Roger F Haskett MD University of Pittsburgh School of Medicine Western Psychiatric Institute and Clinic Medicine, Culture, and Spirituality Conference September 9, 2011

1. New Developments in the Treatment of Mood Disorders Roger F Haskett MD University of Pittsburgh School of Medicine Western Psychiatric Institute and Clinic

3. Psychotherapy

4. Genetics of resilience

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.

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

12. Interpersonal psychotherapy

13. Psychodynamic psychotherapy

14. Marital and Family therapy

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)

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

24. Could explain how early life experiences can leave an indelible mark on the brain and influence both behavior and physical health later in lifeG Miller Science 2010

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.

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

36. “I still don’t have the answers,but I’m beginning to ask the right questions.”

38. Magnetic Seizure Therapy

39. Transcranial Magnetic Stimulation (rTMS)

40. Vagus Nerve Stimulation (VNS)

41. Cortical Brain Stimulation

44. No electrical current passes deep through the brain

45. Electromagnetic pulse passes into brain without resistance

46. MST stimulus more focused

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