גישות חדשות בדיכאון פרופ' לאון גרינהאוס המרכז הירושלמי לברה"נ

1. גישות חדשות בדיכאון פרופ' לאון גרינהאוס המרכז הירושלמי לברה"נ

2. Depression is 4th most • disabling medical condition • worldwide • Predicted to be 2nd only • to chronic heart disease • with regards to disability • by year 2020 • The management of TRD • is a major public health • problem worldwide • Need to consider multiple • forms of depression: • Unipolar • Bipolar • Dysthymia • With Chronic Pain

3. “The Sad News About Major Depression” • Common, typically recurrent, often chronic disabling disorder • Life-long prevalence of 4.9-17.9% • Women twice as likely to have depression • More frequent in patients with a general medical condition • Episodic disorder, one episode every 5 years • 20-35% experience a chronic unremitting course • Early-onset dysthymia is also common and has milder but also chronic depressive symptoms • Relapse and recurrence more common in those with a history of dysthymia and in those with partial recovery • Longer episodes appear more difficult to treat

4. Life-time and 12-Month Prevalence of Major Depression in Israel

5. Age-standardized Suicide Rates per 100.000 Population

7. Causes of Disability in the United States, Canada, and Western Europe in 2000 Iglehart, J. K. N Engl J Med 2004;350:507-514

8. Druss el al, Molecular Psychiatry, 2009

9. Druss el al, Molecular Psychiatry, 2009

10. Druss el al, Molecular Psychiatry, 2009

12. Prognosis of Affective IllnessThe Burden of The Illness

13. “Paradigmatic Shift” Unipolar Major Depressive Disorders are viewed as chronic illnesses with episodic recurrences as the norm Brodati et al 2001

14. Typical Symptoms of Affective Disorders Mania Depression Sadness Excessive energy Restless Worthlessness Loss of interest/pleasure Aggression Significant weight gain/loss Insomnia Rapid thoughts and speech Hypersomnia Euphoria Restlessness/ agitation Fatigue Grandiosity Guilt Irritability Decreased libido Poor concentration Recklessness Suicidal tendencies

16. The Bipolar Illness Wide range of syndromes with manic features, associated with episodes of depression Mania Hypomania Normal Depression Severe depression Normal Cyclothymic Cyclothymic Bipolar II Unipolar Bipolar I mood personality disorder disorder mania disorder variation Not shown: recurrent unipolar depression with family history of mania/hypomania Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990

17. The Unipolar Illness Major Depression. Recurrent Episode Major Depression with Residual Symptoms Double Depression Dysthymic Disorder

19. Long Term Studies of Depressive Disorders Demonstrate Repeat episodes in over 75% of patients Stephens &McHugh 1991; Picinelly & Wilkinson 1999; O’Leary & Lee 1996; Mueller et al 1999 Readmission of 35-62% Lee &Murray 1988; Smith & North 1988; Stephens & McHugh 1991; Thornicroft &Sartorius, 1993 Chronicity or Persistance of 5-25% Winokur & Morrison 1973; Angst 1988, 1997,1993; Thornicroft &Sartorius, 1993 Judd 1997; Judd et al 1998 10-year G.A.F. in moderate to severe scores in > 25% Surtees & Barkley 1994 Fair to poor occupational status in 30% of patients Winokur & Tsuang 1979

20. Time Spent in Specific Bipolar Disorder Affective Symptoms % of Weeks Asymptomatic Depressed Manic/hypomanic Cycling/mixed 1% 6% 2% 9% 53% 46%* 50% 32% 146 bipolar I patientsfollowed 12.8 years 86 bipolar II patientsfollowed 13.4 years *%s do not add to 100 due to rounding Judd LL et al. Arch Gen Psychiatry. 2002;59:530-537. Judd LL et al. Arch Gen Psychiatry. 2003;60:261-269.

21. Prognosis of Affective Disorders Paradigmatic shift • Complex life-long disorders • Often misdiagnosed and as a consequence poorly treated • Current treatment is a combination of “science and art” • Proven treatment algorrhytms and RTC’s are sorely needed • Comorbidity with psychiatric and medical conditions common

22. Comorbidities… The Rule, Not the Exception: The Multidimensionality of Depressive and Bipolar Disorder Diabetesmellitus Cardio-vascular Paindisorders Obesity Migraine Mood Disorder Substance abuse Personalitydisorders Eatingdisorders ADHD Anxietydisorders Impulsecontrol Osteoporosis McIntyre RS, et al. Hum Psychopharmacol. 2004;19(6):369-386.

23. Long-Term Antidepressants for Depressive Disorder and Risk for Diabetes Mellitus Andersohn et al. Am J Psychiatry. 2009;166:591-8

25. The Antidepressants

26. The evolution of antidepressants 2000s 1950s 1960s 1970s 1980s 1990s Phenelzine Isocarboxazid Tranylcypromine Imipramine Clomipramine Nortriptyline Amitriptyline Desipramine Maprotiline Amoxapine Mianserin Fluoxetine Sertraline ParoxetineFluvoxamine Citalopram Bupropion Mirtazapine Venlafaxine Duloxetine Milnacipran Reboxetine Moclobemide Escitalopram Agomelatine

27. Outcome of Depression treatment - Citalopram Complete absence of symptoms (HDRS < 7 or QIDS-SR< 5) Reduction of 50% in HDRS or QIDS-SR Remission Recovery Relapse Recurrence x Response STAR*D citalopram trial N=2,876 x Symptoms x Syndrome Continuation 4-9 Months Maintenance ?1 Year Acute 6-12 Weeks Treatment Phases QIDS-SR:Quick Inventory of Depressive Symptomatology, Self-Report Remission rate at 8 weeks was 27.5%-32.9 Response rate at 8 weekswas 47% Trivedi MH et al., Am J Psychiatry 163:28-40, 2006

28. Multifunctional Drugs for Neurotherapeutics “Targeting multiple components of pathobiology through a single drug molecule is gaining increasing acceptance in the treatment of complex disorders in the CNS (like MDD)” Van Der Schyf and Youdim 2009

29. Treatments in Development • Triple inhibitors of monoamine reuptake • Agents blocking both 5-HT reuptake and inhibitory 5-HT autoreceptors. Bimodal antidepressants acting as 5-HT2C or 5-HT2A receptor antagonists • Novel antidepressants with antagonist properties at 5-HT3 receptors • Dual 2-AR autoreceptor antagonists/monoamine reuptake inhibitors • Hybrid, monoaminergic/nonmonoaminergic antidepressants • Histamine H3, nicotinic, and GABAB receptors as targets: improving cognitive function • Glutamatergic receptors as targets: ionotropic and metabotropic hypotheses • Neuropeptidergic receptors as targets: focus on Neurokinin1 (NK1) receptor antagonists/SRI • Innovative neuroendocrine mechanisms: calming HPA axis overdrive and recruiting melatonin receptors • Drugs affecting intracellular cascades, BDNF, and more

30. American College of Physicians 2008 Recommendation 1: The American College of Physicians recommends that when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences Recommendation 2: The American College of Physicians recommends that clinicians assess patient status, therapeutic response, and adverse effects of antidepressant therapy on a regular basis beginning within 1 to 2 weeks of initiation of therapy Recommendation 3: The American College of Physicians recommend that clinicians modify treatment if the patient does not have an adequate response to pharmacotherapy within 6 to 8 weeks of the initiation of therapy for major depressive disorder Recommendation 4: The American College of Physicians recommends that clinicians continue treatment for 4 to 9 months after a satisfactory response in patients with a first episode of major depressive disorder. For patients who have had 2 or more episodes of depression, an even longer duration of therapy may be beneficial

31. American College of Physicians 2008 “The available evidence does not support clinically significant differences in efficacy, effectiveness, or quality of life among SSRIs, SNRIs, SSNRIs, or other second generation antidepressants for the treatment of acute-phase MDD”

32. Maintenance Prevents Relapse! Imipramine treated groups

35. Therapeutic Neuromodulation: A Welcomed Change in Psychiatry

36. 21st Century Neuromodulation Therapies in Psychiatry Psychiatry treatment may be at similar threshold as cardiology 25 years ago, in terms of potential for devices to improve our therapeutics Effective medications & psychosocial interventions help many but by no means all of our patients Devices have potential to help our severely ill patients and clearly warrant intensive research going forwards

37. Definitions Neurotherapeutics Treatments for nervous systems disorders through pharmacological or other modalities Neuromodulation-Neurostimulation The therapeutic alteration of activity in the central, peripheral or autonomic nervous systems, electrically or pharmacologically*, by means of implanted devices. *(today we must add also magnetically, and through light or ultrasound waves)

40. Neuronetics - Positioning System

43. Paus 2002

45. A Seizure May Not Be Always Necessary ….. TMS VNS DBS

46. Lobotomy • Goodman and Insel: • The scientific and clinical community must assure the public that the kind of mistakes made before are not repeated

47. Therapeutic Neuromodulation • Electroconvulsive Therapy (ECT) • Transcranial Magnetic Stimulation (TMS) • Magnetic Seizure Therapy (MST) • Vagus Nerve Stimulation (VNS) • Deep Brain Stimulation (DBS) • Neurofeedback • Low Intensity Low Frequency Ultrasound (Lilfu) • Optogenetics

48. Variations in electrical treatments • ECT: • Brief pulse ECT • Ultrabrief pulse ECT • Localized seizure ECT • Transcranial direct current stimulation (tDCS) • Transcranial alternating current stimulation (tACS)

49. Role of ECT in 21st century ECT remains a gold standard treatmentfor severe depression and has yet to be superseded by medication or by any other brain stimulation treatment In recent multicenter trials remission rates with ECT are about 75%. This is 3-4 fold superior to antidepressants Relapse and recurrence rates unreasonably high

50. Variations of TMS • Theta burst stimulation (TBS) • Changes in shape and direction of magnetic pulse • Quadripulse stimulation • Paired associative stimulation • Magnetic seizure therapy • Controllable pulse and shape TMS devices • Deep TMS