The Glutamatergic Effects of Clinical Repetitive Transcranial Magnetic Stimulation in Depressed Populations: A Preliminary Meta-Analysis of Proton Magnetic Resonance Spectroscopy Studies.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) alleviates symptoms of major depressive disorder, but its neurobiological mechanisms remain to be fully understood. Growing evidence from proton magnetic resonance spectroscopy (1HMRS) studies suggests that rTMS alters excitatory and inhibitory neurometabolites. This preliminary meta-analysis aims to quantify current trends in the literature and identify future directions for the field. METHODS: Ten eligible studies that quantified Glutamate (Glu), Glu+Glutamine (Glx), or GABA before and after an rTMS intervention in depressed samples were sourced from PubMed, MEDLINE, PsychInfo, Google Scholar, and primary literature following PRISMA guidelines. Data were pooled using a random-effects model, Cohen's d effect sizes were calculated, and moderators, such as neurometabolite and 1HMRS sequence, were assessed. It was hypothesized that rTMS would increase cortical neurometabolites. RESULTS: Within-subjects data from 224 cases encompassing 31 neurometabolite effects (k) were analyzed. Active rTMS in clinical responders (n = 128; k = 22) nominally increased glutamatergic neurometabolites (d = 0.15 [95% CI: -0.01, 0.30], p = 0.06). No change was found in clinical nonresponders (p = 0.8) or sham rTMS participants (p = 0.4). A significant increase was identified in Glx (p = 0.01), but not Glu (p = 0.6). Importantly, effect size across conditions were associated with the number of rTMS pulses patients received (p = 0.05), suggesting dose dependence. CONCLUSIONS: Clinical rTMS is associated with a nominal, dose-dependent increase in glutamatergic neurometabolites, suggesting rTMS may induce Glu-dependent neuroplasticity and upregulate neurometabolism. More, larger scale studies adhering to established acquisition and reporting standards are needed to further elucidate the neurometabolic mechanisms of rTMS.

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Transcranial magnetic stimulation maintenance as a substitute for maintenance electroconvulsive therapy: a case series.

BACKGROUND: Transcranial magnetic stimulation (TMS) is an efficacious, well-tolerated, noninvasive brain stimulation treatment for major depressive disorder. Electroconvulsive therapy (ECT) is an effective maintenance treatment for depression but is not tolerated by some patients and declined by others. OBJECTIVE: We evaluated the effectiveness of TMS as a substitution strategy for successful maintenance ECT. METHODS: A consecutive clinical case series (n = 6) of maintenance ECT patients were transitioned to maintenance TMS because of adverse effects from ECT or because of specific patient request and preference. Patients were in either full remission or had clinical response to ECT at the time of transition. Primary outcome was the change in the Beck Depression Inventory (BDI) score from initiation of TMS maintenance sessions to the last observation time point. Relapse of depressive symptoms was also documented. RESULTS: Mean age of patients was 64 years, and most were female (n = 5). The majority (5 of 6) were diagnosed with major depressive disorder. Reasons for transition from ECT to TMS were, in order of frequency, cognitive adverse effects, fear of general anesthesia, time burden, lack of remission with ECT, and stigma associated with ECT. The mean frequency of TMS sessions was 1 every 3.5 weeks. Based on BDI scores, all patients maintained or improved their clinical status achieved with ECT at 3 and 6 months of TMS treatment. At last observation (range, 7-23 months), 4 patients maintained or improved their clinical status (total BDI score remained constant or decreased by 1-8 points). Two patients had a relapse after 8 and 9 months. Stimulation was well tolerated with adverse effects limited to headache and scalp discomfort. CONCLUSIONS: In this case series, TMS was effective and safe when used as a substitution strategy for successful maintenance ECT.

Acute and maintenance electroconvulsive therapy for treatment of severe major depression during the second and third trimesters of pregnancy with infant follow-up to 18 months: case report and review of the literature.

Electroconvulsive therapy (ECT) is considered to be a safe and effective treatment in the management of severe mood disorders during pregnancy. Nevertheless, for the clinician in practice, decision making regarding ECT administration in this special population is challenging. This is due both to the risks of untreated or inadequately treated mental illness for the mother and the fetus as well as the risks of complications from ECT itself during pregnancy. Special measures and modifications of ECT procedures are required to minimize the risk of complications in pregnant patients undergoing ECT. Here we report the successful and safe administration of acute and continuation ECT in a 39-year-old pregnant patient with severe major depression. A total of 18 bilateral-bifrontal treatments were administered in the second and third trimesters of pregnancy with presession and postsession fetal monitoring. Following an elective cesarean delivery at 37 weeks of a healthy female infant, a total of 13 additional ECT treatments were administered as maintenance treatment in the first 6 months postpartum during which time the patient was successfully transitioned to antidepressant medication. Development of the child has been assessed as fully normal in all follow-up visits with the pediatrician out to 18 months.

Electroconvulsive therapy for treatment of major depression in a 100-year-old patient with severe aortic stenosis: a 5-year follow-up report.

Although there is no specific age cutoff for electroconvulsive therapy (ECT) and no absolute contraindication to its use, very old age and the presence of cardiac conditions such as aortic stenosis are factors that may negatively affect the physician's decision to administer ECT in individual cases. We report our follow-up of a 100-year-old woman with severe aortic stenosis who has received ECT safely for 5 years now. No cardiac complications have emerged during this period. Her prior unipolar depressive episode with catatonic features remains in remission with a single prophylactic ECT session every 3 months. We have observed from our experience with this unique case that periodic multidisciplinary re-evaluation of the evolving risk-benefit profile of ECT is essential along with the inclusion of family members in this dialogue. Our patient's course illustrates that neither advanced age nor severe aortic stenosis is an absolute contraindication to ECT even over an extended period of time. Each case needs to be evaluated on its merits. To our knowledge, this case represents the oldest patient in the literature where ECT has been administered safely for such an extended period in the setting of severe aortic stenosis.

Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression: A Decade of Clinical Follow-Up.

Objective: Deep brain stimulation (DBS) is an emerging therapy for treatment-resistant depression (TRD) that has shown variable efficacy. This report describes long-term outcomes of DBS for TRD.Methods: A consecutive series of 8 patients with TRD were implanted with ventral capsule/ventral striatum (VC/VS) DBS systems as part of the Reclaim clinical trial. Outcomes from 2009 to 2020 were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Demographic information, MADRS scores, and data on adverse events were collected via retrospective chart review. MADRS scores were integrated over time using an area-under-the-curve technique.Results: This cohort of patients had severe TRD-all had failed trials of ECT, and all had failed a minimum of 4 adequate medication trials. Mean ± SD follow-up for patients who continued to receive stimulation was 11.0 ± 0.4 years (7.8 ± 4.3 years for the entire cohort). At last follow-up, mean improvement in MADRS scores was 44.9% ± 42.7%. Response (≥ 50% improvement) and remission (MADRS score ≤ 10) rates at last follow-up were 50% and 25%, respectively. Two patients discontinued stimulation due to lack of efficacy, and another patient committed suicide after stimulation was discontinued due to recurrent mania. The majority of the cohort (63%) continued to receive stimulation through the end of the study.Conclusions: While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this small open-label study demonstrates that some patients achieve meaningful and sustained clinical benefit. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. Particular attention to factors including patient selection, integrative outcome measures, and long-term observation is essential for future trial design.Trial Registration: ClinicalTrials.gov identifier: NCT00837486.

Deep Brain Stimulation Is Effective for Treatment-Resistant Depression: A Meta-Analysis and Meta-Regression.

Major depressive disorder (MDD) is a leading cause of disability and a significant cause of mortality worldwide. Approximately 30-40% of patients fail to achieve clinical remission with available pharmacological treatments, a clinical course termed treatment-resistant depression (TRD). Numerous studies have investigated deep brain stimulation (DBS) as a therapy for TRD. We performed a meta-analysis to determine efficacy and a meta-regression to compare stimulation targets. We identified and screened 1397 studies. We included 125 citations in the qualitative review and considered 26 for quantitative analysis. Only blinded studies that compared active DBS to sham stimulation (k = 12) were included in the meta-analysis. The random-effects model supported the efficacy of DBS for TRD (standardized mean difference = -0.75, <0 favors active stimulation; p = 0.0001). The meta-regression did not demonstrate a statistically significant difference between stimulation targets (p = 0.45). While enthusiasm for DBS treatment of TRD has been tempered by recent randomized trials, this meta-analysis reveals a significant effect of DBS for the treatment of TRD. Additionally, the majority of trials have demonstrated the safety and efficacy of DBS for this indication. Further trials are required to determine the optimal stimulation parameters and patient populations for which DBS would be effective. Particular attention to factors including electrode placement technique, patient selection, and long-term follow-up is essential for future trial design.

Lack of effect of transcranial direct current stimulation (tDCS) on short-term smoking cessation: Results of a randomized, sham-controlled clinical trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) has been shown to improve measures of executive cognitive function and reduce cigarette consumption. Studies conducted to date have been small, and the results are mixed. METHODS: This randomized, double-blind, parallel arm clinical trial tested the effects of active anodal tDCS targeted to the left dorsolateral prefrontal cortex (versus sham) on 7-day smoking cessation in 106 treatment-seeking smokers. Participants received three sessions of sham (n = 35), 1 mA (n = 35), or 2 mA (n = 36) tDCS in the context of a validated smoking lapse paradigm then received brief smoking cessation counseling and completed a monitored quit attempt. The primary outcome was total number of days of abstinence confirmed via exhaled carbon monoxide. RESULTS: During the quit period, there were no effects of dose group on days of abstinence (sham, M (SD): 2.5 days (±2.5); 1 mA: 2.5 days (±2.5); 2 mA: 2.4 days (±2.3); ß = -0.08; p = 0.76) or on change in daily smoking rate (sham, M (SD): 12.6 CPD (±4.8); 1 mA: -11.8 CPD (±4.4); 2 mA: -11.7 CPD (±5.3); ß = 0.42, p = 0.49), nor were there effects of dose group on latency to smoke or number of cigarettes smoked during the smoking lapse paradigm. Side effects of tDCS were generally mild (<5 out of 10), and participants were not able to distinguish between active and sham treatment. CONCLUSIONS: These results do not support the efficacy of tDCS targeted to the left dorsolateral prefrontal cortex (DLPFC) for smoking cessation.

Uncommon but serious complications associated with electroconvulsive therapy: recognition and management for the clinician.

Electroconvulsive therapy (ECT) is a safe and effective treatment for severe mood disorders. Rarely there can be serious complications, such as postictal agitation, cardiovascular compromise, prolonged seizures, and status epilepticus, all of which are important for the clinician to recognize and treat. Postictal agitation can be severe, requiring emergent intervention and subsequent prophylactic measures to avoid premature ECT discontinuation. Cardiovascular responses to ECT include significant hemodynamic changes that may result in complications, even in patients without preexisting cardiovascular conditions. However, preexisting cardiovascular conditions per se are not contraindications to ECT in patients with disabling psychiatric disease. Recognizing and treating prolonged seizures is essential to prevent progression to status epilepticus. Failure to recognize and treat any of these events may result in increased mortality and morbidity. Understanding such complications and their management strategies avoids unnecessary treatment discontinuation due to manageable ECT complications.

Unexpected reduction in migraine and psychogenic headaches following rTMS treatment for major depression: a report of two cases.

Our objective is to report a coincident reduction in headache pain in patients treated with repetitive transcranial magnetic stimulation (rTMS) for major depressive disorder (MDD). Two patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD, non-responsive to prior antidepressant treatment who were enrolled in a sham-controlled, double-blind study of rTMS for MDD. After the study, it was revealed that both were in the active-treatment arm. Both patients suffered from near daily headaches and kept logs of headache frequency and severity before, during, and after the study. Headache pain was significantly reduced under double-blind conditions with rTMS treatment, but returned to baseline following cessation of rTMS treatment. Ultimately, when receiving rTMS post-study as a maintenance intervention for MDD (approximately 2 rTMS sessions/week), the positive effects on headache amelioration were sustained. Headache pain is frequently comorbid with mood disorders and has been reported as the most common side effect with rTMS. In these subjects, rTMS was, in fact, associated with relief of depressive symptoms and preexisting headache pain. This indicates that rTMS may be beneficial for both disorders in some patients.

Critical appraisal of selegiline transdermal system for major depressive disorder.

INTRODUCTION: Although safer and easier to use antidepressants (ie.,SSRIs/SNRIs) have largely displaced MAOIs, these medications still have a role in difficult to treat conditions. Efforts to improve MAOIs benefit-risk profile resulted on the reversible MAOI and in the first antidepressant patch (selegiline transdermal delivery system-STS). The later had been available in the US since 2006. Thus a review on its safety profile and comparative efficacy is timely. AREAS COVERED: This review provides an overview of STS's clinical pharmacology and summarizes what has been learned across nearly a decade of experience. Product labels and the search engine PubMed were used to obtain relevant information. EXPERT OPINION: STS remains a unique treatment option. It is the only FDA-approved antidepressant for patients with significant problems ingesting, tolerating, or absorbing oral medications. It remains the only MAOI that can be initiated without dietary restrictions at a therapeutic dose and has a low incidence of side effects when compared to other MAOIs. STS also provides an interesting option for depressed patients suffering from Parkinson's disease. However these advantages are counterweighted by drawbacks including the need for wash-out periods and the lack of convincing data illustrating its utility for treatment of more severe, treatment refractory depression.

Drug safety evaluation of olanzapine/fluoxetine combination.

INTRODUCTION: Bipolar disorder and treatment-resistant depression (TRD) are common and recurrent conditions associated with significant disability, morbidity and mortality. Despite the clear need for effective treatments, only a few medications have been approved in the US for these indications. The combined formulation of olanzapine-fluoxetine (OFC) has been available for a decade now, thus a review on its safety profile and comparative efficacy is timely and can help clinicians to determine the benefit/risk profile of OFC within the context of other treatment alternatives. AREAS COVERED: This paper summarizes the rationale and evidence supporting the use of OFC for both bipolar I depressive episodes and TRD with a focus on safety and tolerability. Product labels and the search engine PubMed was used to obtain relevant information on this subject. EXPERT OPINION: Although further comparative studies are needed, the literature confirms that the OFC is an effective treatment for bipolar I depressive episodes, as well as major depressive episodes that have not responded to several adequate courses of antidepressant therapy. Its use as a first-line treatment for bipolar I depressive episodes and at a higher rung of algorithms for patients with TRD is limited by its propensity to cause weight gain and associated metabolic symptoms.

Other therapeutic psychiatric uses of superficial brain stimulation.

The majority of literature on superficial brain stimulation for the treatment of psychiatric conditions is focused on transcranial magnetic stimulation (TMS) for major depressive disorder. Given its versatility and mode of action, TMS use has been now extended to other psychiatric disorders including anxiety disorders, bipolar disorder, psychotic disorders, and disorders of executive function. In this chapter we review the rationale and available evidence for the use of TMS as a treatment option in conditions other than major depression - post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, generalized anxiety disorder, attention-deficit/hyperactivity disorder, catatonia, schizophrenia, and bipolar disorder. Although the rationale for its use in the treatment of the above-mentioned conditions is strong, the available evidence is mixed and limited. At this juncture no definitive conclusions or recommendations can be drawn; however, given the existing positive signals and the significant limitations of the presented evidence, further research is warranted to assess the actual role of TMS in the treatment of psychiatric conditions other than unipolar depression.

Effectiveness of transcranial magnetic stimulation in clinical practice post-FDA approval in the United States: results observed with the first 100 consecutive cases of depression at an academic medical center.

INTRODUCTION: Transcranial magnetic stimulation (TMS) is a US Food and Drug Administration-approved treatment for major depressive disorder (MDD) in patients who have not responded to 1 adequate antidepressant trial in the current episode. In a retrospective cohort study, we examined the effectiveness and safety of TMS in the first 100 consecutive patients treated for depression (full DSM-IV criteria for major depressive episode in either major depressive disorder or bipolar disorder) at an academic medical center between July 21, 2008, and March 25, 2011. METHOD: TMS was flexibly dosed in a course of up to 30 sessions, adjunctive to current medications, for 85 patients treated for acute depression. The primary outcomes were response and remission rates at treatment end point as measured by the Clinical Global Impressions-Improvement scale (CGI-I) at 6 weeks. Secondary outcomes included change in the Hamilton Depression Rating Scale (HDRS); Quick Inventory of Depressive Symptomatology, self-report (QIDS-SR); Beck Depression Inventory (BDI); Beck Anxiety Inventory (BAI); and the Sheehan Disability Scale (SDS). Enduring benefit was assessed over 6 months in patients receiving maintenance TMS treatment. Data from 12 patients who received TMS as maintenance or continuation treatment after prior electroconvulsive therapy (ECT) or TMS given in a clinical trial setting were also reviewed. RESULTS: The clinical cohort was treatment resistant, with a mean of 3.4 failed adequate trials in the current episode. Thirty-one individuals had received prior lifetime ECT, and 60% had a history of psychiatric hospitalization. The CGI-I response rate was 50.6% and the remission rate was 24.7% at 6 weeks. The mean change was -7.8 points in HDRS score, -5.4 in QIDS-SR, -11.4 in BDI, -5.8 in BAI, and -6.9 in SDS. The HDRS response and remission rates were 41.2% and 35.3%, respectively. Forty-two patients (49%) entered 6 months of maintenance TMS treatment. Sixty-two percent (26/42 patients) maintained their responder status at the last assessment during the maintenance treatment. TMS treatment was well tolerated, with a discontinuation rate of 3% in the acute treatment phase. No serious adverse events related to TMS were observed during acute or maintenance treatment. CONCLUSIONS: Adjunctive TMS was found to be safe and effective in both acute and maintenance treatment of patients with treatment-resistant depression.

Effectiveness and safety of vagus nerve stimulation for severe treatment-resistant major depression in clinical practice after FDA approval: outcomes at 1 year.

OBJECTIVE: To describe the outcomes of a consecutive series of depressed patients treated with vagus nerve stimulation (VNS) following US Food and Drug Administration (FDA) approval of this intervention. METHOD: We implanted a VNS device in 15 consecutive outpatients with treatment-resistant major depressive episodes, including 10 with major depressive disorder and 5 with bipolar disorder (DSM-IV criteria), between November 2005 and August 2006. Existing antidepressant treatment remained fixed as far as clinically possible. The primary outcome was change from baseline in the Beck Depression Inventory (BDI) score. Outcomes were assessed at 6 and 12 months postimplant and compared to those of the VNS pivotal efficacy trial that led to FDA approval of VNS. RESULTS: The BDI score decreased significantly compared to baseline at 6 months (P < .05) and 12 months (P < .01), from a mean of 37.8 (SD = 7.8) before VNS activation to a mean of 24.6 (SD = 11.4) at 12 months. By 1 year, 28.6% (n = 4) of the sample responded to VNS and 7.1% (n = 1) remitted according to the BDI. Secondary outcomes on the Hamilton Depression Rating Scale 24-Item showed similar improvement at 1 year, with a 43% response rate (n = 6) and 14.3% remission rate (n = 2). No obvious predictors of response were detected. Side effects of VNS included hoarseness (73%), dyspnea (47%), nausea (40%), pain (33%), and anxiety (20%); no patient terminated treatment due to intolerable side effects. CONCLUSIONS: We found that a substantial minority of patients with extremely difficult-to-treat depressive disorders benefited from VNS in an ambulatory clinical practice, with outcomes comparable to those observed in previous VNS efficacy studies and with a similar side effect profile.

The role of quetiapine extended release in the treatment of bipolar depression.

Bipolar disorder is a common, recurrent, and chronic condition associated with significant morbidity and reduced longevity mainly due to the depressive pole of the illness. Despite the great need for effective therapies, relatively few randomized controlled trials have been conducted and, to date, only two agents have been approved by the United States Food and Drug Administration for treatment of bipolar depression (olanzapine/fluoxetine combination and quetiapine). Quetiapine is the first approved monotherapy for treatment of bipolar depression, and an extended-release (XR) form of quetiapine is now available. This once-daily, bioequivalent formulation represents a useful alternative for patients who cannot tolerate twice-daily, immediate-release (IR) quetiapine. Here, we summarize the evidence supporting the efficacy of quetiapine for treatment of bipolar depression, and also review the similarities and differences between the two formulations. Additional research on longer-term use of quetiapine XR is needed to establish the durability of therapeutic effects and tolerability over months or years of therapy, both alone and in combination with other mood stabilizers. Studies on the potential utility of lower doses of quetiapine XR and head-to-head studies to evaluate relative efficacy and cost-effectiveness also are needed.

Electroconvulsive therapy in a 96-year-old patient with severe aortic stenosis: a case report and review of the literature.

We report the safe administration of a course of electroconvulsive therapy (ECT) in a 96-year-old woman with severe aortic stenosis. The patient experienced a relapse of her severe depression when ECT had been withheld because of increased concerns regarding medical risk given her age and degree of aortic stenosis. Reassessment of the case confirmed severe stenosis with a valve area of 0.5 cm2 and a peak pressure gradient across the valve of 110 mm Hg. The ventricular ejection was normal at 70% however, and after a careful weighing of the risk of ECT treatment versus the risk of withholding ECT, it was decided to proceed with ECT in this case. In the event, ECT was very well tolerated by the patient, and she experienced a full remission of symptoms. She continues to receive maintenance ECT successfully at a once-per-month frequency. This case illustrates that neither age nor aortic stenosis by itself precludes ECT in the setting of severe depression. Rather, in each case, a careful weighing of the risks both of proceeding with and withholding ECT is warranted.