Open prospective study of ziprasidone in patients with schizophrenia with depressive symptoms: A multicenter study

Authors


Abstract

Aims

The goal of this study was to examine the efficacy and safety of ziprasidone to treat depressive symptoms in Korean patients with schizophrenia who showed stable symptoms.

Methods

In this 8-week, open-label, prospective, non-randomized, multicenter study, 34 patients with schizophrenia who showed a stable response to previous medications, maintained a stable dose, and who had depressive symptoms, were recruited. Ziprasidone was the only antipsychotic agent allowed for 8 weeks after a 2–7-week washout period.

Results

Steady decreases were observed on the Montgomery–Asberg Depression Rating Scale, the Calgary Depression Scale for Schizophrenia, the Positive and Negative Syndrome Scale, and the Clinical Global Impression-Severity Scale scores. The Montgomery–Asberg Depression Rating Scale score was 20.26 ± 4.77 at baseline and 12.21 ± 7.94 at the end-point (P < 0.01). The Calgary Depression Scale for Schizophrenia score was 9.76 ± 4.11 at baseline and 5.00 ± 3.94 at the end-point (P < 0.01). The Positive and Negative Syndrome Scale total score was 75.24 ± 22.63 at baseline and 66.53 ± 24.28 at the end-point (P < 0.01). The Clinical Global Impression-Severity Scale score was 3.44 ± 0.66 at baseline and 3.15 ± 0.86 at the end-point (P < 0.05). No significant differences were observed for total scores on the Simpson and Angus Rating Scale, the Barnes Akathisia Rating Scale, or the Abnormal Involuntary Movement Scale between the baseline and end-point.

Conclusions

Ziprasidone was effective for improving depressive symptom scores and was well tolerated. Switching to ziprasidone is a good strategy in patients with schizophrenia who are experiencing depressive symptoms.

Although positive and negative symptoms conceptualize the core domains of schizophrenia, additional symptom domains, including depressive symptoms, have been verified in patients with schizophrenia.[1] Depressive symptoms are not rare in psychotic disorders, as demonstrated by point-prevalence figures of 7–75% in patients with schizophrenia.[2]

Depressive symptoms in patients with schizophrenia must be evaluated and managed because they are associated with less favorable clinical outcomes, including increased rates of relapse and rehospitalization, poor social functioning, greater cognitive impairment, poor quality of life, increased mortality related to suicide, and poor response to pharmacological treatments. Therefore, early detection and treatment of depressive symptoms in patients with schizophrenia is very important, and optimal management should concurrently treat patients for all schizophrenia symptom domains.[3]

Depression commonly occurs in patients with schizophrenia and has clinical significance. Few studies have demonstrated the possible clinical advantage of using antidepressants to manage depression in patients with schizophrenia, suggesting that the use of antidepressants is unreliable.[4] The efficacy of treatment with antidepressants is restricted and antidepressants can aggravate psychosis during the acute phase.[5] In addition, there is a hazard of pharmacokinetic interactions, particularly with selective serotonin reuptake inhibitors.[6]

Atypical antipsychotics have emerged as a new choice for managing depressive symptoms in patients with schizophrenia. Several studies have reported that several atypical antipsychotics, such as risperidone, olanzapine, quetiapine, ziprasidone and amisulpride, are beneficial to treat concurrent depressive symptoms in patients with schizophrenia.[7-12] In particular, results of a double-blind, placebo-controlled, multicenter study of 139 patients with an acute exacerbation of schizophrenia or schizoaffective disorder showed that ziprasidone is significantly more effective than placebo for improving depression cluster and anergia cluster scores.[13] In another 6-week, multicenter, double-blind study, ziprasidone and olanzapine treatment both resulted in rapid improvement in positive and negative symptoms and depressive symptoms in acutely ill inpatients with schizophrenia and schizoaffective disorder.[14]

However, previous studies included mostly acutely ill patients with schizophrenia, and recent clinical findings show that depressive symptoms during the acute phase respond well to antipsychotic treatment and are positive prognostic factors, whereas depressive symptoms in the post-psychotic phase are linked with poor prognosis and respond poorly to antidepressants.[4] Studies in Korea to identify the antidepressive effect of ziprasidone in patients with schizophrenia and the stabilized symptoms are rare or have shown limited results due to a relatively small number of subjects.

Therefore, the objective of this study was to examine the efficacy and safety of ziprasidone to treat depressive symptoms in Korean patients with schizophrenia who showed stable symptoms.

Methods

This was an 8-week, open-label, prospective, non-randomized, multicenter study.

Participants

The study was conducted at eight hospital sites in Korea. It included patients aged 18–60 years who met the DSM-IV diagnostic criteria for schizophrenia, who showed a stable response to previous medications and maintained a stable dose for 2 weeks, and who had depressive symptoms as defined by a score of 14–32 on the Montgomery–Asberg Depression Rating Scale (MADRS) and had a score of ≤2 on the MADRS suicide items.

Patients were excluded from the trial for: (i) meeting DSM-IV criteria for abuse or dependence on alcohol or other substances; (ii) having a serious and unstable medical or surgical illness; (iii) using an antidepressant during the previous 2 weeks; (iv) scoring ≥33 on the MADRS; and (v) scoring ≥4 on the MADRS suicide items. Pregnant or lactating women were also excluded.

Written informed consent was obtained from all enrolled patients. This trial was approved by the institutional review board of Pusan National University Hospital, Korea.

Study design

Patients receiving antipsychotics underwent a washout period of 2–7 days as judged by a clinician. During the washout period, minimal doses of anticholinergics or benzodiazepines were used to control withdrawal symptoms from previous antipsychotics or aggravation of psychotic symptoms. The initial dose of ziprasidone was 40 mg/day. The dose was increased to 80–160 mg/day within 8 weeks and divided into two doses per day. Titration of dosing was conducted every 7 days depending on the patient's condition. However, titration was conducted at a 2-day interval when required clinically.

Concomitant anticholinergics, benzodiazepines, or hypnotics were allowed for side-effects or insomnia if required during the study, but were not administered prophylactically, and were used at a minimal dose for a minimal duration. Ziprasidone was the only antipsychotic agent, and no other antipsychotics or mood stabilizers were permitted.

Assessments

Data on demographic and clinical characteristics at baseline were obtained (age, sex, and age of onset). This study focused on depressive symptoms in patients with schizophrenia; thus, the primary outcome was to measure depressive symptoms using the Calgary Depression Scale for Schizophrenia (CDSS) and the MADRS at baseline, and at weeks 2, 4, and 8. The CDSS was developed to measure depressive symptoms in patients with schizophrenia. A study on the reliability and validity of the Korean version of the CDSS reported that the K-CDSS is correlated with the MADRS in Korean patients with schizophrenia.[3] However, the reliability and specificity of the MADRS for evaluating depressive symptoms in patients with schizophrenia has not been estimated in a foreign study to the same extent as they have for the CDSS.[15] Therefore, we used both MADRS and CDSS to enhance the accuracy of measuring depressive symptoms in patients with schizophrenia.

Additionally, the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression Severity scale score (CGI-S) at baseline, and at weeks 2, 4, and 8 were also measured to assess the efficacy of ziprasidone. Adverse effects related to extrapyramidal syndrome (EPS) were evaluated using the Simpson and Angus Rating Scale (SAS), the Barnes Akathisia Rating Scale (BARS), and the Abnormal Involuntary Movement Scale (AIMS) at baseline, and weeks 2, 4, and 8. In addition, any spontaneous self-reports and observed adverse effects were recorded throughout the trial.

Statistical analyses

An intent-to-treat analysis was used to evaluate the overall efficacy and safety of ziprasidone. Regardless of inclusion criteria, protocol violation, and dropout, the end-point analysis included results from all subjects who took ziprasidone. Missing values due to dropout were analyzed with the last observation carried forward (LOCF) method in which missing values are replaced by the last observed value for that variable. Total scores on the CDSS, MADRS, PANSS, and CGI-S, SAS, BARS, and AIMS at baseline, weeks 2, 4, and 8 (end-point) were analyzed with the paired t-test.

The response to treatment at the end-point was defined as ≥50% reduction in baseline MADRS and CDSS total scores. Remission to treatment was defined as a CDSS total score <8 at the end-point.[15, 16]

Results

Demographic and clinical characteristics of the patients

Thirty-four subjects with an average age of 41.06 ± 8.62 years were enrolled (14 men, 41% and 20 women, 59%). Five subjects dropped out, and their last available assessment after baseline was used as the end-point with the LOCF approach. Twenty-nine subjects completed the 8-week trial.

Age at onset of schizophrenia was 27.65 ± 7.38 years. Total scores on the MADRS, CDSS, PANSS, and CGI-S at baseline were 20.26 ± 4.77, 9.76 ± 4.11, 75.24 ± 22.63, and 3.44 ± 0.66, respectively (Table 1). Thirty patients were given antipsychotic monotherapy before washout (quetiapine, one subject; amisulpride, one subject; clozapine, one subject; zotepine, two subjects; haloperidol, four subjects; olanzapine, five subjects; aripiprazole, five subjects; risperidone, 11 subjects) and four patients were given antipsychotic combination therapy (haloperidol + chlorpromazine, one subject; risperidone + zotepine, one subject; haloperidol + quetiapine, two subjects).

Table 1. Demographic and clinical characteristics of the patients (n = 34)
Characteristicsn (%) or mean
  1. CDSS, Calgary Depression Scale for Schizophrenia; CGI-S, Clinical Global Impression scale; MADRS, Montgomery–Asberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale.
Age41.06 ± 8.62
Sex 
Male14 (41%)
Female20 (59%)
Age at onset of schizophrenia27.65 ± 7.38
At baseline, total score of 
MADRS20.26 ± 4.77
CDSS9.76 ± 4.11
PANSS75.24 ± 22.63
CGI-S3.44 ± 0.66

Dosing and concomitant medications

The end-point daily doses of ziprasidone were 114.71 ± 34.92 mg/day (maximum 160 mg/day).

The percentages of patients who received benztropine, beta-adrenergic antagonists, or benzodiazepines at any time during the study were 26% (nine subjects), 6% (two subjects), and 53% (18 subjects), respectively. Stilnox (four subjects) and trazodone (one subject) for sleep control, valproate (three subjects) for impulse control, piprinhydrinate (one subject) as an antihistamine for rash and itching control, amlodipine (one subject) as a calcium channel blocker for hypertension, and aspirin (one subject) for preventing atherosclerosis were used by judgment of a physician during the study.

Efficacy

Decreases were steadily observed on the MADRS, CDSS, PANSS, and CGI-S scores as time passed. However, the first time to significant improvement on each scale was different. Significant reductions in MADRS and CDSS scores were identified as quickly as week 2. However, significant improvements in the PANSS and CGI-S total scores were observed on weeks 4 and 8, respectively.

The MADRS score was 20.26 ± 4.77 at baseline and 12.21 ± 7.94 at the end-point (P < 0.01). The CDSS score was 9.76 ± 4.11 at baseline and 5.00 ± 3.94 at the end-point (P < 0.01). The PANSS total score was 75.24 ± 22.63 at baseline and 66.53 ± 24.28 at the end-point (P < 0.01). The CGI-S score was 3.44 ± 0.66 at baseline and 3.15 ± 0.86 at the end-point (P < 0.05) (Table 2).

Table 2. Changes in the four scores (mean ± SD) of the efficacy measures over time (n = 34)
 MADRSCDSSPANSSCGI-S
  1. *P < 0.05; **P < 0.01 compared with baseline.
  2. CDSS, Calgary Depression Scale for Schizophrenia; CGI-S, Clinical Global Impression scale; MADRS, Montgomery–Asberg Depression Rating Scale; PANSS, Positive and Negative Syndrome Scale.
Baseline20.26 ± 4.779.76 ± 4.1175.24 ± 22.633.44 ± 0.66
Week 217.26 ± 4.65**7.79 ± 3.53**72.97 ± 22.633.44 ± 0.66
Week 413.74 ± 7.24**5.97 ± 3.97**68.47 ± 23.74*3.41 ± 0.74
Week 812.21 ± 7.94**5.00 ± 3.94**66.53 ± 24.28*3.15 ± 0.86*

At the end-point, 44% (n = 15) and 53% (n = 18) of the patients met the response criteria as measured by the MADRS and CDSS. A total of 74% (n = 25) of patients met remission criteria as measured by the CDSS. All patients who met the response criteria as measured by the CDSS also met the remission criteria as measured by the CDSS at the end-point.

Safety and tolerability

No significant differences were observed for total scores on the SAS, BARS, and AIMS between the baseline and end-point (Table 3).

Table 3. Scores (mean ± SD) for the extrapyramidal side-effect measures over time (n = 34)
 SASBARSAIMS
  1. AIMS, Abnormal Involuntary Movement Scale; BARS, Barnes Akathisia Rating Scale; SAS, Simpson and Angus Rating Scale.
Baseline2.62 ± 3.480.88 ± 1.510.65 ± 1.79
Week 22.85 ± 3.891.03 ± 1.920.74 ± 1.91
Week 42.44 ± 3.691.09 ± 2.380.38 ± 0.82
Week 82.06 ± 3.240.53 ± 1.210.35 ± 0.73

Discussion

The primary objective of this study was to examine the efficacy and safety of ziprasidone for treating depressive symptoms in Korean patients with schizophrenia who showed stable symptoms. Overall, scores on the MADRS, CDSS, PANSS, and CGI-S decreased as time passed. At the end-point, nearly half of the patients met the response criteria as measured by the MADRS and CDSS. Total scores on the SAS, BARS, and AIMS were not significantly different between baseline and the end-point, and 85% of the patients completed the 8-week trial. These results indicate that ziprasidone has efficacy and tolerability for treating depressive symptoms in patients with schizophrenia.

Another study in Korea supported these results. Zhao et al. verified that ziprasidone is effective for managing positive, negative, and depressive symptoms during first-episode psychosis. In that study, significant improvements in PANSS total and positive subscale scores appeared as quickly as 1 week and significant improvement in the CDSS score was detected on week 8 after administration of ziprasidone, although 16 patients dropped out among the 27 enrolled patients.[17] In the present study, a significant reduction in depressive symptoms scores was identified as quickly as week 2. However, significant improvements in the PANSS total score were observed at week 4. These difference may have been caused by patient selection (present study, schizophrenia with stabilized symptom vs first episode psychosis in Zhao's study) and end-point ziprasidone doses (present study, 114.71 ± 34.92 mg/day vs 131.85 ± 51.22 mg/day in Zhao's study). A significant reduction in depressive symptoms may not indicate an indirect effect secondary to reduction of schizophrenic symptoms if the improvement order of symptom domains is considered in the present study.

In addition, other studies have been conducted on the anti-depressive effect of ziprasidone in patients with schizophrenia. Daniel et al. reported that depressive symptoms in patients with acute exacerbated schizophrenia and clinically significant depression at baseline improved with 160-mg/day ziprasidone compared with those in a placebo group.[18] Kim et al. reported significant reductions in scores on the CDSS and Beck Depression Inventory at the end-point after switching from aripiprazole to ziprasidone.[19] According to our results and those of previous studies, ziprasidone can be used as an option for treating depressive symptoms in Korean patients with schizophrenia.

Ziprasidone is an atypical antipsychotic with a high serotonin-2/dopamine-2 (5-HT2/D2) receptor-binding ratio and binds to several receptors.[10] Ziprasidone has high affinity for dopamine D2, D3, serotonin 5HT1A, 5HT1D, 5HT2A, and 5HT2C receptors and relatively moderate affinity for histamine H1 and adrenergic-α receptors. It has low affinity for dopamine D1 and α2 receptors and negligible affinity for adrenergic β and muscarinic, nicotinic receptors. Also, ziprasidone inhibits 5HT and norepinephrine re-uptake moderately. The actions of ziprasidone as a potent 5HT1A receptor agonist, a potent 5-HT1D and 5-HT2C receptor antagonist, and a moderate inhibitor of norepinephrine and serotonin re-uptake are expected to be effective for affective as well as positive and negative symptoms.[13] Therefore, the significant improvement in the depressive symptom scale shown in the present study may be a result of a direct anti-depressant effect of ziprasidone.

The higher ratio of affinity for 5HT2A receptors compared to D2 receptors means that it is less likely to induce extrapyramidal side-effects. Depressive symptoms in patients with schizophrenia are similar to EPS. In particular, drug-induced parkinsonism may look like a depressive state.[20] In the present study, the dropout rate was relatively low and there was no exacerbation of EPS scales. A significant reduction in depressive symptoms may not indicate an indirect effect on EPS in the present study considering the lack of a significant difference in total scores of the SAS, BARS, and AIMS between the baseline and end-point. Therefore, ziprasidone was well tolerated by Korean patients with schizophrenia and depressive symptoms.

There were several limitations in the present study. This was an open-prospective study that might be biased in evaluating patients. In addition, it was not a randomized controlled study. Therefore, there was no comparative group. However, compared with previous studies, we identified an anti-depressive effect of ziprasidone in patients with schizophrenia and stable symptoms.

Conclusion

We examined the efficacy and safety of ziprasidone for treating depressive symptoms in Korean patients with schizophrenia who showed stable symptoms. We found that ziprasidone was effective for improving depressive symptom scores and was well tolerated. These results indicate that ziprasidone is effective for treating depressive symptoms in Korean patients with schizophrenia. Switching to ziprasidone is a good strategy in patients with schizophrenia who are experiencing depressive symptoms simultaneously.

Acknowledgments

This study was supported by Pfizer Pharmaceuticals Korea. The authors had no conflicts of interest in conducting this study or preparing the manuscript.

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