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Keywords:

  • aripiprazole;
  • efficacy;
  • first-episode schizophrenia;
  • tolerability

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Aims:  Aripiprazole is an atypical antipsychotic indicated for the treatment of adult patients with schizophrenia. It is effective and well tolerated in patients with schizophrenia or schizoaffective disorder. The aim of the present study was to investigate therapeutic efficacy and tolerability of aripiprazole in patients with first-episode schizophrenia.

Methods:  Twenty-one patients meeting the DSM-IV criteria for schizophrenia were recruited. The Positive and Negative Symptom Scale (PANSS) and the Clinical Global Impressions Scale (CGI) were completed at the beginning of the study and again after 1, 2, 4, and 8 weeks of aripiprazole treatment. Side-effects were analyzed using the Udvalg for Kliniske Undersøgelser Side-Effect Rating Scale. Weight was checked at each testing session, and prolactin levels were measured at baseline and after 8 weeks of aripiprazole treatment.

Results:  Significant benefits were observed after the first week of treatment. After 1 week of aripiprazole treatment, subscale and total scores on the PANSS had decreased significantly. This significant decrease was maintained throughout the study period. The mean score of CGI severity was also significantly different after 2 weeks of aripiprazole administration when compared to baseline score, and the significance was maintained thereafter. Weight did not significantly change after aripiprazole administration. Although mean prolactin level was decreased at 8 weeks, the difference was not significant.

Conclusions:  Aripiprazole is an effective and well-tolerated antipsychotic agent in patients with first-episode schizophrenia. Further investigations with larger samples are needed.

THE FIRST EPISODE of schizophrenia typically occurs during adolescence or early adulthood. For the majority of patients, schizophrenia is a recurrent or chronic disorder accompanied by significant impairment in psychosocial functioning. A growing body of evidence indicates that early intervention with appropriate pharmacological treatment can contribute to improving the course of the illness.1–3 A delay in initial treatment is associated with slower and less complete symptom response and overall poorer outcome.1

Patients experiencing their first episode of schizophrenia should be treated early and optimally with antipsychotic agents to lessen the morbidity of the first episode and possibly improve the course of the illness. At an early stage of the illness, patients are more responsive to pharmacological treatment but are also more susceptible to side-effects.4

Low doses of antipsychotic agents have been reported as effective and well tolerated in first-episode psychosis.5 Moreover, a common perception has been that first-episode patients should be treated with lower doses of some atypical antipsychotics than patients in the chronic stages of this disorder.6

First-episode patients are highly responsive to pharmacologic treatment, and the first treatment intervention in drug-naive patients represents a critical therapeutic opportunity with the potential to influence the course and outcome of what could be a lifelong illness.7 This is particularly significant because longer first episodes of psychosis have been associated with poorer treatment responses and outcomes.8

Aripiprazole is a new atypical antipsychotic with a unique receptor binding profile that combines partial agonist activity at dopamine 2 receptor (D2) and serotonin 1A receptor (5HT1A) with potent antagonism at serotonin 2A receptor (5HT2A).9 Aripiprazole appears to be well tolerated, with most studies suggesting a frequency of adverse effects similar to placebo;9 it also has a low propensity for causing clinically significant weight gain, hyperprolactinemia, and extrapyramidal symptoms in patients with schizophrenia or schizoaffective disorder.10 Few studies, however, have been specifically designed to test the safety and efficacy of aripiprazole for the treatment of first-episode schizophrenia. The aim of the present study was therefore to investigate the therapeutic efficacy and tolerability of aripiprazole for treating first-episode schizophrenia following 8 weeks of treatment in routine clinical conditions.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Subjects

Twenty-one patients experiencing their first episodes of schizophrenia, diagnosed according to DSM-IV criteria,11 were recruited from among patients visiting the Korean University Medical Center Anam Hospital between January 2006 and March 2008. Antipsychotic-naïve patients aged 18–65 years were interviewed by two psychiatrists for diagnostic purposes. Those diagnosed initially with schizophreniform disorder were followed for up to 6 months to confirm the diagnosis of schizophrenia. The mean duration of the illness prior to treatment was determined by interviewing the closest available relative of each participant.

Subjects with alcohol or substance dependence or who had comorbid diagnoses of organic brain pathology or dementia based on DSM-IV criteria were excluded from the study. Patients with serious or unstable medical illnesses were also excluded. Pregnant and lactating women were not eligible to participate in the study.

After initial ratings were obtained, all patients were treated with aripiprazole monotherapy at an initial dose of 5 mg daily. Initially, we were able to increase the dose weekly to 10 mg at 1 week and to 15 mg at 2 weeks. At 4 weeks, we increased the dose to 30 mg or decreased the dose in response to specific situations. Benztropine was administered as needed for extrapyramidal symptoms. Patients could also receive lorazepam if a sedative/hypnotic was required. None of the patients had taken other psychotropic medications within the last 2 weeks. No other antipsychotics were used.

Signed informed consent forms were obtained from patients and/or their legal guardians or representatives with sufficient understanding of the objectives of the study. The study protocol was approved by the Ethics Committee of the Korean University Anam Hospital.

Clinical evaluation

The positive and Negative Symptom Scale (PANSS)12 was administered by trained raters at the beginning of the study and at 1, 2, 4, and 8 weeks of aripiprazole administration. Additional ratings, including the Clinical Global Impression Scale (CGI), were administered by a psychiatrist. Side-effects were measured using the Udvalg for Kliniske Undersøgelser (UKU) side-effect rating scale at all follow-up visits.13 This instrument consists of four subscales: neurologic, psychic, autonomic, and other.

Laboratory evaluations

Physical examinations and laboratory investigations included complete blood counts and differentials, blood urea nitrogen levels, electrolyte levels, thyroid hormones, fasting blood sugar and prolactin levels. Weight was checked at each testing session.

Statistical analyses

All statistical analyses were performed with SPSS version 12.01 for Windows. The Wilcoxon signed–ranks test was used to compare the scale scores obtained at each period to those obtained before aripiprazole administration. Completer analysis was used, and last observation carried forward (LOCF) for missing data was also used to analyze efficacy, which included all patients who received medication at least once and who had at least one efficacy or safety measurement taken. Statistical significance was defined as two-tailed P < 0.05.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

Subject characteristics

Twenty-one patients were clinically evaluated and completed 1 week of the study, and five patients refused the treatment. Twenty patients finished the evaluations at 2 weeks, and one patient refused treatment. Nineteen patients finished 4 weeks of the study, and one patient was lost to follow up. Fifteen patients finished 8 weeks of the study because two patients were lost to follow up, one patient refused treatment, and one patient chose to get psychiatric treatment from a hospital closer to his home because of a leg fracture. The mean dose of aripiprazole was 9.3 mg at 1 week, 12.5 mg at 2 weeks, 17.6 mg at 4 weeks and 24.7 mg at 8 weeks.

Table 1 shows demographic data of the subjects. Of the 21 patients who were evaluated clinically, 13 were male and eight were female. The mean age for the sample was 33.1 ± 11.8 years (mean ± SD). Six patients were married and five patients had experienced stressful events at the time of the onset of schizophrenia. One patient had a family history of schizophrenia and three patients had a family history of mood disorders. Ten patients were admitted to an inpatient ward and 11 patients were treated in the outpatient department. The mean duration of education was 12.8 ± 2.9 years. The mean period between treatment and onset was 33.0 ± 35.4 months.

Table 1.  Subject data
 Data
Age (years)33.1 ± 11.8
Sex (male/female)13/8
Family history 
 Mood disorder3
 Other psychiatric disorder1
Inpatients/outpatients10/11
Education (years)12.8 ± 2.9
Duration of illness (months)33.0 ± 35.4

Therapeutic efficacy

Table 2 lists the clinical characteristics of the patients. Baseline PANSS subscale and total scores were as follows: positive subscale score, 22.5 ± 3.3; negative subscale score, 22.3 ± 6.8; general subscale score, 46.7 ± 9.0; and total score, 92.0 ± 14.0. After 1 week of aripiprazole administration, the subscale and total scores significantly decreased (P < 0.05): positive subscale score, 19.4 ± 4.0; negative subscale score, 19.2 ± 5.7; general subscale score, 41.1 ± 10.0; and total score, 75.4 ± 23.4. This significant difference from baseline scores was maintained throughout the study period. The change of PANSS total score after aripiprazole administration is shown in Fig. 1. The baseline CGI severity score was 4.9 ± 1.0. After 1 week of aripiprazole administration, the CGI severity score was 4.7 ± 1.3, which was not significantly different from the score at baseline. A significant difference from baseline appeared at 2 weeks (4.2 ± 1.1) and was maintained thereafter. When compared with LOCF, the therapeutic efficacy of aripiprazole was similar to that of completer analysis.

Table 2.  Subject clinical characteristics (OC)
 Baseline1 week2 weeks4 weeks8 weeks
(n = 21)(n = 21)(n = 20)(n = 19)(n = 15)
  • *

    P < 0.05 (when compared to baseline),

  • **

    P < 0.01 (when compared to baseline).

  • Wilcoxon signed–ranks test, P = 0.88 (when compared to baseline).

  • CGI, Clinical Global Impression Scale; OC, observed case; PANSS, Positive and Negative Symptom Scale; UKU, Udvalg for Kliniske Undersøgelser Side-effect Rating Scale.

Mean doses     
 Aripiprazole (mg)NA9.3 ± 1.812.5 ± 3.017.6 ± 4.224.7 ± 7.6
 Benztropine (mg)NA0 (n = 0)0.5 (n = 1)1.0 ± 0.5 (n = 7)1.1 ± 0.5 (n = 12)
 Lorazepam (mg)NA1.7 ± 1.0 (n = 15)1.6 ± 1.0 (n = 17)1.7 ± 0.9 (n = 18)2.1 ± 1.7 (n = 15)
PANSS     
 Positive22.5 ± 3.319.4 ± 4.0**17.9 ± 4.4**16.3 ± 3.3**14.1 ± 0.4**
 Negative22.3 ± 6.819.2 ± 5.7*17.4 ± 4.5**16.6 ± 5.8**14.6 ± 4.1**
 General46.7 ± 9.041.1 ± 10.0**37.8 ± 10.2**37.4 ± 8.3**33.3 ± 8.3**
 Total92.0 ± 14.075.4 ± 23.4**73.1 ± 16.9**69.8 ± 15.6**62.6 ± 15.5**
CGI     
 Severity4.9 ± 1.04.7 ± 1.34.2 ± 1.1**3.8 ± 1.0**3.2 ± 1.1**
 ImprovementNA3.3 ± 0.82.9 ± 0.92.6 ± 1.12.5 ± 1.1
UKU     
 PsychicNA1.9 ± 1.91.5 ± 2.31.2 ± 1.62.7 ± 2.9
 NeurologicalNA0.1 ± 0.40.2 ± 0.51.1 ± 1.40.3 ± 0.7
 AutonomicNA0.3 ± 0.60.9 ± 1.51.3 ± 2.50.9 ± 2.3
 OtherNA0.1 ± 0.40.1 ± 0.20.3 ± 0.70.2 ± 0.5
 TotalNA2.3 ± 2.52.6 ± 3.73.1 ± 2.74.1 ± 4.4
Weight61.9 ± 14.061.7 ± 13.660.7 ± 13.661.1 ± 13.563.5 ± 13.4
Prolactin (ng/mL)15.6 ± 22.0NANANA8.5 ± 5.8
Glucose (mg/dL)96.1 ± 16.4NANANA90.1 ± 17.1
image

Figure 1. The change of Positive and Negative Symptom Scale (PANSS) total score after aripiprazole administration. **P < 0.01 vs baseline.

Download figure to PowerPoint

Side-effects

The UKU scores after 1 week of aripiprazole administration were as follows: psychic, 1.9 ± 1.9; neurologic, 0.1 ± 0.4; autonomic, 0.3 ± 0.6; other, 0; and total score, 2.2 ± 2.4. The weight of participants did not significantly change between baseline and subsequent visits. Prolactin and fasting blood glucose levels after 8 weeks of aripiprazole administration were not significantly different from those at baseline. Severe adverse effects were not observed.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

We investigated the therapeutic efficacy and tolerability of aripiprazole among patients experiencing first-episode schizophrenia. We found that aripiprazole had good efficacy and acceptable levels of safety and tolerability during the 8-week treatment of patients with first-episode schizophrenia. The results also showed that the subscale and total PANSS scores significantly decreased from those at baseline after 1 week of aripiprazole administration, and this significance was maintained at each evaluation. A significant difference from CGI baseline scores appeared at 2 weeks and was maintained for the remainder of the study. Thus, a significant therapeutic effect occurred during the initial period of aripiprazole treatment among patients with first-episode schizophrenia. Consistent with these results, many prior studies have demonstrated that first-episode patients have good therapeutic responses to antipsychotic medications.14,15 Results of a naturalistic study showed that aripiprazole was effective for both long- and short-term treatment among both inpatients and outpatients.16 In an open multicenter naturalistic study, aripiprazole decreased the severity of psychotic symptoms and improved the global level of functioning.17 Compared with placebo, aripiprazole had superior efficacy in the short-term treatment of acute schizophrenia.18,19 Compared with such active comparators as typical antipsychotic agents,18,20 risperidone,19,21 and ziprasidone,22 aripiprazole has shown comparable efficacy in the short-term treatment of acute schizophrenia. Many findings have emerged from similar studies regarding the effectiveness of aripiprazole in patients with schizophrenia. Moreover, similar evidence has been found for risperidone, olanzapine, and quetiapine.23 Few studies, however, have been specifically designed to test the efficacy of aripiprazole in the treatment of patients with first-episode schizophrenia. The present study indicates that aripiprazole might represent one of the antipsychotic agents appropriate for treating first-episode schizophrenia.

We demonstrated the tolerability of aripiprazole in first-episode schizophrenia. Prolactin levels were not significantly increased after aripiprazole treatment in the present study. Hyperprolactinemia, a common side-effect of many atypical antipsychotics, is associated with a number of distressing clinical manifestations including sexual dysfunction, gynecomastia, galactorrhea, infertility, bone mineral loss, and possibly breast cancer.24–27 Consistent with the present study, review articles have shown that aripiprazole offers significant advantages over typical and atypical antipsychotics insofar as aripiprazole has been associated with lower rates of hyperprolactinemia.28 In the present study, weight and fasting blood glucose levels were not significantly changed after aripiprazole treatment. Weight gain is a common side-effect of antipsychotic drugs, particularly atypical agents.29 The American Psychiatric Association's Practice Guideline for the Treatment of Schizophrenia endorses second-generation antipsychotics (other than clozapine) as the preferred initial antipsychotics.30 The data on efficacy and tolerability indicate that aripiprazole could be a candidate antipsychotic for first-episode schizophrenia. These results suggest that aripiprazole is an effective and tolerable antipsychotic agent among patients with first-episode schizophrenia.

The present study has some limitations. First, it is premature to draw conclusions on the basis of so few subjects and an open-label design. Second, comparative efficacy of aripiprazole can never be known due to lack of active comparator (vs other atypicals). Third, long-term effect of aripiprazole could not be determined because of a relatively short-term follow-up period. Notwithstanding the aforementioned limitations, this is the first study to examine the therapeutic efficacy and tolerability of aripiprazole in a Korean population with first-episode schizophrenia.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES

This study was supported by grants from the Korea Health 21 R&D Project, Ministry of Health, Welfare and Family, Republic of Korea (03-PJ10-PG13-GD01-0002, A050047).

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. ACKNOWLEDGMENTS
  7. REFERENCES
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