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Abstract

Aim:

The supposed superiority of second-generation antipsychotic medication over first-generation antipsychotic medication has been challenged recently by several studies. This naturalistic retrospective study aims to compare outcomes between patients admitted for the first time with first-episode schizophrenia-spectrum disorders who were started on either haloperidol or risperidone. Would choice of antipsychotic affect length of admission and three-month outcome?

Methods:

Seventy-seven patients from the Early Psychosis Intervention Programme at the Institute of Mental Health were included in this study. Length of stay was obtained from hospital electronic records. Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Functioning (GAF) scores at three months were used to assess severity of psychopathology and level of functioning respectively. A secondary analysis was also done to measure time to discontinuation for any reason.

Results:

There was a significant reduction in PANSS total, positive, negative and general psychopathology scores in both groups at three months, with the patients on risperidone showing a greater reduction in PANSS negative scores compared to the patients on haloperidol. However, there were no statistically significant differences between length of hospitalization and total PANSS score at three months between the two groups. Time to discontinuation was longer in the risperidone group compared to the haloperidol group.

Conclusion:

The findings of this study suggest that risperidone has a better effect on negative symptoms and is better tolerated, resulting in a longer time to discontinuation. Thus, starting a patient with first-episode schizophrenia-spectrum disorder on risperidone would result in a better short-term outcome as compared to starting the same patient on haloperidol.

Keywords

Haloperidol risperidone first-episode schizophrenia effectiveness

Introduction

Schizophrenia is a serious and potentially chronic mental disorder with a profound impact on patients, their families, and society. Worldwide, psychotic illnesses rank third among the most disabling conditions and impose an enormous burden in economic cost and human suffering.¹ Thus, it has become of much interest to establish what is the most effective way to treat this condition. Antipsychotic medication remains the mainstay of treatment for schizophrenia. When second-generation antipsychotics were introduced, they were marketed as offering greater efficacy in reducing psychotic symptoms while reducing side effects.² However, this supposed superiority over first-generation antipsychotics has been challenged in recent times.³

The efficacy of second-generation antipsychotics in treating both the positive and negative symptoms of psychosis has been proven in many studies.^4,5 However, most of these studies were in the form of randomized controlled trials that were performed in controlled situations which did not reflect the conditions faced by clinicians in actual day to day practice.

Two studies in particular have challenged the assumption that second-generation antipsychotics are superior to first-generation antipsychotics in schizophrenia by comparing their effectiveness in real world situations. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE),⁶ involved 1493 patients with schizophrenia recruited from 57 sites in USA and randomly assigned to receive olanzapine, perphenazine, quetiapine or risperidone for up to 18 months. The CATIE study showed that the efficacy of the only first-generation antipsychotic medication in the trial, perphenazine, appeared to be similar to that of other second-generation antipsychotic medications, but adherence to therapy was highly affected by tolerability, with approximately 74% of patients discontinuing their medications before 18 months of treatment. Olanzapine was the most effective in terms of rates of discontinuation but was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

The Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1)⁷ was a pragmatic, multisite, randomized controlled trial of antipsychotic drug classes which was conducted over 56 weeks in England. This study tested the hypothesis that second-generation antipsychotics would be associated with a clinically significant improvement in quality of life across one year compared with the use of first-generation antipsychotics. They also examined impact on patient satisfaction and total health care costs. The study revealed that there was no disadvantage in terms of quality of life, symptoms or costs of care in using first-generation antipsychotic medications when compared with risperidone, olanzapine, quetiapine, and amisulpride.

In patients with first-episode schizophrenia, one study has attempted to compare the effectiveness of second-generation antipsychotic drugs, (amisulpride, olanzapine, quetiapine, and ziprasidone) with that of low-dose haloperidol (mean dose 3 mg), namely the European First-Episode Schizophrenia Trial (EUFEST).⁸ The primary outcome was all-cause discontinuation, and the study population was 489 individuals with first-episode schizophrenia. Overall, the combined discontinuation rate was 47% over one year, varying between 33% for olanzapine and 72% for haloperidol. In terms of efficacy, it could not be concluded that second-generation antipsychotics were more efficacious than haloperidol.

Studies that have compared the effectiveness of risperidone and haloperidol in the treatment of first-episode psychosis have found that risperidone was more effective,⁹ prevented relapse for a longer time, and induced less abnormal movements compared to haloperidol.¹⁰

From an economic point of view, the largest expense during the lifetime of a patient with schizophrenia has always been inpatient hospitalization. Some epidemiological studies have found that the second-generation antipsychotics have reduced rehospitalization by about 12 hospital days per patient per year.¹¹ There has been one study that examined the economic outcomes among patients with first-episode schizophrenia who were treated with second-generation antipsychotics, (clozapine, olanzapine, quetiapine, risperidone, and zotepine) compared with each other and haloperidol.¹² They found that patients treated with second-generation antipsychotics had a lower number and shorter duration of hospitalizations than did patients treated with haloperidol. Olanzapine was associated with the lowest hospitalization rate, and economic analysis revealed that individuals prescribed haloperidol were ‘the most expensive’ due to total hospitalization costs.

This issue is also pertinent in Singapore as hospitalization is only partially subsidized by the government and lengthy admissions to hospital could result in a considerable financial burden on both the patient and their family. So far, there have been no studies that investigate the impact of either risperidone or haloperidol on the length of hospitalization and three-month outcomes of patients newly diagnosed with first-episode schizophrenia-spectrum disorders in Singapore. The need for this study stems from the fact that currently patients with first-episode psychosis in Singapore can be started on either a first-generation or a second-generation antipsychotic medication on admission to hospital.¹³ This is different from the clinical practice guidelines recommended by other countries that state that all first-episode psychosis patients should be started on a second-generation antipsychotic medication.^14,15

It is our hypothesis that commencing a patient newly diagnosed with first-episode schizophrenia-spectrum disorders on haloperidol results in longer duration of stay and poorer short term outcome than for those patients prescribed risperidone.

Methods

Data from 77 consecutive inpatients from March 2001–June 2005 accepted into the Early Psychosis Intervention Program (EPIP) who were initially prescribed either haloperidol or risperidone were included in this naturalistic study in which rating scales such as the Positive and Negative Syndrome Scale (PANSS)¹⁶ and Global Assessment of Functioning (GAF)¹⁷ scale were administered prospectively and any changes to or discontinuation of medications examined retrospectively. They were all admitted for the first time to the Institute of Mental Health/Woodbridge Hospital and fulfilled the following criteria: (a) age between 18–40 years; (b) first-episode schizophrenia-spectrum disorder (schizophrenia, schizophreniform or schizoaffective disorder) with no prior or minimal treatment; (c) no current history of substance abuse and (d) no history of major medical or neurological illness. Risperidone and haloperidol were chosen for this study as they were the most commonly prescribed second- and first-generation antipsychotic medications in the program.

EPIP is a comprehensive, integrated and patient-centered program led by a multidisciplinary team of psychiatrists, psychologists, case managers, social workers, nurses and occupational therapists. The aims of the program have been to raise awareness of and reduce stigma associated with psychosis, establish links with primary health care providers and collaborate in the detection, referral and management of those with psychosis and to improve the outcome of patients and reduce the burden of care for their families. Pharmacological management is based on a treatment algorithm that emphasizes use of antipsychotic monotherapy (either first- or second-generation) at low dose.

All patients accepted into EPIP are given an introduction letter where the EPIP services are described in more detail. In that same letter, the patients are informed about the collection of sociodemographic data and administration of clinical ratings to help evaluate and improve the service. All data is kept confidential and no individual is identified in the data analyses. In addition, the EPIP database is registered with and has been approved by the National Healthcare Group IRB as a standing database (that is, electronic data stored for the purposes of patient care/services and/or as a potential resource for future research). As such, individual patient consent is waived.

All patients’ diagnoses were established with the Structured Clinical Interview for DSM-IV, patient version (SCID-P), and their socio-demographic data were obtained using a semi-structured questionnaire. The choice of a particular antipsychotic medication for the patient was based primarily on the clinical decision of the treating clinician, in discussion with the patient and family members where possible.

Duration of untreated psychosis (DUP) was defined as the time in months between onset of psychotic symptoms (delusions, hallucinations and/or disorganized thinking or behavior) and the time when a definitive diagnosis and treatment were established. Patients and the primary caregivers were interviewed and asked to date the onset of psychotic symptoms and the DUP was estimated after combining information from the interviews and case records. Severity of psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS) and the Global Assessment of Functioning (GAF) scale used to assess the level of functioning. These assessments are done routinely for all patients of the EPIP on first presentation (baseline), three months, six months, one year, and two years later. The ratings were done by experienced psychiatrists who were trained in the use of these rating instruments. All raters participated in periodic inter-rater reliability sessions to avoid rater drift.

The primary outcome measurement for effectiveness was length of hospitalization and PANSS score at three months. The length of hospitalization was used as a measure of the overall effectiveness of either haloperidol or risperidone in treating the acute episode of schizophrenia-spectrum disorders because it was reasoned that the most effective medication would result in a shorter length of hospitalization. The total length of hospitalization for each patient was obtained from the hospital’s electronic data system. The PANSS score at three months was also considered to be a good measure to evaluate the effectiveness of either haloperidol or risperidone in controlling the acute symptoms of the illness.

A secondary analysis was done to measure the time to discontinuation for any reason. This outcome is regularly encountered in our clinical setting and is a real concern to the clinician as it could result in a negative outcome for the patient. The specific reasons for discontinuation of the initial antipsychotic medication were categorized into (a) lack of efficacy, (b) intolerability of side effects (i.e. extrapyramidal side-effects, metabolic dysregulations or any other adverse reactions), (c) patient’s request, (d) defaulted/non-compliance with treatment and (e) other reasons (i.e. lack of specific reasons given for discontinuation or transferred to other medical facilities). This data was collected by reviewing patients’ medical records.

Statistical analysis

Descriptive statistics were computed for the basic demographic and clinical variables. Mean and standard deviations (SDs) were calculated for continuous variables and frequencies and percentages for categorical variables. Normality of quantitative data was checked using the Kolmogorov-Smirnov 1-sample test. Differences between the two groups at baseline were tested by independent t-test and Mann-Whitney U test for normal and non-normal continuous variables whenever appropriate. Rating scores measured over time (PANSS) was subjected to repeated measures analysis of variance (ANOVA) analyses where time effect (within-group factors) was modeled. Assumptions of the repeated measures ANOVA including sphericity assumption which was checked using Mauchly’s test; model fitness was checked by residual plots and lack-of-fit test. Kaplan-Meier survival curves were utilized to estimate time to discontinuation for any reason, and time to discontinuation for specific reasons. A Cox proportional hazards regression model was used to compare the two treatment groups. Level of significance was set at p value<0.05. All statistical analyses were performed using SPSS 16.0.

Results

Baseline clinical and demographic characteristics of patients

Of the 77 patients, 44 (57.1%) patients were prescribed haloperidol and 33 (42.9%) patients were on risperidone. As a whole, the mean age (SD) of the patients was 29.3 (6.8) years. There were 38 males (49.4%) and 39 females (50.6%). The majority were Chinese (56/72.7%) and single (62/80.5%). (Table 1) Their median DUP was 15 months. Their mean (SD) PANSS total score and GAF scale total score at baseline were 65.4 (13.7) and 35.4 (14.2), respectively.

Table 1.

Socio-demographic characteristics of the sample (n=77).

Variable		Mean (SD)
Age (in years)		29.3 (6.8)
Years of schooling		10.9 (3.2)
		n (%)
Gender	Male	38 (49.4)
Gender	Female	39 (50.6)
Race	Chinese	56 (72.7)
	Malay	15 (19.5)
	Indian	5 (6.5)
	Others	1 (1.3)
Marital status	Single	62 (80.5)
	Married	9 (11.7)
	Divorced	6 (7.8)

SD: standard deviation.

There were significant differences between the two groups in years of education (p value=0.025), age (p value=0.023) and use of anti-cholinergic medication (p value=0.045). There were no statistically significant differences between the two groups in terms of gender (p value=0.742), race (p value=0.577), marital status (p value=0.708), DUP (p value=0.253), PANSS total score (p value=0.559), positive score (p value=0.374), GPS score (p value=0.557), negative score (p value=0.059) and GAF total score (p value=0.245), symptom score (p value=0.430), disability score (p value=0.556) at baseline. (Table 2)

Table 2.

Socio-demographic and clinical characteristics compared between those with risperidone (n=33) and haloperidol (n=44).

Variable		Risperidone	Haloperidol	p Value
Variable		Mean (SD)	Mean (SD)	p Value
Age (in years)		27.4 (6.1)	30.7 (7.0)	0.023
Years of schooling		11.8 (2.8)	10.2 (3.3)	0.025
		n (%)	n (%)
Gender	Male	17 (51.5)	21 (47.7)	0.742
Gender	Female	16 (48.5)	23 (52.3)	0.742
Race	Chinese	25 (75.8)	31 (70.5)	0.577
	Malay	5 (15.2)	10 (22.7)
	Indian	2 (6.1)	3 (6.8)
	Others	1 (3.0)	0 (0)
Marital status	Single	28 (84.8)	34 (77.3)	0.708
	Married	3 (9.1)	6 (13.6)
	Divorced	2 (6.1)	4 (9.1)
Anticholinergic medication	Yes	14 (43.8)	29 (65.9)	0.045
(at 3 months)	No	18 (56.3)	15 (34.1)
		Mean (SD)	Mean (SD)
PANSS score baseline	Total	66.1 (13.9)	64.8 (13.8)	0.559
	Positive	19.5 (4.5)	20.3 (5.0)	0.374
	Negative	14 (7.3)	12.7 (8.6)	0.059
	GPS	32.6 (8.1)	32.0 (7.6)	0.557
PANSS score month 3	Total	35.4 (8.6)	38.6 (10.1)	0.084
	Positive	8.4 (2.9)	8.5 (3.1)	0.924
	Negative	8.0 (2.2)	9.7 (4.8)	0.100
	GPS	19.0 (4.7)	20.5 (4.8)	0.079
GAF baseline	Total	38.0 (15.2)	33.5 (13.2)	0.245
DUP		36.5 (15.9)	33.2 (13.8)	0.253
Length of stay of 1^st admission		15.8 (8.6)	15.6 (9.2)	0.951

GAF: Global Assessment of Functioning; PANSS: Positive and Negative Syndrome Scale; SD: standard deviation.

Length of stay of first admission

The mean length of stay in days of first admission (SD) was higher in the risperidone group, 15.8 (8.6) compared to the haloperidol group, 15.6 (9.2). However, this difference was not statistically significant (p value=0.951)

Total PANSS score at three months

Figure 1 shows the effects of medication on PANSS scores. The PANSS (SD) total score at three months for the patients on haloperidol and for those on risperidone was 38.6 (10.1) and 35.4 (8.6) respectively. The difference was not statistically significant (p value=0.084). Over the three-month period, there were significant reductions in PANSS total (p value <0.001), positive (p value<0.001), negative (p value<0.001) and general psychopathology scores (p value<0.001) among those taking haloperidol and risperidone. However, in terms of time-group interaction effect, there were no significant differences between the groups in PANSS total, PANSS positive and PANSS GPS scores. There was a significant difference in the reduction in PANSS negative scores between the two groups, with the risperidone group showing a greater reduction in scores at three months (p value=0.05).

Figure 1.

Mean Positive and Negative Syndrome Scale (PANSS) scores over three months showing (a) total scores; (b) positive; (c) negative; and (d) GPS scores.

Discontinuation of treatment

As a whole, 40 (51.9%) of patients discontinued their antipsychotic medication for any reason within three months. As a group, the mean survival time for prescribing risperidone and haloperidol was 44.9 days (95% confidence interval (CI): 23.9–65.9) and 17.6 days (95% CI: 9.7–25.5), respectively. The median survival time for prescribing risperidone and haloperidol was 43 days (95% CI: 0.9–85.1) and 11 days (95% CI: 7.2–14.8) respectively (Figure 2). Those on haloperidol had a two-fold higher risk (hazard ratio=2.7; CI: 1.2–6.0, p=0.018) of discontinuing their antipsychotic medication for any reason compared to those prescribed risperidone.

Figure 2.

Days of discontinuation between those with haloperidol and risperidone medication.

Of those who discontinued haloperidol, 28.6% did so due to lack of efficacy compared to 25.0% in the risperidone group who discontinued their medication for the same reason. The proportion of those who discontinued their medication for reasons of intolerability of side effects was 50.0% in the haloperidol group and 25.0% in the risperidone group.

Discussion

The findings suggest that there is no significant difference in length of first admission between the two groups and total PANSS at three months; however it was found that patients on risperidone had a more significant decrease in PANSS negative scores at three months and a longer time to treatment discontinuation.

Baseline characteristics of patients

Although there were statistically significant differences between the two groups in terms of age and years of education, this was not considered clinically relevant. Otherwise, the two groups were comparable to each other.

Length of admission

It is interesting that the length of admission for both groups was not statistically significant as other studies have shown that risperidone may reduce the total hospitalization cost compared to first-generation antipsychotic medication.¹⁸ This finding may not be applicable as the patient population in that particular study had chronic schizophrenia whereas the patients in this study were all newly diagnosed with first-episode schizophrenia-spectrum disorders.

Short-term response to treatment

With regards to the finding that there was no significant difference in total PANSS score at three months between the two groups; this echoes several studies, such as the CATIE and EUFEST studies discussed earlier that found there was no difference in efficacy between first- and second-generation antipsychotic medication. A recent meta-analysis of first- versus second-generation antipsychotic medication in first-episode psychosis found that there were no differences in either discontinuation rates or symptom efficacy.¹⁹

A randomized controlled trial that examined short-term outcomes in patients with first-episode schizophrenia started on either haloperidol or risperidone found that at the end of eight weeks, there were significantly fewer drop-outs and longer discontinuation time in the risperidone group compared to the haloperidol group. Both haloperidol and risperidone appeared to be equally effective in treating negative and other symptoms of first-episode schizophrenia.²⁰

The negative symptoms of schizophrenia, namely apathy, social withdrawal, paucity of speech, and blunted affect, are difficult to treat and are said to contribute more to poor functional outcome and quality of life for patients with schizophrenia than do positive symptoms.²¹ In this study, risperidone was found to cause a statistically significant reduction in PANSS negative scores compared to haloperidol. This is consistent with its more potent action as a 5-HT2 receptor antagonist. In a study comparing risperidone and chlorpromazine, it was found that both medications significantly decreased the positive and general symptoms of patients with schizophrenia, but risperidone was more effective in treating negative symptoms.²² It is possible that risperidone’s propensity to cause less extrapyramidal side-effects also played a part in reducing the PANSS negative scores compared to haloperidol.

Discontinuation of treatment

Discontinuation of treatment for whatever reason remains a challenge to the clinician who treats patients with schizophrenia. As previous studies such as the CATIE study have shown, discontinuation rates are very high and ultimately lead to a poor prognosis in this group of patients. One study examining the relapse rate in people in the five years after their first hospitalization for a psychotic illness found that it was over 80% and the two main independent risk factors predicting relapse were poor adherence to prescribed antipsychotic medication and pre-morbid level of functioning.²³ A longer time to discontinuation is strongly associated with better symptomatic improvement²⁴ and functional outcome,²⁵ which makes the choice of which antipsychotic to initiate all the more important.

Treatment effectiveness can be subdivided into the constituents of efficacy, tolerability, and adherence. Efficacy is a crucial component, but an efficacious treatment only works if it is acceptable and used on a regular basis by the patient. In this study, the time to discontinuation for risperidone was longer compared to haloperidol.

The two main reasons for discontinuation in this study were lack of efficacy and lack of tolerability of side-effects. This finding has been replicated in other studies, which found that there was better adherence to and tolerability for second-generation antipsychotics than for low-dose first-generation antipsychotics in first-episode psychosis.²⁶ In terms of discontinuation due to lack of efficacy, patients were switched to a different antipsychotic as soon as it was apparent that they were not responding to either haloperidol or risperidone by 4–6 weeks of treatment. This is in line with the program’s treatment algorithm which is based on studies that show early response is a significant predictor of response and remission later on.²⁷

Side-effects do play a large part in determining adherence to medications, and in the case of first-generation antipsychotic medications, their propensity to cause extrapyramidal side-effects has shown to lead to earlier discontinuation of treatment.²⁸ In this study, the number of patients on anticholinergic medication was higher in the haloperidol group, indicating that they were experiencing more extrapyramidal side effects compared to those on risperidone. This in turn led to a significant number of them discontinuing their medications within three months.

There was a relatively significant proportion of patients in this study who fell into the category of discontinuation of medications due to other reasons. The possible explanations for this could be cultural factors within the Asian population. For example it is still common to attribute mental illness to the workings of spirits or black magic.²⁹ Also, being diagnosed with a mental illness leads to considerable stigmatization within society and this will influence a person’s willingness to seek or maintain psychiatric treatment.³⁰

Limitations

There are limitations to this study. Firstly, this is a naturalistic and retrospective study. As a result, inevitable biases that are present in real world clinical situations exist; for example, patients’ and clinicians’ notions of their antipsychotic medications and different clinicians’ thresholds in switching medication. Second, the number of patients studied was quite small. A larger sample may have rendered more significant results. As this was a naturalistic study, patients were allowed to be on other non-antipsychotic medications and drug-drug interactions between combinations of these medications could lead to adverse side-effects that would not be attributable solely to the antipsychotic medications per se. Thirdly, as the discontinuation rate was high in both groups, it is difficult to comment on the difference or lack of difference in short-term efficacy between the two medications.

Strengths

This is the first naturalistic study of Asian patients admitted with first-episode schizophrenia-spectrum disorders that looks into the difference in short-term outcome when starting a first- or second generation antipsychotic medication.

Conclusion

It is without a doubt that the introduction of antipsychotic medications has radically changed the treatment and outcome of patients with schizophrenia.³¹ The studies discussed earlier point to the fact that there does not seem to be a differential efficacy between first- and second-generation antipsychotics and that good management of the patients, regardless of which antipsychotic is used, will eventually make the difference in outcome. The latest recommendations from the British Association of Psychopharmacology on the treatment of schizophrenia focuses on side effects rather than class of antipsychotic, and recommends low starting doses in first-episode psychosis with careful side effect monitoring.³²

This study found that there was no difference between haloperidol and risperidone when it came to treating the first admission for first-episode schizophrenia-spectrum disorders and outcome at three months; however, risperidone did seem to have a better effect on negative symptoms and was better tolerated, resulting in a longer time to discontinuation for any reason. Thus, in terms of the clinical relevance of this study, our findings suggest that starting a patient with first-episode schizophrenia-spectrum disorders on risperidone will lead to a better short-term outcome as compared to starting the same patient on haloperidol. Ultimately, clinicians will continue to base prescribing decisions on a variety of rational and non-rational factors, but it is of most importance to individualize treatment selection by considering patient- and medication-related factors.

Footnotes

Declaration of Conflicting Interest

The authors declare that there is no conflict of interest.

Funding

This paper was written without any funding from any source and the authors have no industrial links or affiliations.

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Short term effectiveness of haloperidol versus risperidone in first-episode schizophrenia

Abstract

Aim:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Statistical analysis

Results

Baseline clinical and demographic characteristics of patients

Length of stay of first admission

Total PANSS score at three months

Discontinuation of treatment

Discussion

Baseline characteristics of patients

Length of admission

Short-term response to treatment

Discontinuation of treatment

Limitations

Strengths

Conclusion

Footnotes

Declaration of Conflicting Interest

Funding

References