Effect of Antidepressants on Sex Hormone Levels and Sexual Functioning

• Sponsor: Weill Medical College of Cornell University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00611975
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 83
• Arms: 2
• Duration (Months): 35

Study Details

Study Description

Brief Summary

This study will evaluate the effect of antidepressants on sex hormone levels in women and if the potential changes in sex hormone levels are related to sexual side effects.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Fluoxetine; Drug: Bupropion	Phase 4

Detailed Description

Depression is a leading cause of disability in women, with women being two times more likely than men to develop depression. Depression affects a person's body, thoughts, mood, and behavior, often making normal day-to-day functioning difficult. Fortunately, depression is a condition that is highly treatable with one or more of the antidepressant medications and forms of psychotherapy available. Serotonin reuptake inhibitors (SRIs) are a recent class of antidepressants that have been successful in alleviating symptoms of depression. Although the side effects of SRIs are less than those of other types of antidepressants, a number of people taking SRIs experience sexual dysfunction, including reduced desire and difficulty with orgasm. It is believed that SRI treatment may interfere with gonadal production of steroid hormones, thus leading to changes in sexual function. This study will compare the effects of the SRI fluoxetine with the effects of the non-SRI bupropion on circulating levels of sex hormones in healthy women and on any related sexual side effects.

Participation in this study will last 3 months. Potential participants will undergo initial screening, which will involve a blood draw, drug and pregnancy tests, physical exam, electrocardiogram, and psychiatric diagnostic interview. Participants will also complete an interview and questionnaire about sexual functioning. All eligible participants will then be asked to return for a total of 9 study visits over 3 months.

Participants will undergo 1 month of baseline hormonal sampling and 2 months of daily treatment with either fluoxetine or bupropion. The study visits will be scheduled around three points in the menstrual cycle (early follicular, ovulatory, and luteal), with each visit including a blood draw and repeat questionnaire on sexual functioning. Participants will be asked to perform daily urine tests, beginning 10 days after the start of menstruation and continuing for up to 8 days until detection of the luteinizing hormone surge, which signals ovulation. Participants will be asked to keep a diary of luteinizing hormone surges, dates of menstruation, and sexual activities. At the Month 3 visit, participants will discontinue their assigned medication and will complete their final blood draw and questionnaire.

Study Design

• Study Type: Interventional
• Actual Enrollment: 83 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Health Services Research
• Official Title: Effect of Serotonin Reuptake Inhibitors on Gonadal Steroid Hormones
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: Sep 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: A Participants will receive treatment with fluoxetine for 2 months	Drug: Fluoxetine; Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.; Other Names: Prozac, Sarafem
Experimental: B Participants will receive treatment with bupropion for 2 months	Drug: Bupropion; Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.; Other Names: Wellbutrin, Zyban

Outcome Measures

Primary Outcome Measures

1. Change in 17-OH Pregnenolone [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Effects of the two antidepressant treatments and menstrual cycle on hormone level were examined.

Secondary Outcome Measures

1. Change in Arizona Sexual Experiences Scale (ASEX) [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   A five-item scale with each item scored from 1 to 6. Score range is 5 to 30. Higher scores indicate more sexual dysfunction. Scores at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on ASEX scores were examined.

2. Change in Free Testosterone [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Free testosterone was calculated from total testosterone ng/ml divided by sex hormone binding globulin (SHBG) nmol/l multiplied by 100. Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.

3. Change in Estradiol [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.

4. Change in Prolactin [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.

5. Change in Progesterone [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Hormone levels at early follicular, ovulation, and luteal phase of the cycle were averaged for the baseline pre-treatment month and compared to average values during the 1st and 2nd months of antidepressant treatment.

6. Change in Dehydroepiandrosterone Sulfate (DHEA-S) [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.

7. Change in Androstenedione [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

   Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.

8. C-reactive Protein [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

9. Inflammatory Cytokines [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

10. Lymphocyte Activation Markers [Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Regular menstrual cycles that are 25 to 35 days in length during the 1 year prior to study entry

• Willing to engage in sexual activity, alone or with a partner, at least weekly for the duration of the study

• Willing to use effective birth control (e.g., condom, diaphragm with spermicide, tubal ligation, nonhormonal intrauterine device,, partner with vasectomy) for the duration of the study

Exclusion Criteria:

• Medical illness that may contribute to sexual dysfunction or affect steroid hormone levels

• Body mass index (BMI) greater than 30

• Elevated testosterone at screening

• History of seizure disorder

• Consumes more than 10 alcoholic beverages per week

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Weill Medical College of Cornell University
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Margaret Altemus, MD, Weill Medical College of Cornell University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Weill Medical College of Cornell University
• ClinicalTrials.gov Identifier: NCT00611975
• Other Study ID Numbers: R21MH071543; R21MH071543; DNBBS 73-MCR
• First Posted: Feb 11, 2008
• Last Update Posted: Dec 10, 2020
• Last Verified: Nov 1, 2020

• Keywords provided by Weill Medical College of Cornell University: Gonadal Steroid Hormones; Healthy Volunteers; Antidepressant Side Effects; Fluoxetine; Bupropion; Prolactin; Testosterone; Estradiol; Progesterone; Sexual Function; Serotonin Reuptake Inhibitors; 17-OH Pregnenolone
• Additional relevant MeSH terms: Bupropion; Fluoxetine

Study Results

Participant Flow

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Period Title: Overall Study
STARTED	45	38
COMPLETED	40	30
NOT COMPLETED	5	8

Baseline Characteristics

Arm/Group Title	Fluoxetine	Bupropion	Total
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.	Total of all reporting groups
Overall Participants	45	38	83
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.4 (5.5)	27.9 (6.4)	27.6 (5.9)
Sex: Female, Male (Count of Participants)
Female	45 100%	38 100%	83 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 17.8%	6 15.8%	14 16.9%
Not Hispanic or Latino	37 82.2%	32 84.2%	69 83.1%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	8 17.8%	6 15.8%	14 16.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	10 22.2%	14 36.8%	24 28.9%
White	25 55.6%	18 47.4%	43 51.8%
More than one race	2 4.4%	0 0%	2 2.4%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Change in 17-OH Pregnenolone
Description	Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Effects of the two antidepressant treatments and menstrual cycle on hormone level were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	120 (14)	158 (17)
Baseline month ovulation	171 (46)	170 (23)
Baseline month luteal	141 (18)	189 (22)
Treatment month 1 follicular	151 (15)	184 (39)
Treatment month 1 ovulation	122 (20)	142 (22)
Treatment month 1 luteal	109 (14)	163 (20)
Treatment month 2 follicular	101 (9)	138 (19)
Treatment month 2 ovulation	174 (32)	176 (20)
Treatment month 2 luteal	167 (32)	161 (21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.8
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.4
	Comments
	Method	Mixed Models Analysis
	Comments

2. Secondary Outcome

Title	Change in Arizona Sexual Experiences Scale (ASEX)
Description	A five-item scale with each item scored from 1 to 6. Score range is 5 to 30. Higher scores indicate more sexual dysfunction. Scores at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on ASEX scores were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing questionnaire samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	13.1 (.5)	12.9 (.7)
Baseline month ovulation	11.3 (0.6)	12.1 (1.1)
Baseline month luteal	14.0 (0.8)	12.4 (0.7)
Treatment month 1 follicular	15.1 (.9)	13.6 (10.9)
Treatment month 1 ovulation	15.0 (1.0)	12.6 (1.0)
Treatment month 1 luteal	14.8 (.7)	13.8 (0.8)
Treatment month 2 follicular	14.4 (0.7)	14.3 (0.9)
Treatment month 2 ovulation	13.6 (1.2)	15.2 (1.4)
Treatment month 2 luteal	15.1 (0.7)	14.4 (1.0)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Asex questionnaires were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for ASEX scores were re-assigned to phase based on time to onset of next menstrual period. Follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-2 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.6
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on ASEX scores
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.6
	Comments
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Change in Free Testosterone
Description	Free testosterone was calculated from total testosterone ng/ml divided by sex hormone binding globulin (SHBG) nmol/l multiplied by 100. Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	.41 (.03)	.44 (.02)
Baseline month ovulation	.52 (.05)	.69 (.09)
Baseline month luteal	.47 (.04)	.47 (.04)
Treatment month 1 follicular	.39 (.02)	.51 (.04)
Treatment month 1 ovulation	.41 (.04)	.65 (.13)
Treatment month 1 luteal	.49 (.04)	.48 (.05)
Treatment month 2 follicular	.36 (.03)	.40 (.04)
Treatment month 2 ovulation	.50 (.04)	.81 (.20)
Treatment month 2 luteal	.50 (.07)	.44 (.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.01
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.01
	Comments
	Method	Mixed Models Analysis
	Comments

4. Secondary Outcome

Title	Change in Estradiol
Description	Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	42 (5)	38 (3)
Baseline month ovulation	131 (14)	134 (20)
Baseline Month Luteal	107 (7)	109 (8)
Treatment month 1 follicular	41 (5)	42 (6)
Treatment month 1 ovulation	91 (12)	121 (19)
Treatment month 1 luteal	126 (11)	108 (12)
Treatment month 2 follicular	40 (6)	35 (3)
Treatment month 2 ovulation	122 (19)	113 (13)
Treatment month 2 luteal	112 (9)	101 (10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.4
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments

5. Secondary Outcome

Title	Change in Prolactin
Description	Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	11.2 (0.7)	11.0 (1.2)
Baseline month ovulation	15.9 (1.7)	14.1 (1.6)
Baseline month luteal	16.4 (1.4)	15.4 (1.6)
Treatment month 1 follicular	12.1 (1.1)	11.7 (1.5)
Treatment month 1 ovulation	12.9 (1.4)	16.0 (2.9)
Treatment month 1 luteal	14.0 (1.4)	16.6 (1.9)
Treatment month 2 follicular	12.8 (1.0)	10.8 (1.4)
Treatment month 2 ovulation	17.1 (3.3)	18.3 (4.4)
Treatment month 2 luteal	13.7 (1.0)	12.1 (0.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.7
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments

6. Secondary Outcome

Title	Change in Progesterone
Description	Hormone levels at early follicular, ovulation, and luteal phase of the cycle were averaged for the baseline pre-treatment month and compared to average values during the 1st and 2nd months of antidepressant treatment.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	0.66 (0.2)	0.5 (0.4)
Baseline month ovulation	2.4 (0.6)	2.8 (0.9)
Baseline month luteal	9.5 (0.9)	9.6 (1.1)
Treatment month 1 follicular	0.7 (0.2)	0.7 (0.2)
Treatment month 1 ovulation	2.4 (0.7)	3.9 (1.2)
Treatment month 1 luteal	8.4 (1.1)	7.4 (1.0)
Treatment month 2 follicular	0.6 (0.2)	0.6 (0.08)
Treatment month 2 ovulation	2.9 (0.8)	3.2 (1.2)
Treatment month 2 luteal	8.6 (1.2)	8.1 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.9
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.0001
	Comments
	Method	Mixed Models Analysis
	Comments

7. Secondary Outcome

Title	Change in Dehydroepiandrosterone Sulfate (DHEA-S)
Description	Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	1.6 (0.1)	1.8 (0.1)
Baseline month ovulation	1.8 (0.2)	2.0 (0.2)
Baseline month luteal	1.6 (0.1)	1.9 (.01)
Treatment month 1 follicular	1.6 (0.1)	1.9 (0.1)
Treatment month 1 ovulation	1.7 (0.2)	1.9 (0.2)
Treatment month 1 luteal	1.7 (0.2)	1.9 (0.2)
Treatment month 2 follicular	1.6 (0.2)	1.8 (0.2)
Treatment month 2 ovulation	1.9 (0.3)	1.8 (0.2)
Treatment month 2 luteal	1.9 (0.2)	1.9 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.9
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.9
	Comments
	Method	Mixed Models Analysis
	Comments

8. Secondary Outcome

Title	Change in Androstenedione
Description	Hormone levels at early follicular, ovulation, and luteal phase of 3 menstrual cycles which included baseline month, month 1 of daily antidepressant treatment and month 2 of daily antidepressant treatment. Differential effects of the two antidepressant treatments and menstrual cycle on hormone levels were examined.
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

All subjects enrolled were included in the mixed model analysis. For mean results at each timepoint in the data table below, some subjects were not included due to missing blood samples or samples collected outside the specified cycle phase window.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	45	38
Baseline month follicular	0.84 (0.05)	0.89 (0.05)
Baseline month ovulation	1.13 (0.07)	1.28 (0.10)
Baseline month luteal	1.31 (0.10)	1.14 (0.07)
Treatment month 1 follicular	0.89 (0.07)	0.84 (0.06)
Treatment month 1 ovulation	1.13 (0.10)	0.96 (0.06)
Treatment month 1 luteal	1.04 (0.06)	1.13 (0.08)
Treatment month 2 follicular	0.79 (0.05)	.85 (.06)
Treatment month 2 ovulation	1.07 (0.12)	1.00 (0.13)
Treatment month 2 luteal	1.13 (0.09)	1.12 (0.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	Blood draws were scheduled for early follicular, ovulatory and luteal phases. Menstrual phase for blood samples were re-assigned to phase based on time to onset of next menstrual period. Early follicular(35-21 days before next menstrual period (NMP)), Ovulatory (16-12 before NMP) luteal (11-3 days before NMP).
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.1
	Comments
	Method	Mixed Models Analysis
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Fluoxetine, Bupropion
	Comments	This secondary analysis examined main effect of menstrual cycle phase on hormone levels
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.7
	Comments
	Method	Mixed Models Analysis
	Comments

9. Secondary Outcome

Title	C-reactive Protein
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

This measure was not performed due to lack of anticipated supplementary funding.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	0	0

10. Secondary Outcome

Title	Inflammatory Cytokines
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

This measure was not performed due to lack of anticipated supplementary funding.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	0	0

11. Secondary Outcome

Title	Lymphocyte Activation Markers
Time Frame	Measured in baseline menstrual cycle and during antidepressant treatment for two menstrual cycles

Outcome Measure Data

Analysis Population Description

This measure was not performed due to lack of anticipated supplementary funding.

Arm/Group Title	Fluoxetine	Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.	Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
Measure Participants	0	0

Adverse Events

Time Frame	Each subject was assessed for 3 months.
Arm/Group Title	Fluoxetine		Bupropion
Arm/Group Description	Participants will receive treatment with fluoxetine for 2 months Fluoxetine: Participants will begin taking 10 mg of fluoxetine, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 20 mg of fluoxetine once a day after 7 days, to be maintained until the luteal phase (start of ovulation) of menstrual cycle 3. If side effects are intolerable, the dose will be lowered to 10 mg of fluoxetine per day. Participants will undergo a total of 2 months of treatment with fluoxetine.		Participants will receive treatment with bupropion for 2 months Bupropion: Participants will begin taking 150 mg of bupropion, once a day by mouth, on the first day of their second menstrual cycle during the study. Dosage will be increased to 300 mg of bupropion once a day after 7 days, to be maintained until the luteal phase of menstrual cycle 3. If side effects are intolerable, the dose will be decreased to 150 mg of bupropion per day. Participants will undergo a total of 2 months of treatment with bupropion.
All Cause Mortality
	Fluoxetine		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/45 (0%)		0/38 (0%)
Serious Adverse Events
	Fluoxetine		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/45 (2.2%)		2/38 (5.3%)
Nervous system disorders
seizure	0/45 (0%)		1/38 (2.6%)
Pregnancy, puerperium and perinatal conditions
pregnancy	1/45 (2.2%)		1/38 (2.6%)
Other (Not Including Serious) Adverse Events
	Fluoxetine		Bupropion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/45 (73.3%)		21/38 (55.3%)
Gastrointestinal disorders
reduced appetite	9/45 (20%)	9	11/38 (28.9%)	11
dry mouth	5/45 (11.1%)	5	10/38 (26.3%)	10
diarrhea	6/45 (13.3%)	6	5/38 (13.2%)	5
nausea	9/45 (20%)	9	12/38 (31.6%)	12
General disorders
fatigue	11/45 (24.4%)	11	7/38 (18.4%)	7
insomnia	6/45 (13.3%)	6	4/38 (10.5%)	4
Nervous system disorders
yawning	8/45 (17.8%)	8	4/38 (10.5%)	4
headache	14/45 (31.1%)	14	6/38 (15.8%)	6
tinnitus	3/45 (6.7%)	3	4/38 (10.5%)	4
Psychiatric disorders
anxiety	3/45 (6.7%)	3	2/38 (5.3%)	2
Reproductive system and breast disorders
reduced orgasm	10/45 (22.2%)	10	6/38 (15.8%)	6
reduced libido	9/45 (20%)	9	3/38 (7.9%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.