
==== Front
Curr Neuropharmacol
Curr Neuropharmacol
CN
Current Neuropharmacology
1570-159X
1875-6190
Bentham Science Publishers

37711125
CN-22-1406
10.2174/1570159X21666230913152344
Medicine, Neurology, Pharmacology, Neuroscience
Efficacy of Low-dose Olanzapine in Combination with Sertraline on Negative Symptoms and Psychosocial Functioning in Schizophrenia: A Randomized Controlled Trial
Xiu Meihong 1
Zhao Lei 2
Sun Qianqian 2
Lang Xiaoe 3*
1 Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, China;
2 Qingdao Mental Health Center, Qingdao, China;
3 Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China
* Address correspondence to this author at the Department of Psychiatry, First Hospital of Shanxi Medical University, Taiyuan, China; E-mail: langxiaoe@yeah.net
19 9 2023
2024
22 8 14061413
05 1 2023
26 2 2023
12 3 2023
© 2024 The Author(s). Published by Bentham Science Publishers
2024
The Author(s)
https://creativecommons.org/licenses/by/4.0/ © 2024 The Author(s). Published by Bentham Science Publishers. This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode.
Background

Evidence for the efficacy of a low dose of olanzapine (OLA) in combination with antidepressants has been limited and without positive trials in first-episode (FE) patients with schizophrenia (SCH). This study aimed to compare the efficacy in treating negative and depressive symptoms between those FE patients with SCH treated with a combination of OLA plus sertraline and those treated with OLA monotherapy.

Methods

One hundred and ninety-six first-episode and drug naïve patients with SCH were randomized to receive low-dose OLA (7.5-10 mg/day) combined with sertraline (50-100 mg/day) (OS group) or normal-dose OLA monotherapy (12.5-20 mg/day) (NO group). Clinical symptoms were evaluated by the Positive and Negative Syndrome Scale (PANSS), and the depressive symptoms were evaluated by the Hamilton Depression Scale (HAMD). Psychosocial functioning was assessed by the Personal and Social Performance Scale (PSP).

Results

In the intent-to-treat efficacy analysis, the OS group had greater decreases in negative and depressive symptoms (pall < 0.01) and a greater increase in PSP total score compared with the NO group (p < 0.01). Moreover, reductions in HAMD total score and PANSS negative subscore and sex were associated with the improvements in psychosocial functioning from baseline to week 24, after controlling for baseline psychosocial function, age, and onset age.

Conclusion

This study demonstrates that low-dose OLA in combination with sertraline had clinically meaningful improvements not only in the negative and depressive symptoms but also in psychosocial functioning in patients with FE-SCH, while not affecting positive symptoms.

Keywords

Schizophrenia
olanzapine
first-episode
sertraline
efficacy
negative symptoms
psychosocial functioning
==== Body
pmc1 INTRODUCTION

Schizophrenia (SCH) is a chronic and debilitating disease with a lifetime prevalence of 1% in the general population [1]. Patients with SCH usually exhibit psychotic features as well as impairments in multiple domains of cognitive functions and social functioning. According to a recent Global Burden of Disease study, SCH ranked highest among 235 physical and psychiatric disorders in terms of function burden [2]. Even though current antipsychotics are commonly effective to alleviate certain psychotic symptoms related to SCH (e.g. hallucinations and delusions), efficacy is limited for negative symptoms and psychosocial functioning [3].

Based on data from clinical trials, real-world settings, meta-analyses, and pooled analyses, OLA is one of the most studied antipsychotics with proven efficacy in treating SCH [4-9]. It has strong inhibitory action in vitro at dopamine D1, D2, D4, serotonin (5-HT) 5-HT2A, 5-HT2C, histamine H1, and α1-adrenergic receptors, the important neurotransmitters involved in etiology and pathophysiology of SCH [10, 11]. Its structural characteristics and pharmacological effects are similar to those of the atypical antipsychotic clozapine, and its tolerance is better than that of the typical antipsychotic haloperidol. Compared to typical antipsychotics, OLA produced differential effects on the nigrostriatal and mesolimbic systems within the central nervous system and was associated with noticeably fewer adverse movement problems and a low induction of extrapyramidal symptoms [12, 13].

Although OLA treatment can significantly improve the positive symptoms of patients with SCH, there is clear evidence that it improves negative symptoms to a smaller extent than positive ones. Negative symptoms of SCH refer to the absence or diminution of normal emotional and mental activities, and the ability for independent action [14, 15], which hampers the patients’ recovery and has a negative impact on their life quality [16]. In current clinical practice, recovery for SCH patients with negative symptoms has remained elusive. Antidepressant has been a common choice for the treatment of negative symptoms in patients with SCH because of their pharmacological mechanism involving related neurotransmitters in the aetiological hypotheses of negative symptoms [17]. In addition, previous studies also support that antidepressants along with antipsychotic drugs were more efficacious in treating the negative symptoms of SCH than antipsychotic monotherapy [18-20]. Taking into account the limited efficacy of OLA on negative symptoms for patients with SCH, a combination with antidepressants is a good choice to alleviate negative symptoms of SCH.

We hypothesized that a low daily dose of OLA combined with sertraline would be superior to a standard dose of OLA in alleviating negative symptoms and improving psychosocial functioning in first-episode (FE) SCH patients. Thus, this clinical trial was designed to investigate the efficacy after 24 weeks of treatment and solve the following questions. 1) Whether there is a difference in the efficacy between the low-dose OLA combined with the sertraline group (OS) and the OLA monotherapy group (NO group)? 2) Whether there is favorable efficacy in the psychosocial functioning in the OS group compared with the NO group? and 3) Whether there is a difference in terms of improvements in depressive symptoms between the two groups?

2 METHODS

2.1 Patients

We included outpatients diagnosed with SCH by DSM-IV according to the inclusion and exclusion criteria. All recruited patients were drug-naïve FE patients with SCH. The inclusion and exclusion criteria were kept to the minimum required to be able to address the questions in this study. Inclusion criteria included: (1) SCH confirmed by the Structured Clinical Interview for DSM-IV (SCID); (2) age of 15-45 years; (3) less than five years of disease duration; (4) less than 2 weeks of lifetime antipsychotic use; and (5) ability to sign the informed consent. Exclusion criteria included: (1) major psychiatric illnesses diagnosis other than SCH; (2) current or a history of substance abuse except for nicotine and alcohol; (3) major somatic comorbidity; (4) abnormal routine biochemical measurements; and (5) a history of intolerance to OLA.

This study was conducted at First Hospital of Shanxi Medical University. The study procedures and protocol were approved by the Ethics Committee of First Hospital of Shanxi Medical University. Written informed consent was provided by the individual participant after the cluster randomization.

2.2 Study Design

This was a randomized open-label study conducted over 6 months. Participants were randomly in a 1:1 ratio assigned to receive low-dose OLA (7.5-10 mg/day) combined with sertraline (50-100 mg/day) in the OS group or normal-dose OLA monotherapy (12.5-20 mg/day) in the NO group.

Randomization occurred via a web-based system, with a unique randomization number assigned to each participant for use in case report forms. An independent investigator made random allocation cards using computer-generated random numbers. The randomization procedure was described in our previous study [20]. This clinical trial consisted of 5 visits, conducted at the end of weeks 0, 4, 8, 12, and 24. Nurses ensured treatment adherence during the study period. Clonazepam (2-3 mg/d) was permitted to treat sleep problems and relieve acute agitation during the early phase of treatment.

2.3 Outcomes

The primary measure outcome was clinical symptoms assessed at baseline and the end of weeks 4, 8, 12, and 24 by the Positive and Negative Syndrome Scale (PANSS) [21] and the Hamilton Depression Rating Scale (HAMD) [22] and the Clinical Global Impressions-S (CGI-S) [23]. The endpoint of outcomes was the difference in patients with SCH in the OS group versus those in the NO group in the pre- versus after 24 weeks of treatment in both groups.

The secondary outcome was the Personal and Social Performance Scale (PSP) [24], which was also assessed at baseline and 4 follow-up time points.

2.4 Statistical Analysis

All efficacy analyses were conducted for an intent-to-treat (ITT) analysis set that included the patients who received at least 4 weeks of treatment and had a valid baseline and at least 1 valid post-treatment follow-up.

The treatment efficacy on the primary and secondary measures between the two groups was analyzed by using a repeated-measures analysis of variance (RMANOVA). In the group comparison model of endpoint differences, clinical symptoms and psychosocial functioning assessed over 5 time points were added as the dependent variable, treatment group (OS vs. NO groups) was added as the independent variable, and sex, age, and onset age were covariates. We focused more on the interaction effect of time by treatment group. If there was a significant interaction effect, we then ran an analysis of covariance (ANCOVA) with the measurements at baseline as covariates to examine the differences in the different efficacy endpoint measures (Week 4, 8, 12, and 24) between the OS and NO groups. Additionally, ANCOVA was also conducted to compare the changes of primary and secondary measures from baseline to the different endpoints between the two groups.

Linear regression analysis was used to investigate the potential key factors associated with the improvement in psychosocial functioning. The following variables were included in this regression model: baseline psychosocial functioning, sex, age, age at onset, and the reductions in clinical symptoms.

Data were analyzed using SPSS software Version 22.0. Multiple tests correction was performed by the Bonferroni method. Significance was set at p < 0.05 for all analyses.

3 RESULTS

3.1 Patient Characteristics

Of the 206 SCH patients screened, 196 patients met the inclusion and exclusion criteria. All patients were randomized to the OS group (n=98) and the NO group (n=98). A total of 11 patients withdrew their consent on the first visit. Eighteen patients dropped out in the follow-up (n=6 in the OS group and n=12 in the NO group). In the NO group, 9 patients discontinued for side effects caused by antipsychotics (e.g. weight gain, abnormal blood sugar, and lipids), and 3 patients were lost to follow-up. In the OS group, 2 patients discontinued for side effects caused by antipsychotics (e.g. weight gain and abnormal blood lipids), and 1 patient was lost to follow-up. The rate of dropout was higher in the NO group (n=12) than in the OS group (n=6) (Fig. S1). A total of 185 were included in the efficacy ITT-population analysis.

At baseline, there were no significant differences in age, sex, duration of illness, and onset age between the OS and NO groups (Pall>0.05). Yet, we found that individuals in the OS group had higher scores in negative symptoms, general psychopathology, the PANSS total score, and HAMD than the NO group (Pall<0.05) (Table 1).

3.2 Efficacy

Treatment with OLA combined with sertraline demonstrated statistically significant changes in PANSS negative symptoms (Fig. 1B), PANSS total score (Fig. 1D), and CGI-S scores (Fig. 1E) after Bonferroni correction (pBonferroni<0.01). In addition, HAMD was also significantly decreased after treatment in both groups, and the OS group showed a significant difference from the NO group (pBonferroni <0.01) (effect size, from 0.63 to 4.02) (Table 2) (Fig. 2). In RMANOVA analysis, significant interaction effects of the group by the time were observed in PANSS total score, negative symptom subscore, CGI-S scores, and HAMD total score (pall<0.001). Statistically significant differences from the control group in these clinical symptoms were observed at the week 4 assessment and continued through the week 24 assessment with combination therapy (Fig. 1B, D, and E). Additionally, there were significant differences in the clinical symptoms from week 4 and continued through week 24 in the OS group. However, we did not find any significant interaction effect on positive symptoms or general psychopathology (Figs. 1A and 1C).

Furthermore, patients in the OS group also met another key secondary endpoint with a significant change in PSP score from baseline to week 24 versus the control group (mean difference: 14.5, 95% CI: 13.7 to 16.0).

In addition, we found that patients in the OS group had fewer adverse effects as measured by the Treatment Emergent Symptom Scale (TESS) (Table 3).

3.3 Related Factors with Social Function Improvement

We further analyzed the factors related to the improvements in psychosocial functioning. Correlation analysis found that there were significant positive associations between the increase in PSP total score and the reductions in PANSS negative symptom from baseline, PANSS total score, CGI total score, and HAMD total score with an r-value ranging from 0.24 to 0.45 (pall<0.01). Linear regression analysis confirmed the association between the improvement of psychosocial function and the reductions in PANSS negative symptoms (β = 4.3, t = 7.8, p < 0.001), HAMD total score (β = 5.4, t = 7.8, p < 0.001), CGI total score (β = 5.4, t = 7.8, p < 0.001), after controlling for sex, age, onset age, and baseline PSP total score (R2 = 0.60).

4 DISCUSSION

This study found that compared with standard-dose OLA monotherapy, low doses of OLA plus sertraline significantly reduced negative symptoms and increased psychosocial functioning commonly observed with antipsychotic treatment in patients with FE-SCH. In addition, the efficacy of low doses of OLA in combination with sertraline on positive symptoms of SCH was comparable to that of standard dose OLA monotherapy.

Treatment with low-dose OLA in combination with sertraline significantly improved negative symptoms, as assessed with the PANSS scale relative to OLA monotherapy in patients. This finding is in line with previous studies as well as the meta-analyses, suggesting that sertraline as an add-on combination treatment to antipsychotics was more effective in treating negative symptoms than antipsychotic monotherapy [18]. The statistically significant overall effect size of 0.92 for the combination therapy with sertraline may be considered large using Cohen’s guidelines for the magnitude of the effect size [25]. Interestingly, in line with other studies, sertraline add-on to OLA was effective in improving depressive symptoms in SCH patients [20, 26-29]. A previous study using combination pharmacotherapy with a standard dosage of OLA (15-20 mg/day) and sertraline to treat patients with depressive symptoms found that combination therapy was associated with higher remission rates and was comparably superior in clinical symptoms than OLA monotherapy [30]. A possible explanation for the reported clinical efficacy is associated with the modulatory effect on the 5-HT system of sertraline for negative symptoms and depressive symptoms, as dysfunctions of dopaminergic and 5-HT neurons have been linked to SCH. Additionally, sertraline appears to improve the negative symptoms by inhibiting dopamine transporters and reuptake and by enhancing central dopaminergic neuron activity [31, 32]. Considering not only the statistical significance but also its clinical significance, a low dose of OLA combined with sertraline for negative and depressive symptoms in patients with SCH may appear justified.

It should be noted that this study found that combination therapy of low-dose OLA showed comparable efficacy for positive symptoms of SCH compared with standard dose monotherapy. Although previous studies reported a higher dose of OLA provided more efficacious benefits for patients compared to the usual dose range recommended in the protocol [33], our findings demonstrate that decreased dose of OLA showed no impact on the efficacy of positive symptoms relative to a usual dose of OLA. We speculate that it may be due to the modulatory effect of sertraline on transmitters in the combination therapy, and then the effect on the negative and depressive symptoms [34]. This study provides a new combination of the antipsychotic regimen used to treat several domains of clinical symptoms of SCH.

More importantly, this study reported a better efficacy of the combination pharmacotherapy for psychosocial functioning. The positive findings must be considered regarding the reductions in negative and depressive symptoms by sertraline, which has been confirmed by the regression analysis. The beneficial effects of sertraline on depressive symptoms may be the potential mechanism of the advantages of this promising combination treatment strategy for patients with SCZ. Patients with SCH often show deficits in several domains of psychosocial functioning [35-38], and as a result, they are usually at high risk of unemployment, less likely to engage in social activities, and have no or few satisfying intimate relationships [39]. Our study demonstrates that add-on antidepressants are an important aspect in the effective clinical management of depressive and negative symptoms, because additional symptom relief may help to increase psychosocial functioning and improve quality of life in patients with FE-SCH.

Some limitations should be noted in this study. First, this was a short-term cohort study. A 24-week treatment duration may not address the maintenance of efficacy, which should be assessed after long-term combination therapy. Second, it was not a placebo-controlled, double-blinded clinical trial. Although the nurses did not tell the patients which medications they were taking, the patients may have identified the intervention as the OS group took two capsules of medication and the control group took one. Third, SCH patients recruited in this study had to meet specific inclusion and exclusion criteria, which may limit the generalization of the findings to a broader population.

CONCLUSION

Despite the limitations, this is the first trial to suggest that FE-SCH patients on low doses of OLA in combination with sertraline showed greater improvements in negative symptoms and psychosocial functioning than usual doses of OLA monotherapy. Furthermore, the efficacy of combination treatment was comparable in terms of positive symptoms relative to OLA medication alone. Previous combination therapy with the usual dosage incurred more adverse effects and higher costs. Our study of low-dose OLA combined with antidepressants provides a promising treatment option for the early stages of SCH, which may benefit patients in clinical practice.

ACKNOWLEDGEMENTS

Declared none.

AUTHORS’ CONTRIBUTIONS

MX and XL were responsible for study design, statistical analysis, and manuscript preparation. MX, ZL, and QS were responsible for recruiting the patients, performing the clinical rating, and collecting the clinical data. XL and MX were evolving the ideas and editing the manuscript. XL and MX were involved in writing the protocol and co-wrote the paper. All authors have contributed to and approved the final manuscript.

LIST OF ABBREVIATIONS

CGI-S Clinical Global Impressions-S

HAMD Hamilton Depression Rating Scale

ITT Intent-to-Treat

PANSS Positive and Negative Syndrome Scale

PSP Social Performance Scale

SCH Schizophrenia

TESS Treatment Emergent Symptom Scale

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

It was approved by the Ethics Committee of First Hospital of Shanxi Medical University, China.

HUMAN AND ANIMAL RIGHTS

This study was conducted according to the guidelines of the Declaration of Helsinki and approved by Ethics Committee.

CONSENT FOR PUBLICATION

Informed, written consent was obtained from all subjects involved in the study.

AVAILABILITY OF DATA AND MATERIALS

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

FUNDING

This study was supported by A Nation Funded Project for Regional Science and Technology Development (Basic Research) Project (No. YDZJSX2022A064), Key Research Project in Shanxi Province (201803D31098), and Grant for clinical research by Wu Jieping Medical Foundation (320.6750.18336). The funding for this study had no further role in study design, data analysis, and the decision to submit the paper for publication.

CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

SUPPLEMENTARY MATERIAL

Supplementary material is available on the publisher’s website along with the published article.

Fig. (1) Mean Changes in the Positive and Negative Syndrome Scale (PANSS) total Score and Clinical Global Impression-Severity of Illness (CGI-S) and mean changes in the positive and negative symptom and general subscales. Note: *p < 0.01 compared with control group by a repeated-measures analysis of variance (RMANOVA).

Fig. (2) Mean changes in the Psychosocial Functioning (PSP) and the Hamilton Depression Rating Scale (HAMD). Note: *p < 0.001 compared with control group by a repeated-measures analysis of variance (RMANOVA).

Table 1 Demographic and clinical characteristics data in combination therapy group (OS) and control group (NO) (mean ± SD).

Variable	OS Group (n = 98)	NO Group (n = 87)	F or X2 (p Value)	
Gender (male/female)	52/46	40/47	0.9(0.34)	
Age (years)	24.5 ± 7.1	24.0 ± 6.4	0.2(0.62)	
Age of onset (years)	21.9 ± 6.0	21.9 ± 5.8	0.002(0.96)	
Duration of illness (years)	2.5 ± 1.7	2.0 ± 1.5	3.1(0.08)	
P	25.8 ± 6.9	27.2 ± 6.7	2.1(0.15)	
N	26.8 ± 7.4	24.4 ± 5.8	5.7(0.02)	
G	59.6 ± 8.9	56.8 ± 8.4	4.8(0.03)	
PANSS total score	112.1 ± 12.4	108.4 ± 11.5	4.4(0.04)	
HAMD total score	23.6 ± 5.5	22.1 ± 5.0	4.0(0.048)	
PSP total score	32.3 ± 4.9	33.6 ± 4.3	2.9(0.09)	
CGI-S total score	5.3 ± 0.5	5.5 ± 0.5	3.7(0.06)	
Note: 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.

Table 2 PANSS scores, HAMD score, CGI-S and PSP at baseline, week 4, week 8, week 12 and week 24 in patients treated with OLA plus sertraline (OS) group and OLA monotherapy (NO) group (mean ± standard deviations).

-	Baseline	Week 4	Week 8	Week 12	Week 24	Group Effect F (p Value)a	Interaction Effect F(p Value)a	
PANSS Positive Subscore	1.1(0.29)	6.1(0.014)	
OS group	25.8 ± 6.9	19.9 ± 5.8	14.1 ± 5.0	10.8 ± 3.9	9.2 ± 3.2	-	-	
NO group	27.2 ± 6.7	18.7 ± 6.3	15.5 ± 6.1	11.7 ± 4.7	10.4 ± 4.5	-	-	
PANSS Negative Subscore	2.2(0.14)	27.3(<0.001)	
OS group	26.8 ± 7.4	22.0 ± 7.2	17.1 ± 6.2	14.2 ± 5.0	10.3 ± 3.3	-	-	
NO group	24.4 ± 5.8	22.0 ± 6.0	18.7 ± 5.6	15.8 ± 5.4	12.9 ± 5.1	-	-	
PANSS General Psychological Subscore	0.002(0.98)	5.7(0.02)	
OS group	59.6 ± 8.9	47.1 ± 9.8	37.0 ± 9.3	24.6 ± 8.0	22.3 ± 5.8	-	-	
NO group	56.8 ± 8.4	44.7 ± 9.6	36.1 ± 10.1	26.4 ± 8.0	24.0 ± 8.7	-	-	
PANSS Total Score	2.6(0.11)	10.1(0.002)	
OS group	112.1 ± 12.4	88.1 ± 14.4	68.3 ± 14.0	49.5 ± 10.6	41.7 ± 11.2	-	-	
NO group	108.4 ± 11.5	85.5 ± 13.2	70.3 ± 14.5	53.9 ± 14.1	47.2 ± 16.1	-	-	
CGI-S Score	38.1(<0.001)	76.1(<0.001)	
OS group	5.3 ± 0.5	4.6 ± 0.5	3.5 ± 0.5	2.6 ± 0.6	1.8 ± 0.6	-	-	
NO group	5.5 ± 0.5	4.6 ± 0.5	3.7 ± 0.4	3.3 ± 0.5	2.6 ± 0.5	-	-	
HAMD Total Score	24.6(<0.001)	32.1(<0.001)	
OS group	23.6 ± 5.5	17.2 ± 5.0	10.3 ± 3.0	6.6 ± 2.7	4.1 ± 3.1	-	-	
NO group	22.1 ± 5.0	16.9 ± 4.5	13.0 ± 4.0	10.5 ± 4.0	7.9 ± 4.2	-	-	
PSP Total Score	50.5(<0.001)	69.7(<0.001)	
OS group	32.5 ± 5.0	43.8 ± 4.5	62.6 ± 6.9	77.6 ± 9.4	88.1 ± 11.5	-	-	
NO group	33.9 ± 4.4	43.8 ± 4.5	60.4 ± 7.5	66.5 ± 9.4	72.6 ± 12.0	-	-	
Note: aAdjusted F value controlling for sex, age and onset age.

Table 3 Comparison of adverse effects using treatment emergent symptom scale between the OS group and NO group.

-	OS Group
(n = 98)	NO Group
(n = 87)	
Adverse events	n (%)	n (%)	
Tremor	3(3.1)	3(3.5)	
Akathisia	2(2.0)	7(8.2)	
Insomnia	2(2.0)	1(1.2)	
Somnolence	4(4.1)*	18(21.2)	
Constipation	5(5.1)	8(9.4)	
Nausea	4(4.1)	3(3.5)	
Dizziness	5(5.1)	7(8.2)	
Weight gain	28(28.6)*	85(97.7)	
Electrocardiographic changes	1(1.0)	3(3.5)	
Muscle rigidity	1(1.0)	2(2.4)	
Dry mouth	3(3.1)	3(3.5)	
Note: *p < 0.05.
==== Refs
REFERENCES

1 Kahn R.S. Sommer I.E. Murray R.M. Meyer-Lindenberg A. Weinberger D.R. Cannon T.D. O’Donovan M. Correll C.U. Kane J.M. van Os J. Insel T.R. Schizophrenia. Nat. Rev. Dis. Primers 2015 1 1 15067 10.1038/nrdp.2015.67 27189524
2 Salomon J.A. Haagsma J.A. Davis A. de Noordhout C.M. Polinder S. Havelaar A.H. Cassini A. Devleesschauwer B. Kretzschmar M. Speybroeck N. Murray C.J.L. Vos T. Disability weights for the Global Burden of Disease 2013 study. Lancet Glob. Health 2015 3 11 e712 e723 10.1016/S2214-109X(15)00069-8 26475018
3 Cheng Z. Yuan Y. Han X. Yang L. Cai S. Yang F. Lu Z. Wang C. Deng H. Zhao J. Xiang Y. Correll C.U. Yu X. 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 10.1177/0269881119872193 31487208
4 Kahn R.S. Fleischhacker W.W. Boter H. Davidson M. Vergouwe Y. Keet I.P.M. Gheorghe M.D. Rybakowski J.K. Galderisi S. Libiger J. Hummer M. Dollfus S. López-Ibor J.J. Hranov L.G. Gaebel W. Peuskens J. Lindefors N. Riecher-Rössler A. Grobbee D.E. Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: An open randomised clinical trial. Lancet 2008 371 9618 1085 1097 10.1016/S0140-6736(08)60486-9 18374841
5 Haro J.M. Suarez D. Novick D. Brown J. Usall J. Naber D. Three-year antipsychotic effectiveness in the outpatient care of schizophrenia: Observational versus randomized studies results. Eur. Neuropsychopharmacol. 2007 17 4 235 244 10.1016/j.euroneuro.2006.09.005 17137759
6 Kishimoto T. Hagi K. Nitta M. Kane J.M. Correll C.U. 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 10.1002/wps.20632 31059621
7 Leucht S. Cipriani A. Spineli L. Mavridis D. Örey D. Richter F. Samara M. Barbui C. Engel R.R. Geddes J.R. Kissling W. Stapf M.P. Lässig B. Salanti G. Davis J.M. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis. Lancet 2013 382 9896 951 962 10.1016/S0140-6736(13)60733-3 23810019
8 Citrome L. McEvoy J.P. Todtenkopf M.S. McDonnell D. Weiden P.J. A commentary on the efficacy of olanzapine for the treatment of schizophrenia: The past, present, and future. Neuropsychiatr. Dis. Treat. 2019 15 2559 2569 10.2147/NDT.S209284 31564881
9 Meftah A.M. Deckler E. Citrome L. Kantrowitz J.T. New discoveries for an old drug: A review of recent olanzapine research. Postgrad. Med. 2020 132 1 80 90 10.1080/00325481.2019.1701823 31813311
10 Bhana N. Foster R.H. Olney R. Plosker G.L. Olanzapine. Drugs 2001 61 1 111 161 10.2165/00003495-200161010-00011 11217867
11 Olanzapine. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. Bethesda, MD National Institute of Diabetes and Digestive and Kidney Diseases 2012
12 Leucht S. Pitschel-Walz G. Abraham D. Kissling W. Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr. Res. 1999 35 1 51 68 10.1016/S0920-9964(98)00105-4 9988841
13 Davis J.M. Chen N. Glick I.D. A meta-analysis of the efficacy of second-generation antipsychotics. Arch. Gen. Psychiatry 2003 60 6 553 564 10.1001/archpsyc.60.6.553 12796218
14 Buchanan R.W. Persistent negative symptoms in schizophrenia: An overview. Schizophr. Bull. 2007 33 4 1013 1022 10.1093/schbul/sbl057 17099070
15 Javitt D.C. Management of negative symptoms of schizophrenia. Curr. Psychiatry Rep. 2001 3 5 413 417 10.1007/s11920-996-0036-9 11559479
16 Mäkinen J. Miettunen J. Isohanni M. Koponen H. Negative symptoms in schizophrenia—A review. Nord. J. Psychiatry 2008 62 5 334 341 10.1080/08039480801959307 18752104
17 González-Maeso J. Sealfon S.C. Psychedelics and schizophrenia. Trends Neurosci. 2009 32 4 225 232 10.1016/j.tins.2008.12.005 19269047
18 Singh S.P. Singh V. Kar N. Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: Meta-analysis. Br. J. Psychiatry 2010 197 3 174 179 10.1192/bjp.bp.109.067710 20807960
19 Shi H. Xu J. Lang X. Wu H.E. Xiu M.H. Zhang X.Y. Comparison of efficacy and safety between low-dose ziprasidone in combination with sertraline and ziprasidone monotherapy for treatment-resistant patients with acute exacerbation schizophrenia: A randomized controlled trial. Front. Pharmacol. 2022 13 863588 10.3389/fphar.2022.863588 35559243
20 Zhu C. Guan X. Wang Y. Liu J. Kosten T.R. Xiu M. Wu F. Zhang X. Low-dose ziprasidone in combination with sertraline for first-episode drug-Naïve patients with schizophrenia: A randomized controlled trial. Neurotherapeutics 2022 19 3 1037 1046 10.1007/s13311-022-01242-7 35467271
21 Kay S.R. Fiszbein A. Opler L.A. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr. Bull. 1987 13 2 261 276 10.1093/schbul/13.2.261 3616518
22 Hamilton M. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 1960 23 1 56 62 10.1136/jnnp.23.1.56 14399272
23 Guy W. ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare 1976 217 222
24 Morosini P.L. 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 funtioning. Acta Psychiatr. Scand. 2000 101 4 323 329 10.1111/j.1600-0447.2000.tb10933.x 10782554
25 Choen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed Lawrence Erlbaum Associates 1988
26 Mulholland C. Lynch G. King D.J. Cooper S.J. A double-blind, placebo-controlled trial of sertraline for depressive symptoms in patients with stable, chronic schizophrenia. J. Psychopharmacol. 2003 17 1 107 112 10.1177/0269881103017001713 12680747
27 Tollefson G.D. Birkett M.A. Kiesler G.M. Wood A.J. Double-blind comparison of olanzapine versus clozapine in schizophrenic patients clinically eligible for treatment with clozapine. Biol. Psychiatry 2001 49 1 52 63 10.1016/S0006-3223(00)01026-X 11163780
28 Conley R.R. Kelly D.L. Gale E.A. Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse. Schizophr. Res. 1998 33 1-2 95 101 10.1016/S0920-9964(98)00062-0 9783349
29 Volavka J. Czobor P. Sheitman B. Lindenmayer J.P. Citrome L. McEvoy J.P. Cooper T.B. Chakos M. Lieberman J.A. Clozapine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am. J. Psychiatry 2002 159 2 255 262 10.1176/appi.ajp.159.2.255 11823268
30 Meyers B.S. Flint A.J. Rothschild A.J. Mulsant B.H. Whyte E.M. Peasley-Miklus C. Papademetriou E. Leon A.C. Heo M. A double-blind randomized controlled trial of olanzapine plus sertraline vs olanzapine plus placebo for psychotic depression: The study of pharmacotherapy of psychotic depression (STOP-PD). Arch. Gen. Psychiatry 2009 66 8 838 847 10.1001/archgenpsychiatry.2009.79 19652123
31 Popli A. Fuller M. Jaskiw G. Sertraline and psychotic symptoms: A case series. Ann. Clin. Psychiatry 1997 9 1 15 17 10.3109/10401239709147769 9167832
32 Richelson E. Pharmacology of antidepressants characteristics of the ideal drug. Mayo Clin. Proc. 1994 69 11 1069 1081 10.1016/S0025-6196(12)61375-5 7967761
33 Kinon B.J. Ahl J. Stauffer V.L. Hill A.L. Buckley P.F. Dose response and atypical antipsychotics in schizophrenia. CNS Drugs 2004 18 9 597 616 10.2165/00023210-200418090-00005 15222776
34 Sax K.W. Stephen M.S. Strakowski P.K. Vidya H.U. Scott A.W. Susan L.M. Relationships among negative, positive, and depressive symptoms in schizophrenia and psychotic depressionbeijing huilongguan hospital. Br. J. Psychiatry 2018 168 1 10
35 Vita A. Barlati S. Recovery from schizophrenia. Curr. Opin. Psychiatry 2018 31 3 246 255 10.1097/YCO.0000000000000407 29474266
36 Kossmann C. Heller J. Brüne M. Schulz C. Heinze M. Cordes J. Mühlbauer B. Rüther E. Timm J. Gründer G. Juckel G. Assessment of psychosocial functioning in a large cohort of patients with schizophrenia. Psychiatr. Q. 2021 92 1 177 191 10.1007/s11126-020-09773-y 32519208
37 Schaub D. Brüne M. Jaspen E. Pajonk F.G. Bierhoff H.W. Juckel G. The illness and everyday living: Close interplay of psychopathological syndromes and psychosocial functioning in chronic schizophrenia. Eur. Arch. Psychiatry Clin. Neurosci. 2011 261 2 85 93 10.1007/s00406-010-0122-1 20652295
38 Suttajit S. Arunpongpaisal S. Srisurapanont M. Thavichachart N. Kongsakon R. Chantakarn S. Chantarasak V. Jariyavilas A. Jaroensook P. Kittiwattanagul K. Nerapusee O. Psychosocial functioning in schizophrenia: are some symptoms or demographic characteristics predictors across the functioning domains? Neuropsychiatr. Dis. Treat. 2015 11 2471 2477 10.2147/NDT.S88085 26491325
39 Hakulinen C. McGrath J.J. Timmerman A. Skipper N. Mortensen P.B. Pedersen C.B. Agerbo E. The association between early-onset schizophrenia with employment, income, education, and cohabitation status: Nationwide study with 35 years of follow-up. Soc. Psychiatry Psychiatr. Epidemiol. 2019 54 11 1343 1351 10.1007/s00127-019-01756-0 31456027
