Hanipsych, resistant depression


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  • The purpose of this section is to
    educate the audience about the importance of early use and appropriate length of treatment
    explore the likelihood of a successful recovery vs. relapse
    Remind them of the importance of remission as an outcome
    Discuss strategies to optimise the chances of remission
  • Adapted from ………….
    5 R’s:
    Response,and remission defined.
    Response is normally defined as improvement in symptoms so pts no longer fully syndromal but may be still exhibiting some symptoms. Remission is (essentially) asymptomatic.
    Also define relapse(same episode of depression re-presenting - inside 6 months of response), recovery ( maintained well for 6 months) & recurrence( new episode of depression in long term treatment phase).
    The risk of relapse appears to be highest immediately after discontinuation of acute treatment & diminishes over the following months.
    Then maintenance ( prophylaxis) phase which is intended to prevent new episodes (recurrences) of depression. NB. WHO guidelines recommend A/D treatment continued for at least 6 months.
    McGrath P. Am J Psychiatry 2006; 163:1542–1
    “Relapse during antidepressant treatment is common and troublesome (1, 2), although the efficacy of continuation and maintenance pharmacotherapy is well supported (3–6). The aetiology of such relapses, which occur in up to 40% of patients, is unknown (3, 7–14). Possible mechanisms include loss of placebo effect, diminished treatment adherence, increasing medication catabolism over time, and development of pharmacologic resistance to drug action”.
    An A/D that is effective in acute treatment is NOT necessarily effective in long term treatment.
    “The dose that gets you well keeps you well”
  • What is the desired outcome for antidepressant treatment? Traditionally, response was the desired outcome for treatment, and is generally considered a 50% reduction in symptoms. However, it is now widely recognised that remission is the optimal outcome of treatment.
  • Note: Greden JF, J Clin Psychiatry 2001; 62 (suppl 16), Burden of Disease for TRD, 26-31
    NOTE: differ by measure; time for measure; number of prior trials, definition of adequacy
    Definition must be able to be operationally defined and clinically applied in order to be useful. How do we think about it?
  • Background: Treatment-Resistant Depression
    A portion of patients who have experienced an inadequate response from a clinical perspective may also go on to have their depression defined as treatment resistant if it also fail to respond to subsequent treatment strategies. Treatment resistance is variably defined but usually refers to depression that has not responded to at least two trials of medication that have been of adequate dose and duration. Some definitions suggest that the failures should be to medications of different classes, but this is not universally accepted. Monitoring adherence to antidepressants is sometimes difficult, but nonadherence may account for up to 20 percent of patients classified as having treatment-resistant depression. Similarly, there is the potential for pseudoresistance or nonresponse to inadequate treatment. All this would suggest the difficulty of defining and capturing subjects who have had treatment failure and related subgroups. It may also reflect heterogeneity across studies evaluating the efficacy of selective serotonin-reuptake inhibitors within this patient population.
    Berlim MT, Fleck MP, Turecki G. Current trends in the assessment and somatic treatment of resistant/refractory major depression: an overview. Ann Med. 2008;40(2):149-59. PMID: 18293145.
    Souery D, Amsterdam J, de Montigny C, et al. Treatment resistant depression: methodological overview and operational criteria. Eur Neuropsychopharmacol. 1999;9(1-2):83-91. PMID: 10082232.
  • If someone appears treatment resistant, what questions do you consider in assessment?
  • Hanipsych, resistant depression

    1. 1. 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
    2. 2. No disclosures / conflicts of interest
    3. 3. Agenda • Introduction • Size of the problem • Definitions • Causes • Solutions
    4. 4. Introduction to Major Depression
    5. 5. 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
    6. 6. 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
    7. 7. 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)
    8. 8. Ten leading causes of burden of disease, world, 2004 and 2030
    9. 9. 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
    10. 10. 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
    11. 11. Course of Depression Adapted from Kupfer DA. J Clin Psychiat 1991; 52 (5): 28-34
    12. 12. 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
    13. 13. Response and Remission
    14. 14. 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
    15. 15.  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.
    16. 16. ‘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.
    17. 17. 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.
    18. 18. 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
    19. 19. What Are the Clinical Features Associated With TRD? • Patient factors • Compliance • Unusual pharmacokinetics • Physician factors • Underdosing • Inadequate length of treatment
    20. 20. 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
    21. 21. 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.
    22. 22. 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.
    23. 23. 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
    24. 24. Pseudoresistant • Inadequate dosing/ early treatment discontinuation • Patient noncompliance • Misdiagnosis
    25. 25. 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
    26. 26. 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
    27. 27. 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)
    28. 28. 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).
    29. 29. 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)
    30. 30. 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
    31. 31. 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.
    32. 32. Lithium • Most research support • Least used • Used more often in whites and those with previous hospitalizations than in others
    33. 33. 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
    34. 34. Where Does Psychotherapy Fit In? • Cognitive behavioral therapy has received the greatest amount of study.
    35. 35. Atypical Neuroleptic Augmentation • Olanzapine, Risperidone, Quetiapine, Ziprasidone • Effective • High efficacy and rapid response onset • Mild side effects • Limited research
    36. 36. 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.
    37. 37. 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.
    38. 38. 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
    39. 39. 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
    40. 40. 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