Objective: We want to determine the effectiveness of rTMS in patients with bipolar depression who did not respond to two or more adequately dosed medication trials, using an adequately powered pragmatic RCT. We hypothesize that active rTMS, compared…
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Source
Brief title
Condition
- Manic and bipolar mood disorders and disturbances
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary clinical outcome is determined by testing the treatment effect on the
course of depression severity, measured by the Structured Interview Guide for
the Hamilton Depression Rating Scale with Atypical Depression Supplement
(SIGH-ADS) during 5 weeks of active or sham rTMS.
Secondary outcome
a) Economic evaluation based on the general principles of a cost-effectiveness
(utility) analysis, which will be performed alongside the intervention by
comparing patients treated with active rTMS with those receiving sham rTMS.
Patient-reported outcome measures (i.e., quality-adjusted life years) will be
determined. Additionally, societal costs and health consumption will be
assessed for the economic evaluation at baseline and 12 weeks post-treatment.
b) Response rate defined as 50% reduction of depressive symptoms, based on the
SIGH ADS, directly after 25 active or sham rTMS sessions.
c) Remission rates directly after 25 active or sham rTMS sessions. Remission is
defined as a Hamilton score (derived from the SIGH ADS) of 8 and lower.
d) The sustained response rate, i.e., those participants, who at 4 weeks and 12
weeks post-treatment, maintain a 50% reduction of depressive symptoms.
e) The sustained response rate after 21 weeks post-treatment (in real rTMS
group).
f) Prevalence of side effects, including a possible switch to mania
g) Description of facilitators and barriers with regard to implementation.
h) Changes in negative and positive affect. Presence of negative mood
(depressed mood) and anhedonia (lack of interest and pleasure) are considered
core symptoms of depression, while absence of positive mood is not taken into
account in questionnaires on assessing the severity of depression. The Leuven
Affect and Pleasure Scale (LAPS) provides the opportunity to not only study
changes in depressed mood, but also assesses changes in positive affect.
Other outcome parameters: We want to explore the possible effects of different
patient characteristics, determined at baseline, on outcome of treatment in
patients treated with rTMS. The following demographic and clinical factors,
that have been studied in relation to the course of bipolar depression, have
not been studied in relation to outcome in patients treated with rTMS: type of
bipolar disorder, duration of index episode, age of onset of bipolar disorder,
duration of bipolar disorder, number of previous mood episodes, family history
of bipolar depression, psychiatric comorbidity. In addition, we want to explore
the effects of metabolic and vascular risk factors on outcome of bipolar
depression since these risk factors are strongly associated with onset and
course of unipolar and bipolar depression. Again, these factors have not been
studied in relation to outcome of treatment in bipolar patients treated with
rTMS: height, weight, waist:hip ratio, ankle arm index (a measure to determine
peripheral atherosclerosis), CRP, triglyceride, HDL cholesterol, total
cholesterol and HbA1c levels. We hypothesize that these risk factors influence
outcome of bipolar depression. At last, we want to determine possible
electrophysiological biomarkers using TMS-EEG measurements in bipolar
depressive patients, compared to healthy controls.
Background summary
Background of the study: Bipolar disorder is a severe, chronic psychiatric
disorder with patients suffering from recurrent depressive, (hypo)manic, and/or
mixed episodes, and affects approximately 1.3% of the Dutch population.
Depression is the predominant burden of illness in both bipolar I and bipolar
Il disorder, with patients suffering from depressive symptoms in more than 30%
of their time. Suicide rates in patients with bipolar disorder are
approximately 10-fold higher than that in the general population, especially
during depressive episodes and mixed states. Bipolar depression is a
challenging, unresolved condition with severe unmet needs that is far less
studied compared to unipolar depression. More than 35% of patients with bipolar
depression, despite receiving psychotherapy or medication, do not experience
sufficient reduction in depressive symptoms. These patients are twice as likely
to be hospitalized. Moreover, persistent depression can nearly double both
direct and indirect employer costs. Only a limited number of effective
treatments are available for depression in bipolar patients. The Dutch
guideline on bipolar disorder suggests that there are three additional options
for patients with bipolar depression who do not respond to two or more
pharmacological interventions. First, two mood-stabilizing drugs can be used as
combination therapy; second, a mood-stabilizing drug or antipsychotic can be
used in combination with an antidepressant drug (including a monoamine oxidase
inhibitor). However, by combining drugs, the risk of side effects increases,
moreover, some of these drugs require strict monitoring or adhering to a strict
diet. Third, for patients irresponsive to sequential medication,
electroconvulsive therapy (ECT) remains the only possible biological treatment.
Although ECT is an effective treatment for bipolar depression, it is not
accepted or tolerated by a majority of patients. Most patients choose to
refrain from ECT due to feared cognitive side effects, logistic difficulties
(patients have to be observed by friends or relatives until 24 hours after ECT
or have to be admitted to a psychiatric ward), or fear and stigma associated
with ECT. There are no available data from large trials concerning the effect
of adhering to a sequenced medication algorithm on treatment response in
patients with bipolar depression, contrary to the reports of previous studies
in patients with unipolar depression. The STAR-D study showed that adhering to
a sequenced medication algorithm is mainly effective in patients who received
one or two antidepressant drugs, whereas those who required more than two
sequential medication trials had the lowest response rates and the highest
relapse rates. Expert opinion in the field of bipolar depression holds that
similar response rate patterns are also observed in patients with bipolar
depression. Findings from two small RCTs suggest that in bipolar depression
addition of a mood stabilizing drug increases the response rate to
approximately 20%. Adjunctive antidepressant treatment is controversial and has
limited effect in patients with bipolar depression. These findings are in line
with the results of observational studies, showing that 35% of patients with
bipolar depression are medication resistant Therefore we argue that lack of
sufficient response to two sequential medication trials is a predictor of poor
prognosis in terms of efficacy, relapse, and future medication tolerance and
warrants the use of novel treatment modalities with different mechanisms of
action.
Repetitive transcranial magnetic stimulation (rTMS), a non-invasive
neuromodulatory therapy, has recently been added to the treatment arsenal for
unipolar depression. TMS is based on the principle of electromagnetic induction
by applying magnetic pulses to the brain. This magnetic pulse induces an
electrical current in the underlying neurons. When TMS pulses are applied
repetitively (rTMS), this effect outlasts the time of stimulation and leads to
enduring effects on cortical excitability. It is recognized as a valuable novel
therapeutic option in medication-resistant unipolar depression. RCTs have
consistently demonstrated the efficacy and safety of rTMS in
medication-resistant unipolar depression, with response rates of 40%. Depending
on the parameters of stimulation, rTMS can modulate cortical excitability in
focal areas, with low-frequency rTMS being inhibitory and high-frequency rTMS
usually excitatory. In unipolar depression, low-frequency rTMS over the right
dorsolateral prefrontal cortex (DLPFC) is equally effective as high-frequency
rTMS over the left DLPFC. Low-frequency rTMS is associated with a low risk of
inducing epilepsy during rTMS and is easier to tolerate than high-frequency
rTMS, therefore it is likely to be more accepable by patients. The risk of
developing side effects is low; transient headache and localized scalp pain are
the most common side effects and are eminently treatable with paracetamol.
There is preliminary evidence showing that rTMS is also effective in
(medication-resistant) bipolar depression; however, to date, only a few
underpowered studies have been performed. Two meta-analysis tried to determine
the efficacy of rTMS in patients with bipolar depression. The first
meta-analysis of 19 of these studies (consisting of 181 patients) showed that
the overall treatment response rates were 44% in patients treated with active
rTMS and 25% in those treated with sham rTMS. Findings from the second
meta-analysis showed similar results (n=279). The findings of these
meta-analyses were hampered. First, the participating patients consisted of
predominantly patients with unipolar depression and only few patients with
bipolar depression. Second, the number of patients in the meta-analysis was
small n=181 and n=279. Third, there were no data available on the number of
medication-resistant patients. Finally, no follow-up data were available.
Therefore, a well-powered RCT is needed to determine the efficacy of rTMS in
patients with medication-resistant bipolar depression according to the criteria
of Hidalgo-Mazzei, i.e., lack of remission for eight consecutive weeks after
two different adequate medication trials with at least two recommended
monotherapy treatments or at least one monotherapy treatment and another
combination treatment. In this RCT the choice for low-frequency rTMS rather
than high-frequency rTMS was made because the data from the meta-analysis
suggested that those receiving low-frequency rTMS had the highest response
rates; 60% for those receiving active rTMS vs 7% in the sham rTMS group.
However, the number of patients receiving low frequency rTMS was low (n=30).
The second reason for choosing low-frequency rTMS is that it is easier to
tolerate by patients, and because low-frequency rTMS is associated with a low
risk of inducing epilepsy.
In addition, we will perform an explorative cost-effectiveness study and obtain
data on implementation. Finally we want to further explore the effects of
different patient characteristics on outcome of treatment, including, age,
gender, type of depression, i.e. atypical or melancholic depression, duration
of index episode, duration of bipolar disorder, number of previous mood
episodes and presence of the cardiovascular risk factors We hypothesize that
these patients characteristics including presence of cardiovascular risk
factors contribute to a poorer outcome after rTMS treatment in patients with
bipolar depression.
Clinical electrophysiological studies in patients with bipolar depression
Furthermore, we would like to investigate the electrophysiology (i.e., cortical
excitability) of the patients suffering from bipolar depression. More specific,
the direct changes in cortical excitation and inhibition following the
administration of TMS pulses. This additional study is
Study objective
Objective: We want to determine the effectiveness of rTMS in patients with
bipolar depression who did not respond to two or more adequately dosed
medication trials, using an adequately powered pragmatic RCT. We hypothesize
that active rTMS, compared to sham rTMS, will result in a greater difference in
treatment effect on the course of depression severity, after 5 weeks of active
or sham rTMS. Our RCT is of utmost importance since all RCTs in this field are
underpowered and predominantly consist of patients with unipolar depression and
relatively few patients with bipolar depression.
Study design
We will conduct a pragmatic multicentre double-blind randomized sham-controlled
rTMS trial to determine the efficacy of rTMS in
166 patients with moderate to severe medication-resistant bipolar depression.
In this study, medication-resistant bipolar depression is defined according to
the criteria of Hidalgo-Mazzei, i.e., lack of remission for eight consecutive
weeks after two different adequate medication trials with at least two
recommended monotherapy treatments or at least one monotherapy treatment and
another combination treatment. This study has 3 phases. In phase 1 participants
will be randomly assigned to one of the two treatment groups, and will receive
active or sham rTMS, for 25 rTMS sessions in 5 weeks. Monitoring takes place on
a weekly basis. Phase 2 comprises of 12 weeks follow-up (17 weeks after the
start of participation of the RCT) after treatment with active or sham rTMS.
After 12 weeks of follow up, patients allocated to sham rTMS will be offered
active rTMS. All patients will be followed for 21 weeks to determine sustained
response rate, Phase 3. Alongside this RCT, we will also conduct an economic
evaluation and evaluate facilitators and barriers related to implementation in
the group of researcher and health care professionals involved in this study.
The funding agency, i.e. ZonMw doelmatigheidsonderzoek, explicitly wants that
the trial is based in normal care.
If patients agree on participating with the optional TMS-EEG measurement (in
Amsterdam), this will take place before the start of the 25 rTMS treatments;
after the screening (T0) and before the baseline measurements (T1).
Participants will follow the METC approved TMS-EEG protocol of the randomized
clinical trial named TIPICCO (TMS-induced plasticity improving cognitive
control in OCD; dossier number NL67067.029.18). Which consists of two separate
appointments:
1) Day one: Neuropsychological measurement & MRI scan session
2) Day two: TMS-EEG measurements
For this we will inform and include patients that are participating the T-BIDE
study.
Intervention
Adults with current bipolar depression who meet the inclusion criteria will
receive 25 rTMS sessions once daily five times a week, for five weeks, in
adjunction to ongoing treatment as usual. If patients miss up to a maximum of 4
rTMS sessions during the five week treatment period, treatment will be extended
to obtain the prescribed 25 rTMS sessions. If patients miss more than 4
sessions they will be registered as a drop out. Low-frequency rTMS will be
applied at an intensity of 120% of the resting motor threshold to the right
DLPFC: 1,500 pulses per session will be delivered continuously, with a
treatment duration of 25 minutes. The localization of the right DLPFC target
will be determined using the International 10-20 system, corresponding to the
F4 location. The International 10-20 system is a method that allows placement
of electroencephalogram electrodes to be standardized. This system accounts for
variability in patient skull size by using certain percentages of the
circumference and distances between four basic anatomical landmarks of the
skull. Beam developed a new, simpler, and faster way to find the F4 position in
2009, using only three skull measurements, allowing for easy and reliable use
in clinical settings to target the right DLPFC. Because this is a pragmatic
RCT, the five different study sites will use different rTMS machines, i.e.
machines from the following manufacturers Mag and More, Magstim, Mag Venture en
DeyMed.
Comparison
Adults with current bipolar depression who met the inclusion criteria will
undergo 25 sham rTMS sessions once daily five times a week, for five weeks, in
adjunction to ongoing treatment as usual. If patients miss up to a maximum of 4
sham rTMS sessions during the five week treatment period, treatment will be
extended to obtain the prescribed 25 sham rTMS sessions. For sham rTMS, a sham
coil will be used that delivers the same auditory effect, in order that the
same procedural will be obtained.
TMS-EEG
Patients who agreed on participating TMS-EEG measurements shall receive the
following intervention before the start of the rTMS treatments according to the
T-BIDE protocol:
After determining the motor threshold, the set-up of the neuronavigation and
preparing the 64-channel EEG cap on the participant*s head, a protocol existing
of single and double pulse TMS will be administered at the right DLPFC, left
DLPFC and the primary motor cortex (same spot as where the motor threshold was
determined). The duration of the protocol is 12 minutes (times three brain
areas).
Study burden and risks
Benefits: Treatment of depressive symptoms in bipolar patients with rTMS,
initially in those receiving active rTMS. We will also offer active rTMS after
12 weeks of follow up, in participants who received sham rTMS. In the
Netherlands, only a small numbers of unipolar depressed patients are treated
annually, whereas virtually no bipolar patients are being treated with rTMS.
Knowledge gained from this study will allow adequate positioning of rTMS
treatment in the algorithm to treat bipolar depression. On a participant level,
all participants will be treated with rTMS, i.e., those receiving sham rTMS
will be offered active rTMS after a 12 week observation period. For the TMS-EEG
appointments, if the patient decides to participate, they will receive an
additional financial compensation.
Burden for participants: Total time for participants will be 23 hours and 5
minutes, including rTMS treatment
Risk: rTMS is a proven safe treatment, however it is associated with a low risk
to develop mania, a low suicide risk, a low risk to develop a seizure, and a
moderate risk to develop transient headache. For the patients who decide to
participate in the TMS-EEG study will have a total of two additional visits.
Which means that we ask these patients a bit more of investment of their time.
Boelelaan 1108
Amsterdam 1081HZ
NL
Boelelaan 1108
Amsterdam 1081HZ
NL
Listed location countries
Age
Inclusion criteria
Eligibility criteria:
- 18 years or older of age;
- Sufficient level of spoken and written Dutch;
- Ability to freely provide written informed consent;
- patients with bipolar I or Il disorder, who have a medication-resistant
bipolar depression, i.e., lack of remission for eight consecutive weeks after
two different adequate medication trials with at least two recommended
monotherapy treatments or at least one monotherapy treatment and another
combination
- A score > 16 points on the Hamilton depression rating scale for atypical
depression (SIGH-ADS).
- A current DSM-5 diagnosis of bipolar depression, ascertained by the Mini
International Neuropsychiatry Interview (MINI-plus).
- Or have tried at least two monotherapies in the previous depressive episode,
which must have occurred within 12 months previous of the present episode but
not more than three depressive episodes within these 12 months.
- Stable medication 4 weeks prior to study, including anti-manic medication,
consisting of lithium, valproate, carbamazepine and all anti-psychotic drugs,
in patients with bipolar I disorder. Patients with a bipolar 2 disorder using
anti-depressant medication will also need to use anti-manic medication. Dosages
of anti-manic medications will be determined between the participant/patient
and his/her psychiatrist. Stable medication also includes stable use of
benzodiazepines up to a dosage equivalent of 3.0 mg lorazepam.
Exclusion criteria
Partcipants meeting any of the following criteria will be excluded from
participation in this study:
- A (hypo)manic episode within 3 months before the start of the trial.
- A Young Mania Rating Scale score > 12, before the start of the trial.
- Current psychotic disorder, including psychotic depression, assessed at the
baseline interview.
- Dementia, assessed with a dementia screening tool, i.e. the Montreal
Cognitive Assessment (34), assessed at the baseline interview.
- Active suicidal thoughts and intent to act on it, assessed at the baseline
interview and before the start of the trial. This assessment is based on the
Columbia suicide severity rating scale, i.e. question 5 is answered positive
"Have you started to work out or worked out the details of how to kill
yourself? Do you intend to carry out this plan?".
- Metallic devices implanted above the neck, assessed at the baseline
interview.
- Patients diagnosed with epilepsy, by a neurologist, assessed at the baseline
interview.
- Patients with bipolar Il disorder who use anti-depressant medication without
anti-manic medication or patients with bipolar I disorder, not using anti-manic
medication.
- Substance abuse 4 weeks prior to the study, including high dosage of
benzodiazepine, a dosage equivalent higher than 3.0 mg lorazepam, assessed at
the baseline interview.
- Pregnancy, If there is any doubt a pregnancy test is performed, at baseline.
- Known with rapid cycling.; e.g. more than 3 mood cycles per year.
- Inability to understand or comply with study requirements as judged by the
investigators, assessed at the baseline interview.
- Earlier experiences with rTMS (as treatment or in a study)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL77251.029.21 |