Depression
Conditions
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.
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.
Interventions
DRUGvenlafaxine
venlafaxine IR 150mg
Sponsors
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, 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.
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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). |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Venlafaxine IR (Effexor) Five weeks of treatment with venlafaxine IR | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Venlafaxine IR (Effexor) |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants |
| Age, Continuous | 46.5 years STANDARD_DEVIATION 1 |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 2 | 0 / 4 |
| serious Total, serious adverse events | 0 / 2 | 0 / 4 |
Outcome results
Primary
Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over 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).
Time frame: 1-week placebo lead-in
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Antidepressant Treatment-experienced | Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over 1 Week Placebo lead-in. | -0.54 Z-score | Standard Deviation 0.44 |
| Antidepressant Treatment-naive | Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over 1 Week Placebo lead-in. | -0.09 Z-score | Standard Deviation 0.46 |
Primary
Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (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).
Time frame: Average over 4 weeks
Population: Antidepressant-experienced subjects; n=2 and antidepressant-naive subjects; n=4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Antidepressant Treatment-experienced | Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks). | PFC change after placebo lead-in | -0.54 z-score | Standard Deviation 0.44 |
| Antidepressant Treatment-experienced | Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks). | PFC at Baseline | -0.09 z-score | Standard Deviation 0.86 |
| Antidepressant Treatment-naive | Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks). | PFC change after placebo lead-in | -0.09 z-score | Standard Deviation 0.46 |
| Antidepressant Treatment-naive | Changes in Quantitative Electroencephalogram (qEEG) Prefrontal Cordance (PFC) Over Time (4 Weeks). | PFC at Baseline | -0.88 z-score | Standard Deviation 1.55 |
p-value: 0.55t-test, 2 sided
Comparison: 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.p-value: 0.32t-test, 2 sided