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  • Stress and Treatment Resistant Depression:The Role of Electroconvulsive TherapyandNeuromodulation Therapies
    Nelson F. Rodriguez, M.D., FAPA
    Staff 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.
    Cardiovascular disease
    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:
    Back pain
    Diabetes mellitus
    Kidney disease
    Lung disease
    Roger Mannell U Waterloo; Robert Brook, UNSW; HPRT lecture
  • Psychological Effects
    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.
  • Summary of Manic and Depressive Symptoms Criteria in DSM-IV-TR Mood Disorders
  • Comorbidity and Symptom Sharing(Gordon, MO, et al, Arch Ophthalmology 2002, 120:714-720)
  • Treatment Approach
    Major Depressive Disorder
    Group Therapy
  • 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
    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
    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
    High suicide risk
    Substantial cognitive impairment
    Severely incapacitated
    Patients at risk for serious complications
    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
    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
    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
    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
    Efficacy – 70%-90% (APA, 2010)
    Memory Effects are more prominent
    Mostly covered by third-party payers -Insurance, Medicare, etc
    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 Therapies
  • Prevention
  • 7 Best Practices to Deal with Stress
    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.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
    Paul E. Keck, Jr., M.D.
    President and Chief Executive Officer, Lindner Center of HOPE
    Professor, University of Cincinnati College of Medicine