2. Resistant DepRession
Prof. Hani Hamed Dessoki, M.D.Psychiatry
Prof. Psychiatry
Chairman of Psychiatry Department
Beni Suef University
Supervisor of Psychiatry Department
El-Fayoum University
APA member

3. No disclosures / conflicts of interest

4. Agenda
• Introduction
• Size of the problem
• Definitions
• Causes
• Solutions

5. Introduction to Major Depression

6. Digestive
disorder (6%) Musculoskeletal
disorders (4%)
Endocrine (4%)
Neuropsychiatric
disorders (28%)
Cancer (11%)
Cardiovascular
disease (22%)
Sense organ
impairment (10%)
Other non-communicable
diseases (7%)
Respiratory
disease
(8%)
Schizophrenia
Bipolar disorder
Dementia
Substance-use and
alcohol-use disorders
Other mental disorders
Epilepsy
Other neurological disorders
Other neuropsychiatric disorders
MDD
2%
10%
2%
2%
4%
3%
1%
2%
3%
Prince et al. Lancet 2007;370(9590):859–877
Contribution (%) by different non-communicable diseases to
disability-adjusted life-years (DALYs) worldwide in 2005
Psychiatric disorders
– underestimated and disabling conditions

7. Health Burden Of Depression
• MDD is common and recurrent and can be disabling
• Lifetime prevalence ~ 10-15%
• Women are affected more than men
• Over 2/3 of people have recurrences
• Depressed adults have twice the annual health care costs as
non-depressed

8. The global burden of disease, 1990−2020
• Lower Respiratory
Infections
• Diarrheal Diseases
• Perinatal conditions
• Depression
• Heart Diseases
• Cerebrovascular D/O
• Heart Diseases
• Depression
• Traffic accidents
• Cerebrovascular D/O
• COPD
• Lower Respiratory
Infections
Lopez et al :Global burden of disease and risk factors, Oxford University
Press, New York (2006)

9. Ten leading causes of burden of disease,
world, 2004 and 2030

10. Economic Impact of Depression in the US
Inpatient
11%
Outpatient
8%
Pharmaceutical
12%
7%
Sick Days
44%
Productivity Loss
18%
Total Cost in US Dollars for the Year 2000 = $83.1 billion
Greenberg P, et al. J Clin Psychiatry. 2003;64:1465-1475.
Suicide-related Costs: $5.4 billion
Workplace Costs: $51.5 billion Direct Costs: $26.1 billion

11. Depression in bipolar disorder
Bipolar depression:
• is more resistant and longer-lasting
• up to 50% may still be depressed at one year (Hlastala et al, Depress
Anxiety 1997, 5, 73–83)
• may respond to mood stabilisers
• e.g. lithium, valproate, carbamazepine etc
• is susceptible to manic switch, especially in first 12 weeks
• use lowest switch risk drugs, eg. SSRIs, mirtazapine
• Beware of inducing a mixed state in bipolar III
• risk of self-harm/suicide is high

12. Course of Depression
Adapted from Kupfer DA. J Clin Psychiat 1991; 52 (5): 28-34

13. Terminology
• Non-response: poor response requiring a change in
treatment plan (<50% HAM-D)
• Response: good enough response so that a change in
treatment isn’t necessary
• Remission: 2 consecutive months of an asymptomatic
stage (HAM-D ≤ 7)
• Recovery: ≥ 6 months of remission
• T-resistant: partial response to treatment; patient meets
non-response criteria
• T-refractory: no response to treatment; symptoms are
unchanged or worse

14. Response and Remission

15. What Is Treatment Resistant Depression?
• There is no single accepted definition
• It may mean a failure to reduce depressive severity by at
least 50% following treatment
• It may mean a failure to reduce absolute depressive score
below a specific cut point
• It may mean a failure of symptoms to entirely remit
• It may mean failure to respond to one or more prior
antidepressant trials

16.  Treatment resistance usually describes depression that has
not responded to at least two trials of medication that have
been of adequate dose and duration.
 Nonadherence may account for up to 20 percent of patients
classified as having treatment-resistant depression.
Background: Treatment-Resistant Depression
Berlim MT, Fleck MP, Turecki G. Ann Med. 2008;40(2):149-59. PMID: 18293145.
Souery D, Amsterdam J, de Montigny C, et al. Eur Neuropsychopharmacol. 1999;9(1-2):83-91. PMID: 10082232.

17. ‘Resistant Depression’
• Coined by the World Psychiatric Association in 1974 to describe
patients who showed no response to tricyclic antidepressant
treatment at a suggested dose of 150mg/day of imipramine or
equivalent given over a period of four to six weeks*
* World Psychiatric Association. Symposium on therapy resistant depression. Pharmacopsychiatry. 1974;7:69-74.

18. Factors Associated with
Treatment Resistance
• Misdiagnosis
• Specific depressive subtypes
• Psychotic depression, atypical depression, melancholic features
• Psychiatric comorbidities
• Anxiety disorders, panic disorder, personality disorder
• Age at onset before 18 years
• Substance abuse
• Depression severity
• Chronicity
• Medical comorbidities
• Patient noncompliance with treatment
• Pharmacokinetics, pharmacogenetics
Gaynes B. J Clin Psychiatry. 2009;70(S6):10-15.

19. What Are the Clinical Features Associated
With TRD?
• Incorrect primary diagnosis
• Is there a primary disorder (e.g., substance-induced mood
disorder) not being treated?
• Is there a primary medical condition not being treated?
• Is there an unrecognized depressive subtype?
• Psychotic depression
• Bipolar disorder

20. What Are the Clinical Features Associated
With TRD?
• Patient factors
• Compliance
• Unusual pharmacokinetics
• Physician factors
• Underdosing
• Inadequate length of treatment

21. Statistics
• 60-70% tolerant patients respond to
1st
line monotherapy
• Up to 50% treated with single antidepressant
don’t reach full remission
• 1/3+ become treatment resistant

22. Nonremission is Common
• 35–45% remission
• 10–20% response with residual symptoms
• 15% partial response
• 25% nonresponse
• 7–15% intolerant
Depression in Primary Care, Vol. 2. Treatment of Major Depression. Rockville, MD: US Dept. of Health
and Human Services, AHCPR Publication No. 93-0550, 1993.

23. Why Target Remission?
• Compared with patients who achieve full remission, those with residual
symptoms have:
• Greater risk of relapse and recurrence
• More chronic depressive episodes
• Shorter duration between episodes
• Continued professional and social impairment
• Increased overall mortality
• Increased morbidity and mortality from comorbid medical disorders, including
 Stroke, diabetes, myocardial infarction, cardiovascular disease, congestive heart
failure, HIV
• Ongoing increased risk of suicide
Papakostas G. J Clin Psychiatry. 2009;70(S6):16-25.

24. Predictors of Non-Response
• Axis II personality disorders
• Anxiety comorbidities
• Delays in initiating treatment or chronicity
• Substance abuse
• +Family history
• Extremes in age of onset
• Depression subtypes

25. Pseudoresistant
• Inadequate dosing/ early treatment
discontinuation
• Patient noncompliance
• Misdiagnosis

26. Paradigms Which Contribute to Faulty TRD Labeling
• Failure to diagnose and manage bipolar
• Failure to diagnose and manage psychotic
• Failure to diagnose and manage melancholic depression
• Diagnosing and/ or managing non-melancholic as
melancholic depression
• Misdiagnosing secondary depression
• Failing to identify organic determinants
Parker et al 2005, J of Affect Dis

27. Usual therapeutic doses for depression
SSRIs:
• Citalopram (Cipramil) 20-40mg
• Escitalopram (Cipralex) 10mg
• Fluoxetine (Prozac) 20mg
• fluvoxamine (Faverin) 150-300mg?
• Paroxetine (Seroxat) 20-30mg
• Sertraline (Lustral) 50-100mg
Tricyclics:
• amitriptyline, clomipramine (Anafranil),
dothiepin/dosulepin, doxepin (Sinequan),
imipramine, nortriptyline, trimipramine
(Surmontil) – 125-150mg/d
• Lofepramine (Gamanil) 140-210mg
Newer:
• Mirtazapine (Zispin) 30-45mg
• Venlafaxine (Efexor) 75-225mg
• Duloxetine (Cymbalta) 60-120mg
• Trazodone (Molipaxin) 150mg?
• Reboxetine (Edronax) 8-12mg
• Moclobemide (Manerix) 300mg
MAOIs:
• Phenelzine 45mg?
• Isocarboxazid 30mg?
• Tranylcypromine 30mg?
• Mianserin, tryptophan, flupenthixol
(Fluanxol), agomelatine (soon)
• St. John’s wort

28. Onset of action of antidepressants
“Antidepressants take 4 weeks to work”
Wrong!
• 23% of all drug-placebo differences occur within the first week and 57%
were apparent by week 2
(s=47, n=8500, d/b, p/c, Pasternak and Zimmerman, J Clin Psych 2005, 66, 148-58)
• “Time to substantial remission” may take 4 weeks in clinical trials
• In 90% cases substantial improvement occurs within the first 2 weeks
but that the benefit continues to build over several weeks.
(review by Mitchell, B J Psych 2006, 188, 105-6)

29. Markers of
antidepressant response
• If no improvement (even minimal) after 4 weeks of a therapeutic dose,
should switch to another one
• With minimal improvement, continue until week 6 but there is only benefit
in continuing in about 10% pts
(n=593, Quitkin et al, Arch Gen Psychiatry 1996, 53, 785-92
• If there is no response by 8 weeks then the trial should “be declared a
failure”
(n=840, 12/52, open, Quitkin et al, Am J Psych 2003, 160, 734-40)
• Only 58% people take antidepressants for more than 28 days
(n=829, Offson et al, Am J Psych 2006, 163, 101-8).

30. Duration of antidepressant therapy summary
• 40% of people may relapse after an index depressive episode within 2
years, and 60% within 5 years
First episode:
• Six months after recovery at same dose minimises risk of relapse
(n=839, RCT, one-year, Reimherr et al, Am J Psych 1998, 155, 1247-53
Second episode:
• 1-2 years
Third or subsequent episode:
• 3-5 years or longer
(Frank and Kupfer, Arch Gen Psych 1990 and 1992)

31. Pharmacological Options After Failure of First
Antidepressant
• Optimize dose and address adherence
• Change to another antidepressant
• Same class
• Different class
• Add a second antidepressant
• Add a non-antidepressant
• Lithium or other mood stabilizer
• Thyroid hormone
• Psychostimulant
• Atypical antipsychotic

32. Strategies for
Refractory Depression
• Switch to a different antidepressant (within class or across class)
• Augment the treatment regimen with a non-antidepressant agent
• Combine the initial antidepressant with a second antidepressant
Papakostas G. J Clin Psychiatry. 2009;70(S6):16-25.

33. Lithium
• Most research support
• Least used
• Used more often in whites and those with previous
hospitalizations than in others

34. Low Use of Lithium
• Concerns about safety, convenience, tolerability, stigma
• Therapeutic doses close to toxic levels
• Med/ blood level monitoring
• Early side effects
• Potential diminishing efficacy with SSRI
• Popularity of SSRI to replace tricyclic agents
• Lack of advertising
• Dated articles and studies

35. Where Does Psychotherapy Fit In?
• Cognitive behavioral therapy has received the greatest
amount of study.

36. Atypical Neuroleptic Augmentation
• Olanzapine, Risperidone, Quetiapine, Ziprasidone
• Effective
• High efficacy and rapid response onset
• Mild side effects
• Limited research

37. Start and optimize a 1
st
-line
antidepressant
Evaluate degree of improvement
using a validated rating scale
Evaluate side effects
and residual symptoms
Evaluate side effects
and symptoms
Evaluate as
treatment-resistant
depression
No improvement
(< 20% change)
or intolerant
Remission
(score in normal range)
If less than
full remission
Some improvement
(≥ 20% change)
but not in remission
Remission
(score in normal range)
Evaluate
risk factors for
recurrence
Switch to a
2
nd
agent
with evidence of
superiority
Add-on
treatment with
another agent
(augment/combine)
Maintain
1
2
3
4
5
6
7
2
Algorithm for Managing Limited Improvement with First-line Antidepressant
Lam R, et al. J Affect Disord. 2009;117:S26-S43.

38. Switch Therapy or Add-on?
Monotherapy switch:
• No drug interactions
• No additive side effects
• Dosing simplicity
Add-on therapy:
• Faster onset of response
• Address specific residual symptoms or side effects
• Psychological advantage
• Late responders
Primarily a clinical decision (lack of evidence) based on whether there is at least a partial response to initial
treatment
Primarily a clinical decision (lack of evidence) based on whether there is at least a partial response to initial
treatment
Lam R, et al. J Affect Disord. 2009;117:S26-S43.

39. 1st
Line
2nd
Line
3rd
Line
Choosing an Add-on Strategy
Level 1 Evidence
• Lithium
• Aripiprazole
• Olanzapine
• Quetiapine XR*
Level 2 Evidence
 Bupropion
 Mirtazapine/mianserin
 Quetiapine IR
 Triiodothyronine
Adapted from Lam R, et al. J Affect Disord. 2009;117:S26-S43.
*Bauer M, et al. J Clin Psychiatry. 2009;70:540-549.
Level 3 Evidence
• Other antidepressant
Level 2 Evidence
 Buspirone
 Modafinil
Level 3 Evidence
• Stimulants
* Recently published data not included in the 2009 CANMAT MDD
guidelines
Level 2 Evidence
• Risperidone

40. Take Home Message
Treatment Resistant Depression
1. Is the diagnosis correct?
2. Is the patient medication compliant?
3. Change agents-Within/between classes
4. Antidepressant combinations
-Complementary mechanisms of action
5. Add psychotherapy
6. Augmentation strategies
• Lithium Thyroid hormone
• Antipsychotic Estrogen
7. ECT/Focal Brain Stimulation

41. On the Horizon
• Corticotropin releasing factor-1 (CRF1) antagonists
• Glucocorticoid receptor antagonists
• Substance P receptor antagonists
• NMDA receptor antagonists
• Melanocyte inhibiting factor (nemifitide)
• Omega -3 fatty acids
• Melatonin receptor antagonists
• Focal and deep brain stimulation therapies