Depression: DBS and ECT

Educational Objectives

The goal of this program is to provide updated information about the use of deep brain stimulation (DBS) and electro­convulsive therapy (ECT) in the treatment of depression. After hearing and assimilating this program, the clinician will be better able to:

1.   Recognize that many people with depression do not respond to medication or psychotherapy.

2.   Describe the most recent advances in DBS for treating depression.

3.   Refer patients with depression for inclusion in studies of DBS.

4.   Discuss the indications and contraindications for ECT.

5.   Help patients decide whether to try ECT as treatment for their depression.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Mayberg assigned the patent for a device to Advanced Neuromodulation Systems (ANS), and con­sulted on the use of and participated in trials to study the device. Dr. Li and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Mayberg was recorded at Unambiguous, Unsurpassable Utterances from Umbelliferous Ubermensch, held No­vember 7-8, 2008, in Madison, WI, and sponsored by the University of Wisconsin School of Medicine and Public Health and the Madison Institute of Medicine, Inc. Dr. Li was recorded at New Frontiers in Depression Research and Treatment, held February 21-23, 2008, in San Francisco, CA, and sponsored by the University of California, San Francisco, School of Medicine.  The Audio-Digest Foundation thanks the speakers and the sponsors for their cooper­ation in the production of this program.

Deep Brain Stimulation (DBS)

Helen S. Mayberg, MD, Professor of Psychiatry and Behavioral Sciences and Neurology, Emory University School of Med­icine, Atlanta, GA

Historical context: Sequenced Treatment Alternatives to Relieve Depression (STAR*D) showed that <40% of pa­tients with depression achieve remission; »10% of patients become treatment-resistant over time; Consortium for Research on ECT (electroconvulsive therapy; CORE) showed that patients for whom ³4 medication trials failed had greatly reduced chance of getting well and staying well; trials of vagal nerve stimulation (VNS) and repetitive transcranial magnetic stimulation (rTMS) show these treatment options work best in people in whom single medi­cation failed; response rates low in patients in whom ³2 medications failed; biomarkers needed to help determine appropriate initial treatment trial for each patient; novel therapies developed due to use of structural and functional brain imaging and advances in stereotactic neurosurgery

Scientific rationale: first developed as replacement for creating surgical lesions to alleviate parkinsonian tremor in patients with Parkinson’s disease; to apply same technology to treatment of depression required determining brain circuits involved in depression, response pathways, which changes were critical, optimal target, and which patients appropriate for treatment

Depression circuits: studies suggest various treatment modalities suppress Brodmann area 25 and increase frontal cortex; further studies showed increase in area 25 in patients who did not respond to treatments; these findings suggested area 25 is convergence zone for regulation of all behaviors associated with major depressive episodes

Mechanism of action: developed to replace creation of lesions in brain (stimulation can be modulated, whereas le­sions cannot); approved devices available in several formats, but all use electrode in brain (placed through burr hole in skull) and implantable impulse generator (IPG) implanted under skin of chest and connected to electrode by wire tunneled under skin; IPG serves as battery pack and can be adjusted in several dimensions (eg, frequency, pulse width, voltage, cycle); electrode placed in Brodmann area 25 under guidance from positron emission to­mography (PET) and structural magnetic resonance imaging (MRI)

Pilot study: 6 patients (3 men, 3 women) identified as appropriate for safety study; DBS device implanted, and open active stimulation enacted for 6 mo; no changes made to patients’ medication regimens; patients awake in operating room (OR) and asked to report any sensations; patient selection  —  all patients middle-aged and had been in current episode >5 yr; none suicidal; onset of depression in young adulthood; numerous episodes, with productive periods in between; documented failed response to >4 medications; failed response to cognitive be­havioral therapy or other psychotherapy; failed response to or refusal of ECT; no psychiatric or neurologic co­morbidity; 4 patients responded to treatment, 2 did not; responders reported  —  sudden sense of intense calm, quiet, and relief; dissipation of visceral symptoms; resolution of sensations of pain, dread, void, and mental heaviness; this was followed in OR by increased interest, energy, awareness, attention, motor speed, and sponta­neous speech; in all cases, acute effects less dramatic when retested later, but Hamilton Depression Rating Scale­scores never returned to baseline; PET showed down-regulation of area 25 and up-regulation of frontal cortex

Follow-up study: 13 patients with mix of unipolar and bipolar type 2 depression; placebo-controlled trial; of first 11 patients, 7 had unambiguous intraoperative response, and all were still responding at 6 mo; 4 patients had no re­sponse; early response appears predictive of long-term outcome; studies ongoing

Conclusions: procedure safe; surgery well tolerated; treatment adjustable and reversible; location and stimulation parameters important; optimal patient selection criteria needed; placebo-controlled trials under way; follow-up therapy, especially psychotherapy, important

Electroconvulsive Therapy (ECT)

Descartes Li, MD, Associate Clinical Professor, Department of Psychiatry, University of California, San Francisco, School of Medicine; and Chief, Bipolar Disorder Program, Langley Porter Psychiatric Hospitals and Clinics, San Francisco, CA

Indications for ECT: most commonly, unipolar or bipolar major depression; occasionally, mania or psychosis; rarely, delirium, Parkinson’s disease, neuroleptic malignant syndrome, and intractable epilepsy; generally pre­ferred in cases in which  —  treatment resistance or failure present; rapid definitive treatment needed (eg, psycho­sis, catatonia, inability to eat, severe weight loss, severe suicidal ideation); medical issues highly complex (eg, cachexia, inability to tolerate medication trials); patient prefers

Contraindications: no absolute contraindications; medical conditions associated with increased risk include space-occupying cerebral lesion, recent intracerebral hemorrhage, unstable aneurysm or malformation, conditions that cause increased intracerebral pressure, recent myocardial infarction, pheochromocytoma, and high anesthetic risk

Efficacy: supported by numerous studies, including ECT vs sham ECT and ECT vs medications; compares favorably with drug therapy for depression; efficacy most clear in depression; factors associated with efficacy  —  catatonic features; melancholic features; psychotic features (eg, delusional depression); previous response to ECT; suicidal ideation; factors associated with variable response  —chronicity; medication refractoriness; relative lack of neuro­vegetative signs; comorbid substance abuse; comorbid personality disorder

Consent and legal issues: legal issues vary from state to state; in California (where speaker practices)  —  detailed ex­planation of procedure must be provided 24 hr before consent form can be signed; patient must consent, and con­sent must be reviewed by another board-certified psychiatrist every 30 days; family must be notified, or notification of family must be specifically rejected by patient; ECT banned for minors <12 yr of age

Anesthesia issues: ECT done under general anesthesia; in general, patient anesthetized first, then given muscle relax­ant; anesthesia provider determines each patient’s ability to tolerate anesthesia and selects appropriate agents

Adverse effects of ECT: headache; muscle aches; posttreatment confusion  —  affected by stimulus waveform and in­tensity, electrode placement, number and frequency of treatments, patient’s age, and preexisting cognitive dys­function; patient can also have “spaciness” that lasts for several days to weeks, requiring careful monitoring over course of ECT

Memory impairment: ECT affects retrograde memory more than anterograde, and autobiographical memory more than impersonal (eg, public events); research to determine effects of ECT on memory complex because 1) de­pression often presents with associated cognitive deficits (pseudodementia), 2) medications can cause memory problems, 3) normal forgetting must be factored into studies, and 4) patient selection may influence outcomes; Ribot’s law  —  amnesia more likely for recent events (compared to distantly remote events) and for less salient events; amnestic effects of ECT greater and more persistent for knowledge about world (impersonal memory) than for knowledge about self (personal or autobiographical memory); majority of patients describe improved memory and cognitive functioning after treatment (correlating with improved mood); persistent memory deficits beyond 6 mo rare, but do occur; cost-benefit analysis generally favors ECT; treatment generally initiated with right unilateral lead placement and titrated to 500% of seizure threshold (speaker estimates that 25%-30% of pa­tients do not respond to unilateral treatment and are switched to bilateral, with good response)

Mechanism of action: unknown

Neurotransmitter hypothesis: many substances released during and immediately after ECT; prolactin release (in­creased 10-50 times, 10-20 min after ECT) returns to baseline in 2 hr, and associated with antidepressant efficacy (but most likely as marker); no causality demonstrated

Anticonvulsant hypothesis: postictal suppression of electroencephalography (EEG) correlated with antidepressant response; however, patients whose seizure thresholds increase over course of ECT tend to do less well; in addi­tion, seizure alone necessary, but not sufficient, to account for antidepressant action of ECT (as demonstrated in studies of low-dose unilateral ECT)

Seizure generalization hypothesis: antidepressant response dependent on efficiency of seizure generalization throughout brain; EEG amplitude and coherence, cardiovascular response, duration of seizure, and amount of prolactin released predict antidepressant response

Diencephalic model: diencephalon involved in therapeutic effect; bitemporal lead placement may be more effec­tive than unilateral

Prefrontal model: seizures initiated in prefrontal area most likely to induce antidepressant activity

Anatomico-ictal theory: combines diencephalic and prefrontal models; posits that ECT-induced seizures have most antidepressant effect when seizure initiated in prefrontal areas of brain, then spreads maximally through cortex and subcortex, and especially diencephalon

Treatment course: pretreatment evaluation for anesthesia, including history, physical examination, and laboratory tests; electrocardiography (ECG) sometimes done, but not necessary; certain medications (eg, benzodiazepines, anticonvulsants, lithium) must be stopped or decreased in advance; however, ECT can cause temporary increase in blood pressure, so antihypertensives should be continued; generally requires 6 to 12 treatments given 3 times per week; high relapse rate if no follow-up treatment given; continuation or maintenance treatment often re­quired; alternatively, patient restarted on medications after initial response to ECT

Procedure: preparation  —  patient instructed to take nothing by mouth after midnight night before procedure (ex­cept certain medications, taken with small sips of water); in morning on day of procedure, intravenous line in­serted; patient given anesthetic, then muscle relaxant; treatment  —  stimulus delivered; patient has seizure that lasts 30 to 120 sec; patient awakens after 5 to 10 min and taken to postanesthesia care unit; recovery  —  patient usually fully recovered in £1 hr; majority of treatments performed in outpatient setting

Summary: efficacy of ECT comparable or superior to other treatments for depression; comorbid personality disor­ders and substance abuse, and chronicity of disease predict less efficacy; possible adverse reactions include head­ache, nausea, posttreatment confusion, and memory impairment; informed consent regulated by state law and requires documentation by 2 board-certified psychiatrists or neurologists every 30 days; procedure brief, requires general anesthesia, and may require inpatient hospitalization for initial treatments; typical course, 6 to 12 treat­ments; high rate of relapse without continuation of pharmacotherapy (combination of lithium and nortriptyline most studied)

Suggested Reading

Dukakis K, Tye L. Shock: The Healing Power of Electroconvulsive Therapy. New York: Avery; 2006; Feske U et al: Clinical outcome of ECT in patients with major depression and comorbid borderline personality disorder. Am J Psy­chiatry. 161:2073, 2004; Fink M. Electroshock: Healing Mental Illness. New York: Oxford University Press; 2002; Goldapple K et al: Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cogni­tive behavior therapy. Arch Gen Psychiatry 61:34, 2004; Gutman DA et al: A tractography analysis of two deep brain stimulation white matter targets for depression. Biol Psychiatry 65:276, 2009; James GA et al: Exploratory structural equation modeling of resting-state fMRI: applicability of group models to individual subjects. Neuroimage 45:778, 2009; Kellner CH et al: Continuation electroconvulsive therapy vs pharmacotherapy for relapse prevention in major depression: a multisite study from the Consortium for Research in Electroconvulsive Therapy (CORE). Arch Gen Psychiatry 63:1337, 2006; Krüger S et al: State and trait influences on mood regulation in bipolar disorder: blood flow differences with an acute mood challenge. Biol Psychiatry 54:1274, 2003; Lisanby SH et al: The effects of electroconvulsive therapy on memory of autobiographical and public events. Arch Gen Psychiatry 57:581, 2000; Lozano AM et al: Subcallosal cingulate gyrus deep brain stimulation for treatment-resistant depression. Biol Psychi­atry 64:461, 2008; Mayberg HS et al: Deep brain stimulation for treatment-resistant depression. Neuron 45:651, 2005; Mayberg HS et al: Regional metabolic effects of fluoxetine in major depression: serial changes and relation­ship to clinical response. Biol Psychiatry 48:830, 2000; Mayberg HS: Modulating dysfunctional limbic-cortical cir­cuits in depression: towards development of brain-based algorithms for diagnosis and optimized treatment. Br Med Bull 65:193, 2003; Mayberg HS: Positron emission tomography imaging in depression: a neural systems perspec­tive. Neuroimaging Clin N Am 13:805, 2003; McCall WV et al: Titrated moderately suprathreshold vs fixed high-dose right unilateral electroconvulsive therapy: acute antidepressant and cognitive effects. Arch Gen Psychiatry 57:438, 2000; Nelson JC: The STAR*D study: a four-course meal that leaves us wanting more. Am J Psychiatry 163:1864,2006; Palomero-Gallagher N et al: Receptor architecture of human cingulate cortex: Evaluation of the four-region neurobiological model. Hum Brain Mapp Nov 25, 2008; [Epub ahead of print]; Prudic J et al: Effective­ness of electroconvulsive therapy in community settings. Biol Psychiatry 55:301, 2004; Sackeim HA et al: A pro­spective, randomized, double-blind comparison of bilateral and right unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry 57:425, 2000; Sackeim HA et al: The cognitive effects of electroconvul­sive therapy in community settings. Neuropsychopharmacology 32:244, 2007.