This document summarizes research on using quetiapine as an augmentation strategy for treatment-resistant depression. Six studies are reviewed that examine adding quetiapine to ongoing antidepressant treatment. The studies generally found quetiapine augmentation led to greater improvement in depression symptoms compared to placebo, especially when starting at dosages of 150-300 mg/day. The most common side effects were dry mouth, drowsiness, and weight gain. Overall, the research suggests quetiapine may be a valid option for improving outcomes for patients with treatment-resistant depression.

1. TREATMENT
RESISTANT
DEPRESSION
DR. RAKESH MEHTA
NGMC

3. INTRODUCTION
• Major Depressive Disorder (MDD)
Major depressive disorder (MDD) is characterized by at
least one discrete depressive episode lasting at least 2
weeks and involving clear-cut changes in mood, interests
and pleasure, changes in cognition and vegetative
symptoms

4. • The percentage of people suffering from MDD worldwide
was 4.4% in 2010.
• Across the lifespan, prevalence of MDD increases
steadily between 3 and 19 years; peaks between 20 and
64 years; decreased between 65 to 74 years.

5. MDD IS THE SECOND LEADING CAUSE
OF YEARS LIVED WITH DISABILITY2
Rank
Lower back pain 1
Major depressive disorder 2
Iron-deficiency anaemia 3
Neck pain 4
COPD 5
Other musculoskeletal disorders 6
Anxiety disorders 7
Migraine 8
Diabetes 9
Falls 10

6. MAJOR DEPRESSIVE DISORDER AND
SUICIDE
• Patients with MDD are almost 20-fold more likely to die
by suicide than the general population.
• Estimated that up to 50% of the 800,000 suicides per
year worldwide occur within a depressive episode

7. • Evidence from meta-analyses of longitudinal studies has
revealed that the relative risk (RR) of various diseases is
increased in those with major depressive disorder
(MDD) compared with those who do not have MDD

8. PHARMACOTHERAPY OF DEPRESSION
SNRI
Venlafaxine
Milnacipran
Duloxetine
TCA
Clomipramine
Imipramine
Amitriptyline
MAOI
Phenelzine
NARI
Reboxetine
NDRI
Bupropion
SSRI
Paroxetine
Fluoxetine
Sertraline
Fluvoxamine
Citalopram
Escitalopram
Receptor
antagonists
Mirtazapine
Trazodone
Mianserin
MT1,MT2 Agonist
5-HT2C Antagonist
Agomelatine

9. TREATMENT RESISTANT
DEPRESSION
• The term Treatment resistant depression usually refers
to Major Depressive Disorder that do not respond
satisfactorily after two trails of antidepressant
monotherapy.
• Approx 1/3rd of the depressed patient is considered
Treatment Resistant.

10. • Given that approx 1/3rd of depressed patient are
considered treatment resistant , this group accounts
for largest burden of disease, underscoring
importance for innovation and discovery in this area.

11. EVALUATION OF PATIENT
• Diagnose before you treat.
• Assess non adherence
• Cost
• Family and friends ambivalent
• Side effects : adjust dose
• Assess Co-morbidity
• OCD
• Substance use
• Anemia
• Hypothyroidism
• Psychotic Depression

12. • Cognitive Deficits may make patient difficult to follow
instruction
• Involve family members and care givers
• Adequate dose / duration
• Drug –Drug interaction : may interfere metabolism

13. TREATMENT STRATEGIES
• SACO: Switching , Augmenting, Combining, Optimization.
• Psychotherapy.
• ECT
• Trans cranial Magnetic Stimulation
• Deep Brain Stimulation
• Vagal Nerve Stimulation
• Light Based Therapy
• Exercise
• Acupuncture
• Yoga

14. PSYCHOPHARMACOLOGICAL
TREATMENT STRATEGIES
Dialogues Clin Neurosci. 2015;17:111-126.

15. • Optimization:
• 1st step particularly when drug is well tolerated.
• Increase medication dose as tolerated at least to standard
maximal dose for 4-6 weeks.
• Advantages: cost, same S/E profile, simple dosing

16. • Augmentation
• Addition of non anti depressant medication or augmentation
• Given when partial response to initial agent.
• 1st line
• Atypical Antipsychotic
• Lithium
• Bupropion

17. • 2nd line
• Ketamine
• Lamotrigine
• T3
• Others
• Folate
• Omega 3 fatty acid
• Buspirone
• BZD

18. ATYPICAL ANTIPSYCHOTICS
• Atypical Antipsychotic are the most studied class for
augmentation.
“FDA approved” Aripiprazole
Quetiapine
Olanzapine
• A study done by Berman et al found 2 fold higher
odds for reaching remission compared to placebo.

19. • Target dosing:
• Aripiprazole 5-10 mg/day
• Quetiapine 150-300 mg/day
• Olanzapine 5-10 mg/day

20. LITHIUM
• Lithium augmentation compared with
placebo had better rate (41.2% vs
14.4%) in decreasing depressive
symptoms.
• 250-1200 mg is used
• Aim for plasma level 0.4-0.8 mmol/l

21. THYROID AGUMENTATION
• T3 Agumentation (25-50 ug/day) is used.
• A study found by Aronson & Collegue found that
patient achieved response twice likely than placebo
• In STAR-D , T3 augmentation resulted in 25%
remission rate compared with 16% with lithium
augmentation.
• A comparison study done by trivedi et al found that T3
better tolerated and safer than lithium.

22. BENZODIAZEPINE
• Anxious depression, benzodiazepine are frequently used
as augmenting agents.
• One double blind placebo controlled study found benzodiazepines
augmentation was superior to antidepressant alone
• Benzodiazepines augmentation was superior to
antidepressant monotherapy for treating depressive
symptoms in first 3 weeks.
• BZD + SSRI resulted in rapid control in baseline anxiety as
well reduced SSRI induced anxiety at the beginning to
treatment and improved adherence to Antidepressant
therapy.

23. CELECOXIB
• Briefly, inflammation has been suggested to play a
role in pathophysiology of depression
• A meta analysis of 4 trails of celecoxib (NSAID) showed
significant antidepressant efficacy compared with
placebo.

24. • Modafinil
• stimulating agent has been studied as augmentation
agent for depression with fatigue with significant
improvement compared to placebo.
• 100-400 mg/day

25. • Omega 3 fatty acid have anti inflammatory properties has shown
some insignificant benefits.
• Folate an essential amino acid play a role in neurotransmitter
synthesis (5mg/day) may have role in antidepressant augmentation.
• Zinc
• 25mg has shown good result in one study
• Tryptophan
• 2-3g /day has long history of successful use

26. SWITCHING
• Following monotherapy failure the efficacy of switching
medication vs augmentation appears comparable.
• Done when
• poor tolerability
• complete non response
• Patient who fail 2 trails of one class of antidepressant
should be switched to another class on 3rd attempt
• Gradual tappering + increase of another class of
treatment reduce withdrawal side effect

27. COMBINATION
• 2 or more antidepressant from 2 different classes
• Drug- drug interaction should be kept in mind eg:
SSRI + MAOIS
• One metanalysis found that patients were 3 times
more likely active remission when started initially in
combination therapy.

28. KETAMINE
• Non-monoaminergic antidepressant
• NMDA receptor antagonist
• Subanesthetic (0.5 mg/kg over 40 min)/ (2 mg/kg
rapidly for anesthetic) has shown rapid (within 1 day),
sustained (7 days) anitidepressant efficacy.
• Decrease suicidal intention and decrease anhedonia

29. • Lamotrigine
• 100-400mg can be used to augment
• Scopolamine
• IV scopolamine rapidly decrease symptoms of depression.

30. QUETIAPINE

31. STUDY 1: AUGMENTATION WITH ATYPICAL
ANTIPSYCHOTICS FOR TREATMENT-RESISTANT
DEPRESSION
Objective To review the clinical studies evaluating the efficacy of SGA as
add-on therapy in TRD
No of pts Sixteen RCTs
Methodology Comprehensive search on PUBMED, Medline and PsychINFO of all
randomized clinical trials (RCTs) assessing the augmentation
with antipsychotics in TRD, published from January 2000 until
March 2020
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

32. RESULTS:
• Add-on therapy with aripiprazole could be beneficial in the treatment of TRD.
• RCTs on quetiapine augmentation support its use in TRD, especially when comorbid
anxiety or insomnia are present.
• Effects of risperidone and olanzapine as add-on in TRD were less studied, but preliminary
data indicated an efficacy respect to placebo, making them a possible therapeutic option
in TRD
 Conclusion:
 Overall, the RCTs studies seem to support the hypothesis that the augmentation with
SGAs, in particular aripiprazole and quetiapine, which are a valid therapeutic option for
TRD.
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

33. STUDY 2: EXTENDED-RELEASE QUETIAPINE AS
ADJUNCT TO AN ANTIDEPRESSANT IN PATIENTS
WITH MAJOR DEPRESSIVE DISORDER
Trial POPULATION OF
TRD AFFECTED
PATIENTS
APS ANTIDEPRESSANT
S AND PRIOR
FAILED TRIALS
QUALTIY OF
EVIDENCE
RESULTS Safety
Bauer et al,
2009
Total sample (n =
487)
Age and gender not
specified
QTP 300
mg/day vs
QTP 150
mg/day vs
placebo
Duration: 6
week
Rating
Scale:
MADRS
SSRI/SNRI; 1
historical
High The
mean
MADRS change
for both QTP
groups showed
a significant
difference from
placebo
starting from
week 1
maintained up
to week 6
(end-point).
Withdrawal rates due to
adverse events were 11.7%,
6.6% and 3.7%nwith the
three
Groups respectively.
The most common adverse
events were dry mouth
(35.6%. 20.4% 6.8%)
And somnolence (23.3%,
16.8%, 3.1%).
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

34. STUDY 3: QUETIAPINE AUGMENTATION OF
TREATMENT-RESISTANT DEPRESSION:
Trial POPULATION OF
TRD AFFECTED
PATIENTS
APS ANTIDEPRESSA
NTS AND PRIOR
FAILED TRIALS
QUALTIY OF
EVIDENCE
BASED ON
GRADE
PRINCIPLES
Results Safety
Dorèe et
al., 2007
Total sample
(n = 17)
QTP group (n
= 10)
Li group (n
=10)
QTP (average
final dose 430
mg/day) vs
Lithium (adjusted
to reach a level of
0.8– 1.2 mmol/L)
Duration: 8 week
Rating Scale:
MADRS
HAM-D
Various;
1
historical
High Significant
improvement
in HAM-D
mean scores in
both QTP
group and Li
group.
QTP
group showed
a greater
improvement
than the Li
group.
No serious
adverse events
occurred in
either group.
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

35. STUDY 4: IN PATIENTS WITH AN
INADEQUATE RESPONSE TO
ONGOING ANTIDEPRESSANT
TREATMENT
Trial POPULATION OF
TRD AFFECTED
PATIENTS
APS ANTIDEPRESSAN
TS AND PRIOR
FAILED TRIALS
QUALTIY OF
EVIDENCE
Results Safety
El-Khalili
et al.,
2010
Total sample
(n = 258)
• QTP XR 150
mg/day (n =
143)
• QTP XR 300
mg/day (n =
146)
• Placebo (n =
143)
QTP (mean
250–400
mg/day) vs
QTP (mean
150– 250
mg/day) vs
Placebo
Duration: 6 week
Rating Scale:
MADRS
HAM-D
SSRI/SN
RI; 1
historica
l
High For QTP 150
mg/day:
nonsignificant
improvements
from placebo.
For QTP 300
mg/day:
significant
improvement
compared to
placebo for
MADRS total
scores after
one week, and
for HAM-D
from week 6.
Most common adverse
effects with QTP were dry
mouth, somnolence,
sedation, dizziness,
constipation, nausea,
insomnia, headache, and
fatigue.
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

36. STUDY 5: COMBINED TREATMENT OF
VENLAFAXINE AND QUETIAPINE FOR
TREATMENT-RESISTANT DEPRESSION
Trial POPULATION OF
TRD AFFECTED
PATIENTS
APS ANTIDEPRESSAN
TS AND PRIOR
FAILED TRIALS
QUALTIY OF
EVIDENCE
Results Safety
Li et al.,
2013
Total sample
(n = 95)
QTP + VNL (n
= 49)
VNL (n = 46)
VNL + QTP
(mean
dose
324.42
mg) vs VNL
Duration: 8 week
Rating Scale:
HAM-D
HAM-A
VNL; 1
prospective
Moderate The QTP+VNL
group showed
a significantly
higher rate of
efficacy
compared to
placebo.
Lower HAM-D
and HAM-A for
QTP+VNL total
scores
compared to
placebo.
The experimental group
showed a greater incidence
of excessive sedation and
weight gain, and a lower
incidence of insomnia.
Overall adverse reaction
Rate did not differ
significantly between the
two groups.
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

37. STUDY 6: QUETIAPINE ADJUNCT TO SELECTIVE
SEROTONIN
REUPTAKE INHIBITORS OR VENLAFAXINE
Trial POPULATION OF
TRD AFFECTED
PATIENTS
APS ANTIDEPRESSAN
TS AND PRIOR
FAILED TRIALS
QUALTIY OF
EVIDENCE
Results Safety
McIntyre
et al.,
2007
Total sample
(n = 58)
QTP (n = 29)
Placebo (n =
29)
QTP (200 -
600
mg/day) vs
Placebo
Duration: 8 week
Rating Scale:
HAMD-
17
SSRI/SNRI; 1
or
more trial
High QTP
significantly
improved
symptoms of
depression and
anxiety
compared to
placebo.
Sedation was the most
Commonly reported adverse
effect in both groups and
was most often mild to
moderate in intensity,
Decreasing over time.
Filippo Cant`u , et al, Journal of Affective Disorders (2020),

38. • Conclusion
• In setting of non –remission, it is important to re evaluate
diagnosis, adherence, co morbid condition and to consider
dose optimization, switching , augmentation as well as
combining ADs.

39. Thank You