1. Treatment Resistant Depression Anita S. Kablinger, M.D. Associate Professor Departments of Psychiatry and Pharmacology

2. TRD 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 D: partial response to treatment; patient meets non-response criteria T-refractory D: no response to treatment; symptoms are unchanged or worse

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

4. 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

5. TRD - Common Diagnosis No clearly defined criteria Often misdiagnosed - primary and secondary (organic) causes should be determined Often inadequately treated - treatment response criteria (dose, duration, compliance) - # of trials before labeled non-responsive

6. Pseudoresistant Inadequate dosing/ early treatment discontinuation Patient noncompliance Misdiagnosis

7. Assessing Treatment Outcome Comorbidity Psychosocial Stressors

8. Current TRD “criteria” No response after: Maximum tolerable dosage -varies depending on patient -affected by pharmacokinetics 4-6 weeks

9. 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

10. TRD *-Accurate diagnosis -Different classes of antidepressants are more effective for specific forms of depression -Some forms of depression have longer recovery times -Some medical conditions contribute to TRD Treatment response criteria # of adequate trials required Adequate treatment guidelines

11. TRD Current Guidelines CPMP Guidelines Thase and Rush Staging Model Massachusetts General Hospital Staging Method Souery et al Operational Criteria

12. CPMP Guidelines Committee for Proprietary Medicinal Products “Consecutive treatment with 2 products of different classes, used for a sufficient length of time at an adequate dose, fail to induce an acceptable effect” Dose and duration undefined

13. Thase and Rush Staging Model I: Failure of at least 1 adequate trial of 1 major class of antidepressant II: Stage I resistance + failure of an adequate trial of an antidepressant in a different class from that used in stage I III: Stage II resistance + failure of adequate trial of TCA IV: Stage III resistance + failure of adequate trial of MAOI V: Stage IV resistance + failure of a course of bilateral ECT

14. T and R model (cont.) Dosing and duration of each trial aren’t thoroughly explained Stage I: Does no response to 1 trial mean resistance? What about 2 consecutive SSRI trials? (Patient may be resistant to particular compound but not to all in that class) Implies hierarchy of treatment Implies greater difficulty in treating non-response after 2 trials of agents from 2 diff classes than with 2 trials from same class No combo/ augmentation strategies considered

15. Massachusetts General Hospital Staging Method Quantitative with continuous variable Considers # of failed trials + intensity and optimization of treatments No antidepressant hierarchy assumed Includes augmentation/ combo treatments More predictive of remission than T and R method

16. Souery et al Operational Criteria Similar to MGH Method 2 consecutive failed trials required Addresses chronic resistant depression which may develop after 1 year of non-response to multiple therapies

17. Studies More studies necessary for: -current staging models -non-response and resistance predictors -effectiveness of current strategies: optimization of dose combo/ augment therapy switching therapy

18. Current (or future) Treatment Options Vagus Nerve Stimulation Triple Reuptake Inhibitors Antidepressant Augmentation Lithium Atypical Neuroleptic Augmentation Novel Antipsychotics Med Switches Augmentation/ Combination Treatments

19. Triple Reuptake Inhibitors (TRI) Target all three of brain’s monoamines (serotonin, norepinephrine, dopamine) Expected on the market by 2010 Better efficacy and tolerability, faster acting, less side effects, treats broader range of symptoms

20. Antidepressant Augmentation Whites, young, previous hospitalization, comorbidities are more likely to receive augmentation Most common augmenting agents: -2 nd antidepressant -2 nd generation antipsychotic * why not lithium

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

22. 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 –Efficacy with tricyclic agents Lack of advertising –Dated articles and studies

23. Atypical Neuroleptic Augmentation Olanzapine, Risperidone, Quetiapine, Ziprasidone Effective cross-overs between atypicals High efficacy and rapid response onset Mild side effects Limited research

24. Novel Antipsychotics Act on dopamine, serotonin, glutamate and other receptors Beneficial effects on depressive symptoms 50% response 25% remission Direct effects vs. augmenting actions –More research is necessary

25. SSRIs Used first b/c high tolerability/ low toxicity No response from SSRI (or intolerable) -What’s the next step? Med switches Augmentation

26. Med Switches 1 in 4 patients on SSRI’s have a response on 2 nd drug: –Bupropion-SR –Sertraline –Venlafaxine-XR Within class 1 st SSRI may be ineffective/ intolerable 2 nd SSRI may be effective/ tolerable Out-of-class Dual-action agent

27. Augmentation Sustained release bupropion group Buspirone group Similar response and remission rates BUT Bupropion had greater symptom reduction and tolerability

28. 1 st Line Treatments? Skip 1 st step of only SSRIs Augmentation or combination treatments 1 st Faster and larger remission rates

29. Acknowledgements Atiq, Rafay. “Treatment-Resistant Depression.” Hospital Physician. Vol 10. Part 1. February 2006. pp. 2-11. Barbee, Conrad, Jamhour. “The effectiveness of Olanzapine, Risperidone, Quetiapine, and Ziprasidone as Augmentation Agents in Treatment Resistant Major Depressive Disorder.” Journal of Clinical Psychaitry. Vol 65. No 7. July 2004. pp.975-981. Rosack, Jim. “Companies Desperately Seek Antidepressant Breakthrough.” Psychiatric News. June 2, 2006. pp. 22-23. Rush, et. Al. “Buropion-SR, Sertralie, or Venlafaxine-XR after failure of SSRIs for depression.” New England Journal of Medicine. Vol 354, No 12. March 23, 2006. pp.1231-1242

30. Acknowledgments Cont. Shelton, Richard. “Novel Antipsychotics for Treatment-Resistant Depression”. Psychiatric Times. October 2004. pp.72-74. Trivedi, Souery, Papakostas. “Treatment- Resistant Depression.” Journal of Clinical Psychiatry. Vol 67. Supplement 6, 2006. pp.16- 22. Trivedi, et.al. “Medicatio Augmentation after Failure of SSRIs for Depression.” New England Journal of Medicine. Vol 354. No 12. March 23, 2006. PP. 1243-1252. Valenstein, et.al. “What Happened to Lithium? Antidepressant Augmentation in Clinical Settings.” American Journal of Psychiatry. Vol 163. No 7. July 2006. pp.1219-1225.