Background

The clinical efficacy of repetitive transcranial magnetic stimulation (rTMS) in treatment resistant patients (at least 4 medication trials) appears to be well accepted and forms the coverage policies and rTMS's use in many of the largest US payers. However, less is known about rTMS's use in patients who have undergone ≤1 failed medication trial. The purpose of this analysis was to determine the clinical efficacy of rTMS in patients after ≤1 medication trials.

Methods

A systematic review of the literature was undertaken to identify all articles which addressed the use of rTMS in ≤1 medication trial. All types of study designs were included and assessed for quality and strength of evidence using: GRADE and CEBM. Searches of peer reviewed articles were undertaken for the year 2000 to the present. All languages were considered. Electronic databases were searched and included: PubMed and EBSCO. Evidence assessment websites were also searched and included: Cochrane, NICE, AHRQ, and ICER. Additionally, the clinical guidelines for specialty societies which use rTMS was searched. Hand searches of the reference sections of identified articles was also undertaken.

Results

Electronic and other sources identified 165 after duplicates were removed. Twenty two articles were assessed for eligibility and ultimately 10 articles were included in the systematic review and graded. Six articles were graded high quality (CEBM/GRADE: 1c/B) demonstrating that the use of rTMS was clinically efficacious in patients after ≤1 medication trial. Four additional trials demonstrated a positive effect of rTMS in patients after ≤1 medication trial but were of a lower quality.

Conclusion

The use of rTMS in patients after ≤1 medication trial should be considered. US payers should consider revising their coverage policies to include the use of rTMS in these patients.

Major depressive disorder is among the most disabling illnesses and, despite best practices with medication and psychotherapy, many patients remain ill even after several treatment trials. For many of these patients with treatment-resistant or pharmacoresistant depression, treatment with neuromodulation offers an alternative. Options range from systems that are implanted to others that are entirely noninvasive. This review surveys recent literature to update readers on 3 particular interventions: deep brain stimulation, transcranial magnetic stimulation, and trigeminal nerve stimulation. Additional comparative research is needed to delineate the relative advantages of these treatments, and how best to match individual patients to neuromodulation intervention.

Management of Major Depressive Disorder (MDD) might be improved by a biomarker to predict whether a selected medication is likely to lead to remission. We previously reported on a quantitative electroencephalogram-based biomarker, the Antidepressant Treatment Response (ATR) index, that integrated recordings at baseline and after one week of treatment. The present study prospectively tested whether treatment directed by the biomarker increased the likelihood of remission; we hypothesized that continued treatment with a drug predicted to lead to remission (i.e., high ATR values) would be associated with better outcomes than if the drug was predicted not to lead to remission (i.e., low ATR values). We enrolled 180 adult outpatients with unipolar MDD from the community. After one week of escitalopram treatment to determine the biomarker, stratified randomization (high vs. low ATR) was used to assign subjects to either continued escitalopram or a switch to bupropion as a blinded control condition, for seven additional weeks. For the 73 evaluable subjects assigned to continued escitalopram treatment, the remission rate was significantly higher for those in whom ATR had predicted remission versus non-remission (60.4% vs. 30.0%, respectively, p = 0.01). Accuracy was enhanced by combining 1-week depressive symptom change with ATR (68.6% vs 28.9%). This prospective validation study supports further development of the ATR biomarker, alone or together with early symptom change, to improve care by identifying individuals unlikely to remit with their current treatment, and support the decision to change treatment after one week rather than after failing a full, prolonged course of medication.

Objective

This study aimed to investigate the effect of brief reminder-focused positive psychiatry and suicide prevention (RFPP-S) on suicidal ideation, posttraumatic stress disorder (PTSD) symptoms, and clinical outcomes among youths with PTSD treated in psychiatric emergency rooms.

Methods

This study included youths with PTSD and suicidality who received either RFPP-S (N=50) or treatment as usual (N=150). The Columbia Suicide Severity Rating Scale (C-SSRS), Clinician-Administered PTSD Scale for children and adolescents, University of California, Los Angeles Trauma Reminder Inventory, Patient Health Questionnaire-9, Positive Emotion, Engagement, Relationships, Meaning, and Accomplishment Scale, and positive psychiatry test batteries were administered at baseline, on day 2, and 1 week and 1 month after discharge.

Results

On day 2, the RFPP-S group showed a greater reduction in PTSD symptoms (55%) and reactivity to trauma and loss reminders (80%) compared with the control group (10% for both) (p=0.001). A significantly greater reduction in C-SSRS score for RFPP-S (80%), compared with treatment as usual (15%), was noted (p=0.001), and RFPP-S showed more rapid stabilization (mean±SD=2.0±0.5 days) and enhanced postdischarge follow-up (100%) compared with treatment as usual (5.0±2.0 days and 50%, respectively) (p<0.05). RFPP-S, but not treatment as usual, was associated with significant increases in well-being, flexible thinking, and coping skills (p<0.05). Hospital readmission due to suicidality 1 month after discharge was 0% for the RFPP-S group and 20% for the control group.

Conclusions

RFPP-S was associated with reduced PTSD symptoms, enhanced coping skills while experiencing trauma reminders, adoption of safety skills, rapid stabilization of acute crises of PTSD with suicidality, adherence to post-emergency room visits and treatment, and favorable clinical outcomes.

Objective

Repetitive Transcranial Magnetic Stimulation (rTMS) commonly is used for the treatment of Major Depressive Disorder (MDD) after patients have failed to benefit from trials of multiple antidepressant medications. No analysis to date has examined the cost-effectiveness of rTMS used earlier in the course of treatment and over a patients' lifetime.

Methods

We used lifetime Markov simulation modeling to compare the direct costs and quality adjusted life years (QALYs) of rTMS and medication therapy in patients with newly diagnosed MDD (ages 20-59) who had failed to benefit from one pharmacotherapy trial. Patients' life expectancies, rates of response and remission, and quality of life outcomes were derived from the literature, and treatment costs were based upon published Medicare reimbursement data. Baseline costs, aggregate per year quality of life assessments (QALYs), Monte Carlo simulation, tornado analysis, assessment of dominance, and one way sensitivity analysis were also performed. The discount rate applied was 3%.

Results

Lifetime direct treatment costs, and QALYs identified rTMS as the dominant therapy compared to antidepressant medications (i.e., lower costs with better outcomes) in all age ranges, with costs/improved QALYs ranging from $2,952/0.32 (older patients) to $11,140/0.43 (younger patients). One-way sensitivity analysis demonstrated that the model was most sensitive to the input variables of cost per rTMS session, monthly prescription drug cost, and the number of rTMS sessions per year.

Conclusion

rTMS was identified as the dominant therapy compared to antidepressant medication trials over the life of the patient across the lifespan of adults with MDD, given current costs of treatment. These models support the use of rTMS after a single failed antidepressant medication trial versus further attempts at medication treatment in adults with MDD.

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. Pilot data addressed these hypotheses in healthy never-depressed women who had previously received four weeks of venlafaxine IR, 150 mg (antidepressant-experienced subjects; n=2) or matching placebo (antidepressant-naive subjects; n=4) under double-blind conditions. Six-and-a-half years later, we treated these six women with placebo for one week, followed by four weeks of double-blind treatment with venlafaxine IR, 150 mg. Brain functional changes over the course of treatment were assessed using quantitative electroencephalography (qEEG) to compare prefrontal neurophysiologic responses between subjects who had, versus had not, previously been exposed to venlafaxine. Antidepressant-experienced versus antidepressant-naive subjects showed greater decreases in prefrontal cordance (PFC) during venlafaxine administration (sensitization hypothesis) but did not show significantly different PFC changes during treatment with placebo in this small pilot sample (classical conditioning hypothesis). Data suggest that brief treatment with antidepressant medication may have an enduring impact on neurophysiologic responses to a subsequent course of antidepressant treatment. Hypotheses should be tested in larger samples.

Background

Pill-taking, expectations and therapeutic alliance may account for much of the benefit of medication and placebo treatment for major depressive disorder (MDD). Aims To examine the effects of medication, placebo and supportive care on treatment outcome, and the relationships of expectations and therapeutic alliance to improvement.

Method

A total of 88 participants were randomised to 8 weeks of treatment with supportive care alone or combined with double-blind treatment with placebo or antidepressant medication. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were measured (trial registration at ClinicalTrials.gov: NCT00200902).

Results

Medication or placebo plus supportive care were not significantly different but had significantly better outcome than supportive care alone. Therapeutic alliance predicted response to medication and placebo; expectations of medication effectiveness at enrolment predicted only placebo response.

Conclusions

Pill treatment yielded better outcome than supportive care alone. Medication expectations uniquely predicted placebo treatment outcome and were formed by time of enrolment, suggesting that they were shaped by prior experiences outside the clinical trial.