Antidepressant Medication Plus Donepezil for Treating Late-life Depression

• ClinicalTrials.gov Identifier: NCT00177671
• Recruitment Status: Completed
• First Posted: September 15, 2005
• Results First Posted: June 8, 2011
• Last Update Posted: February 6, 2013
• Sponsor: University of Pittsburgh
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): University of Pittsburgh

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Depression; Dementia
• Interventions: Drug: Escitalopram; Drug: Donepezil; Drug: Venlafaxine; Drug: Placebo; Drug: Duloxetine
• Enrollment: 220

Participant Flow

Recruitment Details	220 signed consent; 158 participants completed pre-randomization testing; 130 participants were randomized. Of these 130, 67 randomized to donepezil augmentation and 63 to placebo.
Pre-assignment Details	28 enrolled participants were not randomized due to the following reasons: dementia (19), consent withdrawal (4), con-compliance with research procedures (3), supervening medical problems that precluded participation (2).

Arm/Group Title	Donepezil	Placebo
Arm/Group Description	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo
Period Title: Overall Study
Started	67	63
Month 12	45	57
Month 24	42	49
Completed	42	49
Not Completed	25	14
Reason Not Completed
Withdrawal by Subject	5	6
medical complications	2	0
Adverse Event	6	0
Physician Decision	12	8

Baseline Characteristics

Arm/Group Title		Donepezil	Placebo	Total
Arm/Group Description		Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo	Total of all reporting groups
Overall Number of Baseline Participants		67	63	130
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	67 participants	63 participants	130 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	67 100.0%	63 100.0%	130 100.0%
Age Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	67 participants	63 participants	130 participants
		73.1 (6.5)	73.9 (5.8)	73.5 (6.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	67 participants	63 participants	130 participants
	Female	49 73.1%	51 81.0%	100 76.9%
	Male	18 26.9%	12 19.0%	30 23.1%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	67 participants	63 participants	130 participants
		67	63	130

Outcome Measures

1. Primary Outcome

Title	Global Cognitive Performance
Description	Cognitive performance was assessed with 17 well established and validated individual tests measuring multiple domains. We transformed raw scores for individual tests into Z-scores using the baseline distribution of a non-depressed, cognitively normal, older adult comparison group (N=36)of similar age, education, and medical health recruited concurrently with the depressed participants. These Z-scores were averaged within each neuropsychological area to produce domain scores and then averaged over all 17 tests to calculate a global cognition performance score.
Time Frame	Measured at baseline and Years 1 and 2 in maintenance

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Donepezil	Placebo
Arm/Group Description:	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo
Overall Number of Participants Analyzed	67	63
Mean (Standard Deviation); Unit of Measure: Z-score
Baseline (N=67;N=63)	-0.47 (0.88)	-0.47 (0.76)
Year 1 (N=45; N=57)	-0.23 (0.79)	-0.65 (0.81)
Year 2 N=42; N=49)	-0.31 (0.92)	-0.56 (0.90)

2. Primary Outcome

Title	Cognitive Instrumental Activities of Daily Living (IADL)
Description	The PASS (a performance-based assessment of instrumental activities of daily living)generates a composite measure of 13 cognitive IADL items capturing performance on activities such as shopping, bill paying, medication management, and home safety. We report the percentage of subjects at each assessment point adjudged to have independent functioning. This was determined by a clinician rater observing subjects perform each task and rating them according to predetermined criteria on a 4 point scale, ranging from 0 (unable) to 3 (independent).
Time Frame	baseline, year 1 and year 2

Outcome Measure Data

Analysis Population Description

Some participants refused this testing.

Arm/Group Title	Donepezil	Placebo
Arm/Group Description:	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo
Overall Number of Participants Analyzed	33	34
Measure Type: Number; Unit of Measure: Percentage of participants
Baseline (N=33; N=34)	54.10	61.82
Year 1 (N=23; N=25)	62.16	54.35
Year 2 (N=11; N=17)	36.67	47.22

3. Primary Outcome

Title	Number of Participants With Recurrence of Major Depression
Description	Recurrence of major depressive episodes as determined by SCID/DSM IV: two weeks of low mood and/or anhedonia, together with at least five of the following symptoms: suicidal ideation, low energy, sleep disturbance, appetite disturbance, psychic anxiety or somatic anxiety. In addition, a diagnosis of major depression requires evidence of distress or impairment.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Donepezil	Placebo
Arm/Group Description:	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo
Overall Number of Participants Analyzed	67	63
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: participants
	19; (16 to 31)	11; (6 to 18)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Donepezil, Placebo
	Comments	We followed the intention to treat principle. We used Kaplan-Meier curves to quantify the percentage of participants who were free of depression recurrence over time. Cox proportional hazard models quantified hazard ratios comparing the 2 treatment groups.
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	.05
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.97
	Confidence Interval	(2-Sided) 95%; 1.00 to 4.41
	Parameter Dispersion	Type: Standard Deviation; Value: 2.09
	Estimation Comments	[Not Specified]

4. Post-Hoc Outcome

Title	Percentage of Participants With Mild Cognitive Impairment Converting to Dementia.
Description	Conversion to dementia was ascertained by the University of Pittsburgh Alzheimer Disease Research Center (ADRC), using data on neuropsychological performance and IADL functioning, as well as other relevant clinical data. Diagnoses were made according to National Alzheimer Coordinating Center criteria.
Time Frame	2 year

Outcome Measure Data

Analysis Population Description

This is the percent of participants with mild cognitive impairment (MCI) in each arm of the study.

Arm/Group Title	Donepezil	Placebo
Arm/Group Description:	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo
Overall Number of Participants Analyzed	30	27
Measure Type: Number; Unit of Measure: Percent of Participants
	10	33

Adverse Events

Time Frame	2 years
Adverse Event Reporting Description	We determined adverse events by structured clinical interview.
Arm/Group Title	Donepezil		Placebo
Arm/Group Description	Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus donepezil (5mg to 10mg daily)		Treatment with antidepressants (escitalopram (10mg to 20mg daily), venlafaxine (150mg to 300mg daily), duloxetine(20mg to 120mg daily) plus placebo
All-Cause Mortality
	Donepezil		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Donepezil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/67 (4.48%)		1/63 (1.59%)
Cardiac disorders
Myocardial infarcation with congestive heart failure † 1	1/67 (1.49%)	1	0/63 (0.00%)	0
Death due to heart attack in person with history of coronary heart disease and hypertension. † 1	0/67 (0.00%)	0	1/63 (1.59%)	1
Nervous system disorders
stroke † 1	1/67 (1.49%)	1	0/63 (0.00%)	0
Psychiatric disorders
Suicide Attempt † 1	1/67 (1.49%)	1	0/63 (0.00%)	0
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, standard terminology
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Donepezil		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/67 (0.00%)		0/63 (0.00%)

Limitations and Caveats

Observations about dementia conversion rates were obtained from post hoc subgroup analyses of participants with mild cognitive impairment (N=57) and participants with normal cognition at time of randomization (N=63).

More Information

Certain Agreements

Principal Investigators are NOT 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.

Results Point of Contact

• Name/Title: Charles F. Reynolds III, MD
• Organization: University of Pittsburgh
• Phone: 412-246-6414
• EMail: reynoldscf@upmc.edu

Publications:

Reynolds CF 3rd, Butters MA, Lopez O, Pollock BG, Dew MA, Mulsant BH, Lenze EJ, Holm M, Rogers JC, Mazumdar S, Houck PR, Begley A, Anderson S, Karp JF, Miller MD, Whyte EM, Stack J, Gildengers A, Szanto K, Bensasi S, Kaufer DI, Kamboh MI, DeKosky ST. Maintenance treatment of depression in old age: a randomized, double-blind, placebo-controlled evaluation of the efficacy and safety of donepezil combined with antidepressant pharmacotherapy. Arch Gen Psychiatry. 2011 Jan;68(1):51-60. doi: 10.1001/archgenpsychiatry.2010.184.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Diniz BS, Reynolds CF 3rd, Begley A, Dew MA, Anderson SJ, Lotrich F, Erickson KI, Lopez O, Aizenstein H, Sibille EL, Butters MA. Brain-derived neurotrophic factor levels in late-life depression and comorbid mild cognitive impairment: a longitudinal study. J Psychiatr Res. 2014 Feb;49:96-101. doi: 10.1016/j.jpsychires.2013.11.004. Epub 2013 Nov 20.

Andreescu C, Tudorascu DL, Butters MA, Tamburo E, Patel M, Price J, Karp JF, Reynolds CF 3rd, Aizenstein H. Resting state functional connectivity and treatment response in late-life depression. Psychiatry Res. 2013 Dec 30;214(3):313-21. doi: 10.1016/j.pscychresns.2013.08.007. Epub 2013 Oct 18.

Sheffrin M, Driscoll HC, Lenze EJ, Mulsant BH, Pollock BG, Miller MD, Butters MA, Dew MA, Reynolds CF 3rd. Pilot study of augmentation with aripiprazole for incomplete response in late-life depression: getting to remission. J Clin Psychiatry. 2009 Feb;70(2):208-13. Epub 2009 Feb 10.

Karp JF, Whyte EM, Lenze EJ, Dew MA, Begley A, Miller MD, Reynolds CF 3rd. Rescue pharmacotherapy with duloxetine for selective serotonin reuptake inhibitor nonresponders in late-life depression: outcome and tolerability. J Clin Psychiatry. 2008 Mar;69(3):457-63.

• Responsible Party: University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00177671
• Other Study ID Numbers: R01MH043832-03 ( U.S. NIH Grant/Contract ); R01MH043832 ( U.S. NIH Grant/Contract ); 0312018; DATR A4-GPS
• First Submitted: September 13, 2005
• First Posted: September 15, 2005
• Results First Submitted: February 18, 2011
• Results First Posted: June 8, 2011
• Last Update Posted: February 6, 2013