Prolonged transcranial magnetic stimulation in a pregnant patient with treatment-resistant depression: a case report

Abstract

Introduction

Perinatal depression is a serious and highly prevalent medical condition in the USA. Nearly 85% of individuals with perinatal depression go untreated, leading to significant morbidity and mortality. There is an urgent need to develop and advance safe and effective treatments for perinatal depression. Transcranial magnetic stimulation is an established intervention for depression in non-pregnant individuals yet is not well studied in perinatal depression.

Case presentation

A 33-year-old pregnant Latina female presented with severe, recurrent, treatment-resistant depression and suicidal ideation. The patient had previously trialed psychotherapy, multiple antidepressants, and mood stabilizers and had achieved remission with lithium prior to pregnancy. Due to pregnancy and fetal safety concerns, the patient discontinued lithium and consequently suffered progressive worsening of perinatal depression. At 24 weeks gestation and after additional failed medication trials, a prolonged course of transcranial magnetic stimulation was initiated. Following 46 transcranial magnetic stimulation treatments over 9 weeks using two protocol types (repetitive transcranial magnetic stimulation and intermittent theta burst stimulation), she achieved near-remission of perinatal depression and resolution of suicidal ideation. There were no identified maternal or fetal adverse events at 6 weeks post-delivery.

Conclusion

To our knowledge, this is the first published case of a pregnant individual with perinatal depression who received and tolerated a prolonged transcranial magnetic stimulation course with two distinct protocols (repetitive transcranial magnetic stimulation and intermittent theta burst stimulation) with clinically significant response. Transcranial magnetic stimulation is a well-tolerated and effective intervention that warrants further investigation for use in treatment-resistant perinatal depression.

Key Points

• Perinatal depression is a serious and potentially life-threatening condition with long-term maternal and fetal adverse outcomes.

• While antidepressants and psychotherapy are considered first-line treatments for perinatal depression, there is limited efficacy in treatment-resistant perinatal depression.

• Transcranial magnetic stimulation has potential as an effective, well-tolerated, alternative modality for treatment- resistant perinatal depression that warrants further investigation.

• Future studies of transcranial magnetic stimulation in treatment-resistant perinatal depression should explore different protocols to determine the optimal approach for this population.

Introduction

Depression is one of the most common and serious medical conditions affecting pregnant and postpartum people, impacting more than 1 in 10 individuals in this population [1]. Pregnancy causes changes in the hypothalamic–pituitary–adrenal axis that can worsen depression. Some individuals are more sensitive to changes in reproductive hormone levels during pregnancy and after delivery, which may increase their risk of developing perinatal depression (PND) [1]. In the USA, 50–75% of PND cases go undiagnosed and nearly 85% of individuals with PND go untreated [2]. Untreated PND is associated with preterm birth, low birth weight, lower Apgar scores, pregnancy-associated hypertension, and impaired maternal–infant bonding [3]. Furthermore, according to national mortality data approximately one in five pregnancy-related deaths in the USA are related to a maternal mental health condition [4].

Early treatment of PND may reduce the risk of associated adverse outcomes. Treatment guidelines from the American Psychiatric Association and American College of Obstetrician and Gynecologists recommend psychotherapy as first-line treatment for mild to moderate PND, and antidepressant medication as first-line treatment for moderate to severe PND [5]. However, depression remission can be difficult to achieve with medications alone, as only 28–33% of patients achieve remission after 4–6 weeks on a therapeutic dose [6]. Other augmentation strategies for perinatal unipolar and bipolar depression include second generation antipsychotics (SGAs), though these are known to cross the blood–placental barrier, and few studies have examined their fetal effects [3, 7, 8]. Mood stabilizers (e.g., lithium, valproic acid) are widely utilized in treating and preventing acute depressive episodes but are less frequently utilized in PND due to potential fetal teratogenic effects in the first trimester [9]. To address the maternal mental health crisis in the USA, additional safe and effective treatment modalities are urgently needed.

Transcranial magnetic stimulation (TMS) is a non-invasive, well tolerated, US Food and Drug Administration (FDA)-approved treatment for treatment-resistant depression that uses magnetic fields to alter the excitability of brain nerve cells [11]. TMS is a less invasive alternative to electroconvulsive therapy (ECT), the gold standard for treatment-resistant depression, and has potential to be an effective and safe treatment option for treatment-resistant PND. Repetitive TMS (rTMS) is delivered in an outpatient setting with each session lasting 15–20 min. A new form of TMS, intermittent theta burst stimulation (iTBS), was approved by the FDA in 2021 and has been adopted into clinical practice [12]. In clinical trials with non-pregnant individuals, iTBS was non-inferior to rTMS. Additionally, iTBS can be delivered in less time relative to rTMS due to a more efficient temporal pattern (total delivery time < 5 min) [13]. Both TMS protocols have been used clinically for treatment-resistant unipolar and bipolar depression [14].

While TMS is highly efficacious in treating depression among non-pregnant individuals, its efficacy and safety profile has not been clearly established during pregnancy. A recent review of TMS safety in PND included 10 case reports and 1 RCT for a total of 67 cases of pregnant individuals who were treated with different TMS protocols between 1999 and 2020. Of the 67 cases reviewed, iTBS was utilized in only 5 cases. There were no clinically significant maternal or fetal side effects reported among these studies [15]. Data from the only RCT to date demonstrated that TMS is an effective and safe intervention in treating depression in pregnant individuals [16]. On average, pregnant individuals received 20 TMS treatment sessions. Overall, this preliminary evidence suggests that rTMS may be a safe and effective treatment for PND, but evidence for iTBS in this population remains sparse.

Case presentation

Our patient, a 33-year-old primigravida who identifies as a Latina female and presented at 24 weeks gestational age with worsening depression and suicidal ideation (SI) since the beginning of pregnancy. The patient had a family history of depression (mother and sibling) and bipolar depression (maternal aunt). The patient denied any history of abuse including physical, emotional, or sexual abuse. During her second depressive episode while in college, she was initially diagnosed with major depressive disorder. She was trialed on citalopram 20 mg daily without clinical response and could not tolerate 40 mg dose due to side effects of anxiety, activation, and insomnia. She was subsequently treated with multiple antidepressant medications without clinical response, including venlafaxine, duloxetine, and bupropion. The major features of her depressive episodes included difficulty functioning, fatigue, anhedonia, hypersomnia, and passive SI. In her late 20s, she was hospitalized with severe depression. Based on historical selective serotonin reuptake inhibitor (SSRI)-induced activation and insomnia, she was diagnosed with bipolar depression at that time.

Timeline of current depressive episode

During the 2 years leading up to her pregnancy, she was treated with a combination of lamotrigine 150 mg and lithium 450 mg daily. She found that the addition of lithium stabilized her mood and largely prevented severe depressive episodes, although she continued to experience periods of worsening mood that coincided with beginning of fall and winter. She denied experiencing hypomanic or manic symptoms. In preparation for pregnancy, lithium was discontinued due to concern for Ebstein anomaly, a rare congenital cardiac condition associated with lithium use during pregnancy. Lamotrigine was continued. During the first 2 months of pregnancy, depressive symptoms continued to worsen. She briefly trialed sertraline 50 mg daily during the first trimester, which was ultimately discontinued due to restlessness, dysphoria, and concern about the risk of fetal exposure to medications. She developed intolerable cognitive side effects with lamotrigine titration to 300 mg daily.

As she entered the second trimester, her mood significantly declined. She endorsed worsening sadness, hypersomnia, increased crying spells, difficulty concentrating and finishing tasks daily. She reported more frequent SI with transient periods of contemplating plans to ingest antifreeze, although she denied any intent to act on these thoughts. She had no manic or psychotic symptoms. Augmentation with an SGA or restarting lithium in the second trimester were discussed as potential treatment options. However, she declined these options due to concern about potential fetal adverse effects. Due to the severity of depression, ongoing suicidality, and concerns about the fetal side effects of oral psychotropics, she was referred to a treatment-resistant depression clinic for further evaluation.

Investigations

The patient completed a comprehensive consult including a detailed psychiatry history, psychiatry review of system, physical exam, mental status exam, medical history, family history, and social history. The self-rated Quick Inventory of Depressive Symptomatology (QIDS-SR) score at gestational age 24 weeks was 17, indicative of severe depression.

Diagnostic assessment

The patient’s presentation and QIDS-SR score was consistent with a depressed episode. Based on a history of multiple failed antidepressant trials and lack of distinct manic or hypomanic episodes, our working diagnosis was treatment-resistant unipolar depression, though could not rule out bipolar disorder due to her past response to SSRIs.

Based on the severity of her depression, ongoing passive SI, limited response to first line treatments (SSRIs) and psychotherapy and her desire to avoid other indicated psychopharmacological options due to concerns about adverse fetal side effects, she was considered a candidate for TMS. After thorough discussion of risks and benefits, she was agreeable to proceed with TMS treatment.

Therapeutic intervention

After completing a safety screening assessment for TMS by the consulting team, she was cleared for TMS treatment. At the first TMS visit, resting motor threshold (RMT) was measured by applying single TMS pulses to the left motor cortex and noting the lowest stimulation intensity (amplitude) that elicited visible movement in the right thumb or fingers on three of five trials. RMT was 50% of maximum machine output. To identify the left dorsolateral prefrontal cortex (DLPFC) stimulation target, the adjusted Beam F3 location was determined using the 10–20 system and an online calculator tool (clinicalresearcher.org). The MagVenture R30 stimulator and cool-B65 coil were used. All stimulation was delivered with a treatment intensity of 60% (1.2× RMT). Weekly QIDS-SR scores were obtained over the course of treatment to determine response (Table 1).

Table 1.

Summary of the participant’s TMS (iTBS and rTMS) treatment course and clinical response during pregnancy

Treatment type/settings	Week of treatment	Cumulative number of daily treatment sessions	QIDS-SR*	Gestational age (GA), weeks
iTBS/600 pulses/session	0	0	17	24
	1	5	19	26
	2	11	13	27
	9-day pause—patient on vacation
	3	12	14	29
	4	17	13	30
	5	21	12	31
	6	25	14	32
rTMS (10 Hz)/3000 pulses/session	7	36	13	33
rTMS (10 Hz)/4000 pulses/session	8	41	10	34
	9	46	9	35

^*Self-reported Quick Inventory of Depressive Symptomatology (QIDS-SR) score interpretation: 0–5 subclinical depression, 6–10 mild depression, 11–15 moderate depression, 16–20 severe depression, 21–27 very severe depression

The initial stimulation protocol employed intermittent theta-burst stimulation (iTBS; bursts of three pulses separated by 20 millisecond, 2-second trains delivered at 5 Hz, with an 8-second intertrain interval, 600 pulses/session). The patient received a series of 29 daily iTBS treatments over a 47-day period, including a 9-day pause while she was away on vacation. Treatments were well tolerated, reporting only mild scalp discomfort at the stimulation site. She reported no major mood shifts with iTBS but reported feeling “a little lighter” with less frequent SI during the initial treatment phase.

Despite initial improvement, patient response plateaued with no further improvement after a total of 29 daily iTBS treatments between weeks 3 and 6. Based on diagnostic uncertainty and emerging efficacy data of regular high frequency rTMS in bipolar depression [17, 18], the protocol was switched to conventional high-frequency rTMS (10 Hz, 4-second trains, 11-second intertrain interval, 3000 pulses/session) with the same DLPFC target. After 7 daily treatments with the new protocol, she and her family noted significant improvement in mood and energy. Due to positive clinical response and good tolerability of the treatments, the 10-Hz stimulation protocol was extended to 4000 pulses/session. At the 9th week of TMS treatment series and after ten additional daily treatments, she reported continued improvement in mood, energy, interest, and SI. Her QIDS item 12 score was 0 indicating “I do not think of death or suicide.” Her appetite and sleep were still somewhat disturbed, which she attributed to pregnancy. She reported that her core symptoms of depression were near remission. Throughout the TMS series, lamotrigine was continued without dose adjustments.

Follow-up and outcome

From an obstetrical perspective, her pregnancy was uncomplicated. Initial obstetric abdominal ultrasound performed at gestational age of 18 weeks and 6 days showed normal anatomy. A follow up ultrasound at gestational age of 31 weeks and 3 days showed normal growth with a potentially enlarged right kidney that was deemed a normal anatomic variant. Regular monthly prenatal visits were completed without any documented maternal or fetal abnormalities.

In the postpartum period, rTMS was tapered to 25 treatments over 4 months (10 Hz, 4000 pulses/session) with good durability of clinical response. In total, she received 71 TMS sessions (178,400 TMS pulses). She had a spontaneous vaginal delivery at 37 weeks and 5 days without complication. The infant had an Apgar score of 7 at 1 minute and 9 at 5 minutes and weighed 2955 g. Both the patient and her infant had an unremarkable postpartum and neonatal course through 6 weeks post-delivery.

Discussion

Here we present a case of a patient with PND who was successfully treated with an extended TMS series. To our knowledge, this is the first case to describe a prolonged TMS course in PND with iTBS and rTMS protocols. Our patient underwent TMS treatment after demonstrating poor response to medications for severe depression with suicidality during pregnancy. She had limited improvement with iTBS protocol initially, followed by a remarkable response to conventional high frequency rTMS. By the end of the treatment course, she achieved near-remission of PND and total resolution of SI without any observed maternal or fetal complications.

There was a marked difference in response to TMS protocol type, which suggests that treatment type and settings may be important factors to consider in patients with PND. The diagnostic uncertainty in her case is also relevant. Our patient clearly presented with PND, though it was uncertain whether this was a manifestation of an underlying unipolar or bipolar mood disorder. While the efficacy of rTMS in treating unipolar depression in nonpregnant individuals has been well established in the literature since 2008, its efficacy in treatment of bipolar depression is still debated. McGirr et al. found no difference in a randomized controlled trial comparing iTBS and sham TMS in nonpregnant patients with acute bipolar depression [17]. In contrast, a recent meta-analysis of rTMS in bipolar depression found that rTMS was superior to sham in three out of nine sham-controlled randomized controlled trials [18]. Given our patient’s robust response after changing the protocol from iTBS to rTMS, clinicians may consider switching TMS protocols in the case of treating pregnant patients with possible bipolar depression. Bipolar depression may require different paradigms for TMS treatment and requires further investigation in both pregnant and nonpregnant individuals.

It must also be considered that the prolonged duration of treatment and hence relatively high number of total treatment sessions alleviated our patient’s depressive symptoms. This is consistent with the recently introduced concept that delivering a higher “dose” of TMS can improve response rate to treatment. This concept has been well established with ECT but more recently has been applied to TMS through the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) protocol, which delivers 10 iTBS treatments daily for 5 consecutive days (90,000 total TMS pulses) and is associated with remission rates up to 87% [19].

This case is novel in that it explores the efficacy and safety of two TMS approaches in a case of treatment-resistant PND. Our observations support the existing yet limited evidence that TMS may be a safe and effective treatment option for PND. The main limitation of this case is that we were unable to evaluate the sustainability of her mood remission with long term postpartum follow-up.

Conclusion

Neuromodulation therapies for PND are understudied in the literature and present an opportunity to develop novel treatment modalities with high clinical impact. Future investigations should focus on further establishing safety data for utilizing TMS in PND and examining the efficacy of different TMS treatment protocols and pulse strength among this patient population.

Author contributions

RJ and BJM oversaw the participants’ treatment course. RJ prepared the manuscript for publication. All authors read and approved the final manuscript.

Funding

No external funding was received for this work.

Availability of data and materials

Data sharing is not applicable to this article as no datasets were generated or analyzed during the present study.

Declarations

Ethics approval and consent to participate

The case did not require review by the University of Utah Institutional Review Board.

Consent for publication

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

Competing interests

The authors declare that they have no competing interests.