Abstract
Many patients with schizophrenia (SCZ) discontinue antipsychotics, frequently due to dose-related multiple and severe adverse effects. We hypothesized that a low-dose ziprasidone plus sertraline would reduce serious side effects without affecting treatment efficacy. Therefore, this clinical trial was designed to investigate the efficacy, safety, and tolerability of adding sertraline to ziprasidone in order to substantially reduce ziprasidone dose and potential side effects in first-episode and drug-naive (FEDN) patients with SCZ. This 24-week randomized, double-blinded, controlled clinical trial randomly allocated 452 FEDN SCZ patients to receive a usual dose of ziprasidone (control group) or half the dose of ziprasidone in combination with sertraline (ZS group). Treatment outcome included the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and the Personal and Social Performance Scale (PSP) at baseline and weeks 2, 4, 8, 12, and 24. Repeated measures ANCOVA showed significant treatment by time interactions on the PANSS general psychopathology and total scores, as well as CGI-S, HAMD, and PSP scores (all p < 0.05). Furthermore, the ZS group had greater reductions in PANSS general psychopathology, total scores, HAMD, and CGI-S (all p < 0.05) and greater increases in the PSP total score (p < 0.01) than the control group. Importantly, adverse effects were lower in the ZS than control group. The reduction in PANSS, CGI-S, or HAMD scores was not correlated with the increase in PSP. Sex and duration of disease predicted PSP improvement from baseline to week 24 in the ZS group. Our FEDN patients with SCZ were effectively treated for their psychotic and depressive symptoms while experiencing significantly fewer adverse effects using half the usual ziprasidone dose when combined with sertraline. ClinicalTrials.gov, NCT04076371.
Supplementary Information
The online version contains supplementary material available at 10.1007/s13311-022-01242-7.
Keywords: Schizophrenia, First-episode, Ziprasidone, Sertraline, Efficacy
Introduction
Schizophrenia (SCZ) is a major public health concern, affecting approximately 1% of people worldwide [1]. The high rate of relapse, disability, and premature mortality of SCZ cause extensive suffering to their families and society [2]. To date, antipsychotic medications based on anti-dopaminergic activity have been used to alleviate the symptoms of the patients with SCZ [3]. However, their efficacy is far from satisfactory and roughly 30% of patients do not respond to antipsychotic medications [4, 5].
Several types of symptoms characterize SCZ, including positive symptoms and negative symptoms. Both atypical and typical antipsychotic drugs are generally effective for the positive symptoms, but are ineffective against negative symptoms in SCZ [6]. Negative symptoms persist after the alleviation of positive symptoms in 20–40% of patients with SCZ and are a major cause of chronic disability [7]. Clinically, patients with SCZ often experience both positive and negative symptoms [8]. The negative symptoms may be related to a relative deficiency of dopamine (DA) and serotonin (5-HT) in the prefrontal cortex, while the positive symptoms may be related to subcortical DA hyperfunction [9–11]. Therefore, the optimal treatment for SCZ may be a combination of medications that improve DA and 5-HT function in the frontal lobe of the cortex, while reducing the subcortical DA hyperfunction. This medication combination might increase D1 receptors in the cortex, while blocking subcortical D2 receptors.
Antipsychotics vary considerably in their affinity for different synaptic receptors, leading to possible diverging efficacy and safety profiles. Numerous clinical trials comparing the efficacy of different atypical antipsychotics for treating patients SCZ did find that the efficacy of different antipsychotics varies, and the side effects caused by drugs are also different in patients with a first episode of psychosis [12, 13]. More recently, a systematic review and network meta-analysis of 18 antipsychotics revealed marked difference between different types of antipsychotic treatment for inducing severe metabolic disturbances. Olanzapine and clozapine exhibited the worst metabolic profiles, while ziprasidone, brexpiprazole, cariprazine, lurasidone, and aripiprazole exhibited the most benign profiles [14]. The largest systematic review and network meta-analysis of 32 antipsychotics reported that clozapine, amisulpride, zotepine, olanzapine, and risperidone were significantly more efficacious for the efficacy outcome than other antipsychotics. Ziprasidone is ranked on the middle of the rankings concerning efficacy and no efficacy differences with other antipsychotics, but side effects showed more marked differences [15].
Exploring new medication combinations with antipsychotic drugs is a major challenge for increased efficacy and reduced side effects in treating SCZ. Ziprasidone, a selective dopamine D2 receptor blocker, can inhibit dopamine hyperfunction in subcortical structures and effectively reduce the positive symptoms of patients with SCZ. Moreover, it also has a low incidence of extrapyramidal adverse effects, little effect on serum prolactin levels, blood lipids, blood glucose, and weight gain [31 32]. However, the clinical application of ziprasidone is limited because it carries a risk of fatal arrhythmias by prolonging the QT interval by more than 60 ms above baseline, causing torsades de pointes (TdP) and even sudden cardiac death [16, 17]. In addition, to alleviate the side effects of ziprasidone, this study adopted a low-dose ziprasidone plus sertraline to explore a clinical pharmacological treatment with few clinical side effects and comparable efficacy to standard dose of ziprasidone. To then address the negative symptoms of SCZ, we sought a selective serotonin reuptake inhibitor (SSRI) that would essentially be devoid of cardiac effects and might also have dopaminergic effects. Sertraline is the only SSRI that increases extracellular dopamine concentrations in the nucleus accumbens and striatum [18, 19]. While bupropion also increases dopamine more strongly than any SSRI, its potential cardiac toxicity from prolonged QT intervals made this a poor combination with ziprasidone [20]. Therefore, its potential to improve the depressive symptoms of SCZ as an augmentation therapy in combination with antipsychotics might result from both its general SSRI activity and its increase in brain dopamine levels in the nucleus accumbens, which has been associated with reward and reduced depressive symptoms [21]. Furthermore, sertraline has effectively improved post-psychotic depressive symptoms in SCZ patients [22].
In this study, we hypothesized that sertraline in combination with ziprasidone at a low daily dose (60–80 mg/day) was superior to the standard dose of ziprasidone monotherapy of 120–160 mg/day in improving psychotic symptoms and especially reducing side effects in first-episode and drug-naive (FEDN) SCZ patients. We also assessed personal and psychosocial functioning as compared to the control group in a 24-week, double-blind and randomized trial in FEDN patients with SCZ.
Methods
Patients
We conducted this study in the First Hospital of Shanxi Medical University from January 2012 to December 2018. We recruited patients and determined their diagnostic eligibility base on the Structured Clinical Interview for DSM-IV (SCID). The study protocol was approved by the Institutional Review Board of First Hospital of Shanxi Medical University and each participant signed the written informed consent form. The clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier NCT04076371).
The participants were first-episode drug-naïve patients (FEDN) with SCZ who also met the following inclusion criteria: (1) Han nationality; (2) age 16–45 years; (3) disease course less than 5 years; (4) medication naïve; (5) school education at least 9 years. Exclusion criteria were as follows: (1) abuse or substance dependence; (2) having major medical somatic comorbidities, such as diabetes, hypertension, or cardiac disease including recent acute myocardial infarction, decompensated heart failure, or a history of prolonged QT interval (including congenital long QT syndrome); (4) having severe arrhythmia, sinus bradycardia, or elevated myocardial enzymes; (5) having current self-injury or destructive and unprovoked violence or suicide; (6) having abnormal values on routine biochemical tests; (7) taking oral medications that prolong the QT interval.
Intervention
This is a 24-week, randomized controlled clinical trial. The study group comprised 226 FEDN patients who received capsules containing ziprasidone (60–80 mg/day) and sertraline 50 mg/day (ZS group). The control group comprised 226 FEDN patients who received identically looking capsules of ziprasidone (120–160 mg/day) monotherapy (control group). The randomization number was generated by a computer. Then, the independent third party randomly divided the patients to the ZS and control groups based on their assigned randomization number. The patients and raters were unaware of treatment allocation. Only a nurse who did not participate in this study was aware of the group assignment.
Patients reached their experimental ziprasidone dose by the end of the second week. Sertraline was given at a dose 25 mg/day for the first week, and then 50 mg/day from week 2 until the end of the trial. Then, no antipsychotic adjustments were allowed during the clinical trial.
However, patients in both groups were allowed to take 2–3 mg/day oral clonazepam during the first 4 weeks of treatment to improve sleep and reduce anxiety and acute agitation. We obtained medical histories, electrocardiograms, and physical examinations from all patients.
As shown in Fig. 1, 210 patients in ZS group and 196 patients in the control group completed the 24-week treatment.
Fig. 1.
Consort flow diagram of this study. Note: ZS group, ziprasidone plus sertraline; Control group, ziprasidone monotherapy
Objectives and Outcomes
The primary outcome measures were psychotic symptoms evaluated by the Positive and Negative Syndrome Scale (PANSS) [23] and CGI-Severity (CGI-S) [24]. In this study, a PANSS 5-factor model was also used to capture the validity of the clinical symptom dimension, which consists of five factors, namely, positive, negative, disorganization, excitement, and depression factors [25]. The secondary outcome measures were depressive symptoms evaluated by the Hamilton Depression Rating Scale (HAMD) [26] and psychosocial functioning evaluated by Personal and Social Performance Scale (PSP) [27]. Psychotic symptoms, depressive symptoms, and psychosocial functioning were evaluated at baseline, at the end of weeks 4, 8, 12, and 24. The raters received a training course before the clinical trial began. After training, the inter-observer correlation coefficients for HAMD total score and PANSS total score were maintained at >0.8 during repeated assessments (Fig. 2).
Fig. 2.
The trajectory of the PANSS total scores in each treatment group (mean ± standard deviation)
Assessment of Adverse Events
All patients underwent electrocardiogram monitoring for cardiac side effects, checking for any significant arrhythmias or other serious abnormalities at baseline and at follow-up. Moreover, we used the Treatment Emergent Symptom Scale (TESS) to evaluate adverse treatment effects [28].
Statistical Analysis
We compared demographic characteristics, baseline psychotic symptoms, depressive symptoms, and psychosocial functioning between the ZS and control groups using analysis of variance (ANOVA) or chi-square (Table 1).
Table 1.
Demographic characteristics and clinical data in combination therapy group (ZS) and control group (mean ± standard deviations)
| Variable | Control group (n = 226) |
ZS group (n = 226) |
F or X2 (p value) |
|---|---|---|---|
| Gender (male/female) | 133/93 | 119/107 | 1.8 (0.19) |
| Age (years) | 27.2 ± 5.9 | 26.3 ± 5.6 | 3.1 (0.08) |
| Education (years) | 12.5 ± 2.5 | 12.0 ± 2.5 | 4.9 (0.03) |
| Lab results | |||
| QTC | 394.0 ± 9.9 | 392.9 ± 10.1 | 1.3 (0.26) |
| HR | 83.0 ± 4.7 | 81.7 ± 6.1 | 6.3 (0.01) |
| CK | 91.8 ± 32.9 | 86.9 ± 28.6 | 2.8 (0.10) |
| CK-MB | 8.8 ± 2.9 | 8.4 ± 2.8 | 2.6 (0.11) |
| LDH | 152.4 ± 27.0 | 155.4 ± 26.4 | 1.4 (0.23) |
| HBD | 124.2 ± 17.5 | 123.1 ± 18.9 | 0.4 (0.53) |
| Age of onset (years) | 24.9 ± 5.2 | 24.1 ± 5.1 | 2.7 (0.10) |
| Duration of illness (years) | 2.4 ± 1.8 | 2.3 ± 1.7 | 0.9 (0.34) |
CK creatine kinase, CK-MB creatine kinase-MB, HBD hydroxybutyrate dehydrogenase, LDH lactate dehydrogenase, SD standard deviation, P positive subscore, N negative subscore, G general psychopathology subscore, CGI-S Clinical Global Impression-severity, PSP Personal and Social Performance Scale, HAMD Hamilton Depression Rating Scale, HAMA Hamilton Anxiety Scale
Our main hypothesis was tested by the repeated measures multivariate analysis of variance (MANOVA) to compare the efficacy of the two treatment strategies. Last observation carried forward (LOCF) analysis was performed on patients who dropped out after treatment. All data were analyzed using an intention to treat design (ITT). After the two-way repeated measures MANOVA, the significant multivariate omnibus tests were followed with a test of individual univariate effects. For the dependent variables, 6 time points (baseline, week 4, 8, 12, and 24) were used as the repeated measures within-effect, and group (monotherapy vs combination) was used as the between-effect. In each repeated measures ANOVA model, the independent variables were PANSS scores, HAMD scores, CGI scores, and PSP scores over time, respectively. If there was significant difference in the group and time interactions, the ANCOVA with the baseline score as a covariate was performed to investigate the group differences at week 4, 8, 12, and 24. Further regression analyses were used to assess those factors that correlated with the changes in the outcomes, such as psychotic symptoms and psychosocial functioning. The following factors were potentially associated with the changes in outcomes and thus were included in the regression analysis as independent variables: baseline PANSS or PSP, age, disease duration, onset age, sex, and years of education. If the group × time interaction effect was not significant, further statistical testing was not required. To adjust for multiple testing, the Bonferroni corrections were applied. All statistical analyses were conducted in PASW Statistics, version 22.0 (SPSS, Inc., Chicago). The threshold for significance was set at p < 0.05.
Results
Demographic and Basic Descriptive Data
In this study, 46 patients (16 in ZS group and 30 in control group) dropped out during treatment, including non-compliance with physician recommendations for discharge (N = 12), withdraw consent (N = 2), lack of efficacy (N = 4), and treatment adverse events (N = 28).
At baseline, there was significant difference in education level between ZS group (n = 226) and control group (n = 226), but no statistical differences in age, sex, disease duration, and onset age. Also, there was no significant difference in baseline PANSS total score and subscores, CGI-S and HAMD total scores (all p > 0.05). However, the patients in the ZS group had higher PSP total scores than the control group (all p < 0.05) (Table 2). HR was higher in the control group than in the ZS group (p = 0.01), but no significant differences in QTC, CK, CK-MB, HBD, and LDH were found between the two groups (all p > 0.05). At baseline, we also found that the PANSS total score was positively correlated with the HAMD total score (r = 0.37, p < 0.001), and negatively correlated with the PSP total score (r = −0.35, p < 0.001).
Table 2.
PANSS scores, HAMD score, CGI-S, and PSP at baseline, week 4, week 8, week 12, and week 24 in first episode drug-naïve patients with schizophrenia treated with ziprasidone with sertraline (ZS) group and ziprasidone monotherapy (control) group (mean ± standard deviations)
| Baseline (n = 452) |
Week 4 (n = 452) |
Week 8 (n = 452) |
Week 12 (n = 452) |
Week 24 (n = 452) |
Group (p value)a |
Group × Time F (p value)a |
|
|---|---|---|---|---|---|---|---|
| PANSS positive subscore | 0.3 (0.56) | 1.3 (0.42) | |||||
| Control group | 27.6 ± 6.6 | 21.5 ± 6.8 | 16.5 ± 7.7 | 12.6 ± 7.2 | 11.5 ± 7.3 | ||
| ZS group | 27.0 ± 6.6 | 20.1 ± 5.9 | 15.2 ± 5.9 | 11.5 ± 5.2 | 10.0 ± 5.2 | ||
| PANSS negative subscore | 3.8 (0.053) | 0.9 (0.38) | |||||
| Control group | 24.4 ± 6.2 | 21.5 ± 6.2 | 18.3 ± 5.6 | 15.1 ± 4.9 | 11.7 ± 3.7 | ||
| ZS group | 25.4 ± 6.6 | 20.3 ± 6.3 | 15.3 ± 5.1 | 12.3 ± 3.5 | 9.2 ± 1.5 | ||
| PANSS general psychological subscore | 3.2 (0.07) | 12.3 (<0.001) | |||||
| Control group | 57.7 ± 8.5 | 47.1 ± 10.5 | 39.2 ± 12.7 | 29.0 ± 13.1 | 26.2 ± 14.0 | ||
| ZS group | 58.5 ± 7.9 | 46.1 ± 9.5 | 35.8 ± 10.6 | 25.4 ± 9.7 | 23.1 ± 10.3 | ||
| PANSS total score | 8.4 (0.004) | 17.9 (<0.001) | |||||
| Control group | 109.8 ± 12.2 | 90.6 ± 16.3 | 75.0 ± 20.9 | 58.0 ± 23.2 | 51.2 ± 25.6 | ||
| ZS group | 110.9 ± 11.4 | 87.1 ± 15.4 | 67.1 ± 17.7 | 50.3 ± 18.1 | 43.5 ± 19.6 | ||
| Positive factor | 9.9 (0.002) | 1.7 (0.17) | |||||
| Control group | 16.2 ± 3.3 | 14.3 ± 4.3 | 12.2 ± 4.7 | 10.4 ± 4.7 | 8.8 ± 4.6 | ||
| ZS group | 15.4 ± 2.9 | 13.4 ± 4.3 | 10.9 ± 4.5 | 9.0 ± 4.3 | 7.6 ± 4.0 | ||
| Negative factor | 0.001 (0.99) | 10.5 (<0.001) | |||||
| Control group | 21.0 ± 5.0 | 19.8 ± 6.5 | 17.5 ± 6.3 | 15.9 ± 6.4 | 12.4 ± 5.3 | ||
| ZS group | 21.7 ± 5.0 | 19.0 ± 6.3 | 16.9 ± 6.1 | 15.5 ± 5.9 | 11.5 ± 5.1 | ||
| Cognitive factor | 5.5 (0.02) | 4.7 (0.008) | |||||
| Control group | 11.5 ± 2.9 | 10.3 ± 3.1 | 9.5 ± 3.3 | 8.0 ± 3.2 | 6.6 ± 3.2 | ||
| ZS group | 11.3 ± 3.2 | 9.6 ± 3.4 | 8.6 ± 3.5 | 7.1 ± 3.2 | 5.8 ± 2.9 | ||
| Depression factor | 4.3 (0.04) | 10.0 (<0.001) | |||||
| Control group | 9.1 ± 4.4 | 8.3 ± 4.3 | 7.5 ± 4.2 | 6.9 ± 4.2 | 6.0 ± 4.1 | ||
| ZS group | 8.5 ± 3.8 | 7.5 ± 3.4 | 6.4 ± 3.2 | 5.7 ± 3.1 | 5.1 ± 3.0 | ||
| Excitement factor | 1.1 (0.30) | 1.6 (0.16) | |||||
| Control group | 15.0 ± 4.4 | 13.1 ± 4.2 | 9.6 ± 4.2 | 8.4 ± 4.0 | 7.2 ± 4.0 | ||
| ZS group | 15.4 ± 4.4 | 13.5 ± 4.3 | 9.8 ± 4.4 | 8.6 ± 4.1 | 7.2 ± 4.1 | ||
| CGI-S score | 39.0 (<0.001) | 76.1 (<0.001) | |||||
| Control group | 5.7 ± 0.6 | 5.0 ± 0.6 | 4.1 ± 0.9 | 3.5 ± 1.0 | 3.1 ± 1.3 | ||
| ZS group | 5.7 ± 0.7 | 4.9 ± 0.5 | 3.7 ± 0.8 | 2.8 ± 1.0 | 2.0 ± 1.3 | ||
| HAMD total score | 44.7 (<0.001) | 78.3 (<0.001) | |||||
| Control group | 23.1 ± 5.0 | 18.9 ± 5.3 | 14.8 ± 5.7 | 12.0 ± 6.3 | 9.3 ± 7.0 | ||
| ZS group | 23.4 ± 4.7 | 17.4 ± 4.5 | 10.3 ± 4.7 | 7.0 ± 5.1 | 4.7 ± 5.5 | ||
| PSP total score | 24.3 (<0.001) | 55.0 (<0.001) | |||||
| Control group | 34.1 ± 3.9 | 43.6 ± 5.2 | 59.5 ± 10.8 | 67.6 ± 13.7 | 73.6 ± 16.2 | ||
| ZS group | 33.2 ± 5.0 | 44.0 ± 5.2 | 63.7 ± 10.2 | 75.5 ± 13.7 | 84.3 ± 15.8 | ||
aAdjusted F value controlling for sex, age, and onset age
Primary Outcomes
We compared the PANSS and CGI-S scores using the covariates of age, sex, and onset age and found a group × time interaction (Wilks’ lambda F = 50.6, p < 0.001). Using univariate repeated measured ANCOVA, we found significant group-by-time interactions for the PANSS total score (F = 17.9, p < 0.001) and on general psychological sub-scores (F = 12.3, p < 0.001). Further analysis showed significant group-by-time interactions for negative factor (F = 10.5, p < 0.001), cognitive factor (F = 4.7, p = 0.008), and depression factor (F = 10.0, p < 0.001). We also found a significant group × time interaction on the CGI-S (F = 76.1, p < 0.001) (Table 2).
After covarying for the confounding factors, we found that after 24 weeks of treatment, the PANSS total score (F = 13.0, p < 0.001), PANSS general psychological sub-scores (F = 7.8, p = 0.005), and CGI-S (F = 115.1, p < 0.001) were significantly lower in the ZS than in the control group. However, we found no significant association between the reduction in the PANSS or CGI-S total scores and the reduction in the HAMD (all p > 0.05).
Secondary Outcomes
We showed significant group × time interactions for the PSP (F = 55.0, p < 0.001) and HAMD (F = 78.3, p < 0.001) with the PSP significantly higher and HAMD lower in the ZS than in the control group at 24-week follow-up (PSP: F = 50.7, p < 0.001; HAMD: F = 65.6, p < 0.001). We also found significant positive associations between the reduction from baseline in the PSP and HAMD (r = −0.18, p = 0.008), CGI-S (r = −0.22, p = 0.002), and PANSS total scores (r = −0.37, p < 0.001). Since sex and disease duration also were correlated with changes in the PSP scores (all p < 0.05), we included sex, disease duration, age, baseline PSP, and reductions in the PANSS, HAMD, and CGI-S scores as covariates in a regression analysis, which showed that sex (β = 5.4, t = 7.8, p < 0.001) and disease duration (β = −0.6, t = −3.6, p < 0.001) were predictors of PSP improvement from baseline to week 24 in the ZS group.
Treatment Side Effects
Twenty-eight patients withdrew due to severe side effects of QTC interval prolongation > 485 or sinus bradycardia, including 22 in the control group, significantly more than the 6 in the ZS patients (9.7% vs. 2.7%). In addition, we found that ZS patients had fewer side effects as measured by TESS (Table 3).
Table 3.
Comparison of adverse effects using Treatment Emergent Symptom Scale between ZS group and control group
| Adverse events | ZS group (n = 226) | Control group (n = 226) | X2 (p) |
|---|---|---|---|
| n (%) | n (%) | ||
| Tremor | 18 (8.0) | 23 (10.2) | 0.7 (0.41) |
| Akathisia | 9 (4.0) | 11 (4.9) | 0.2 (0.65) |
| Insomnia | 22 (9.7) | 34 (15.0) | 2.9 (0.09) |
| Somnolence | 6 (2.7) | 7 (3.1) | 0.08 (0.78) |
| Constipation | 4 (1.8) | 7 (3.1) | 0.8 (0.36) |
| Nausea | 0 | 7 (3.1) | 7.1 (0.008) |
| Dizziness | 9 (4) | 15 (6.6) | 1.6 (0.21) |
| Weight gain | 4 (1.8) | 7 (3.1) | 0.8 (0.36) |
| Electrocardiographic changes | 6 (2.7) | 22 (9.7) | 9.7 (0.002) |
| Muscle rigidity | 20 (8.8) | 23 (10.2) | 0.2 (0.63) |
| dry mouth | 6 (2.7) | 15 (6.6) | 4.0 (0.044) |
Discussion
We found that after 24 weeks of treatment, low-dose ziprasidone in combination with sertraline was more efficacious than ziprasidone monotherapy in FEDN patients. Moreover, compared to the monotherapy, patients under combination therapy presented better psychosocial functioning at the end of follow-up.
To our present knowledge, it is the first study to assess the efficacy of a low-dose ziprasidone in combination with sertraline on the symptoms of FEDN patients. Although the side effects of atypical antipsychotic are significantly lower than those of typical antipsychotics, long-term use of medium or high dose of antipsychotics often has been related to serious or even fatal side effects. Compared with other atypical antipsychotics, ziprasidone is suitable for the treatment of first-episode patients based on its pharmacological mechanism. It can not only effectively reduce the psychotic symptoms of patients, but also have a low incidence of metabolic side effects. Indeed, in this clinical trial, we found that the combined treatment was superior to the usual dose of ziprasidone monotherapy in reducing psychotic and depressive symptoms and side effects. We found that reducing the daily dose of ziprasidone for treating SCZ not only ensured the efficacy in FEDN SCZ, but also reduced the prolongation of the QTC interval, which correlates with the dose of ziprasidone, thus reducing the risk of TdP. Therefore, the present study supports new drug combination treatment with low dose of ziprasidone for SCZ.
In addition, it is worth mentioning that patients in the ziprasidone alone and SCZ groups were on the same titration schedule to reach the experimental doses. After an acute treatment initiation in the control group with the higher ziprasidone dose following a more aggressive treatment initiation, it is possible that secondary effects such as side effects may be probably more frequent in the higher ziprasidone dose group than in the lower ziprasidone dose group plus sertraline. This may explain some differences in the results between two treatment groups, especially with regard to side effects.
One possible explanation for the efficacy of combination treatment in FEDN patients with SCZ is related to sertraline’s regulation of the 5-HT system. Atypical antipsychotics mainly are DA blockers and act on D2 receptors in the brain, which reduce positive symptoms such as hallucinations and delusions, but have little effect on negative symptoms, depressive symptoms and cognitive impairments [29]. Negative symptoms are the common cause of SCZ relapse and chronically impair social functioning, which are still unmet and persistent treatment targets [6]. Since negative symptoms are related to insufficient activation of DA and 5-HT neurons in the prefrontal cortex, the combination’s efficacy for the negative symptoms in SCZ patients may be due to the sertraline’s selective inhibition of serotonin reuptake. Notably, sertraline also enhances dopaminergic activity by blocking DA transporters and reuptake [30, 31]. Sertraline can improve fatigue, decreased motivation, poor concentration, anxiety, and depression, thereby reducing negative and cognitive symptoms. Indeed, we found that after combination treatment for 24 weeks, FEDN patients showed lower HAMD scores on the combination compared with ziprasidone monotherapy. Moreover, sertraline can also reduce psychotic symptoms in patients with depressive disorder by binding to the sigma-1 receptor [32]. SCZ patients often have anxiety and depression, which are related to the pathogenesis and persistence of psychotic symptoms [33, 34]. Studies have found that depressive symptoms are associated with an increase in auditory hallucinations and persecutory delusions [35, 36], while persistent anxiety is a predictor of sub-clinical levels of paranoia and delusions [37, 38]. Hence, the rapid reductions in depression and anxiety by sertraline may also improve the positive symptoms of SCZ patients. Moreover, the positive symptom of SCZ patients is closely related to the hyperfunction of central DA [39]. The increase of central 5-HT levels may also inhibit the activity of DA [40] and further alleviate the positive symptoms of patients. Previous studies support that sertraline combined with antipsychotics improved the positive symptoms of SCZ patients [41, 42]. To sum up, the above pharmacological mechanisms of sertraline probably underly the success of this combination therapy for SCZ patients. However, the failure of the reduction in HAMD score to be associated with the reductions in PANSS or CGI-S suggests that the negative symptoms of SCZ are somewhat different from the typical symptoms of major depressive disorders, as the HAMD assesses.
Importantly, we found that the side effect rate was lower with combination therapy than with ziprasidone monotherapy. Our findings did not support previous reviews reporting that antipsychotic combination therapy increased the total dose of antipsychotics, adverse interactions, and the overall risk of antipsychotics-related side effects [43]. Multiple studies support that both the efficacy of ziprasidone and its side effects on the heart are dose-dependent [17, 44]. Although a recent cross-sectional study with a small sample size (N = 22) found no relationship between QTc interval prolongation and plasma antipsychotic levels [45], our much larger study in 452 patients clearly supports that low-dose of ziprasidone significantly reduces the occurrence of cardiac side effects with a fivefold lower risk of significant cardiac side effects (2.6% vs 10%) using this combination compared to the higher dose monotherapy in the control group. Moreover, sertraline also has shown almost no significant anticholinergic effects or side effects on the heart, and even has some cardioprotective properties [46].
We also found that combination therapy significantly improved the psychosocial functioning of FEDN patients with SCZ as indicated by the increase in PSP scores. Approximately 80% of SCZ patents have persistent and severe social dysfunction, and clinical remission has a close relationship with improving social dysfunction [47]. Previous studies found that psychosocial functioning was associated with psychotic symptoms, particularly negative symptoms [48]. We similarly found that baseline PSP scores were correlated with baseline PANSS scores in our FEDN patients with SCZ. Thus, improvement in social dysfunction appears associated with improvements in psychotic symptoms including negative symptoms, and we found similar associations at baseline between these domains of SCZ in our study [49, 50]. However, we did not find a correlation between the reduction in psychotic or depressive symptoms and the increase in PSP assessment of social dysfunction in the multiple linear regression analysis, which may reflect limitations in the sensitivity to improvement on the PSP in this initially hospitalized population or in the 24 weeks duration of assessment. Longer-term assessments of social functioning may be needed to provide sufficient change in FEDN SCZ patients.
However, it is noteworthy that some atypical antipsychotics which have demonstrated to be as or even more efficacious than ziprasidone (and that have proven to be more effective), have pretty similar receptor binding profiles compared to the combination of ziprasidone and sertraline (and less risk for cardiac events than high doses or even low doses of ziprasidone combination). Consistent with our findings, a recent meta-analysis by Sabe et al. and some others in the last 2 years demonstrate the paradigm of a low-dose antipsychotic approach, specially, for the treatment of negative symptoms (in the case of ziprasidone, no significant benefits over 70–80 mg/day) [51, 52]. We speculate that the combination approach is simply applicable for the case of ziprasidone, because it would be a better choice to employ lower doses. However, this is not possible to demonstrate with this study, since we did not compare the efficacy and side effects of other antipsychotics in combination with sertraline.
The study has several limitations. First, the sample size was reasonably large for a pharmacotherapy study examining symptomatic outcomes such as on the PANSS, but relatively small for expecting substantial changes in social functioning or comparing rates of important, but relatively uncommon medical side effects such as cardiac QT interval prolongations. Therefore, a longer duration trial with a large size sample is warranted to verify the improvements in social dysfunction and critical reduction in serious cardiac side effects in our study. Second, this is only a short/medium-term longitudinal clinical trial. We may have underestimated the longer-term improvement in psychotic symptoms and psychosocial functioning. Third, the main limitation is that it is not a placebo-controlled, double-blind clinical trial design. Patients were hospitalized for the first 12 weeks of treatment and were able to follow double-blind treatment. However, patients did not remain blinded at the 24-week follow-up. In addition, although the patients were not told what drugs they were taking during the trial, and patients were not mutually aware of the number of capsules taken, patients were able to recognize the intervention because those who were assigned to the ZS group needed to take 2 capsules while those who were assigned the control group needed to take 1 capsule. Fourth, we did not collect detailed doses of ziprasidone in each treatment group in this study. Fifth, we did not collect the important measures such as duration of untreated psychosis and duration of untreated illness. In addition, we did not have information concerning the usage of concomitant medication. As a matter of fact, these data should have been included as covariate on the analyses as it may have an impact (or not) on the results, which should be remedied in future studies.
In summary, this clinical trial found that a combination of low-dose ziprasidone with low-dose sertraline had a better treatment outcome than higher dose ziprasidone alone for the negative and depressive symptoms in FEDN patients. Most previous comparative clinical trials compared two or more antipsychotics at medium to high doses, or medium to high doses of antipsychotics combined with standard dose antidepressants to reduce SCZ symptoms, rather than a single antipsychotic at a high and low dose, while adding the antidepressant for only the low-dose group. Although some of these previous studies have shown improved symptoms, these combination treatments incurred higher medical costs and more serious drug side effects. This study, to our best knowledge, for the first time found that, compared with conventional treatment doses of an antipsychotic, low-dose sertraline combined with low-dose ziprasidone can improve the positive symptoms and reduce the negative symptoms in FEDN patients with SCZ. At the same time, the combination therapy showed lower side effects on the heart and better patient compliance, which may benefit patients in clinical practice.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
MHX, FW, and XYZ were responsible for study design, statistical analysis, and manuscript preparation. YCW, XG and MHX were responsible for recruiting the patients, performing the clinical rating, and collecting the clinical data. TRK, JHL, and XYZ were evolving the ideas and editing the manuscript. CZ, XYZ, and MHX were involved in writing the protocol, and cowrote the paper. All authors have contributed to and have approved the final manuscript.
Required Author Forms
Disclosure forms provided by the authors are available with the online version of this article.
Funding
Funding for this study was provided by the CAS Pioneer Hundred Talents Program.
Availability of Data and Materials
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
Declarations
Conflict of Interest
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Cheng Zhu and Xiaoni Guan contributed equally to this work.
Contributor Information
Fengchun Wu, Email: 13580380071@163.com.
Xiangyang Zhang, Email: zhangxy9@gmail.com.
References
- 1.Barnett R. Schizophrenia. Lancet. 2018;391(10121):648. doi: 10.1016/S0140-6736(18)30237-X. [DOI] [PubMed] [Google Scholar]
- 2.McCutcheon RA, Marques TR, Howes OD. Schizophrenia-an overview. JAMA Psychiat. 2020;77(2):201–210. doi: 10.1001/jamapsychiatry.2019.3360. [DOI] [PubMed] [Google Scholar]
- 3.Cheng Z, Yuan Y, Han X, Yang L, Cai S, Yang F, et al. An open-label randomised comparison of aripiprazole, olanzapine and risperidone for the acute treatment of first-episode schizophrenia: Eight-week outcomes. J Psychopharmacol. 2019;33(10):1227–1236. doi: 10.1177/0269881119872193. [DOI] [PubMed] [Google Scholar]
- 4.Howes OD, McCutcheon R, Agid O, de Bartolomeis A, van Beveren NJ, Birnbaum ML, et al. Treatment-resistant schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group consensus guidelines on diagnosis and terminology. Am J Psychiatry. 2017;174(3):216–229. doi: 10.1176/appi.ajp.2016.16050503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Lehman AF, Lieberman JA, Dixon LB, McGlashan TH, Miller AL, Perkins DO, et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):1–56. [PubMed]
- 6.Căpățînă OO, Micluția IV, Fadgyas-Stănculete M. Current perspectives in treating negative symptoms of schizophrenia: a narrative review (Review) Exp Ther Med. 2021;21(3):276. doi: 10.3892/etm.2021.9707. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Javitt DC. Management of negative symptoms of schizophrenia. Curr Psychiatry Rep. 2001;3(5):413–417. doi: 10.1007/s11920-996-0036-9. [DOI] [PubMed] [Google Scholar]
- 8.Rehn AE, Rees SM. Investigating the neurodevelopmental hypothesis of schizophrenia. Clin Exp Pharmacol Physiol. 2005;32(9):687–696. doi: 10.1111/j.1440-1681.2005.04257.x. [DOI] [PubMed] [Google Scholar]
- 9.Chertkow Y, Weinreb O, Youdim MB, Silver H. The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex. Int J Neuropsychopharmacol. 2006;9(3):287–296. doi: 10.1017/S1461145705005626. [DOI] [PubMed] [Google Scholar]
- 10.Rao ML, Möller HJ. Biochemical findings of negative symptoms in schizophrenia and their putative relevance to pharmacologic treatment. A review. Neuropsychobiology. 1994;30(4):160–172. doi: 10.1159/000119156. [DOI] [PubMed] [Google Scholar]
- 11.Trichard C, Paillère-Martinot ML, Attar-Levy D, Recassens C, Monnet F, Martinot JL. Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry. 1998;155(4):505–508. doi: 10.1176/ajp.155.4.505. [DOI] [PubMed] [Google Scholar]
- 12.Vázquez-Bourgon J, Mayoral-van Son J, Gómez-Revuelta M, Juncal-Ruiz M, Ortiz-García de la Foz V, Tordesillas-Gutiérrez D, et al. Treatment discontinuation impact on long-term (10-year) weight gain and lipid metabolism in first-episode psychosis: results from the PAFIP-10 cohort. Int J Neuropsychopharmacol. 2021;24(1):1–7. doi: 10.1093/ijnp/pyaa066. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Kishimoto T, Hagi K, Nitta M, Kane JM, Correll CU. Long-term effectiveness of oral second-generation antipsychotics in patients with schizophrenia and related disorders: a systematic review and meta-analysis of direct head-to-head comparisons. World Psychiatry. 2019;18(2):208–224. doi: 10.1002/wps.20632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(1):64–77. doi: 10.1016/S2215-0366(19)30416-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–951. doi: 10.1016/S0140-6736(19)31135-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Viskin S. Long QT syndromes and torsade de pointes. Lancet. 1999;354(9190):1625–1633. doi: 10.1016/S0140-6736(99)02107-8. [DOI] [PubMed] [Google Scholar]
- 17.Camm AJ, Karayal ON, Meltzer H, Kolluri S, O'Gorman C, Miceli J, et al. Ziprasidone and the corrected QT interval: a comprehensive summary of clinical data. CNS Drugs. 2012;26(4):351–365. doi: 10.2165/11599010-000000000-00000. [DOI] [PubMed] [Google Scholar]
- 18.Doogan DP, Caillard V. Sertraline: a new antidepressant. J Clin Psychiatry. 1988;49(Suppl):46–51. [PubMed] [Google Scholar]
- 19.Kitaichi Y, Inoue T, Nakagawa S, Boku S, Kakuta A, Izumi T, et al. Sertraline increases extracellular levels not only of serotonin, but also of dopamine in the nucleus accumbens and striatum of rats. Eur J Pharmacol. 2010;647(1–3):90–96. doi: 10.1016/j.ejphar.2010.08.026. [DOI] [PubMed] [Google Scholar]
- 20.Isbister GK, Balit CR. Bupropion overdose: QTc prolongation and its clinical significance. Ann Pharmacother. 2003;37(7–8):999–1002. doi: 10.1345/aph.1C481. [DOI] [PubMed] [Google Scholar]
- 21.Ikemoto S, Panksepp J. The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking. Brain Res Brain Res Rev. 1999;31(1):6–41. doi: 10.1016/s0165-0173(99)00023-5. [DOI] [PubMed] [Google Scholar]
- 22.Mulholland C, Lynch G, King DJ, Cooper SJ. A double-blind, placebo-controlled trial of sertraline for depressive symptoms in patients with stable, chronic schizophrenia. J Psychopharmacol. 2003;17(1):107–112. doi: 10.1177/0269881103017001713. [DOI] [PubMed] [Google Scholar]
- 23.Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261–276. doi: 10.1093/schbul/13.2.261. [DOI] [PubMed] [Google Scholar]
- 24.Guy W. Clinical Global Impression. In: ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare. 1976:217–222.
- 25.Wallwork RS, Fortgang R, Hashimoto R, Weinberger DR, Dickinson D. Searching for a consensus five-factor model of the Positive and Negative Syndrome Scale for schizophrenia. Schizophr Res. 2012;137(1–3):246–250. doi: 10.1016/j.schres.2012.01.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23(1):56–62. doi: 10.1136/jnnp.23.1.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV Social and Occupational Functioning Assessment Scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand. 2000;101(4):323–329. [PubMed] [Google Scholar]
- 28.Zhang MY. Treatment Emergent Symptom Scale (TESS) Shanghai Arch Psychiatry. 1984;2:24. [Google Scholar]
- 29.Marsden CA. Dopamine: the rewarding years. Br J Pharmacol. 2006;147(Suppl 1):S136–S144. doi: 10.1038/sj.bjp.0706473. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Popli AP, Fuller MA, Jaskiw GE. Sertraline and psychotic symptoms: a case series. Ann Clin Psychiatry. 1997;9(1):15–17. doi: 10.1023/a:1026274123689. [DOI] [PubMed] [Google Scholar]
- 31.Richelson E. Pharmacology of antidepressants–characteristics of the ideal drug. Mayo Clin Proc. 1994;69(11):1069–1081. doi: 10.1016/s0025-6196(12)61375-5. [DOI] [PubMed] [Google Scholar]
- 32.Albayrak Y, Hashimoto K. Sigma-1 receptor agonists and their clinical implications in neuropsychiatric disorders. Adv Exp Med Biol. 2017;964:153–161. doi: 10.1007/978-3-319-50174-1_11. [DOI] [PubMed] [Google Scholar]
- 33.Hartley S, Barrowclough C, Haddock G. Anxiety and depression in psychosis: a systematic review of associations with positive psychotic symptoms. Acta Psychiatr Scand. 2013;128(5):327–346. doi: 10.1111/acps.12080. [DOI] [PubMed] [Google Scholar]
- 34.Lysaker PH, Salyers MP. Anxiety symptoms in schizophrenia spectrum disorders: associations with social function, positive and negative symptoms, hope and trauma history. Acta Psychiatr Scand. 2007;116(4):290–298. doi: 10.1111/j.1600-0447.2007.01067.x. [DOI] [PubMed] [Google Scholar]
- 35.Smith B, Fowler DG, Freeman D, Bebbington P, Bashforth H, Garety P, et al. Emotion and psychosis: links between depression, self-esteem, negative schematic beliefs and delusions and hallucinations. Schizophr Res. 2006;86(1–3):181–188. doi: 10.1016/j.schres.2006.06.018. [DOI] [PubMed] [Google Scholar]
- 36.Fowler D, Hodgekins J, Garety P, Freeman D, Kuipers E, Dunn G, et al. Negative cognition, depressed mood, and paranoia: a longitudinal pathway analysis using structural equation modeling. Schizophr Bull. 2012;38(5):1063–1073. doi: 10.1093/schbul/sbr019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Freeman D, Pugh K, Antley A, Slater M, Bebbington P, Gittins M, et al. Virtual reality study of paranoid thinking in the general population. Br J Psychiatry. 2008;192(4):258–263. doi: 10.1192/bjp.bp.107.044677. [DOI] [PubMed] [Google Scholar]
- 38.Vorontsova N, Garety P, Freeman D. Cognitive factors maintaining persecutory delusions in psychosis: the contribution of depression. J Abnorm Psychol. 2013;122(4):1121–1131. doi: 10.1037/a0034952. [DOI] [PubMed] [Google Scholar]
- 39.Kegeles LS, Abi-Dargham A, Frankle WG, Gil R, Cooper TB, Slifstein M, et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Arch Gen Psychiatry. 2010;67(3):231–239. doi: 10.1001/archgenpsychiatry.2010.10. [DOI] [PubMed] [Google Scholar]
- 40.Thakore JH, Berti C, Dinan TG. An open trial of adjunctive sertraline in the treatment of chronic schizophrenia. Acta Psychiatr Scand. 1996;94(3):194–197. doi: 10.1111/j.1600-0447.1996.tb09848.x. [DOI] [PubMed] [Google Scholar]
- 41.Opoka SM, Lincoln TM. The effect of cognitive behavioral interventions on depression and anxiety symptoms in patients with schizophrenia spectrum disorders: a systematic review. Psychiatr Clin North Am. 2017;40(4):641–659. doi: 10.1016/j.psc.2017.08.005. [DOI] [PubMed] [Google Scholar]
- 42.Terevnikov V, Joffe G, Stenberg JH. Randomized controlled trials of add-on antidepressants in schizophrenia. Int J Neuropsychopharmacol. 2015;18(9). [DOI] [PMC free article] [PubMed]
- 43.Fleischhacker WW, Uchida H. Critical review of antipsychotic polypharmacy in the treatment of schizophrenia. Int J Neuropsychopharmacol. 2014;17(7):1083–1093. doi: 10.1017/S1461145712000399. [DOI] [PubMed] [Google Scholar]
- 44.Yoshida K, Takeuchi H. Dose-dependent effects of antipsychotics on efficacy and adverse effects in schizophrenia. Behav Brain Res. 2021;402:113098. doi: 10.1016/j.bbr.2020.113098. [DOI] [PubMed] [Google Scholar]
- 45.Høimark L, Uhrskov Sørensen L, Vukelic Andersen L. Plasma concentrations of antipsychotics and QTc prolongation: a pilot study. Nord J Psychiatry. 2020;74(5):374–379. doi: 10.1080/08039488.2020.1729857. [DOI] [PubMed] [Google Scholar]
- 46.Fernandez A, Bang SE, Srivathsan K, Vieweg WV. Cardiovascular side effects of newer antidepressants. Anadolu Kardiyol Derg. 2007;7(3):305–309. [PubMed] [Google Scholar]
- 47.Vita A, Barlati S. Recovery from schizophrenia: is it possible? Curr Opin Psychiatry. 2018;31(3):246–255. doi: 10.1097/YCO.0000000000000407. [DOI] [PubMed] [Google Scholar]
- 48.Best MW, Law H, Pyle M, Morrison AP. Relationships between psychiatric symptoms, functioning and personal recovery in psychosis. Schizophr Res. 2020;223:112–118. doi: 10.1016/j.schres.2020.06.026. [DOI] [PubMed] [Google Scholar]
- 49.Mucci A, Galderisi S, Gibertoni D, Rossi A, Rocca P, Bertolino A, et al. Factors associated with real-life functioning in persons with schizophrenia in a 4-year follow-up study of the Italian Network for Research on Psychoses. JAMA Psychiatry. 2021. [DOI] [PMC free article] [PubMed]
- 50.Cowman M, Holleran L, Lonergan E, O'Connor K, Birchwood M, Donohoe G. Cognitive predictors of social and occupational functioning in early psychosis: a systematic review and meta-analysis of cross-sectional and longitudinal data. Schizophr Bull. 2021. [DOI] [PMC free article] [PubMed]
- 51.Leucht S, Crippa A, Siafis S, Patel MX, Orsini N, Davis JM. Dose-response meta-analysis of antipsychotic drugs for acute schizophrenia. Am J Psychiatry. 2020;177(4):342–353. doi: 10.1176/appi.ajp.2019.19010034. [DOI] [PubMed] [Google Scholar]
- 52.Sabe M, Zhao N, Crippa A, Kaiser S. Antipsychotics for negative and positive symptoms of schizophrenia: dose-response meta-analysis of randomized controlled acute phase trials. NPJ Schizophr. 2021;7(1):43. doi: 10.1038/s41537-021-00171-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.