Dgim project summary final

DGIM Project Summary
Name of Project: "Neurosteroid Metabolism and the Antidepressant Effects of Serotonin Specific Reuptake Inhibitors (SSRI's)."
Nickname: "BRAIN, BIOLOGY AND MOOD STUDY". CHR Approval # 10-00825, Approval Expires 01/14/2014
PI: Owen Wolkowitz, MD ([email protected])
Co-I: Synthia Mellon, PhD ([email protected])
Co-I: Mitchell Feldman MD ([email protected]) Co-I: Victor Reus, MD ([email protected])
Co-I: Elissa Epel, PhD ([email protected])
PRIMARY CONTACT: Laura Mahan, SRA
([email protected])

Research question(s): Patients with major depressive disorder (MDD) have a higher likelihood of developing serious
medical conditions, e.g., cardiovascular disease, stroke, dementia, diabetes, etc. Depressed individuals, especially untreated
ones, may have accelerated cellular aging, at least in their immune cells, as demonstrated by shortened leukocyte telomeres.
Our goals in the current study are to determine whether:
1. Un-medicated depressed individuals have shorter leukocyte telomeres than matched healthy controls; 2. Leukocyte telomere length is inversely correlated with inflammatory cytokines and measures of oxidative stress. 3. Leukocyte telomere length is inversely correlated with severity and duration of depression The above "Baseline" hypotheses wil be tested in a single outpatient visit on the UCSF GCRC (CTSI). If depressed subjects and their DGIM
physicians wish, and if it is clinical y warranted, UCSF psychiatry faculty wil also offer optional 8-weeks of standard clinical SSRI
antidepressant treatment at no charge to the subject (CHR approval pending). In such cases, three additional hypotheses wil be examined:
1. Baseline markers of cel aging predict response to antidepressants 2. Antidepressant treatment normalizes cel aging markers and their putative mediators (inflammation and oxidation) 3. Antidepressant-associated clinical improvement is directly correlated with normalization of cell aging markers and putative mediators. Brief Background/Significance:
This study wil help determine if un-medicated patients with MDD have an accelerated biological aging phenotype and if this is linked to over-activation of inflammatory cytokines and oxidative stress. This wil be assessed in blood, urine and saliva samples (although participants may elect not to col ect saliva or urine samples) and a low dose dexamethasone suppression test . The results may help explain the high medical co-morbidity in depressed patients and may identify new biological treatment targets.
INCLUSION CRITERIA (Study staff wil review these criteria with subjects to minimize burden to the DGIM referring clinician):
Age 18-70 y.o.; Good general medical health (No current severe unstable medical il ness.) Clinical labs (electrolytes, liver function test, CBC) with no clinical y significant abnormalities (Testing wil performed at no-charge by the study); Negative urine toxicology (drugs of abuse) screen. Not pregnant. Taking no drugs likely to interfere with the study objectives (including birth control pills); Taking no antidepressant,
mood-stabilizing or anti-anxiety medication for a minimum of 4 weeks (with the exception of prn benzodiazepines)
Additional criteria for Depressed Participants:
Current DSM-IV diagnosis of Major Depressive Disorder, unipolar, without psychotic features (co-morbid anxiety diagnoses are permitted) At least mild-moderate severity depression Not actively suicidal. Additional criteria for Normal Controls:
No DSM-IV Axis I diagnoses Method of contact/ recruitment
1. We wil provide brochures and flyers for the waiting area of DGIM 2. We wil provide PCPs with a detailed description of the study and our inclusion/ exclusion criteria with a request that they consider suggesting the study to potentially eligible patients in their care. Benefits/burden for participants
1. Antidepressant Treatment (optional): We are using drugs from the antidepressant class called Serotonin Selective
Reuptake Inhibitors (SSRIs). The specific drugs we will use are: fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine
(Paxil®), citalopram (Celexa®) or escitalopram (Lexapro®). These drugs are among the most commonly prescribed
antidepressants in the United States and world-wide. Each of these drugs is FDA-approved for treating depression in the
doses we will use in this study. This class of drugs generally has a benign side effect profile, and most side effects dissipate
within 2-3 weeks (e.g., GI side effects, activation, sedation, etc.), although side effects of sexual dysfunction (e.g., low libido,
anorgasmia, delayed orgasm, difficulty achieving arousal) and weight gain may persist until the drug is stopped. The
placebo-adjusted rates of side effects with these five SSRI's are presented in the Table. Other potential side effects are
pharmacokinetic interactions with other drugs the individual may be taking. The physician-investigator of this study, who will
be prescribing and monitoring the SSRI, is familiar with these interactions, and the potential for drug-drug interactions will
weigh into the decision as to which antidepressant to select. Abrupt antidepressant discontinuation may result in transient,
mild withdrawal symptoms, e.g., "flu-like" feelings or dizziness or parasthesias. Subjects will be advised against
discontinuing their antidepressant abruptly. If subjects do experience withdrawal symptoms after stopping the
antidepressant, they will be offered a brief course (up to two-four weeks) of open-label, gradually tapered antidepressant to
facilitate their withdrawal. The FDA placed a "black box" warning on the labeling of all antidepressants, including SSRI's,
noting that antidepressant use may be associated with an increased risk of suicidal thinking in children and adolescents. In
pre-marketing studies, 4% of depressed child and adolescent and young adult patients treated with antidepressants
exhibited suicidal thinking or behavior compared to 2% of patients treated with placebo The increased risk was not seen in adults over 24 years old, in whom the risk of suicidality was unchanged or less than with placebo. Real-world risk of this occurrence has been debated within the psychiatric profession, but there is no doubt that these medications effectively treat depression and suicidality in the majority of patients taking them (Boerner and Moller 1999; Mendlewicz and Lecrubier 2000). We carefully screen out participants with current suicidality, and the development of suicidality would be cause for terminating a participant's participation in the study and referring the participant to standard clinical care. We follow participants closely during this study, with mandatory psychiatric evaluations at Baseline and at Weeks 1, 2, 3, 4, and 8 of treatment, plus additional clinical contact as clinically determined. We feel this risk: benefit ratio is warranted, since these depressed participants would generally be candidates for such clinical intervention regardless of their participation in this study. If participants experience objectionable side effects, the investigators may lower the drug dose or discontinue it. Participants are free to withdraw from the study at any time. TABLE: Placebo-adjusted incidence of side effects with SSRI's (%)
2. Venipuncture. Standard venipuncture risks are pain, possible infection and fainting. The total amount of blood to be drawn during the Baseline and Week 8 visits wil be approximately 190cc per visit. Saliva col ection: This is without risk except for the mild inconvenience some participants may experience. 24 hour urine collection: This is without risk except for inconvenience. 3. Dexamethasone Suppression Test: This very low dose of dexamethasone (one oral dose of 0.25 mg.) has no known risks. 4. Behavioral ratings: These are generally without risk except for the inconvenience and time required. 5. Confidentiality: Participation in research may involve a loss of privacy, but information wil be handled as confidentially as possible. Dizziness Insomnia Appetite change Dry mouth Any benefits or burden to DGIM practitioners?
The possible benefits to DGIM practitioners include: (1) psychiatric assessment of their patients' depression by a UCSF faculty
psychiatrist; (2) a no-cost 8-week clinical SSRI antidepressant trial for their patients with a report of their patients' response to
treatment at the end of the 8 weeks (with patients' consent). (3) With the patients' consent, reports of all clinical laboratory tests
(performed at no charge) wil be sent to the DGIM physician.
The possible burden to DGIM practitioners is minimal. They will receive only one letter from us, providing information about the
study and offering to provide brochures that they can pass along to their depressed patients.
Timeline for recruitment (projected start and stop dates)
For our DGIM recruitment, we would like to start sometime in June OR July 2013. The study wil continue into 2015.
Funding source
NIH: National Institute of Mental Health, Award # A114651
Potential for DGIM collaborators?
At the moment, we are col aborating with Dr. Mitchel Feldman. However, we are open to col aborating with other DGIM physicians (and residents) if they have an interest. Do you agree to notify us when recruitment is completed? Yes.
Date form completed: Form completed 06/04/13 by Laura Mahan. Updated 6/12/13 by Laura Mahan.
Please note: A prior version of this study, shown on the following pages,
was already approved by the DGIM. The present version has several
changes (e.g., no MRI scan)
PREVIOUSLY APPROVED PROJECT FOR DGIM:
DGIM Project Summary
Name of Project: "Neurosteroid Metabolism and the Antidepressant Effects of
Serotonin Specific Reuptake Inhibitors
(SSRI's)."
Nickname: "MDD STUDY". CHR Approval # 10-00825, Approval Expires 01/14/2012
Investigators:
Principal Investigator: Owen Wolkowitz, MD
Email: [email protected] Co-Investigators:

Mitchell Feldman, MD, MPhil
[email protected]
Steven Hamilton, MD, PhD
[email protected]
Primary Contact:
Laura Balch, Study Coordinator
Email: [email protected]
Elissa S. Epel, PhD
[email protected]
Synthia H. Mellon, PhD
[email protected]
R. Scott Mackin, Ph.D
[email protected]
Victor I. Reus, MD
[email protected]
Research question(s):
We are seeking to test the following hypotheses.
PRIMARY HYPOTHESES:
1. Neuroprotective factors are deficient in depression, and antidepressant treatment
stimulates these factors.
2. Depression is a chronic stress syndrome which results in accelerated cellular aging
and a higher oxidative stress index.
3. Genetic abnormalities interact with early trauma history to increase the
vulnerability to depression.
SECONDARY HYPOTHESES
1. Specific memory functions are disturbed in depression, and these are related
to deficient neuroprotective factors. 2. Depression is associated with chronic changes in appetitive behavior with
resultant physiological and metabolic disturbances
Brief Background/Significance:
It has been demonstrated that chronic stress results in a shortening of telomeres. It is possible that major
depression, as a form of chronic stress, also results in shortening of telomeres. There may also be interactions
between the action of SSRI's and telomere length, as well as levels of telomerase.
Inclusion/exclusion criteria (list)
INCLUSION CRITERIA
All participants must meet the following criteria:
Age 18-70 y.o.; Good general medical
health: Clinical labs (electrolytes, liver function test, CBC) with no clinically significant abnormalities; Negative
urine toxicology (drugs of abuse) screen; Taking no medication or drugs likely to interfere with the study
objectives (including birth control pills), except as allowed by protocol; Free of any antidepressant, mood-
stabilizing or anti-anxiety medication for a minimum of 6 weeks before entry into the study (with the exception of
prn benzodiazepine, anxiolytic or sedative-hypnotic use, < 3 nights per week); No current diagnosis of PTSD; No
history of angina or known coronary artery disease.; Lab results demonstrate an Hct of 36-48 for females and 38-
54 for males, or a Hgb of between 12.5-20, for all participants regardless of an age.
Additional criteria for Depressed Participants:
Current DSM-IV Axis I diagnosis of Major Depressive Disorder,
unipolar, without psychotic features (co-morbid diagnoses of Panic, Generalized Anxiety Disorder, or Phobias are
permitted).; Baseline 17-item Hamilton Depression Rating Scale (HDRS) rating of > 17; Baseline HDRS item #3
("suicidality") rating of < 1, and clinician's determination of absence of active suicidal intent.; No anticipated
changes in psychotherapeutic interventions during the study. Additional criteria for Normal Controls:
No DSM-IV
Axis I diagnoses
Method of contact/recruitment (be specific)
1. We will have an assistant do a STOR search for patients who are diagnosed with depression and who are not
currently on antidepressants. We will then send a letter to their primary physician describing the study and
expressing our interest in the patient. Instead of sending one letter per patient, we will send each physician
one letter
Page 1 of 2
inquiring about all of his or her patients that are of interest to us.They physician will have an opportunity to
decline on behalf of the patient. Then, we will send a letter to the patient, describing the study and giving them an
opportunity to decline participation. Then we will call them and screen them by phone. Then we will invite them
for an in-person screening visit. 2. We will also be recruiting participants through ads on Craigslist, and flyers, but
those methods do not specificially involve DGIM.
Benefits/burden for participants (clearly identify potential for harm)
1. Sertraline Treatment: We are using sertraline (Zoloft), which is a highly selective SSRI shown to be effective in
treatment of major depression. Sertraline is the most commonly prescribed FDA-approved antidepressant in the
US. In the doses used in this study, it is considered very safe. We screen out participants with current suicidality,
and development of suicidality would be cause for terminating participation and referring the participant to
standard clinical care. We follow participants closely, with mandatory clinical evaluations at Baseline and at
Weeks 1, 2, 3, 4, and 8 of treatment, plus additional clinical contact as needed. Significant clinical deterioration
(judged by the investigators or by the subject) will lead to discontinuation and referral to clinical care.
2. Limitation on Other Treatments: Participants are only eligible to participate in this study if they have not been
taking psychotropic medications for six weeks prior to beginning the study, and no new non-study related
psychotropic medications may begin during the course of the study. No new courses of psychotherapy may begin
during the study.
3. Venipuncture. Standard venipuncture risks are pain, possible infection and fainting. The total amount of blood
to be drawn during the Baseline visit and during the Week 8 visit will be approximately 190cc per visit. Thus, the
healthy controls have approximately 190 cc of blood drawn, and the depressed participants have approximately
380 cc of blood drawn over an 8-week period.
4. Saliva collection: This is without risk except for the mild inconvenience some participants may experience.
5.
24 hour urine collection: This is without risk except for inconvenience.
6. Dexamethasone Suppression Test: The
dexamethasone (up to 0.5 mg.) has no known risks associated with it,
because it is a very low dose and single administration of synthetic glucocorticoid.
7. Body measurements: There
is no except possible embarrassment.
8. Behavioral ratings: These are generally without risk except for the
inconvenience and time required.
9. Genetic Studies: Donating genetic material could result in a loss of
confidentiality. We make every effort to
preserve the confidentiality of genetic ands well as complete health information.
10. Confidentiality: Participation
in research may involve a loss of privacy, but information will be handled as
confidentially as possible.
11. MRI: The MR apparatus attracts certain metals so there is the small possibility that
magnetic objects will accidentally fly into the magnet. This risk is greater at 4.0 Tesla field strength. Subjects who
have metal in their bodies that may interfere with the magnet may not be admitted to the study. This will be
determined on a case-by-case basis. Clothing (including undergarments that contain metal) may not be allowed
in the 4.0 Tesla MR unit. Instead, we provide subjects with a hospital garment to wear for the MR procedure.
NOTE: The MRI is currently removed from our study due to lack of funding, but it may return in the future if and
when more funding becomes available.
12. Actigraphy: This may produce slight discomfort from prolonged wear.
That is the only known risk.
13. BIA (bioelectric impedance analysis): May involve slight social discomfort. That is
the only known risk.
Any benefits or burden to DGIM practitioners?
The possible benefit or burden to DGIM practictioners is minimal. They will receive only one letter from us, which
they only need to respond to if they object to us contacting their patient.
Timeline for recruitment (projected start and stop dates)
For our DGIM recruitment, we would like to start sometime in May 2011. Then, we may do it again once every 3-
6 months for approximately the next 5 years.
Funding source
NIH: National Institute of Mental Health, Award # A114651
Potential for DGIM collaborators?
At the moment, we are only planning on collaborating with Mitch Feldman and the administrative assistant whom
we will hire. However, we are open to collaborating with other DGIM physicians (and residents) if they have an
interest.
Do you agree to notify us when recruitment is completed? Yes.
Date form completed:
Form completed 04/18/11 by John Coetzee. Updated 07/10/11 by John Coetzee.

Source: https://dgim.ucsf.edu/research/summaries/wolkowitz_july2013.pdf