Study of the Effects of an Antidepressant Medication and Placebo on the Brain Functioning of Normal Subjects

• Sponsor: University of California, Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT00634283
• Collaborator: (none)
• Enrollment: 6
• Location: 1
• Arms: 2
• Duration (Months): 12
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study examines the effects of an antidepressant medication and placebo on the brain functioning of normal subjects. In this study, recordings of brain electrical activity are being used to detect and monitor the response to treatment with venlafaxine IR (Effexor), a drug used for the treatment of depression. The intent of this study is to test specific hypotheses regarding:

1. long-term brain effects of a single course of antidepressant treatment

2. pharmaco-conditioning effects underlying antidepressant tolerance/sensitization

3. brain functional response to initial versus subsequent antidepressant trials in normal healthy subjects.

Condition or Disease	Intervention/Treatment	Phase
Depression	Drug: venlafaxine	Phase 4

Detailed Description

Major Depressive Disorder (MDD) is a lifelong and recurrent illness, such that many individuals require multiple courses of antidepressant medication treatment. While some patients respond completely to each course of treatment, many do not, and with each unsuccessful antidepressant trial the likelihood that a patient will respond decreases. This raises the possibility that neurophysiologic response in subsequent antidepressant treatment may be influenced by learning processes including sensitization, habituation, and/or classical conditioning. Classical conditioning would entail the association of cues such as pill-taking (conditioned stimuli; CS) with the effects of active medication (unconditioned stimulus; US), such that later presentation of the CS alone would come to elicit a conditioned response (CR). Such effects could be revealed by blinded administration of placebo following a period of treatment with active medication. Habituation effects (tolerance), or sensitization effects (increased response), which require only repeated exposure to a stimulus, might be evidenced after repeated courses of antidepressant treatment. Knowledge of how learning processes impact neurophysiologic response to successive courses of antidepressant treatment would have relevance for clinical populations. Specific hypotheses, however, may be tested in healthy non-clinical samples to avoid potential confounding factors related to severity or chronicity of illness. Learning theories would suggest two hypotheses: (1) neurophysiologic response to placebo will differ between subjects who were previously treated with antidepressant treatment as compared to placebo (classical conditioning hypothesis); and (2) neurophysiologic response to an initial course of antidepressant treatment will differ from response to a repeated course of antidepressant treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Subjects are assigned to one of two groups (antidepressant-experienced and antidepressant-naive) and receive parallel treatment (1 week of placebo followed by 4 weeks of venlafaxine) for the duration of the study. Subjects and assessors were blinded to treatment condition.Subjects are assigned to one of two groups (antidepressant-experienced and antidepressant-naive) and receive parallel treatment (1 week of placebo followed by 4 weeks of venlafaxine) for the duration of the study. Subjects and assessors were blinded to treatment condition.
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Masking Description: We compared EEG outcomes for those subjects who had been randomly assigned to blinded treatment with venlafaxine (antidepressant-experienced, n=2) vs. placebo (antidepressant-naive, n=4). All subjects received 1 week of placebo followed by 4 weeks of venlafaxine. Subjects were blinded to the treatment during both phases of the study using lookalike capsules. Outcomes assessors and the treating physician also were blinded to treatment condition.
• Primary Purpose: Other
• Official Title: Physiologic Monitoring of Antidepressant Medication Effects in Normal Healthy Subjects II
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Feb 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: antidepressant-experienced Subjects who had previously been exposed to active antidepressant medication (venlafaxine)	Drug: venlafaxine; venlafaxine IR 150mg; Other Names: Effexor
Placebo Comparator: antidepressant-naive Subjects who had previously been exposed to placebo only (and never to active antidepressant medication)	Drug: venlafaxine; venlafaxine IR 150mg; Other Names: Effexor

Outcome Measures

Primary Outcome Measures

1. Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks). [Average over 4 weeks]

   Cordance values were calculated from conventional 'absolute' and 'relative' qEEG power measures using a three-step procedure. First, EEG power values were computed using a re-attributional electrode montage. Second, the absolute and relative power values were z-transformed to measure deviation from the mean values for each electrode site s in each frequency band f for that recording, yielding Anorm(s,f) and Rnorm(s,f), respectively. Third, these z-scores were summed to yield a cordance "intensity" value, Z, for each electrode in each frequency band where Z(s,f) = Anorm(s,f) + Rnorm(s,f). Analyses for this report focused on changes-from-baseline theta-band (8-12Hz) cordance in the prefrontal region (electrodes Fp1, Fpz, Fp2). Results are defined in terms of positive and negative change where a positive change represents an increased physiologic and behavioral response to the drug (sensitization) and a negative change represents an increased tolerance to the drug (habituation).

2. Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over 1 Week Placebo lead-in. [1-week placebo lead-in]

   Cordance values were calculated from conventional 'absolute' and 'relative' qEEG power measures using a three-step procedure. First, EEG power values were computed using a re-attributional electrode montage. Second, the absolute and relative power values were z-transformed to measure deviation from the mean values for each electrode site s in each frequency band f for that recording, yielding Anorm(s,f) and Rnorm(s,f), respectively. Third, these z-scores were summed to yield a cordance "intensity" value, Z, for each electrode in each frequency band where Z(s,f) = Anorm(s,f) + Rnorm(s,f). Analyses for this report focused on changes-from-baseline theta-band (8-12Hz) cordance in the prefrontal region (electrodes Fp1, Fpz, Fp2). Results are defined in terms of positive and negative change where a positive change represents an increased physiologic and behavioral response to the drug (sensitization) and a negative change represents an increased tolerance to the drug (habituation).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Subject age is 18-75 years

• Subject must be in overall good health (i.e., free of any medical condition known to affect brain function).

• Subject must have participated in former study, Physiologic Monitoring of Antidepressant Medication Effects in Normal Controls Subjects (IRB#: 00-11-038-13)

• Subject has had a normal physical exam within one year prior to entry of the study

• Capacity to give Informed Consent

Exclusion Criteria:

• Subject has serious medical illness, such as high blood pressure, heart disease, renal impairment, or cirrhosis of the liver.

• Subject meets DSM-IV Axis I criteria for a mood, anxiety, cognitive, or psychiatric disorder; or meets criteria for cluster A or B axis II diagnoses. These disorders will be determined on the basis of a structured assessment with the MINI (Mini International Neuropsychiatric Interview for DSM-IV Axis I Disorders)

• Subject has a history of current or past active suicidal ideation or suicide attempts.

• Subject has received treatment with an antidepressant medication or any medications that could influence brain function since his/her participation in the initial study

• Subject is using any of the following medications which interfere with EEG measures of brain function: Anticholinergics, Barbiturates, Benzodiazepines, Sedating Antihistamines (e.g. diphenhydramine (Benadryl) would be exclusionary, but not loratadine (Claritin))

• Subject has a history of seizures, brain surgery, skull fracture, significant head trauma, or previous abnormal EEG

• Subject is pregnant or planning on becoming pregnancy during course of the study

• Subject is a UCLA student or staff member directly under instruction or employment of any of the investigators

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Los Angeles (UCLA)	Los Angeles	California	United States	90024

Sponsors and Collaborators

• University of California, Los Angeles

Investigators

• Principal Investigator: Andrew Leuchter, MD, University of California, Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Andrew F. Leuchter, Principal Investigator, University of California, Los Angeles
• ClinicalTrials.gov Identifier: NCT00634283
• Other Study ID Numbers: 07-10-051
• First Posted: Mar 13, 2008
• Last Update Posted: Mar 9, 2020
• Last Verified: Feb 1, 2020

• Additional relevant MeSH terms: Depression; Venlafaxine Hydrochloride

Study Results

Participant Flow

Recruitment Details	All 142 research subjects were enrolled at the Laboratory of Brain, Behavior and Pharmacology from 8/19/05-9/30/08.
Pre-assignment Detail	Subjects were required to wash out from any exclusionary medication for at least two weeks. Subjects taking fluoxetine were required to wash out for at least 30 days prior to treatment assignment.

Arm/Group Title	Venlafaxine IR (Effexor)
Arm/Group Description	Five weeks of treatment with venlafaxine IR
Period Title: Overall Study
STARTED	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Venlafaxine IR (Effexor)
Arm/Group Description	Five weeks of treatment with venlafaxine IR
Overall Participants	6
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	6 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46.5 (1)
Sex: Female, Male (Count of Participants)
Female	6 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	6 100%

Outcome Measures

1. Primary Outcome

Title	Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks).
Description	Cordance values were calculated from conventional 'absolute' and 'relative' qEEG power measures using a three-step procedure. First, EEG power values were computed using a re-attributional electrode montage. Second, the absolute and relative power values were z-transformed to measure deviation from the mean values for each electrode site s in each frequency band f for that recording, yielding Anorm(s,f) and Rnorm(s,f), respectively. Third, these z-scores were summed to yield a cordance "intensity" value, Z, for each electrode in each frequency band where Z(s,f) = Anorm(s,f) + Rnorm(s,f). Analyses for this report focused on changes-from-baseline theta-band (8-12Hz) cordance in the prefrontal region (electrodes Fp1, Fpz, Fp2). Results are defined in terms of positive and negative change where a positive change represents an increased physiologic and behavioral response to the drug (sensitization) and a negative change represents an increased tolerance to the drug (habituation).
Time Frame	Average over 4 weeks

Outcome Measure Data

Analysis Population Description

Antidepressant-experienced subjects; n=2 and antidepressant-naive subjects; n=4

Arm/Group Title	Antidepressant Treatment-experienced	Antidepressant Treatment-naive
Arm/Group Description	Subjects in this group had prior exposures to antidepressant medication (venlafaxine)	Subjects in this group had never before been exposed to antidepressant medication
Measure Participants	2	4
PFC change after placebo lead-in	-0.54 (0.44)	-0.09 (0.46)
PFC at Baseline	-0.09 (0.86)	-0.88 (1.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Antidepressant Treatment-experienced, Antidepressant Treatment-naive
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.55
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Antidepressant Treatment-experienced, Antidepressant Treatment-naive
	Comments	Change in PFC over the one-week placebo lead-in period was compared between antidepressant-experienced and antidepressant-naive groups using a between groups t-test.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.32
	Comments	The a priori threshold was set at 0.05, 2-tailed, without adjustment for multiple comparisons.
	Method	t-test, 2 sided
	Comments
Other Statistical Analysis		Group differences in PFC changes over time during administration of venlafaxine were assessed using mixed-model analysis. we compared brain functional changes over the course of venlafaxine treatment between antidepressant-experienced and antidepressant-naïve subjects using linear mixed model analysis (random intercept model) conducted using full maximum likelihood estimation (MLE). Changes in PFC were calculated from the end of placebo lead-in to 48 hours, and 1, 2, and 4 weeks, yielding a within-group factor of time with four levels. We employed a first-order autoregressive covariance structure to reflect our assumption that PFC measurements closer together in time would be more highly correlated.

2. Primary Outcome

Title	Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over 1 Week Placebo lead-in.
Description	Cordance values were calculated from conventional 'absolute' and 'relative' qEEG power measures using a three-step procedure. First, EEG power values were computed using a re-attributional electrode montage. Second, the absolute and relative power values were z-transformed to measure deviation from the mean values for each electrode site s in each frequency band f for that recording, yielding Anorm(s,f) and Rnorm(s,f), respectively. Third, these z-scores were summed to yield a cordance "intensity" value, Z, for each electrode in each frequency band where Z(s,f) = Anorm(s,f) + Rnorm(s,f). Analyses for this report focused on changes-from-baseline theta-band (8-12Hz) cordance in the prefrontal region (electrodes Fp1, Fpz, Fp2). Results are defined in terms of positive and negative change where a positive change represents an increased physiologic and behavioral response to the drug (sensitization) and a negative change represents an increased tolerance to the drug (habituation).
Time Frame	1-week placebo lead-in

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Antidepressant Treatment-experienced	Antidepressant Treatment-naive
Arm/Group Description	Subjects in this group had prior exposures to antidepressant medication (venlafaxine)	Subjects in this group had never before been exposed to antidepressant medication
Measure Participants	2	4
Mean (Standard Deviation) [Z-score]	-0.54 (0.44)	-0.09 (0.46)

Adverse Events

Arm/Group Title	Antidepressant Treatment-experienced		Antidepressant Treatment-naive
Arm/Group Description	Healthy subjects who have been previously exposed to venlafaxine		Healthy subjects who have never been previously exposed to antidepressant medication
All Cause Mortality
	Antidepressant Treatment-experienced		Antidepressant Treatment-naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Antidepressant Treatment-experienced		Antidepressant Treatment-naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	Antidepressant Treatment-experienced		Antidepressant Treatment-naive
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/4 (0%)

Limitations/Caveats

[Not Specified]

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.