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TREATMENT RESISTANT DEPRESSION

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TREATMENT RESISTANT DEPRESSION IS A AREA THAT IS NOT EXPLORED MUCH, BUT IT REALLY NEEDS LOT OF ATTENTION AS IT IS ONE OF THE MOST COMMON OBSTACLE IN ACHIEVING COMPLETE REMISSION IN DEPRESSION

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TREATMENT RESISTANT DEPRESSION

  1. 1. Dr. B C MALTHESH JR-3 BJGMC
  2. 2. Epidimiology   1-year prevalence of 3–5%, Lifetime prevalence varying from 10 to 30% [Hasin et al. 2005; Waraich et al. 2004].  Depression is ranked by the WHO as the 3rd highest cause of disability across the world.  Projected to become the second by 2020 [Murray and Lopez, 1997; World Bank, 2004].
  3. 3. Operational definitions of treatment response  Remission >75% Response 50% - 74% Partial Response 25% - 49% Nonresponse <25% Recovery – failure to meet criteria for MDD for at least 8 wks.
  4. 4. Operational definitions of treatment response 
  5. 5. STAR*D Cumulative Remission Rates  80 70 60 50 40 30 20 10 0 33% 50% Level 1 Level 2 Level 3 Level 4 Cumulative Remission Rate (%) Gaynes B, et al. Clev Clin J Med. 2008;75(1):57-65. 63% 67%
  6. 6. Rates of Response   Only a third of patients achieve full remission after their first antidepressant treatment in naturalistic conditions [Rush et al. 2006]  30-45% - Fail to respond to adequate trial of antidepressant.  10-15% - show partial response.  20-35% - are nonresponsive
  7. 7. Is Achieving Remission Important?   High risk of relapse and recurrence  TRD is more likely to cause suicide or a suicide attempt,  Confers poor prognosis kindling, episode frequency increases.  Poor functioning (e.g., work, family)  Psychiatric or general medical complications (e.g., substance abuse)  Increased Health service utilization  Death from Medical comorbidities also increase
  8. 8. Definition of TRD   Poorly defined term  Failure to respond to a trial of more than one antidepressant drug in a dose equivalent to 250-300 mg of IMN given for duration of 6-8 wks.  Unremitting depression despite treatment with at least 2 different antidepressant or an antidepressant & a course of ECT.
  9. 9. Definition of TRD   Failure to respond to 2 adequate trials (adequate dosage for adequate duration) of different chemical classes.  Several Staging Methods  Thase & Rush (1997)  Massachusetts General Hospital  CPMP Guidelines
  10. 10. Thase and Rush stages  STAGE I FAILURE OF AT LEAST ONE ADEQUATE TRIAL OF ANTI DEPRESSANT MONOTHERAPY STAGE II STAGE I +FAILURE OF TRAIL OF DIFFERENT ANTIDEPRESSANT CLASS STAGE III STAGE II +FAILURE OF TRAIL OF TCA STAGE IV STAGE III +FAILURE OF TRIAL OF MAO-I STAGE V STAGE IV +FAILURE OF ECT COURSE
  11. 11. Causes of Resistance   Incorrect primary diagnosis  Is there any other primary Psychiatric 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 depression  Depressive severity  Chronicity of depression (illness lasting 2 years or more)  Greater number of somatic symptoms  History of childhood emotional abuse and sequelae Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
  12. 12. Causes of Resistance  Factors related to antidepressant treatment  Inadequate treatment of earlier episodes may lead to kindling and sensitization at the receptor/synaptic levels leading to the development of resistance. Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
  13. 13. Causes of Resistance   Primary Medical diagnosis -hypercholesterolemia, hypothyroidism, diabetes, Cushing’s syndrome, Parkinson’s disease, Huntington’s disease, cerebrovascular disease, and seizure disorder.  Comorbid psychiatric disorders  Anxiety disorders  Commonly coexist with major depression  Increase the likelihood of more severe depressive symptoms, suicide attempts, decreased responsiveness, and greater susceptibility to side effects  Substance abuse  Personality disorders  Eating disorders Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
  14. 14. Causes of Resistance   Patient factors  Compliance  Individual differences in drug metabolism  Nutritional status - deficiencies in folate, thiamine, vitamin B6, vitamin B12, copper, and zinc  psychosocial stressors and poor social support.  Physician factors  Underdosing  Inadequate length of treatment Pseudo resistance Parik MR et al, Current perspectives in the management of treatment-resistant depression ; Dialogues in Clinical Neuroscience - Vol 6 . No. 1 . 2004
  15. 15. Management   Re-evaluation of pts history & presentation  Assessment of treatment adequacy  Dose  Duration  Drug compliance  Drug monitoring  Treatment strategies –  Pharmacological - optimization, augmentation, combination, switching.  Somatic treatments. – DBS, VNS, rTMS  Non pharmacological.
  16. 16. Optimization   Ensure that the current drug is being used for sufficient duration(6-8 weeks), at the ideal dosage with maximum adherence.  Does may have to be decreased or increased  Address adherence issues by using pill dairy or pill counts or supervised medications.
  17. 17. Augmentation strategies  • Augmentation – adding an agent that is not conventionally used as monotherapy to an existing antidepressant. • Advantages – rapid onset of action, no withdrawal sxs, no loss of partial response. • Disadvantage – drug-drug interaction, increased cost, compliance.
  18. 18. Augmentation strategies   Lithium  0.5 - O.8 meq/lt  Most of the literature available is regarding TCA augmentation with Lithium, sparse data available on SSRI augmentation with Lithium  Side effects monitoring and blood level monitoring has to be done stringently. Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression: A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)
  19. 19. Augmentation strategies   Triiodothyronine (T3) – 20-50 micg/day  generally well tolerated and has a favourable side effect profile compared to lithium.  Similar to lithium augmentation, much of the data supporting thyroid augmentation comes from studies with TCA  Repeat TFTs may be needed  Antiepileptic drugs  Valproate, CBZ, Lamotrigine  Pindolo (5mg TDS)  Mainly to accelerate the response than to overcome resistance
  20. 20. Atypical antispychotics   Olanzapine, Quetiapine (300-600mg/day) and to some extent aripiprazole (5-20mg/day) have good supportive data from controlled clinical trials as augmenters of SSRIs Eg: Olanz + Floux combination  Data for risperidone (0.5-2 mg/day) are not robust, but can be used as an augmenting agent  Research supporting the augmentation effects of ziprasidone is much more limited  Use of Clozapine is limited due to its adverse effect profile, but can be used as last resort after other Aps fail RC Shelton, GI Papakostas - Augmentation of antidepressants with atypical antipsychotics for treatment‐resistant major depressive disorder Acta Psychiatrica Scandinavica, 2008
  21. 21. Stimulants as Augmenting drug   Amphetamine, Methylphenidate, Modafinil can be used  Methylphenidate enhances Dopaminergic transmission and has euphorigenic action  Stimulants mainly decrease fatigue and apathy  Risk of abuse in patients with history of substance use disorder.
  22. 22. Summary of Augmentation options
  23. 23. Combination therapy   The use of at least 2 antidepressants that have well established efficacy.  Advantages & disadvantages similar to augmentation.  SSRI + bupropion / Buspirone.  TCA + SSRI.  SSRI or SNRI can be combined with Mirtazapine / trazodone.  SSRI + SNRI I not a good combination  TCA & MAOI may lead to seratonin syndrome.  SSRIs, venlafaxine, or clomipramine should not be combined with MAOIs
  24. 24. Switching Strategies   Switching can be either within same class or between two classes of drugs.  Advantages – improved compliance, fewer adverse effects, cost effective.  Disadvantages – withdrawal sxs, time lag between initiation of new drug & treatment response.  Switching to older class of drug can also be done like : SSRI  TCA or SSRI  MAOI, Philip et al.,Pharmacologic Approaches to Treatment Resistant Depression: A Re-examination for the Modern Era; Expert Opin Pharmacother. 2010 April ; 11(5)
  25. 25. Switching Strategies   SSRI ► SSRI (Zarate et al, 1996)  SSRI ► SNRI (Poirier&Boyer,1999)  SSRI ► Bupropion (Fava et al, 2003)  SSRI ► TCA (Fava, 2001)  SSRI ► MAOI (Thase & Rush, 1995)
  26. 26. Al-Harbi ., Treatment-resistant depression: therapeutic trends, challenges, and future directions.; Patient Preference and Adherence 2012:6 ,369–388
  27. 27. Summary of the findings of the above studies   Response rate 26%–76%; remission rate 28%–87%.  TCA might prove to be a strategy of first choice for patients who do not respond to an SSRI;  Intolerance to one SSRI does not necessarily mean intolerance to the whole class of SSRI;  Between-class switch is a good treatment option.  In patients unresponsive to SSRI, administration of antidepressants with different mechanisms of action is an effective switching strategy.
  28. 28. rTMS for Treatment Resistant Depression   24 studies (n = 1092 patients) compared active & sham rTMS in TRD  Active rTMS was significantly superior to sham conditions in producing clinical response.  The pooled response and remission rates were 25% and 17%, and 9% and 6% for active rTMS and sham conditions, respectively.  Relatively low response and remission rates, the short durations of treatment, and the relative lack of systematic follow-up studies suggest that further studies are needed. Lam RW, Chan P, Wilkins-Ho M, Yatham LN. Repetitive transcranial Magnetic stimulation for treatment resistant-depression: a systematic review and metaanalysis. Can J Psychiatry 2008 ; 53(9): 621-31.
  29. 29. DBS for Treatment Resistant Depression   DBS for TRD is an experimental area of investigation.  costs and the risks related to the surgical procedure are limiting factors,  Used only in most treatment-refractory cases of depression.  The data on efficacy in TRD are limited to a series of open-label studies.  DBS is not a treatment indicated for acute worsening, as the effects of stimulation can take weeks to months to manifest. Cusin and Dougherty, Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS., Biology of Mood & Anxiety Disorders 2012, 2:14
  30. 30. VNS for Treatment Resistant Depression   Useful in case of mild to moderate treatment resistance, but not in severe resistance  VNS is usually considered as an adjunct to pharmacologic treatment, and it can safely be combined with ECT in case of an acute relapse Cusin and Dougherty, Somatic therapies for treatment-resistant depression: ECT, TMS, VNS, DBS., Biology of Mood & Anxiety Disorders 2012, 2:14
  31. 31. Bilateral Epidural Prefrontal Cortical Stimulation (ECS) for TRD   Leads are placed through a burr hole in the skull but above the dura mater and thus remain separated from the underlying cortical region by the arachnoid space.  ECS is more direct than transcranial magnetic stimulation (TMS) or vagus nerve stimulation (VNS) and potentially safer than deep brain stimulation (DBS),  Appears relatively safe, feasible.  Five adults with an average of 5.8 failed antidepressant treatments and currently depressive episode were enrolled  At 7 month follow up 3 had reached remission, almost all had shown response Nahas et al.,Bilateral Epidural Prefrontal Cortical Stimulation for Treatment Resistant Depression; Biol Psychiatry. 2010 January 15; 67(2):
  32. 32. Cognitive Behavioral Therapy   Efficacy of CBT was analyzed in STAR-D study.  CBT is both an acceptable switch and augmentation option in the second step of STAR-D  Benefit of CBT as augmentation was slower (up to 3 weeks) compared to augmenting with medication.
  33. 33. Ketamine Mechanism of action   Ketamine acts as antagonist at NMDA receptor, potentiates transmission at AMPA,  Increased stress hormones in depression leads to disruption in hippocampal LTP, which is NMDA dependent process.  Acts on m-TOR pathway to leading to increased synaptic signaling  Increases BDNF concentration  Through these mechanisms it causes enhanced synaptic plasticity Murrough et al.,Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression; Biol Psychiatry. 2013 August 15; 74(4)
  34. 34. Ketamine infusions for TRD   24 patients of TRD were selected  They underwent a washout of antidepressant medication followed by a series of up to six intravenous (IV) infusions of ketamine (0.5 mg/kg) over 12 days.  Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion.  Overall response rate at study end was 70.8%.  There was a large mean decrease in Montgomery–Asberg Depression Rating Scale (MADRS) score at two hours following the first ketamine infusion  Suicidal ideation (SI) rapidly decreased within 6 hours of 1st infusion, even among study non-responders.  But even Among responders, median time to relapse following the last ketamine infusion was 18 day Murrough et al.,Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression; Biol Psychiatry. 2013 August 15; 74(4)
  35. 35. Dopamine Agonists for TRD   Six studies (1996-2010) have investigated the effect of adjunctive dopamine agonists in the treatment of refractory depression  These studies have generally found marked improvement in depressive symptoms. however, most of these studies targeted stage I treatment-resistant depression, with only one study for stage II refractory depression which evaluated Pramipexole.  It is thus suggested that pramipexole augmentation, among various dopamine agonists, may be a worthwhile option for refractory depression. Hori H et al.,The Efficacy of Pramipexole, a Dopamine Receptor Agonist, as an Adjunctive Treatment in Treatment-Resistant Depression: An Open-Label Trial.; The Scientific World Journal Volume 2012,
  36. 36. S-adenosyl metheonine for TRD   Used as an Augmenting agent  SAM-e has shown antidepressant efficacy that is superior to placebo and equivalent to the effects of TCAs in a meta- analytic studies. Seo RJ et al.,Atypical Antipsychotics and Other Therapeutic Options for Treatment of Resistant Major Depressive Disorder.; Pharmaceuticals 2010, 3, 3522-3542
  37. 37. Melatonin Receptor Agonists   Agomelatine  Agonist at MT1 & MT2.. Antagonist at 5HT2C  Given 25mg/day in HS dosage.
  38. 38. Metyrapone in treatment-resistant depression   There is blunted ACTH response to CRH.  Dysregulation of the HPA axis has been found to be linked to nonresponse to antidepressants and relapse following successful treatment.  Metyrapone – a cortisol synthesis inhibitor, targeted at altered HPA axis.  With repeated administration of Metyrapone the plasma cortisol level normalises and the ACTH levels increase to normal level. Ther Adv Psychopharmacol (2012) 2(4) 139 –149
  39. 39. Metyrapone in treatment-resistant depression   Rogoz and colleagues did a open-label trial of augmentation of imipramine with metyrapone in patients with TRD.  Patients were treated with imipramine for first 6 weeks, followed by 6 weeks of the addition of metyrapone (250 mg twice daily) treatment  Metyrapone augmentation significantly reduced the scores on the depression rating scales [HDRS (46%) and Beck Depression Inventory (39%)]. Rogoz, Z., Skuza, G., Wojcikowski, J., Daniel, W.A., Wrobel, A., Dudek, D. et al. (2004) Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression. Pol J Pharmacol 56: 849–855.
  40. 40. Metyrapone in treatment-resistant depression   Jahn et al did a double-blind randomized, placebo-controlled study of augmentation of serotonergic antidepressants with either metyrapone or placebo for 3 weeks.  At 5 weeks post intitiation of the study, metyrapone (1gm) group showed significantly more improvement in HDRS scores compared to placebo group . Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A. and Wiedemann, K. (2004) Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry 61: 1235–1244.
  41. 41. Erythropoietin in treatment-resistant depression   It has got few direct neurobiological actions mediated through a non-haematopoietic Epo receptor situated in the brain.  Systemically administered Epo crosses the blood-brain barrier (BBB) and has neuroprotective and neurotrophic effects in animal models of acute brain damage and chronic neurodegenerative conditions.  With Epo administration there is rapid up-regulation of neuroplasticity mechanisms including BDNF and neurogenesis, and anti-inflammatory actions.
  42. 42. Erythropoietin in treatment-resistant depression   Miskowiak et al (2007-2008)  4 articles on the effect of erythropoeitin on mood, cogniotion, face detection  Epo improves recognition of all facial expressions, in particular of low intensity happiness. This is similar to behavioural effects observed with acute administration of serotonergic antidepressants.  Epo improved self-reported mood for all 3 days post-administration.  Epo directly modulates brain responses to emotional information in humans in a manner consistent with the actions of conventional antidepressants. Miskowiak et al. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder Trials 2010, 11:97
  43. 43. Erythropoietin in treatment-resistant depression   One ongoing study to assess the effects of long term administration of Epo. Results are awaited.  Miskowiak et al did a double-blind, placebo-controlled, parallel-group design.  40 patients with treatment-resistant major depression are recruited and randomised to receive weekly infusions of Epo (Eprex; 40,000 IU) or saline (NaCl 0.9%) for 8 weeks.  The primary outcome parameters for the two studies are: depression severity measured with the Hamilton Depression Rating Scale 17 items (HDRS-17). Miskowiak et al. Effects of erythropoietin on depressive symptoms and neurocognitive deficits in depression and bipolar disorder Trials 2010, 11:97
  44. 44. Summary   A working definition of TRD: Failure to remit after 8-12 weeks at a adequate doseage  Key considerations with TRD  Clarify diagnosis and potential risk factors for persistence  Patient factors: compliance and/or rare pharmacokinetics  Physician factors: underdosing and/or inadequate treatment length
  45. 45. Summary   No clear direction for augmenting vs. switching  Each appear successful for ~ 50% of patients  If patient tolerating, first try to maximize dose  When switching antidepressants after one failure, within class or different class choices are reasonable  Available evidence supports lithium and T3 as most effective augmenting agents
  46. 46. Summary – We don’t know   We Have Little Evidence Guiding Treatment Choice After the first drug fails  We Have No Evidence For Those with Two or More Treatment Failures  We Do Not Know Where Psychotherapy is helpfull  Reviews suggest that psychotherapy plays a significant role in the management of treatment resistant depression  We do not know about the benefits of switching to psychotherapy compared to augmenting medications with psychotherapy  Vast majority of studies excluded patients with common general medical and psychiatric comorbidities
  47. 47. References   Hasin, D.S., Goodwin, R.D., Stinson, F.S. and Grant, B.F. (2005) Epidemiology of major depressive disorder: results from the National Epidemiologic Survey on Alcoholism and Related Conditions. Arch Gen Psychiatry 62: 1097–1106.  Waraich, P., Goldner, E.M., Somers, J.M. and Hsu, L. (2004) Prevalence and incidence studies of mood disorders: a systematic review of the literature. Can J Psychiatry 49: 124–138.  Rush, A.J., Trivedi, M.H., Wisniewski, S.R., Nierenberg, A.A., Stewart, J.W., Warden, D. et al. (2006) Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 163: 1905–1917.  Rogoz, Z., Skuza, G., Wojcikowski, J., Daniel, W.A., Wrobel, A., Dudek, D. et al. (2004) Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression. Pol J Pharmacol 56: 849–855.  Jahn, H., Schick, M., Kiefer, F., Kellner, M., Yassouridis, A. and Wiedemann, K. (2004) Metyrapone as additive treatment in major depression: a double-blind and placebo-controlled trial. Arch Gen Psychiatry 61: 1235–1244.
  48. 48. References   Miskowiak K, O'Sullivan U, Harmer CJ: Erythropoietin reduces neural and cognitive processing of fear in human models of antidepressant drug action. Biol Psychiatry 2007, 62:1244-1250.  Miskowiak K, O'Sullivan U, Harmer CJ: Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci 2007, 27:2788-2792.  Miskowiak K, Inkster B, O'Sullivan U, Selvaraj S, Goodwin GM, Harmer CJ: Differential effects of erythropoietin on neural and cognitive measures of executive function 3 and 7 days post-administration. Exp Brain Res 2008, 184:313-321.  Miskowiak K, Inkster B, Selvaraj S, Wise R, Goodwin GM, Harmer CJ: Erythropoietin improves mood and modulates the cognitive and neural processing of emotion 3 days post administration. Neuropsychopharmacology 2008, 33:611-618.

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