In 2008, the U.S. Food and Drug Administration (FDA) cleared repetitive transcranial magnetic stimulation (TMS) for treatment of major depressive disorder (MDD) in adults failing to receive benefit from antidepressant medications. Additional research and clinical practice confirmed the safety and efficacy of TMS in MDD (George et al. 2010), and clinicians and researchers rapidly began exploring the utility of TMS for other populations. Early work suggests that this noninvasive form of brain stimulation may be beneficial for other indications, such as bipolar depression (Dell’Osso et al. 2011), perinatal depression (Kim et al. 2015), adolescent depression (Donaldson et al. 2014), and late-life depression (Blumberger et al. 2015), thereby offering new options to impaired populations with limited effective therapeutics. Bipolar depression is pathophysiologically distinct from unipolar depression, carries a substantial disease burden, and has an inadequate evidence base to guide clinical treatment. Furthermore, recent drug development efforts for bipolar depression have concentrated on second-generation antipsychotics, which have an unacceptable side-effect burden for long-term use. Perinatal depression is a common and impairing condition that unfortunately is often undertreated. Depression in adolescence is a global public health problem contributing to academic failure, delays in social development, substance use, teen pregnancy, and completed suicide. Current treatment options for adolescent depression, which rely primarily on selective serotonin reuptake inhibitors (SSRIs) and evidence-based psychotherapeutic approaches such as cognitive-behavioral therapy (CBT), are often ineffective. Late-life depression is frequently undiagnosed; however, even when it is properly identified and treated, it follows a more insidious course than depression in younger populations. In this chapter, we survey recent research and clinical experience focused on the use of TMS in bipolar depression, perinatal depression, adolescent depression, and late-life depression. Existing information is nascent and larger randomized controlled trials are under way, but initial experience suggests that TMS may be a safe and effective alternative treatment for these indications. Although unique risk factors (e.g., the potential induction of mania and unknown, untoward effects on neurodevelopment) must be carefully considered, the consequences of untreated or inadequately treated depression in bipolar disorder, during the perinatal period, in adolescence, and later in life are significant. Existing knowledge may inform clinicians considering the off-label use of TMS in these populations. Within the scope of mood disorders, bipolar depression is especially difficult to manage. Treatment practice typically utilizes antidepressants combined with mood-stabilizing agents, despite the absence of clear evidence supporting efficacy of such treatment. Findings from the National Institute of Mental Health–funded Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large study that sought to identify best treatment practices in bipolar disorder, supported the notion that antidepressants added to mood stabilizers do not improve outcomes and may even carry the risk of precipitating a mixed or manic episode (El-Mallakh et al. 2015; Truman et al. 2007). The International Society for Bipolar Disorder published a consensus statement about the use of antidepressants in bipolar depression (Pacchiarotti et al. 2013), citing the striking incongruity of their wide use despite a weak evidence base for both safety and efficacy. Although the panel did not endorse the use of antidepressants, it did suggest that SSRIs and bupropion may have a lower risk than aminergic agents such as tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors in causing a manic switch and that patients with bipolar I depression are at higher risk than patients with bipolar II depression for negative outcomes. The current FDA-approved evidence base for the treatment of bipolar depression is limited to three second-generation antipsychotics, one of which is paired with an SSRI (i.e., quetiapine, lurasidone, and olanzapine plus fluoxetine) (Nierenberg et al. 2015). Their high side-effect burden (especially weight gain, sedation, and metabolic syndrome) makes them an unacceptable choice for many patients. One of the problems in developing safe and effective treatments for bipolar depression is that this population is quite heterogeneous, with subgroups that possibly require different pharmacological interventions (Altshuler et al. 2003; Goldberg et al. 2015). Another problem with the use of antidepressants is that it is hard, if not impossible, to target only one pole of a cyclical disorder with medications impacting nerve cells and receptor sites over extended periods of time. For patients with rapid-cycling bipolar disorder, continued use of antidepressants was found to be associated with worse outcomes (El-Mallakh et al. 2015). This raises the question as to whether neurostimulation such as TMS can provide briefer, episode-based interventions for bipolar depression without the risk of manic switches or mood destabilization. Although interest in the use of TMS to treat bipolar depression extends back two decades, the development of a clear evidence base is hampered by the lack of cohesiveness in the treatment paradigms used across multiple small studies. Studies have looked at left-sided high-frequency stimulation (>5 Hz), right-sided low-frequency stimulation (1 Hz), and sequential bilateral stimulation over the dorsolateral prefrontal cortex (DLPFC), with treatment course durations varying between 2 and 4 weeks. A meta-analysis looking at 19 different randomized clinical trials in patients with bipolar disorder (N=181) demonstrated efficacy for right-sided low-frequency stimulation and left-sided high-frequency stimulation but not for sequential bilateral stimulation (McGirr et al. 2016). Another heartening statistic was the very low rate of mood switching, with no significant difference between sham-controlled and active treatment groups (0.9% active vs. 1.3% sham) and no significant adverse events. A more recent study of 49 patients with bipolar and unipolar depression also did not find efficacy for sequential bilateral treatment (Fitzgerald et al. 2016), but this protocol used a very low number of pulses (i.e., 1,000, which is about one-third the normal dose) for each session of left-sided treatment, which may account for a diminished response rate. Another study (N=30) comparing right-sided low-frequency treatment with sequential bilateral treatment found that the latter produced a higher response rate (i.e., 80% vs. 47%) but an equal remission rate (i.e., 40%) (Kazemi et al. 2016). A randomized sham-controlled trial of deep TMS using the H1 coil in 50 patients with bipolar depression (20 treatments at 18 Hz with 55 two-second trains) showed a statistically significant separation by change in rating scale score (P=0.03), only a trend in categorical rate of response (P=0.08), and no separation by remission at 8-week follow-up (Tavares et al. 2017). The existing evidence base is heterogeneous for treatment delivery, type of bipolar disorder (e.g., I or II), and use of concomitant medication (subjects were generally not taking antidepressants but may have been taking mood stabilizers, depending on the study). There does, however, appear to be a trend that unilateral treatment (either left-sided high-frequency or right-sided low-frequency) may be more effective than sequential bilateral stimulation for bipolar depression. However, there has not been a head-to-head trial to guide clinicians on the most optimal stimulation protocol, and there is a need for larger trials with better defined homogeneous populations and unified treatment paradigms. Clinicians providing TMS to patients for bipolar depression have reported varied results, likely due, in part, to population heterogeneity and varying treatment parameters. A summary of the larger cohorts (with more than 10 patients) is provided in Table 8–1. In a retrospective study of 100 consecutive patients treated for depression in a university-based TMS clinic, Connolly et al. (2012) reported a 35% response rate and a 15% remission rate in the 20 patients with bipolar depression treated for 6 weeks with adjunctive TMS. The treatment was well tolerated, and there were no reports of manic symptoms, but the overall response and remission rates were lower in this subgroup than in the patients with major depression. In the largest study to date, a retrospective analysis of 39 patients with bipolar I or II depression treated at a specialized hospital-based TMS clinic, Aaronson and Daddario (2016) found higher response rates in the bipolar group than in the unipolar group. All patients were treated with left-sided high-frequency stimulation at 10 Hz, the standard protocol for major depression. Every patient was taking at least one mood stabilizer, and four of the patients with bipolar II disorder continued taking antidepressant medication. All patients had experienced at least two and up to six adequate medication trial failures for their depressive episodes. For the patients with bipolar I disorder, the response rate was 72% (13/18) and the remission rate was 44% (8/18). For the patients with bipolar II disorder, the response rate was 67% (14/21) and the remission rate was 28% (5/18). These data are shown in Figure 8–1. Agitation leading to discontinuation was seen in 17% (3/18) of the bipolar I group and 5% (1/21) of the bipolar II group. The agitation occurred within the first 2 weeks of treatment and did not meet criteria for mania or hypomania. Among those achieving remission, the average number of treatments to remission was 22. Compared with the 175 patients with unipolar depression treated at the same center, the patients with bipolar disorder had a higher average remission rate (36% vs. 31%), higher response rate (69% vs. 62%), and shorter course to remission (i.e., 22 vs. 29 sessions). Other than agitation there were no significant adverse events. As often happens in medicine, the clinical use of TMS in bipolar depression has outpaced the creation of a clear evidence base to support the safest and most effective use of this intervention. For a population as clinically underserved as individuals with bipolar depression, TMS may indeed offer a nonpharmacological treatment option that can be used episodically for depressive mood episodes and with a remarkably benign side-effect profile compared with systemically administered medications. However, some questions remain: Table 8–1. Open-label transcranial magnetic stimulation studies in bipolar depression (N>10) Reference N Treatment location; coil type Frequency; intensity; pulses/day Sessions Outcomes; measurement Side effects 11 R-DLPFC; Figure eight 1 Hz; 110% MT; 300 pulses 15 over 3 weeks 54.5% response, 36.4% remission; HDRS No mania/hypomania 19 L-DLPFC; H coil 20 Hz; 120% MT; 1,680 pulses 20 over 4 weeks 52.6% response, 63.2% remission; HDRS No mania/hypomania One generalized seizure 20 L-DLPFC; Figure eight 10 Hz; 120% MT; 3,000 pulses 30 over 6 weeks 35% response, 15% remission; CGI No serious adverse events 39 L-DLPFC; Figure eight 10 HZ; 120% MT; 3,000 pulses Up to 30 over 6 weeks BP1: 44% response, 72% remission BP2: 67% response, 27% remission; MADRS Treatment-emergent agitation in 17% of BP1 and 5% of BP2 No mania/hypomania Note. BP1=patients with bipolar I disorder; BP2=patients with bipolar II disorder; CGI=Clinical Global Impression Scale; HDRS=Hamilton Depression Rating Scale; L-DLPFC=left dorsolateral prefrontal cortex; MADRS=Montgomery-Åsberg Depression Rating Scale; MT=motor threshold; R-DLPFC=right dorsolateral prefrontal cortex. Figure 8–1. Response and remission rates in patients with bipolar I and II depression. Source. Adapted from Aaronson and Daddario 2016. Table 8–2 lists treatment considerations and recommendations that have been extrapolated from the existing evidence and clinical experience with the management of bipolar disorder, as well as from TMS treatment of unipolar depression. Table 8–2. Treatment considerations and recommendations for transcranial magnetic stimulation (TMS) in bipolar depression Establish a clear diagnosis with regard to the phase of the bipolar illness. Patients with bipolar I disorder are at higher risk for mixed or manic switches than are patients with bipolar II disorder and may need more protection with mood stabilizer support. Generally, patients in the mixed or manic phase of bipolar disorder are not good candidates for TMS, and there is no evidence to support its use. It is also doubtful that TMS can alleviate psychotic symptoms. Consider mood stabilizer support. History of each patient’s illness should help guide clinical decisions. Patients with higher risk of cycling or intensity of mania may do better with lithium or valproate plus a second-generation antipsychotic. Patients with low risk of instability may be managed with lamotrigine. Patients should take a mood stabilizer for a minimum of 2 weeks before starting TMS. Remember that antidepressants may be problematic. There is no clear evidence to support the use of antidepressants in this population. Give the patient at least 1–2 weeks to taper off antidepressants. Evaluate patients with bipolar disorder at least weekly while they are receiving TMS. This population is at higher risk for manic switches and is more likely to see earlier response and remission. Furthermore, these patients are at risk for premature discontinuation of TMS secondary to treatment-emergent agitation. Consider using the Young Mania Rating Scale (YMRS) and the Generalized Anxiety Disorder 7-item scale (GAD-7) to monitor for treatment-emergent agitation or subsyndromal manic symptoms. Use a depression rating scale such as the Montgomery-Åsberg Depression Rating Scale (MADRS) to determine severity of illness, and consider stopping TMS if remission criteria are met or if improvement has plateaued for 2 weeks after at least 25 treatments. Keep in mind that treatment parameters do not have a clear evidence base. The meta-analysis supported benefit for right-sided low-frequency and left-sided high-frequency treatment, but the evidence to justify sequential bilateral treatment was less clear (McGirr et al. 2016). Most TMS centers use the same parameters for bipolar depression as for unipolar depression—that is, left-sided high-frequency stimulation. Collect data and measure symptom improvement with both patient questionnaires and validated clinician rating scales. The more extensive the clinical experience, the more information can be gathered to optimize treatment with TMS in patients with bipolar depression. CLINICAL VIGNETTE The patient is a 40-year-old single woman who is a successful entrepreneur. She has been depressed for the past 6 months and mostly housebound because of her symptoms. Trials of several antidepressants from different classes were unsuccessful because of lack of response at adequate dose and duration or intolerable agitation and insomnia. Her initial diagnosis was unipolar depression, but consultation indicated a long history of psychomotor agitation, decreased need for sleep, and frequent racing thoughts. One parent also had a history of bipolar disorder. Subsequent interviews elicited that the patient has a complex pattern of cycling in her work: she is unable to function for months at a time but then has weeks of extreme productivity, somewhat marred by a pressure of speech, a brusque interpersonal style, the ability to function on 2 hours of sleep, and a sharp increase in alcohol consumption. Her diagnosis is changed to bipolar I disorder, and she begins taking lithium. After 4 weeks with an adequate blood level of the medication, her depression persists and she is recommended for a trial of TMS, which is administered over the left DLPFC at 10 Hz. She experiences a significant improvement in mood after 1 week and full remission after 15 sessions, without manic activation. Acute TMS treatment is then tapered. She has minor recurrences of her depression when she returns to work, but she responds to one TMS session every 2 weeks to successfully maintain remission. Perinatal (antenatal and postpartum) depression is a common disabling condition that is underdiagnosed and undertreated. Treatment is often suboptimal, with the potential for substantial untoward effects on mothers, fetuses, and developing neonates. For example, depression during the perinatal period is associated with problematic lifestyle choices such as nicotine and alcohol use, substandard self-care, and a considerable risk for suicide. All of these factors may present long-term negative consequences for child development given that exposure to maternal depression can create physiological and psychological stressors for the developing fetus or infant. These adverse effects impact placental epigenetic changes, fetal brain development, language development, and mother-infant bonding. Offspring of depressed mothers have an increased risk for depression, anxiety, and functional impairment (Kim et al. 2015; Stewart and Vigod 2016; Susser et al. 2016). Treatment of perinatal depression typically involves evidence-based psychotherapeutic approaches such as CBT or interpersonal psychotherapy, pharmacotherapy with SSRIs, or the combination of psychotherapy and antidepressants. Lack of access to screening and psychiatric expertise contributes to undertreatment, but studies also demonstrate that mothers are ambivalent about the use of psychotropic medications during pregnancy or while breastfeeding (Kim et al. 2015; Myczkowski et al. 2012; Stewart and Vigod 2016; Susser et al. 2016). Thus, neuromodulation modalities such as TMS may be important options, with advantages including the lack of systemic effects that could theoretically impact a developing fetus or an infant who is breastfeeding. Furthermore, no concurrent medications are administered with TMS, whereas electroconvulsive therapy (ECT) requires anesthetic agents (Kim et al. 2015; Myczkowski et al. 2012). The existing published literature that focuses on TMS for perinatal depression is summarized in Table 8–3. Although evidence from case studies and open-label trials must be interpreted with caution, early results are promising and underscore the necessity of further systematic research. Notably, a variety of low- and high-frequency dosing schedules, coil locations, and relatively brief treatment courses have been undertaken in all trimesters, as well as postpartum. Initial results demonstrate good outcomes in terms of depressive symptom improvement and maternal-fetal health. Early experience indicates that after 24 weeks of pregnancy, women receiving TMS should be positioned on their left side with a wedge cushion under the right lower back for a 30-degree tilt to avoid inferior vena cava compression syndrome, thus mitigating supine hypotension (Kim and Wang 2014; Kim et al. 2015). Researchers examined children (mean age=32.4 months; range 16–64 months) of mothers who had received TMS for depression during pregnancy and a control group of children (mean age=29.04 months; range 14–63 months) whose mothers had a history of untreated depression during pregnancy. In the TMS-treated group, two infants had jaundice and one infant had febrile convulsions. In the untreated group, three infants had jaundice and one infant had low birth weight. Mothers treated with TMS reported a perceived language delay in their children, but there was no actual difference when compared with children of untreated mothers. Results suggested that there were no cognitive or motor delays associated with antenatal TMS treatment for depression. Although these early results are encouraging (Eryılmaz et al. 2015; Kim et al. 2015), further systematic studies are warranted. Notably, we could not find any published reports using the deep TMS H-coil system in this population. Table 8–4 reviews clinical considerations for the use of TMS in treating perinatal depressions. Table 8–3. Published experience with transcranial magnetic stimulation (TMS) for perinatal depression Reference N Status of pregnancy Treatment location Frequency; intensity Sessions Outcomes 1 Second trimester L-DLPFC 5 Hz; 100% MT 14 Rapid improvement in depression and anxiety. Delivered healthy infant at term. 2 Second trimester L-DLPFC High-frequency; 100% MT 15 Healthy term delivery. Venlafaxine 225 mg/day concurrently. Third trimester R-DLPFC Low-frequency; 100% MT 15 Infant delivered at 36 weeks; mother had 1 week of “irritability” but healthy otherwise. 3 Early pregnancy Not reported Not reported Not reported “Significant” improvement in depressive symptoms. Uneventful deliveries with healthy infants. 9 Postpartum L-DLPFC 10 Hz; 120% MT 20 Significant improvement in depressive symptoms by week 2 (HDRS-24). 8 patients reached remission by week 4. At 6 months, 7 patients met criteria for remission without further treatment.
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Transcranial Magnetic
Stimulation for the
Treatment of Other
Mood Disorders
Bipolar Depression
CURRENT TREATMENT PARADIGM
EVIDENCE BASE FOR TMS IN BIPOLAR DEPRESSION: RANDOMIZED SHAM-CONTROLLED TRIALS AND A META-ANALYSIS
CLINICAL EXPERIENCE WITH TMS IN BIPOLAR DEPRESSION: OPEN-LABEL TRIALS AND CASE REVIEWS
OPEN QUESTIONS
TREATMENT CONSIDERATIONS AND RECOMMENDATIONS
Perinatal Depression
Related posts:
Transcranial Magnetic Stimulation and Other Neuromodulation Therapies
Clinical Applications and Patient Selection
Transcranial Magnetic Stimulation for Disorders Other Than Depression
Transcranial Magnetic Stimulation Therapy for Treatment-Resistant Depression
Transcranial Magnetic Stimulation and Psychotherapy
Current FDA-Cleared TMS Systems and Future Innovations in TMS Therapy
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