Stress and Treatment Resistant Depression:The Role of Electroconvulsive

Therapyand

Neuromodulation Therapies

Nelson F. Rodriguez, M.D., FAPAStaff Psychiatrist

Lindner Center of HOPE

Personal Background

• Staff Psychiatrist• Lindner Center of HOPE - Mason, Ohio

• Academic Affiliation• Assistant Professor, Psychiatry, 2008-present

• University of Cincinnati College of Medicine

• Assistant Professor, Family Medicine, 2002 - present• University of Kentucky College of Medicine

• Fellowship, 1997-1998• The Cambridge Hospital, Cambridge, MA• Harvard Medical School Consolidated Department of Psychiatry

• Residency, 1993-1997• Harvard So. Shore Psychiatry Training Program, Brockton, MA• Harvard Medical School Consolidated Department of Psychiatry

• Medical School, 1985• University of Santo Tomas, Manila, Philippines

Objectives:

• Discuss chronic stress and its effects.• Discuss depression and treatment-

resistant depression.• Discuss neuromodulation and treatment

modalities.• Discuss advances in the field.

Video

Stress

• Acute Stress

• Chronic Stress

• Stress modifies disease-relevant biological processes in humans. • Depression• Cardiovascular disease• HIV/AIDS• Cancer

Cohen et al, Psychological Stress and Disease, JAMA 2007;298(14), 1685-1687

Response to Stress

• Fight or Flight

• Chronic Stress- increased glucocorticoids

Charney, A m J Psych, 2004

Effects of Chronic Stress

• Longitudinal study of anxiety disorders among primary care physicians; n=502

• Strong Association with PTSD:• Anemia• Arthritis• Asthma• Back pain• Diabetes mellitus• Eczema• Kidney disease• Lung disease• Ulcer

• Roger Mannell U Waterloo; Robert Brook, UNSW; HPRT lecture

Psychological Effects

• Resilience• Demoralization• Adjustment Disorder• Major Depressive Disorder• Anxiety Disorder• Mood and /or Psychotic Disorder• Substance Abuse or Dependence

Major Depressive Disorder

• In the US, prevalence of MDD is 17%, affecting almost 1 in 5 persons. (Kessler, 2005)

• In persons aged 15-44 years, depression is the most disabling medical illness. (Murray 1997)

• Up to 20% of patients fail to respond to first-line therapeutic interventions, (APA ,2000)

• Correct Diagnosis is very important.

Major Depressive Episode Manic Episode Hypomanic Episode

Five (or more) of the following symptoms present nearly every day for 2 weeks and represent change in functioning - Depressed mood - Diminished interest or pleasure - Insomnia or hypersomnia - Psychomotor agitation or retardation - Fatigue or loss of energy - feelings of worthlessness or guilt - Difficulty concentration or indecisiveness - Recurrent thoughts of death

Symptoms cause significant distress or impairmentNot due to direct physiological effects of a substance or GMC

Distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary)

During the period of mood disturbance, 3 or 4 symptoms: - Distractibility - Insomnia - Grandiosity or inflated self-esteem - Flight of ideas/ racing thoughts - Activity increased - Speech is pressured -Sufficiently severe to cause marked impairment, necessitates hospitalization, or has psychotic features

Distinct period of persistently elevated, expansive or irritable mood, lasting at least 4 days,

Same Symptoms as a manic episode.

The episode is associated with unequivocal change in functioning that is uncharacteristic of the person.

The disturbance in mood is observable by others.

The episode is not severe enough to cause marked impairment, does not necessitate hospitalization, and does not have psychotic features.

Summary of Manic and Depressive Symptoms Criteria in DSM-IV-TR Mood Disorders

Disorder Manic Symptom Depressive Symptom

Major Depressive Disorder No history of mania or hypomania

History of major depressive episodes (single or recurrent)

Dysthymic disorder No history of mania or hypomania

Depressed mood, more days than not, for at least 2 years (but not meeting criteria for MDD)

Bipolar I disorder History of manic or mixed episodes

Major depressive episodes typical but not required for diagnosis

Bipolar II disorder One or more episodes of hypomania; no manic or mixed episodes

History of major depressive episodes

Cyclothymic disorder For at least 2 years, the presence of numerous periods with hypomanic symptoms

Numerous periods with depressive symptoms that do not meet criteria for MDD

Bipolar disorder, NOS Manic symptoms present, not met criteria for BD I, BD II

Not required for diagnosis

Comorbidity and Symptom Sharing(Gordon, MO, et al, Arch Ophthalmology 2002, 120:714-720)

Mania MDD ADHD ODD Anxiety

Elevated MoodIrritability 67% Low Frustration

tolerance

TouchyEasily annoyed Irritability

Hyperactivity/AgitationDistractibility

Agitation

Poor Concentration

Hyperactivity

Distractibility

RestlessnessAgitationDifficulty in concentration

Flight of Ideas Communication disorders

GrandiosityPoor judgmentReduced Sleep need

Insomnia

ImpulsivityTrouble sittingWakes early Initial insomnia

Treatment Approach

• Major Depressive Disorder• Psychotherapy• Group Therapy• Medications

• SSRI• SNRI• Antipsychotic• TCA, MAOI

• Neuromodulation

STAR*D - NIMH Trial

• Sequential Treatment Alternatives to Relieve Depression (STAR*D) Trial• Largest National Institute of

Mental Health (NIMH) prospective study

• Conducted by 14 regional centers across the US

• >4,000 patients over a three year period

• STAR*D Treatment Levels• Level 1: SSRI-citalopram• Level 2: Randomized to different arms:

• Switch to another: SSRI-sertraline, venlafaxine XR or bupropion SR

• Switch to cognitive therapy• Augmentation with bupropion SR or

buspirone• Augmentation with cognitive therapy

• Level 3: Randomized to diff arms• Switch to mirtazapine or nortriptyline• Augment with lithium or T3 thyroid

hormone

• Level 4: Randomized to one of the ff:• Switch to MAOI- tranylcypromine• Switch to combination mirtazapine and

venlafaxine XR

Response and Remission on STAR*D

• Response rate: 47%

• Remission rates: • Level 1: 28%-33%• Level 2: 18%-25% (switch); 30% (with augmentation)• Level 3: 12%-20%• Level 4: 7%-14%

• Relapse Rate: 33% to 50% in one year

Zifra, Gilmer, STAR*D Lessons Learned for Primary Care, Primary Psychiatry , accessed 11/13/2010

Treatment Resistant Depression

Treatment Resistant Depression

• Most experts would agree that a lack of response following four adequate trials would constitute treatment resistant depression (TRD).

• Dougherty, D. 2010

• The gold standard treatment for TRD is electroconvulsive treatment.

• Dougherty, D, Psych Annals;40: Oct 2010, 458

Stages of Treatment Resistance

• Stage I: Failure of at least one adequate trial of one major class of antidepressant

• Stage II: Stage I resistance plus failure of an adequate trial of an antidepressant in a distinctly different class from that used in Stage 1.

• Stage III: Stage II resistance plus failure of an adequate trial of a TCA.

• Stage IV: Stage III resistance plus failure of MAOI trial• Stage V: Stage IV resistance plus failure of bilateral ECT

Thase, ME, Rush, AJ, J. Clin Psych 1997

Therapeutic Neuromodulation

Therapeutic Neuromodulation

• Using electrical and magnetic stimulation to alter neurocircuitry in the brain.

Therapeutic Neuromodulation

• Electroconvulsive therapy (ECT)• Vagal Nerve Stimulation (VNS)• Transcranial Magnetic Stimulation (TMS)• Deep Brain Stimulation (DBS)

Neuronal networks implicated in psychiatric illness.

Tye S J et al. Mayo Clin Proc. 2009;84:522-532

© 2009 Mayo Foundation for Medical Education and Research

Therapeutic Neuromodulation

• Therapeutic neuromodulation: Categorization based on risk

• Noninvasive, nonseizurogenic  TMS, tDCS, CES

• Noninvasive, seizurogenic  ECT, MST, FEAST

• Invasive, nonseizurogenic  VNS, DBS, EpCS

• CES: cranial electrotherapy stimulation; DBS: deep brain stimulation; ECT: electroconvulsive therapy; EpCS: epidural prefrontal cortical stimulation; FEAST: focal electrically administered seizure therapy; MST: magnetic seizure therapy; tDCS: transcranial direct current stimulation; TMS: transcranial magnetic stimulation; VNS: vagus nerve stimulation

Janicak, P, Dowd S, Rado J et al, The Ree=-emerging role of therapeutic neuromodulation, Current Psychiatry,;9: Nov 2010 (accessed at www.currentpsychiatry.com 11/6/10

Electroconvulsive Therapy (ECT)

• ECT is a procedure in which generalized seizures lasting 25-150 seconds, induced by the passage of an electrical current through the brain under general anesthesia, and muscle relaxation are used for therapeutic purposes.

Comprehensive Textbook of Psychiatry, Kaplan HI, Sadock BJ, ed, 1995

History of ECT

• 16th Century – Phillipus Paracelsus • 1764 – Dr. Leopold Auenbrugger of Vienna

• Seizures produced by camphor were used to treat psychosis and mania

• 1900 – Dr. Manfred Sakel – Insulin coma therapy• 1938 – development of Electroconvulsive Therapy. Ugo Cerleti

and Lucio Bini (Rome, Italy)• 1940 – US started using electroshock therapy.• 1950-1960s – 1970’s = “shock factories”- 300 thousand patients

per year• 1970-1980 = One Flew Over the Cuckoo’s Nest• 1990- current: ECT’s quiet comeback (100,000 per year in the US)

APA on ECT

• 1978 – American Psychiatric Association published landmark report on “Electroconvulsive Therapy”

• 1990 – APA published the first edition of The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging

• 2001 – APA published the second edition

Mechanism of Action

• Hypothesis: ECT stabilizes dysregulated intracellular signaling linked to multiple transmitter system.

• Alterations in Neurotransmitter and Receptor Function• NE : Down-regulation and desensitization of B-receptors• 5HT: Upregulation and sensitization of post-synaptic 5HT2 receptors• Ach: Increased brain and CSF acetylcholine concentration

• Down-regulation of cortical muscarinic receptors– Could be related to ECT-induced amnesia

• DA: Increased dopamine-mediated behaviors• Increased CSF levels of brain-derived neurotrophic factor (BDNF)Kaplan and Saddock. Comp Textbook of Psych, 1995

Indications for ECT

• Primary Use of ECT• A need for rapid, definitive response because of the severity of a psychiatric or medical condition• When the risks of other treatments outweigh the risks of ECT• A history of poor medication response or good ECT response in one or more previous episodes

of illness• The patient’s preference

• Secondary Use of ECT• Treatment resistance • Intolerance to or adverse effects with pharmacotherapy• Deterioration of the patient’s psychiatric or medical condition

• Principal Diagnostic Indications• Major depressive disorder• Bipolar disorder, mania• Schizophrenia, catatonic type

The Practice of Electroconvulsive Therapy 2nd ed 2001

APA Practice Guideline for the Treatment of Patients with Major Depressive Disorder, (Third Edition , October 2010)

• ECT is recommended as a treatment of choice for patients with severe MDD that is not responsive to psychotherapeutic and/or pharmacological interventions, particularly in those with significant impairment or have not responded to numerous medication trials.

• ECT is also recommended for MDD• With associated psychotic or

catatonic features• Those with urgent need for

response (e.g. patients who are suicidal or nutritionally compromised due to refusal of food or fluids)

• Those who prefer ECT or have had a previous positive response to ECT

ECT in Special Populations

• Elderly• ECT may be used regardless of age; doses of medications be modified; ECT

stimulus adjusted – seizure threshold increases with age

• Pregnancy and Puerperium• Obstetric consultation

• Children and adolescents• Concurrence by two consultants

• Concurrent Medical Illness• Neurologic• Cardiovascular• Diabetes Mellitus

Suicide Risk and ECT

• Suicide – 11th leading cause of death in the US• Suicide has biological, psychological, sociological factors• Suicide affects family, clinical providers, community and society.

• American Psychiatric Association• Canadian Agence d’Evaluation des Technologies et des Modes

d’Intervention en Sante• U.K. National Institute for Clinical Excellence

• Cited the reduction of suicide risk as a justification for the use of ECT.

Kellner et al, Am J Psych 2005;162:077-982

Relief of Expressed Suicide Intent by ECT

• Consortium for Research in Continuation ECT (CORE Study)

• Multisite, collaborative, NIMH-funded study• Compare the efficacy of continuation pharmacotherapy (lithium plus

nortriptyline) and continuation ECT

• Remission rate for depression in the 355 patients who completed the course of treatment was 85.6%.

• Among 102 patients in the high expressed suicidal intent group who completed acute course of ECT, 87.3% had scores drop to 0.

Kellner CH, Fink M, Knapp R, et al, Am J Psych 2005;162:977-982

Suicidality in Depression Resolved Rapidly With ECT

• Patients received bilateral ECT 3X/week• After a mean of 2.9 sessions, 95% of patients had HAM-

D question 3 ratings of 0• By the 3rd ECT session, more than 2/3 had become non-

suicidal• By the 7th, 90% were nonsuicidal

Kellner, C., Poster Presentation, New Clinical Drug Evaluation Unit, 2002

ECT Treatment Areas

Pre-ECT Evaluation

• Psychiatric history and examination• Medical evaluation

• There is no “absolute contraindication” for ECT

• Evaluation by ECT psychiatrist• Anesthetic evaluation• An Informed Consent

Treatment Setting

• Inpatient• High suicide risk• Psychosis• Substantial cognitive

impairment• Severely incapacitated• Patients at risk for

serious complications

• Outpatient• The type and

seriousness of the patient’s mental illness do not present a significant risk to management on an outpatient basis

Airway Management

• Establishing an airway• Oxygenation• Protecting Teeth and other oral structures

Medications Used with ECT

• Anticholinergic Agents• Atropine or Glycopyrrolate

• Anesthetic Agents• Methohexital 0.5-1.0 mg/kg• Propofol, thiopental, etomidate

• Muscle Relaxants• Succinylcholine 0.5-1.0 mg /kg

• Agents Used to Modify the Cardiovascular Response to ECT

Use of Medications During ECT

• Medications typically continued through the ECT course• Medications administered prior to each treatment

• Antihypertensive, antiarrhythmics (except lidocaine), antireflux, bronchodilators (except theophylline), glaucoma (except long-acting anticholinesterase agents), corticosteroids

• Medications witheld until after each treatment• Diuretics, hypoglycemic medications, psychotropic medications

• Medications often decreased or withdrawn prior to or during the ECT course

• Theophylline - status epilepticus• Lithium – higher risk of delirium and prolonged seizure• Benzodiazepines, Anticonvulsants medications – reduced seizures• Monoamine oxidase inhibitors

• Pharmacologic Augmentation of ECT• Antipsychotic Medications; antidepressant medications

Post -ECT Pharmacotherapy

• Compared with placebo, continuation pharmacotherapy with tricyclic antidepressants and/or lithium reduced the rate of relapses in people who had responded to ECT.

NICE-UK 2010

Treatment Following Completion of the Index ECT

• Lack of Response to an Index ECT Course• Switching to bilateral electrode placement

and/or increasing stimulus intensity• Removing or diminishing the dose of

medications with anticonvulsant properties• Provide at least 10 treatments

Adverse Effects of ECT

• Cardiovascular Complications• Prolonged Seizures• Prolonged Apnea• Headache, Muscle soreness, and Nausea• Treatment-Emergent Mania• Postictal Delirium• Cognitive Side-Effects

Memory and Cognitive Deficits

• 20 patients in each group (BD with ECT and BD w/o ECT); bilateral treatments; from 6-72 treatments

• Average interval between last ECT treatment and participation= 45 months.• Cognitive Failure Questionnaire (CFQ)

• Patients who had ECT perceived more memory impairment than did patients who had never received ECT

• California Verbal Learning Test• Continuous Verbal Memory Task

• Both patient groups had significant impairment on measures of verbal learning and recollection (memory deficits

• BD with ECT performed at lower levels than those w/o ECT

• “The long-term impact of treatment with electroconvulsive therapy on discrete memory systems in patients with bipolar disorder”

• McQueen G, Parkin, C, et al• J Psychiatri Neurosci 2007,;32(4):241-249

NICE Statement about ECT and Memory

• ECT may cause short- or long-term memory impairment for• past events (retrograde amnesia) and current events• (anterograde amnesia). • As this type of cognitive impairment• is a feature of many mental health problems it may• sometimes be difficult to differentiate the effects of ECT• from those associated with the condition itself. In addition• there are differences between individuals in the extent of• memory loss secondary to ECT and their perception of the• loss. • However, this should not detract from the fact that a• number of individuals find their memory loss extremely• damaging and for them this negates any benefit from ECT.

National Institute for Clinical Excellence (NICE-UK) Technology Appraisal 59. Guidance on the use of electroconvulsive therapy, Update May 2010.

Mortality from ECT

• There was no evidence to suggest that the mortality• associated with ECT is greater than that associated with• minor procedures involving general anaesthetics, and there• were limited data on mortality extending beyond the trial• periods.

• The six reviewed studies that used brain-scanning• techniques did not provide any evidence that ECT causes• brain damage.

• (NICE-UK May 2010)

Other Neuromodulation Therapies

Vagal Nerve Stimulation (VNS)

• VNS is an implanted device.• Established efficacy in pharmaco-

resistant epilepsy.• Approved for pharmacoresistant

epilepsy in Europe in 1994 and in the US in 1997.

• July 2005, FDA approved VNS for severe, chronic or recurrent unipolar and bipolar depression, with a history of failure of the depression to respond to at least four antidepressant interventions.

Groves, Brown: Neurosci Biobehav Rev, 2005

Reardon JP et al, Psychiatry , 2006

Transcranial Magnetic Stimulation (TMS)

• A noninvasive procedure that uses highly focused magnetic pulses to target specific mood circuits in the brain.

• Recently approved by the Food and Drug Administration for Major depressive disorder.

ECT or TMS

ECT

• Efficacy – 70%-90% (APA, 2010)

• Memory Effects are more prominent

• Mostly covered by third-party payers -Insurance, Medicare, etc

TMS

• Preliminary studies indicate that ECT is more effective than repetitive transcranial magnetic stimulation. (NICE-UK)• LCOH date: 40% Efficacy

• No significant memory impairment

• Limited third-party coverage

Deep Brain Stimulation (DBS)

• DBS is a reversible, neurosurgical procedure consisting of implanting electrodes at specific anatomical location- ventral capsule/ventral striatum (VC/VS) for OCD; and subgenual cingulate gyrus (SCG) for TRD.

• First published report of DBS for psychiatric illness – 1990s

• 2009 – FDA approved DBS at VC/VS for intractable OCD under Humanitarian device exemption (HDE)

Psychiatric Annals, 40(10), Oct 2010

Left, Intraoperative photograph during deep brain stimulation (DBS) surgery.

Tye S J et al. Mayo Clin Proc. 2009;84:522-532

© 2009 Mayo Foundation for Medical Education and Research

Possible therapeutic mechanisms of action of deep brain stimulation.

Tye S J et al. Mayo Clin Proc. 2009;84:522-532

© 2009 Mayo Foundation for Medical Education and Research

Magnetic Seizure Therapy (MST)

• MST is the induction of seizure through magnet stimulation.

• Still in experimental stage in Europe and US

• May have less cognitive side effects

Neuromodulation TherapiesECT VNS TMS DBS Medications

Indication MDDBipolar maniaCatatonic Schizophrenia

MDD MDD OCDParkinson’s and dystonic reactions

MDD

Efficacy 70-90 %AcuteContinuationMaintenance

15 – 25%

Maintenance

40-50%Acute

33-60%

Side-effects MemoryGeneral anesthesia risks – CV, Resp

Voice alteration 50%

Headache and discomfort at site of tx

Cost/Coverage Mostly covered

$25,000 out-of-pocket

$9,000 to $10,000 for 30 txs

varies

Prevention

7 Best Practices to Deal with Stress

• ARSENAL• Awareness• Rest• Support• Exercise• Nutrition• Attitude• Learning

The Stress Effect by Henry L. Thompson

Awareness

“Watch your thoughts, they become words.

Watch your words, they become actions.

Watch your actions, they become habits.

Watch your habits, they become character.

Watch your character, it becomes your destiny.” – Lao Tze

More Positive Quotes

• “Fear, uncertainty and discomfort are your compasses toward growth”. - Unknown

• “Between stimulus and response there is a space. In that space is our power to choose our response. In our response lies our growth and freedom”. - Victor Frankl

References

• The Practice of Electroconvulsive Therapy Recommendations for Treatment, Training, and Privileging, 2nd Edition, 2001.

• Comprehensive Textbook of Psychiatry, 6th Ed, 1995• Practice Guideline for the Treatment of Patients with Major

Depressive Disorder, Third Edition, Am J Psych, 167(10), Oct 2010

• Current Psychiatry• Psychiatric Annals, Vol 40(10), Oct 2010• National Institute for Clinical Excellence (NICE) May 2010• Positivity app with iPhone

Thank You.

An Innovative Mental Health Center

“It is our vision to provide the most advanced diagnostic and treatment services in the region, and to be a national leader in innovative treatment and research. The Lindner Center of HOPE will be a resource to our community and will bring hope to people suffering from mental illness.”

Paul E. Keck, Jr., M.D.President and Chief Executive Officer, Lindner Center of HOPEProfessor, University of Cincinnati College of Medicine

Paul E. Keck, Jr., M.D. Lindner Center of HOPE, President and CEO University of Cincinnati College of Medicine, The Craig and Frances Lindner Professor of Psychiatry and Neuroscience and Executive Vice Chairman of the Department of Psychiatry