Conditions: Post Partum Depression
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 1
Healthy volunteers: no

Brief summary:
Postpartum depression is a non-psychotic major or minor depressive episode that occurs during pregnancy or within 12 months of post-partum period. The nature of symptoms is same as depressive episode characterized by depressed mood, anxiety, sleep difficulties, suicidal thoughts, tiredness and diminished interest in pleasurable activities. Severe maternal depression affects children by increasing the risk of emotional and behavioral and physical health problems and cognitive difficulties. Thus early screening and intervention is critical in reducing the negative impact of PND in the mother and child, family and the community.

The purpose of this study is to assess the safety, pharmacokinetics and antidepressant efficacy of sub-anesthetic dose of intravenous ketamine in perinatal depression.

Detailed description:

Arms:
arm 1: single intravenous infusion of Ketamine (0.5 mg/kg), washout period of seven days, and then single intravenous infusion of Ketamine (0.2 mg/kg) arm 2: single intravenous infusion of Ketamine (0.2 mg/kg), washout period of seven days, and then single intravenous infusion of Ketamine (0.5 mg/kg)

Interventions: intervention 1: Ketamine 0.5 mg/kg intervention 2: Ketamine 0.2 mg/kg
Intervention descriptions: intervention 1: single intravenous infusion of Ketamine (0.5 mg/kg) intervention 2: single intravenous infusion of Ketamine (0.2 mg/kg)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFFICACY AND TOLERABILITY OF SUB-ANESTHETIC KETAMINE IN POSTPARTUM DEPRESSION 
 
NCT04011592 
 
Version Date: 06/26/2019 
 
 


id allopregn
ng promisi 
EFFICACY AND TOLERABILITY OF SUB-ANESTHETIC KETAMINE IN POSTPARTUM DEPRESSION 
 
 
Principal Investigator: Sudhakar Selvaraj, M.B.B.S. DPhil, Assistant Professor of Psychiatry 
 
Co-Investigators: 
 
Dr. Salih Selek, MD, Visiting Associate Professor, Department of Psychiatry & Behavioral Sciences 
 
Dr. Jair C. Soares, MD, Ph.D., Professor, and Chairman of the Department of Psychiatry and Behavioral 
Sciences 
 
Dr. Giovana Zunta-Soares, MD, Assistant Professor of Psychiatry 
 
Dr. Davide Cattano, MD, Ph.D. Professor of Anesthesiology 
 
Dr. Baha M Sibai, Professor, Department of Obstetrics, Gynecology and Reproductive Sciences 
 
Dr. Jerrie Refuerzo, Professor, Department of Obstetrics, Gynecology and Reproductive Sciences. 
 
Population: 10 female patients, age: 18-45 
Number of Sites: 1 
Study Duration: 2 years 
 
General Information 
 
Perinatal Depression (PND) is a seriously disabling form of mood disorder that occurs during pregnancy or within 
12 months of the post-partum period(1). An untreated or protracted form of PND can adversely impact on mother, 
child and family well-being. PND is relatively common, affecting one in 8 women in the general population (2). 
Current treatments, including psychotherapy and antidepressants, are only effective in about half of PND patients 
and may take a few weeks to work. The current project aims to bridge this gap by studying the feasibility, safety, 
and effect of a single administration of a sub-anesthetic dose of ketamine on mood in patients with severe PND. 
BACKGROUND AND RATIONALE 
Perinatal depression (PND) is a non-psychotic major or minor depressive episode that occurs during pregnancy 
or within 12 months of the post-partum period (1). The nature of symptoms is the same as a depressive episode 
characterized by depressed mood, anxiety, sleep difficulties, suicidal thoughts, tiredness and diminished interest 
in pleasurable activities. The prevalence of PND is estimated to be 10-15% and may be even higher up to 25 % 
in low-income women (2). History of depression, experiencing anxiety and stressful life events during pregnancy 
and poor social support are considered as strong predictors of PND (2). Women with severe PND are at 
increased risk of self-harm and suicide, marital difficulties, and significant parenting difficulties (3). Severe 
maternal depression affects children by increasing the risk of emotional and behavioral and physical health 
problems and cognitive difficulties and (3). Thus early screening and intervention are critical in reducing the 
negative impact of PND in the mother and child, family and the community. 
 
The Edinburgh Postnatal Depression Scale (EPDS) is the most commonly used screening tool for PND (2). 
Analysis of a large sample of EPDS (N=663) by international postpartum depression consortium (19 international 
sites) found that anxiety and anhedonia were the prominent symptom dimensions with post-partum onset in PND 
(8). Moderate and severe anxious subtypes are the most common subtype during a late postpartum  
period representing about 70 % of PND. Psychotherapeutic and pharmacological interventions are the current 
standard of care for moderate and severe PND. A systematic review of SSRIs have shown to have a modest 
effect in PND (Remission rates (46.0% vs. 25.7%; pooled risk ratio, 1.79)(9). However, current modalities take 
longer (>6 weeks for SSRI and >8-12 sessions for therapy)(3) but access to specialist therapists is not widely 
available (3). Despite some progress, nearly 50% of depressed patients do not unfortunately, fully respond to 
pharmacological treatment (10). The aetiopathogenesis of PND is less known and various neurobiological and 
psychosocial models have been proposed. Pregnancy is associated with marked changed changes in 
reproductive hormones (estradiol and progesterone) and therefore, such changes cause depression  in  
vulnerable women (11). It is proposed that rapid changes in gonadal hormone may cause changes in brain γ- 
aminobutyric  acid  (GABA)  and  glutamate  and  therefore  cause  a  cortical  excitatIoRrByN-iUnMhiBbEitRo:rHySiCm-MbaS-l1a8n-c04e1,6 
which may contribute to depression (12). Interestingly novel neurostero 
 aIRnBoloAnPeP,RaOVpoAsLitDivAeTaEll:o0s6t/e26ri/c2019 
modulator of γ-aminobutyric acid (GABAA) receptors, has   been showi 
ng treatment for post-partum 


80%) and 
etic data in 
depression (12). Identifying novel therapeutic targets for PND is a critical priority as prolonged illness can lead 
to the poor functional outcome (3). Consequently, there are two primary challenges in antidepressant research: 
(a) developing rapidly acting, safe and effective antidepressant treatments, and (b) developing noninvasive 
clinically useful biomarkers of antidepressant response with a focus on early indicators of treatment response. 
 
Clinical studies of Ketamine in depression: The serendipitous discovery of the rapid antidepressant effect of 
ketamine, a widely used anesthetic drug, has opened up development of novel glutamate-based antidepressant 
treatment strategies. Sub-anesthetic dose (0.5 mg/kg over 40 minutes) of ketamine improves depression 
symptoms in patients with TRD (4, 5, 13), bipolar depression (14) and post-traumatic stress disorder (15) and 
also in reducing suicidal ideation (SI) in depressed patients (16, 17). The improvement in depression scores w 
seen as early as 2 hours; with 71 % of patients deemed as responders at 24 hours (defined as 50% improvement 
on 21 items HDRS) and the antidepressant effects persisted in up to 35% of the patient at the end of 7 days (4). 
A subsequent study found that early antidepressant response to the first infusion was highly predictive of 
a sustained response to subsequent infusions (18). Ketamine improved depression symptoms in patients 
with anxious depression with a longer time to relapse than those with nonanxious depression (19). In summary, 
ketamine’s beneficial effects on mood and suicidality are very promising but further research is required to 
understand the ketamine’s rapid antidepressant effect. The exact underlying neural mechanisms involved in 
ketamine’s rapid antidepressant effect is currently unclear (20). Emerging evidence suggests that ketamine 
induces early increases in the excitatory synaptic drive through glutamate activity likely through AMPA and 
initiates synaptic plasticity processes in cortico-limbic regions presumably mediating the antidepressant effects 
(21, 22). 
Preliminary Studies: To assess the safety, pharmacokinetics and antidepressant efficacy of a sub- 
anesthetic dose of intravenous ketamine in depression. We studied the effect of ketamine in five patients 
(n=5) with TRD who received a single intravenous infusion dose of ketamine (0.5 mg/kg) for 40 mins. Four out 
of five patients successfully responded to ketamine at 24 hrs and tolerated ketamine well; thus supporting the 
feasibility of the procedure. However, the therapeutic effect of ketamine has not been studied in PND. 
 
PRIMARY HYPOTHESES AND SPECIFIC AIMS 
Severe Perinatal Depression (PND) is a major depressive episode that occurs during pregnancy or onset within 
12 months of the birth of a child. The prevalence of severe PND in the general population is estimated to be 5- 
10% (2). PND is a seriously disabling condition and can increase the risk of self-harm and health complications 
in mother can deleteriously affect the cognitive, emotional and social development of the child and increases the 
substantial economic burden on families and society (3). Selective Serotonin Reuptake Inhibitors (SSRIs) and 
psychotherapy are the main available treatment modalities for PND. While they are effective in some, it takes 
longer to work and half of the patients do not fully recover from depression. A faster onset of antidepressant 
action will be critical in enabling faster relief from depression and may increase the chance of full recovery. The 
main objective of this study is to investigate the rapid antidepressant effect of low sub-anesthetic dose of 
ketamine in PND. 
 
Aims 
To assess the safety, pharmacokinetics and antidepressant efficacy of a sub-anesthetic dose of 
intravenous ketamine in perinatal depression 
A single, intravenous, sub-anesthetic dose of ketamine in patients with Treatment-Resistant Depression (TRD) 
induces a significant (50%) reduction in depression symptoms within 2 hours of administration with 65% of 
depressed patients respond by 24 hours and up to 35% maintain response until the end of 1 week (4). Our in- 
house pilot data, in consistent with worldwide studies, show that ketamine (N=5) can be safely administered to 
depressed patients and improves depression symptoms when assessed at 24 hrs post infusion. Ketamine has 
not been studied in the treatment of PND where there is a significant unmet need. 
The dosing of ketamine (0.5 mg/kg over 40 mins) for antidepressant treatment was developed from research 
studies in the 1990s based on use in healthy participants (36). However, newer studies show some patients 
respond to lower dose and tolerated better (fewer side effects) by the patients (37). IV Ketamine reaches a peak 
within a few mins with an elimination half-life of 2–3 hrs (38). Ketamine’s clearance may be 20% higher in women 
than  in  men  (39).  Ketamine is  mostly  metabolized  in  norketamine  ( 
peIRrsBisNtsUMmBoEreR:tHhaSCn-M5 Sh-18a-f0t4e1r6 
administration (38). It is important to evaluate ketamine’s pharmacokin 
 PNIRDB tAoPiPmRpOrVovAeLsDaAfeTtEy: f0o6r/2th6/e2019 


ntinuously 
monitored
breastfeeding mother and the baby. Ketamine and its metabolites will be evaluated in PND patients receiving 
ketamine 0.5 mg/kg or 0.2 mg/kg at 30 mins, 2 hours and 4-5 hrs after ketamine infusion. All adverse medical 
and psychiatric events with onset or worsening after the administration of ketamine will be included in the 
analysis. 
The proposed experiment will be a proof-of-concept study in which we will evaluate the safety, pharmacokinetics, 
and efficacy of ketamine 0.5 mg/kg and 0.2 mg/kg over 40 minutes in a double-blinded and crossover fashion 
separated over one week (5) (dose used in antidepressant clinical trials) in PND patients who are not currently 
breastfeeding. The primary outcome measure of efficacy will be the Hamilton Depression Rating Scale (HAMD- 
17) at 24 hours and additional secondary anxiety and mood scales. (6). Any adverse medical and psychiatric 
events will be recorded and summarized. Ketamine and its metabolites will be evaluated at 30 mins, 2 hours and 
24 hrs. 
 
 
Hypothesis 1): Ketamine will significantly decrease (>50%) in HAM-D17 scores at 24 hrs after infusion from 
baseline. The 0.5 mg/kg dose will be more efficacious that 0.2 mg/kg in improving depression symptoms. 
Hypothesis 2) Ketamine will improve anxiety symptoms in PND (as measured using HAM-Anxiety and EPDS) 
at 24 hrs after infusion in patients with PND. Anxious subtypes are the most common subtype during a late 
postpartum period representing about 70 % of PND. (40) 
Hypothesis 3) Ketamine infusion will be tolerated well by the patients with fewer side effects at 0.2 mg/kg 
compared to 0.5 mg/kg. 
 
METHODS 
Research Design and Methods: All human subjects’ research will be conducted with full approval from the IRB 
at the University of Texas Health Science at Houston. We will recruit PND patients (N=10) who will be 
administered a single intravenous infusion of Ketamine either at 0.5 mg/kg or 0.2 mg/kg over 40 minutes in a 
double-blinded and crossover fashion separated by minimum 7 days, with the order being randomized and 
balances across subjects. Two doses will help decide the safe, tolerable and effective dose for PND subjects 
will undergo a standard screening interview visit to confirm eligibility evaluations including SCID-4 interview (27) 
and collection of demographic, clinical and medical history. To ensure medical stability, each patient will have a 
physical examination and urine toxicology screen to rule out the recent undisclosed use of illicit substances. It 
will also be requested that the patient provide a record of lab results to indicate adequate health for inclusion. 
We will pre-screen potential participants over the phone to minimize the invitation to non-eligible participants. 
Eligible patients that want to participate in the study will be scheduled to have a screening visit to review consent 
and determine eligibility. 
 
The total duration of the commitment of the study is minimum of 4 weeks. Extension of the timeline can occur 
depending on the time between the screening visit and the first infusion dose. The total commitment should not 
exceed 3 months. There will be a minimum 7 days between the 2 infusions. Patients who qualify will complete 
the infusions on another day at UTHealth Clinical Research Unit at Memorial Hermann-TMC, Houston. University 
of Texas Health Science Center at Houston Memorial Hermann-TMC 6411 Fannin St.or at our Harris County 
Psychiatric Center (HCPC) where they will be given the ketamine infusion by the study nurse. Patients will be 
advised to follow the American Association Preoperative Fasting Guidelines prior to infusion. 
 
There will be two appointments where they will be administered a single intravenous infusion of Ketamine either 
at 0.5 mg/kg or 0.2 mg/kg over 40 minutes in the first infusion visit and a second infusion visit where they will 
receive the infusion that was not given on the first visit, where there will be a minimum of 7 days between 
infusions. 
 
Before the infusion, the psychiatrist and anesthesiologist will evaluate the patient. During the infusion, patients will 
be asked constantly about “how they feel” and will be monitored co 
byIRthBeNrUeMgiBstEeRre: HdSnCu-rMseS-1u8n-d04e1r6 
the supervision of an Anesthesiologist. EKG and pulse-oximetry will be 
 tIhRrBouAgPhPoRuOtVtAheL pDrAoTcEe:d0u6r/e26t/o2019 


check for hemodynamic changes. After the completion of 40 min infusion, patients will rest for two-four hours 
under the observation of clinical nurse.. After the infusion both psychiatrist and anesthesiologist will evaluate the 
patient. Patients may complete clinical questionnaires after this session at HCPC or CRU for approximately 30 
minutes. After the first infusion, patients will be contacted one day after over the phone and after the second 
infusion, patients will be contacted one day after and 7 days after the infusion. During the phone call, patients 
will be asked about their physical health, will be asked about adverse events and respond questionnaires that 
evaluate mood status. 
Recruitment: The current project will ensure robust and timely recruitment through coordination with ongoing 
studies at the UT Center of Excellence on Mood Disorder (CEMD) (Dr. Jair Soares, Departmental Chair). Dr. 
Selvaraj runs a perinatal clinic focused on pregnant or postpartum women with mood disorders in the psychiatry 
department. Dr. Selvaraj also collaborates with Dr. Sibai, UTHealth Department of Obstetrics, Gynecology and 
Reproductive Sciences on a postpartum research project. Additionally, a large research participant registry has 
been set up by this UT center (n = 4952 over the last 5 years, of which 80% have a mood disorder history). 
Recruitment will also be facilitated through the UT Research Match program. On average, 200 patients have a 
higher report of depression and mental health problems in the last year and of which nearly 100 patients had 
higher EPDS scores that meet PND criteria. The perinatal psychiatry clinic will facilitate clinical recruitment. 
Subject recruitment will include initial identification of cohort pool using selection criteria and subsequent review 
of identified patient records before final vetting and consent. 
Study Population: We will enroll 10 patients with Perinatal Depression (PND) in this study. Participants will be 
female adults, aged 18-45 years, who meet the criteria for PND. Participants will be recruited without regard to 
race, religion or ethnicity. Participants will be postpartum and no longer breastfeeding or will be willing to stop 
breastfeeding during the study. Participants will be recruited through flyers and clinic referrals in the Houston 
area. Women of all ethnic backgrounds will be recruited to participate. It is anticipated that the subject 
demographic profile will closely mirror the larger population of individuals with PND from which they are recruited. 
We will do so by posting flyers at community medical clinics, outpatient mental health clinics and local business 
in the area 
 
Inclusion Criteria: 
1) Female subjects, ages 18-45 years 
2) Experienced a major depressive episode in the postpartum period beginning within the first 4 weeks 
following delivery and with moderate or severe symptoms (>12 EPDS or >14 HAM-D). 
3) No or partial response to adequate doses of SSRI medications to treat PND for longer than 6 weeks. 
4) PND patients will be requested to maintain a stable dose of antidepressants while enrolled in the study trial. 
5) Patients that can speak and read the English language are able to understand the study procedures and 
sign the informed consent 
 
Exclusion Criteria: 
1) No current or past psychosis or severe personality disorder. 
2) No current substance abuse or dependence. 
3) No serious and imminent suicidal or homicidal risk. 
4) No recent or history of major and unstable medical problems that affect brain anatomy, neurochemistry, or 
function. 
5) Not diagnosed with cardiovascular disorders. 
6) No increased risk of laryngospasm or active upper respiratory infections. 
7) Not diagnosed with intellectual disability or neurodegenerative diseases. 
8) Mothers that are currently breastfeeding. 
9) No current pregnancy. 
 
Clinical and diagnostic assessments: 
IRB NUMBER: HSC-MS-18-0416 
IRB APPROVAL DATE: 06/26/2019 


Screening evaluation will obtain family history and demographic data. An estimated duration of a complete 
screening visit will be approximately 3 hours or less. Copies of any recent medical evaluations (past medical 
history, physical exam, etc.) will be requested from treating clinicians and health care providers. We will perform 
a urine drug screening (UDS) to rule out the recent undisclosed use of illicit substances. Also we will perform a 
urine pregnancy test. We will also complete a physical examination, height and weight and vital signs. 
Demographic information is obtained through a standardized form and covers: age, race, gender, education 
(information both on siblings and their parents), religion, and socioeconomic status. 
Patients will complete mood questionnaires rating the severity of the clinical symptoms: 
1) SCID–I Interview 
2) Hamilton Depression Rating Scale (HAMD-17) 
3) Montgomery-Asberg Depression Rating Scale (MADRS) 
4) Edinburgh Postnatal Depression Scale (EPDS) scale 
5) Young Mania Rating Scale (YMRS) 
6) Clinical global improvement (CGI) 
7) Brief Psychiatric Rating Scale (BPRS) 
8) Generalized Anxiety Disorder (GAD-7) 
9) Columbia Suicide Severity Rating Scale (C-SSRS) 
10) Hamilton Anxiety Rating Scale (HAM-A) 
11) Beck Depression Inventory (BDI) 
12) Snaith-Hamilton pleasure scale (SHAPS) (29). 
 
We will also collect exploratory data on subjective anhedonia (SHAPS) measurements to investigate ketamine’s 
effect on specific reward and motivation functioning in this spectrum of psychiatric patients. 
 
All aforementioned assessments may be administered in a standard manner involving researcher or self-report 
questionnaires on paper, or they may be administered using Qualtrics, which is a HIPAA compliant electronic 
data collection tool widely used in research. When the latter is used, participants will be invited to complete 
questionnaires on a computer or tablet. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18-0416 
06/26/2019 
Assessment 
Screening 
(at BBSB) 
Infusion Day 
1 
(at HCPC or 
CRU) 
Infusion Day 
2 
(at HCPC or 
CRU) 
Follow up post 
infusion 1 and 
again post 
infusion 2 Day 1 
(by phone) 
Follow 
up post infusion 2 
Day 7 
(by 
phone) 
Before 
Infusion 
After 
Infusion 
Before 
Infusion 
After 
Infusion 
Post 
infusion 
1 
Post 
infusion 
2 
Post infusion 2 
Informed Consent 
X 
Eligibility Review 
X 
X 
X 
Demographics and 
Psychiatric/Medical 
History 
X 
Physical Examination 
X 
X 
X 
Assessment by 
anesthesiologist and 
psychiatrist. 
X 
X 
Urine Drug screen 
X 
X 
X 
IRB N
IRB A
UMBER: HSC-MS-
PPROVAL DATE: 


4-5 hours af
rsed for trans 
. 
Urine pregnancy test 
X 
X 
X 
Vital Signs 
X 
X 
X 
Height and Weight 
measurement 
X 
Blood Collection 
X 
X1 
X 
X2 
Structured Clinical 
Interview for DSM-IV 
Axis I Disorders 
(SCID-I) 
X 
Hamilton Depression 
Rating Scale (HAMD- 
17) 
X 
X 
X 
X 
X 
X 
X 
Montgomery-Asberg 
Depression Rating 
Scale (MADRS) 
X 
X 
X 
X 
X 
X 
X 
Edinburgh Postnatal 
Depression Scale 
(EPDS) scale 
X 
X 
X 
X 
X 
X 
X 
Young Mania Rating 
Scale (YMRS) 
X 
X 
X 
Clinical global 
improvement (CGI) 
X 
X 
X 
Brief Psychiatric 
Rating Scale (BPRS) 
X 
X 
X 
Generalized Anxiety 
Disorder (GAD-7) 
X 
X 
X 
X 
X 
X 
X 
Columbia Suicide 
Severity Rating Scale 
(C-SSRS) 
X 
X 
X 
Hamilton Anxiety 
Rating Scale (HAM- 
A) 
X 
X 
X 
Snaith-Hamilton 
pleasure scale 
(SHAPS) 
X 
X 
X 
Beck Depression 
Inventory (BDI) 
X 
X 
X 
X 
X 
X 
X 
AE Report 
X 
X 
X 
X 
X 
Concomitant 
Medications 
X 
X 
X 
Study Contact Card 
given 
X 
X 
 
 
 
 
1  Done at 30 minutes after infusion (+/-10), 2 hours after infusion (+/- 30 minutes) and 
tIeRr BinfNuUsioMnB. ER: HSC-MS-18-0416 
Patients that are unable to arrive to the appointment with a caregiver will be reimbu  
poIRrtBatAioPnPuRpOtoVA$5L0DdlAlsT. oEn: 06/26/2019 
infusion days. They will receive a phone call that same day to ensure safe arrival home 


blurred vi 
ce, we do 
All of the above clinical questionnaires will be completed at the screening visit as well as on the ketamine infusion 
day, except the SCID-I, which will only be completed at the screening. 
 
All data collected on paper forms will be stored in locked cabinets, while electronic data is stored on our secure 
password protected server (maintained by the UTHealth Medical School Information Technology Department). 
All electronic records will identify study participants only by a study code, and the electronic file linking codes to 
individual identifiers will be destroyed once data collection is complete. 
 
Patients will arrive fasting from midnight on study visit day have blood draws and complete questionnaires at our 
clinical research suite at UTHealth’s Biomedical and Behavioral Sciences building (BBSB) at 1941 East Road, 
Houston TX 77054 or at UTHealth CRU at Memorial Hermann-TMC, Houston. University of Texas Health 
Science Center at Houston Memorial Hermann-TMC 6411 Fannin St.or at UT Health Harris County Psychiatric 
Center (HCPC) 
 
Placement of IV: For both of the infusion days, after the initial evaluation is done, patients will be placed 
one intravenous line in each arm. One line will be used for the ketamine infusion and the other line will 
be used for the collection of blood samples and to reduce discomfort for patients with frequent blood 
draws. If the sample is not obtained from the IV line due to clotting, the patient will be asked if they would 
like to have a blood draw using a BD Vacutainer. 
 
Medical Monitoring: During the infusion, patients will receive continuous monitoring from the nurse and 
the attending and after the completion of 40 min infusion, patients will rest for two hours under the 
observation of clinical nurse and reassessed again by anesthesiologist/psychiatrist (advance life support 
trained) at 2 hours after infusion. Patients will be discharged from the hospital unit between 2-4 hours 
after the infusion with a responsible adult for the study visit. Patients will be contacted on days 1, 2 and 
7 post-infusion for a follow-up assessment of mental state by telephone and will be scheduled for study 
visits. 
 
Stopping Rules: Any worsening of depression symptoms - if patients score a 3 on item 3 of the HDRS 
or 3 on item 10 of the MADRS or total HDRS score (first 21-items) increases by 5 points or more from 
one visit to the next weekly visit. The C-SSRS will be administered to monitor suicidal ideation and 
behavior. Increased observation consists of daily phone calls with study physicians and/or increasing 
visit frequency based on the PI’s clinical judgment. 
 
Blood tests: Ketamine and norketamine plasma levels will be collected before and 30 minutes, 2 hours 
and 4 to 5 hours after the infusion. Samples will be stored at BBSB for analysis. Analyses will be 
performed by Gas Chromatograph-Mass Spectrometer (30). 
 
Clinical measures - Clinical rating and questionnaires will be administered. Treatment response will be 
operationally defined as 50% improvement from baseline in the HAM-D17 scores. 
 
POTENTIAL RISKS/DISCOMFORTS 
 
Diagnostic procedures and questionnaires: Some of the questions asked during the screening may be 
considered sensitive information, including drug use history and psychiatric history. Answering these questions 
may be psychologically discomforting to some subjects. There are also risks associated with loss of 
confidentiality. 
 
Ketamine infusion: The most commonly reported side effects during the 4 hour period after each infusion include 
feeling strange or unreal (58.3%), abnormal sensations (54.2%), 
 sIiRoBn N(5U0M.0B%ER),:fHeSeClin-Mg Sd-r1o8w-0s4y16 or 
sleepy (48.5%) and headaches (30-40%). Based on previous eviden 
noIRt BexApPePcRt OkVetAaLmDinAeTtEo: 0im6/p2a6/i2r019 


of serious 
lace  to en 
cognitive functions such as memory, attention or language. If patients are currently taking certain medications 
on a daily basis within 24 hours prior to and/or after receiving ketamine, they will not be able to take these 
medication(s) while receiving a ketamine infusion without clearance or approval of the physicians involved in 
administering ketamine. Medications include: Sedatives (e.g., clonazepam, lorazepam, alprazolam); Antibiotics 
(e.g., azithromycin, clarithromycin); Antifungal agents (e.g., ketoconazole); Tramadol. This is due to concerns 
for potentially increased sedation or trouble breathing. One third of the patients exposed to standard repeated 
infusions of IV ketamine reported some kind of hemodynamic change such as elevated blood pressure (BP) 
and/or heart rate (Murrough et al., 2013b) that usually resolves shortly after the ketamine infusion (aan het Rot 
et al., 2010; Murrough et al., 2013b). It has been reported that initial hypertensive episodes and transient 
tachycardia are predictive of hemodynamic changes with subsequently repeated ketamine infusions (aan het 
Rot et al., 2010). Ventricular premature contractions, hypotension, and non-significant changes in oxygen 
saturation have also been reported with low-dose (0.5mg/kg) ketamine infusions over 40 minutes. 
 
Confidentiality: Loss of confidentiality is a highly unlikely but potential risk associated with this study. Some 
participants may find questions annoying or intrusive and neuropsychological testing might induce some fatigue 
and sensation of boredom. The venipuncture (insertion of small IV due to the need for IV infusion of ketamine) 
might produce some mild pain, bruising, bleeding, infection, and in some cases, even induce fainting. Side effects 
associated with ketamine injection are rare and, if any, of transient duration. The most commonly reported side 
effects during the 4-hour period after each infusion include feeling strange about body sensations58.3%), or 
abnormal sensations (54.2%), blurred vision (50.0%), feeling drowsy or sleepy (45.8%) (Murrough et al., 2013b) 
and headaches (30-40%) (aan het Rot et al., 2010). Based on the previous evidence, we do not expect ketamine 
to impair cognitive functions such as memory, attention, and language (aan het Rot et al., 2010). 
 
The Human derived biological sample (HDBS) bank administered by the University of Texas Health Science 
Center Houston (UTHSC-H) will remain with UTHSC-H unless the UTHSC-H agrees to release and/or transfer 
the samples. Please be aware that if the PI leaves the University, the samples within the HDBS bank will remain 
the property of UTHSC. The University’s ownership includes the right to transfer ownership to other parties, 
including commercial sponsors. 
 
Adequacy Of Protection Against Risks 
 
Recruitment and Informed Consent: Participants will be self-referred in response to various study 
advertisements via flyers. Individuals who call for information will be given a brief description of the study. Those 
interested will then be asked to answer questions about their disease status. A trained research assistant will 
conduct this telephone-screening interview. Eligible subjects will be scheduled for an in-person screening visit 
at the BSBB. 
 
Once eligible for the study screening visit, they will be invited for study Day #1, which will begin with the 
presentation of the informed consent form. The consent form will detail the requirements of study participation 
(e.g., # of visits, type of data collected, time commitment, etc.) Subjects will be told that the purpose of the study 
is to evaluate neurophysiological measures to study the effect of ketamine on PND. Subjects will be informed 
that they will have to attend a total of 2 visits (screening/baseline and 1 study visit) and 2 follow up phone calls. 
Other information on the consent form will include a full description of study requirements, reimbursement, risks, 
benefits, alternatives, and the role of the local IRB. All questions will be answered before written consent is 
requested. Informed consent will be obtained only by the PI or a trained senior member of the staff (e.g. study 
coordinator). 
 
The research protocol, consent form, and all assessment/advertising materials will be reviewed and approved 
by the Committee for the Protection of Human Subjects (CPHS) at UTH. 
 
Protections against risk 
1. 
Risks related to diagnostic procedures/questionnaires: As noted above, the primary risks related to these 
procedures are participant  discomfort and loss of confidentiality. Regarding participant  discomfort, we   
will make clear that we ask for this sensitive information as part of the consent process. Further, while 
subjects may be uncomfortable reporting these issues, the risks 
 sIReqBuNeUlaMeBaErRe:eHxStCre-m
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Regarding  confidentiality,  we  have  rigorous  procedures  in  p 
sIuRrBe AcPoPnRfOidVeAntLiaDlitAyTEo:f 06d/a2t6a/2, 019 


including locked cabinets for confidential files, participant coding, secure computer systems, and rigorous 
training of personnel. Computer systems are secure and strictly monitored by University IT staff. 
Laboratory staffers are trained in confidentiality of participant information. No information is allowed to 
leave the lab or to be accessed by a computer outside of the university’s secure computer system, and 
all data are further protected by permissions and passwords given only to necessary research personnel. 
No information will be published in a form in which the participant can be identified. We will also obtain a 
Certificate of Confidentiality for this study to provide additional protection for sensitive information. 
 
2. 
Risks related to study medication: The following procedures will be taken to safeguard against adverse 
medication events: (1) careful initial intake evaluation to determine eligibility based on inclusion/exclusion 
criteria; (2) thorough physical evaluation prior to infusion, consisting of physical examination, standard 
laboratory tests, electrocardiogram, urine toxicology screen, pregnancy test and vital signs; (3) Monitoring 
of concomitant illicit drug use at each visit with self-report, urine and/or breath testing; (4) Review of 
medication response, adverse events, and medication compliance with the study nurse; (5) Regular 
evaluation of all medical information. In the event that contraindicated medical conditions and/or other 
serious adverse symptoms arise after initiation of the medication, medication will be discontinued and 
the subject will be examined. 
 
3. 
Risks related to alternative treatments: As noted above, we believe that our therapeutic interventions 
provide treatment that is considerably superior to most, if not all, treatment opportunities in the 
community. Nevertheless, we will refer patients to other facilities upon request or when required by other 
circumstances. We will also conduct regular literature searches on alternative treatments, and in the 
event that an alternative treatment emerges with clearly superior efficacy, we would suspend the current 
study and provide all participants with referrals for this alternative treatment. 
 
4. 
Study withdrawal: The research study and participation is completely voluntary. Participants can withdraw 
from the study at any time without giving a reason and without any consequence. A decision not to take 
part or to stop being a part of the research project will not change the services available to them from the 
UTHSC-H, Department of Psychiatry or HCPC or CRU. The investigators could stop participation if an 
unfavorable or unexpected reaction is noticed. 
 
5. 
Unanticipated Hospitalizations: If a patient needs to be hospitalized for worsening of symptoms or for 
their own personal safety, they will be removed from their study participation and their study treatment 
will end at that time. 
 
6. 
Risks of blood draw: There are minimal risks involved in having the blood draw for the study. The blood 
sample will be drawn from a peripheral vein by a trained staff person. The risks involved are related to 
local bruising but these will be minimized by the use of trained personnel. 
 
Potential benefits of the proposed research to the participants and others 
All assessment and services provided in these studies will be free. The treatments may help in PND and prevent 
relapse. Subjects will be told if the unusual information is discovered during the study that will make a difference 
in treatment for this or other problems. By taking part in this research, subjects will help others with similar 
problems because this study is likely to identify how the treatment works and could also lead to the development 
of biomarkers for monitoring treatment response. 
 
Importance of the knowledge to be gained 
Research participation will help the patients in curing PND and possibly preventing relapse. The selected 
medication has shown preliminary evidence of benefit in helping patients with PND. PND is highly prevalent and 
leads to devastating consequences on a personal and societal level. Further, this study will pilot new approaches 
to evaluating treatments that may lead to more personalized and effective treatments for PND. The above-stated 
risks are relatively mild in degree and procedures have been designed to minimize their probability. We believe 
this protocol has an extremely favorable risk/benefit ratio. The psychiatry department has an excellent track 
record in conducting similar controlled trials with the utmost attention to safety. 
IRB NUMBER: HSC-MS-18-0416 
IRB APPROVAL DATE: 06/26/2019 


Reimbursement 
Patients will be provided $20 for their participation in the screening visit if they qualify to complete the rest of the 
study. Patients will also be compensated $100 if they complete the ketamine infusion study visit. 
 
 
Transportation during infusion days 
Patients will be asked to be accompanied by a caregiver that will be able to transport them after the ketamine 
infusion and to ensure that the patients arrive home safely. If patients are unable to provide a caregiver that can 
transport them, we will pay for transportation up to $50 for infusion days and will call the patient to ensure safe 
arrival. 
 
 
Follow up plan 
Patients considered as participants of the study will be referred to Dr. Selvaraj as a treating psychiatrist if they 
are not his patients. Patients who are referred by existing providers will return under the care of their care. If they 
have successful treatment with ketamine, they will be referred to a list of providers in the area of Houston that 
provide ketamine infusions as treatment for depressive symptoms, if the patient would want to consider 
continuing with the treatment as needed. 
 
Data and Safety Monitoring Plan 
 
The principal investigator will be responsible for the Data and Safety monitoring of the study. 
 
Data monitoring plan 
Data will be collected and stored as described above in Sources of Material and analyzed with primary outcomes 
as described in the Statistical Plan. Trained research assistants will enter data into an existing, relational 
database. Allowable input values will be restricted to standardized Access entry forms so as to maintain data 
integrity. All observations will be double-entered to verify the accuracy, with any problems detected discussed 
with the PI. If necessary, the re-training of research assistants will be conducted. Due to the comparatively small 
and initial nature of the current trial, interim data analysis is not planned. 
 
 
Safety monitoring plan 
During the screening, study applicants will undergo a complete psychological and physical exam to determine 
their eligibility and safety of their participation in this study, per inclusion/exclusion criteria detailed above. During 
the treatment phase of the study, participants will be asked about adverse events at each clinic visit and vital 
signs will be continuously monitored during the infusion and two hours after the infusion. 
 
All adverse events (AEs) occurring during the course of the study will be collected, documented, and reported to 
the Principal Investigator. The occurrence of AEs will be assessed at baseline and each visit during the treatment 
phase of the study. The PI, in consultation with the co-investigators, will review any AE’s as soon as they are 
reported. The study investigators will follow all AEs to the point of a satisfactory resolution. A study participant 
may have their medication discontinued of may be withdrawn from the study if the Study Physician determines 
it is the best decision in order to protect the safety of a participant. All AEs will be assessed to determine if they 
meet criteria for an SAE. 
 
Serious adverse events (SAEs), as defined by the FDA, will be evaluated at each visit. Any SAE, whether or not 
related to study medication, will be reported to the IRB within 24 hours. The initial SAE report will be followed by 
submission of a completed SAE report within 2 days. In the event that a patient either withdraws from the study 
or the investigator decides to discontinue a patient due to SAE, the patient will have appropriate follow-up medical 
monitoring. Monitoring will continue until the problem requiring hospitalization has resolved or stabilized with no 
further change expected, is clearly unrelated to study medication, or results in death. The outcome of SAEs will 
be periodically reported to IRB. 
Inclusion of Women 
IRB NUMBER: HSC-MS-18-0416 
IRB APPROVAL DATE: 06/26/2019 


 
 
 
 
 
The subjects will include only females, ages 18-45 years old, from various race/ethnic backgrounds, as reflected 
in the local community in the greater Houston area. 
 
Inclusion of Minorities 
Our study will include minority groups in proportions that will be representative of the ethnic/racial composition 
of the local community in Houston, Texas. Our projected numbers for minority enrollment are detailed in the 
enrollment table attached. 
 
Inclusion of Children 
Children will not be included in the study. The inclusion of children at this early stage would increase substantially 
the number of subjects needed for the overall project and would not be conducive to the perinatal nature of the 
study. At this time, we will focus on an adult population (ages 18-45 years old). 
 
Prisoners and pregnant women 
We are aware of the special protections afforded to prisoners per federal regulations. We will not actively recruit 
people who are incarcerated to participate in this study. We do, however, acknowledge the possibility of research 
participants in our target population being incarcerated during the study. If an active participant is incarcerated 
for an extended period of time, disenrollment from the study will be necessary. No research interaction or 
intervention will take place until an incarcerated participant is released from jail. Finally, neither the pregnant 
woman nor neonates will be enrolled in this study. Women will only be recruited postpartum and after having 
weaned their child. 
 
DATA ANALYSIS PLAN - General Data Analysis: The data analytic strategy will use generalized linear 
modeling. Statistical analyses will use SAS v.9.3. Preliminary data analyses will inspect baseline, treatment from 
baseline differences as well as correlations between baseline variables and specified outcomes. Baseline 
characteristics will be compared within groups using Student’s t-tests for continuous data and chi-square tests 
for categorical data. 
Sample size justification: our power calculation is guided by a previous study - intravenous ketamine 
in TRD patients (28) with effect size (Cohen’s d = 1.46) or Brexanolone in PND (effect size 1.2) (12, 32). 
For an effect size 1.2, a total of 10 PND patients will be required for within-subject design with probability 
95 % that the study will detect a treatment difference at a one-sided 0.05 significance level. 
Hypothesis: Based on previous studies (33, 34) and our pilot Ketamine TRD patient data, we predict 
that ketamine infusion compared to baseline will significantly decrease HAM-D scores in PND patient at 
24 hrs. The severe anxious subtype will have prominent improvement. 
Analysis: We will use linear regression to assess associations between improvements in depressive 
symptoms (change in the HAM-D from baseline using LOCF). A paired t-test was performed to evaluate 
the key efficacy measure - change from baseline in HAMD total score. We will also perform a secondary 
analysis comparing change from baseline to endpoint using last observation carried forward (LOCF) 
using a paired sample t-test. Secondary outcomes are safety and tolerability measures, including 
treatment-emergent AEs and changes from EPDS, GAD-7, PHQ-9, and C-SSRS. We will also investigate 
specific markers for treatment response. 
Alternate plans: The proposal applies the widely used ketamine sub-anesthetic dose (0.5 mg/kg) as a treatment 
for PND. If the effect is less clear or patient experiences any adverse effects, alternate strategies will be explored 
(two doses of ketamine instead of single or low dose 0.3 mg/kg if adverse effects etc. respectively). Patient safety 
and tolerability will be the most important guiding principle. This will require an amendment in the protocol and 
an updated consent. 
 
JUSTIFICATION - Research in PND is of critical importance due to its substantial burden on mother, family and 
child’s emotional, cognitive and behavioral development. Rapid and effective treatment of severe PND is a 
significant unmet need. The primary goal of the project is to evaluate the safety and efficacy of sub-anesthetic 
antidepressant dose ketamine treatment in severe PND patients. This proposal will be the first systematic 
investigation of ketamine’s antidepressant effect in PND. The study design is simple and robust that can provide 
 
 
 
 
 
 
 
IRB NUMBER: HSC-MS-18-0416 
IRB APPROVAL DATE: 06/26/2019 


and future
early treatment response signal without significant additional discomfort for patients. The results from this pilot 
proposal could potentially yield critical information regarding markers of treatment response in PND - a potentially 
high impact research area. the 
Having a placebo group in this research project would not we warranted at this place since the aim is to determine 
if a lower ketamine dose would be as effective and with lower side effects for PND patients. 
 
Data Handling and Record Keeping 
 
This study will acquire, use and create individually identifiable health information (known as Protected Health 
Information or PHI). Confidentiality will be protected at all times by having research records identified by code 
number only. All research information will be stored in locked files at all times. Only authorized research staff will 
have access to the information gathered in this study. Only subjects capable of providing consent will be included 
in the study. 
 
As per the Health Insurance Portability and Accountability Act (HIPAA), all individuals who are eligible and agree 
to participate in this research study will be required to sign a HIPAA research authorization prior to participation. 
If an individual refuses to sign the HIPAA research authorization, they will not be able to participate in this study. 
The HIPAA form is part of the official consent form. 
 
Data will be stored separately from the participants’ identifiers. Both will be stored on encrypted drives on 
computers in locked offices. Confidentiality will be protected by having research records identified by code 
number only. All research information will be stored in locked files at all times. Only authorized research staff will 
have access to the information gathered in this study. All paper data will be stored on the 3rd floor of the UT 
Department of Psychiatry, at the BBSB (room number 3260) in a double-locked cabinet. The electronic data will 
be stored on the L drive, in a subfolder labeled “BPRC”, located under the subfolder “UT Center of Excellence 
on Mood Disorders". An Accounting of Disclosure (AOD) will be created and maintained for any disclosure of 
individually identifiable information (III) outside the UTHSC-H. The manual spreadsheet will include the date of 
the disclosure, nature or description of the III disclosed the purpose of each disclosure and the name and address 
of a person or agency to which the disclosure was made.. Strict monitoring of hemodynamic and respiratory 
changes as well as psychiatric screening will be performed during each infusion of ketamine. 
 
Ethics 
IRB approval will be sought from CPHS for the University of Texas Health Science Center at Houston. Written 
informed consent will be obtained directly from the subject. Privacy and confidentiality will be maintained with a 
special number to be used to identify the subject in the study and only the investigator and his research staff will 
know their name. 
 
Quality control and assurance 
No plans to have ongoing third-party monitoring. However, we will conduct routine (bimonthly) reviews of 
consistency, reliability, and accuracy of data collected for any paper records. Similar checks for any data in 
electronic form will also be conducted but in an automated fashion (e.g checking for accurate time/date stamps, 
file sizes etc.). 
 
Publication Plan 
We plan to present preliminary versions of the findings at conferences during the first and second year. 
Definitive publication of findings will occur in the 6-12 months following the end of the two-year award period. 
 
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IRB NUMBER: HSC-MS-18-0416 
IRB APPROVAL DATE: 06/26/2019