Efficacy, Acceptability, and Safety of Atypical Antipsychotics in First Episode Schizophrenia

Achaia Taltoan, Mercer University College of Pharmacy

The American Psychiatric Association (APA) schizophrenia guidelines recommend all second-generation (“atypical”) antipsychotics as first-line treatment for first episode schizophrenia. [1] Unlike the APA guidelines, the 2009 schizophrenia PORT statements recommend risperidone, quetiapine, aripiprazole, and ziprasidone as first line therapy but not olanzapine due to the associated metabolic side effects. [2]

While trials such as the EUFEST and the CATIE trial have compared second-generation antipsychotics to first-generation antipsychotics, there is a lack of guidance whether one second-generation antipsychotic is better than the other in certain situations for the treatment of first episode schizophrenia. [3] This trial attempts to provide data to enhance the understanding of the efficacy, discontinuation rate, and adverse events of the second-generation antipsychotics in comparison with one another.

The efficacy, acceptability, and safety of five atypical antipsychotics in patients with first episode drug-naïve schizophrenia: a randomized comparative trial
Design Randomized controlled, open-label, single blinded; N= 175
Objective To determine if there are differences in efficacy, acceptability, and safety between five atypical antipsychotics in the treatment of first-episode schizophrenia
Study Groups Aripiprazole (n= 39), risperidone (n= 43), quetiapine (n= 39), olanzapine (n= 35), ziprasidone (n= 19)

Exclusion Criteria

§  Severe or unstable physical disease and intolerance to antipsychotic treatment

§  Age of onset ≥50 years old

§  Duration of schizophrenia≥ 5 years

§  Pregnant or lactating females


Treatment naïve first episodic schizophrenic patients were randomized to study groups for six to eight weeks. The initial dose was titrated gradually depending on patient’s tolerability within the first or second week. Based on clinician judgement, antipsychotics were added or discontinued within the first two weeks. The Brief Psychiatric Rating scale (BPRS) was used to rate psychopathological symptoms at baseline after six to eight weeks of treatment. Clinical efficacy was assessed using the BPRS total score deduction rate. Acceptability was assessed by the discontinuation rate and use of medication at the end of the study period. Safety was assessed by occurrence of extrapyramidal symptoms, blood routine test, liver function test, and electrocardiogram tests. Categorical variables were tested with a chi-square test, and continuous variables were tested with a paired t test before and after the study for each study group. Covariance analysis was performed on the deduction rate of BPRS total scores after the study between the study groups.

Duration October 2012-November 2014
Primary Outcome Measure Clinical efficacy, acceptability, and adverse events between the antipsychotics, measured by BPRS deductions, discontinuation of treatment, and adverse events respectively
Baseline Characteristics
Groups n Gender (M/Fa, n) Age(years) Marital Status (M/U/Db) Duration of Illness (months) Baseline BPRS
Aripiprazole 39 21/18 26.31±9.09 16/22/1 10.29±13.29 54.49±10.46
Risperidone 43 22/21 32.37±8.45 26/15/2 10.34±15.67 54.12±10.21
Quetiapine 39 18/21 28.77±8.31 19/17/3 4.41±8.01 56.72±11.46
Olanzapine 35 17/18 25.54±5.41 15/19/1 9.29±13.22 57.40±14.90
Ziprasidone 19 3/16 22.26±5.41 7/12/0 7.31±12.96 57.79±15.34
X2 /F 849 7.38 8.36 1.45 0.65
p- value > 0.05 < 0.01 > 0.05 > 0.05 > 0.05



aM/F: Male/Female

bM/U/D: Married/Unmarried/Divorced



Results Table 2. Changes of BPRS total scores of patients who fully or partly maintained the initial treatment from baseline to endpoint among the five kinds of antipsychotic drugs


Groups n BPRS total score at baseline BPRS total score at endpoint Deduction rate of BPRS total score
Aripiprazole 23 54.00±10.39 29.96±9.05 0.44±0.13
Risperidone 23 56.04±10.39 24.87±7.05 0.55±0.12ab
Quetiapine 27 58.48±11.16 28.74±6.21 0.50±0.11
Olanzapine 21 53.10±11.5 26.90±4.75 0.47±0.15
Ziprasidone 7 58.71±14.59 25.86±4.91 0.54±0.13
F value 0.97 1.95 2.97
p-value > 0.05 > 0.05 0.023

Deduction rate of BPRS score: (baseline BPRS total scores-post treatment BPRS total scores)/ baseline BPRS total scores


a Comparison of risperidone with aripiprazole, (p< 0.01)

b Comparison of risperidone with olanzapine, (p< 0.05)




Table 3. Acceptability between the five kinds of antipsychotic groups after 6-8 weeks of treatment (N, %)


Groups n Discontinuation of initially assigned Antipsychotics Use of concomitant Antipsychotics Maintaining initially assigned Antipsychotics
Aripiprazole 39 16 (0.41) 8 (0.21) 15 (0.38)
Risperidone 43 20 (0.47) 3 (0.069) 20 (0.47)
Quetiapine 39 12 (0.31) 4 (0.10) 23 (0.59) a
Olanzapine 35 14 (0.4) 0 21 (0.60) a
Ziprasidone 19 12 (0.63) 2 (0.1) 5 (0.26)

n: number of patients

a Comparison of quetiapine and olanzapine with ziprasidone, both with p<0.05



The risk of treatment discontinuation of the initial antipsychotic was significantly higher in female patients when compared to males. Odds ratio of treatment discontinuation was 0.37 (95%CI 0.198-0.693) (p= 0.002).


Table 5. Comparison of adverse events between the five kinds of antipsychotics after 6-8 weeks of treatment


Groups n EPS Abnormal ECG Abnormal liver function Constipation Leukopenia
Aripiprazole 15 6 4 5 1 0
Risperidone 20 6 4 6 2 0
Quetiapine 23 3 8 7 3 4
Olanzapine 21 1 8 5 1 2
Ziprasidone 5 3 3 1 0 0
X2 12.23 3.75 0.64 1.60 6.899
p- value < 0.05 > 0.05 > 0.05 > 0.05 > 0.05

n: number of patients; EPS: extrapyramidal symptoms


Metabolic disturbances and sexual function were not analyzed due to incomplete data records and short study period.



Adverse Events Common Adverse Events: (Aripiprazole vs. Risperidone vs. Quetiapine vs. Olanzapine vs. Ziprasidone, n)

Extrapyramidal symptoms (6 vs. 6 vs. 3 vs.1 vs. 3)

Abnormal electrocardiogram (4 vs. 4 vs. 8 vs. 8 vs.3)

Abnormal liver function (5 vs. 6 vs.7 vs. 5 vs.1)

Constipation (1 vs. 2 vs. 3 vs.1 vs. 0)

Leukopenia (0 vs.0 vs. 4 vs. 2 vs. 0)

Serious Adverse Events: Not disclosed
Percentage that Discontinued due to Adverse Events: Not disclosed
Study Author Conclusions Risperidone was more effective than aripiprazole and olanzapine in treating first episode schizophrenia. Quetiapine and olanzapine were associated with less severe extrapyramidal adverse events and lower treatment discontinuation rates. The risk of treatment discontinuation was lower in males than females. There was no difference in adverse events of the antipsychotics.


The study had a relatively large sample size, limiting sampling bias and increasing the internal validity. Additionally, using the BPRS score system also strengthens the study’s internal and external validity as it is a reliable and validated method to evaluate schizophrenia symptoms. However, the study included a predominately Asian population, which may limit the applicability of the findings to other ethnicities, although the role of genetics/ethnicity in antipsychotics responses is unclear. The randomization of study groups helped eliminate bias; however, the open-label single-blinded design could have introduced bias as clinicians’ pre-conceived attitudes about the medications could have skewed their BPRS scoring and assessment of symptoms.

Although the study showed no differences in side effects, metabolic and sexual adverse effects were not analyzed due to the short duration of study and lack of recorded data; consequently, the observed safety outcomes may not be a true reflection of the drugs’ safety profiles. The study was conducted at an inpatient setting where adherence may be close to optimal (adherence was not assessed in the study); therefore, it is possible that the outcomes may differ in outpatient settings where patients may have poor adherence. Prior to treatment period, certain antipsychotics were discontinued or combined with another antipsychotic based on clinical needs but therapy response assessments and treatment decisions were not standardized. Therefore, individual clinician bias may have been present.

The mean daily doses used in this study were within the recommended dosage range suggesting the results may be applicable to general clinical practice. Overall, based on the study, risperidone may be an appropriate first-line agent among the atypical antipsychotics for first-episode schizophrenia; however, it is important to assess other drug interactions as well as long-term side-effects for optimal patient care.



[1] Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 Schizophrenia PORT Psychopharmacological Treatment Recommendations and Summary Statements. Schizophr Bull. 2010;36(1):71-93.

[2] Lehman AF, Lieberman JA, Dixon LB, et al. American Psychiatric Association Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 suppl):1–56.

[3]Zhu Y, Krause M, Huhn M, et al. Antipsychotic drugs for the acute treatment of patients with a first episode of schizophrenia: a systematic review with pairwise and network meta-analyses. Lancet Psychiatry.2017;4(9):694-705.

[4] Wang C, Shi W, Huang C, Zhu J, Huang W, Chen G. The efficacy, acceptability, and safety of five atypical antipsychotics in patients with first-episode drug-naïve schizophrenia: a randomized comparative trial. Ann Gen Psychiatry. 2017; 16:47.





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