1. MAJOR DEPRESSION
AND ITS TREATMENT

2. CONTENTS:
Introduction to depression
Relationship between suicide and depression
Drug treatment for different aspects associated
with depression
Recent advances in drug therapy for depression

3. WHAT IS MAJOR DEPRESSION ?
Major Depression is a mental disorder, characterized by
• sadness
• loss of interest or pleasure
• feelings of guilt or low self-worth
• disturbed sleep or appetite
• feelings of tiredness
• poor concentration.

4. MECHANISMS INVOLVED IN PATHOPHYSIOLOGY OF MAJOR
DEPRESSION

7. DISADVANTAGES OF CURRENTLY AVAILABLE
ANTIDEPRESSANTS (despite their efficacy):
 Several weeks taken to exert full efficacy
 Inadequate response of patients
 Poor tolerance problems
 Co-morbid symptoms not well controlled.

8. MAJOR SIDE EFFECT OF ANTIDEPRESSANTS?
OR
OUTCOME OF UNTREATED MAJOR DEPRESSIVE
DISORDER?

9. CORRELATION BETWEEN MDD,SSRIs AND
SUICIDE

10. The Serotonergic system
In these people,there are fewer presynaptic serotonin
transporter sites in the prefrontal cortex ,hypothalamus,
occipital cortex and brainstem.
Impaired serotonin input in suicide affects ventromedial
prefrontal cortex

11. TPH activity not
affected here

12. 5HT 1A & 5HT
2A receptors
Upregulated
(compensatory)
Low serotonin
Levels*
VENTROMEDIAL PREFRONTAL CORTEX
*determination of serotonin and its major metabolite 5-hydroxy indole acetic acid
In the case of 5-
HT2A receptors,
this
upregulation
involves increased
gene expression.

13. No deficiency in the number of serotonin neurons, and TPH
immunoreactivity is higher in the dorsal raphe nucleus of
suicide victims with a history of major depression. The
increase in TPH immunoreactivity might be a homeostatic
feedback effect of low intrasynaptic concentrations of
serotonin.
Photomicrographs of brainstem sections stained with an antibody against tryptophan
hydroxylase at the rostral level of the dorsal raphe nucleus from a control subject
and a suicide victim. Note the higher immunoreactivity in the suicide victim.
(Images courtesy of V. Arango and M. Underwood.)

14. Low serotonin levels in
Dorsal raphe nucleus
Hence,TPH activity is
increased
(compensatory)
No deficiency in number of serotonin neurons is however noticed !

15. • Lower number of NA neurons (MDD)
– Effect of stress
• Stress induces greater release of NA
• Depletion of NA follows soon
• TH activity increases(compensatory)
• Number of alpha2 receptors increases(compensatory)
NORADRENERGIC SYSTEM
So, more TH and α2-adrenergic binding could indicate
noradrenergic depletion.

17. DOPAMINERGIC SYSTEM
*D4 receptor binding not affected
*Serotonin antagonizes the effect of dopamine
*SSRIs on chronic use raise serotonin levels but indirectly reduce
dopamine activity

18. *Low HVA(homovanillic acid) seen in CSF in suicide attempters
with MDD
*HVA is a major metabolite of dopamine
*The dopamine system seems to be hypofunctional in major
depression

19. Other correlation factors
*Signal transduction and gene expression abnormalities
*In MDD,reduced PKc activity : low CREB
*Abnormalities in Mitogen activated protein(MAP) kinase
*Decreased number of cortical neurons
*Environment and stress
*Child abuse,improper upbringing of child

20. Concluding thoughts
*Antidepressants (working through serotonin pathway) :
initially raise serotonin levels and activity
*On chronic use : down-regulation of post synaptic receptors :
suicidal tendencies
MDD  TREATMENT  CHRONIC  SUICIDE
MDD  UNTREATED -----------------SUICIDE
Solution?
Look for alternative pathways.
REFERENCE: Nature reviews/neuroscience Vol 4 Oct 2003

21. DRUG TREATMENT FOR DIFFERENT ASPECTS
ASSOCIATED WITH DEPRESSION

22. SAFETY & EFFICACY OF REPEATED-DOSE INTRAVENOUS KETAMINE
FOR TREATMENT OF RESISTANT DEPRESSION
•Dose : 40 minutes IV infusion of Ketamine (0.5mg/kg) & 4 hrs
monitoring period.
• Repeated dose of IV ketamine is feasible for acute treatment
of resistant depression.
•Studies clearly demonstrated that IV ketamine is safe & has a
rapid & profound short term effect on depressive symptoms,
including suicidality, even among patients considered treatment
resistant to standard medication or ECT.
REFERENCE: www.sobp.org (Journal:BIOLPSYCHIATRY,2010)

23. SERTRALINE TREATMENT OF MAJOR DEPRESSION IN
PATIENT’S WITH ACUTE MI OR UNSTABLE ANGINA
•Dose : 50 to 200 mg/d ay or placebo.
•MDD occurs in 15-23% of patients with acute coronary syndromes.
•Intervention with sertraline has the potential to provide depressed patients
with cardiac disease relief from their depressive symptoms , improvement in
quality of life & a potential benefit in their cardiovascular risk profile.
REFERENCE: www.jama.com August 2002 Vol.288

24. COMPARATIVE EFFICACY OF ESCITALOPRAM IN TREATMENT OF
MAJOR DEPRESSIVE DISORDER
• Meta analysis studies using escitalopram showed superior effficacy
compared with citalopram and with SSRIS combined.
• Escitalopram shows similar efficacy to SNRIS but the number of trials
for these comparisons are limited; but these trials have shown clinically
relevant efficacy differences especially in more severely depressed
patients.
• Escitalopram shows increased efficacy because of dual mechanism
where it acts both on the primary and allosteric binding sites of serotonin
transporter.
• Apart from efficacy of the drug the side effect profile,drug
interactions,simplicity of use and cost effectiveness must be considered.
• while making clinical decision for a first choice antidepressant .
REFERENCE: www.dovepress.com (Neuropsychiatric disease and
treatment 2011)

25. RECENT ADVANCES IN DRUG THERAPY FOR
DEPRESSION

26. • Use of me-too drugs: example-Desvenlafaxine (Pristiq)
which is Venlafaxine’s (Effexor) main metabolite.
Advantage: The side effect and efficacy profile for such drugs
show slight differences which can be helpful to patients.
• Augmentation of antidepressants: Addition of an atypical
antipsychotic to an antidepressant can boost its
effectiveness.
• Glutamate system and depression: example-NMDA receptor
antagonists like Ketamine and Riluzole which are under
study for treatment of resistant depression
• Triple Reuptake Inhibitors
• Melatonin

27. MONOAMINE REGULATION OF MOOD BEHAVIOUR

28. TRIPLE REUPTAKE INHIBITORS:A PREMISE
AND PROMISE
• This is a new class of psychoactive medications which inhibit neuronal
reuptake of 5-HT,NE and Dopamine
• These TRI’S may also have efficacy in obesity, addiction and pain
syndromes
• TRI’s exert their activity by treating more symptoms of MD and/or
attenuate some side effects observed for the traditional antidepressants
Example: Dopamine component of TRI may prevent sexual dysfunction
induced by increase in brain 5-HT

29. SOME TRIPLE REUPTAKE INHIBITORS (TRI’S):
• BICIFADINE (approved TRI)
TRI’S which are in Phase II clinical trials:
• NS2330
• SEP225289
• DOV216303
• DOV21947
• 21947

30. PRE-CLINICAL IN VITRO PROPERTIES OF TRI’S
The analysis of the binding properties indicate that the more important
property of TRI’S is their relative balanced binding profile rather than their
potency at blocking monoamine transporters.

31. CLINICAL PROPERTIES OF TRI’S
• Drugs that block dopamine transporter have a potential reinforcing property
and abuse liability.
• But it is found that to induce such reinforcing effects the dopamine
transporter blocking drugs must induce more than 50% blockade
• Dopamine reuptake inhibitors are of two types:
• Type I : produce addiction, euphoria
• Type II : do not produce above effects
• This should be considered carefully with agents like TRI’s.
REFERENCE: www.intechopen.com (A new class of antidepressants in the
treatment of psychiatric disorders:The Triple Reuptake Inhibitors)
Journal:Psychiatric disorders: Trends and development.

32. A DRUG WHICH ACTS THROUGH NON-MONOAMINERGIC
SYSTEM: AGOMELATINE
In depression, sleep is greatly disturbed.
Melatonin produced by the pineal gland is an important
regulator of circadian rhythms/sleep cycle
Chemically melatonin is N-acetyl-5-methoxytryptamine.
Agomelatine(naphthalene derivative of melatonin) acts on
both the melatonergic(MT1 and MT2)and 5HT2C receptors
co-localized in the SCN of the brain.

33. (VALDOXAN/THYMANAX)

34. REFERENCE: www.nature.com/reviews/drugdisc (Agomelatine:The first melatonergic
antidepressant:discovery,characterization and development) August 2010, Vol 9

35. HERBAL REMEDY FOR DEPRESSION

36. ST. JOHN’S WORT FOR TREATMENT OF MAJOR
DEPRESSION
• St. John’s Wort or Hypericum perforatum is a plant which
grows in the wild and is widely prescribed for depression in
Europe
• Mechanism of action : Partially understood but is similar to
that of SSRI’s
• Clinical trials carried out have found it as effective as a
commonly prescribed antidepressant
• But the FDA has not approved it as a OTC prescription drug
• This herb shows many side effects and drug interactions:
• Combining antidepressants and SSRI’s leads to
serotonin syndrome
• Psychosis is also possible
• It can induce metabolism of drugs like:
• Cyclosporine, Digoxin, Warfarin, Birth control pills
,Indinavir etc.

37. AUGMENTATION THERAPY
In case of inadequate response to conventional antidepressant
therapy augmentation therapy is followed which includes combining of
an augmenting agents along with the conventional antidepressant
Augmentation therapy, can avoid patients from unnecessary switching
between antidepressants which may jeopardize the remission rates
and even aggravate existing side effects
Augmentation:
the action or
process of making
or becoming
greater in size or
amount

38. THE POSSIBLE AUGMENTING AGENTS

39. The possible augmenting agents:
A. Lithium Augmentation
B. Triiodothyronine (T3) Augmentation
C. Benzodiazepine Augmentation
D. S-Adenosyl-L-Methionine (SAMe) Augmentation
E. Atypical Antipsychotic Augmentation Treatments

40. A.Lithium Augmentation
Lithium augmentation, synergistically increase serotonergic action
of antidepressants on brain 5-HT pathways
There is positive association between lithium levels and
presynaptic formation, storage, and release of serotonin
It can be combined with TCA & MAOI without any adverse effects
It can also be combined with SSRI as well but it may potentiate
serotonin syndrome
Combination of lithium and fluoxetine resulted in mania and
hypomania

41. Optimum level of lithium in blood = 0.6 - 1.2 mEq/L
Dose = 900 – 2400 mg/day (2 – 4 divided doses)
Lithium carbonate is given in form of lithium carbonate (Lithobid,
Eskalith tablets)

42. Serotonin syndrome

43. B. Triiodothyronine (T3) Augmentation
A viable, safe, inexpensive and effective augmentation treatment
T3 hold a slight advantage over lithium in efficacy and tolerability and
also is easier to use and there is no need for blood monitoring
T3 augmentation of patients with MAOIs and TCAs showed clinical
improvement with no significant adverse effects
T3 dose = 25-50 µg/day
Cytomel and thyrovin tablets are available in the market

44. C. Benzodiazepine Augmentation
Benzodiazepine augmentation is shown to be beneficial in
depression
It was found that compared to antidepressant treatment alone,
adjunctive benzodiazepines decrease drop outs from treatment
But potential benefits should be weighed against possible
complications related to benzodiazepine augmentation, such as
* the development of dependence
* decline in the drug’s effect over time
* accident proneness
Clonazepam 0.5 to 1 mg/day with fluoxetine

45. D. S-Adenosyl-L-Methionine (SAMe)
Augmentation
SAMe is a naturally occurring molecule in the body
SAMe with SSRIs has shown better efficacy with sufficient tolerability
and safety

46. Atypical Antipsychotic Augmentation
Treatments
 Aripiprazole Augmentation
 Olanzapine Augmentation
 Quetiapine Augmentation
 Risperidone Augmentation
 Ziprasidone Augmentation

47. Targeting inflammation as a new approach
for the treatment of
Depression

49. Major Depression is accompanied with an increased production of
pro-inflammatory cytokines like Interlukin-6 (IL-6), Interlukin-1 (IL-1),
Tissue Necrosis factor α.
Tissue Necrosis Factor (TNF) antagonist INFLIXIMAB is used in the
trial for treatment of Treatment resistant Depression
INFLIXIMAB: monoclonal antibody against tumor necrosis factor α
Three infusions of infliximab (5 mg/kg) or placebo at baseline and
week 2 and week 6 of a 12-week trial.

51. C-reactive protein :
Protein found in blood whose level rise in response to
inflammation
It is used as marker of inflammation in this trial
A high-sensitivity CRP (hs-CRP) test measures low levels of CRP
using laser nephelometry. The test gives results in 25 minutes with
a sensitivity down to 0.04 mg/L
Normal concentration = 10 mg/L
Mild Inflammation = 10-40 mg/L
Acive Inflammation = 40-200 mg/L

52. Result
Response is considered if 50% reduction in HAM-D score at any
point of 12 week trial
% of patient Therapy
62 % Infliximab treated
33 % Placebo
TNF antagonist does not have generalized efficacy but may improve
symptom in patient with high baseline inflammatory biomarkers

53. 1. Oxidative stress: causes & consequence of disease
2. Neurotropic support and oxidative stress: converging effects in the normal &
diseased nervous system
3. CORRELATION BETWEEN MDD,SSRIs AND SUICIDE
Nature reviews/neuroscience Vol 4 Oct 2003
4. COMPARATIVE EFFICACY OF ESCITALOPRAM IN TREATMENT OF MAJOR
DEPRESSIVE DISORDER
www.dovepress.com (Neuropsychiatric disease and treatment 2011)
5. SAFETY & EFFICACY OF REPEATED-DOSE INTRAVENOUS KETAMINE FOR
TREATMENT OF RESISTANT DEPRESSION
www.sobp.org (Journal:BIOLPSYCHIATRY,2010)
6. SERTRALINE TREATMENT OF MAJOR DEPRESSION IN PATIENT’S WITH
ACUTE MI OR UNSTABLE ANGINA
www.jama.com August 2002 Vol.288
7. www.intechopen.com A new class of antidepressants in the treatment of
psychiatric disorders:The Triple Reuptake Inhibitors
Journal:Psychiatric disorders: Trends and development.
REFERENCES:

54. 8. www.nature.com/reviews/drugdisc (Agomelatine:The first melatonergic
antidepressant:discovery,characterization and development) August 2010,
Vol 9
9. www.nccam.nih.gov/health/stjohnswort fordepression
www.psychcentral.com/stjohnswortfordepression
10. Atypical Antipsychotics and Other Therapeutic Options for
Treatment of Resistant Major Depressive Disorder
Rubo J. Seo, Holly MacPherson and Allan H. Young *
www.mdpi.com/journal/pharmaceuticals
11. An Evidence-Based Approach to Augmentation and Combination
Strategies for
Treatment-Resistant Depression
Jeremy Barowsky, MD and Thomas L. Schwartz, MD
13. Role of S-adenosyl-L-methionine in the treatment of depression:a
review of the evidence
David Mischoulon and Maurizio Fava
The American journal of clinical nutrition

55. 14. The inflammatory & neurodegenerative (I&ND) hypothesis of depression:
leads for future researchand new drug developments in depression
Michael Maes & Raz Yirmyia & Jens Noraberg & Stefan Brene & Joe Hibbeln
& Giulia Perini & Marta Kubera & Petr Bob & Bernard Lerer & Mario Maj 2008
15. Cytokines and major depression
Olga J.G. Schiepers,
Marieke C. Wichers Michael Maes
Department of Psychiatry and Neuropsychology, Maastricht University, P.O.
BOX 616, 6200 MD Maastricht, The Netherlands
16. Inflammation and Its Discontents: The Role of Cytokines in the
Pathophysiology of Major Depression, Andrew H. Millera, Vladimir Maleticb,
Charles L. Raison
17. A Randomized Controlled Trial of the Tumor Necrosis Factor Antagonist
Infliximab for Treatment-Resistant DepressionThe Role of Baseline
Inflammatory Biomarkers
Charles L. Raison, MD; Robin E. Rutherford, MD; Bobbi J. Woolwine, MSW;
Chen Shuo, MS; Pamela Schettler, PhD; Daniel F. Drake, PhD; Ebrahim
Haroon, MD; Andrew H. Miller, MD
JAMA Psychiatry. 2013;70(1):31-41. doi:10.1001/2013.jamapsychiatry.4.