Major depression is a serious mental health issue that affects hundreds of millions of people worldwide. Some key points about depression from the document include: - Approximately 450 million people suffer from depression globally according to the WHO. - Depression is the leading cause of disability worldwide and will be the second leading cause of disease burden by 2020. - Prevalence of depression is increasing due to factors like urbanization, stress, and substance abuse. - Depression has significant social and economic costs due to disability, suicide, and impacts on work productivity. Effective treatment of depression is therefore important for public health.

1. Major Depression..
The Story and Treatment
Prof. Yaser Abdel Razek
Professor of Psychiatry
Institute of Psychiatry, Ain Shams University
WHO Collaborative center for training and research

2. Unipolar Major Depression /2010
• Number of 6,865,820,500
population
• Life time prevalence 1,513,322,000
of UMD
• Point prevalence 450,088,420
UMD (WHO- 2008 )
• 15% will try suicide 67,513,263
• Died by suicide 426.463
(2010)
www.peterrussell.com/WorldClock

3. • 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)

4. • 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.

5. • 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.

6. 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

7. That’s Why
Finding
an effective treatment
for depression
is therefore a key consideration
for the health service

8. 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).

9. L e a d in g C a u s e s o f D A L Ys in
2020
( D is a b ilit y A d ju s t e d f o r L if e
Ye a r s )
Both sexes Males Females
Disease or injury Disease or injury Disease or injury
All causes All causes All causes
Ischaemic heart Ischaemic heart Unipolar major
1-
disease disease depression
Unipolar major Road traffic Ischaemic heart
2-
depression accidents disease
Road traffic Cerebravascular Cerebravascular
3-
accidents disease disease
Chronic Chronic
Cerebravascular obstructive obstructive
4-
disease pulmonary pulmonary
disease disease
Chronic obstructive Unipolar major Road traffic
5-
pulmonary disease depression accidents
Ustun et al (2004) Brit. J. Psychiat.

10. 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

11. Recognition of general practice
patients
Up to 50% of general practice
patients may have some
depressive symptoms.
Approximately 5% of these
will have major depression
defined by DSM-III-R
criteria.
Freeling and Tylee (1992); Regier et al (1988); Vazquez-Barquero et al (1987)

12. M
Depression
Dysthymia
Mixed anxiety depression
Adjustment disorders
with depressive symptoms
Depressive symptoms

13. 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

14. Bed days: depression vs chronic
medical condition
No chronic condition
Back problem
Lung problem
GI problem
Arthiritis
Angina only
Coronary artery disease
Diabetes
Hypertension
Depressive symptoms
0 0.5 1 1.5 2 2.5
Bed days / past month
Wells et al., 1989

15. The Effects of Depression Beyond Symptoms
Disability of Daily Functioning: Depression
Compared with Chronic Medical Conditions
Physical Social Role Bed Days
Hypertension
Diabetes
Heart
Arthritis
Lung
Depression has more disability (P < 0.05)
Depression has less disability (P < 0.001)
No difference (P > 0.05) Wells et al. JAMA. 1989; 262 (7): 914-919

16. Work-Loss Days by Health
Condition
3 2.77
2.5
1.78
2 1.74 1.6
1.41
Days
1.5 1.21
0.83
1
0.5
0
Depression Diabetes History of Immune
Heart isease Disorder
Grzywacz JG. SL. TEN. 2000; 2(6): 41-46.

17. Public perceptions of Mental
• 71% Due to emotional weakness
illness
• 65% Caused by bad parenting
• 43% Incurable
• 35% Consequence of sinful behaviour
• 10% Has a biological basis; Involves the
brain

18. 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

19. Treatable Disease
Depression is one of the most treatable
untreated diseases
80% can be successfully treated with
medication, psychotherapy or a
combination of the two

20. Treatment
of
depression
Depressed Patients
(100%)
Receive Untreated patients
antidepressant
(95.6%)
(4.4%)
- Do not seek help
Adequately - Undiagnosed
treated
- Diagnosed but untreated
(?%)
- Treated but non compliant
*
Tylee A et al, Int Clin Psychopharmacol,1999,14(3):139–51;Lépine, JP et
al., Int Clin Psychopharmacol, 1997,12:19–29.

21. 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

22. Clinical features
• To diagnose depression We should
have two criteria out of each group of
the following symptoms

23. First group
1-Depressed mood
• Continuous unexplained bad mood with
spontaneous crying from time to time
2-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

24. 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

25. Other key symptoms
– Irritability and anxiety in addition
or instead of pure depression
symptoms
– Predominant somatic symptoms
– Headache
– General aches and pains
– Libido decrease

26. How do patients with major depression
usually present in primary care?
Presenting complaint % patients
0 10 20 30 40 50 60
Cardiological
Chest pain
Tachycardia/irregular heart beat
Neurological
Headache
Dizziness
Syncope/seizures
Gastrointestinal
Epigastric pain
Diarrhoea
Pulmonary
Dyspnoea
‘Asthma’
* DSM-IV-TR™ 2000 Wa yn e K a to n

27. Types of depression
• There are more than 50 type of depressive
disorder, all types share some symptoms and
differ in some other symptoms

28. Different forms
Unipolar Bipolar
Major depressive Bipolar I
disorder
Dysthymia Bipolar II
Cyclothymia
Mixed states
Adjustment disorder with
American Psychiatric Association (1994)
depressive sym

29. 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.

30. Bipolar depression
• Depression is alternating with episodes of
hypomania or mania.

31. Major depression Adjustment disorder
• Previous manic features (BP) • No manic F
• Stress May not present • Stressor Must be present
• Early morning awakening 2 • Delayed sleep onset
hours
• Diurnal variation (bad at • May be worst at the night
morning)
• Marked Change of • Not marked
psychomotor activity
• No delusions or
• Delusions and hallucinations
hallucinations
• Worse just before menses • Not related to menses
• Post partum attacks • No postpartum attacks
• Recovery may be delayed • Recovery within 6 months

32. Differential Diagnosis
• Debilitating physical illness
• Organic depression
• Substance induced depression

33. Debilitating physical illness as
cancers may be presented by
• Loss of weight
• Easy fatigability
• Disturbed sleep
• Somatic symptoms

34. 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.

35. The association between
depression and medical illness
M e d ic a l F r equenc y of
C o n d it io n M a j o r De p r e s s io n
x Coronary Artery Disease 30-60%
x Emphysema 20-40%
x HIV infection 20-35%
x Hypothyroidism 10-30%
x Stroke 10-25%
x Diabetes Mellitus 10-20%
x Renal Failure 5-20%
Kaplan HI, 1994

36. 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%

37. Drugs that can cause depression
• All substances of abuse
• Beta blockers
• Some antihypertensive drugs
• Contraceptive pills

38. Co-morbidity

39. Comorbid major depression and INTRODUCTION TO ANXIETY DISORDERS
anxiety disorders
Lifetime comorbidity
48% of patients with PTSD1
50% to 65% of patients with PD2
PTSD Panic
disorder
Major
depression
GAD
SAD 8% to 39% of
patients with GAD5
OCD
34% to 70% of
patients with SAnD4, 6 67% of patients with OCD3
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)

40. 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.

41. Treatment of depression
Hospitalization
May be necessary if patient has
• Suicidal
• Severe psychomotor retardation or agitation
• Absolute insomnia

42. Groups of ADDs currently
• Tricyclic ADDs
available
– Tryptizol (amitryptiline)
– Anafranil (clomipramine) • NaSSA
• SSRIs – Mirtazepine
– Cipram (Citalopram) • SNRIs
– Cipralex (escitalopram) – Venlafaxine
– fluoxetine – Duloxetine
– fluvoxamine
– paroxetine
– sertraline

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

44. Electroconvulsive Therapy
It is safe
It is not painful
No long lasting brain changes
It has rapid onset relief of symptoms

45. Non-
response Respond
Partial
Response
Partial Response
Non-response
Respond

46. Major depressive episode
Euthymia
Symptoms
Major
Syndrome depressive
episode
Criteria and
Severity Adapted from Thase and Kupfer (1996)
duration

47. treatment
Euthymia Remission Recovery
Symptoms Recurrence
Response
Major
Syndrome depressive
episode
Maintenance
treatment
Maintenance
Recurrence Predictors Adapted from Thase and Kupfer (1996)
treatment

48. Maintenance Treatment
Maintenance treatment
85% remain well 15% Recurrence
No Maintenance Treatment
(drug stopped after patient responded to
drug)
50% remain well 50% Recurrence
(more difficult to treat)

49. Predictors of long-term, maintenance
antidepressant therapy
• At least three episodes
 Two episodes and potential risk factor
• late onset (at age 60 years or over)
• early onset (before 40 years of age)
• short interval between episodes
• rapid onset of previous episodes
• positive family history with affective disorders
• co-morbidity
• severity of index episode
• poor symptom control in continuation phase
• low work adjustment

50. 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

51. 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

52. In elderly
• Take care of
• Comorbid physical disorders
• Drug selection
• Drug interactions
• Suicide

53. During Pregnancy
• Take care of
• No drugs in first trimester
Psychotherapy for mild cases
ECT for severe cases
• Second and third trimester
consent from patient
most of drugs are not injurious but
frequent ultrasonography for fetus

54. Breast Feeding
• Most of drugs secreted in breast milk
• Follow up the baby for any anticholinergic
effects or sedation

55. In Children
• Assessment by psychiatrist is a must
• Depression may take different faces
• Phobic depression
• Enuretic depression
• Conduct depression
• Somatic symptoms
• School refusal

56. Treatment
of
depression
Depressed Patients
(100%)
Receive Untreated patients
antidepressant
(95.6%)
(4.4%)
- Do not seek help
Adequately - Undiagnosed
treated
- Diagnosed but untreated
(?%)
- Treated but non compliant
*
Tylee A et al, Int Clin Psychopharmacol,1999,14(3):139–51;Lépine, JP
et al., Int Clin Psychopharmacol, 1997,12:19–29.

57. Do ADD work in the real
world?

58. Placebo response

59. 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

60. 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

61. Definitions
• Response: 50% or greater decrease in
score of any depression rating scales
• Remission :
– Symptom free
– HAM-D 17 less than 8
– Good functions

62. Is there a price to pay for a
partial response?

63. 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;307-317
Bocking et al 2006; J Clin Psychiatry 67;747-755

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

65. If My patient is better but not well
Should we
Switch
Augment or
Combine?

67. Response and Remission rates
Patients Response Remission
no
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%)

68. Importance of remission from STAR
D
Relapse rate of Relapse rate of
non remitted remitted
Level I 59% 34%
Level II 68% 47%
Level III 76% 43%
Level IV 83% 50%

69. 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

70. 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;28-40
Cohen et al 2006 Arch Gen Psychiatry 63;50-56

71. To what extent this remission is
attributed to the drug?
• No placebo group
• Excellent patient characteristics

72. 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

73. 46% of cases
did not complete the study
Level Non remitted Dropped cases
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

74. Lessons from STAR D
• Only about one third of depressed patients
remit (30%) with a first ADD trial.

75. 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.

76. 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.

77. 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.

78. 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;10:79
Susham et al 2008 Journal of ECT. 24(3):191-194

79. For whom?
Predictors of remission

80. 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, 2008
Ann Clin Psychiatry. 2008 Oct-Dec;20(4):209-18

81. 20% reduction at day 14
may predict remission
• A 20% reduction of HAMD total
baseline is a sensitive predictor
for remission (80%). 795
Henkel et al 2008
J Affect Disord. 2008 Nov 21

82. 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 9:818-821
Joyce et al Arch Gen Psychiatry. 1989 Jan;46(1):89-99.

83. Can we Find Biomarkers that
predict remission?
• DST
• Quantitative EEG and REM latency
• Imaging
• Genetics

84. Early Normalization of DST
• Remitters were characterized by a more
pronounced early normalization of an 842
initially dysregulated HPA-axis.
• Early partial response within 2 weeks is
important positive predictor for achieving
remission.
Hennings et al, 2008
J Psychiatr Res. 2008 Jun 30.

85. 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 , 2002
J Psychiatry Neurosci. 2002 January; 27(1): 40–46.

86. 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, 2007
Journal of Nuclear Medicine Vol. 48 No. 8 1273-1278

87. 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, 2004
Am J Psychiatry 161:1957-1966, November 2004

88. 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

89. How to increase chances of
remission?

90. Before anything be sure that non
remission is not due to
• Non adherence
• Latent bipolarity
• Latent psychosis
• Latent physical illness
• Substance abuse

91. 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

92. Factors in choosing pharmacotherapy
in major depression
• Efficacy
• Prior response
• Pharmacokinetic profile
• Affordability
• Mechanism of action

93. Switch
• Better between different
classes
• Better from mono to dual or
triple action reuptake
inhibitors.

94. 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)

95. 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

96. Severe, Psychotic and Melancholic
• Combinations
– SSRI + NRI ( SNRI)
– Mirtazepine + SSRI or SNRI
• Augmentations
– Atypical antipsychotics
– ECT
– Folic acid

97. Anxious Depression
• Combinations
– SSRI + NRI ( SNRI)
• Augmentations
– BDZ
– Buspirone
– Pindolol
– Anticonvulsant

98. Depression with
Fatigue/Sleepiness
• Combinations
– SSRI + NRI ( SNRI)
– SSRI + Bupropion
• Augmentation
– Modafinil
– Thyrpoid extract

99. New And Future Lines Of
Treatment

100. Mechanism of actions of ADD
Transporter, Receptors
G protein and cAMP ++ Calcium ++
Activate Protein kinase
Phosphorylation of transcription factors as CREB and BDNF
Gene
product
hippocampus receptors Trk B
ADD effect

101. 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

102. 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

103. 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

104. Focal Brain Stimulation
• Vagus nerve stimulation
• Transcranial magnetic stimulation
• Magnetic seizure therapy
• Deep brain stimulation ( phase I and II)

105. 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
ADD
Patel et al, 2007 MedGenMed. 9(4): 62
Matthews et al, 2003 The British Journal of Psychiatry 183: 181-183

106. Mechanism of action of VNS
Afferent sensory fibres
nucleus of the tractus solitarius
raphe nucleus & locus coereuleus
cortical and limbic structures

107. 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): 62
Matthews et al, 2003 Br J Psych 183: 181-183

108. 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, 2008
Curr Opin Psychiatry. 2008 Nov;21(6):640-4

109. 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 , 2008
Br J Psychiatry. 2008 Aug;193(2):152-5

110. 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 2008
Am J Psychiatry 165:671-674

111. 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 2008
Am J Psychiatry 165:671-674

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

113. 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, 2001
Health Technology Assessment ; Vol. 5: No. 35

114. 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

115. 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

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.
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