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.

In this open-label naturalistic study, we assess the feasibility, tolerability, and effectiveness of a repetitive transcranial magnetic stimulation protocol with a reduced total pulse number for treating patients suffering from bipolar disorder type II. All patients received one rTMS treatment session of 1000 pulses for 20 consecutive working days, accumulating to 20.000 rTMS pulses applied over 4 weeks. We measured the patients’ symptoms before the start, halfway through, directly after, and one month after treatment. We quantified the depression symptoms using both the Beck depression inventory scale and the symptom checklist-90 depression subscale. Patients showed a significant reduction in depression symptoms directly after treatment and an even further reduction one month after treatment. The remission rates were at 26% halfway through treatment (after the 10th session), 61% directly after treatment (after the 20th session), and increased to 78% at the 1-month follow-up. Importantly, the protocol proved to be feasible and highly tolerable in this patient population, with no adverse effects being reported. Considering these positive results, further research should focus on replicating these findings in larger clinical samples with control groups and longer follow-up periods, while potentially adding maintenance sessions to optimize the treatment effect and stability for bipolar disorder type II patients.

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.

Introduction: Subthreshold bipolar disorder (SBD), also referred to as unspecified bipolar disorder, is frequently encountered in patients with treatment-resistant depression. It presents with depressive and subthreshold manic and mixed symptoms. Sustained remission with full functional recovery is the aim of treatment in mood disorders as residual symptoms may cause disability, while relapse may be associated with increased morbidity or mortality. To date, evidence for achieving sustained remission in SBD is absent, with no studies reporting sustained remission outcomes. The only available evidence to remission is at level 2 in a previous study by the author employing combined high-dose levothyroxine (HDT) and repetitive transcranial magnetic stimulation (rTMS). The management of SBD during pregnancy is particularly challenging due to the absence of evidence-based guidance. Method: We describe a retrospective case series of three women with longstanding treatment-resistant depressive presentations with a threat to life, later conceptualized within the bipolar spectrum. All patients had achieved sustained remission before pregnancy using a treatment approach combining HDT with rTMS (the Zamar Protocol), with or without low-dose quetiapine. Following shared decision making and counseling regarding the extremely limited evidence base, treatment was continued during pregnancy due to concerns about the riskof relapse and risk to life. All three patients maintained clinical stability during pregnancy, the postpartum period, and beyond. Across the three cases, five pregnancies occurred while patients remained on HDT-based treatment, with adjunctive rTMS used during selected periods. No maternal, obstetric, neonatal, or early developmental adverse outcomes were reported during the available follow-up. In one case, clinical deterioration followed a dose reduction and improved after re-escalation. The consistent biochemical pattern of elevated FT4 relative to FT3 (low FT3/FT4 ratio) previously reported was observed across cases, which differed from typical thyrotoxic profiles. Variants in the deiodinase-related genes and the thyroid hormone transport pathways were identified, in keeping with previously published literature. Conclusion: This small retrospective case series suggests that continuation of HDT-based treatment, with or without adjunctive rTMS, may be a feasible option in carefully preselected patients with pre-pregnancy blood and genetic biomarkers and pre-pregnancy clinical response when presenting with severe life-threatening bipolar spectrum disorder presenting as treatment-resistant depression. These findings established safety and efficacy at a low level of evidence (level 4 CEBM) and highlight the need for more robust prospective research. Careful discussion with the patient and spouse exploring the risk–benefit ratio and any evidence-based available acceptable alternatives, particularly when there exists a risk to life, is necessary.