Major Depression..The Story and Treatment

Prof. Yaser Abdel RazekProfessor of Psychiatry

Institute of Psychiatry, Ain Shams UniversityWHO Collaborative center for training and research

Unipolar Major Depression /2010• Number of

population• Life time prevalence

of UMD• Point prevalence UMD (WHO- 2008 )

• 15% will try suicide • Died by suicide

(2010)

6,865,820,500

450,088,420

426.463

1,513,322,000

www.peterrussell.com/WorldClock

67,513,263

• Worldwide, 450 million patient, with high comorbid, social and economic costs

( WHO 2008)• Prevalence of Unipolar depressive

disorders is 17% (NCS-R Kessler et al, 2003)

• Average life time prevalence from studies 19-21% ( Kaplan and Sadock, 2005)

• In the UK and in 2005 there were in excess of 29 million prescriptions for ADD.

• The direct cost of treatment for depression in the National Health Service (£887

million) > both that for hypertension and diabetes combined (£439 and £300 million

respectively).• In 1994 an estimated 1.5 million disability-

adjusted life years were lost each year in the developed world as the result of

depression.

• In the U.S., more than 21 million adults suffer from some kind of depressive disorder, according to the

National Institute of Mental Health. • Most patients who have one major depressive episode are likely to have another within 5 years.

• Overall, as many as 20% of patients with major depression do not respond to 2 or more adequate

treatment regimens for depression.

Prevalence of depressive disorders will increase !!!!!!!

• More industrialization and urbanization• Globalization

• Increasing Stress ( education , competition, unemployment, delayed marriage, economic

problems)• Increase life span

• Genetic anticipation• Substance abuse

That’s WhyFinding an effective treatment

for depression is therefore a key consideration

for the health service

Some Facts and Figures about Depression

• 3/10 employees will have a mental health problem in any one year, mainly depressive

and anxiety disorders. • By the year 2020, major depression will be

second only to chronic heart disease as an international health burden (this is measured by its cause of death, disability, incapacity to

work and the medical resources it uses).

Leading Causes of DALYs in 2020 (Disability Adjusted for Life Years)

Both sexes Disease or injury

Males Disease or injury

Females Disease or injury

All causes All causes All causes1- Ischaemic heart

diseaseIschaemic heart disease

Unipolar major depression

2- Unipolar major depression

Road traffic accidents

Ischaemic heart disease

3- Road traffic accidents

Cerebravascular disease

Cerebravascular disease

4- Cerebravascular disease

Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease

5- Chronic obstructive pulmonary disease

Unipolar major depression

Road traffic accidents

Ustun et al (2004) Ustun et al (2004) Brit. J. Psychiat. Brit. J. Psychiat.

Why depression? (cont.)• 15% of depressive disorders cases attempt suicide

• 50% of completed suicidal cases are major depression• Prevalence of depressive disorders is 20% in women and 12%

in men• Prevalence of Unipolar Major depressive disorder is increasing

– 1% for those born before 1905– 6% for those born after 1955

• Many persons with Depression are disabled and have a bad quality of life

• It is an expensive disorder

Freeling and Tylee (1992); Regier et al (1988); Vazquez-Barquero et al (1987)

Recognition of general practice Recognition of general practice patientspatients

Up to 50% of general practice Up to 50% of general practice patients may have some patients may have some depressive symptoms.depressive symptoms.

Approximately 5% of these Approximately 5% of these will have major depression will have major depression

defined by DSM-III-R defined by DSM-III-R criteria.criteria.

M Depression

Dysthymia

Mixed anxiety depression

Adjustment disorders with depressive symptoms

Depressive symptoms

Prevalence of depressive disorders will increase due to:

• More industrialization and urbanization• Globalization

• Increasing Stress ( education , competition, unemployment, delayed marriage, economic

problems)• Increase life span

• Genetic anticipation• Substance abuse

Bed days: depression vs chronic medical condition

0 0.5 1 1.5 2 2.5Bed days / past month

Depressive symptomsHypertension

DiabetesCoronary artery disease

Angina onlyArthiritis

GI problemLung problemBack problem

No chronic condition

Wells et al., 1989Wells et al., 1989

The Effects of Depression Beyond SymptomsDisability of Daily Functioning: Depression Compared with Chronic Medical Conditions

PhysicalPhysical SocialSocial RoleRole Bed DaysBed Days

HypertensionHypertension

DiabetesDiabetes

HeartHeart

ArthritisArthritis

LungLung

Depression has more disability (P < 0.05)Depression has more disability (P < 0.05)

Depression has less disability (P < 0.001)Depression has less disability (P < 0.001)

No difference (P > 0.05)No difference (P > 0.05) Wells et al. JAMA. 1989; 262 (7): 914-919Wells et al. JAMA. 1989; 262 (7): 914-919

Work-Loss Days by Health Condition

2.77

1.781.74 1.6

1.41

1.210.83

0

0.5

1

1.5

2

2.5

3

Days

Depression Diabetes History ofHeart isease

ImmuneDisorder

Grzywacz JG. SL. TEN. 2000; 2(6): 41-46.

Public perceptions of Mental illness• 71% Due to emotional weakness

• 65% Caused by bad parenting

• 43% Incurable

• 35% Consequence of sinful behaviour

• 10% Has a biological basis; Involves the

brain

Etiology of major depression• Major Depression has no environmental cause or

disproportional to the cause • Neurotransmitter disturbance

• Genetic factors• Neuroendocrinal disturbance

• Disturbed immune function• Disturbed sleep cycle

• Environmental stressors may play role but alone are not enough to cause depression

Treatable DiseaseTreatable Disease

Depression is one of the Depression is one of the most treatablemost treatable untreateduntreated diseases diseases

80%80% can be successfully treated can be successfully treated with with medication, psychotherapy or a medication, psychotherapy or a combination of the two combination of the two

Treatment of depression

Tylee A et al, Int Clin Psychopharmacol,1999,14(3):139–51;Lépine, JP et al., Int Clin Psychopharmacol, 1997,12:19–29.

- Do not seek help- Undiagnosed- Diagnosed but untreated- Treated but non compliant

*

Receive antidepressant

(4.4%)

Adequately treated

(?%)

Untreated patients (95.6%)

Depressed Patients (100%)

The hidden cost of not treating Mood Disorders

Dysfunctional families

Absenteeism

Decreased productivity

Job-related injuries

Adverse effect on quality control in the workplace• Although suicide is rare in our countries it is common in

depression

Clinical features• To diagnose depression We should have two criteria out of each group of

the following symptoms

First group1-Depressed mood• Continuous unexplained bad mood with

spontaneous crying from time to time2-Loss of interest

• Loss of all pleasurable activities like sports, watching TV, reading, spending, visiting

friends, etc.3-Easy fatigability

• patients complained of inability to do anything with marked reduction of energy and easy

fatigability on minor effort

Second Group• 1-Change of appetite

• 2-Change of sleep• 3-Change of psychomotor activity

• 4-Guilt• 5-Death wishes

• 6-Lack of concentration, indecisiveness• 7-Loss of confidence

Other key symptoms

– Irritability and anxiety in addition or instead of pure depression

symptoms–Predominant somatic symptoms

–Headache –General aches and pains

–Libido decrease

How do patients with major depression usually present in primary care?

Tachycardia/irregular heart beat

Presenting complaint

CardiologicalChest pain

NeurologicalHeadacheDizziness

Syncope/seizuresGastrointestinalEpigastric pain

Diarrhoea

‘Asthma’

PulmonaryDyspnoea

0 10 20 30 40 50 60% patients

Wayne Katon (1984)

* DSM-IV-TR™ 2000

Types of depression• There are more than 50 type of depressive disorder, all types share some symptoms and

differ in some other symptoms

Different formsUnipolar

American Psychiatric Association (1994)

Major depressive Major depressive disorderdisorder

DysthymiaDysthymia

BipolarBipolar

Bipolar IBipolar I

Bipolar IIBipolar II

CyclothymiaCyclothymia

Mixed statesMixed states

Adjustment disorder with depressive sym

Dysthymia

• A less severe type of depression. • It involves long-term, continuous symptoms

• However, people with dysthymia do not function well

• Many people with dysthymia also experience major depressive episodes at some time in their

lives.

Bipolar depression

• Depression is alternating with episodes of hypomania or mania.

Major depression• Previous manic features (BP)

• Stress May not present• Early morning awakening 2

hours• Diurnal variation (bad at

morning)• Marked Change of

psychomotor activity• Delusions and hallucinations• Worse just before menses

• Post partum attacks• Recovery may be delayed

Adjustment disorder• No manic F

• Stressor Must be present• Delayed sleep onset

• May be worst at the night

• Not marked• No delusions or

hallucinations• Not related to menses• No postpartum attacks

• Recovery within 6 months

Differential Diagnosis

• Debilitating physical illness• Organic depression

• Substance induced depression

Debilitating physical illness as cancers may be presented by

• Loss of weight• Easy fatigability• Disturbed sleep

• Somatic symptoms

Medical disorders with Depression (organic)

• AIDS• Cancer – Intracranial tumors, Pancreatic Ca., and others

• Diabetes• Heavy metal toxicity – Lead, Mercury etc

• Hypo and hyperthyroidism• Hyperadrenalism (Cushing’s disease)

• Adrenocortical insufficiency (Addison’s disease)• Hypoparathyroidism• Pernicious anaemia

• Systemic lupus erythemetosis• Viral infections; Hepatitis, Pneumonia.

Medical Condition Frequency of Major Depression

Coronary Artery Coronary Artery DiseaseDisease

30-60%

EmphysemaEmphysema 20-40% HIV infectionHIV infection 20-35% HypothyroidismHypothyroidism 10-30% StrokeStroke 10-25% Diabetes MellitusDiabetes Mellitus 10-20% Renal FailureRenal Failure 5-20%

Kaplan HI, 1994

The association between The association between depression and medical illnessdepression and medical illness

Neurological disorders• Parkinson’s 50%

• Post stroke 20%

• Dementia 20-30% major depression

• Seizure 20-50% in recurrent seizure

• Huntington’s 30%

• Multiple sclerosis 50%

Drugs that can cause depression

• All substances of abuse• Beta blockers

• Some antihypertensive drugs• Contraceptive pills

Co-morbidity

Comorbid major depression and Comorbid major depression and anxiety disordersanxiety disorders

INTRODUCTION TO ANXIETY DISORDERS

Lifetime comorbidity

1. Kessler et al (1995); 2. APA, DSM-IV; 3. Rasmussen & Eisen (1988);4. Van Ameringen et al (1991); 5. Brawman-Mintzer & Lydlard (1996); 6. Stein & Kean (2000)

PTSD Panic disorder

SAD

GAD

OCD

48% of patients with PTSD1

50% to 65% of patients with PD2

34% to 70% of patients with SAnD4, 6 67% of patients with OCD3

8% to 39% of patients with GAD5

Major depression

What are symptoms of anxiety? Anxiety can be experienced in a number of

different ways. • Psychological symptoms

– Inner tension. – Agitation.

– Fear of losing control. – Dread that something catastrophic is going to happen, such as a blackout, seizure,

heart attack or death. • Physical symptoms

– Racing heart beat (palpitations). – Breathing fast, feeling short of breath or finding it hard to 'get breath'.

– Chest tightness. – Dry mouth, butterflies in the stomach, feeling sick.

– An urge to pass urine. – Tremors – Sweating.

Treatment of depressionHospitalization

May be necessary if patient has • Suicidal

• Severe psychomotor retardation or agitation• Absolute insomnia

Groups of ADDs currently Groups of ADDs currently availableavailable

• Tricyclic ADDs – Tryptizol (amitryptiline)

– Anafranil (clomipramine)• SSRIs

– Cipram (Citalopram)– Cipralex (escitalopram)

– fluoxetine– fluvoxamine– paroxetine– sertraline

• NaSSA– Mirtazepine• SNRIs – Venlafaxine– Duloxetine

Doses of ADD in major depressionDrug Starting dose (mg/day)Mean dose (mg/day)Amitriptyline 25-50 100-300Imipramine 25-50 100-300Clomipramine 25-50 100-250Fluoxetine 5-20 20-80Fluvoxamine 100-200 150-250Sertraline 50-100 50-200Paroxetine 20 20-80Citalopram 20 20-40Escitalopram 10 10-20

Electroconvulsive TherapyIt is safe

It is not painfulNo long lasting brain changes

It has rapid onset relief of symptoms

Non-response Respond

Partial Response

Partial ResponseNon-response

Respond

Major depressive episode

Adapted from Thase and Kupfer (1996)Criteria and duration Severity

Euthymia

Symptoms

Major depressive

episodeSyndrome

treatment

Adapted from Thase and Kupfer (1996)Recurrence Maintenance treatment

Euthymia

Symptoms

Major depressive

episodeSyndrome

Remission

Response

Recovery

Predictors

Maintenance treatment

Recurrence

Maintenance TreatmentMaintenance Treatment

85% remain well 15% Recurrence

Maintenance treatment

No Maintenance Treatment

50% remain well 50% Recurrence(more difficult to treat)

(drug stopped after patient responded to drug)

Predictors of long-term, maintenance antidepressant therapy

• At least three episodes

Two episodes and potential risk factorTwo episodes and potential risk factor late onset (at age 60 years or over)late onset (at age 60 years or over) early onset (before 40 years of age)early onset (before 40 years of age) short interval between episodesshort interval between episodes rapid onset of previous episodesrapid onset of previous episodes positive family history with affective disorderspositive family history with affective disorders co-morbidityco-morbidity severity of index episodeseverity of index episode poor symptom control in continuation phasepoor symptom control in continuation phase low work adjustmentlow work adjustment

What to say to patient?• You have depression

• Depression is a chemical disorder• You are not sin or kafer. You are ill• Drugs will take time to improve your

condition• Drugs are not addictive

• Drugs have no marked side effects

What to say to patient? (Cont.)

• First to improve is your sleep and appetite• The last to improve is your mood

• Recovery is expected within 2-3 months• One drug is enough in most of cases

• There are many effective drugs . if one failed we will try another

• Drugs should be continued till 1 year from recovery

• ECT is not a bad choice

In elderly

• Take care of• Comorbid physical disorders

• Drug selection• Drug interactions

• Suicide

During Pregnancy

• Take care of• No drugs in first trimesterPsychotherapy for mild cases

ECT for severe cases• Second and third trimester

consent from patientmost of drugs are not injurious butfrequent ultrasonography for fetus

Breast Feeding

• Most of drugs secreted in breast milk• Follow up the baby for any anticholinergic

effects or sedation

In Children

• Assessment by psychiatrist is a must• Depression may take different faces

• Phobic depression• Enuretic depression• Conduct depression• Somatic symptoms

• School refusal

Treatment of depression

Tylee A et al, Int Clin Psychopharmacol,1999,14(3):139–51;Lépine, JP et al., Int Clin Psychopharmacol, 1997,12:19–29.

- Do not seek help- Undiagnosed- Diagnosed but untreated- Treated but non compliant

*

Receive antidepressant

(4.4%)

Adequately treated

(?%)

Untreated patients (95.6%)

Depressed Patients (100%)

Do ADD work in the real world?

Placebo response

Some Studies Found That

• ADD Are of value in severe depression more than in mild to moderate cases.

As difference from placebo effect is not significant

Half empty or half full?

• Most of depressed patients treated with ADD get better

• But fewer get entirely well

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

Definitions

• Response: 50% or greater decrease in score of any depression rating scales

• Remission :– Symptom free– HAM-D 17 less than 8– Good functions

Is there a price to pay for a partial response?

Residual symptoms and quality of life

• Poor function• More recurrence• More treatment discontinuation• Chronicity is related to loss of

employment, loss of social relations, marital troubles, etc.

Fava et al, 2007 Psychol med 37;307-317Bocking et al 2006; J Clin Psychiatry 67;747-755

STAR*D Project• Naturalistic study• 6-year duration• $35 million • "next best" steps for patients with major

depressive disorder.

If My patient is better but not well

Should weSwitch

Augment or Combine?

Response and Remission ratesPatients

noResponse Remission

Citalopram 3671 48.6 1346 ( 36.8%)

Step 2 1439 28.5 439(30.6%)

Step 3 390 16.8 53 (13.7%)

Step 4 123 16.3 16 (13%)

Total 1854 (50.5%)

Importance of remission from STAR D

Relapse rate of non remitted

Relapse rate of remitted

Level I 59% 34%

Level II 68% 47%

Level III 76% 43%

Level IV 83% 50%

TIME TO RELAPSE FROM STAR D

non remitted remitted

Level I 3.6 4.4 M

Level II 3.2 4.5M

Level III 3 3.9 M

Level IV 3.5 2.5 M

Factors associated with greater chance for remission STAR*D

• Employment• Greater income• Greater education• Caucasian• Female gender• No Comorbidity• Greater functioning• Married • private insurance• Fewer concurrent general medical and psychiatric conditions• A shorter index episode

Trivedi et al, 2006 Am J psychiatry 163;28-40Cohen et al 2006 Arch Gen Psychiatry 63;50-56

To what extent this remission is attributed to the drug?

• No placebo group• Excellent patient characteristics

Problems with STAR*D

• No placebo arm• No ECT group• Selection of drugs did not based on

wisdom clinical experience• Did not discuss the issue of generic drugs• Little Number of cases in subgroups

46% of cases did not complete the study

Level Non remitted cases

Dropped cases

I (3671) 2325

II ( 1439) 1000 886

III (390) 337 610

IV (123) 107 214

Total 1710 (46%)

Non compliance and intolerable side effects

Lessons from STAR D

• Only about one third of depressed patients remit (30%) with a first ADD trial.

Lessons From STAR*D• None of the late-sequence STAR*D

options emerged as a miracle intervention for patients with treatment-resistant depression.

• Clearly, one take-home message is that after patients with depression fail to obtain adequate benefit from two treatment trials only modest responses can be expected from each subsequent treatment trial.

Lessons from STAR*D• Even after four sequential trials, 49.5% of

the patients – Did not achieve remission ( resistant

depression)– Intolerable side effects– Non compliant

• Clearly, we urgently need more effective treatments for depression.

Lessons from STAR*D

• First and second drug are the best chance for a patient to remit so proper selection from the start is very important.

Maintenance Electroconvulsive Therapy

• 2 years before ECT, 26 m during mECT, and up to 4 years after cessation of mECT.

• The findings suggest that mECT – Increases remission rate– Reduces rate of hospitalization– Reduces duration of stay in each

hospotaization

Kellner et al, 2007 Evidence-Based Mental Health 2007;10:79Susham et al 2008 Journal of ECT. 24(3):191-194

For whom?Predictors of remission

Factors with poor response

• More score of HAMD• More Duration of current episode• Fatigue • Retarded depression • HAMD anxiety/somatization subscale• Anxiety related comorbid conditions• overall pain • Medical comorbidity • Atypical depression

Howland et al, 2008Ann Clin Psychiatry. 2008 Oct-Dec;20(4):209-18

20% reduction at day 14 may predict remission

• A 20% reduction of HAMD total baseline is a sensitive predictor for remission (80%).

Henkel et al 2008J Affect Disord. 2008 Nov 21

795

Clinical predictors• Lithium has a place in bipolar depression• TCA and SNRI for depression with painful

physical symptoms• ECT or additional antipsychotic drugs are

frequently necessary in very severe and delusional depressions.

• MAOIs for atypical and anergic depression

Thase ME 2004, CNS Spectrum 9:818-821Joyce et al Arch Gen Psychiatry. 1989 Jan;46(1):89-99.

Can we Find Biomarkers that predict remission?

• DST• Quantitative EEG and REM latency• Imaging• Genetics

Early Normalization of DST• Remitters were characterized by a more

pronounced early normalization of an initially dysregulated HPA-axis.

• Early partial response within 2 weeks is important positive predictor for achieving remission.

Hennings et al, 2008J Psychiatr Res. 2008 Jun 30.

842

Sleep Microstructure• REM latency and REM density changes

are common in depressed patients.• Decreased amplitude of delta and theta

waves during REM ( over temporal lobes). • These changes tend to improve rapidly in

patients who respond to ADD.

Liscombe et al , 2002J Psychiatry Neurosci. 2002 January; 27(1): 40–46.

SPECT before and after treatment

• Baseline rCBF was lower in depressed patients than in controls in the frontal cortex and subcortical nuclei bilaterally.

• A response to medication was associated with normalization of rCBF deficits,

Kohn et al, 2007Journal of Nuclear Medicine Vol. 48 No. 8 1273-1278

Meta-Analysis of MRI Studies • Several studies have found reduced hippocampal

volume in patients with depression.• A meta-analysis of the 12 studies of unipolar depression.

The sample comprised 351 patients and 279 healthy subjects. The weighted average showed a reduction of hippocampal volume of 8% on the left side and 10% on the right side.

• The total number of depressive episodes was significantly correlated to hippocampal volume reduction.

• Effective ADD are associated with increased volume of hippocampus ( neurogenesis – animal studies)

Videbech et al, 2004Am J Psychiatry 161:1957-1966, November 2004

Genetics • STAR*D reported an association between genetic

variation in the HTR2A gene and GRIK4 gene, outcome of citalopram treatment. Homozygote carriers of these markers were more likely to respond to citalopram.

• GenPOD Trial , this study aims to investigate the influence of a polymorphism in the 5HT transporter in altering response to SSRI medication.

Paddock et al, 2007 Am J Psychiatry 164:1181-1188, Thomas et al, Trials. 2008; 9: 29. Published online 2008 May 22

How to increase chances of remission?

Before anything be sure that non remission is not due to

• Non adherence• Latent bipolarity• Latent psychosis• Latent physical illness• Substance abuse

APA PRACTICE GUIDELINES• If a patient is considered medication

resistant on the basis of unsatisfactory response to an antidepressant agent for 6-8 weeks, the preferred treatment is– A trial of alternative non MAO Inhibitor drug

with a different chemical profile– Co administration of lithium or thyroxin– Co administration of a second antidepressant

Factors in choosing pharmacotherapy in major depression• Efficacy

• Prior response• Pharmacokinetic profile• Affordability• Mechanism of action

Switch

• Better between different classes

• Better from mono to dual or triple action reuptake inhibitors.

Augmentation• No FDA approval • No washout• Faster mechanism of action• May be able to target residual symptoms• As

– Lithium– T3 and T4– APD– AED– Buspirone– Pindolol – Nutrients ( omega 3, folic acid)

The best evidence with T3 and T4

• Well tolerated• Better in females more than males

Nierenberg et al, 2006 Am J Psych 163:1519-1530

• Combinations– SSRI + NRI ( SNRI)– Mirtazepine + SSRI or SNRI

• Augmentations– Atypical antipsychotics– ECT– Folic acid

Severe, Psychotic and Melancholic

• Combinations– SSRI + NRI ( SNRI)

• Augmentations– BDZ– Buspirone – Pindolol– Anticonvulsant

Anxious Depression

• Combinations– SSRI + NRI ( SNRI)– SSRI + Bupropion

• Augmentation– Modafinil– Thyrpoid extract

Depression withFatigue/Sleepiness

New And Future Lines Of Treatment

Mechanism of actions of ADDTransporter, Receptors

++Calcium ++G protein and cAMP

Gene

product

Phosphorylation of transcription factors as CREB and BDNF

ADD effect

hippocampus receptors Trk B

Activate Protein kinase

Future Expectations• All through 46 years we still working outside the

cell• Within 30 years we have only two groups of

ADD• At the last 15 years we have more than 10 new

groups of ADD• So it is expected within 10 years to have

additional groups with different mechanisms • Drugs working inside the cell are under trials

Three primary approaches are currently being taken

• 1) optimizing the pharmacologic modulation of monoaminergic neurotransmission,

• 2) developing medications that target neurotransmitter systems other than the monoamines

• 3) directly modulating neuronal activity via focal brain stimulation.

Holtzheimer AND Nemeroff Curr Psychiatry Rep. 2008 Dec;10(6):465-73

New Drugs• Triple monoamine reuptake inhibitors, • Dopamine receptor agonists• Corticotropin -releasing factor-1 receptor antagonists• Glucocorticoid receptor antagonists• N-methyl-D-aspartate receptor antagonists• Drugs that are selective to hippocampus• Drugs that directly increases cAMP, calcium • Drugs decrease breakdown of cAMP• Drugs that act directly on BDNF • Drugs directly act on Trk B receptors• omega-3 fatty acids, and melatonin receptor agonists

Focal Brain Stimulation

• Vagus nerve stimulation• Transcranial magnetic stimulation• Magnetic seizure therapy• Deep brain stimulation ( phase I and II)

Please can you switch me on doctor?

• Pulse generator • Programmed by telemetry using a

control software on a PC• Approved by FDA July 2005• A treatment for medication-

refractory epilepsy.• Physicians can adjust the timing

and amount of stimulation • The therapy assures patient

adherence.• No serious adverse • Decreased doses of common

ADDPatel et al, 2007 MedGenMed. 9(4): 62

Matthews et al, 2003 The British Journal of Psychiatry 183: 181-183

Mechanism of action of VNS

Afferent sensory fibres

nucleus of the tractus solitarius

raphe nucleus & locus coereuleus

cortical and limbic structures

VNS IN REFRACTORY DEPRESSION• The response and remission rates were

55% and 27% respectively at 1 year. • "That's an incredible response for this

group (These are people who haven't been well for years).

• The most common side effect was voice alteration or hoarseness which was generally mild and related to output current intensity.

Corcoran et al 2006, Br J Psych 189: 282-283. Sackeim et al, 2001 Neuropsychopharmacology 25 713-728

Patel et al, 2007 MedGenMed. 9(4): 62Matthews et al, 2003 Br J Psych 183: 181-183

TMS• There is strong evidence of the safety and

tolerability of TMS when standard protocols are used.

• The efficacy of the stimulation of the dorsolateral prefrontal cortex in depression is well documented.

lopez-ibor, 2008Curr Opin Psychiatry. 2008 Nov;21(6):640-4

Magnetic seizure therapy• A new 100 Hz magnetic seizure therapy

device• Seizures are elicited with a high-frequency

magnetic field• Limited cognitive side-effects. • The mean duration of magnetically induced

seizures is 30 sec• Exceptionally quick recovery time (mean 7-

15 min) shorter than with ECT in the same patients

Kirov et al , 2008Br J Psychiatry. 2008 Aug;193(2):152-5

Therapeutic Nihilism• 55-year-old woman • Depression began at age 9 • Adequate doses and durations of 15

different antidepressants • 10 diverse medications for augmentation• Bilateral ECT • No improvement and "incapacitated" by

depression• Several suicide attempts

Yudofsky June 2008Am J Psychiatry 165:671-674

SURGERY • Bilateral stereotactic

ablative cingulotomy.• Symptomatic improvement

during the year following cingulotomy.

• Deep brain stimulation in the Cg25 region of this patient’s brain.

• Significant improvement till remission .

• Currently celebrating two years in remission

Yudofsky June 2008Am J Psychiatry 165:671-674

What Therapy Doesn't Teach and Medication Can't Give ?

Talking and Pill Taking

• Patients receiving any variant of psychotherapy were significantly more likely to remit.

• Patients receiving CBT were significantly more likely than those receiving PDT or IPT .

Churchill et al, 2001Health Technology Assessment ; Vol. 5: No. 35

Cognitive therapy, STAR D level II• The best remission rate 41.9% BUT

– Very expensive– need extensive training– Suitable only for certain types of patients

Psychosocial Interventions

• Drugs can not solve problems• Drugs can not teach life• Drugs can not be prescribed in

psychosocial vacuum• Effective drugs must be combined with

effective psychosocial intervention

04/10/23 116

Conclusion• Depression is a common illness • Prevalence of depressive disorders will increase .• Depression is the worst illness as it lead to poor quality of life

and suicide• Depression is under diagnosed .• Depression is one of the most treatable untreated diseases .• It represents an unmet need to come up with

antidepressant drugs of greater efficacy and improved tolerability

• A lot of new drugs are in trials• If we have The best drug we will take 20 years to know it. • Psychiatrists need to be aware of every treatment option

available and to overcome resistance to change.