Aripiprazole in the Treatment of Schizophrenia

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


Clin Drug Invest. 2007;27(1):1-13. 

In This Article

Use of Aripiprazole in the Treatment of Schizophrenia: Consensus Report

The advantageous benefit/risk profile of atypical antipsychotic agents over conventional agents is reflected in recommendations that atypical agents be used not only as first-line treatment of schizophrenia in general, but also for patients experiencing unacceptable adverse events (mainly EPS with conventional agents), patients in relapse who have previously experienced unsatisfactory symptom management and patients who have experienced safety issues with other agents.[41,42]Aripiprazole was licensed for use in the EU in June 2004. Because of the favourable efficacy and adverse-effect profile of aripiprazole, aripiprazole is well positioned among the first choice medications for schizophrenia and may be a particularly appealing choice for patients with first onset of psychosis or patients who have experienced problems with side effects while receiving other antipsychotic medications.[27] Aripiprazole has a convenient once-daily administration schedule, and can be taken with or without food.[43] Notably, preference of medicine ratings from the US BETA (Broad Effectiveness Trial with Aripiprazole), an 8-week clinical trial of the effectiveness of aripiprazole conducted in an outpatient setting, showed that 64% of patients and 55% of caregivers assigned aripiprazole the highest preference of medicine questionnaire rating of much better than their previous medication.[44] In the BETA trial, >1200 outpatients with schizophrenia or schizoaffective disorder were switched from their previous antipsychotic medication to aripiprazole because of suboptimal efficacy and/or inability to tolerate adverse effects. Another group of patients (n = 302) were switched to an antipsychotic medication other than aripiprazole (olanzapine, risperidone, quetiapine or ziprasidone); only 34% of patients and 19% of caregivers in this group considered they had switched to a much better than previous medication.

The recommendations contained in the current consensus report are based on the clinical experience acquired with aripiprazole in real practice settings by experts in the treatment of schizophrenia. The main objective of these guidelines is to provide simple and clear indications for the use of aripiprazole in the treatment of schizophrenia. Two distinct treatment phases are considered: treatment of the acute episode and long-term maintenance treatment for the prevention of relapse. It must be stressed that the optimal dosage of aripiprazole depends on the characteristics of each patient, on the presenting symptoms and on treatment settings. Factors such as age, previous treatment, drug sensitivity, family history, co-morbidities and concomitant treatments must all be considered. Dosage adjustments are not routinely indicated on the basis of age, sex, race or renal or hepatic impairment, but the normal aripiprazole dose should be reduced by at least one-half when potential cytochrome P450 enzyme (CYP) 3A4 inhibitors, such as ketoconazole, or potential CYP2D6 inducers, such as fluoxetine or paroxetine, are co-administered.[43] When a poteniential CYP3A4 inducer, such as carbamazepine, is added to therapy with aripiprazole, the aripiprazole dose should be increased (doubled in the specific case of carbamazepine).[43] The management of concomitant symptoms and adverse effects in aripiprazole-treated schizophrenia is documented in Table 2 and applies to all patient groups discussed below. Our recommendations are similar to those of recent UK consensus guidelines,[27] and also reflect practices reported in the BETA trial.[44]

Active psychosis adversely affects a patient's functional status and quality of life, and the associated behaviours can be dangerous to the safety of self and others. The objectives of treatment of an acute episode are rapid relief from positive psychotic symptoms and agitation, followed by stabilisation and preparation of the patient for long-term maintenance therapy. Prompt intervention in the patient with acute symptoms is very important, since a delay in initiating drug treatment results in a worse long-term outcome.[42,45,46,47] Another important point in this context is that the treatment of schizophrenia is a lifelong process. Any schizophrenia therapy should be designed, where possible, right from the start to take the long-term maintenance phase into account.[42] We stress the importance of developing a therapeutic alliance by engaging the patient and his/her family in a collaborative treatment relationship. It is important that there are no gaps in service delivery as patients are vulnerable to relapse after discharge and need support while adapting to life in the community.

Patients experiencing a first episode of schizophrenia are likely to be more sensitive to the adverse events of treatment, which may subsequently impact upon future adherence to therapy and long-term prognosis.[41] In agreement with the UK consensus group,[27] we feel that the favourable, easily manageable safety and tolerability profile of aripiprazole may prove to be particularly beneficial in these patients.

In Italy, aripiprazole is available in 5mg, 10mg and 15mg dosage strengths. The manufacturer recommends an initial dosage of 10-15 mg/day and a target dosage of 15 mg/day.[43] In clinical trials, aripiprazole has been shown to be effective in a dose range of 10-30 mg/day,[43] and, although higher doses than the recommended 10-15 mg/day target dose have not necessarily exhibited greater efficacy in dose-ranging studies, some patients may need to titrate up from the 15 mg/day dose.

Control of agitation at the beginning of treatment of any acute episode is extremely important. Because aripiprazole is not a sedating drug and has low affinity for histaminic and muscarinic receptors, patients treated with aripiprazole may need to be treated with sedating medication to control anxiety or agitation. It is recommended that a benzodiazepine or a drug with antihistaminic or anticholinergic properties, such as hydroxyzine, niaprazine, diphenhydramine or chlorpromazine (in the case of treatment-resistant patients for whom the use of two neuroleptic agents may be indicated), be added to aripiprazole therapy. It is also suggested that aripiprazole 30 mg/day, which may have more of a sedating effect than lower doses, be considered for most acute episode inpatients. Treatment with aripiprazole may be commenced in either the hospital or outpatient setting, with a slower progression to maximum dosage recommended for outpatients. As for other antipsychotic drugs, outpatients starting aripiprazole treatment should be monitored regularly with phone calls or other contact with caregivers for the first 2 to 3 weeks of treatment. Table 3 outlines proposed aripiprazole dosage and administration schedules that have been, in our experience, effective in the management of the acute episode in schizophrenia patients.

Treatment-Naive and Drug-Free Patients. As the treatment-naive patient is generally experiencing a psychotic episode for the first time, prompt intervention is essential to reduce the severity of the acute episode; however, it is equally important to ensure the diagnosis of schizophrenia is correct. In general, once the diagnosis of schizophrenia has been confirmed, if aripiprazole is the chosen first-line treatment, first-episode patients should be treated with a 10-15 mg/day starting dose, but in drug-sensitive patients, the recommended starting dose may be 5 mg/day for 1 or 2 weeks, after which the need to increase the dose to 10 or 15 mg/day should be assessed. Because aripiprazole does not appear to have significant sedative effects at recommended therapeutic doses, additional sedation may be required, particularly in the agitated patient. Benzo-diazepines (lorazepam) have been used extensively in this context.[48,49,50] Alternatively, drugs such as valproic acid and gabapentin have been used to control agitation.[51,52] In agitated, aggressive treatment-naive patients it is preferable to commence treatment in a hospital setting, if possible, with the subsequent dose adjustment performed in the outpatient setting as symptoms stabilise.

Occurrence of an acute episode in a patient who is currently drug-free, but has formerly been treated with an antipsychotic agent, may require an initial dose of 15 mg/day. If control of agitation is a major problem, the maximum dose of 30 mg/day, which may have some sedative effects,[35] can be achieved on day 2 in the hospital setting. If tolerability problems occur with high doses of aripiprazole, we recommend reducing the dose (from 30 mg/day to 15 mg/day or from 15 mg/day to 10 mg/day). In our experience, aripiprazole 30 mg/day is generally well tolerated and no significant differences in occurrence of adverse effects have been noted in the 10-30 mg/day range. As mentioned above, lorazepam can be used to help control agitation during the acute phase with good results;[48,49,50] alternatively, drugs such as valproic acid or gabapentin can be used.[51,52]

Low/Non-Compliant Patients. In a low/non-compliant patient who relapses during therapy with his or her currently prescribed antipsychotic, it is important to find out when the treatment was interrupted (how long the patient has been drug-free) and why the treatment was interrupted. Reasons for low/non-compliance may include residual or refractory symptoms and adverse effects of the treatment. In this group of patients, it is important to be aware of the use of a previous antipsychotic agent and its possible effects on the different neurotransmitter systems. Withdrawal symptoms are not uncommon if the previously administered drugs had strong antihistaminic or anticholinergic activity. Co-administration of sedative drugs (benzodiazepines) during relapse is therefore recommended.

Aripiprazole dosages for low/non-compliant patients are similar to those recommended for the drug-free agitated acute patient. If control of agitation is a problem, the maximum dose of 30 mg/day can be achieved on day 2 in the hospital setting. For safety reasons, in an outpatient setting, the acutely agitated, low/non-compliant patient may benefit from an initial aripiprazole dose of 15 mg/day, which may be more gradually increased to 30 mg/day according to the clinical response to treatment.

In non-agitated patients, an initial dose of 10 mg/day is recommended, with evaluation after 2 weeks to increase the dosage to 15 mg/day if required. If therapeutic response is insufficient, the dose may be increased up to 30 mg/day. If tolerability problems occur, it is recommended the dose be reduced to 10 mg/day.

To avoid relapse in the schizophrenic patient, it is important to continue antipsychotic treatment following stabilisation of the patient after an acute episode. However, even relatively stable patients receiving maintenance therapy with another anti-psychotic (typically a second-generation anti- psychotic agent) may need to switch to aripiprazole because of lack of efficacy or inherent adverse effects of their treatment. These may include EPS, weight gain, hyperglycaemia, hyperlipidaemia, cardiovascular conditions and serum prolactin increase. Additional reasons may include low compliance, an incomplete response to treatment or less than satisfying quality of life. Some of the main strengths of aripiprazole are its efficacy with regard to positive and negative symptoms, cognitive benefits and its favourable tolerability profile in terms of EPS, weight, lipid profiles and prolactin levels. In terms of safety, the favourable metabolic profile of aripiprazole could be viewed as an important factor in long-term treatment. Additionally, the lack of sedative effects at clinically effective (10 mg/day and 15 mg/day) doses may help to motivate patients to continue maintenance therapy with aripiprazole. When considering maintenance therapy, it is important to remember also that once the main symptoms, positive and negative, are under control, the patient greatly benefits from a combination of pharmacotherapy and psychosocial treatment. This strategy should help patients to make the most of the potential for improved social functioning facilitated by the broad-spectrum activity of aripiprazole.

Switch Strategy. Relapse may occur during therapy with any anti-psychotic agent as a consequence of lack of efficacy of medication or because of progression of the disease. If the relapse is the result of incorrect application of the therapy, the previous antipsychotic treatment should be adjusted and reassessed prior to switching medication. Likewise, the reasons for non-compliance should be understood before a change in treatment is made. Following confirmation that compliance with treatment was acceptable and that the previous treatment was administered correctly, a switch to another antipsychotic can be recommended.

When changing treatment regimens in a currently medicated patient, it is important to adopt a strategy that avoids possible rebound reactions resulting from the switch to an antipsychotic with a different receptor profile.[53]

Table 4 outlines our recommended strategy for switching to aripiprazole from another antipsychotic agent. Although there is more than one potentially safe switching strategy,[54] we suggest that, where possible, a cautious, gradual approach involving tapering of the original medication be employed. For safety reasons, we also recommend that agitated outpatients experiencing a relapse during adequate maintenance therapy with another agent be given a lower starting dose of aripiprazole than hospitalised patients (10 mg/day as opposed to 15 mg/day). Non-agitated hospitalised and ambulatory patients experiencing an acute episode may benefit from the same switch strategy described for agitated outpatients. Aripiprazole has markedly more reduced histaminic and cholinergic affinity than most other antipsychotics, and, if the switch is conducted too rapidly, withdrawal symptoms may be observed, especially if the previous antipsychotic had sedating antihistaminic or anticholinergic activity.[55] Such adverse events can be controlled by the administration of anticholinergic or antihistaminic drugs, but switching from agents with strong anticholinergic and/or antihistaminic activity needs to be done slowly, incorporating overlap of the prior medication with aripiprazole for 4-6 weeks so as to avoid inducing a withdrawal syndrome that can mimic re-emergence of psychosis or agitation, akathisia, anxiety or insomnia.[55]

Another reason for employing a gradual switch to aripiprazole is that it is conceivable that, because of its partial dopamine receptor agonism, aripiprazole may exert exaggerated dopamine agonistic activity if the first antipsychotic is withdrawn too quickly, leaving an environment of up-regulated dopamine receptors.[24]

Additionally, the long half-life of aripiprazole may require up to 7-10 days of treatment to achieve adequate antidopaminergic activity to compensate sufficiently for a rapid reduction in dopamine blockade when the first agent is withdrawn abruptly.[55] Agitation in the course of any antipsychotic treatment can be interpreted incorrectly as an indication that the drug is not effective. It is important to be aware that antipsychotic drugs generally reach steady-state after 1-2 weeks and that it is therefore advisable to monitor for and control any symptoms that may reflect exacerbation of schizophrenia over this period of time. Our preference for a conservative approach to switching patients to aripiprazole conforms with recommendations in the literature favouring a conservative approach with regard to switching strategies for antipsychotic agents in general.[56]

The switch strategy to aripiprazole takes a different approach to that described above when the patient is being switched from clozapine. Because clozapine is restricted to patients who are resistant to other treatments, a switch to another antipsychotic agent should be recommended only in those cases with serious adverse effects related to clozapine. Switching from clozapine to aripiprazole should be carried out very slowly. In some cases, the switch may take months to complete. Clinical experience with this situation is somewhat limited and we have found that it is difficult to eliminate clozapine completely. However, the dose can be reduced gradually to 50% of the maintenance dose without many problems, and a possible strategy for decreasing the adverse effects of clozapine while maintaining antipsychotic efficacy is to add aripiprazole to a maintenance regimen of low-dose clozapine (50% of usual maintenance dose).

In agreement with findings from clinical trials,[29,30,31,32,34,35] the most common adverse effects related to aripiprazole in our practices include headache, nausea, insomnia and akathisia. During the switch to aripiprazole, diarrhoea has occasionally been observed in our patients. The 30 mg/day dosage may result in more sedation than lower doses, but is still well tolerated.[35] Treatment of adverse effects is important to maintain compliance with the treatment regimen.

Headache and nausea are often transient and usually disappear after a few days of treatment. Nausea, if present, tends to occur mainly in the first days of treatment and may be controlled by reducing the aripiprazole dose or administering the drug with food. If unresolved by these methods, an antiemetic may be required.

Insomnia can generally be controlled by either changing to morning administration of aripiprazole or adding sedative therapy, such as a benzo-diazepine or an antihistaminic agent. Some of our patients have reported good relief with splitting the once-daily dose into two half-daily doses taken at morning and night.

Akathisia appears in some patients when treatment is started, is generally transient and of mild to moderate severity, and can be controlled with benzodiazepines, β-adrenoceptor antagonists or, in some cases, gabapentin. The advantage of benzodiazepines is that they may also control anxiety, agitation, insomnia, tension and mild nausea in patients with an acute episode. Akathisia may sometimes require a decrease in the dose of aripiprazole, but, conversely in our experience, it is possible that when akathisia closely resembles agitation an improvement may be seen with an increase in dose.


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