Electroconvulsive therapy (ECT) has demonstrated 80% to 90% efficacy in patients with major depressive disorder (MDD), an illness that is often refractory to medication.1 ECT is favored among clinicians whose patients are psychotic, suicidal, or have failed on medication.1

Why Researchers Measure BDNF

To determine who would most benefit from ECT, researchers have turned to biomarkers for objective measurement.1 Brain-derived neurotrophic factor (BDNF) is part of the neurotrophin group that influences much of the central nervous system, particularly in the cerebral cortex and hippocampus.1 Because BDNF stimulates and develops new neurons, it is considered a surrogate marker for MDD.1 In previous studies, patients with MDD treated with antidepressants showed a rise in serum BDNF levels.2

Sorri and colleagues sought to associate serum and plasma BDNF levels with improvement in patients with MDD treated with ECT.1 Thirty patients (mean age, 57.1 years; 40% women) had their serum and plasma BDNF levels tested at baseline, as well as after their first, fifth, and final (sixth) ECT sessions. Although the plasma BDNF levels fluctuated during the ECT sessions, neither plasma nor serum BDNF levels correlated with depression remission, as measured by the Montgomery-Asberg Depression Rating Scale.1 Moreover, the plasma and serum BDNF levels were inconsistent with each other.1

To predict whether the biomarker could effectively measure improvement after ECT, Mikoteit and colleagues examined BDNF levels after ECT in a 6-week study.3 The 25 patients with MDD (mean age, 43.7 years; 32% women) were treated with duloxetine and ECT. Their MDD was measured by the Hamilton Depression Rating Scale (HDRS) and the serum BDNF levels at baseline and 1, 2, and 6 weeks after treatment.3

Response to treatment was defined as ≥50% reduction from baseline in the HDRS score, and remission as an HDRS score of <8.3 Although the baseline measures of low serum BDNF correlated with low HDRS scores, the BDNF levels were not predictive of ECT outcomes.3

“As there is a latency of at least 2 weeks until an antidepressant starts to work, and treatment response can be evaluated not earlier than after 4 weeks of treatment, this costs a lot of time, suffering, and money,” explained Thorsten Mikoteit, MD, associate professor of psychiatry and psychotherapy at the University of Basel, Switzerland. “There is a demand for a more sophisticated, more precise, and personalized choice of an antidepressant to shorten time of acute treatment and time to improvement. To find the right drug for the individual patient, we need objective markers beyond unreliable clinical symptom observation to predict treatment outcome.”

Even Positive ECT Results Do Not Parallel BDNF Levels

In a study in 21 patients with treatment-resistant depression (mean age, 63.5 years; 91% women), Rapinesi and colleagues discovered that effective ECT does not necessarily change serum BDNF levels.4 Although ECT significantly reduced depression, as measured by the HDRS, the Brief Psychiatric Rating Scale, and the Clinical Global Impressions scale, serum BDNF did not change. Patients with treatment-resistant depression had low serum BDNF levels at baseline and after ECT.4

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Although ECT has demonstrated its effectiveness, it does face stigma among clinicians and the public alike. “We were unable to test possible attitude modifications as to clinical practice related to either ECT, which is practically banned from Italy, nor clinicians’ attitudes, both as related to endorsing ECT for a given MDD patient, nor for prescribing serum BDNF level assays,” explained Georgios D. Kotzalidis, MD, from the neurosciences, mental health, and sensory organs department at Sapienza University of Rome School of Medicine and Psychology in Italy. “The fact that ECT is either no longer available or its use became extremely difficult to enforce in public facilities (for example, none in Rome, our workplace), and has been rendered inconvenient even for private practices, makes it unlikely that we will ever be able to test the genetic underpinnings of ECT response.”

A year later, a 9-study meta-analysis (N=207 patients with MDD) by Rocha and colleagues demonstrated the utility of using serum or plasma BDNF levels to measure ECT efficacy.5 In 7 of the 9 studies, BDNF levels increased after ECT treatment. The sustained effects, however, resulted in low response rates.5

“Although our study points to a potential role of BDNF as a marker of treatment response in patients with MDD after ECT, we must be careful with this interpretation,” said Maria Inês da Rosa, MD, from the Universidade do Extremo Sul Catarinense, Criciúma, Brazil. “Indeed, given the wide range of pathologies in which ECT presents itself as an effective tool, probably there is not a single mechanism of action involved, but rather several concurrent phenomena.”

BDNF Does Not Correlate With MDD Severity

To determine whether BDNF can be a surrogate for depression, Ryan and colleagues measured plasma BDNF levels in medicated patients with MDD (n=61) and healthy control patients (n=50).6 Plasma BDNF levels were measured at baseline and after treatment with ECT. The researchers found not only no association between depression severity and BDNF levels, but also no correlation between plasma BDNF levels and response to ECT.6

“To date, most studies looking at either serum or plasma BDNF have not found any clinically relevant correlations, so the practical clinical take-home message is that peripheral blood levels of BDNF are not useful as a biomarker for clinical practice,” said Declan M. McLoughlin, PhD, MRCPI, MRCPsych, professor of psychiatry at Trinity College Dublin, Ireland. “Despite much effort, there are no blood-based molecular biomarkers of sufficient sensitivity and specificity to be useful for clinical practice. This most likely reflects the complexity of depression, its heterogeneous nature, and the difficulties of identifying peripheral blood changes that reflect what is going on within the brain.”

Summary & Clinical Applicability

Predicting outcomes of ECT for major depressive disorder using biomarkers is still a work in progress. Despite ECT’s stigma among clinicians and patients, it has yielded positive results in patients refractory to antidepressant therapy.

Limitations & Disclosures

None.

References

  1. Sorri A, Järventausta K, Kampman O, et al. Effect of electroconvulsive therapy on brain-derived neurotrophic factor levels in patients with major depressive disorder [published online October 1, 2018]. Brain Behav. doi: 10.1002/brb3.1101
  2. Molendijk ML, Spinhoven P, Polak M, Bus BA, Penninx BW, Elzinga BM. Serum BDNF concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N=9484).Mol Psychiatry. 2014;19(7):791-800.
  3. Mikoteit T, Beck J, Eckert A, et al. High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression. Psychopharmacology (Berl). 2014;231(15):2955-2965.
  4. Rapinesi C, Kotzalidis GD, Curto M, et al. Electroconvulsive therapy improves clinical manifestations of treatment-resistant depression without changing serum BDNF levels. Psychiatry Res. 2015;227(2-3):171-178.
  5. Rocha RB, Dondossola ER, Grande AJ, et al. Increased BDNF levels after electroconvulsive therapy in patients with major depressive disorder: a meta-analysis study. J Psychiatr Res. 2016;83:47-53.
  6. Ryan KM, Dunne R, McLoughlin DM. BDNF plasma levels and genotype in depression and the response to electroconvulsive therapy. Brain Stimul. 2018;11(5):1123-1131.