Neurophysiologic Predictors of Outcome With rTMS Treatment of Major Depressive Disorder
Condition: Depression
MeSH terms: Depression; Depressive Disorder; Depressive Disorder, Major
Study type: Interventional
Phase: Phase 4

Summary: 
      Transcranial magnetic stimulation (TMS) therapy has proven to lead to symptom improvement in
      many individuals with major depressive disorder (MDD), yet there is heterogeneity in outcome,
      with some patients showing robust remission and other showing minimal symptom change.
      Identifying which individuals are likely to benefit from TMS therapy early in the course of
      treatment would support continued treatment for those predicted to do well, and consideration
      of alternative treatments for others individuals. This study will test specific hypotheses
      about the relationships between early neurophysiologic changes and later clinical outcome
      with TMS treatment.
    

Detailed description: 
      A critical challenge in the management of major depressive disorder (MDD) is the selection of
      treatment for each individual patient. Although treatments with depression can restore
      people's lives, with any treatment modality there are some individuals who do not achieve
      complete remission of symptoms, whether the intervention is pharmacological, psychological,
      or somatic. While predictors for some treatments have been proposed for groups of patients,
      the translation of these predictors to individualized patient care has remained elusive. In
      an analysis of data from the NCT 00104611 multi-site, randomized, sham-controlled trial of
      TMS, it was found that a larger number of prior treatment failures, longer duration of the
      current episode, and the presence of comorbid anxiety were individual patient characteristics
      associated with poorer acute outcomes with TMS treatment in the randomized period (Lisanby et
      al., in press). This publication did not report standard predictor metrics (e.g.,
      sensitivity, specificity, positive- or negative-predictive accuracy, ROC curves), so it is
      difficult to assess the value of these clinical factors in treatment planning for individual
      patients. A predictor that could distinguish between individuals likely to remit with TMS
      versus those likely to need a different intervention would be of great use to clinicians and
      patients in making treatment decisions.

      Our prior work (Cook et al., 2001, 2002, 2005; Leuchter et al. 2002) has studied a new
      physiologic biomarker of response to SSRI and mixed-action antidepressants. The EEG-based
      cordance biomarker can detect the physiologic effects of successful antidepressant treatment
      at 48 hours, 1 week, and 2 weeks of treatment; in contrast, symptom differences between
      responders and non-responders did not separate until 4 weeks of treatment in our
      placebo-controlled trials. Additionally, the magnitude of early physiologic change was
      associated with the completeness of clinical response. Our biomarker has been independently
      studied and our findings replicated (Kopecek et al., 2006; Bareš et al., 2007, 2008). The
      cordance biomarker can be considered as a leading indicator or predictor of treatment
      outcome. As a non-invasive probe of brain physiology, it may detect early neurophysiologic
      changes associated with accelerated clinical response from TMS.

      More recent work with a related EEG-based measure, the Antidepressant Treatment Response
      Index (ATR) has led to a simplified monitoring system; a physician can record
      clinically-useful data from a 15-minute in-office procedure with electrodes located on the
      forehead and ears (Leuchter et al., in submission). The ATR uses physiologic data collected
      prior to treatment and after one week of exposure, and was shown to be predictive of outcome
      with antidepressant medication. We are able to assess both cordance and ATR measures with EEG
      measurements made prior to treatment and after 5 treatment sessions with TMS to evaluate the
      predictive properties of both metrics.

      On a related issue, some of the variation in outcome may be related to treatment factors.
      Quantitative models and direct in vivo measurements (Wagner et al, 2004, 2008) indicate that
      the electrical currents induced by TMS are predominantly confined to a brain region directly
      under the treatment coil. The procedure for positioning the coil over the cortical target is
      described in the NeuroStar TMS System User Manual (volume 2, sections 6 and 7) and involves
      first determining a location where stimulation leads to a contraction of the abductor policis
      brevis muscle (visualized with a thumb twitch on the right hand) and then positioning the
      coil 5.5 cm anterior to that position along the left Superior Oblique Angle line. While this
      target can be located with good reproducibility and was associated with therapeutic outcome
      in the NCT trial, it is not clear that this positions the coil over the best target within
      the DLPFC for all patients. Indeed, individual differences in gyral anatomy and in gross
      brain size both add variability to the specific neuroanatomic region being stimulated, and
      this may impact treatment efficiency.

      Exposure to even a brief train of TMS pulses can elicit an acute physiologic change (cf
      Siebner and Rothwell, 2003), and so a test procedure can be performed that will assess the
      distance from the standard treatment position to the point eliciting a maximal acute
      physiologic response. We propose a 9-locus mapping procedure, involving the assessment of
      changes in brain activity from stimulation at locations including and around the standard
      treatment target. The nine locations will be the usual treatment location and 8 other points,
      1.5 and 3.0 cm anterior, posterior, rostral, and caudal of the primary target. Test
      stimulation will be for 15 seconds (=150 pulses @ 10 Hz) at each location, followed by 5
      minutes of continuous EEG recording to examine acute changes in regional brain activity in
      response to a brief stimulation exposure. All therapeutic stimulations will take place in the
      standard location, and we will be able to evaluate what proportion of variance in clinical
      outcome is explained by distance from the location of maximal acute physiologic response.

      Based on these previous studies, we propose to assess patients during treatment with TMS,
      using clinical symptom ratings and brain physiology with EEG.
    

Intervention name(s): Transcranial Magnetic Stimulation
Intervention type(s): Device
Intervention description(s): Neurophysiologic Predictors of Outcome with rTMS Treatment of Major Depressive Disorder
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: depression; major depressive disorder; transcranial magnetic stimulation; TMS; EEG; electroencephalography; Major Depression,