A double-blind, randomized, sham-controlled clinical trial of cerebellar intermittent theta burst stimulation for bipolar disorder: Safety, tolerability, mood and cognitive effects

Classified as probably not a substantial claim.

In subjects with schizophrenia, CBM-iTBS positively impacts affective and cognitive symptoms.

“In subjects with schizophrenia, CBM-iTBS can alter brain metabolism and cerebellar-frontal functional connectivity (Basavaraju et al., 2021; Brady et al., 2019; Cho et al., 2012; Halko et al., 2014; Singh et al., 2019), as well as positively impact affective and cognitive symptoms (Basavaraju et al., 2021; Demirtas-Tatlidede et al., 2010; Garg et al., 2016; Shinn et al., 2023; Zhu et al., 2021).”

• cites Basavaraju et al., 2021 sourceDisputed

  The Results (Mixed Models Repeated Measures analysis; page unavailable) report that cognitive measures improved over time in both the real and sham groups, with no significant difference between them on clinical or cognitive changes. The Discussion likewise states that real stimulation did not significantly outperform sham stimulation on negative or cognitive symptoms. Thus this trial does not show the attributed positive effect of CBM-iTBS on affective and cognitive symptoms. (LLM, conf=0.86)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Demirtas-Tatlidede et al., 2010 sourceSupported
• cites Garg et al., 2016 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Cerebellar lesions and peri-cerebellar cysts are associated with a higher risk of bipolar disorder symptom presentation.

“Additionally, cerebellar lesions and peri-cerebellar cysts have been associated with a higher risk of bipolar disorder symptom presentation (Ewald et al., 2022; Lauterbach, 1996).”

• cites Ewald et al., 2022 sourcePartly supported

  The Introduction reports that posterior fossa arachnoid cysts occurred more often in participants with bipolar disorder than in controls, and the Discussion describes a connection between the cysts and bipolar-disorder-associated symptoms. But the study does not establish that cerebellar lesions or cysts increase the risk of symptom presentation; its Discussion cautions against causal conclusions, and its Results suggest milder symptoms in the bipolar group with cysts than in the bipolar group without them. Page numbers were not available in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Lauterbach, 1996 sourceNot checked — no full text of the source

May combine two claims.

There is not yet a TMS protocol for treating bipolar disorder that is in widespread clinical use, with recent protocols showing mixed results.

“There is not yet a TMS protocol for treating bipolar disorder that is in widespread clinical use, with recent protocols showing mixed results (Goldwaser et al., 2020; McGirr et al., 2016; McGirr et al., 2021; Myczkowski et al., 2018).”

• cites Goldwaser et al., 2020 sourceSupported
• cites McGirr et al., 2016 sourcePartly supported

  In “Clinical efficacy and safety of repetitive transcranial magnetic stimulation in acute bipolar depression” (page not supplied), the meta-analysis reports differing outcomes by stimulation target: right- and left-sided stimulation outperformed sham, while bilateral stimulation did not. It also calls the evidence preliminary and says larger trials are needed. It does not address whether any TMS protocol is in widespread clinical use, so that part of the claim is unsupported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites McGirr et al., 2021 sourcePartly supported

  The Discussion (page unavailable) describes preliminary evidence for several rTMS protocols in bipolar depression, inconclusive findings for theta-burst protocols, and this trial’s negative result. The Conclusions (page unavailable) say further standardized trials are needed to determine TMS’s role in bipolar depression. The paper does not establish whether any TMS protocol is in widespread clinical use, so that part of the claim remains unsupported. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Blinding effectiveness was assessed via the James Blinding Index.

“Blinding effectiveness was assessed via the James Blinding Index (Bang et al., 2004; Kolahi et al., 2009).”

• cites Bang et al., 2004 sourceNot checked — no full text of the source
• cites Kolahi et al., 2009 sourceSupported

Classified as probably not a substantial claim.

The cerebellar regions most frequently implicated in psychiatric disorders include the posterior cerebellum and cerebellar vermis, which are functionally connected to limbic and prefrontal brain networks involved in cognition and emotion regulation.

“The cerebellar regions that tend to be the most frequently implicated in psychiatric disorders include the posterior cerebellum and cerebellar vermis, which are functionally connected to limbic and prefrontal brain networks involved in cognition and emotion regulation (Buckner et al., 2011).”

• cites Buckner et al., 2011 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Other studies suggest a prominent placebo effect for CBM-iTBS.

“However, other studies suggest a prominent placebo effect (Basavaraju et al., 2021).”

• cites Basavaraju et al., 2021 sourceSupported

May combine two claims.

Cerebellar abnormalities (reduced volumes, abnormal functional connectivity, abnormal metabolism) are present in bipolar disorder compared to neuronormative populations.

“In bipolar disorder, subjects show reduced cerebellar volumes (Baldacara et al., 2011; DelBello et al., 1999; Mills et al., 2005), abnormal cerebellar functional connectivity (Liang et al., 2013), and abnormal cerebellar metabolism (Johnson et al., 2018; Magnotta et al., 2022) compared to neuronormative populations.”

• cites Baldacara et al., 2011 sourceNot checked — no full text of the source
• cites Liang et al., 2013 sourcePartly supported

  Table 3 (Results, §2) reports decreased regional homogeneity (ReHo) in the right anterior cerebellum of bipolar-disorder patients compared with controls. The Introduction describes ReHo as local synchronization of fMRI signals, but the Discussion distinguishes this method from functional-connectivity analysis. The paper therefore supports a cerebellar functional abnormality, not a direct finding of abnormal cerebellar functional connectivity. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Johnson et al., 2018 sourcePartly supported

  Johnson et al. report increased cerebellar T1ρ relaxation times in all three bipolar mood-state groups compared with healthy controls (Results, “Mood States vs. Controls”). The Discussion says this is consistent with reduced pH that may reflect metabolic variation, but does not establish abnormal cerebellar metabolism directly. The citation is attached to metabolism, not to the separate volume or connectivity claims. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Patients with cerebellar damage have demonstrated impairments in reconstructing a sequence of events.

“patients with cerebellar damage have demonstrated impairments in reconstructing a sequence of events (Leggio et al., 2008)”

• cites Leggio et al., 2008 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

TMS coils with deeper magnetic field penetration may more effectively engage cerebellar targets.

“TMS coils with deeper magnetic field penetration may more effectively engage cerebellar targets (Galea et al., 2009; Hardwick et al., 2014)”

• cites Galea et al., 2009 sourcePartly supported

  The Experimental procedures (TMS of the cerebellum and brainstem; page not provided) describe using a double-cone coil over the cerebellum, and the Cerebellar excitability section describes using TMS there to assess cerebello-brain inhibition. The paper does not say that this coil penetrates more deeply or that deeper penetration improves engagement of cerebellar targets. (LLM, conf=0.78)

  Experimental — accuracy not yet measured
• cites Hardwick et al., 2014 sourceSupported

Classified as probably not a substantial claim.

Studies suggest that cerebellar modulation is possible with TMS.

“studies suggest that cerebellar modulation is possible with TMS (Hardwick et al., 2014; Siebner et al., 2022)”

• cites Hardwick et al., 2014 sourceSupported
• cites Siebner et al., 2022 sourceSupported

May combine two claims.

CBM-iTBS was well-tolerated, with the only affective switching to mania or mixed state occurring during follow-up in one active and one sham participant.

“Importantly, CBM-iTBS was well-tolerated, with the only affective switching to mania or mixed state occurring during follow-up in one active and one sham participant.”

May combine two claims.

The active group outperformed sham on measures of life satisfaction, meaning, self-efficacy, and reduced anger at varied time-points.

“The active group outperformed sham on measures of life satisfaction, meaning, self-efficacy, and reduced anger at varied time-points, with broad mood improvements in both groups.”

May combine two claims.

Statistically, a significant reduction in MADRS scores was observed with no active/sham group differentiation.

“Statistically, a significant reduction in MADRS scores was observed with no active/sham group differentiation.”

May combine two claims.

The Picture Sequence Memory Test (PSMT) demonstrated significant improvement in the active but not the sham group.

“the Picture Sequence Memory Test (PSMT) demonstrated significant improvement in the active but not the sham group”

May combine two claims.

Average VAS ratings of stimulation site pain were low in both groups (active = 3.2/10; sham = 1.4/10; p < 0.0001).

“Average visual analogue scale (VAS) ratings of stimulation site pain were low in both groups (active = 3.2/10; sham = 1.4/10; p < 0.0001), and gradually decreased over the course of the sessions (Fig. 3).”

May combine two claims.

For CPT omission, commission, and hit-rate reaction time measures, the only significant between-group difference was in reaction time at the 8-week timepoint, with the active group exhibiting atypically fast reaction times (p = 0.01).

“For the omission, commission, and hit-rate reaction time measures, the only significant between-group difference was in reaction time at the 8-week timepoint, with the active group exhibiting atypically fast reaction times (p = 0.01, Table 9).”

May combine two claims.

Only one subject (randomized to sham) discontinued the intervention due to headaches; no other side effects were significant enough to result in patient dropout or stimulation protocol termination.

“After treatment was initiated, only one subject (randomized to the sham arm) discontinued the intervention due to headaches; no other side effects were significant enough to result in patient dropout or stimulation protocol termination.”

May combine two claims.

Two participants were psychiatrically hospitalized and another developed suicidal ideation; all these events occurred in subjects in the sham arm during the follow-up period.

“Regarding serious adverse events, two participants were psychiatrically hospitalized and another developed suicidal ideation. All these events occurred with subjects in the sham arm during the follow-up period.”

May combine two claims.

For the sham group, PHQ-9 scores were significantly reduced compared to baseline at post-Tx, 1-week, 3-week, and 8-week (all p < 0.05; 1-week and 3-week significant after Bonferroni correction).

“For the sham group, post-Tx, 1-week, 3-week, and 8-week scores were significantly reduced compared to baseline (all p < 0.05; 1-week and 3-week scores significant after Bonferroni correction).”

May combine two claims.

Treatment-emergent hypo/mania symptoms did not occur during CBM-iTBS treatment, although one participant in each group developed symptoms during the two-month follow-up period.

“Treatment-emergent hypo/mania symptoms, a concern with any bipolar disorder treatment (Lupo et al., 2018; McGirr et al., 2021), did not occur during CBM-iTBS treatment, although one participant in each group developed symptoms during the two-month follow-up period.”

May combine two claims.

A trend towards greater baseline depression severity in the sham group was seen (p = 0.08), but no significant between-group differences in symptom change from baseline were detected at any timepoint.

“A trend towards greater baseline depression severity in the sham group was seen (p = 0.08), but no significant between-group differences in symptom change from baseline were detected at any timepoint (Table 6).”

May combine two claims.

In the depressed subset, remission rates were 29-71 % in the active group and 33-75 % in the sham group.

“Remission rates were 29–71 % in the active group and 33–75 % in the sham group.”

May combine two claims.

Active group CGI scores were significantly higher than sham group scores at baseline (p < 0.05), but no significant between-group differences were detected at other time-points.

“Active group scores were significantly higher than sham group scores at baseline (p < 0.05), but no significant between-group differences were detected at other time-points (Table 5).”

May combine two claims.

Stimulation pain and discomfort was rated higher in the active group, although still mild and consistent with pain ratings in other iTBS studies.

“Stimulation pain and discomfort was rated higher in the active group, although still mild and consistent with pain ratings in other iTBS studies (Blumberger et al., 2018).”

• cites Blumberger et al., 2018 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Two additional active CBM-iTBS participants were one MADRS point away from achieving response and remission status.

“Two additional active CBM-iTBS participants were one MADRS point away from achieving response and remission status”

May combine two claims.

The NIH cognitive toolbox fluid composite score and multiple individual tests showed significant increases relative to baseline broadly across multiple timepoints within both the sham and active groups (all p < 0.02 except for the active group post-treatment time-point).

“The NIH cognitive toolbox fluid composite score and multiple individual tests showed significant increases relative to baseline broadly across multiple timepoints within both the sham and active groups (all p < 0.02 except for the active group post-treatment time-point).”

May combine two claims.

Two patients dropped out of the study due to difficulties tolerating the stimulation, one in each group.

“Two patients dropped out of the study due to difficulties tolerating the stimulation, one in each group.”

May combine two claims.

No significant effects of time or time x treatment interactions on VAS pain were detected.

“No significant effects of time (F (2.600, 67.31) = 0.93, p = 0.42) or time x treatment (F (9, 233) = 0.97, p = 0.46) interactions were detected.”

May combine two claims.

CBM-iTBS delivered twice daily for ten sessions does not have clear, robust antidepressant or cognitive-enhancing effects separable from the sham response.

“CBM-iTBS delivered twice daily for ten sessions does not have clear, robust antidepressant or cognitive-enhancing effects separable from the sham response”

• AssumptionThe authors state this as an assumption: The sham condition produced a placebo (non-specific) response.
• AssumptionRests on an assumption: The active CBM-iTBS was delivered at an adequate intensity to engage cerebellar targets.

May combine two claims.

A protocol of ten sessions of CBM-iTBS in patients with schizophrenia has reduced negative symptoms, improved mood, and improved cognitive functioning.

“Specifically, a protocol of ten sessions of CBM-iTBS (delivered over 1–2 weeks) in patients with schizophrenia has demonstrated safety and tolerability (Demirtas-Tatlidede et al., 2010), reduced negative symptoms, improvements in mood, and improvements in cognitive functioning (Garg et al., 2016), with significant findings up to 24 weeks following treatment in controlled trials (Zhu et al., 2021).”

• cites Garg et al., 2016 sourceNot checked — no full text of the source

Classified as probably not a substantial claim. May combine two claims.

All subjects who had outcomes data at baseline and at least one follow-up timepoint were included in the analysis (n = 30), consistent with a modified intent-to-treat approach.

“All subjects who had outcomes data at baseline and at least one follow-up timepoint were included in the analysis (n = 30), consistent with a modified intent-to-treat approach.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The description of sham control conditions during the consent process was intentionally vague and lacked details necessary for participants to distinguish between the methods being applied.

“Finally, the description of sham control conditions during the consent process was intentionally vague and lacked the details necessary for participants to distinguish between the methods being applied.”

Classified as probably not a substantial claim. May combine two claims.

Active and sham sides of the coil were visually indistinguishable and produced similar auditory and tactile stimulation.

“To maintain participant and research TMS technician blinding, active and sham sides of the coil were visually indistinguishable and produced similar auditory and tactile stimulation.”

May combine two claims.

34 participants were enrolled and data from 30 participants were analyzed, at which point an interim analysis demonstrated futility in relation to separation of active and sham stimulation arms for the primary outcome endpoints and further data collection was terminated.

“34 participants were enrolled in the study and data from 30 participants was analyzed, at which point an interim analysis demonstrated futility in relation to separation of active and sham stimulation arms for the primary outcome endpoints and further data collection was terminated.”

May combine two claims.

CBM-iTBS is safe, feasible, and tolerable in individuals with bipolar disorder.

“In conclusion, CBM-iTBS is safe, feasible, and tolerable in individuals with bipolar disorder.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The target sample size was 40 participants based on effect sizes from published CBM-iTBS studies in schizophrenia.

“The target sample size for this study was 40 participants based on effect sizes from published CBM-iTBS studies in schizophrenia.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The study was approved by the Institutional Review Board at the University of Iowa and pre-registered on ClinicalTrials.gov (NCT03217110).

“The present study was approved by the Institutional Review Board at the University of Iowa and pre-registered on ClinicalTrials.gov (NCT03217110).”

Classified as probably not a substantial claim. May combine two claims.

The randomization schedule was generated and kept by an unblinded, senior member of the research team in a locked cabinet inaccessible to members of the research team or clinical assessors.

“The randomization schedule was generated and kept by an unblinded, senior member of the research team in a locked cabinet inaccessible to members of the research team or clinical assessors.”

Classified as probably not a substantial claim. May combine two claims.

CGI and MINI were administered by a board-certified, blinded psychiatrist on the research team; all other testing was conducted by a blinded research team member trained in administration of the given instrument.

“CGI and MINI were administered by a board-certified, blinded psychiatrist on the research team; all other testing was conducted by a blinded research team member trained in administration of the given instrument.”

Classified as probably not a substantial claim. May combine two claims.

Randomization was in a 1:1 allocation ratio to active or sham using a random number generator.

“After screening and informed consent, but before iTBS delivery, each participant was randomized in a 1:1 allocation ratio to either the active or sham condition using a random number generator (randomizer.org).”

May combine two claims.

Bipolar disorder type and mood state at pre-treatment were similar between groups.

“Bipolar disorder type and mood state at preTx were similar between groups.”

May combine two claims.

There was variability in the medications prescribed and taken by each patient, including five subjects who had minor psychotropic medication adjustments (four of five in the sham group).

“there was variability in the medications prescribed and taken by each patient, including five subjects who had minor psychotropic medication adjustments (four of five in the sham group)”

May combine two claims.

The present double-blind, sham-controlled clinical trial suggests that CBM-iTBS treatment delivered twice per day for five consecutive days is well tolerated, with side effects within the known safety profile of TMS for this patient population.

“The present double-blind, sham-controlled clinical trial suggests that CBM-iTBS treatment delivered twice per day for five consecutive days is well tolerated, with side effects within the known safety profile of TMS for this patient population.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The variability in medications could alter TMS effects and outcome reporting.

“which could alter TMS effects and outcome reporting”

May combine two claims.

Our primary effectiveness measures suggest that depressive symptoms in bipolar disorder improve with CBM-iTBS, although this improvement was similar to or more robust in the sham group at all timepoints other than the 8-week timepoint, as measured by the MADRS.

“Our primary effectiveness measures suggest that depressive symptoms in bipolar disorder improve with CBM-iTBS, although this improvement was similar to or more robust in the sham group at all timepoints other than the 8-week timepoint, as measured by the MADRS.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The sample included individuals with bipolar I and bipolar II disorder.

“the sample included individuals with bipolar I and bipolar II disorder”

Probably not a substantial claim: may not pass S3 (load-bearing).

Electric field modeling of the TMS was not utilized in this study.

“but it was not utilized here”

Classified as probably not a substantial claim. May combine two claims.

The strong sham (presumed placebo) response could be the result of frequent contact with the treatment team during the experimental protocol or the novelty of the experimental set-up.

“The strong sham (presumed placebo) response could be the result of frequent contact with the treatment team during the experimental protocol or the novelty of the experimental set-up.”

• AssumptionThe authors state this as an assumption: The sham condition produced a placebo (non-specific) response.

Probably not a substantial claim: may not pass S3 (load-bearing).

Evidence suggests that the placebo response in TMS has been increasing over the past two decades.

“evidence suggests that the placebo response in TMS has been increasing over the past two decades (Razza et al., 2018; Xu et al., 2023)”

• cites Razza et al., 2018 sourceNot checked — no full text of the source
• cites Xu et al., 2023Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

We enrolled participants with variable levels of depression and cognitive function without a minimum cut-off for symptom burden.

“We enrolled participants with variable levels of depression and cognitive function without a minimum cut-off for symptom burden”

Probably not a substantial claim: may not pass S3 (load-bearing).

The baseline difference was incorporated into the statistical model.

“was incorporated into the statistical model”

Probably not a substantial claim: may not pass S3 (load-bearing).

There was no mechanism for monitoring target engagement in this study.

“There was no mechanism for monitoring target engagement in this study.”

Probably not a substantial claim: may not pass S3 (load-bearing).

An unanticipated trend toward greater depression severity in the sham group was detected at the pre-treatment timepoint (p = 0.08).

“An unanticipated trend toward greater depression severity in the sham group was detected at the pre-treatment timepoint (p = 0.08), although baseline differences were factored into the statistical model.”

Probably not a substantial claim: may not pass S3 (load-bearing).

The posterior cerebellum has been implicated in sequence learning.

“the posterior cerebellum has been implicated in sequence learning (Pu et al., 2020)”

• cites Pu et al., 2020Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Numerically higher baseline depression ratings in the sham group, and mild to moderate levels of depression severity overall, may have impacted our ability to detect treatment response differences between groups.

“Numerically higher baseline depression ratings in the sham group, and mild to moderate levels of depression severity overall, may have impacted our ability to detect treatment response differences between groups.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Both of these decisions introduced additional demographic variability to the sample.

“Both of these decisions introduced additional demographic variability to the sample.”