Hanipsych, resistant depression
-
Upload
hani-hamed -
Category
Health & Medicine
-
view
179 -
download
1
Transcript of Hanipsych, resistant depression
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