Clinical trial NCT01783574
Conditions: Depression
Keywords: Depression Major Depressive Disorder (MDD)
Sponsor: Massachusetts General Hospital
Start date: 2013-08-01; Completion date: 2017-01-27
Enrollment: 101 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The investigators' hypotheses are: Low-dose testosterone augmentation improves depressive symptoms in women with Major Depressive Disorder (MDD) and antidepressant partial/nonresponse, adjunctive low-dose testosterone is safe and well-tolerated in women with MDD and antidepressant partial/nonresponse, and low-dose testosterone augmentation improves fatigue and sexual dysfunction.

Detailed description:

Arms: arm 1: Testosterone cream will be applied to skin for 8 weeks. Starting dose is 10 mg daily and will be titrated based on blood levels. arm 2: Placebo cream will appear identical to the testosterone cream and will be applied to skin for 8 weeks.
Interventions: intervention 1: Testosterone intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_002.pdf: 
 
 
 
Testosterone Antidepressant Augmentation in 
Women 
 
 
 
 
NCT01783574 
 
 
 
 
Version Date: May 19, 2017 


PARTNERS HUMAN RESEARCH COMMITTEE 
PROTOCOL SUMMARY 
Partners Human Subjects Research Application Form  
 
Filename: Protocol Summary 
Version Date:  June 1, 2005 
 
  
1 
 
Answer all questions accurately and completely in order to provide the PHRC with the relevant 
information to assess the risk-benefit ratio for the study.  Do not leave sections blank. 
 
PRINCIPAL/OVERALL INVESTIGATOR 
Karen K. Miller, MD 
 
BIDMC SITE PRINCIPAL INVESTIGATOR 
 
 
PROTOCOL TITLE 
Collaborative Study: Testosterone Antidepressant Augmentation in Women 
 
FUNDING 
 
 
VERSION DATE 
5/19/2017 
 
SPECIFIC AIMS 
Concisely state the objectives of the study and the hypothesis being tested. 
Inadequate response to antidepressant therapy in major depressive disorder (MDD) is 
disabling and highly prevalent, particularly among women.  Although the use of antidepressant 
augmentation strategies is common, there are few effective therapies and few strategies that have 
been studied in a rigorous, controlled fashion. 
Because studies in other female populations suggest that low-dose testosterone 
administration (in which testosterone levels are raised within the normal female range) has 
antidepressant effects with minimal side effects, testosterone is a candidate for a novel 
augmentation treatment for women with MDD. Preliminary studies from our group demonstrate 
antidepressant efficacy of low-dose testosterone administration in women with inadequate 
response to inhibitors of serotonin uptake, as well as in other female relatively androgen-
deficient populations.  We propose to test the efficacy and tolerability of testosterone as an 
augmentation treatment for depressed women with inadequate response to antidepressant therapy 
in a randomized, placebo-controlled trial, which, if positive, will form the basis of a future, large, 
randomized, controlled trial.   
An additional potential benefit of testosterone therapy is that it targets two specific 
persistent/residual symptoms of MDD – fatigue and sexual dysfunction. Fatigue/loss of energy 
and reduced libido/sexual function are common symptoms associated with MDD and ones for 
which few effective therapies are available.  Moreover, data suggest that libido and sexual 
function may be independently and adversely affected by antidepressant therapy administration 
in a substantial subset of women.  Our preliminary data suggest that low-dose testosterone may 
be an effective therapy for these two target symptoms in depressed women with 
partial/nonresponse to antidepressant therapy.  In addition, data suggest that low-dose 
testosterone therapy increases energy and improves libido and sexual function in women.  
However, the specific therapeutic potential of low-dose testosterone augmentation has not been 
tested with a randomized, placebo-controlled study in MDD women with inadequate response to 
antidepressant therapy.   


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
2 
Rigorous, randomized, placebo-controlled trials are necessary to determine whether low-
dose testosterone augmentation will be an effective treatment for depression in women with 
inadequate response to antidepressant therapy.  In this application, a double-blind, placebo-
controlled trial of adjunctive low-dose testosterone for inadequate response to antidepressant 
therapy among MDD women is proposed.   
Specific Aim 1.  Low-dose testosterone augmentation improves depressive symptoms in women 
with MDD and partial/nonresponse to antidepressant therapy. 
Aim 1A.  We will investigate in female antidepressant therapy partial/nonresponders whether 
low-dose testosterone augmentation for 8 weeks leads to a significantly greater reduction in 
depressive symptoms than placebo. 
Aim 1B.  We will investigate whether a key mechanism underlying the effects of testosterone 
administration on depressive symptoms is an increase in neuroactive testosterone 
metabolites, including 3alpha-diol.   
Specific Aim 2.  Adjunctive low-dose testosterone is safe and well-tolerated in women with 
MDD and partial/nonresponse to antidepressant therapy.  We will investigate whether low-dose 
testosterone augmentation therapy for 8 weeks is safe and well-tolerated in female antidepressant 
therapy partial/non-responders compared to placebo. 
Specific Aim 3.  Low-dose testosterone augmentation improves two specific RDoC construct 
symptoms (in the Arousal/Physiologic Processes Domain) in women: fatigue and sexual 
dysfunction.  We will investigate in female antidepressant therapy partial/nonresponders whether 
low-dose testosterone augmentation for 8 weeks improves associated fatigue and sexual 
dysfunction compared to placebo. 
Specific Aim 4. Low-dose testosterone therapy in women with treatment resistant depression will 
cause functional changes in the brain. We will investigate the mechanisms and functional 
neuroanatomy of the effects of testosterone on different regions of the brain in women with 
treatment resistant depression. This will serve as preliminary data for future studies and grants.  
 
Exploratory Aim: We will investigate androgen and other hormonal correlates of 
functional and structural neuroanatomy in women with treatment resistant depression 
compared with healthy, non-depressed controls. This will serve as preliminary data for 
future studies. 
Specific Aim 5. Androgen and neuroactive steroid levels will be lower in postmenopausal 
women with treatment resistant depression than in healthy controls. 
We will investigate androgen and neuroactive steroid levels in postmenopausal women with 
treatment resistant depression in comparison to androgen and neuroactive steroid levels in 
postmenopausal healthy controls without significant psychiatric disease. 
 
 
BACKGROUND AND SIGNIFICANCE 
Provide a brief paragraph summarizing prior experience important for understanding the 
proposed study and procedures. 
 
Although a number of potential augmentation strategies for MDD patients with 
partial/nonresponse to antidepressant therapy have been studied, few have been shown to be 
effective and fewer have acceptable side-effect profiles.  The development of low-dose 
physiologic testosterone therapy for women is an innovative and potentially important approach 
to the prevalent problem of partial/nonresponse to antidepressant therapy among women with 
MDD.  This is an approach that has never been pursued previously in any double-blind, 
randomized fashion.  Furthermore, examination of the effects of experimental manipulation of 
peripheral gonadal hormone concentrations on RDoC candidate constructs (anergia/fatigue and 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
3 
sexual dysfunction) within the domain of Arousal/Regulatory Processes reflects an innovative 
approach. The RDoC perspective we propose involves focus on these constructs independent of 
depression diagnosis, to generate data that may contribute to a larger body of findings supporting 
new ways of classifying mental disorders based on observable behavior and neurobiological 
measures. The classic gonadal steroid dichotomous paradigm (estrogens as the female 
hormone/testosterone as the male hormone) has only recently been understood to be an 
oversimplified framework.  Although testosterone levels in women (and estrogen levels in men) 
are much lower than that in the opposite sex, there is increasing evidence that their role in the 
regulation of brain function may be important.  This new area of investigation is an innovative 
approach that may have important clinical implications and may identify new potential targets 
for drug development in MDD.  Investigation of neuroactive, GABAergic steroid metabolites of 
testosterone as a possible mechanism responsible for brain effects is another innovative 
component. 
Partial/nonresponse to antidepressant therapy is extremely prevalent in the U.S., 
disproportionally affects women, and is associated with substantial morbidity and functional 
impairment. An effective, well-tolerated therapy would have a significant impact on public 
health. Antidepressant treatments with novel mechanisms of action and benign side effect 
profiles are needed.  Preliminary data suggest that low, physiologic doses of testosterone may be 
effective to improve mood among women with partial/nonresponse to antidepressant therapy, yet 
with few side effects.  If these preliminary findings are confirmed, results from the proposed 
study would form the basis for a larger, multi-center trial with active comparators to definitively 
establish that low-dose testosterone augmentation in women with antidepressant therapy 
partial/non-response is effective, well tolerated and exerts durable effects on mood in 
antidepressant-treated women with MDD, through effects on neuroactive steroids. 
 
RESEARCH DESIGN AND METHODS 
Briefly describe study design and anticipated enrollment, i.e., number of subjects to be enrolled 
by researchers study-wide and by Partners researchers.  Provide a brief summary of the 
eligibility criteria (for example, age range, gender, medical condition).  Include any local site 
restrictions, for example, “Enrollment at Partners will be limited to adults although the sponsor’s 
protocol is open to both children and adults.”
Study Design:  After antidepressant therapy partial or nonresponse is established by 
documentation of failure to at least 8 weeks’ treatment with an adequately dosed antidepressant 
therapy,  A minimum of 100 subjects study-wide (60 from MGH) with MADRS³12 will enter 
the double-blind augmentation randomized-placebo-controlled treatment study. 50 of these 
subjects will be on active study drug and 50 will be control subjects on placebo. Eligible subjects 
will undergo baseline assessment of symptoms and biological measures and then be randomized 
to 1 of 2 groups: low-dose physiologic testosterone augmentation by transdermal preparation 
 or placebo. 
Antidepressant dose will be held steady during the trial. Outcome measures will examine the 
antidepressant efficacy of physiologic testosterone treatment (Aim 1), its tolerability (Aim 2) and 
its effects on 2 specific RDoC symptoms (Aim 3).  
 
Subject Enrollment: A total of 330 women will be enrolled study-wide, of which 100 women 
with antidepressant-resistant MDD and 50 women with no psychiatric history will be eligible 
study-wide.  Study subjects for the depressed population will be women, ages 21-75 with failure 
to remit following at least 8 weeks antidepressant trial documented by past treatment history.  
 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
4 
 In addition, 20 healthy controls without 
depression will be recruited for the fMRI substudy healthy control population. 
 
Up to 60 postmenopausal women who do not have current or past psychiatric disorders will also 
be screened to obtain 30 women who will be enrolled 
 
as healthy controls. 
 
Randomized Study Subject Population (n=60) 
 
Inclusion Criteria for Randomized Study Subjects: 
1. Female, age 21-75, who provide written informed consent 
2.   Free testosterone level no higher than the third quartile of the normal range 
3.   Meet DSM-IV criteria (by SCID) for current Major Depressive Disorder and have 
MADRS³12 
4.   Currently treated with an antidepressant (1st, 2nd or 3rd trial in current episode), that has been 
taken at an adequate dose103 for at least eight weeks with sufficient source documentation to 
confirm high level of confidence in treatment details (using the MGH ATRQ). Current 
treatment may include a combination therapy as long as the subject has not exceeded three 
failed trials in the current episode. 
5.   Persistent depression symptom burden of the same dose of the currently (ineffective) 
antidepressant therapy, evidenced by MADRS³12.  
 
Exclusion Criteria for Randomized Study Subjects: 
1. Serious suicide or homicide risk, as assessed by evaluating clinician 
2. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, 
neurologic  
3. Substance use disorder active within last six months, or clinical suspicion of ongoing 
substance use disorder at the discretion of the study clinician at time of screening based on 
history and/or laboratory results. 
4. Any history of psychotic features, bipolar disorder, or primary obsessive compulsive 
disorder, as assessed by SCID 
5. Untreated hypothyroidism. If treated hypothyroidism, change in levothyroxine dose within 
the prior 3 mos 
6. Use of androgens, including testosterone, DHEA and methyltestosterone, within the prior 
three months 
7. Any investigational psychotropic drug within the last 30 days  
8. In the judgment of the study clinician, unlikely to be able to participate safely throughout the 
study period (three or more episodes of self-harm in the past year, documented history of 
poor treatment adherence, or frequent missed appointments (>50%) in the past year) 
9. Alanine aminotransferase (ALT) > 3x upper limit of normal or creatinine> 3x upper limit 
10. History of a hormone-responsive cancer 
11. History of testosterone abuse 
12. Almond allergy (AndroFeme contains almond oil) 
13. History of hypercalcemia or thromboembolism 
14. Women who are breastfeeding 
15. Pregnant women, women who desire to become pregnant, or women of child bearing potential 
who are not using a medically accepted means of contraception (to include condom, diaphragm, 
spermicide, intrauterine device, tubal ligation, or partner with vasectomy) 
 
Additional Exclusion Criteria for Randomized study subjects in fMRI Substudy Only (n=20) 
 
Exclusion criteria for the fMRI substudy participants include routine MRI exclusion criteria as listed 
below: 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
5 
• 
Cardiac pacemaker 
• 
Surgical aneurysm clips 
• 
Neurostimulator 
• 
Implanted pumps 
• 
Metal fragments in body / eyes 
• 
Pregnancy 
• 
Nitroglycerin patch (if non-removable) 
• 
Weight >250  
• 
Severe claustrophobia 
 
Healthy Control fMRI Population (n=20) 
 
Inclusion criteria for fMRI Healthy Control Subjects 
• Match a randomized subject based on: 
o Age (+/- 2 years) 
o BMI (+/- 2 kg/m2) 
o Hormonal status 
 
Exclusion criteria for fMRI Healthy Control Subjects 
• Any history of psychiatric illness including major depressive disorder, bipolar disorder, 
psychotic features, or obsessive compulsive disorder, as assessed by SCID 
• Current or prior use of any psychiatric medications 
• Current or prior substance use disorder  
• Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, 
neurologic  
• Hypothyroidism 
• Use of androgens, including testosterone, DHEA and methyltestosterone, within the prior 
three months 
• Abnormal alanine aminotransferase (ALT) or creatinine 
• Women who are breastfeeding 
• Pregnant women, women who desire to become pregnant, or women of child bearing 
potential who are not using a medically accepted means of contraception (to include condom, 
diaphragm, spermicide, intrauterine device, tubal ligation, or partner with vasectomy) 
• Additional Routine MRI exclusion criteria as listed below: 
o Cardiac pacemaker 
o Surgical aneurysm clips 
o Neurostimulator 
o Implanted pumps 
o Metal fragments in body / eyes 
o Nitroglycerin patch (if non-removable) 
o Weight >250  
o Severe claustrophobia 
 
Inclusion Criteria for Healthy Controls: 
 
1. Female, age 50-75, who provide written informed consent 
2. Free of lifetime psychiatric medication use 
3. Postmenopausal, defined as amenorrhea for greater than one year and/or elevated FSH for 
women with prior hysterectomy 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
6 
 
Exclusion Criteria for Healthy Controls: 
 
1. Unstable medical illness including cardiovascular, hepatic, renal, respiratory, endocrine, 
neurologic 
2. Current or past Axis I psychiatric or substance use disorder (non-prescribed medications, 
recreational drugs, or alcohol) 
3. Use of androgens, including testosterone, DHEA and methyltestosterone, within the prior three 
months 
 
Briefly describe study procedures.  Include any local site restrictions, for example, “Subjects 
enrolled at Partners will not participate in the pharmacokinetic portion of the study.”  Describe 
study endpoints.
Study visits for randomized subjects 
 
Screening Visit: A screening visit will take place to determine eligibility for enrollment.  
Participants will be asked to complete the MGH ATRQ and sign release of information forms to 
request documentation from prescribing clinicians. It is estimated that after review of detailed 
source documents describing past treatment details, 60 women will be confirmed to have 
partial/nonresponse to antidepressant therapy and be eligible for the randomized, placebo-
controlled phase. Screening visit testing will include: 
o complete medical history 
o physical examination, including height and weight  
o 0800h Blood draw for ALT, creatinine, CBC, thyroid stimulating hormone (TSH), free 
testosterone, FSH, urine pregnancy and toxicology 
o diagnostic interview with SCID 
o MDD symptom assessment with MADRS 
o completion of the MGH ATRQ 
If antidepressant-resistance is confirmed following screening procedures, the subject will be 
scheduled for a baseline visit approximately 1-2 weeks.  
 
Baseline Visit for the Randomized, Placebo-Controlled, Augmentation Study: Eligible 
subjects will undergo baseline testing immediately before the augmentation phase of the 
protocol.  Baseline visit testing will include the following. However, the blood draw will not be 
repeated if the Baseline visit occurs within 2 weeks of the screening visit. 
o Weight, vital signs, waist-to-hip ratio, and consumptive habits (alcohol, caffeinated 
beverages) will be recorded 
o Urine pregnancy test (for premenopausal women only).  Postmenopausal is defined as at 
least one year since last menses and FSH in the postmenopausal range  
o Baseline endocrine blood testing: free testosterone, estradiol, neuroactive steroid panel, 
DHEAS, blood cortisol, late night salivary cortisol and 8 a.m. salivary cortisol 
o Baseline safety blood testing:  ALT, creatinine, CBC 
o Depression:  MADRS, IDS-SR, CGI-I, S 
o Cognitive Functioning: CPFQ 
o Persistent/residual symptom assessment:  SF-36, BFI, ESS, FSS, DISF 
o Safety assessments: SAFTEE-SI, CHRT, and hirsutism and skin assessments 
o We will distribute the Study Drug Compliance and Hot Flash Diary or Menopausal 
Symptom Diary 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
7 
o We will also collect DNA to be banked for a future exploratory study into whether 
androgen receptor CAG repeat length moderates androgen-behavior relationships (based 
on data by Seidmanet et al.). 
 
Follow-up Visits (Placebo-Controlled Augmentation Phase):  Subjects will then be 
randomized to receive low-dose testosterone or placebo.  Follow-up visits will take place at 
weeks 2, 4, 6 and 8 post-baseline.  Follow up visits will include: 
o Urine pregnancy test (for premenopausal women only).  Postmenopausal is defined as at 
least one year since last menses and FSH in the postmenopausal range (weeks 2, 4, 6 and 
8) 
o Free testosterone levels (weeks 2, 4, 6 and 8) 
o Skin evaluations to monitor for side effects (weeks 4 and 8) 
o Weight and vital signs will be recorded (weeks 4 and 8) 
o Waist-to-hip ratio (week 8) 
o Depression:  MADRS, IDS-SR, CGI-I, S (weeks 2, 4, 6 and 8) 
o Cognitive Functioning: CPFQ (weeks 2, 4, 6 and 8) 
o Persistent/residual symptom assessment:  SF-36, BFI, ESS, FSS, DISF (weeks 2, 4, 6 
and 8) 
o Safety: SAFTEE-SI, CHRT (weeks 2, 4, 6 and 8) 
o Estradiol levels (weeks 2, 4, 6 and 8) 
o Salivary cortisol (week 8) 
o Medication management sessions (weeks 2, 4, 6 and 8) 
o Neuroactive steroid panel (week 8) 
o We will distribute the Study Drug Compliance and Hot Flash Diary or Menopausal 
Symptom Diary (weeks 2, 4, 6, and 8) 
 
 fMRI Substudy Visits for Randomized Subjects 
o fMRI substudy participants will be further evaluated at the screening visit for 
suitability to undergo MRI using the Martinos Center Patient/Volunteer 
Screening Form.  
o Subjects will undergo urine pregnancy tests throughout the study as noted 
above. 
o One hour fMRI sessions will be scheduled at baseline before intervention 
occurs and at 8 weeks (weeks 0,8) 
o Subjects will be administered the IDS-SR, FSS and BFI before each scan 
(weeks 0, 8) 
o A blood draw to measure blood hormone levels on the day of the fMRI scan 
will occur at both the baseline and 8 week scanning visit.  
 
fMRI Healthy Control Substudy Visits 
 
Screening visit: A screening visit will take place to determine eligibility for enrollment and 
ensure that subjects meet inclusion and exclusion criteria. Twenty women with no history of 
depression or other psychiatric illness will be eligible for the baseline fMRI scan. Screening visit 
testing will include: 
o Complete medical history 
o Diagnostic interview with SCID 
o Physical examination, including height and weight  
o Morning blood draw for ALT, creatinine, CBC, thyroid stimulating hormone (TSH), 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
8 
free testosterone, FSH, and urine pregnancy test 
If a subject is found to be eligible following screening procedures, the subject will be scheduled 
for the baseline fMRI visit in approximately 1-2 weeks. 
 
Baseline fMRI Healthy Control Visit:  
Healthy control subjects will receive one fMRI scan at this visit. Other study procedures include: 
o Urine pregnancy test 
o Study questionnaires: IDS-SR, FSS and BFI 
o A blood draw to measure blood hormone levels on the day of the fMRI scan will occur 
at both the baseline and 8 week scanning visit.  
 
Healthy control Visits 
 
Screening Visit (n=60): A “Screening Visit” will be conducted to determine eligibility.  It is 
estimated that 60 women will need to be screened to obtain 30 eligible study subjects. 
       The screening visit will include:  
o Abbreviated SCID 
o Medical and psychiatric history including past psychiatric medication use  
 
Baseline Visit (n=30): The baseline visit will occur if subjects are found eligible. 
         Baseline visit will include: 
o Psychiatric assessments: MADRS, IDS-SR, CGI-I, S, CPFQ, SF-36, BFI, ESS, FSS, 
DISF, SAFTEE-SI, CHRT 
o Height, weight, vital signs, waist-to-hip ratio, and consumptive habits (alcohol, 
caffeinated beverages) will be recorded 
o Salivary cortisol 
o Blood for androgens including total testosterone, free testosterone, neuroactive 
steroid levels, including allopregnanolone, and cortisol, and other hormones 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  
9 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
  
 
Describe explicitly the methods for ensuring the safety of subjects.  Provide objective criteria for 
removing a subject from the study, for example, objective criteria for worsening disease/lack of 
improvement and/or unacceptable adverse events.  The inclusion of objective drop criteria is 
especially important in studies designed with placebo control groups.
Suicide Prevention: Suicidal ideation will be assessed by the Beck Suicide Index at each visit. 
Patients who develop active suicidal ideation, or who are felt by the study clinician to be at high 
risk for suicide, will be discontinued from the study and referred for hospitalization and further 
treatment if clinically indicated. In addition, each study subject will be extensively interviewed at 
each study visit by a highly trained psychiatrist, who not only has extensive experience in the 
treatment of major depression, but also with these issues in the setting of clinical trial protocols.  
Patients in research protocols have much more access to psychiatrists than patients in the 
community, as a study psychiatrist is available by pager 24 hours per day.  Moreover, the studies 
are performed in hospitals in which patients can be immediately admitted, if necessary to ensure 
safety.   
 
Drug Safety: We will measure free testosterone levels every two weeks and decrease the dose to 
5 mg (0.5 ml) in any subject with a free testosterone level of more than 2x the upper limit of 
normal for females at one visit or 1.5x the upper limit of normal at two visits. If the free 
testosterone level remains above the same limits listed above after the initial dose decrease, the 
dose will be decreased to 2.5mg (0.25ml).  In order to ensure success at raising levels during the 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  10 
trial, dose increases by 5 mg increments (0.5 ml) daily will be made in subjects in whom the free 
testosterone level is less than the mean for age at any visit.   
 
Safety: Patients will be carefully monitored by clinicians for side effects and potential toxicities 
with hirsutism and skin assessments. The blood draws will be performed by trained staff who 
have certificates documenting their ability to draw blood. We are performing a physical 
examination and routine laboratory tests prior to allowing anyone to enter the randomized phase 
of the protocol to ensure that subjects are medically stable.  Close monitoring of patients 
throughout the study will ensure that adverse effects from treatment, exacerbation of symptoms, 
or emergence of suicidality, mania or psychosis will be promptly recognized so that patients can 
be treated appropriately following study discontinuation. All patients will be instructed on how 
to contact study clinicians in the case of an emergency. They will also be instructed on how to 
contact the Acute Psychiatry Service (APS) at MGH and the Patient Assessment Services (PAS) 
at Butler Hospital, which provide emergent psychiatric care on a 24h/day basis.   
 
Every effort will be made to keep patients in the study. Acceptable reasons for early 
discontinuation include: 1) request of patient, 2) decision of physician, 3) serious adverse event, 
4) worsening of depression requiring hospitalization, 5) emergence of hypomania, mania or 
psychotic symptoms, 6) pregnancy. 
 
A Data Safety Monitor will review safety data, including adverse events and free testosterone 
levels twice-a-year and will be available in the interim to consider any urgent matters. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Partners Human Subjects Research Application 
Form 
 
Filename: Protocol Summary 
Version Date:  June 1, 
2005  
  12 
 
 
 
 
  
 
Close skin contact with the area of application within an hour of application by a partner or child 
should be avoided.   
 
AndroFeme contains almond oil.  Therefore, individuals with almond allergies may be allergic to 
this preparation. 
 
Risks of blood sampling: Blood sampling is performed in the study, and there is always a very 
minor risk of infection, bruising, or syncope during a blood draw.  There is also the discomfort of 
having one’s blood drawn.   
 
Discomforts with Questionnaires: Answering detailed questionnaires may create some 
inconvenience for subjects.  
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_003.pdf: 
 
 
 
Testosterone Antidepressant Augmentation in 
Women 
 
 
 
 
NCT01783574 
 
 
 
 
Version Date: February 1, 2017 
 


Study Endpoints and Data Analysis 
Specific Aim 1: We will investigate in women with partial/nonresponse to 
antidepressant therapy whether low-dose testosterone augmentation leads to a 
significantly greater reduction in depressive symptoms compared to a placebo group 
over an 8-week period.  
Experimental Strategy and Endpoints: To investigate the effects of physiologic 
testosterone augmentation on antidepressant therapy partial/nonresponse, 50 women 
with partial/nonresponse to antidepressant therapy randomized to testosterone 
augmentation and 50 to placebo in the 8-week randomized, double-blind placebo 
controlled study delineated in the “Overall Protocol”, will be compared.  Depressive 
symptom endpoints will be measured at baseline and weeks 2, 4, 6 and 8. The primary 
endpoint will be MADRS score in weeks 2-8. 
• These data will determine the effects of low-dose testosterone augmentation 
on depressive symptoms in women with partial/nonresponse to 
antidepressant therapy. 
Data Analysis:  For Aim 1, the data will be analyzed using a mixed-effect linear 
regression model. The randomization will be stratified by site, estrogen use, and one vs. 
more than one adequate antidepressant therapy trial. The model will specify a baseline 
MADRS score and baseline non-responder vs. partial responder as covariates and then 
an "on treatment score,” which is the score from weeks 2 through 8.  The following will 
be entered into the model as covariates:  baseline non-responder vs. partial responder, 
one vs. more than one adequate antidepressant therapy trial, baseline free testosterone 
level, baseline age and site (MGH or Butler Hospital). The on treatment score will have 
a fixed treatment effect and a random patient effect.  We will examine interactions 
between menopausal status and effect to determine whether menopausal status 
moderates the treatment effect.  This model is the same as in a repeated measures 
analysis of (co)variance with the assumption of compound symmetry.  Our pilot data 
shown in Figure 2 fits this model.  Specifically, based on our preliminary data, we expect 
a rapid improvement in depression severity by 2 weeks followed by maintenance of the 
effect of the subsequent 6 weeks.  One advantage of this method is that it allows us to 
use data from patients who drop out early despite our plans to obtain follow-up data on 
all patients randomized and analyze all data obtained.  A subject who drops out in the 
middle of the study will add data to the analysis.  The drop-out rate should be low due to 
the relatively short duration of the study and the anticipated low side effect profile, the 
latter as confirmed in our pilot study in this population in which we had no drop-outs 
over the 8-week period.  This model assumes that the drop-outs are missing at random.  
We will attempt to obtain 8-week observations on all patients, including drop-outs.  
Sensitivity analysis will be performed to determine whether our conclusions are 
sensitive to this assumption (185). Secondary analyses will determine whether the 
response of depressive symptoms to testosterone is affected by baseline androgens 
and neuroactive metabolites (including free testosterone level, DHEAS, and 3α-diol), 
estradiol, blood cortisol, late night cortisol and 8 a.m. salivary cortisol, and changes in 
the same variables over the 8-week period.  Pre-treatment free testosterone level will be 
entered into the model as a covariate along with a treatment baseline interaction.  Other 
covariates that will be explored will be age, menopausal status, baseline MADRS score, 
change in estradiol levels, change in free testosterone levels and BMI.  As a secondary 


endpoint, we will determine the 8-week remission rate in an exploratory analysis.  
Remission will be defined as MADRS score<10.  Comparison of ratios of remitters to 
the total number of study participants in the testosterone and placebo groups will be 
compared using a Fisher Exact test.  Another secondary endpoint will be effects of 
testosterone on functional measures.  The same methods as described for MADRS 
score analyses will be used to analyze functional measures, including the SF-36. 
 
For Aim 1B, the primary analysis will be to determine whether the neuroactive 
metabolite of testosterone, 3α-diol, is an important determinant of the effects of 
testosterone on our primary endpoint, MADRS score.  We expect to be able to 
distinguish the effect of 3α-diol from the effect of an increase in serum free testosterone 
levels because we expect the relative levels of the two hormones will differ, i.e. we 
expect that some study subjects will convert a greater proportion of testosterone to the 
3α-diol metabolite than other study subjects.  Analyzing the effect of both free 
testosterone and 3α-diol on the outcome (MADRS score) by linear regression, we hope 
to determine the relative importance of each hormone as a determinant of outcome.  It 
is conceivable that both will correlate with the MADRS score, simply reflecting 
absorption of testosterone, and it is also possible that one will correlate with MADRS 
score, and the other will not.  For instance, if the coefficient of the metabolite 3α-diol in a 
regression of outcome on 3α-diol and free testosterone is large while that of free 
testosterone is small, then we would conclude that the active factor is 3α-diol rather 
than free testosterone.  If the correlation coefficient between the two of these is large, 
we would not have data to make a determination of which is active.   
 
Specific Aim 2: We will investigate in women with partial/nonresponse to 
antidepressant therapy whether adjunctive low-dose testosterone is safe and well-
tolerated in women with partial/nonresponse to antidepressant therapy. 
Experimental Strategy and Endpoints:  To investigate whether adjunctive physiologic 
testosterone is safe and well-tolerated over the 8-week protocol, we will compare rates 
of adverse events in subjects randomized to testosterone augmentation to those 
receiving placebo using the SAFTEE-SI.  These endpoints will also include increases in 
ALT and hirsutism and skin assessment scores and decreases in HDL cholesterol.  The 
primary endpoint will be adverse effect rate. 
• These data will determine whether adjunctive physiologic testosterone is 
safe and well-tolerated in women with relative partial/nonresponse to 
antidepressant therapy. 
Data Analysis: Rates for each adverse effect will be computed by group. Differences 
between treatment groups in dropout rates will be examined using a Fisher’s Exact test, 
though every effort will be made to retain subjects through the 8-week course. If a trend 
(p < .10) indicative of differential dropout is detected, a more detailed survival analysis 
will be completed to illustrate the timing and magnitude of these differences. 
 
Specific Aim 3: Low-dose testosterone augmentation improves persistent/residual 
symptoms in women with antidepressant-resistant depression. 
Experimental Strategy and Endpoints: To investigate the effects of low-dose 
testosterone augmentation on fatigue and energy in women with antidepressant-
resistant depression, the 50 women with antidepressant-resistant depression 


randomized to testosterone augmentation and 50 to the placebo arm of the 8-week 
randomized, double-blind placebo controlled study delineated in the “Overall Protocol”, 
will be compared.  Energy/fatigue and sexual function/libido endpoints will be measured 
at baseline and weeks 2, 4, 6 and 8.  The primary endpoint will be BFI score weeks 
2-8. 
• 
These data will determine the effects of low-dose testosterone 
augmentation on fatigue and sexual function in women with 
antidepressant-resistant depression. 
Data Analysis:  The data will be analyzed using a mixed-effect linear regression model, 
using methods and assumptions as in Specific Aim 1 Data Analysis, above.