Background: Bipolar spectrum disorders (BSD) are highly disabling, with rapid cycling being treatment resistant. High-dose levothyroxine (HDT) has been reported to be effective. Diagnosis is associated with mutations in thyroid-activating enzymes and cerebral transporter protein carrier. Repetitive transcranial magnetic stimulation (rTMS) has neuroplastic effects. Methods: We report data on 55 severely symptomatic patients with rapid-cycling BSD treated with a combination protocol of HDT and rTMS. Of the patients, 31 patients (56.4%) were female and 40 (72.7%) had at least one additional diagnosis. Results: Patients were evaluated at three monthly intervals after acute treatment. Remission was measured using the Sheehan Disability Scale (SDS). The average number of medications prescribed was 1.8, with 32 patients (58.2%) needing only levothyroxine. The average dose of levothyroxine was 303.7 mcg (50 mcg–1000 mcg). A total of 53 patients were in remission (96.4%), with an average duration of 2.0 years. The SDS scores decreased significantly (Cohen’s d = 2.61 (95% C.I. 1.81 to 2.83, p < 0.001). One patient had reversible side effects. A total of 52 (94.3%) patients had Deiodinase 1 and 2 (DiO1/DiO2) or SLCO1C1 protein carrier gene mutations. Conclusion: The data support the safety and acceptability of combined HDT/rTMS. Patients achieved long remissions with substantial improvements in quality of life.

Bipolar spectrum disorder seems to be challenging to diagnose, particularly unspecified or subthreshold types. The delay in diagnosis in the UK for bipolar I and II types is a staggering 10–13 years, with only 15% correctly diagnosed without delay. In the USA, the delay is 6–8 years, and there is a 60% incorrect diagnosis rate. The HCL-32 questionnaire is adequate, but not sufficient by itself, and patients may find it difficult to complete, particularly if they are unwell. We have investigated a biomarker test which can be used in day-to-day clinical practice to assist diagnosis. We evaluated 199 patients diagnosed with ICD-10 bipolar I, II, and unspecified disorders, using the HCL-32 questionnaire with a cut-off point of 14 and above, supplemented by history taking and examination using the principles of the CIDI 3, interviews of relatives, and longitudinal mood charts where available. The results were compared to the general population and a sample of patients diagnosed with recurrent depression for assessment of sensitivity and specificity. We evaluated four mutations of SLCO1C1, DiO1, and two DiO2alleles as potential biomarkers for bipolar spectrum disorder, and identified three mutations that exhibited high sensitivity, with rates of up to 87% and specificity of up to 46% in distinguishing bipolar spectrum disorders from recurrent depressive disorder. Additionally, mutations in SLCO1C1 and DiO1 exhibited a sensitivity of up to 86% and a specificity of up to 60% in detecting bipolar spectrum disorder compared to the general population within a clinical setting. These biomarkers have the potential to be used as a diagnostic test that is not open to subjective interpretation and can be administered even if patients are very unwell, requiring, though, the patient’s consent. Further studies confirming these results are needed to compare the validity of using individual or a best combination of single nucleotide polymorphisms to identify bipolar spectrum disorders, particularly subthreshold presentations, and to differentiate them from other mood disorders such as major depression and recurrent depressive disorder.