Transcript Slide 1
•
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
• • • • • • • • •
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
Life-time and 12-Month Prevalence of Major Depression in Israel
Lifetime 12-month Gender differences Age group 21-34 N 1627 Total % Wom % Men % Total % 10.6
13.3
8.0
6.3
Wom % 7.8
Men % Lifetime p 12-month p 4.8
.001
.015
35-49 50-64 1302 1069 9.4
6.3
12.4
6.3
6.3
10.1
5.7
6.2
7.6
6.1
3.7
6.3
.000
.634
.002
.876
>65 861 10.0
11.6
8.0
6.0
7.5
4.0
.09
.050
All 4859 10.2
12.3
7.9
6.1
7.3
4.7
.000
.000
Levav and Levinson. The Epidemiology of Affective Disorders in Israel 2009
Age-standardized Suicide Rates per 100.000 Population Years Men Women Total 2000 2001 14.2
14.6
3.7
2.9
8.7
8.5
2002 12.8
3.5
8.0
2003 2004 14.7
13.5
2.8
3.4
8.5
8.3
Bursztein and Apter The Epidemiology of Suicidal Behavior in The Israeli Population, 2009
Causes of Disability in the United States, Canada, and Western Europe in 2000 Iglehart, J. K. N Engl J Med 2004;350:507-514
Druss el al, Molecular Psychiatry, 2009
Druss el al, Molecular Psychiatry, 2009
Druss el al, Molecular Psychiatry, 2009
Prognosis of Affective Illness The Burden of The Illness
“Paradigmatic Shift”
Unipolar Major Depressive Disorders are viewed as chronic illnesses with episodic recurrences as the norm
Brodati et al 2001
Typical Symptoms of Affective Disorders
Mania Excessive energy Restless Aggression Rapid thoughts and speech Insomnia Sadness Depression Worthlessness Loss of interest/pleasure Significant weight gain/loss Hypersomnia Euphoria Grandiosity Irritability Recklessness Restlessness/ agitation Fatigue Guilt Decreased libido Poor concentration Suicidal tendencies
The Bipolar Illness
Mania Hypomania Wide range of syndromes with manic features, associated with episodes of depression Normal Depression Severe depression Normal mood variation Cyclothymic Cyclothymic personality disorder Bipolar II disorder Unipolar mania Bipolar I disorder Not shown: recurrent unipolar depression with family history of mania/hypomania Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990
The Unipolar Illness Major Depression. Recurrent Episode Major Depression with Residual Symptoms Double Depression Dysthymic Disorder
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
Time Spent in Specific Bipolar Disorder Affective Symptoms
9% 6% 1% 2% 32% 53%
146 bipolar I patients followed 12.8 years
46%* % of Weeks Asymptomatic Depressed Manic/hypomanic Cycling/mixed 50%
86 bipolar II patients followed 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.
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
Comorbidities … The Rule, Not the Exception: The Multidimensionality of Depressive and Bipolar Disorder Pain disorders Diabetes mellitus Cardio vascular Migraine Personality disorders Mood Disorder Obesity Substance abuse ADHD Impulse control Anxiety disorders Eating disorders Osteoporosis McIntyre RS, et al. Hum Psychopharmacol. 2004;19(6):369-386.
Long-Term Antidepressants for Depressive Disorder and Risk for Diabetes Mellitus 2.5
2.0
1.84
1.5
1.0
0.5
0.0
Mod-High >24m 1.77
TCA 2.06
SSRI
Andersohn et al. Am J Psychiatry. 2009;166:591-8
The evolution of antidepressants
1950s 1960s 1970s 1980s 1990s 2000s Phenelzine Isocarboxazid Tranylcypromine Imipramine Clomipramine Amoxapine Nortriptyline Amitriptyline Desipramine Maprotiline Mianserin Fluoxetine Sertraline Citalopram Bupropion Mirtazapine Paroxetine Venlafaxine Fluvoxamine Duloxetine Milnacipran Reboxetine Moclobemide Escitalopram Agomelatine
Outcome of Depression treatment - Citalopram Reduction of 50% in HDRS or QIDS SR Symptoms Complete absence of symptoms (HDRS < 7 or QIDS-SR < 5) Remission Relapse Recovery Recurrence Response
x x
STAR*D citalopram trial N=2,876
x
Syndrome Treatment Phases Acute 6-12 Weeks Continuation 4-9 Months Maintenance ?1 Year
QIDS-SR: Quick Inventory of Depressive Symptomatology, Self-Report
Remission rate at 8 weeks was 27.5%-
32.9
Response rate at 8 weeks was 47%
Trivedi MH et al., Am J Psychiatry 163:28-40, 2006
“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
• • • • • • •
Triple inhibitors of monoamine reuptake Agents blocking both 5-HT reuptake and inhibitory 5-HT autoreceptors. Bimodal antidepressants acting as 5-HT2 C HT2 A receptor antagonists or 5 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
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
an adequate response to pharmacotherapy within 6 to 8 weeks modify treatment if the patient does not have
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
“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 ”
Imipramine treated groups
Therapeutic Neuromodulation: A Welcomed Change in Psychiatry
21
st
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
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)
Neuronetics Positioning System
Paus 2002
A Seizure May Not Be Always Necessary …..
TMS VNS DBS
Lobotomy
Goodman and Insel: The scientific and clinical community must assure the public that the kind of mistakes made before are not repeated
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
Variations in electrical treatments
• • •
ECT:
–
Brief pulse ECT
– –
Ultrabrief pulse ECT Localized seizure ECT Transcranial direct current stimulation (tDCS) Transcranial alternating current stimulation (tACS)
Role of ECT in 21
st
century
ECT remains a gold standard treatment for 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
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