Physiologic Monitoring of Antidepressant Treatment Response
Condition: Depression
MeSH terms: Depression
Study type: Interventional
Phase: Phase 4

Summary: 
      Study Objectives:

        -  to identify neurophysiologic effects of venlafaxine treatment in normal controls using
           quantitative EEG (QEEG) cordance

        -  to examine the effects of venlafaxine on different rating scales measuring mood and
           anxiety (e.g., Ham-D, BDI, SCL-90, POMS-BI, Visual Analog Mood Scale, SSRS, SASS,
           Q-LES-Q and SF-36) as well as on measures of cognitive and psychosocial function (i.e.,
           Stroop, PASAT, RAVLT, Trailmaking A and B, Digit-Symbol, Grooved Pegboard,
           Multidimensional Health Locus of Control, Temperament and Character Inventory,
           Interpersonal Support Evaluation List, Godin Leisure-Time Questionnaire, and Pittsburgh
           Sleep Quality Index) in normal control subjects, and the association of changes in
           cordance with changes in thinking and memory.

        -  to identify physiologic effects of venlafaxine treatment in normal controls using heart
           rate and immune function measures
    

Detailed description: 
      Pilot data suggest that in depressed patients treated with fluoxetine or venlafaxine, QEEG
      cordance detects changes of brain function within individual subjects as soon as two days
      after initiation of treatment. Changes in cordance appear to be specific (i.e., do not occur
      in the absence of clinical improvement), and frequently precede examiner ratings of
      improvement (Leuchter et al., 1997; Cook et al., in submission). In addition, patterns of
      cordance at baseline may indicate which patients are most likely to respond to fluoxetine or
      venlafaxine treatment (Cook et al., 1999).

      Findings using cordance contrast with those reported in previous QEEG studies of
      antidepressant medications, performed in depressed as well as normal control subjects. These
      studies have shown QEEG effects of antidepressant medication, such as decreased theta or
      alpha band activity, that are not related to changes in clinical state. In particular, normal
      subjects receiving antidepressant medications have been reported to show changes in
      conventional QEEG power measurements that may be useful characteristics of antidepressant
      medication for medication development purposes. Similar changes in QEEG power have been
      reported in depressed subjects who do not show clinical improvement (Saletu et al 1982, 1983,
      1985, 1986, 1987, 1988; Sannita et al 1983, 1990; Itil et al 1984; Herrmann et al., 1991;
      Luthringer et al., 1996). The relationship of these immediate EEG changes in control subjects
      to eventual clinical response in a depressed population is unclear. Other QEEG work with
      depressed subjects has found that changes from baseline in theta power early in the course of
      treatment may characterize groups of depressed patients who are more likely to respond to
      antidepressant treatment (Ulrich et al., 1994). Unfortunately, the changes lacked the
      specificity to allow response prediction for individual subjects, and the physiologic meaning
      of these changes in theta power is not clear.

      We previously have shown that absolute and relative power are complementary measures of brain
      activity (Leuchter et al., 1993). Cordance is a new QEEG measure that combines information
      from both absolute and relative power measures (Leuchter et al., 1994). In validation against
      data collected simultaneously with 15O positron emission tomography (PET), cordance values in
      the theta frequency band (4-8 Hz) were found to be positively correlated with cortical
      perfusion, and this correlation was stronger than that between perfusion and either absolute
      or relative theta power (Leuchter et al., 1999). The correlation of cordance with regional
      cortical perfusion provides a physiologic context in which to interpret this measure.

      In a series of depressed subjects receiving open-label treatment, we previously have shown
      that cordance detects changes in prefrontal activity (using a within-subjects design) as
      early as after three days of treatment in patients who will later show clinical response to
      antidepressant medication. Subjects who did not respond to antidepressant medication, as well
      as those receiving placebo, did not show these early changes in cordance (Leuchter et al
      1997; Cook et al 1998; Cook et al., in submission). These data suggest that QEEG cordance may
      be a more specific indicator of antidepressant treatment effectiveness than traditional QEEG
      power measures, since antidepressant non-responders and placebo treated subjects showed no
      early change in this measure. It is important, however, to determine if the effects that we
      have observed in depressed subjects during treatment are specific for this population, or are
      seen in normal controls as well. First, examination of specificity in normal controls during
      treatment is a logical first step in the process of examining other groups, eventually
      including other patient groups. Second, examination of normal subjects will help us to
      determine whether the observed changes in brain function are a pharmacodynamic effect of
      antidepressant medication which could be seen in any individual, or an effect seen
      exclusively in depressed subjects early in the course of effective antidepressant treatment.
    

Intervention name(s): venlafaxine (Effexor)
Intervention type(s): Drug
Intervention description(s): Matching capsules containing either venlafaxine 37.5 mg. or placebo will be prepared by the UCLA Pharmacy for the initial phase of the study. For the open-label phase of the study, subjects will receive the medication and dosage that is clinically indicated by the subject's primary physician in the community. After a one-week placebo lead-in, subjects will be randomly assigned to receive one capsule of either venlafaxine or placebo, with the dosage increase every two days until subjects receive four capsules daily (subjects will achieve a dose 150 mg. of venlafaxine after 7 days). The first dose will be administered in the morning, with subsequent capsules added on a b.i.d. schedule.
Intervention MeSH terms: Venlafaxine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: normal controls