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
N
Total
%
Wom
%
Men
%
Total
%
Wom
%
Men
%
Lifetime
p
12-month
p
21-34
1627
10.6
13.3
8.0
6.3
7.8
4.8
.001
.015
35-49
1302
9.4
12.4
6.3
5.7
7.6
3.7
.000
.002
50-64
1069
6.3
6.3
10.1
6.2
6.1
6.3
.634
.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
14.2
3.7
8.7
2001
14.6
2.9
8.5
2002
12.8
3.5
8.0
2003
14.7
2.8
8.5
2004
13.5
3.4
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
Depression
Worthlessness
Loss of
interest/pleasure
Aggression
Rapid thoughts
and speech
Sadness
Insomnia
Significant weight
gain/loss
Hypersomnia
Euphoria
Restlessness/
agitation
Grandiosity
Fatigue
Guilt
Irritability
Recklessness
Decreased libido
Poor concentration
Suicidal tendencies
The Bipolar Illness
Mania
Wide range of syndromes with manic features,
associated with episodes of depression
Hypomania
Normal
Depression
Severe
depression
Normal Cyclothymic Cyclothymic
mood
personality
disorder
variation
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
1%
2%
6%
9%
53%
50%
32%
46%*
% of Weeks
Asymptomatic
Depressed
Manic/hypomanic
Cycling/mixed
146 bipolar I patients
followed 12.8 years
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
Diabetes
mellitus
Pain
disorders
Cardiovascular
Obesity
Migraine
Mood Disorder
Substance
abuse
Personality
disorders
Eating
disorders
ADHD
Impulse
control
Anxiety
disorders
McIntyre RS, et al. Hum Psychopharmacol. 2004;19(6):369-386.
Osteoporosis
Long-Term Antidepressants for Depressive
Disorder and Risk for Diabetes Mellitus
Incidence Rate Ratio
2.5
1.84
2.0
2.06
1.77
1.5
1.0
0.5
0.0
Mod-High >24m
TCA
SSRI
Andersohn et al. Am J Psychiatry. 2009;166:591-8
The evolution of antidepressants
1950s
1960s
1970s
1980s
Phenelzine
Imipramine
Maprotiline Fluoxetine
Isocarboxazid
Clomipramine Amoxapine Sertraline
Tranylcypromine Nortriptyline Mianserin
1990s
Bupropion
Mirtazapine
Paroxetine Venlafaxine
Amitriptyline
FluvoxamineDuloxetine
Desipramine
Citalopram Milnacipran
Reboxetine
Moclobemide
Escitalopram
2000s
Agomelatine
Outcome of Depression treatment - Citalopram
Complete absence of
symptoms (HDRS < 7
Reduction of
50% in HDRS
or QIDS-
or QIDS-SR < 5)
Remission
Recovery
Relapse
Recurrence
SR
Response
x
x
Symptoms
Syndrome
Treatment Phases
QIDS-SR: Quick
Inventory of
Depressive
Symptomatology,
Self-Report
x
Acute
6-12 Weeks
Continuation
4-9 Months
STAR*D
citalopram
trial
N=2,876
Maintenance
?1 Year
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-HT2C or 5HT2A 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
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
“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 acutephase MDD”
Imipramine treated groups
Therapeutic Neuromodulation: A
Welcomed Change in Psychiatry
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
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 21st 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