miRNAs, Suicide, and Ketamine - Plasma Exosomal microRNAs as Novel Biomarkers for Suicidality and Treatment Outcome

Plasma Exosomal MicroRNAs as Promising Novel Biomarkers for Suicidality and Treatment Outcome

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02418195

Enrollment

247

Registered

2015-04-16

Start date

2015-04-20

Completion date

2020-12-30

Last updated

2022-08-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Major Depressive Disorder

Keywords

Depression, Ketamine, Suicide Attempt, Suicidal Ideation, Suicidality

Brief summary

The purpose of this study is to examine whether neural-derived exosomal miRNAs are differentially expressed that are specific to suicidal ideation or behavior, and which by affecting specific miRNA targets and pathways, are associated with suicidal behavior and response to ketamine. The following groups of subjects will be examined: 1) major depressive disorder (MDD) with a recent suicide attempt (in past 2 weeks), 2) MDD with serious ideation (in the past 7 days) without recent suicide attempt (in the past 6 months), 3) MDD without clinically significant suicidal ideation (in the past 7 days) or recent suicide attempt (in the past 6 months), and 4) healthy controls. Both suicidal and non-suicidal MDD will be given ketamine (0.5 mg/kg, IV) and blood will be drawn at predose, 30 min, 180 min, 24 hours, and 14 days post-infusion to measure changes in miRNAs. As of May 2022, study is in data analysis. Final outcomes will be known once analysis is complete. As of July 2022, all data collection is complete. The primary and secondary data outcome measure results are complete. The investigators are working on final analysis of the mRNA samples, to provide final responses to questions posed in the Detailed Description section below and listed here: 1) whether suicidal ideation or behavior is associated with differences in the expression of specific miRNAs, 2) whether anti-suicidal/antidepressant effects of ketamine is associated with miRNAs changes, and 3) whether miRNA/mRNA-regulatory pathways contribute to suicide pathogenesis and treatment response.

Detailed description

Neural MicroRNAs (miRNAs) are responsive to environmental, synaptic, and pathological changes and can be actively secreted by cells such as exosomes from brain into blood. These exosomes bear cell-type specific surface markers. Using a neural specific surface marker, the investigators successfully isolated neural-derived exosomes and found that these exosomes are enriched with miRNAs/Messenger RNA (mRNAs) that are expressed in brain. Using this novel approach the investigators aim to examine whether neural derived exosomal miRNAs are differentially expressed that are specific to suicidal ideation or behavior, and which by affecting specific mRNA targets and pathways, are associated with suicidal behavior and response to ketamine. The following groups of subjects will be examined: 1) major depressive disorder (MDD) with a recent suicide attempt (in past 2 weeks), 2) MDD with serious ideation (in the past 7 days) without recent suicide attempt (in the past 6 months), 3) MDD without clinically significant suicidal ideation (in the past 7 days) or suicide attempt in the past 6 months, and 4) healthy controls. Both suicidal and non-suicidal MDD will be given ketamine (0.5 mg/kg, IV) and blood will be drawn at pre-infusion, 30 minutes and 180 minutes post-infusion to measure changes in miRNAs. Healthy controls will have a one-time blood draw. The investigators also propose a parallel human postmortem brain study to examine whether changes in miRNAs in suicidality correspond to miRNA changes in brain by comparing dlPFC and hippocampus from MDD suicide, MDD non-suicide, and control subjects. With this the investigators attempt to discover 1) whether suicidal ideation or behavior is associated with differences in the expression of specific miRNAs, 2) whether anti-suicidal/antidepressant effects of ketamine is associated with miRNAs changes, and 3) whether miRNA/mRNA-regulatory pathways contribute to suicide pathogenesis and treatment response. Our study will provide a novel avenue for the development of miRNAs as ''molecular tool'' to identify suicidality and treatment response and in generating target based therapies to treat this devastating disorder.

Interventions

DRUGketamine

IV infusion of ketamine 0.5mg/kg at a rate of 40mL over 40 minutes

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Yes

Inclusion criteria

1. Age 18-65 2. Physically healthy and capable of undergoing ketamine infusion 3. Willing and able to provide informed consent 4. Diagnosis of Major Depressive Episode (MDE) as determined by the Mini International Neuropsychiatric Interview (MINI) (MDD participants) 5. Hamilton Depression Rating Scale (HAM-D) 21 score ≥ 16 (MDD participants) 6. Suicide attempt occurred within past 2 weeks (MDD Participants with Suicide Attempt) 7. For the time frame of the past 7 days, Columbia-Suicide Severity Rating Scale (C-SSRS) score ≥ 3 (MDD Participants without Suicide Attempt, with Suicidal Ideation) 8. For the time frame of the past 7 days, C-SSRS score \< 3 (MDD Participants without Suicide Attempt, without SUicidal Ideation)

Exclusion criteria

1. Pregnancy or lactation 2. Post-partum state (being within 2 months of delivery or miscarriage) 3. Homicide risk as determined by clinical interview 4. A lifetime history of psychotic disorder 5. Any history of dissociation or dissociative disorder 6. Bipolar disorder 7. Pervasive developmental disorder 8. Cognitive disorder 9. Cluster A personality disorder 10. Anorexia nervosa 11. Treatment with one of the following medications, known to affect the glutamate-N-methyl-D-aspartate (NMDA) receptor system (specifically: lamotrigine, acamprosate, memantine, riluzole, or lithium) 12. Alcohol or drug dependence (except nicotine and caffeine) within the last month or the use of any hallucinogen (except cannabis), including phencyclidine in the last month 13. Any known hypersensitivity or serious adverse effect associated with ketamine treatment 14. Any clinically-significant medication condition or therapy that would preclude treatment with ketamine, to include: Recent myocardial infarction 15. Unstable angina 16. Active neoplasm in the past 6 months 17. Immunosuppressive or corticosteroid therapy within the last month, with the following exceptions: any inhaled, intranasal, topical or vaginal corticosteroids are allowed. 18. Chemotherapy 19. Head injury of loss of consciousness in the past 6 months 20. If the subject reports any of the following disorders: * Rheumatoid arthritis * Lupus erythematosus * Autoimmune hepatitis * Autoimmune peripheral neuropathy * Autoimmune pancreatitis * Behcet's disease * Chrohn's disease * Autoimmune glomerulonephritis * Grave's disease * Guillain-Barre syndrome (if active) * Hashimoto's thyroiditis * Autoimmune polymyositis or polymyalgia (fibromyalgia is OK) * Myasthenia gravis * Narcolepsy * Polyarteritis nodosa * Scleroderma * Sjogren's syndrome * Transverse myelitis * Wegener's granulomatosis * HIstory of seizures (only childhood febrile seizures allowed) * (HIV and Hepatitis are OK if stable) 21. Systolic blood pressure \> 150 and/or diastolic blood pressure \>90 at screening 22. A Corrected QT Interval (QTc) \> 480 msec as determined by an ECG

Design outcomes

Primary

Measure	Time frame	Description
Beck Scale for Suicide Ideation (BSS)	180 minutes post dose	The Beck Scale for Suicidal Ideation (BSSI) is a 21-item, self-report rating scale that measures the current intensity of specific attitudes, behaviors, and plans to commit suicide. Each item consists of 3 options graded according to intensity on a 3-point scale (0-2). Scores range from 0-42, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Secondary

Measure	Time frame	Description
Beck Depression Inventory (BDI)	180 minutes post dose	The Beck Depression Inventory is a 21-item, self-report rating inventory that measures characteristic attitudes and symptoms of depression. The inventory contains 21 items on a 4-point scale from 0 (symptom absent) to 3 (severe symptoms). Anxiety symptoms are not assessed but affective, cognitive, somatic and vegetative symptoms are covered. Scoring is achieved by adding the highest ratings for all 21 items. The minimum score is 0 and maximum score is 63. Higher scores indicate greater symptom severity. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.
Beck Anxiety Inventory (BAI)	180 minutes post dose	The scale is a 21-item self-report of anxiety. The total score is calculated by finding the sum of the 21 items. The scores range form 0-63, with higher scores indicating more severe symptoms. Score of 0 - 21 = low anxiety Score of 22 - 35 = moderate anxiety Score of 36 and above = potentially concerning levels of anxiety
Beck Hopelessness Scale (BHS)	180 minutes post dose	The Beck Hopelessness Scale is a 20-item self-report index of pessimism about the future, loss of motivation, and negative expectations. Each optimistic response is scored as 0 and each pessimistic response is scored as 1. A total score is calculated by summing the pessimistic responses for each of the 20 items. Minimum possible score is 0. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.
Montgomery Asberg Depression Rating Scale (MADRS)	180 minutes post dose	The Montgomery-Åsberg Depression Rating Scale revised to reflect shorter timeframes will be the primary measure of change in depression. The Montgomery-Asberg Depression Rating Scale is a ten-item diagnostic questionnaire which psychiatrists use to measure the severity of depressive episodes in patients with mood disorders. A total score ranging from 0 to 6 indicates that the patient is in the normal range (no depression), a score ranging from 7 to 19 indicates mild depression, 20 to 34 indicates moderate depression, a score of 35 and greater indicates severe depression, and a total score of 60 indicates very severe depression. Scores range form 0-60, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers
Clinician-Administered Dissociative States Scale (CADSS)	180 minutes post dose	The Clinician-Administered Dissociative States Scale, ascertains the presence or absence of dissociative symptoms. There are 23 clinician-administered items, each scored from 0 (not at all) to 4 (extreme). Scores range from 0-92, with higher scores indicating more severe symptoms. Items assess impairment in body sensation, perception of time and environment, memory impairment, and feelings of unreality. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.
Young Mania Rating Scale (YMRS)	180 minutes post dose	This scale assesses for manic symptoms. The scale has 11 items and is based on the patient's subjective report of his or her clinical condition over the previous 48 hours. 13-19=minimal symptoms; 20-25=mild mania, 26-37=moderate mania, 38-60=severe mania. The YMRS total score ranges from 0 to 60 where higher scores indicate more severe mania.
Systematic Assessment for Treatment Emergent Events (SAFTEE)	180 minutes post dose	The Systematic Assessment for Treatment Emergent Events, is a 56 item, self-report inventory for adverse events. Each item is categorized by severity as: 0-none, 1-mild, 2-moderate, 3-severe. Score range is 0-168, with higher scores indicating more severe symptoms. It is designed to report adverse health events, regardless of whether or not they are suspected to be drug related, in order to reduce the under-reporting of unanticipated events compared with known or expected events. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.
4-item Brief Psychiatric Rating Scale (BPRS)	180 minutes post dose	The Brief Psychiatric Rating Scale is used to assess the presence of psychotic symptoms. This 4-item version assesses conceptual disorganization, suspiciousness/persecution, hallucinatory behavior, and unusual thought content. Each item is rated on a scale from 0 (not present) to 6 (extreme). The scores range from 0-24, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.

Countries

United States

Participant flow

Recruitment details

Participants were enrolled April 2015 through December 2020. The last subject completed their final visit on December 30, 2020. Participants were enrolled through advertising means, such as flyers, physician referrals, sub-I clinic referrals, and chart review, via Impact. As of May 2022, study is in data analysis. Final outcomes will be known once analysis is complete.

Pre-assignment details

A number of participants were excluded for not meeting inclusion or meeting exclusion criteria, in total 51. These were considered screen failures.

Participants by arm

Arm	Count
MDD With Recent Suicide Attempt All subjects with Major Depressive Disorder with a recent Suicide Attempt (in the past 2 weeks) will receive a one-time IV infusion of ketamine at a dose of 0.5mg/kg at a rate of 40mL over 40 minutes. Blood will be drawn at pre-dose, 30 minutes post dose, 180 minutes post dose, 24 hours post dose, and 14 days post dose to measure changes in miRNAs. ketamine: IV infusion of ketamine 0.5mg/kg at a rate of 40mL over 40 minutes	62
MDD With Suicidal Ideation no Attempt All subjects with Major Depressive Disorder with recent Suicidal Ideation (in the past 7 days) without a recent Suicide Attempt (in the past 6 months) will receive a one-time IV infusion of ketamine at a dose of 0.5mg/kg at a rate of 40mL over 40 minutes. Blood will be drawn at pre-dose, 30 minutes post dose, 180 minutes post dose, 24 hours post dose, and 14 days post dose to measure changes in miRNAs. ketamine: IV infusion of ketamine 0.5mg/kg at a rate of 40mL over 40 minutes	63
MDD Without Suicidal Ideation no Attempt All subjects with Major Depressive Disorder without recent Suicidal Ideation (in the past 7 days) without a recent Suicide Attempt (in the past 6 months) will receive a one-time IV infusion of ketamine at a dose of 0.5mg/kg at a rate of 40mL over 40 minutes. Blood will be drawn at pre-dose, 30 minutes post dose, 180 minutes post dose, 24 hours post dose, and 14 days post dose to measure changes in miRNAs. ketamine: IV infusion of ketamine 0.5mg/kg at a rate of 40mL over 40 minutes	61
Healthy Controls Healthy Control subjects without a psychiatric diagnosis will have a one-time blood draw to examine miRNAs.	61
Total	247

Baseline characteristics

Characteristic	MDD With Recent Suicide Attempt	Total	Healthy Controls	MDD Without Suicidal Ideation no Attempt	MDD With Suicidal Ideation no Attempt
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	62 Participants	247 Participants	61 Participants	61 Participants	63 Participants
Age, Continuous	35.53 years STANDARD_DEVIATION 11.7	39.40 years STANDARD_DEVIATION 13.07	37.54 years STANDARD_DEVIATION 12.65	44.62 years STANDARD_DEVIATION 12.26	39.94 years STANDARD_DEVIATION 14.05
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants	6 Participants	1 Participants	2 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	60 Participants	241 Participants	60 Participants	59 Participants	62 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number enrolled	62 Participants	247 Participants	61 Participants	61 Participants	63 Participants
Race (NIH/OMB) American Indian or Alaska Native	2 Participants	2 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	6 Participants	3 Participants	0 Participants	2 Participants
Race (NIH/OMB) Black or African American	13 Participants	47 Participants	13 Participants	11 Participants	10 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	46 Participants	192 Participants	45 Participants	50 Participants	51 Participants
Region of Enrollment United States	62 participants	247 participants	61 participants	61 participants	63 participants
Sex: Female, Male Female	36 Participants	150 Participants	35 Participants	36 Participants	43 Participants
Sex: Female, Male Male	26 Participants	97 Participants	26 Participants	25 Participants	20 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	0 / 62	0 / 63	0 / 61	0 / 61
other Total, other adverse events	47 / 62	58 / 63	60 / 61	1 / 61
serious Total, serious adverse events	5 / 62	1 / 63	1 / 61	0 / 61

Outcome results

Primary

Beck Scale for Suicide Ideation (BSS)

The Beck Scale for Suicidal Ideation (BSSI) is a 21-item, self-report rating scale that measures the current intensity of specific attitudes, behaviors, and plans to commit suicide. Each item consists of 3 options graded according to intensity on a 3-point scale (0-2). Scores range from 0-42, with higher scores indicating more severe symptoms. The participant numbers below correlate to the number of usable lab samples. This is the reason for discrepancy in numbers.