Effect of Esketamine on Perioperative Depressive Symptoms in Patients Undergoing Major Surgery
Phase: PHASE2
Conditions: Depressive Symptoms, Esketamine, Perioperative Complication, Major Surgery
Sponsor: Beijing Tiantan Hospital

 
1 
 
 
 
Effect of esketamine on perioperative depressive symptoms  
in major surgery patients (PASSION II) 
 
STUDY PROTOCOL 
 
Protocol Version 2.0  
Version Date: 20/01/2021 
NCT number: NCT04425473 
 
 
 
Prepared by statistician: Yang Zhou 
Approved by Principal Investigator: Ruquan Han 
 
 

 
2 
Effect of esketamine on perioperative depressive symptoms in major 
surgery patients (PASSION II): study protocol for a randomized 
controlled trial 
Introduction 
Depression is a common mental disorder that has been the primary risk of disability 
and is an important risk factor associated with a high burden of disease; it is estimated 
that more than 300 million people suffer worldwide.1 2 Patients undergoing major 
surgery may have depressive symptoms induced by stress reactions, which could affect 
mental health in the surgery population. Depressive symptoms are characterized by loss 
of interest and low mood, during the perioperative period. Although depressive 
symptoms are different from depression disorder, they could also lead to worse clinical 
outcomes after surgery, such as cognitive dysfunction, delirium, pain, and even 
shortened survival time.3-6 It has been reported that more than 24% of patients have 
depressive symptoms during the perioperative period, and this figure is nearly 44% in 
patients undergoing cardiac surgery or neurosurgery.6-9 However, few interventions 
resolve the depressive symptoms that occur during the perioperative period, and the 
influence of antidepressant effects in the early stage on prognosis in the future remains 
controversial.  
Ketamine, a classic anaesthetic for sedation and analgesia, has been reported that could 
take rapid antidepressant effects in depression patients.10 However, the benefit of 
ketamine administration in patients with depressive symptoms undergoing major 
surgery is inconsistent.11-13 To address this problem, our research team developed the 
PASSION study to explore the effect of ketamine on depressive symptoms in the 
neurosurgery population.14 In the 84 participants that were enrolled, we found that 
ketamine improved depressive symptoms at the third postoperative day, and the 
response rate was higher in the ketamine group than in the placebo group (41.5% vs. 
16.3%), and no adverse events occurred. However, there were several limitations in the 
PASSION study; for example, the degree of remission did not reach desired levels 
chiefly because of the relatively small sample size, a single type of surgery was 

 
3 
involved in the trial, and esketamine has been gradually substituted for ketamine in 
clinical practice. 
Esketamine is a racemic compound of ketamine that has been reported to have rapid 
and marked antidepressant effects.15 Based on studies with ketamine, esketamine was 
developed and has been used for major depression patients since the Food and Drug 
Administration approved its use in 2019. Compared with traditional antidepressants, 
which require more than one week to take effect in depression patients, esketamine 
shortens the reaction period to nearly 1 hour after administration with few adverse 
effects, and the use of esketamine nasal spray has become a novel antidepressant for 
treatment-resistant depression patients.16 Compared with ketamine, esketamine shows 
similar pharmacological characteristics but less side-effect. However, the effects of 
esketamine administration on depressive symptoms are still unknown. Thus, we should 
make further efforts to determine the effect of esketamine on depressive symptoms in 
major surgery patients. 
Safety issues associated with the administration of esketamine during surgery are also 
unclear. It is reported that ketamine could change the intracranial pressure and 
hemodynamics during drug administration, and increase the risk of psychotic 
symptoms, hallucinations, or nausea and vomiting after major surgery. For repeated 
application, ketamine was reported associated with drug abuse and may interact with 
bladder urothelial cells and induce apoptosis.17 Due to esketamine and ketamine having 
similar pharmacological effects, whether the harmful effect mentioned above for single 
administration of esketamine in major surgery patients is not known for certain.  
Based on the previous studies, the depressive symptoms may be a temporary state 
because of the stress by operation or diseases. Thus, we conducted this trial to explore 
the effectiveness of esketamine used in surgery patients with depressive symptoms. It 
is hypothesized that the administration of esketamine intravenously will improve the 
depressive symptoms in the major surgery population. The primary endpoint is the 
remission rate at postoperative day 3, and the secondary endpoints consist of other 
effectiveness and safety-related parameters. 
 
 

 
4 
Methods and analysis  
Trial design 
This study is a multicenter randomized controlled clinical trial to explore the effect of 
esketamine on depressive symptoms screened during the perioperative period (the flow 
chart see figure 1). It was approved by the Institutional Review Board of Beijing Tiantan 
Hospital, Capital Medical University, Beijing, China (KY-2020-058-02). All 
participants or their legal representatives will provide written informed consent after 
screening and before randomization. Registration information has been supplied on 
clinicaltrials.gov (NCT04425473). 
Participants 
The study will be conducted at medical centres in China, and training of the study 
protocol will be held regularly to guarantee the quality of the trial. Major surgery 
patients who are 18 to 65 years old with moderate to severe depressive symptoms will 
be included after informed consent is obtained from their legal representative. Moderate 
to severe depressive symptoms are defined as Patient Health Questionnaire 9 (PHQ-
9)18 19 scores equal to or more than 10 and Montgomery-Åsberg Depression Rating 
Scale (MADRS) scores equal to or more than 22.20 Major surgery is defined as an 
elective operation with an estimate of more than 2 hours and includes neurosurgical 
tumour resection, coronary artery bypass grafting operation, total hip or knee 
arthroplasty surgery, breast cancer surgery, pneumonectomy, or hepatectomy. Patients 
with any of the following will be excluded: aphasia or other conditions that may lead 
to the inability for mental assessments; diseases requiring maintenance of intubation 
after surgery; history of psychotic or bipolar disorder; primary diseases that could 
change hormone levels with laboratory evidence; body mass index more than 30 kg/m2; 
Child-Pugh grade B or C (defined as Child-Pugh scores more than 6 points); history of 
antidepressant therapy in the 2 weeks before screening; repeated suicide attempts 
(evaluated by a score equal to or more than 3 on the 12-item Quick Inventory of 
Depressive Symptomatology); history of adverse events to ketamine or esketamine; 
history of drug use disorder; or current pregnancy or breastfeeding. 
Randomization and grouping 

 
5 
Participants will be randomly assigned to the esketamine group or placebo group at a 
1:1 ratio. Randomization results will be achieved via a real-time, online system before 
surgery. A randomized four-blocks design stratified patients by depressive severity 
(severe depressive symptoms are defined by MADRS scores equal to or more than 30). 
The randomization sequence was created by independent engineers who will keep the 
allocation blind, and all study-related investigators will be blinded to the randomization 
results. 
Intervention and anaesthesia management 
All participants included in this study will receive trial drugs intravenously when the 
incision is being sutured. In the esketamine group, patients will be administered a total 
dose of 0.2 mg/kg esketamine (Hengrui Induction, Jiangsu, China) over 40 mins. 
Patients in the placebo group will receive an equivalent volume of normal saline at the 
same speed. Patients in this study will be under general anaesthesia for major surgery. 
Anaesthesia management will follow the standard procedure. Total intravenous 
anaesthesia or balanced anaesthesia will be implemented to maintain appropriate levels 
of sedation, analgesia, and muscle relaxation. Anaesthetics are administered at 
appropriate dosages based on consideration of the clinical anaesthetists and will include 
sedatives (propofol or etomidate), analgesics (sufentanil or remifentanil), muscle 
relaxants (rocuronium or cisatracurium), or inhaled anaesthetics (sevoflurane). Patient-
controlled analgesia devices will be applied after surgery by using sufentanil and 
ondansetron to maintain numerical rating scale scores equal to or less than 4. Other 
analgesics could be used with the occurrence of severe pain (numerical rating scale 
score more than 7) during the postoperative period. 
Blinding 
The trial drugs will be prepared by an independent person who is not participating in 
screening, intervention, and follow-up procedures (see figure 2). Esketamine will be 
diluted to a concentration of 0.5 mg/ml with normal saline. Both esketamine and normal 
saline will be kept in syringes (50 ml) with the same appearance and labelled with "the 
trial drugs, randomization code". The participants will receive the trial drug at a speed 
of 0.6 ml/h per kilogram of weight for 40 min. The intervention will be completed by 

 
6 
the anaesthesiologists in charge of the surgery. The anaesthesiologists, accessors, and 
patients will be blinded to the type of drug administered during surgery. The 
administered drug will be unmasked, with the agreement of the primary investigator, 
when esketamine-related severe adverse events occur (such as an allergy to the study 
drug) after the intervention and before the termination of surgery. 
Outcomes 
The primary outcome is the proportion of participants attaining remission (defined as a 
MADRS score less than or equal to 10) three days after surgery, based on an evaluation 
by blinded accessors at the bedside. 
Secondary outcomes, including the differences in MADRS scores at three days and five 
days (or discharge) after surgery and the rates of patients achieving a response 
(MADRS scores reduced to or lower than half of the baseline MADRS score), the rate 
of severe pain within 72-hour postoperative period (severe pain is defined by the 
numeric rating scale pain scores equal to or more than 7).21 
Safety outcomes include manic symptoms evaluated by the 11-item Young Mania 
Rating Scale (defined by YMRS scores more than or equal to 5) within the 3-day 
postoperative period,22 psychotic symptoms measured by a nonzero score on four 
particular items of the Brief Psychiatric Rating Scale (unusual thought content, 
suspiciousness, hallucinations, and conceptual disorganization) during the three days 
after surgery,23, 24 dissociative symptoms accessed by a nonzero score on the Clinician-
Administered Dissociative States Scale within three days after the operation,25 and all 
drug-related adverse events during surgery or before discharge. 
Data management 
The clinical data will be recorded and managed with the electronic database. The paper 
version materials including the protocol, the case reported forms, informed consent 
forms, and electronic version database will be preserved by the primary investigator 
and stored in the independently locked strongbox in Beijing Tiantan Hospital.   
Sample size calculation 
It has been reported that the remission rate difference in the antidepressant effects 
between esketamine and ketamine was 3.8% in treatment-resistant depression 

 
7 
patients.26 In the perioperative population with depressive symptoms, the remission rate 
was reported to be 23.1% in the ketamine group and 9.3% in the placebo group based 
on the PASSION study at our research site. We assumed that the remission rate in the 
esketamine group will be 19.3% and that in the placebo group will be 10%. A sample 
size of 506 participants will provide 80% power to show the difference between the 
esketamine group and the placebo group (with a ratio of 1:1), including 1 interim 
analysis by using a 2-sided significance level of 0.05.27 With the consideration of a 10% 
attrition rate, the total sample size is planned to be 564. 
Interim analysis 
The planned interim analysis will be performed after 424 patients (75% of the total 
sample size) completed the follow-up. This interim analysis will be based on the ITT 
principle, and the P value will be set at 0.019 following adjustment by O’Brien-Fleming 
methods.28 
Statistical analysis 
Continuous variables will be reported as the mean (standard division) for normally 
distributed data and the median (interquartile ranges) for skewed distributions. 
Categorical variables will be reported as the number (proportion), and the relative risk 
with its 95% confidence intervals will be calculated. The difference between groups 
will be reported with 95% confidence intervals of absolute differences calculated by 
independent t-tests for continuous variables and using the Hodges–Lehmann method 
for skewed variables. The primary endpoint of remission rate at 3 days after surgery 
will be analyzed by using the chi-square test or Fisher’s exact test. The secondary 
outcomes will be analyzed using t-tests, Mann–Whitney U tests, and chi-square or 
Fisher’s exact tests as appropriate. The adjusted odds ratios will be estimated by using 
a logistic regression model by taking into account the unbalanced baseline variables, 
age, sex, the severity of depressive symptoms, and pain severity after surgery. 
For missing values, both imputations with the mean or median or the last observed 
assessment and multiple imputations will be applied. Sensitivity analysis for different 
imputation plans will be used to explore the statistical nature of the missing data. All 
statistical tests will be 2-sided at a significance level of 0.05 and the effect sizes will 

 
8 
also be reported. Because of the potential for type I errors due to the lack of adjustment 
for multiple comparisons, the findings for secondary outcomes or sensitivity analyzed 
should be interpreted as exploratory. All analyses will be performed by using Stata 
version 14.0. 
Safety consideration 
Once adverse events occurred during drug intervention, the principal investigator will 
be informed immediately. Based on the severity of the adverse events and the relation 
to esketamine, the unmasking process will be considered by the principal investigator. 
All the adverse events that occurred during the trial will be recorded in detail and 
closely monitored until stabilization or the time of the study intervention is not the cause 
for adverse events. All the adverse events will be reported to the Institutional Review 
Board by the principal investigator. 
Patient and public involvement 
Patients and the public were not involved in the trial design. Participants will have 
access to the findings of the study on request. 
Ethics and dissemination 
This study was approved by the Institutional Review Board of Beijing Tiantan Hospital, 
Capital Medical University, Beijing, China on October 30, 2020 (KY-2020-058-02). It 
has been registered on clinicaltrials.gov on June 11, 2020 (NCT04425473). The first 
participant was recruited on February 19, 2021. The conclusions of this study will be 
published in peer-reviewed journals. 

 
9 
Discussion 
This study is a randomized placebo-controlled double-blinded clinical trial that aims to 
explore the effect of esketamine on depressive symptoms in the major surgery 
population. The participants will be administered 0.2 mg/kg esketamine intravenously 
within 40 min with the suturing of the incision. The efficacy and safety endpoints will 
be observed during the perioperative period and in the long term after major surgery. 
In this study, the patients in the control group will receive normal saline rather than 
other antidepressants. To our knowledge, traditional antidepressants need to be 
administrated continuously for more than one week before taking effect, which is not 
suitable for short hospital stays in surgery patients. Besides, traditional antidepressants, 
such as selective serotonin reuptake inhibitors and tricyclic antidepressants, may lead 
to a potential risk for bleeding, arrhythmia, and anaesthetic metabolism dysfunction 
during surgery.29 For ethical concerns, the participants enrolled in this study will be 
provided with a professional consultation from the psychiatrist as necessary.     
Although the PASSION study found that ketamine could alleviate the depressive 
symptoms assessed by clinician-rating scales to some extent in neurosurgery patients, 
there are still several concerns about the evidence of clinical trials regarding the 
resolution for depressive symptoms in the surgery population. First, screening standards 
for depressive symptoms during the perioperative period are lacking, and assessments 
in different depressive populations may affect the results of studies. Minor depressive 
symptoms may induce few adverse outcomes and disappear spontaneously after surgery. 
However, moderate-to-severe depressive symptoms could lead to worsening moods, 
enhanced postoperative pain, or suicidal ideation, and there is an urgent need to resolve 
these symptoms. Second, the rating scale tools are subjective. Self-rating scales have 
commonly been used in previous studies, which also require clinician-rating scales to 
verify the antidepressant effects. Third, small sample size may have led to false-positive 
or false-negative results in previously reported studies. Fourth, the long-term effects of 
ketamine or esketamine on depressive symptoms in patients undergoing major surgery 
remain unclear. Meanwhile, whether the analgesic effect of esketamine is the key factor 
considering the antidepressant effects needs to be investigated. 

 
10 
The safety of esketamine as an antidepressant in the context of surgery is unknown. 
Esketamine, as a novel drug for replacing ketamine, is not approved for intravenous use 
as an antidepressant. The plasma concentration for the antidepressant dosage of 
ketamine was reported to be approximately 70–200 ng/ml, which is far lower than the 
anaesthetic concentration (2000–3000 ng/ml).10 It is essential to explore an appropriate 
and safe dosage of esketamine for antidepressant treatment during surgery. Esketamine 
used in patients undergoing general anaesthesia is theoretically safer than the 
administration in awake patients. However, different anaesthetics administered during 
general anaesthesia may induce synergic effects with esketamine or attenuate treatment 
effectiveness. Thus, it is important to monitor the quality of recovery from general 
anaesthesia. Similar to ketamine, which could lead to psychotic symptoms, 
hallucinations, manic symptoms, or dissociative symptoms, esketamine given at an 
antidepressant dosage may also increase these risks after surgery. Determining the safe 
dosage will also be important for the popularization of esketamine used as an 
antidepressant during the perioperative period. Based on the previous study, both 0.2 
mg/kg and 0.4 mg/kg of esketamine administrated intravenously were reported with 
remarkable anti-depression effects and low-dose of esketamine (0.2 mg/kg) with fewer 
side-effects rate than high-dose of esketamine after drug administration.15 Thus, we 
selected 0.2 mg/kg of esketamine as the intervention dosage in this study. 
In summary, this study is a randomized controlled trial focusing on the mental health 
of perioperative patients. The expected result is that esketamine could markedly 
improve the remission rate after surgery without obvious adverse events, and long-term 
outcomes may also benefit from the administration of esketamine. 
 

 
11 
Footnotes 
Funding: This study was supported by Beijing Municipal Science & Technology 
Commission (No. Z191100006619067) and Beijing Municipal Administration of 
Hospitals Clinical Medicine Development of Special Funding Support 
(DFL20180502). 
Conflicts of interest: The authors declare no competing interests. 
Ethics approval and consent to participate: This study has been approved by the 
Institutional Review Board of Beijing Tiantan Hospital, Capital Medical University, 
Beijing, China (KY-2020-058-02). All participants or their legal representatives will 
provide written informed consent before enrollment. The patient informed consent is 
provided in supplementary file 1. 
Consent for publication: Written informed consent for publication was obtained 
from all participants. 
Availability of data and materials: The datasets will be available from the primary 
investigator (Ruquan Han, Email: ruquan.han@ccmu.edu.cn) upon reasonable request 
after the publication of the study results. 
 

 
12 
Figure legend 
 
Figure 1 Flow diagram for PASSION II. 
 
Figure 2 Schedule of blinding in drug preparation, intervention, and follow-up. 
 

 
13 
References 
1. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years 
lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden 
of Disease Study 2015. Lancet (London, England) 2016;388(10053):1545-602. doi: 10.1016/S0140-
6736(16)31678-6 
2. Disease GBD, Injury I, Prevalence C. Global, regional, and national incidence, prevalence, and years 
lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for 
the Global Burden of Disease Study 2016. Lancet (London, England) 2017;390(10100):1211-59. doi: 
10.1016/S0140-6736(17)32154-2 
3. Vasudev A, Saxby BK, O'Brien JT, et al. Relationship between cognition, magnetic resonance white 
matter hyperintensities, and cardiovascular autonomic changes in late-life depression. Am J Geriatr 
Psychiatry 2012;20(8):691-9. doi: 10.1097/JGP.0b013e31824c0435 
4. Kazmierski J, Kowman M, Banach M, et al. Incidence and predictors of delirium after cardiac surgery: 
Results from The IPDACS Study. Journal of psychosomatic research 2010;69(2):179-85. doi: 
10.1016/j.jpsychores.2010.02.009 
5. De Cosmo G, Congedo E, Lai C, et al. Preoperative psychologic and demographic predictors of pain 
perception and tramadol consumption using intravenous patient-controlled analgesia. Clin J Pain 
2008;24(5):399-405. doi: 10.1097/AJP.0b013e3181671a08 
6. Arnold SD, Forman LM, Brigidi BD, et al. Evaluation and characterization of generalized anxiety and 
depression in patients with primary brain tumors. Neuro Oncol 2008;10(2):171-81. doi: 
10.1215/15228517-2007-057 
7. Orri M, Boleslawski E, Regimbeau JM, et al. Influence of Depression on Recovery After Major 
Noncardiac Surgery: A Prospective Cohort Study. Ann Surg 2015;262(5):882-9; discussion 89-90. doi: 
10.1097/SLA.0000000000001448 
8. Connerney I, Shapiro PA, McLaughlin JS, et al. Relation between depression after coronary artery 
bypass surgery and 12-month outcome: a prospective study. The Lancet, 2001:1766-71. 
9. Mainio A, Hakko H, Niemela A, et al. Depression in relation to anxiety, obsessionality and phobia 
among neurosurgical patients with a primary brain tumor: a 1-year follow-up study. Clin Neurol 
Neurosurg 2011;113(8):649-53. doi: 10.1016/j.clineuro.2011.05.006 
10. Sanacora G, Frye MA, McDonald W, et al. A Consensus Statement on the Use of Ketamine in the 
Treatment 
of 
Mood 
Disorders. 
JAMA 
Psychiatry 
2017;74(4):399-405. 
doi: 
10.1001/jamapsychiatry.2017.0080 
11. Kudoh A, Takahira Y, Katagai H, et al. Small-dose ketamine improves the postoperative state of 
depressed patients. Anesth Analg 2002;95(1):114-8, table of contents. 
12. Jiang M, Wang MH, Wang XB, et al. Effect of intraoperative application of ketamine on postoperative 
depressed mood in patients undergoing elective orthopedic surgery. J Anesth 2016;30(2):232-7. doi: 
10.1007/s00540-015-2096-7 
13. Mashour GA, Ben Abdallah A, Pryor KO, et al. Intraoperative ketamine for prevention of depressive 
symptoms after major surgery in older adults: an international, multicentre, double-blind, randomised 
clinical trial. British Journal of Anaesthesia 2018;121(5):1075-83. doi: 10.1016/j.bja.2018.03.030 
14. Zhou Y, Peng Y, Fang J, et al. Effect of low-dose ketamine on PerioperAtive depreSsive Symptoms 
in patients undergoing Intracranial tumOr resectioN (PASSION): study protocol for a randomized 
controlled trial. Trials 2018;19(1):463. doi: 10.1186/s13063-018-2831-0 
15. Singh JB, Fedgchin M, Daly E, et al. Intravenous Esketamine in Adult Treatment-Resistant 

 
14 
Depression: A Double-Blind, Double-Randomization, Placebo-Controlled Study. Biological psychiatry 
2016;80(6):424-31. doi: 10.1016/j.biopsych.2015.10.018 
16. Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to 
Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA 
Psychiatry 2018;75(2):139-48. doi: 10.1001/jamapsychiatry.2017.3739 [published Online First: 
2017/12/29] 
17. Short B, Fong J, Galvez V, et al. Side-effects associated with ketamine use in depression: a systematic 
review. The Lancet Psychiatry 2018;5(1):65-78. doi: 10.1016/s2215-0366(17)30272-9 
18. Spitzer RL, Kroenke K, Williams JB. Validation and utility of a self-report version of PRIME-MD: 
the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire. 
JAMA 1999;282(18):1737-44. doi: 10.1001/jama.282.18.1737 
19. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. The British 
journal of psychiatry : the journal of mental science 1979;134:382-9. [published Online First: 1979/04/01] 
20. Bech P, Andersen H, Wade A. Effective Dose of Escitalopram in ModerateversusSevere DSM-IV 
Major Depression. Pharmacopsychiatry 2006;39(04):128-34. doi: 10.1055/s-2006-946702 
21. Karcioglu O, Topacoglu H, Dikme O, et al. A systematic review of the pain scales in adults: Which 
to use? Am J Emerg Med 2018;36(4):707-14. doi: 10.1016/j.ajem.2018.01.008 [published Online First: 
2018/01/13] 
22. Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. 
The British journal of psychiatry : the journal of mental science 1978;133:429-35. 
23. Hu YD, Xiang YT, Fang JX, et al. Single i.v. ketamine augmentation of newly initiated escitalopram 
for major depression: results from a randomized, placebo-controlled 4-week study. Psychological 
medicine 2016;46(3):623-35. doi: 10.1017/S0033291715002159 
24. Brousse G, Meary A, Blanc O, et al. Clinical predictors of response to olanzapine or risperidone 
during 
acute 
episode 
of 
schizophrenia. 
Psychiatry 
research 
2010;179(1):12-8. 
doi: 
10.1016/j.psychres.2009.03.003 
25. Bremner JD, Krystal JH, Putnam FW, et al. Measurement of dissociative states with the Clinician-
Administered Dissociative States Scale (CADSS). J Trauma Stress 1998;11(1):125-36. doi: 
10.1023/A:1024465317902 
26. Correia-Melo FS, Leal GC, Vieira F, et al. Efficacy and safety of adjunctive therapy using esketamine 
or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-
inferiority study. J Affect Disord 2020;264:527-34. doi: 10.1016/j.jad.2019.11.086 [published Online 
First: 2019/12/02] 
27. Wu MC, Lan KK. Sequential monitoring for comparison of changes in a response variable in clinical 
studies. Biometrics 1992;48(3):765-79. [published Online First: 1992/09/01] 
28. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35(3):549-
56. [published Online First: 1979/09/01] 
29. Roose SP, Rutherford BR. Selective Serotonin Reuptake Inhibitors and Operative Bleeding Risk. 
Journal of Clinical Psychopharmacology 2016;36(6):704-09. doi: 10.1097/jcp.0000000000000575