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.

Abstract and Introduction

Schizophrenia is generally a chronic and disabling mental illness. Pharmacological therapy, which is used for relief of acute psychotic episodes and prevention of subsequent relapse, is essential for the effective management of schizophrenia. In order to alleviate the positive symptoms of schizophrenia, all antipsychotic agents act on the dopaminergic system. However, strong, high-affinity dopamine D₂-receptor blockade may also be responsible for debilitating extrapyramidal symptoms (EPS) and hyperprolactinaemia. Unlike conventional antipsychotic agents, atypical antipsychotics also exert activity at other receptors, and it is generally acknowledged that, compared with conventional antipsychotics, atypical agents are associated with a broader spectrum of clinical efficacy and are better tolerated. However, other adverse effects such as weight gain and metabolic changes are cause for concern with some atypical antipsychotics. The novel atypical antipsychotic agent aripiprazole is a partial agonist at D₂ receptors that has been shown in clinical trials to be effective in treating both the positive and the negative symptoms of schizophrenia, and to be well tolerated, with a low propensity for EPS and no clinically significant weight gain, hyperprolactinaemia or corrected QT-interval prolongation. Aripiprazole thus provides clinicians with another treatment option, and in October 2005, schizophrenia experts participated in an expert consensus meeting that aimed to agree on a set of guidelines for best-practice use of aripiprazole in the acute and long-term management of schizophrenia in Italy. This report describes the outcome of the meeting. Our recommendations for dosage and administration of aripiprazole are in agreement with the manufacturer's prescribing information. Ideally, optimal dosing should be evaluated on an individual basis, taking into account patients' characteristics such as the presence or absence of agitation. Overall, in our experience, aripiprazole is generally a well accepted, well tolerated, safe and broadly effective first-line antipsychotic agent. Switching to aripiprazole from maintenance therapy with another antipsychotic also works well, provided the change is made gradually, involving tapering of the original medication.

Schizophrenia is a chronic mental disease that is characterised by positive symptoms, such as delusions and hallucinations, and negative symptoms, such as blunted affect and apathy.^[1,2] The disease is also often associated with cognitive impairment and depression.^[3,4] Disease onset is often in early adulthood, and the illness is generally characterised by lifelong episodes of exacerbations, remissions and relapses.^[5,6] In most cases, the disease is disabling, affecting all aspects of life and requiring long-term therapy with antipsychotic medication.^[5,6,7,8] Treatment is aimed at achieving remission of all symptoms, along with maximisation of functional capacity and optimisation of quality of life.^[9] Problems such as residual negative symptoms, depression, cognitive impairment and extrapyramidal symptoms (EPS) can detract from the functional status and quality of life of patients during remission from overt psychosis. When compared with conventional antipsychotic agents in clinical trials, it is acknowledged that atypical agents are associated with a broader spectrum of efficacy, including effects on both positive and negative symptoms and, possibly, cognitive function, and that they are better tolerated, particularly in relation to EPS.^{[4,9,10,11,12]} However, even though the risk of EPS is reduced with atypical agents, the problem has not been completely eliminated, and other adverse effects, such as weight gain, changes in glucose and lipid metabolism, and diabetes risk, are cause for concern with some agents.^[13,14] Additionally, some atypical anti- psychotic agents are associated with hyperprolactinaemia,^[15] the symptoms of which can include gynaecomastia, galactorrhoea, sexual dysfunction, oligomenorrhoea and amenorrhoea.^[16] There has also been some concern regarding corrected QT (QTc) prolongation observed with certain atypical anti- psychotic agents, although these agents may not be as arrhythmogenic as some conventional agents.^[17] Not surprisingly, considering the different receptor-binding profiles of atypical antipsychotics, the precise benefit/risk profile of these agents varies from one drug to another.^[13,18] Because the therapeutic and adverse effects of antipsychotics clearly vary from person to person,^[19] treatment should ideally be adapted for the needs of each individual patient.

The dopamine hypothesis of schizophrenia is classically used to explain the biochemical basis of the disease.^[20,21] According to this hypothesis, positive symptoms arise from a condition of upregulated dopaminergic neural activity in the mesolimbic pathway, whereas negative symptoms and cognitive impairments may result from a dopamine deficit in the mesocortical pathway. Aberrant dopaminergic neurotransmission in thalamic subregions might be another mechanism underlying positive symptoms in schizophrenia.^[22] Ideally, an antipsychotic agent should decrease dopaminergic hyperactivity in the mesolimbic system, while compensating for dopaminergic hypoactivity in cortical brain regions and not affecting brain regions that regulate extra- pyramidal movement and prolactin release.

In comparison with other antipsychotic agents, which act mainly as dopamine D₂-receptor antagonists, aripiprazole is a partial agonist at D₂ receptors.^[23,24] Aripiprazole binds with high affinity to D₂ receptors. Because of its partial agonist activity, aripiprazole reduces D₂-receptor overstimulation in the presence of excessive release of dopamine, as happens during an acute psychotic phase.^[25] Conversely, in brain areas with reduced dopamine, aripiprazole may enhance dopaminergic transmission. The partial D₂-agonist activity of aripiprazole is combined with partial agonist activity at serotonin 5-HT_1A receptors and antagonism at 5-HT_2A receptors, and its affinity for other receptors is relatively low ( Table 1 ).^[23,24] Such a binding profile should result in broad-spectrum atypical antipsychotic efficacy, including efficacy against negative symptoms, combined with anxiolytic and antidepressant activity, and a low risk of EPS and other dopamine, histamine and cholinergic antagonist-related adverse effects.

Aripiprazole, which is recommended as an appropriate first-line atypical antipsychotic agent for the treatment of schizophrenia by a US Expert Consensus survey,^[26] provides clinicians with another treatment option for their patients. In 2005, a consensus document was developed to outline the best practice for appropriate use of this agent in the UK.^[27] Further to this, on 13 October 2005, seven schizophrenia experts working in Italy and the US participated in an expert consensus meeting sponsored and funded by Bristol-Myers Squibb that aimed to agree on a set of guidelines for best-practice use of aripiprazole in the acute and long-term management of schizophrenia in Italy. This report describes the outcome of the meeting.

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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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Aripiprazole in the Treatment of Schizophrenia

Abstract and Introduction

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Authors and Disclosures

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