Resistant Depression

Prof. Hani Hamed Dessoki, M.D.PsychiatryProf. Psychiatry

Chairman of Psychiatry Department

Beni Suef University

Supervisor of Psychiatry Department

El-Fayoum University

APA member

No disclosures / conflicts of interest

Agenda

• Introduction• Size of the problem• Definitions• Causes• Solutions

Introduction to Major Depression

Digestive disorder (6%) Musculoskeletal

disorders (4%)

Endocrine (4%)

Neuropsychiatricdisorders (28%)

Cancer (11%)

Cardiovascular disease (22%)

Sense organ impairment (10%)

Other non-communicable diseases (7%)

Respiratory disease (8%)

Schizophrenia

Bipolar disorder

Dementia

Substance-use andalcohol-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

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

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)

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

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

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

Course of Depression

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

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

Response and Remission

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

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.

‘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.

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.

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

What Are the Clinical Features Associated With TRD?

• Patient factors• Compliance• Unusual pharmacokinetics

• Physician factors• Underdosing• Inadequate length of treatment

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

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.

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.

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.

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

Pseudoresistant

• Inadequate dosing/ early treatment discontinuation

• Patient noncompliance• Misdiagnosis

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

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) 300mgMAOIs: • Phenelzine 45mg?• Isocarboxazid 30mg?• Tranylcypromine 30mg?• Mianserin, tryptophan, flupenthixol

(Fluanxol), agomelatine (soon)• St. John’s wort

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)

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).

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)

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

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.

Lithium

• Most research support• Least used

• Used more often in whites and those with previous hospitalizations than in others

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

Where Does Psychotherapy Fit In?

• Cognitive behavioral therapy has received the greatest amount of study.

Atypical Neuroleptic Augmentation

• Olanzapine, Risperidone, Quetiapine, Ziprasidone• Effective• High efficacy and rapid response onset• Mild side effects• Limited research

Start and optimize a 1st

-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

2nd

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.

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.

1st Line

2nd Line

3rd Line

Choosing an Add-on StrategyChoosing 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.

Nelson JC, Papakostas G. Am J Psychiatry. 2009;166:980-991.

Level 3 Evidence

• Other antidepressant

Level 3 Evidence

• Other antidepressant

Level 2 Evidence

Buspirone

Modafinil

Level 3 Evidence

• Stimulants

Level 3 Evidence

• Stimulants

* Recently published data not included in the 2009 CANMAT MDD

guidelines

* Recently published data not included in the 2009 CANMAT MDD

guidelines

Level 2 Evidence

• Risperidone

Level 2 Evidence

• Risperidone

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

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