CompletedNCT05144789Updated Jul 29, 2026Results posted

Personalized Therapeutic Neuromodulation for Anhedonic Depression

An interventional study of Active TBS-DLPFC and Active TBS-DMPFC in Treatment Resistant Depression, sponsored by Stanford University. Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2026-07-29.

Sponsored by Stanford University · Not applicable, Interventional, and Treatment

Phase: Not applicable
Study type: Interventional
Enrollment: 70
Allocation: Randomized
Ages: 18 Years to 80 Years
Sex: All

Study summary

This study will investigate the anti-anhedonic efficacy of a novel neurostimulation strategy termed accelerated intermittent theta burst stimulation (aiTBS) in participants with treatment resistant depression (TRD).

Read the detailed description

Repetitive transcranial magnetic stimulation (rTMS) is an established therapy for treatment-resistant depression. The approved method for treatment is 10Hz stimulation for 40 min over the left dorsolateral prefrontal cortex (L-DLPFC). This methodology has been effective in real world situations. The limitations of this approach include the duration of the treatment (approximately 40 minutes per treatment session, 5 days per week, for 4-8 weeks). Recently, the investigators have pursued modifying the treatment parameters to reduce treatment times with an accelerated treatment paradigm. This study aims to further study the accelerated protocol and examine changes in neuroimaging biomarkers.

Conditions studied

Treatment Resistant Depression

Browse trials for

Depressive Disorder, Treatment-Resistant 461

Keywords

transcranial magnetic stimulation
theta burst

In context

Depressive Disorder, Treatment-Resistant

461 studies on the registry are indexed under Depressive Disorder, Treatment-Resistant; 148 are open to participants now.

This study's enrollment of 70 is above the median of 53 across 388 interventional studies indexed under Depressive Disorder, Treatment-Resistant.

Browse Depressive Disorder, Treatment-Resistant studies →

Lead sponsor

Stanford University is the lead sponsor of 2,117 studies on the registry; 425 are open to participants now.

Of its 259 completed or terminated interventional studies of FDA-regulated products, 197 (76%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 80 Years
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Male or Female, between the ages of 18 and 80 at the time of screening.
Able to read, understand, and provide written, dated informed consent prior to screening. Proficiency in English sufficient to complete questionnaires / follow instructions during fMRI assessments and aiTBS interventions. Stated willingness to comply with all study procedures, including availability for the duration of the study, and to communicate with study personnel about adverse events and other clinically important information.
Currently diagnosed with Major Depressive Disorder (MDD)and meets criteria for a Major Depressive Episode, according to the criteria defined in the Diagnosis and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5).
The patient has demonstrated a failure of one or more trials of a pharmacological medication as treatment for MDD.
MADRS score of ≥20 at screening (Visit 1).
TMS naive.
Access to ongoing psychiatric care before and after completion of the study.
Must be on a stable antidepressant therapeutic regimen for 6 weeks prior to study enrollment and agree to continue this regimen throughout the study period.
In good general health, as evidenced by medical history.
For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation.
Agreement to adhere to Lifestyle Considerations throughout study duration.

Exclusion criteria

Exclusion Criteria:

Pregnancy
History of or current psychotic disorder or bipolar disorder
Severe borderline personality disorder
Diagnosis of Intellectual Disability or Autism Spectrum Disorder
Primary psychiatric condition other than MDD requiring treatment except stable comorbid anxiety disorder
Current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
Urine screening test positive for illicit substances
Acute suicide risk based on clinical judgement or a suicide attempt within the past 6 months
Any history of ECT (greater than 8 sessions) without meeting responder criteria
Recent (within 4 weeks of any clinical effect) or concurrent use of rapid acting antidepressant agent (i.e., ketamine or a course of ECT)
History of significant neurologic disease, including dementia, Parkinson's or Huntington's disease, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma
Untreated or insufficiently treated endocrine disorder.
Contraindication to receiving rTMS (e.g., metal in head, history of seizure, known brain lesion)
Contraindication to MRI (ferromagnetic metal in their body)
Treatment with an investigational drug or other intervention within the study period
Depth-adjusted aiTBS treatment dose > 65% maximum stimulator output (MSO)
Unstable symptoms between screening and baseline as defined by a ≥ 30% change in MADRS score.
Any other condition deemed by the PD to interfere with the study or increase risk to the participant

Study design

Phase: Not applicable
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment: 70 participants (actual)

Study arms

Active comparator
Active TBS-DLPFC
The active group will receive theta-burst TMS stimulation.
Device: Active TBS-DLPFC
Active comparator
Active TBS-DMPFC
The active group will receive theta-burst TMS stimulation.
Device: Active TBS-DMPFC
Sham comparator
Sham Comparator: Sham TBS-DLPFC or DMPFC
The sham group will receive sham theta-burst TMS stimulation.
Device: Sham TBS-DLPFC or DMPFC

Interventions

DeviceActive TBS-DLPFC
Participants in the active stimulation group will receive intermittent TBS to left DLPFC. The L-DLPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the L-DLPFC using a MagPro TMS system (MagVenture, Denmark).
DeviceActive TBS-DMPFC
Participants in the active stimulation group will receive intermittent TBS to DMPFC. The DMPFC will be targeted utilizing the Localite neuronavigation system. Stimulation intensity will be standardized at 90% of RMT and adjusted to the skull to cortical surface distance (see Nahas 2004). Stimulation will be delivered to the DMPFC using a MagPro TMS system (MagVenture, Denmark).
DeviceSham TBS-DLPFC or DMPFC
The parameters in the sham arm will be as above with the internal randomization of the device internally switching to sham in a blinded fashion.

What researchers measure

Primary outcomes

Percentage Change in MADRS Score
The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item self-survey administered scale, designed to be particularly sensitive to antidepressant treatment effects in patients with major depression. Score range: 0 to 54, higher scores correspond to more severe depressive symptoms.
Time frame: Baseline, immediate post treatment (up to 2 weeks post baseline), 4 weeks and 8 weeks post treatment.
Percentage Change in SHAPS Score
The Snaith-Hamilton Pleasure Scale is a 14-item self-report questionnaire designed to measure the reduced ability to experience pleasure. Score range: 0 to 14, higher scores indicate higher levels of anhedonia.
Time frame: Baseline, immediate post treatment (up to 2 weeks post baseline), 4 week and 8 week post treatment.

Results

Posted Jul 29, 2026

Participant flow

Participants received treatment over a period of 1 week starting approximately 3 - 6 days after baseline, and had follow up assessments at 4 weeks and 8 weeks post treatment.

Participant flow — Overall Study
Milestone	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS
Started	23	23	22
Completed	21	19	21
Not completed	2	4	1

Outcome measures

PrimaryPercentage Change in MADRS Score

The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item self-survey administered scale, designed to be particularly sensitive to antidepressant treatment effects in patients with major depression. Score range: 0 to 54, higher scores correspond to more severe depressive symptoms.

Time frame:: Baseline, immediate post treatment (up to 2 weeks post baseline), 4 weeks and 8 weeks post treatment.
Reported as:: Mean · percentage of change

Percentage Change in MADRS Score
percentage of change	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS
Change Immediately Post Treatment	32.06 ± 34.95	26.30 ± 37.42	25.13 ± 35.61
Change at 4 Weeks Post Treatment	20.10 ± 31.22	23.04 ± 35.40	18.21 ± 37.20
Change at 8 Weeks Post Treatment	16.44 ± 24.86	28.15 ± 23.99	7.61 ± 32.35

PrimaryPercentage Change in SHAPS Score

The Snaith-Hamilton Pleasure Scale is a 14-item self-report questionnaire designed to measure the reduced ability to experience pleasure. Score range: 0 to 14, higher scores indicate higher levels of anhedonia.

Time frame:: Baseline, immediate post treatment (up to 2 weeks post baseline), 4 week and 8 week post treatment.
Reported as:: Mean · percentage of change

Percentage Change in SHAPS Score
percentage of change	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS
Change Immediately Post Treatment	38.17 ± 47.24	18.97 ± 79.58	14.20 ± 80.14
Change at 4 Week Post Treatment	32.10 ± 54.97	29.60 ± 58.51	12.40 ± 56.95
Change at 8 Week Post Treatment	38.07 ± 54.26	36.72 ± 27.34	19.45 ± 56.08

Adverse events

Collected over Adverse events were collected over a 10 week period. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Active TBS-DLPFC	0/23 (0%)	0/23 (0%)	0/23 (0%)
Active TBS-DMPFC	0/23 (0%)	0/23 (0%)	0/23 (0%)
Sham TBS	0/22 (0%)	0/22 (0%)	0/22 (0%)

Baseline characteristics

Participants who completed the protocol

Age, Categorical
Age, Categorical(Participants)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
<=18 years	0	0	0	0
Between 18 and 65 years	16	18	17	51
>=65 years	5	1	4	10

Age, Continuous
Age, Continuous(years)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
Mean	50.2 ± 16.2	38.8 ± 12.4	15.6 ± 15.2	47.2 ± 15.6

Sex: Female, Male
Sex: Female, Male(Participants)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
Female	9	11	13	33
Male	12	8	8	28

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
Hispanic or Latino	1	2	1	4
Not Hispanic or Latino	20	17	19	56
Unknown or Not Reported	0	0	1	1

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
American Indian or Alaska Native	0	0	0	0
Asian	0	3	2	5
Native Hawaiian or Other Pacific Islander	0	0	0	0
Black or African American	0	1	1	2
White	20	14	18	52
More than one race	0	1	0	1
Unknown or Not Reported	1	0	0	1

Montgomery-Asberg Depression Rating Scale (MADRS)
Montgomery-Asberg Depression Rating Scale (MADRS)(score on a scale)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
Mean	28.57 ± 7.14	24.68 ± 2.08	27.43 ± 4.83	26.97 ± 5.93

Snaith-Hamilton Pleasure Scale (SHAPS)
Snaith-Hamilton Pleasure Scale (SHAPS)(score on a scale)	Active TBS-DLPFC	Active TBS-DMPFC	Sham TBS	Total
Mean	9.29 ± 4.11	9.19 ± 2.79	7.16 ± 2.65	8.59 ± 3.36

Study locations

1 site

Department of Psychiatry and Behavioral Sciences, Stanford School of Medicine
Stanford, California 94305, United States

References and documents

Publications

George MS, Lisanby SH, Avery D, McDonald WM, Durkalski V, Pavlicova M, Anderson B, Nahas Z, Bulow P, Zarkowski P, Holtzheimer PE 3rd, Schwartz T, Sackeim HA. Daily left prefrontal transcranial magnetic stimulation therapy for major depressive disorder: a sham-controlled randomized trial. Arch Gen Psychiatry. 2010 May;67(5):507-16. doi: 10.1001/archgenpsychiatry.2010.46. PubMed 20439832 ↗
George MS, Wassermann EM, Williams WA, Callahan A, Ketter TA, Basser P, Hallett M, Post RM. Daily repetitive transcranial magnetic stimulation (rTMS) improves mood in depression. Neuroreport. 1995 Oct 2;6(14):1853-6. doi: 10.1097/00001756-199510020-00008. PubMed 8547583 ↗
Pascual-Leone A, Rubio B, Pallardo F, Catala MD. Rapid-rate transcranial magnetic stimulation of left dorsolateral prefrontal cortex in drug-resistant depression. Lancet. 1996 Jul 27;348(9022):233-7. doi: 10.1016/s0140-6736(96)01219-6. PubMed 8684201 ↗
Chung SW, Hill AT, Rogasch NC, Hoy KE, Fitzgerald PB. Use of theta-burst stimulation in changing excitability of motor cortex: A systematic review and meta-analysis. Neurosci Biobehav Rev. 2016 Apr;63:43-64. doi: 10.1016/j.neubiorev.2016.01.008. Epub 2016 Feb 3. PubMed 26850210 ↗
Jelic MB, Milanovic SD, Filipovic SR. Differential effects of facilitatory and inhibitory theta burst stimulation of the primary motor cortex on motor learning. Clin Neurophysiol. 2015 May;126(5):1016-23. doi: 10.1016/j.clinph.2014.09.003. Epub 2014 Sep 16. PubMed 25281475 ↗
Chung SW, Hoy KE, Fitzgerald PB. Theta-burst stimulation: a new form of TMS treatment for depression? Depress Anxiety. 2015 Mar;32(3):182-92. doi: 10.1002/da.22335. Epub 2014 Nov 28. PubMed 25450537 ↗
Plewnia C, Pasqualetti P, Grosse S, Schlipf S, Wasserka B, Zwissler B, Fallgatter A. Treatment of major depression with bilateral theta burst stimulation: a randomized controlled pilot trial. J Affect Disord. 2014 Mar;156:219-23. doi: 10.1016/j.jad.2013.12.025. Epub 2013 Dec 28. PubMed 24411682 ↗
Prasser J, Schecklmann M, Poeppl TB, Frank E, Kreuzer PM, Hajak G, Rupprecht R, Landgrebe M, Langguth B. Bilateral prefrontal rTMS and theta burst TMS as an add-on treatment for depression: a randomized placebo controlled trial. World J Biol Psychiatry. 2015 Jan;16(1):57-65. doi: 10.3109/15622975.2014.964768. Epub 2014 Nov 28. PubMed 25430687 ↗
Daskalakis ZJ. Theta-burst transcranial magnetic stimulation in depression: when less may be more. Brain. 2014 Jul;137(Pt 7):1860-2. doi: 10.1093/brain/awu123. Epub 2014 May 15. No abstract available. PubMed 24833712 ↗
Thut G, Pascual-Leone A. A review of combined TMS-EEG studies to characterize lasting effects of repetitive TMS and assess their usefulness in cognitive and clinical neuroscience. Brain Topogr. 2010 Jan;22(4):219-32. doi: 10.1007/s10548-009-0115-4. Epub 2009 Oct 28. PubMed 19862614 ↗
Holtzheimer PE 3rd, McDonald WM, Mufti M, Kelley ME, Quinn S, Corso G, Epstein CM. Accelerated repetitive transcranial magnetic stimulation for treatment-resistant depression. Depress Anxiety. 2010 Oct;27(10):960-3. doi: 10.1002/da.20731. PubMed 20734360 ↗
Fung PK, Robinson PA. Neural field theory of synaptic metaplasticity with applications to theta burst stimulation. J Theor Biol. 2014 Jan 7;340:164-76. doi: 10.1016/j.jtbi.2013.09.021. Epub 2013 Sep 21. PubMed 24060620 ↗
Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the motor cortex of resting human brain using echo-planar MRI. Magn Reson Med. 1995 Oct;34(4):537-41. doi: 10.1002/mrm.1910340409. PubMed 8524021 ↗
Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the resting brain: a network analysis of the default mode hypothesis. Proc Natl Acad Sci U S A. 2003 Jan 7;100(1):253-8. doi: 10.1073/pnas.0135058100. Epub 2002 Dec 27. PubMed 12506194 ↗
Fox MD, Snyder AZ, Vincent JL, Corbetta M, Van Essen DC, Raichle ME. The human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9673-8. doi: 10.1073/pnas.0504136102. Epub 2005 Jun 23. PubMed 15976020 ↗
Greicius MD, Supekar K, Menon V, Dougherty RF. Resting-state functional connectivity reflects structural connectivity in the default mode network. Cereb Cortex. 2009 Jan;19(1):72-8. doi: 10.1093/cercor/bhn059. Epub 2008 Apr 9. PubMed 18403396 ↗

Study documents

Protocol and statistical analysis plan · Jul 1, 2024

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jul 29, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT05144789
Lead sponsor: Stanford University
Responsible party: David Spiegel (Professor, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford University) — Principal investigator
First posted: Dec 3, 2021
Start date: May 31, 2022
Primary completion: Jun 6, 2025
Completion: Dec 31, 2025
Results posted: Jul 29, 2026
Last update: Jul 29, 2026

Study contacts

David Spiegel, MD

principal investigator · Stanford University

Oversight

Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: Yes

View the source record on ClinicalTrials.gov ↗

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