headache, nausea, vomiting, lightheadedness, akathisia, insomnia and somnolence.^[35] These adverse effects occurred with an incidence of ≥10% and their incidence was from about 3% to 7% higher than with placebo, but were generally transient and of mild or moderate severity. Discontinuations because of adverse events occurred at a similar rate to placebo. The only treatment-emergent adverse event for which a dose-response relationship may exist for aripiprazole is somnolence.^[35]

Long-Term Treatment. Pooled analysis of two similarly designed 52-week trials has shown aripiprazole to be an effective maintenance treatment for patients undergoing an acute psychotic episode who had previously responded to antipsychotic medications.^[31] Patients were randomised to receive aripiprazole 30 mg/day or haloperidol 10 mg/day, although the trial protocol allowed a one-time dose reduction to aripiprazole 20 mg/day or haloperidol 7 mg/day after the first week of treatment. The primary efficacy endpoint was time to failure to maintain response in responders, with response defined as a 20% reduction in PANSS total score, provided that patients did not have a Clinical Global Impression-Improvement (CGI-I) score of 6 or 7, worsening schizophrenia, or score of 5, 6 or 7 on one of four items of the PANSS psychotic subscale. No statistically significant difference was observed between aripiprazole and haloperidol in mean time to relapse; similarly high proportions of responders in the aripiprazole and haloperidol treatment groups maintained a response at week 52 (77% and 73%, respectively). Aripiprazole exhibited comparable efficacy to haloperidol in improving psychotic symptoms (PANSS total score) and long-term superiority to haloperidol in terms of improving negative and depressive symptoms of schizophrenia, as measured by the PANSS negative subscale score and Montgomery-Åsberg depression rating scale (MADRS) [p < 0.05 vs haloperidol]. In a path analysis model, reductions in PANSS negative symptom scores were attributable to a direct effect of aripiprazole on negative symptoms rather than a consequence of changes in positive or depressive symptoms or EPS.^[39] When compared with haloperidol in a post hoc analysis, aripiprazole was associated with similar improvements in PANSS excitement/hostility cluster symptom scores.^[38] Aripiprazole was associated with significantly lower scores on all EPS assessments than haloperidol, and significantly fewer haloperidol recipients completed the trial compared with aripiprazole recipients.^[31] This difference in completion rates was attributed to a significantly lower rate of discontinuation because of adverse events in the aripiprazole treatment arm. In general, the long-term tolerability profile of aripiprazole was consistent with its profile in short-term trials.

Weight and lipid profile changes were the focus of a 26-week randomised double-blind study comparing aripiprazole 15-30 mg/day with olanzapine 10-20 mg/day in patients with acute relapse of schizophrenia.^[40] Significantly smaller proportions of patients in the aripiprazole treatment group exhibited clinically significant weight gain (≥7%) and new dyslipidaemias than in the olanzapine group. Both drugs reduced plasma prolactin levels from those seen at baseline, which were probably elevated as a result of prior antipsychotic treatment. Clinically robust improvements in antipsychotic symptoms were observed in both treatment groups.

Studies have been conducted with aripiprazole in stable patients with chronic schizophrenia.^[32,34] One of these studies evaluated the utility of aripiprazole for prevention of relapse.^[34] The other study investigated the effects of aripiprazole on neurocognitive parameters.^[32]

Relapse Prevention. Aripiprazole 15 mg/day was superior to placebo in preventing relapse in stabilised patients with chronic schizophrenia.^[34] Relapse was defined as a CGI-I score of ≥5, a score of ≥5 on the PANSS hostility or uncooperativeness subscales on two successive days, or a ≥20% increase in the PANSS total score. Compared with patients randomised to placebo, patients treated with aripiprazole took significantly longer to relapse, and a significantly higher proportion of aripiprazole recipients had not experienced a relapse by the end of the 26-week study. There was no evidence of marked sedation, hyperprolactinaemia or prolonged QTc interval in this study. EPS were comparable in the aripiprazole and placebo groups. Modest mean weight loss and a similarly low rate of clinically significant weight gain was evident in both groups. Aripiprazole was not associated with negative effects on glucose or lipid levels. Spontaneously reported adverse events occurring at a ≥5% incidence with aripiprazole included insomnia, tremor, akathisia, vomiting and nausea. These events occurred with an approximate 1-7% greater incidence in the aripiprazole group than in the placebo group.

Neurocognitive Effects. The neurocognitive effects of aripiprazole 30 mg/day have been reported to be at least as favourable as those of olanzapine 15 mg/day in a randomised open-label trial involving patients with stable schizophrenia or schizoaffective disorder.^[32] Patients in this study were given a series of neurocognitive tests at baseline and at weeks 8 and 26 of treatment. Verbal learning, which was assessed using the California Verbal Learning Test, improved significantly in the aripiprazole treatment group from baseline at week 8 and week 26 (p < 0.0001). There was a between-group effect favouring aripiprazole over olanzapine that was largely attributable to differences occurring at week 8 (p < 0.05). General cognitive function improved from baseline at week 8 in both treatment groups (p < 0.05), but there were no changes from baseline in executive function.

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Cite this: Aripiprazole in the Treatment of Schizophrenia - Medscape - Jan 01, 2007.

Abstract and Introduction
Clinical Profile of Aripiprazole as Reflected by Clinical Trial Data
Use of Aripiprazole in the Treatment of Schizophrenia: Consensus Report
Conclusion
References

Receptor Binding Profile of Aripiprazole and Reference Antipsychotics ^a
Receptor	Aripiprazole	Olanzapine	Risperidone	Quetiapine	Ziprasidone	Clozapine	Haloperidol
D₁	265^b	31	430	455	525	85	210
D₂	0.34^b	11	4	160	5	126	0.7
D₃	0.8^b	49	10	340	7	473	2
D₄	44^b	27	9	1600	32	35	3
5-HT_1A	1.7^b	>10,000	210	2800	3	875	1100
5-HT_2A	3.4^b	4	0.5	295	0.4	16	45
5-HT_2C	15^b	23	25	1500	1	16	>10,000
a₁	57	19	0.7	7	11	7	6
H₁	61^b	7	15	11	50	6	440
M₁	>10,000	1.9	>10,000	120	>1000	1.9	>1500

^aData are expressed as K_i (nmol/L).
^bData refer to cloned human receptors.

Suggestions for the Management of Concomitant Symptoms and Adverse Effects in Patients With Schizophrenia Treated With Aripiprazole
Symptom	Management
Agitation	Benzodiazepines (lorazepam) or Anticholinergic drugs^a or Antihistaminic drugs^a (e.g. diphenhydramine) or Valproic acid or Gabapentin
Nausea	Administer aripiprazole with a meal or Reduce aripiprazole dose or Add an antiemetic (only if above measures fail)
Insomnia	Add an hypnotic agent during the first days of treatment Administer aripiprazole in the morning Divide dose of aripiprazole into two daily half doses (am and pm)
Akathisia	Reduce dose or Benzodiazepines or β-Adrenoceptor antagonist (propranolol) or Gabapentin or Anticholinergic agent

^aConsider previous antipsychotic withdrawal after switching antipsychotic agents and use antihistaminic or anticholinergic drug as appropriate.

Guide to Aripiprazole Dosage and Administration in the Management of the Acute Episode of Schizophrenia in Different Patient Groups ^a
Treatment Setting	Dosage	Dosage Review
Acute Episode in Treatment-naive (First Psychotic Episode) or Drug-free (Previous Treatment) Patients - Agitated^b
Inpatient	Starting dose 15 mg/day	From day 2: dose may be increased up to 30 mg/day if necessary The dose may be reduced to 10 mg/day if tolerability problems arise (also see table II for management of adverse effects)
Outpatient	Starting dose 10-15 mg/day	After 2 weeks: dose may be increased up to 30 mg/day if necessary Dose may be reduced to 10 mg/day if tolerability problems arise (also see table II for management of adverse effects)
Acute Episode in Treatment-naive (First Psychotic Episode) or Drug-free (Previous Treatment) Patients -- Non-agitated
Hospital/Outpatient	Starting dose 10-15 mg/day	Dose may be reduced to 10 mg/day if tolerability problems arise (also see table II for management of adverse effects)
Outpatient (Drug Sensitive)	Patients may need to start with 5 mg/day for 1-2 weeks	After 2 weeks: dose may be increased to 10-15 mg/day according to clinical judgement
Low/non-compliance with Previous Medication - Agitated^a
Hospital	Starting dose 15 mg/day	From day 2: dose may be increased up to 30 mg/day (maximum) if necessary
Outpatient	Starting dose 15 mg/day	After 2 weeks: dose may be increased up to 30 mg/day (maximum) if necessary Dose may be reduced to 10 mg/day if tolerability problems arise (also see table II for management of adverse effects)
Low/non-compliance with Previous Medication - Non-agitated
Hospital/Outpatient	Starting dose 10 mg/day	After 2 weeks: dose may be increased to 15 mg/day if necessary; if therapeutic response is insufficient consider increasing to 30 mg/day after a further 2 weeks Dose may be reduced to 10 mg/day if tolerability problems arise (also see table II for management of adverse effects)

^aTreatment-naive (first psychotic episode) or drug-free (previous treatment) patients may respond to lower doses and be more sensitive to side effects. In these patients, as well as in outpatients with a history of high sensitivity to side effects and/or low complicance, a starting dose of 10mg (or sometimes even 5mg) is usually preferred. Adjunctive agents such as benzodiazepines or antihistaminic agents may be added in the first period of treatment to help control anxiety, agitation, insomnia and hostility.
^bBenzodiazepine or antihistaminic or anticholinergic drug may be added to control anxiety, agitation and hostility.

Strategies for Switching From Another Antipsychotic Agent to Aripiprazole in the Outpatient Setting ^a
Time	Aripiprazole Dose	Previous Medication Dose	Aripiprazole Dosage Variation
Starting Dose	10-15 mg/day	Maintain dose
End Week 2	10-15 mg/day	Reduce by about 50%	Dose may be reduced to 10 mg/day if tolerability problems arise (also see table II for management of adverse effects)
End Week 4	10-30 mg/day	Reduce by about 50%	15 mg/day is the maintenance dose; very few patients may need to increase to 30 mg/day; dose may be reduced to 10 mg/day if tolerability problems arise (also see Table 2 for management of adverse effects)

^aBenzodiazepine or antihistaminic or anticholinergic drugs may be added to aripiprazole in order to control rebound effects due to the discontinuation of medications with high antihistaminic or anticholinergic properties.

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