TREATMENT OF PSYCHIATRIC CONDITIONS SUCH AS RESISTANT DEPRESSION, BIPOLAR DISORDER AND/OR MAJOR DEPRESSIVE DISORDER VIA APPLICATION OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION WITH THYROID HORMONE TREATMENT AND/OR QUETIAPINE

Abstract

The present invention relates to treatment of a psychiatric condition, for example resistant depression (RD), bipolar disorder (either threshold or sub-threshold) and/or major depressive disorder via application of repetitive transcranial magnetic stimulation with a drug treatment, in particular application of repetitive transcranial magnetic stimulation with treatment to modulate the activity of the neurones and induce neuroplasticity and the use of Thyroid hormone treatment to increase quantity or activity of thyroid hormones, for example for treatment of thyroid dysfunction. Patients may be selected for treatment by testing for the presence of normal thyroid function.

Claims

1-27. (canceled)

28. A method for treating a psychiatric condition in a patient, the method comprising administering a medicament selected from at least one of thyroxine, levothyroxine, liothyronine and levothyroxine sodium to the patient and subjecting the patient to repetitive transcranial magnetic stimulation (rTMS).

29. The method according to claim 28, wherein the psychiatric condition is selected from the group consisting of resistant depression, threshold or subthreshold bipolar disorder, ADHD, and/or major depressive disorder.

30. The method according to claim 28, wherein the method further comprises administering a mood stabiliser or neuroleptic to the patient.

31. The method according to claim 28, wherein the method further comprises administering quetiapine to the patient.

32. The method according to claim 28, wherein the method comprises administering one of the following combinations of medicaments to the patient: a) thyroxine and liothyronine; or b) thyroxine and quetiapine; or c) liothyronine and quetiapine; or d) thyroxine and liothyronine and quetiapine.

33. The method according to claim 32, wherein the medicament comprises: a) at least 50 mcg of quetiapine; b) at least 50 mcg of thyroxine; c) at least 50 mcg of levothyroxine; d) at least 50 mcg thyroxine and at least 50 mcg of quetiapine; or e) at least 10 mcg of liothyronine

34. The method according to claim 28, wherein the method excludes administering antidepressants to the patient.

35. The method according to claim 28, wherein the rTMS is performed at the following concentrated regions of the scalp: a) substantially left dorsolateral prefrontal cortex (DLPFC) region, preferably if flatly depressed; or b) substantially right dorsolateral prefrontal cortex (DLPFC) region, preferably if agitated depressed, mixed, racy thoughts or rapid cycling.

36. The method according to claim 28, wherein the preferred electromagnetic frequency for rTMS is: a) below about 20.1 Hz; or b) above about 0.9 Hz.

37. The method according to claim 28, wherein: a) the left side of the brain is targeted with rTMS or iTBS when the patient is depressed; or b) the right side of the brain is targeted with rTMS or cTBS when the patient is diagnosed as having a mixed condition.

38. The method according to claim 28, wherein the rTMS is administered in alternate frequencies, a first electromagnetic frequency and a second electromagnetic frequency optionally wherein the first electromagnetic frequency is substantially 1 Hz and the second electromagnetic frequency is substantially 10 Hz.

39. A method for treating a psychiatric condition in a patient, wherein the psychiatric condition is selected from the group consisting of resistant depression, ADHD, and/or major depressive disorder, the method comprising administering quetiapine to the patient and subjecting the patient to repetitive transcranial magnetic stimulation (rTMS).

40. The method according to claim 39, wherein the method further comprises administering a mood stabiliser or neuroleptic to the patient.

41. The method according to claim 39, wherein the method further comprises administering a medicament for treating thyroid dysfunction to the patient.

42. The method according to claim 41, wherein the medicament for treating thyroid dysfunction is selected from the group consisting of thyroxine, levothyroxine, liothyronine and levothyroxine sodium.

Description

FIGURES

[0160] The above and other aspects of the present invention will now be described in further detail by way of example only, and with reference to the accompanying drawings, in which:

[0161] FIG. 1 is a flow chart illustrating exemplary embodiments of methods of the present invention that may be used for patient evaluation; and

[0162] FIG. 2 is a flow chart illustrating exemplary embodiments of methods of the present invention that may be used for an rTMS treatment protocol.

[0163] Referring to FIG. 1, a patient evaluation and analysis process 100 is provided. This relates to a psychiatric history examination. Preferably, the patient evaluation is performed to determine symptoms of a physiological and/or psychiatric condition, and even more preferably, to determine symptoms of resistant depression. The results from patient evaluation are typically analysed by a healthcare professional.

[0164] At step 102, evaluation, the patient performs a routine psychometric test. For example, a Beck Depression Inventory (BD1-II) and Beck Anxiety Inventory (BAI). At step 104, evaluation, the patient is then asked to complete a Hypomania Symptom Checklist (HCL-32) questionnaire. The tests and questionnaires provide background history about the patient. In some cases these tests and questionnaires may be performed in the clinic, or in further cases, the patient may have been expected to complete the tests and questionnaires before an appointment with a healthcare professional (i.e. offsite).

[0165] During first evaluation and analysis, 106, the patient is interviewed, to determine symptoms of resistant depression. The first patient evaluation 106 is further used to determine if a patient has: sub-threshold racing thoughts; and/or creativity; and/or successful careers; and/or academic performance; and/or being able to perform tasks effectively before or together with depression; and/or agitation; and/or anxiety; and/or bipolarity.

[0166] The evaluation process further comprises asking if he or she has experienced any one or more of the following:—

[0167] racing thoughts, bi-polarity; and/or insomnia; mixed states;

[0168] anxiety on previous or current anti-depressants; and/or

[0169] any sub-threshold signs of racing thoughts; and/or

[0170] any current and/or previous signs of creativity; and/or

[0171] any current and/or previous successful careers; and/or

[0172] any current and/or previous academic performance; and/or

[0173] being able to perform tasks effectively before or together with depression; and/or

[0174] agitation; and/or

[0175] racy thoughts; and/or

[0176] signs of productivity; and/or

[0177] can the patient multi-task?

[0178] A relative and/or an observer interview maybe performed with referencing towards family history. If during any one or more of this evaluation a positive outcome is from any one or more of the above, then at step 108, antidepressant treatment is discontinued and/or reduced and/or tapered gradually. The process then continues at step 118, proceeding thereon.

[0179] If the answer is no, then reference to HCL-32 at step 110 is made. At step 110, evaluation, with reference to the completed questionnaire at 104, the patient HCL-32 results are analysed to see if the store is greater than 14. If the results are greater than 14, then at step 112, anti-depressant treatment is discontinued, reduced or tapered gradually. The process then continues at step 118, proceeding thereon.

[0180] If the HCL-32 is less than 14, then at step 114 the patient is analysed, evaluated and interviewed further, at a second evaluation. Again, particular attention is paid to receiving a positive outcome in response to questions and/or analysis and/or evaluation. A positive outcome being received from sub-threshold racing thoughts; and/or creativity; and/or successful careers and/or academic performance; and/or being able to perform tasks effectively before or together with depression; and/or agitation; and/or anxiety; and/or 10 bipolarity.

[0181] In addition to the first evaluation steps asked at step 106, the second evaluation may also comprise any one or more of the following:—

[0182] a reference towards a patient prospective mood chart; and/or

[0183] a relative/observer interview; and/or

[0184] evaluation of patient family history; and/or

[0185] generally being jovial without exhibiting signs of bipolarity; and/or

[0186] investigating for a history of becoming anxious or agitated with exposure to antidepressants; and/or

[0187] a history of any signs of slight mood elevation whether sustained or episodic; and/or

[0188] investigating the level of the patient premorbid functioning being higher than normal; and/or

[0189] performing a blood test to exclude organic mood disorder; and/or

[0190] performing and analysing a baseline ECG; and/or

[0191] investigating a bipolar spectrum; and/or

[0192] investigating for the emergence of mixed states, including any one or more of: racing thoughts, and/or depression, and/or insomnia, and/or agitation; and/or

[0193] investigating for premorbid ICD-10 subthreshold hypomania; and/or

[0194] investigating for mild signs of cyclothymia; and/or

[0195] investigating for sub-threshold bipolarity

[0196] an ECG

[0197] a blood test

[0198] Furthermore, a high degree of suspicion maybe actioned towards the patient's condition. Patient evaluation may also comprise investigating the level of the patient premorbid functioning. Further patient evaluation may also comprise further interviewing of family, friends, close relatives or the like and/or with or without a high degree of suspicion. It should be noted any one or more of the following above evaluation steps may also occur at step 106.

[0199] If a positive outcome is received, then at step 116 anti-depressant treatment is discontinued, reduced or tapered gradually. The process then continues at step 118, proceeding thereon.

[0200] Prior to treatment, at step 118 the patient is instructed to discontinue any one or more of:—

[0201] methylated xanthines in beverages or medications; and/or

[0202] alcohol including alcoholic beverages; and/or

[0203] illicit drugs; and/or

[0204] stimulants of all kinds, including all energy drinks and/or sports drinks; and/or

[0205] any decaffeinated beverages; and/or

[0206] foodstuff marketed as energy boasting

[0207] It is understood that the definition of “illicit” may vary in definition by country to country. Illicit can mean “illegal”, “non-prescribed”, or “non-medically prescribed”. “Food stuff marketed as energy boasting” may include for example, boast bars, energy bars and/or tablets, and/or supplements that are taken in addition to a main meal.

Prior to treatment, patients undergo blood tests at step 120 to exclude organic mood disorder. Results are reviewed accordingly at step 122. Patients undergo a baseline ECG at step 210. Based on the results of the blood test and/or a baseline ECG, anti-depressant treatment may also be discontinued, reduced or tapered gradually. The method then proceeds from thereon.

[0208] Initial patient evaluation ends at step 124 after baseline ECG, and continues via connector A towards the treatment protocol in FIG. 2.

[0209] Referring to FIG. 2, at step 202, in accordance with prior first 106 and second 114 evaluation, the patient is evaluated to determine if they have experienced any one or more of the following:

[0210] agitation; and/or

[0211] racy thoughts; and/or

[0212] anxiety on anti-depressants; and/or

[0213] do they have a successfully career; and/or

[0214] academic performance;

[0215] being able to perform tasks effectively before or together with depression;

[0216] bipolarity;

[0217] are they productive; and/or

[0218] are they creative; and/or

[0219] can they multi-task

[0220] If a positive outcome is received, i.e. the answer is yes to any one or more of the above it is important that the agitation; and/or racy thoughts; and/or anxiety are suppressed. If the answer is no, i.e. a negative response is obtained, then step 210 begins.

[0221] In some cases, at step 204, quetiapine can be started and pitched at a minimum of 50 mg. Before administering quetiapine, at step 206, it is important to determine if the patient is intolerant or cannot accept. If this is the case, then quetiapine is withheld, and other neuroleptics and/or mood stabilisers may be considered instead of quetiapine.

[0222] Additionally, 50 mcg of thyroxine may be administered. 50 mcg of levothyroxine or levothyroxine sodium may also be administered. A combination may also be administered, for example at least 50 mcg thyroxine and at least 50 mg of quetiapine. Throughout the treatment process an increased dosage of thyroxine of about 50 mcg to 1000 mcg may occur. Other quantities quetiapine, levothyroxine or levothyroxine sodium may include 50 mcg to 400 mcg, 50-650 mcg, 100 mcg to 500 mcg, 250 mcg to 600 mcg, 100 mcg to 650 mcg, 50 mcg to 200 mcg, 400 mcg to 1000 mcg.

For example, when used in combination, from 25-800 mgs of quetiapine or according to blood levels to 50 mcg-1000 mcg of levothyroxine, or liothyronine 10 mcg-160 mcg.

[0223] 1 Hz (electromagnetic frequency) right-sided stimulation (inhibitory treatment) is used until the patient stabilises, wherein the preferred electromagnetic frequency is above about 0.9 Hz and wherein the preferred electromagnetic frequency is below about 20.1 Hz.

[0224] In some further cases, 1 Hz right-sided stimulation in combination with quetiapine may also be administered.

[0225] At step 208, the treatment is continued until agitation; and/or racy thoughts; and/or anxiety have calmed.

[0226] At step 210 the patient is asked if they still remain depressed.

[0227] If the answer is yes, then in some optional cases, at step 212, thyroxine treatment is initiated, which is initiated at 50 mcg, and kept at this level for a period of a week during the initial phases of rTMS treatment. In further cases, rTMS is administered without administering thyroxine at step 214.

[0228] At step 214, left-sided rTMS is performed, at an electromagnetic frequency of preferably about 10.1 Hz (electromagnetic frequency). Preferably, the electromagnetic frequency is below about 20.1 Hz. Preferably, the electromagnetic frequency is above about 0.9 Hz.

[0229] At step 216, patients are followed weekly for progress by a clinician. Special attention is paid to any emergence of mixed states, for example; agitation; and/or racy thoughts; and/or anxiety. If the later are present, then 1 Hz right-sided stimulation is used until the patient stabilises. This runs alongside quetiapine.

[0230] Further treatment of 10 Hz left-sided stimulation should be administered if the patient is intolerant, depression remains, or is not accepting of the treatment, or no response is obtained by 4-5 weeks. Escalation of thyroxine should follow by 50 mcg every three to seven days. An increased dosage of thyroxine of about 50 mcg to a range of up to 1000 mcg may occur. Other quantities may include 50 mcg to 400 mcg, 100 mcg to 500 mcg, 250 mcg to 600 mcg, 100 15 mcg to 650 mcg, 50 mcg to 200 mcg, 400 mcg to 600 mcg.

[0231] ECG and blood tests of full thyroid functioning including TSH, Free T4 and Free T3 are followed.

[0232] At step 218, a third evaluation in combination with previous evaluations is performed to determine if the patient still has depression. This can be performed before or after rTMS treatment.

[0233] Using ECG, special attention should be paid for the free-T4, free-T3 rise ratio following initiation of thyroid which would be unlike non-bipolar patients, whereby the free T4 rise is substantially higher than the free-T3 rise which tends to lag. The improved method generally comprises administering levothyroxine and/or thyroxine. Then, performing a patient ECG and analysing the free-T4 and free-T3 ratio whereby the free-T4 rise is substantially higher than the lagging free-T3 rise after high dose Levothyroxine and/or thyroxine is used. rT3 also rises significantly. This is unlike non-bipolar patients. If it is deemed helpful, in some cases, a patient ECG is also performed prior to administering levothyroxine and/or thyroxine.

[0234] If the patient experiences no mixed states, indicating a significant reduction in depression, then at step 220, following remission of depression, maintenance rTMS on a weekly basis (one-session) is followed for the first month (4-5 weeks), then after the first month, monthly rTMS sessions are followed.

[0235] Optionally, after receiving the rTMS treatment, analysis is made to determine if the patient has recovered using BDII and BAI II, having a cut-off point of 13 and below. Similarly, if the patient has recovered, then maintenance rTMS on a weekly basis (one-session) is followed for the first month, where monthly rTMS sessions are followed. If this is not possible, then cumulative number of sessions is administered over 2-3 months.

[0236] If the patient has not recovered with only depression rather than mixed symptoms or cycling, then, left sided 10 Hz stimulation is followed. Following this, patients are reviewed weekly for progress by a clinician.

[0237] Generally, rTMS treatment is performed at the patients scalp at preferred electromagnetic frequency, and for a time sufficient to modulate said brain activity wherein an improvement in a physiological condition is achieved. The anxiety and/or mixed states treatment is performed at a substantially right region dorsolateral prefrontal cortex (DLPFC) of the scalp at substantially 1 Hz and the depression rTMS treatment is performed at a substantially left DLFPC region of the scalp at substantially 10 Hz.

Example 1—in High Dose Levothyroxine (HDL) Combined with rTMS in 2 Patients

Case Report 1

[0238] A 23-year-old woman with a family history of rapid cycling bipolar Disorder presented with fatigue, over-eating, over-sleeping, low mood & passive suicidal ideation, alternating with mixed affective episodes, namely, depression with flight of ideas complicated by agitation, irritability and anger.

[0239] 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.

[0240] Comprehensive blood tests excluded an organic cause. She started taking Levothyroxine 50 mcg od and increased gradually to supraphysiological doses. Quetiapine, at a licensed dose, was prescribed but discontinued because of weight gain. rTMS was commenced, and she reported significant improvements in her mood but remained symptomatic.

[0241] One month later, she had racing thoughts and increased energy levels. The dose of Levothyroxine increased to 400 mcg once daily.

[0242] Two months later she was in remission and reported feeling the best in a long time. HDL was increased to 500 mcg o.d. for minor residual depressive symptoms. She remains in remission over a year later on HDL including maintenance rTMS with no side effects.

[0243] Taking Levothyroxine 500 mcg o.d., ECG: sinus rhythm, normal QTc. She was clinically euthyroid. Blood tests: TSH <0.01 miu/L (0.27-4.2), fT4 37.1 pmol/L (12-22), fT3 8.4 pmol/L (3.1-6.8). Reverse T3: 30 ng/dL (10-24). Genetic analysis: wild type DIO1, heterozygote polymorphism of DIO2 gene (rs225014; T92A).

Case Report 2

[0244] 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.

[0245] She was diagnosed with ADHD and bipolar disorder with the latter being poorly treated. Her mood deteriorated substantially following a trip to Australia.

[0246] Quetiapine was started, and the dose escalated to 700 mg daily which partially helped her mood. Levothyroxine 50 mcg once daily was commenced and the dose slowly escalated to 400 mcg once daily and her mood stabilised. ECG showed sinus rhythm, rate 63 bpm.

[0247] She unfortunately suffered a relapse a few months later taking these 2 medications and so rTMS was commenced.

[0248] HDL was eventually increased 750 mcg once daily. This, together with rTMS achieved remission, with no side effects.

[0249] She has been in complete remission with HDL 750 mcgs OD, Quetiapine 700 mgs OD and maintenance rTMS for over a year. She reported no side effects and no symptoms of thyrotoxicosis.

[0250] On examination, pulse was 85 bpm and regular, weight 71 kg (no unintentional weight loss). She is clinically euthyroid.

[0251] TSH is suppressed, fT4 77.3 pmol/L (12-22), fT3 11.7 pmol/L (3.1-6.8) and reverse T3 elevated: 79 ng/dl (10-24). Pre-Levo-thyroxine thyroid function was normal: TSH 2.20 miu/L (0.27-4.2), fT4 12.3 pmol/L and fT3 3.6 pmol/L (same reference ranges or fT4 and fT3). She had a heterozygote polymorphism of both the DIO2 (rs225014; T92A) and DIO1 gene (rs2235544; 34C>A).

Discussion

[0252] Two cases of patients with RCBPD, resistant to standard treatments are described who achieved remission of disease using high dose levothyroxine with rTMS.

[0253] There is an association between BPD and dysfunction of the thyroid (HPT) axis.

[0254] Thyroid disease is more likely to be presently in more resistant and rapid cycling forms of BPD. Contentiously, frank disturbances in the HPT axis are unusual in rapid cycling bipolar disorder. Instead a “latent hypofunction of the thyroid axis” has been suggested as a possible mechanism for the response to high dose Levothyroxine.

[0255] Studies have shown that high dose Levothyroxine helped achieve remission in rapid cycling bipolar disorder and was safe with no features of thyrotoxicosis.

[0256] Both our patients had a heterozygote polymorphism of the DIO2 gene and interestingly, an elevated fT4:fT3 ratio.

CONCLUSION

[0257] Rapid cycling bipolar disorder and mixed state affective states are dangerous conditions with high mortality and morbidity rates. [0258] Standard treatments are often ineffective. [0259] Data highlights an association between polymorphisms of the DIO2 gene and bipolar disorder [0260] We speculate that BPD is a form of cerebral hypothyroidism and that HDL helps to overcome the deficit while robust inactivating deiodinases in the periphery protect from systemic thyrotoxicosis. [0261] This is evidenced by findings of normal clinical examination and elevated rT3. [0262] rTMS exercises its well established neuroplastic effect, helping to achieve and maintain remission as an adjunct to HDL.

Example 2—in 20 Patients

[0263] Dr Andy Zamar (Consultant Psychiatrist), Dr Abbi Lulsegged (Consultant Endocrinologist), Dr Robin Roberts (Consultant Cardiologist) and their team at The London Psychiatry Centre have found through genetic testing that over 90% of the bipolar cases randomly and consecutively tested have a deficiency of one, two or both enzymes needed to activate thyroid hormone in the brain and the body.

These patients are unable to activate normal doses of thyroid hormone. The team found that as a result, they can be treated with minimal or no side effects with high dose thyroxine and rTMS, and some may need one additional drug as opposed to the usual requirement of a standard of 3 to 4 drugs which, as a rule, cause significant side effects.
Patients who had the combination of rTMS and high dose thyroid combination saw their condition recover fully after years of unsuccessful treatment with drugs (see below for details of the clinical trial). This effective new process also displays generally a lack of or minimal side effects, which is wonderful news for patients receiving the treatment.

[0264] The fact these patients did not suffer side effects on High dose Thyroxine has been previously reported but the reasons were never understood, and the treatment was never targeted to a specific identifiable population as this was never linked to any thyroid dysfunction, e.g. Deiodinase enzyme deficiency.

Clinical Trial

[0265] Retrospective analysis of 20 consecutive patients with RCBPD who achieved remission for a minimum of 6 months was undertaken.

[0266] All patients fulfilled the ICD-10 criteria for bipolar disorder and were strongly symptomatic. 17 were female, average age 32.4 yrs. All, except one had SNP of either DIO1, DIO2 or both. All but 2 patients were treated with rTMS to induce cerebral neuroplasticity.

[0267] Average pre-treatment fT4 was 17.0 pmol/L (12-22), and fT3 4.5 pmol/L (3.1-6.8), post treatment, FT4 was 59.7 pmol/L. and fT3 5.3 pmol/L. Average fT4:fT3 ratio pretreatment was 3.97:1, and post-treatment, was 5.26:1.

[0268] HDT range was 200-800 mcg for remission. Average of 472 mcg daily.

Discontinuation rate was 0%. One patient required dose reduction (750 mcg to 600 mcg) because of side effects. 12 patients needed 1 mood stabiliser.

[0269] HDL helps to overcome relative deficiency (cerebral) and that the polymorphisms of DIO1 and DIO2 play a role in this deficiency. (ii) Robust inactivating deiodinases in the periphery help protect from systemic thyrotoxicosis.

RCBPD is predominantly cerebral hypothyroidism, presenting with severe psychiatric symptomatology. HDT combined with rTMS for neuroplasticity is considered to be advantageous for remission of psychiatric symptoms.

[0270] Conventional protocols against treatment resistant patients are typically successful in about 25-30% of cases. The inventor has seen success rates of over 60% in real life drug resistant cases.

[0271] Recurrent depressive disorder patients will respond to left sided 10 Hz stimulation as per the normal protocol. Special care and attention has to be given to the sub-threshold bipolar population and/or major depressive disorder patients who could theoretically deteriorate or have deteriorated on antidepressants.

[0272] Although the invention has been particularly shown and described with reference to particular examples, it will be understood by those skilled in the art that various changes in the form and details may be made therein without departing from the scope of the present invention.