• Depression is 4th most Depression is 4th most disabling medical condition disabling medical condition worldwideworldwide• Predicted to be 2nd onlyPredicted to be 2nd only to chronic heart diseaseto chronic heart disease with regards to disabilitywith regards to disability by year 2020by year 2020• The management of TRD The management of TRD is a major public healthis a major public health problem worldwideproblem worldwide• Need to consider multipleNeed to consider multipleforms of depression:forms of depression:

UnipolarUnipolarBipolarBipolarDysthymiaDysthymiaWith Chronic PainWith Chronic Pain

• Common, typically recurrent, often chronic disabling Common, typically recurrent, often chronic disabling disorderdisorder

• Life-long prevalence of 4.9-17.9%Life-long prevalence of 4.9-17.9%• Women twice as likely to have depressionWomen twice as likely to have depression• More frequent in patients with a general medical More frequent in patients with a general medical

conditioncondition• Episodic disorder, one episode every 5 yearsEpisodic disorder, one episode every 5 years• 20-35% experience a chronic unremitting course20-35% experience a chronic unremitting course• Early-onset dysthymia is also common and has milder Early-onset dysthymia is also common and has milder

but also chronic depressive symptomsbut also chronic depressive symptoms• Relapse and recurrence more common in those with a Relapse and recurrence more common in those with a

history of dysthymia and in those with partial recoveryhistory of dysthymia and in those with partial recovery• Longer episodes appear more difficult to treat Longer episodes appear more difficult to treat

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

Lifetime12-monthGender differences

Age group

NTotal

%

Wom

%

Men

%

Total

%

Wom

%

Men

%

Lifetime

p

12-month

p

21-34162710.613.38.06.37.84.8.001.015

35-4913029.412.46.35.77.63.7.000.002

50-6410696.36.310.16.26.16.3.634.876

>6586110.011.68.06.07.54.0.09.050

All 485910.212.37.96.17.34.7.000.000

Levav and Levinson. The Epidemiology of Affective Disorders in Israel 2009

Age-standardized Suicide Rates per 100.000 Population

YearsMenWomen Total

200014.23.78.7

200114.62.98.5

200212.83.58.0

200314.72.88.5

200413.53.48.3

Bursztein and Apter The Epidemiology of Suicidal Behavior in The Israeli Population, 2009

Iglehart, J. K. N Engl J Med 2004;350:507-514

Causes of Disability in the United States, Canada, and Western Europe in 2000Causes of Disability in the United States, Canada, and Western Europe in 2000

Druss el al, Molecular Psychiatry, 2009Druss el al, Molecular Psychiatry, 2009

Druss el al, Molecular Psychiatry, 2009Druss el al, Molecular Psychiatry, 2009

Druss el al, Molecular Psychiatry, 2009Druss el al, Molecular Psychiatry, 2009

Prognosis of Affective IllnessThe 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

Restless

Rapid thoughtsand speech

Excessive energy

Euphoria

Irritability

Grandiosity

Aggression

Recklessness

Mania Depression

Insomnia

Restlessness/agitation

Sadness

Loss ofinterest/pleasure

Significant weightgain/loss

Hypersomnia

Fatigue

Worthlessness

Guilt

Decreased libido

Poor concentration

Suicidal tendencies

The Bipolar Illness

Mania

Hypomania

Depression

Severedepression

Normal Cyclothymic Cyclothymic Bipolar II Unipolar Bipolar Imood personality disorder disorder mania disorder

variation

Normal

Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990

Not shown: recurrent unipolar depression with family history of mania/hypomania

Wide range of syndromes with manic features, associated with episodes of depression

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, 1993Judd 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 patientsWinokur & Tsuang 1979

Time Spent in Specific Bipolar Disorder Affective Symptoms

Time Spent in Specific Bipolar Disorder Affective Symptoms

AsymptomaticAsymptomaticDepressedDepressedManic/hypomanicManic/hypomanicCycling/mixedCycling/mixed

% of Weeks% of Weeks

146 bipolar I patients146 bipolar I patientsfollowed 12.8 yearsfollowed 12.8 years

86 bipolar II patients86 bipolar II patientsfollowed 13.4 yearsfollowed 13.4 years

*%s do not add to 100 due to rounding

53%53%

6%6%

9%9%

32%32%46%*46%*

2%2%1%1%

50%50%

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 DisordersPrognosis of Affective Disorders

Paradigmatic shiftParadigmatic shift• Complex life-long disordersComplex life-long disorders• Often misdiagnosed and as a Often misdiagnosed and as a

consequence poorly treatedconsequence poorly treated• Current treatment is a combination of Current treatment is a combination of

“science and art”“science and art”• Proven treatment algorrhytms and RTC’s Proven treatment algorrhytms and RTC’s

are sorely neededare sorely needed• Comorbidity with psychiatric and Comorbidity with psychiatric and

medical conditions commonmedical conditions common

Comorbidities… The Rule, Not the Exception: The Multidimensionality of Depressive and Bipolar Disorder

McIntyre RS, et al. Hum Psychopharmacol. 2004;19(6):369-386.

Mood Disorder

Impulsecontrol

ADHD

Personalitydisorders

Migraine

Anxietydisorders

Eatingdisorders

Substanceabuse

Obesity

Cardio-vascular

Diabetesmellitus

Paindisorders

Osteoporosis

Long-Term Antidepressants for Depressive Disorder and Risk for Diabetes Mellitus

1.84 1.77

2.06

0.0

0.5

1.0

1.5

2.0

2.5

Inci

den

ce R

ate

Rat

io

Mod-High >24m TCA SSRI

Andersohn et al. Am J Psychiatry. 2009;166:591-8

1950s 1960s 1970s 1980s 1990s

Phenelzine

Isocarboxazid

Tranylcypromine

Imipramine

Clomipramine

Nortriptyline

Amitriptyline

Desipramine

Fluoxetine

Sertraline

Paroxetine

Fluvoxamine

Citalopram

Bupropion

Mirtazapine

Venlafaxine

Duloxetine

Milnacipran

Reboxetine

Moclobemide

Escitalopram

Maprotiline

Amoxapine

Mianserin

The evolution of antidepressants

2000s

Agomelatine

Remission

x

xx

Symptoms

Syndrome

Response

RelapseRecovery

Recurrence

Treatment Phases AcuteAcute6-12 Weeks6-12 Weeks

ContinuationContinuation4-9 Months4-9 Months

MaintenanceMaintenance?1 Year?1 Year

Outcome of Depression treatment - Citalopram

Remission rate at 8 weeks was 27.5%-32.9Response rate at 8 weeks was 47%

Trivedi MH et al., Am J Psychiatry 163:28-40, 2006

Reduction of 50% in HDRS or QIDS-SR

Complete absence of symptoms (HDRS < 7 or QIDS-SR < 5)

STAR*D citalopram trial N=2,876

QIDS-SR: Quick Inventory of Depressive Symptomatology, Self-Report

““Targeting multiple components of Targeting multiple components of pathobiology through a single drug pathobiology through a single drug molecule is gaining increasing molecule is gaining increasing acceptance in the treatment of complex acceptance in the treatment of complex disorders in the CNS (like MDD)”disorders in the CNS (like MDD)”

Van Der Schyf and Youdim Van Der Schyf and Youdim 20092009

• Triple inhibitors of monoamine reuptakeTriple inhibitors of monoamine reuptake• Agents blocking both 5-HT reuptake and inhibitory 5-HT Agents blocking both 5-HT reuptake and inhibitory 5-HT

autoreceptors. Bimodal antidepressants acting as 5-HT2autoreceptors. Bimodal antidepressants acting as 5-HT2CC or 5- or 5-HT2HT2AA receptor antagonists receptor antagonists

• Novel antidepressants with antagonist properties at 5-HT3 Novel antidepressants with antagonist properties at 5-HT3 receptorsreceptors

• Dual 2-AR autoreceptor antagonists/monoamine reuptake Dual 2-AR autoreceptor antagonists/monoamine reuptake inhibitorsinhibitors

• Hybrid, monoaminergic/nonmonoaminergic antidepressantsHybrid, monoaminergic/nonmonoaminergic antidepressants– Histamine H3, nicotinic, and GABAB receptors as targets: Histamine H3, nicotinic, and GABAB receptors as targets:

improving cognitive functionimproving cognitive function– Glutamatergic receptors as targets: ionotropic and metabotropic Glutamatergic receptors as targets: ionotropic and metabotropic

hypotheseshypotheses– Neuropeptidergic receptors as targets: focus on Neurokinin1 (NK1) Neuropeptidergic receptors as targets: focus on Neurokinin1 (NK1)

receptor antagonists/SRIreceptor antagonists/SRI• Innovative neuroendocrine mechanisms: calming HPA axis Innovative neuroendocrine mechanisms: calming HPA axis

overdrive and recruiting melatonin receptorsoverdrive and recruiting melatonin receptors• Drugs affecting intracellular cascades, BDNF, and moreDrugs affecting intracellular cascades, BDNF, and more

Recommendation 1: The American College of Physicians recommends Recommendation 1: The American College of Physicians recommends that when clinicians choose pharmacologic therapy to treat patients that when clinicians choose pharmacologic therapy to treat patients with acute major depression, with acute major depression, they select second-generation they select second-generation antidepressants on the basis of adverse effect profiles, antidepressants on the basis of adverse effect profiles, cost, and patient preferences cost, and patient preferences

Recommendation 2: The American College of Physicians recommends Recommendation 2: The American College of Physicians recommends that clinicians that clinicians assess patient statusassess patient status, therapeutic response, and , therapeutic response, and adverse effects of antidepressant therapy adverse effects of antidepressant therapy on a regular basison a regular basis beginning within 1 to 2 weeks of initiation of therapybeginning within 1 to 2 weeks of initiation of therapy

Recommendation 3: The American College of Physicians recommend Recommendation 3: The American College of Physicians recommend that clinicians that clinicians modify treatment if the patient does not have modify treatment if the patient does not have an adequate response to pharmacotherapy within 6 to 8 an adequate response to pharmacotherapy within 6 to 8 weeksweeks of the initiation of therapy for major depressive disorder of the initiation of therapy for major depressive disorder

Recommendation 4: The American College of Physicians recommends Recommendation 4: The American College of Physicians recommends that clinicians that clinicians continue treatment for 4 to 9 monthscontinue treatment for 4 to 9 months after a after a satisfactory response in patients with a first episode of major satisfactory response in patients with a first episode of major depressive disorder. depressive disorder. For patients who have had 2 or more For patients who have had 2 or more episodes of depression, an even longer duration of episodes of depression, an even longer duration of therapy may be beneficialtherapy may be beneficial

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

Imipramine treated groupsImipramine treated groups

Therapeutic Neuromodulation: A Therapeutic Neuromodulation: A Welcomed Change in PsychiatryWelcomed Change in Psychiatry

2121stst Century Neuromodulation Century Neuromodulation Therapies in PsychiatryTherapies in Psychiatry

Psychiatry treatment may be at similar threshold as Psychiatry treatment may be at similar threshold as cardiology 25 years ago, in terms of potential for cardiology 25 years ago, in terms of potential for devices to improve our therapeutics devices to improve our therapeutics

Effective medications & psychosocial interventions Effective medications & psychosocial interventions help many but by no means all of our patientshelp many but by no means all of our patients

Devices have potential to help our severely ill patients Devices have potential to help our severely ill patients and clearly warrant intensive research going and clearly warrant intensive research going forwardsforwards

DefinitionsDefinitions

NeurotherapeuticsNeurotherapeuticsTreatments for nervous systems disorders Treatments for nervous systems disorders through pharmacological or other modalitiesthrough pharmacological or other modalities

Neuromodulation-NeurostimulationNeuromodulation-NeurostimulationThe therapeutic alteration of activity in the The therapeutic alteration of activity in the central, peripheral or autonomic nervous central, peripheral or autonomic nervous systems, systems, electrically or pharmacologically*electrically or pharmacologically*, by , by means of implanted devices.means of implanted devices.

*(today we must add also magnetically, and *(today we must add also magnetically, and through light or ultrasound waves)through light or ultrasound waves)

Neuronetics -Positioning System

Paus 2002

A Seizure May Not Be Always Necessary..…

TMS VNS DBS

Lobotomy

Goodman and InselGoodman and Insel::The scientific and clinical The scientific and clinical community must assure community must assure

the public that the kind of the public that the kind of mistakes made before are mistakes made before are

not repeatednot repeated

Therapeutic NeuromodulationTherapeutic Neuromodulation

• Electroconvulsive Therapy (ECT)Electroconvulsive Therapy (ECT)

• Transcranial Magnetic Stimulation (TMS)Transcranial Magnetic Stimulation (TMS)

• Magnetic Seizure Therapy (MST)Magnetic Seizure Therapy (MST)

• Vagus Nerve Stimulation (VNS)Vagus Nerve Stimulation (VNS)

• Deep Brain Stimulation (DBS)Deep Brain Stimulation (DBS)

• NeurofeedbackNeurofeedback

• Low Intensity Low Frequency Ultrasound (Lilfu)Low Intensity Low Frequency Ultrasound (Lilfu)

• OptogeneticsOptogenetics

Variations in electrical treatmentsVariations in electrical treatments

• ECT:ECT:– Brief pulse ECTBrief pulse ECT– Ultrabrief pulse ECTUltrabrief pulse ECT– Localized seizure ECTLocalized seizure ECT

• Transcranial direct current stimulation (tDCS)Transcranial direct current stimulation (tDCS)• Transcranial alternating current stimulation (tACS)Transcranial alternating current stimulation (tACS)

Role of ECT in 21Role of ECT in 21stst century century ECT remains a gold standard treatmentECT remains a gold standard treatment for severe for severe depression and has yet to be superseded by depression and has yet to be superseded by medication or by any other brain stimulation medication or by any other brain stimulation treatmenttreatment

In recent multicenter trials remission rates with ECT In recent multicenter trials remission rates with ECT are about 75%. This is 3-4 fold superior to are about 75%. This is 3-4 fold superior to antidepressantsantidepressants

Relapse and recurrence rates unreasonably highRelapse 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