Bipolar spectrum disorder includes Bipolar I, Bipolar II and subthreshold bipolar disorders (BD). The condition is highly prevalent, disabling and associated with high mortality. Failure of diagnosis is high. Subthreshold presentations present as 4 or more changes in polarity, are generally less responsive to standard treatment and as a result, drug combinations are often needed. High Dose Levothyroxine (HDT) has been reported to be safe and effective with this condition. Treatment response has been associated with mutations in thyroid activating enzymes and intra cerebral transporter protein carrier. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to be effective in bipolar depression and has been proved to have neuroplastic effect. Present authors had reported clinical evidence of safe and effective use of a combination treatment protocol. Potential mechanisms of action of the combined treatment protocol and the role of mitochondria function are discussed.

Aim: To report the clinical outcomes of 62 treatment-resistant depressed patients treated with repetitive transcranial magnetic stimulation (rTMS) in the first rTMS clinic in the UK during 2013. Materials & methods: Sixty-two treatment-resistant depressed patients (12 of them bipolar) referred to an rTMS Clinic in London during 2013 completed self-report Beck Depression (BDI-II) and Anxiety Inventories (BAI) at baseline and at the end of their treatment course. Results: Sixty-six percent reached remission, as defined by a score of 12 or below in the BDI-II at the end of the treatment course. Length of illness did not affect the likelihood of recovery. The treatment was generally well tolerated. Conclusions: rTMS appears to be a safe and effective intervention for ‘real world’ treatment-resistant patients.

Bipolar Disorder (BD) is a common psychiatric condition. There is an overall agreement across treatment guidelines of BD type I and BD type II however, there is far less certainty regarding the treatment of subthreshold presentations including Rapid Cycling Bipolar Disorder. We present a patient with treatment-resistant rapid cycling Bipolar Disorder type I who deteriorated on Ketamine treatment but reached full remission with repetitive Transcranial magnetic stimulation, High Dose Levothyroxine, Lurasidone and Lithium Carbonate. This case highlights the previously demonstrated safety and effectiveness of the combined protocol of High Dose Levothyroxine and Transcranial Magnetic Stimulation for this population.

Introduction Rapid cycling Bipolar disorder and mixed affective states are treatment resistant conditions. Standard treatments are ineffective. Homozygous polymorphism of DIO2 gene is associated 3.75-fold risk of bipolar disorder. Objectives High Dose Levothyroxine combined with repetitive transcranial magnetic stimulation (rTMS) in Rapid cycling Bipolar disorder: Is it thyroid disease? Methods 20 RCBPD with ICD-10criteria for bipolar disorder. All were severely symptomatic. TFTs and ECGs were monitored weekly with cardiology and endocrinology backup. Genetic testing was undertaken for DiO1/DiO2 status. Results 17 were female, average age 32.4 yrs. 19/20 had Single nucleotide polymorphisms (SNP) of either DIO1, DIO2 or both. All but two patients were treated with rTMS to induce cerebral neuroplasticity. Average pre-treatment fT4 was 17.0 pmol/L , and fT3 4.5 pmol/L Average post-treatment, fT4 was 59.7 pmol/L and fT3 5.3 pmol/L. Average fT4:fT3 ratio pre-treatment was 4:1, and post-treatment was 5:1. HDL range was 200-800 mcg daily for remission. Average dose 472 mcg daily. Discontinuation rate was 0%. All patients had ECG and cardiac review One patient required a dose reduction because of minimal side effects 12 patients needed one mood stabiliser All were in remission for a minimum of 6 months. Conclusions We speculate that BPD may be a form of cerebral hypothyroidism and that HDL helps to overcome the deficit while robust inactivating deiodinases in the periphery protect from systemic thyrotoxicosis. This is evidenced by findings of normal clinical examination and elevated rT3. rTMS exercises its well established neuroplastic effect, helping to achieve and maintain remission as an adjunct to HDL. Disclosure The London Psychiatry Centre (TLPC) has pending patents for the combined protocol of rTMS and/or Thyroid hormones depending on the territory: - Pending US Patent application: (and/or) US20200384279 - Pending European patent appl

A 23-year-old woman with a family history of rapid cycling bipolar disorder presented with fatigue, over-eating, oversleeping , low mood & passive suicidal ideation, alternating with mixed affective episodes, namely, depression with flight of ideas complicated by agitation, irritability and anger. She also exhibited phases of hypomania (increased energy associated with marked feelings of well-being and happiness). She was taking high dose Citalopram which is contraindicated. Beck Depression Inventory Score was 38 in keeping with severe depression, Beck anxiety inventory 20 and HCL-32 questionnaire was 29 in keeping with an 80% probability of bipolar depression. A diagnosis of rapid cycling bipolar disorder (RCBPD) was made. Case Report 2 A 53-year-old woman presented with a mixed affective state characterised by profound depression and flight of ideas such as relentless racing thoughts, agitation, distress, hopelessness and intense suicidal thoughts. She was diagnosed with ADHD and bipolar disorder with the latter being poorly treated. Her mood deteriorated substantially following a trip to Australia. Quetiapine was started, and the dose escalated to 700mg daily which partially helped her mood. Levothyroxine 50mcg once daily was commenced and the dose slowly escalated to 400mcg once daily and her mood stabilised. ECG showed sinus rhythm, rate 63bpm.