Theta-Burst Stimulation for Bipolar Disorder (TRIBE Trial)
Recruiting in Palo Alto (17 mi)
+1 other location
Age: 18+
Sex: Any
Travel: May be covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Centre for Addiction and Mental Health
No Placebo Group
Approved in 1 jurisdiction
Trial Summary
What is the purpose of this trial?The purpose of this trial is to determine if intermittent theta-burst stimulation (iTBS) can reduce the symptoms of depression in treatment-resistant bipolar disorder. To do this, some of the participants in this study will receive treatment with active iTBS stimulation, while others will receive sham iTBS stimulation. Participants will come for 30 days of either active iTBS or sham iTBS, with a 6-week follow-up period. Symptoms of depression (for determining treatment efficacy) and mania (for determining treatment safety) will be assessed using the 17-item Hamilton Rating Scale for Depression (HRSD-17) and the Young Mania Rating Scale (YMRS) every five treatments during the treatment course, and at 1 week and 6 week after treatment completion.
How is Theta-Burst Stimulation treatment different from other treatments for bipolar disorder?
Theta-Burst Stimulation (TBS) is a non-invasive brain stimulation technique that uses magnetic fields to stimulate nerve cells in the brain, which is different from traditional drug treatments that involve medication. This method is unique because it targets specific brain areas involved in mood regulation, potentially offering a new approach for those who do not respond well to medications like lithium or anticonvulsants.
12457Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you must not start or increase any psychotropic medications for depression 4 weeks before screening. You must also be on a non-anticonvulsant mood stabilizer like lithium or quetiapine, and you cannot take anticonvulsants or more than 2 mg of lorazepam daily.
Is theta-burst stimulation safe for humans?
Research shows that theta-burst stimulation, including intermittent theta-burst stimulation (iTBS) and accelerated intermittent theta-burst stimulation (aiTBS), is generally safe and well-tolerated in humans, with no adverse events reported in studies involving patients with bipolar depression.
6891213What data supports the effectiveness of the treatment Theta-Burst Stimulation for Bipolar Disorder?
Research shows that intermittent theta burst stimulation (iTBS) can be effective for bipolar depression, with high response and remission rates in a small study. This suggests that iTBS might help improve symptoms in people with bipolar disorder, but more research is needed to confirm these findings.
38101113Eligibility Criteria
This trial is for individuals with bipolar disorder who have not responded well to standard treatments for depression. Participants must be able to attend 30 treatment sessions and follow-up visits. Specific criteria will determine eligibility.Participant Groups
The study tests if iTBS, a brain stimulation technique, can alleviate depression in those with treatment-resistant bipolar disorder. Half receive real iTBS; the other half get sham (fake) treatment, decided randomly.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: Active iTBS StimulationExperimental Treatment1 Intervention
Administered once daily over 30 days. Each session will deliver 600 pulses of active iTBS in triplet 50Hz bursts, repeated at 5Hz 2s on 8s off for a total time of \~3 minutes, 9 seconds at a target intensity of 120% of the subject's resting motor threshold.
Group II: Sham iTBS StimulationPlacebo Group1 Intervention
Administered once daily over 30 days, using a sham coil that reproduces auditory and tactile sensations of stimulation and has an identical external appearance. Each session will deliver 600 pulses of sham iTBS in triplet 50Hz bursts, repeated at 5Hz 2s on 8s off for a total time of \~3 minutes, 9 seconds at a target intensity of 120% of the subject's resting motor threshold.
Theta-Burst Stimulation is already approved in United States for the following indications:
🇺🇸 Approved in United States as Intermittent Theta-Burst Stimulation for:
- Treatment-resistant major depressive disorder
- Treatment-resistant bipolar depression
Find A Clinic Near You
Research locations nearbySelect from list below to view details:
Centre for Addiction and Mental HealthToronto, Canada
University Health NetworkToronto, Canada
Loading ...
Who is running the clinical trial?
Centre for Addiction and Mental HealthLead Sponsor
University Health Network, TorontoCollaborator
References
Rapid cycling bipolar disorder: clinical characteristics and treatment options. [2018]Approximately one of six patients who seek treatment for bipolar disorder present with a rapid cycling pattern. In comparison with other patients who have bipolar disorder, these individuals experience more affective morbidity in both the immediate and distant future and are more likely to experience recurrences despite treatment with lithium or anticonvulsants. Particular care should be given to distinguishing rapid cycling bipolar disorder from attention-deficit hyperactivity disorder in children or adolescents and from borderline personality disorder in adults. Perhaps four of five cases of rapid cycling resolve within a year, but the pattern may persist for many years in the remaining patients. As with bipolar disorder in general, depressive symptoms produce the most morbidity over time. Controlled studies have not established that antidepressants provoke switching or rapid cycling, but neither have they been shown consistently to have benefits in bipolar illness. Successful management will often require a sequence of trials with mood stabilizer drugs, beginning with lithium in treatment-naive patients. Efforts to minimise adverse effects, and the recognition that full benefits may not be apparent for several months, will make the premature abandonment of a potentially helpful treatment less likely. Placebo-controlled studies so far provide the most support for the use of lithium and lamotrigine as prophylactic agents. The combination of lithium and carbamazepine, valproate or lamotrigine for maintenance has some support from controlled studies, as does the adjunctive use of olanzapine.
Treatment of rapid-cycling bipolar disorder. [2013]Rapid-cycling bipolar disorder is associated with poorer treatment response, poorer long-term prognosis, and probable higher suicide risk than bipolar disorder without rapid cycling. Patients with rapid cycling tend to experience more depressive than manic episodes, and the depressive episodes tend to be more refractory in nature compared with those in patients without rapid cycling. Results from studies of rapid cycling show that antidepressant use is most likely associated with the onset or worsening of rapid cycling. Controversy also exists as to whether rapid cycling is a transitory phenomenon in the course of bipolar illness or a more chronic condition better characterized as a subtype of the illness. Results from the first 500 patients with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study found an association between rapid cycling and depression and younger age at illness onset. Treatment involves a 3-part pathway to manage rapid cycling that includes reducing or stopping any possible cycle-promoting agents, adding or optimizing mood stabilizers, and using experimental or putative treatments for persistent rapid cycling after more traditional treatments have failed. Effective treatments for some patients with rapid-cycling bipolar disorder currently include lithium, divalproex, lamotrigine, carbamazepine, atypical antipsychotics, and psychosocial therapy.
Corticospinal integrity and motor impairment predict outcomes after excitatory repetitive transcranial magnetic stimulation: a preliminary study. [2016]To identify the effective predictors for therapeutic outcomes based on intermittent theta-burst stimulation (iTBS).
Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains. [2021]Recent advances in genome-wide association studies are pointing towards a major role for voltage-gated ion channels in neuropsychiatric disorders and, in particular, bipolar disorder (BD). The phenotype of BD is complex, with symptoms during mood episodes and deficits persisting between episodes. We have tried to elucidate the common neurobiological mechanisms associated with ion channel signaling in order to provide a new perspective on the clinical symptoms and possible endophenotypes seen in BD patients. We propose a model in which the multiple variants in genes coding for ion channel proteins would perturb motivational circuits, synaptic plasticity, myelination, hypothalamic-pituitary-adrenal axis function, circadian neuronal rhythms, and energy regulation. These changes in neurobiological mechanisms would manifest in endophenotypes of aberrant reward processing, white matter hyperintensities, deficits in executive function, altered frontolimbic connectivity, increased amygdala activity, increased melatonin suppression, decreased REM latency, and aberrant myo-inositol/ATP shuttling. The endophenotypes result in behaviors of poor impulse control, motivational changes, cognitive deficits, abnormal stress response, sleep disturbances, and energy changes involving different neurobiological process domains. The hypothesis is that these disturbances start with altered neural circuitry during development, following which multiple environmental triggers may disrupt the neuronal excitability balance through an activity-dependent molecular process, resulting in clinical mood episodes.
Neurons derived from patients with bipolar disorder divide into intrinsically different sub-populations of neurons, predicting the patients' responsiveness to lithium. [2019]Bipolar disorder (BD) is a progressive psychiatric disorder with more than 3% prevalence worldwide. Affected individuals experience recurrent episodes of depression and mania, disrupting normal life and increasing the risk of suicide greatly. The complexity and genetic heterogeneity of psychiatric disorders have challenged the development of animal and cellular models. We recently reported that hippocampal dentate gyrus (DG) neurons differentiated from induced pluripotent stem cell (iPSC)-derived fibroblasts of BD patients are electrophysiologically hyperexcitable. Here we used iPSCs derived from Epstein-Barr virus-immortalized B-lymphocytes to verify that the hyperexcitability of DG-like neurons is reproduced in this different cohort of patients and cells. Lymphocytes are readily available for research with a large number of banked lines with associated patient clinical description. We used whole-cell patch-clamp recordings of over 460 neurons to characterize neurons derived from control individuals and BD patients. Extensive functional analysis showed that intrinsic cell parameters are very different between the two groups of BD neurons, those derived from lithium (Li)-responsive (LR) patients and those derived from Li-non-responsive (NR) patients, which led us to partition our BD neurons into two sub-populations of cells and suggested two different subdisorders. Training a Naïve Bayes classifier with the electrophysiological features of patients whose responses to Li are known allows for accurate classification with more than 92% success rate for a new patient whose response to Li is unknown. Despite their very different functional profiles, both populations of neurons share a large, fast after-hyperpolarization (AHP). We therefore suggest that the large, fast AHP is a key feature of BD and a main contributor to the fast, sustained spiking abilities of BD neurons. Confirming our previous report with fibroblast-derived DG neurons, chronic Li treatment reduced the hyperexcitability in the lymphoblast-derived LR group but not in the NR group, strengthening the validity and utility of this new human cellular model of BD.
Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomised non-inferiority trial. [2022]Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.
Current understanding of bipolar disorder: Toward integration of biological basis and treatment strategies. [2020]Biological studies of bipolar disorder initially focused on the mechanism of action for antidepressants and antipsychotic drugs, and the roles of monoamines (e.g., serotonin, dopamine) have been extensively studied. Thereafter, based on the mechanism of action of lithium, intracellular signal transduction systems, including inositol metabolism and intracellular calcium signaling, have drawn attention. Involvement of intracellular calcium signaling has been supported by genetics and cellular studies. Elucidation of the neural circuits affected by calcium signaling abnormalities is critical, and our previous study suggested a role of the paraventricular thalamic nucleus. The genetic vulnerability of mitochondria causes calcium dysregulation and results in the hyperexcitability of serotonergic neurons, which are suggested to be susceptible to oxidative stress. Efficacy of anticonvulsants, animal studies of candidate genes, and studies using induced pluripotent stem cell-derived neurons have suggested a relation between bipolar disorder and the hyperexcitability of neurons. Recent genetic findings suggest the roles of polyunsaturated acids. At the systems level, social rhythm therapy targets circadian rhythm abnormalities, and cognitive behavioral therapy may target emotion/cognition (E/C) imbalance. In the future, pharmacological and psychosocial treatments may be combined and optimized based on the biological basis of each patient, which will realize individualized treatment.
Twice-daily neuronavigated intermittent theta burst stimulation for bipolar depression: A Randomized Sham-Controlled Pilot Study. [2020]The safety and efficacy of neuronavigated intermittent theta burst stimulation (iTBS) in patients with bipolar depression has not yet been investigated. We hypothesized the superiority of active iTBS over sham. Twenty-six patients were randomly allocated to receive either active (n=12) or sham (n=14) iTBS. Response and remission rates according to changes in depression MADRS score were high following active iTBS (72% and 42% for response and remission rates, respectively), but no significant difference was found after sham stimulation (42%and 25%). No adverse events were observed. This study revealed the safety and tolerability of twice daily iTBS in patients with bipolar depression. Larger controlled studies are warranted to prove iTBS superiority in treatment-resistant bipolar depression.
A randomized sham controlled comparison of once vs twice-daily intermittent theta burst stimulation in depression: A Canadian rTMS treatment and biomarker network in depression (CARTBIND) study. [2022]Intermittent theta burst stimulation (iTBS) is a newer form of repetitive transcranial magnetic stimulation (rTMS) for patients with treatment resistant depression (TRD). Applying multiple daily iTBS sessions may enable patients to achieve remission more rapidly.
Intermittent theta burst stimulation (iTBS) versus 10 Hz high-frequency repetitive transcranial magnetic stimulation (rTMS) to alleviate treatment-resistant unipolar depression: A randomized controlled trial (THETA-DEP). [2022]Recently intermittent theta burst stimulation (iTBS) proved to be non-inferior to conventional repetitive transcranial magnetic stimulation (10 Hz rTMS) in unipolar depression after failure of one antidepressant trial, but to date no randomized control trial assessed the ability of iTBS to improve depression level and quality of life in more resistant features of depression with a long-term (6 month) follow-up in comparison to 10 Hz rTMS.
Safety and Efficacy of Continuous Theta Burst "Intensive" Stimulation in Acute-Phase Bipolar Depression: A Pilot, Exploratory Study. [2023]Repetitive transcranial magnetic stimulation efficacy in unipolar depression is known, but its efficacy in acute-phase bipolar depression is at best modest. Citing differential right dorsolateral prefrontal cortex hyperconnectivity implicated in BD, we aimed to study the effect of novel continuous theta burst stimulation (cTBS) targeting right dorsolateral prefrontal cortex in a randomized rater blinded placebo control design.
Accelerated intermittent theta burst stimulation for major depressive disorder or bipolar depression: A systematic review and meta-analysis. [2023]We aimed to systematically evaluate the clinical efficacy and safety of accelerated intermittent theta burst stimulation (aiTBS) for patients with major depressive disorder (MDD) or bipolar depression (BD). A random-effects model was adopted to analyze the primary and secondary outcomes using the Review Manager, Version 5.3 software. This meta-analysis (MA) identified five double-blind randomized controlled trials (RCTs) comprising 239 MDD or BD patients with a major depressive episode. Active aiTBS overperformed sham stimulation in the study-defined response. This MA found preliminary evidence that active aiTBS resulted in a greater response in treating major depressive episodes in MDD or BD patients than sham stimulation.
Adjunctive continuous theta burst stimulation for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled studies. [2023]As a novel type of theta burst stimulation (TBS), continuous TBS (cTBS) has been shown to have mixed therapeutic effects for major depressive disorder (MDD) or bipolar depression (BD). Thus, we performed a meta-analysis of randomized controlled trials (RCTs) of cTBS for treating major depressive episodes in patients with MDD or BD.