We are studying a treatment for depression called accelerated Transcranial Magnetic Stimulation (TMS) among pregnant and postpartum individuals. TMS is a focal, non-invasive form of brain stimulation that is cleared by the Food and Drug Administration for depression. Typically, traditional TMS involves daily treatments for 6-8 weeks. In this study, we will offer an accelerated form of TMS that involves multiple daily treatments for 5 days.

Perinatal depression is underdiagnosed, undertreated, and understudied. Approximately one in five individuals will experience perinatal depression, which spans from conception to one year after birth. Untreated perinatal depression increases the risk of stillbirth, preterm birth, substance abuse, parental suicide, and developmental delay. There are limited empirical data to guide treatment of perinatal depression. Psychotherapy can be effective for mild-to-moderate depression, but it is slow acting and difficult to access. Antidepressants show inconsistent benefits and safety; moreover, patients report feeling anxious or guilty about taking them.

Transcranial magnetic stimulation (TMS) is FDA cleared treatment for major depressive disorder, adolescent depression, late life depression, and anxious depression. It has also shown promise as a safe and effective biological intervention for perinatal depression for both the mother and fetus. One of the most exciting new developments in neurostimulation is accelerated intermittent theta burst stimulation (iTBS), a TMS protocol that involves multiple daily treatments rather than once daily treatment. A specific accelerated TMS protocol called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) was FDA cleared in September 2022 because of its rapid and robust antidepressant effects. In an open-label study (n=21), SNT significantly reduced depression in one day and yielded 90.5% remission after five days. Importantly, there is no evidence that accelerated TMS protocols pose more risk than conventional TMS protocols that have a strong safety profile.

While SNT is a potential breakthrough treatment, it has not been tested in peripartum individuals. Accelerated iTBS may expedite depressive symptom improvement and reduce the need for pharmacotherapy for individuals struggling with perinatal depression. If tolerable and efficacious, this treatment modality may increase the viable treatment options available to peripartum women with depressive symptoms.

In this pilot trial, patients who are currently pregnant or postpartum with treatment-resistant depression (n=12) will receive a modified SNT with neuronavigation. Treatment site location will be guided by MRI when possible given the promising internal findings highlighted above. However, if neuroimaging is not chosen by the patient, unsafe for the patient for any reason, or not tolerable for the patient, we will offer treatment with scalp-based measurement (i.e., TMS targeting based on Beam F3 method). Overall, this study is critically important for informing the viability of future accelerated iTBS trials in a peripartum population and may shape the future of affective treatment options in this patient group.

Inclusion Criteria:

• Age 18-55
• All individuals must be 14-34 weeks gestational age or within one year of delivery at the time of treatment. The odds of delivery nears 10% after 36 weeks, which would limit participants from being able to complete the study and interfere with the primary study aim to understand safety and tolerability. Additionally, after 36 weeks, the standard of care is weekly obstetric check-in visits, which would be challenging for patients to complete given the time demands of the study protocol.
• Patients will not be scanned after 32 weeks gestational age due to the time needed to construct the individualized treatment target. Individuals seeking treatment beyond 32 weeks will be offered scalp-based target localization so as not to limit patient access to care.
• English proficiency sufficient for informed consent, questionnaires/tasks, and treatment
• Primary diagnosis of major depressive disorder per DSM-V criteria (MINI International Neuropsychiatric Interview/ Structured Clinical Interview for DSM-5): >20 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and moderate to severe level of treatment resistance (Maudsley Staging Method)
• Stable antidepressant medication regimen, or remain medication free, for 4 weeks prior to treatment and to remain on this regimen throughout the treatment course. We request that this regimen remain stable until the 1 month post-treatment if clinically appropriate.
• Primary clinician (e.g. psychiatrist, therapist, psychologist, APRN, PA, etc.) responsible for psychiatric care before, during, and after the trial in addition to an obstetric provider responsible for obstetric care.
• Agreement to lifestyle considerations: Continue usual intake patterns of caffeine- or xanthine-containing products (e.g. coffee, tea, soft drinks, chocolate) throughout treatment

Exclusion Criteria:

• Concurrent use of rapid acting antidepressant agent (ketamine/esketamine/ECT)
• Receiving or planning to receive other TMS treatments during course of participation
• Obstetric concerns: Preeclampsia and/or current frequent, painful contractions (more than one every 10 minutes)
• History of: Neurosurgical intervention for depression, autism spectrum disorder, intellectual disability, severe cognitive impairment, significant neurological illness (e.g., dementia, Parkinson's, Huntington's, brain tumor, seizure disorder, subdural hematoma, multiple sclerosis, brain lesion), untreated or insufficiently treated endocrine disorder, and/or treatment with investigational drug or intervention during the study period
• ≥ 30% change in MADRS score between screening and baseline
• Anyone presenting with: Mania or hypomania, psychosis, active suicidal ideation with plan and some intent to act or a suicide attempt (defined by C-SSRS) within the past 3 months, neurological lesion, contraindications to either TMS or MRI (e.g., metallic implants, severe insomnia > 4 hours per night with hypnotic, etc.), and/or current moderate or severe substance use disorder or demonstrating signs of acute substance withdrawal
• Existing tinnitus (ringing in the ears) that causes functional impairment
• History of retinal detachment or other retinal pathology
• Severe borderline personality disorder
• Any other condition deemed by the PI to interfere with the study or increase risk to the participant