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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.
      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.
    • 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
      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 Therapies
    • 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.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