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New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
New Developments in the Treatment of Mood Disorders
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New Developments in the Treatment of Mood Disorders

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Roger F Haskett MD …

Roger F Haskett MD
University of Pittsburgh School of Medicine Western Psychiatric Institute and Clinic


Medicine, Culture, and Spirituality Conference
September 9, 2011

Published in: Health & Medicine
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  • 1. New Developments in the Treatment of Mood Disorders
    Roger F Haskett MD
    University of Pittsburgh School of Medicine
    Western Psychiatric Institute and Clinic
  • 2. Outline
    • Pharmacotherapy
    • 3. Psychotherapy
    • 4. Genetics of resilience
    • 5. Brain stimulation
  • Recovery from Depression
    Weeks From Intake
    From Keller et al, 1992
  • 6. The Evolution of Antidepressants
    1950s
    1960s
    1970s
    1980s
    1990s
    2000s
    imipramine amitriptyline desipramine nortriptyline clomipramine
    bupropion
    fluoxetine sertraline
    paroxetinefluvoxamine citalopram
    escitalopram
    venlafaxine mirtazapine
    duloxetine
    desvenlafaxine
    maprotiline amoxapine
    trazodone
    phenelzine isocarboxazid tranylcypromine
  • 7. Classes of Antidepressants
    Tricyclic Antidepressants (TCAs)
    Monoamine Oxidase Inhibitors (MAOI)
    Selective Serotonin Antidepressants (SSRIs)
    Serotonin and Norepinephrine Reuptake Inhibitors
    Other Novel Antidepressants
    bupropion, trazodone, mirtazapine
  • 8. *Remission rates are after 12 weeks of treatment and are based on the HRSD-17
    35
    30.1%(n=86)
    29.7%(n=83)
    27.5%(n=790)
    30
    24.8%(n=62)
    24.7%(n=18)
    25
    21.3%(n=51)
    19.8%(n=24)
    17.6%(n=42)
    20
    15.9%(n=11)
    % of Patients Remitting
    13.7%(n=7)
    12.3%(n=14)
    15
    10
    6.9%(n=4)
    5
    0
    Citalopram
    (n=2,876)
    Bupropion(n=279)
    Buspirone(n=286)
    Venlafaxine(n=250)
    Bupropion(n=239)
    Sertraline(n=238)
    Mirtazapine(n=114)
    Nortriptyline(n=121)
    Lithium(n=69)
    T3(n=73)
    Tranylcy-promine(n=58)
    Venlafaxine + Mirtazapine (n=51)
    Level 1(n=2,876)1
    Level 2 (Augment)(n=565)2
    Level 3 (Switch)(n=235)5
    Level 2 (Switch)(n=727)3
    Level 3 (Augment)(n=142)4
    Level 4 (Switch)(n=109)6
    STAR*D Results Demonstrate Diminishing Effectiveness of Treatments in TRD
    1Trivedi MH, et al. Am J Psychiatry 2006;163:28. 2Trivedi MH, et al. N Engl J Med 2006;354:1243. 3Rush AJ, et al N Engl J Med 2006;354:1231. 4Nierenberg AA, et al. Am J Psychiatry 2006;163:1519. 5Fava M, et al. Am J Psychiatry 2006;163:1161. 6McGrath PJ, et al. Am J Psychiatry 2006;163:1531.
  • 9. Treatment Resistant Depression
    First treatment: 28% remit
    Second treatment: 17% - 30% remit
    Third treatment: 12% - 25% remit
    Fourth treatment: 7% - 14% remit
    • After 4 well-delivered treatments, 30% of patients will not have remitted
  • Strategies to Address Incomplete Response
    Maximize initial treatments
    Change to other treatments
    Non-MAOI antidepressant in same or different class
    Adding or changing to a depression-focused psychotherapy
    Augmenting and combining treatments
    APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition
  • 10. Stepped Approach toTreatment Resistant Depression
    SSRI - increase dose, extend duration, switch
    bupropion, venlafaxine, duloxetine, mirtazapine
    lithium augmentation
    TCA trial with plasma levels
    thyroid augmentation (T3, T4)
    combination antidepressants
    augmentation with second generation antipsychotics
    electroconvulsive therapy
  • 11. Psychotherapies
    • Cognitive-behavioral therapy
    • 12. Interpersonal psychotherapy
    • 13. Psychodynamic psychotherapy
    • 14. Marital and Family therapy
    • 15. Combination pharmacotherapy and psychotherapy
  • Personalized Medicine
  • 16.
  • 17. DNA
  • 18. Gene-Environment Interaction Studies
    Functional polymorphism in the promoter region of the gene encoding MAO moderates effect of child maltreatment.
    Low levels of MAO expression increased frequency of conduct disorder, antisocial personality and adult violent crime.
    Functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene moderates influence of stressful life events on depression.
    1 or 2 copies of the 5-HTT “short” allele associated with more depression following stressful life events than2 copies of the 5-HTT “long” allele.
    Caspi et al, 2002,2003
  • 19. Exposure to Adverse Rearing, Genotype and ACTH levels
    Caspi et al.Nature Reviews Neuroscience 7, 583–590 (July 2006)
  • 20. Exposure to Adverse Rearing, Genotype and ACTH levels
    • Influence of exposure to early stress (peer rearing) on subsequent exaggerated responses of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) responses to stress is conditioned by serotonin transporter gene promoter variation (rh-5HTTLPR) in rhesus macaques.
    • 21. When exposed to stress later in life, peer-reared animals with the short/long genotype had higher ACTH levels than animals with the long/long genotype.
    • 22. There were no differences between genotypes among animals reared with their mothers.
    Barr et al, Biol Psychiatry 2004
  • 23. Behavioral Epigenetics
    • Epigenetic mechanisms of gene regulation alter the activity of genes without changing their DNA sequence
    • 24. Could explain how early life experiences can leave an indelible mark on the brain and influence both behavior and physical health later in life
    G Miller Science 2010
  • 25. Adverse Environment during Development
    • Bdnf gene is down-regulated in the hippocampus of adultmice exposed to social stress in the form of chronic bullyingby a bigger mouse.
    • 26. This reduction in Bdnf activity linked to epigenetic modificationsinvolving histones, tiny protein spools that keep DNA wrappedup.
    • 27. Chronic stress triggered increase in histonemethylation that suppresses gene activity by keeping the DNAcontaining the Bdnf gene tightly wound.
    • 28. Conversely anti-depressant drugs boosted histone acetylation, which helpsunwind DNA from histones and promote Bdnf activity.
    • 29. Epigenetic modifications could be an important linkbetween adverse life experiences and the risk of psychiatricdisorders such as depression and anxiety.
    E Nestler 2006
  • 30. Neurotrophic Hypothesis of Depression
    Loss of Brain-Derived Neurotrophic Factor (BDNF) contributes to hippocampal atrophy that underlie aspects of depression.
    Antidepressants mediate therapeutic effects by increasing expression of neurotrophic factors (BDNF) in this region.
  • 31.
  • 32. Neurotrophic Response to Antidepressants
    Increased BDNF in the DG
    Increased survival and maturation of newborn granule cells
    Enhanced synaptic plasticity
    Adachi et al, Biol Psychiatry 2008
  • 33. Stress and Depression
    Long term antidepressant treatment, including ECS, increases BDNF protein and mRNA levels and reverses the stress-induced downregulation of BDNF.
    Exercise followed by similar changes in BDNF levels, neurogenesis, and behavioral swim tests
  • 34. HPA axis and Depression
    Hyperactivity present in majority of depressed patients
    increased expression of CRF in hypothalamus
    increased CRF levels in CSF
    reduced feedback inhibition by CRF and glucocorticoids
    CRF serves as a neurotransmitter in amygdala and BNST
    amygdala involved in negative emotional memory and anxiety-like behavior
  • 35.
  • 36. “I still don’t have the answers,but I’m beginning to ask the right questions.”
  • 37. Therapeutic Brain Stimulation
    • Electroconvulsive Therapy
    • 38. Magnetic Seizure Therapy
    • 39. Transcranial Magnetic Stimulation (rTMS)
    • 40. Vagus Nerve Stimulation (VNS)
    • 41. Cortical Brain Stimulation
    • 42. Deep Brain Stimulation (DBS)
  • Transcranial Magnetic Stimulation
    Barker et al 1985
  • 43. Differences between ECT and MST
    • Seizure originates in superficial cortex
    • 44. No electrical current passes deep through the brain
    • 45. Electromagnetic pulse passes into brain without resistance
    • 46. MST stimulus more focused
    • 47. No direct electrical stimulation of medial temporal lobe structures
  • Administration of rTMS
    Stimulation site - left dorsolateral prefrontal cortex
    Determine resting motor threshold
    Set stimulation intensity (120%), frequency (10 pulses/sec) and train duration (On 4 sec) & intertrain interval (Off 26 sec)
    Typical treatment session > 30 min for total 3,000 stimulations
    Treat 5 times / week for max 6 weeks (30 sessions)
    O’Reardon et al, 2007
  • 48. Advantages of rTMS
    No anesthetic required
    No cognitive disruption or impairment
  • 49. Current status of rTMS
    In pivotal study, efficacy did not separate from placebo on primary outcome measure
    Recent NIH supported Study George et al 2010
    Mutisite, randomized, active sham-controlled
    3 weeks left prefrontal rTMS; 3 more weeks in improvers
    OR for remission 4.2 for active rTMS (95% CI 1.32 - 13.24)
    Significant interaction between AD resistance and clinical benefit
    Remitters had lower degree of treatment resistance
    No seizures, high retention rate
    Possible role
    Intermediate strategy
    Augmentation
    Pregnancy, PPD
  • 50. The Vagus Nerve Stimulator
  • 51. Rationale for VNS in Depression
    Mood improvement with anticonvulsant therapies
    anticonvulsant drugs
    ECT
    Mood improvement in VNS-treated epilepsy patients
    not correlated with reduced seizure frequency
  • 52. cingulate gyrus
    orbitofrontal
    cortex
    hypothalamus
    amygdala
    parabrachial nucleusnucleus (PB) locus coeruleus
    nucleus
    track solitaire
    Vagal nerve: Afferent Pathway to the Brain
    George MS, et al. Biol Psychiatry. 2000
  • 53. Vagus Nerve Stimulation (VNS)
    Pacemaker generator
    Model 101: 8-10 years battery life
    Bipolar helical stimulation electrode
    Intermittent stimulation with typical on : off time ratio of 30s : 5 min
    Magnet allows on-demand patient control
  • 54. VNS Programming
  • 55. VNS Implant Procedure
    1- to 2- hour case length
    General or regional/local anesthesia
    Does NOT involve the brain
    Chest/armpit incision for generator
    Neck incision for electrode
    Outpatient or inpatient
    Minimal complications
  • 56. 25
    23
    20
    17
    17
    17
    15
    % Remission
    15
    13
    12
    11
    10
    10
    8
    10
    7
    7
    6
    5
    0
    IDS-SR
    HRSD24
    MADRS
    Remission Rates Increase Over Time During Adjunctive VNS Therapy
    3 Months
    (n=203-205)
    6 Months
    (n=192-197)
    9 Months
    (n=184-186)
    12 Months
    (n=180-181)
    24 Months
    (n=157)
    Remission; IDS-SR30 raw score 14; HRSD24 raw score 9; MADRS raw score 10
    Evaluable Observed
    Rush AJ, et al. Biol Psychiatry. 2005;58:355-363. 24-month Data, Cyberonics, Inc.Depression Physician’s Manual. Houston, Tex.
  • 57. Deep Brain Stimulation
  • 58. DBS of the subcallosal cingulate gyrus (SCG), including Brodmann area 25,
    subcallosal cingulate gyrus (SCG), including Brodmann area 25,
    Hamani, Mayberg et al 2009
  • 59. DBS for TRD: 3 – 6 year follow-up
  • 60. Yogi Berra
  • 61. It's tough to make predictions, especially about the future
    If you don't know where you are going, you might wind up someplace else
    You can observe a lot just by watching
    Yogi Berra
    Conclusions

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