Transcranial Pulsed Electromagnetic Fields (T-PEMF) for Difficult-to-Treat Bipolar Depression: Treatment Outcomes, Safety, and Tolerability from a Naturalistic Cohort
DOI: Pending DOI
Synopsis
Transcranial pulsed electromagnetic fields (T-PEMF) is a low-intensity TMS technology with promising effects in treatment-resistant unipolar depression, but evidence in bipolar depression remains limited. We conducted a naturalistic cohort study of fifteen patients with difficult-to-treat bipolar depression receiving adjunctive, self-administered T-PEMF (30 min/day for 8 weeks). Depressive symptoms improved significantly (HDRS-17: 21.1 to 15.5; p=0.025). Response and remission rates were 20%. WHO-5 Well-Being Index scores increased significantly (14 to 32; p=0.015). Treatment was generally well tolerated with high adherence and only mild adverse effects, though one patient developed hypomanic/manic symptoms. These findings support further evaluation in randomized controlled trials.
Background
Low-field magnetic stimulation has shown promising results in depression(1). One such modality is transcranial pulsed electromagnetic fields (T-PEMF). A widely used system, the Re5-NTS (Neuro Treatment System), delivers subthreshold magnetic pulses at 50 Hz via seven scalp-mounted coils, producing diffuse, multifocal stimulation(2). The device is suitable for self-administration and is approved for treatment of major depressive disorder in adults under the EU Medical Device Regulation (EU MDR 2017/745).
T-PEMF has been incorporated into treatment algorithms at several psychiatric centers in Denmark. Evidence from randomized, sham-controlled trial(3) and cohort studies(4–7) demonstrates clinically meaningful response and remission rates, high adherence, and a favorable safety profile in patients with treatment-resistant unipolar depression.
However, evidence for T-PEMF in bipolar depression remains limited, despite the fact that up to one-third of patients do not respond to medications(8), underscoring the need to expand current therapeutic strategies with novel interventions(9). We therefore investigated the treatment outcomes, tolerability, and safety of adjunctive T-PEMF in a real-world cohort of patients with difficult-to-treat bipolar depression.
Methods
We included fifteen patients initiating a first self-administered 8-week course of adjunctive T-PEMF (30 min/day) between July 2020 and June 2025 at the Research and Treatment Program for Bipolar Disorder at Aalborg University Hospital, Denmark. All met ICD-10 criteria for bipolar affective disorder with a current depressive episode without psychotic features (F31.3 and F31.4). Data collection was conducted in accordance with the Danish Health Act and approved by hospital management (North Denmark Region registry K2025-021); individual patient consent and separate ethical approval were not required.
T-PEMF was delivered using the Re5-NTS device, applying 4.5 ms biphasic pulses at 50 Hz via seven scalp-mounted coils (temporal, parietal, occipital regions; peak electric field 0.18 V/m, magnetic field 5.5 mT)(10). Treatment was self-administered by patients at home.
Baseline demographic and clinical data, including bipolar disorder subtype, illness duration, current episode duration, comorbidities and medication, were extracted retrospectively from medical records. Psychometric assessments were conducted at baseline and endpoint (typically 8 weeks). Data were managed using web-based Research Electronic Data Capture (REDCap) software.
The primary outcome was change in Hamilton Depression Rating Scale17-items (HDRS-17) score; secondary outcomes were response (≥50% reduction) and remission (≤7) rates. WHO-5 Well-Being Index (WHO-5) scores was assessed exploratorily.
Descriptive statistics summarized baseline and outcome measures. Continuous variables are presented as mean (SD) or median (IQR), and categorical variables as n (%). Statistical significance was set at p≤0.05.
Results
Fifteen patients were included (6 male (40%); mean age 52 years, SD 9.3), of whom 6 (40%) had bipolar I disorder, 8 (53%) bipolar II disorder and 1 (7%) bipolar disorder NOS. The median time since diagnosis was 5 years (IQR 3–11.5). Psychiatric comorbidity was present in four patients (borderline personality disorder, avoidant personality disorder, ADHD, PTSD), and 13 (87%) patients had at least one treatment-requiring somatic comorbidity. The cohort was highly treatment-resistant, with a median current episode duration of 27 months (IQR 11–33), a median of 5 prior treatment trials (IQR 3–6), and 6 (40%) having received ECT. Fourteen patients were receiving psychotropic medication during T-PEMF (11 (79%) receiving ≥2 drugs and 6 (43%) ≥3 drugs), most commonly lithium, lamotrigine, and quetiapine. Medication remained unchanged for at least 4 weeks prior to T-PEMF initiation and throughout the treatment period.
Twelve patients (80%) completed the 8-week protocol. One patient discontinued voluntarily, one due to emergent hypomanic/manic symptoms after 47 sessions, and one received an extended treatment course. T-PEMF was generally well tolerated, with only mild adverse effects reported (headache 27%, nausea 13%, fatigue 7%) and high adherence.
Depressive symptoms improved significantly. Mean HDRS-17 scores decreased from 21.1 (SD 3.1) at baseline to 15.5 (SD 7.2) at endpoint (p=0.025). WHO-5 scores increased significantly from a median of 14 (IQR 10–19.5) at baseline to 32 (IQR 12–40) at endpoint (p=0.015).
Three of 15 patients initiating T-PEMF (20%) achieved both response and remission on the HDRS-17, including one following extended treatment course. No significant differences were found between bipolar I and II subtypes for either response or remission.
Discussion
This study provides a descriptive evaluation of outcomes in a small, naturalistic cohort without a control group. Accordingly, causal inferences cannot be made, and it remains unclear to what extent the observed improvements are attributable to T-PEMF, concomitant pharmacological treatment, placebo effects, or the natural course of illness. The sample size was limited, reducing statistical power and generalizability, and the heterogeneity of the cohort, including comorbidities and concurrent medications, may have influenced outcomes.
The occurrence of hypomanic/manic symptoms in one patient highlights the need for careful monitoring in bipolar populations.
Despite these limitations, the study reflects real-world clinical practice and suggests that adjunctive T-PEMF is feasible and generally well tolerated in a difficult-to-treat bipolar depression population. These preliminary findings support the need for adequately powered, randomized controlled trials to more rigorously evaluate efficacy and safety.
Disclosures
REN has, within the past 3 years, been an investigator for Compass Pharmaceuticals and Boehringer-Ingelheim for clinical trials; has received speaking fees from Lundbeck, Teva Pharmaceuticals, Janssen-Cilag and Boehringer-Ingelheim.
All other authors declare no financial disclosures.
References
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