Combined Levothyroxine and Transcranial Magnetic Stimulation Safe in Bipolar Disorder

Combination levothyroxine and repetitive transcranial magnetic stimulation therapy can lead to prolonged remission and requires less medication compared with existing treatment.

Rapid-cycling bipolar spectrum disorder (BSD) treated with a combined protocol of high-dose levothyroxine (HDT) and repetitive transcranial magnetic stimulation (rTMS) may result in long remissions and improved quality of life, according to study findings published recently in Journal of Clinical Medicine.

Researchers conducted a real-world cohort study that included 55 symptomatic patients (56% women; mean age, 37.3 years; range 18-69 years) with rapid-cycling BSD from a private outpatient facility in the United Kingdom. There were 40 patients with at least 1 additional diagnosis, with the most common diagnoses being posttraumatic stress disorder and attention-deficit/hyperactivity disorder. The study participants (mean age at onset, 21.5 years; range 7-44 years) were treated for rapid-cycling symptoms with predominant severe depressive, hypomanic, mixed, and depressive cycles.

Participants were given a choice to either start treatment with  levothyroxine or rTMS, or start both simultaneously. Patients were asked to discontinue use of any substance affecting mitochondrial function (ie, caffeine and alcohol).

Participants were evaluated at 3 month intervals following acute treatment with data collection lasting from March 2021 to September 2021. The researchers noted that 32 patients required only levothyroxine, but that 1.8 was the average number of medications prescribed per patient.

[T]he combination of HDT and rTMS is safe, acceptable, and well tolerated by patients.

All patients started levothyroxine at 50 mcg and increased by 50 mcg every 4 days up to 150 mcg. The average levothyroxine dose was 303.7 mcg (median, 300 mcg; range, 50-600 mcg), with 53 patients in remission (average duration, 2.0 years). The mean duration for patients to reach remission was 42.6 weeks (median, 10.5 weeks; range 1-737 weeks). Among the 55 participants, 2 never reached remission and 5 patients relapsed following remission.

Researchers reported the average levothyroxine dose at each patient’s most recent review was 423.2 mcg (median, 400 mcg; range, 50-1000 mcg). All patients were treated with rTMS right-sided low-frequency (1 HZ) stimulation for 1 week followed by high-frequency right side (20 HZ) stimulation. If anxiety was prominent, low-frequency stimulation was extended beyond the first week.

Sheehan Disability Scale scores decreased significantly from 7.33 at the start of treatment to 1.27 (median, 0.3; range, 0.0-8.6) at the time of review (Cohen d=2.61; 95% CI, 1.81-2.83; P <.001). It was noted that 1 patient had reversible side effects. No other side effects were reported. A total of 52 patients had Deiodinase 1 and 2 or SLCO1C1 protein carrier gene mutations.

There was a nonsignificant increase in T3 thyroid hormone levels and a significant increase at the review time point. Levels of T4 increased significantly across all measurement times. There was also a significant early increase in the T4/T3 ratio, which then decreased significantly at review to a similar baseline ratio.

Limitations of the study include the real-world cohort study design, lack of consistent treatment parameters, lack of control group, and lack of randomization.

Study authors concluded, “[T]he combination of HDT and rTMS is safe, acceptable, and well tolerated by patients. The combination leads to a prolonged period of remission and requires less medication as opposed to existing treatment, hence reducing the risk of interactions and side effects.”

Disclosure: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Zamar AC, Kouimtsidis C, Lulsegged A, Roberts R, Koutsomitros T, Stahl D. A new treatment protocol of combined high-dose levothyroxine and repetitive transcranial magnetic stimulation for the treatment of rapid-cycling bipolar spectrum disorders: a cohort evaluation of 55 patients. J Clin Med. September 30, 2022;11(19):5830. doi:10.3390/jcm11195830