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Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling * Steven Cole, MD Professor of Psychiatry Stony.

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Presentation on theme: "Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling * Steven Cole, MD Professor of Psychiatry Stony."— Presentation transcript:

1 Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling * Steven Cole, MD Professor of Psychiatry Stony Brook University Medical Center and Thomas Oxman, MD Professor of Psychiatry Dartmouth School of Medicine

2 PHARMACOTHERAPY Effective –Major depression –Dysthymia (chronic depression) Possibly effective –Minor depression

3 Initial Acute Phase Treatment Elicit patient preference Assess suicidality Generally start with SSRI Provide educational messages Elicit commitment to take medication regularly Arrange early follow-up (1 to 3 weeks) Repeat PHQ-9 every month until remission Start at or increase dose every week up to adequate dose Once at adequate dose, re-evaluate dose q/month;; APA

4 CHOOSING AGENTS:GENERIC SSRIs Citalopram (Celexa)/sertraline (Zoloft)  in short term) –effective for anxiety (  in short term) –may need to increase dose (60 mg/200 mg) for efficacy –low-moderate drug interactions Fluoxetine (Prozac) –long half-life –P450 inhibition at low doses –effective for  –effective for anxiety (but  anxiety in short term) –Possible  –Possible  insomnia (short term) Paroxetine (Paxil) –possibly sedating –effective for anxiety –possible weight gain –P450 inhibition at low doses –more frequent withdrawal symptoms –measurable anti-cholinergic activity

5 OTHER GENERIC NEW AGENTS Bupropion SR, XL (Wellbutrin) –100/200 mg (SR); 150/300 mg (XL) –somewhat activating; don’t give HS –do not give if there is seizure risk –unless using XL, don’t give >200 mg /dose –don’t prescribe >450 mg/day –XL can be prescribed once/day –fewer sexual side-effects –once day dosing available (XL) Mirtazapine (Remeron) –frequent appetite / weight gain –very sedating at low dose –few drug interactions –Sol-tabs available

6 CASE #1 A 40-year-old male reports a little (but not marked) improvement after 2 weeks on escitalopram (Lexapro) 10 mg a day. What do you do next?

7 CASE #1 POINTS TO CONSIDER Usually takes 3-4 weeks to attain maximal clinical effects from one dosage of an antidepressant Probably because of prolonged time needed to effect receptor architecture or function

8 Post-Synaptic Signal Transduction Effects neurogenesis Oxman, 2005

9 Synaptic Signaling Receptor/ Transporter Regulation Intracellular Signaling & Posttranslational Modification Gene Expression Neuroplasticity/ Neurogenesis Hours DaysDays WeeksMonths Years TIME COURSE OF BIOLOGICAL CHANGES WITH ANTIDEPRESSANTS Oxman, 2005

10 KEY EDUCATIONAL MESSAGES Antidepressants only work if taken every day. Antidepressants are not addictive. Benefits from medication appear slowly. Continue antidepressants even after you feel better. Mild side effects are common, and usually improve with time. If you’re thinking about stopping the medication, call me first. The goal of treatment is complete remission; sometimes it takes a few tries.

11 CASE #2 After 8 weeks on sertraline (Zoloft) 50 mg bid, a patient is considerably better, but not back to baseline. What do you do?

12 CASE #2 POINTS TO CONSIDER Treat patients aggressively until they reach remission Increase dose as tolerated to 200 mg Patients who do not attain remission (even those who experience a 50% or greater response) are at greater risk for relapse and continued functional impairment

13 OUTCOME TARGETS USING THE PHQ-9 Clinically significant improvement (CSI) = 5 point decrease in PHQ-9 score Response = 50% decrease in PHQ-9 score Remission = PHQ-9 score < 5 for two months


15 CASE #3 A 30-year-old female complains of anorgasmia on citalopram (Celexa) 40 mg/day What should you do and when?

16 CASE #3 POINTS TO CONSIDER Sexual dysfunction with all SSRIs approaches 50% prevalence (anorgasmia, decreased libido, erectile problems) Does not improve over time RCT indicates sildenafil can be helpful for male sexual problems Consider lower dose, switch medications, add bupropion (limited, inconsistent data)

17 CASE #4 After three days of treatment, this 30 year- old female on fluoxetine (Prozac) 20mg a day complains of agitation and insomnia. What do you do?

18 CASE #4 POINTS TO CONSIDER Fluoxetine (and other SSRIs) often cause increased anxiety and/or insomnia in early stages of treatment This usually resolves within several days or a week or two Consider starting at low doses in patients with anxiety Consider prescribing “escape” medicine

19 SIDE EFFECTS (SSRIs) Agitation/insomnia GI distress Sexual dysfunction

20 SIDE EFFECTS (OTHER NEW AGENTS)  bupropion - agitation;  seizure risk duloxetine - nausea (up to 40%) mirtazapine - sedation; weight gain  venlafaxine - SSRI effects; 1-3%  BP

21 MANAGING SIDE EFFECTS Sedation –Give medication HS GI distress –Give medication with meals Anticholinergic effects –Bulk in diet, lemon drops Postural hypotension –Hydration, change position slowly, support hose

22 MANAGING SIDE EFFECTS (con’t) Insomnia/agitation –Use adjunctive sedating agent –Switch to mirtazapine Sexual dysfunction –Switch to bupropion, mirtazapine –Consider bupropion, sildenafil, yohimbine, cyproheptadine

23 Case #5 70 year old female, widow of one year, complains of depression, with PHQ9=21 History of previous depression, age 51, responded well to paroxetine (Paxil) Patient has AF, anxiety, migaine HA S/p MI, breast cancer Current meds –Tamoxifen –Aspirin –Risperidone –Metoprolol, –Sumatriptan In view of past history, should paroxetine be prescribed?

24 Paroxetine inhibits P450 All SSRIs inhibit platelet function All SSRIs are highly protein-bound All SSRIs have warning about triptans and serotonin syndrome Paroxetine Drug Interactions

25 Tamoxifen –pro drug requires P450 –paroxetine lowers drug levels of active metabolite Risperdal – paroxetine increases blood levels of most psychotropics 2-4 x (eg atomoxetine) –adjust dose of psychotropic Metoprolol –paroxetine may increase blood level (no data) –observe

26 SSRI Drug Interactions SumatriptanSumatriptan –Potential risk of serotonin syndrome - observe Aspirin –concern about increased bleeding; consider PPI

27 PUTATIVE ALTERNATIVES BASED ON CYTOCHROME P450 INTERACTIONS Inter-individual and clinical variability Monitor effects and blood levels when available Consider the antidepressants with relatively lower effect on metabolic enzymes –citalopram (and escitalopram) –sertraline –mirtazapine –venlafaxine (and desvenlafaxine)

28 GENERAL DRUG INTERACTIONS Obtain medication history Be aware that all drugs can affect the action and serum levels of other drugs Monitor the clinical effects and serum levels of all medications Use electronic data base

29 CASE #6 You decide to start antidepressants for a 30-year-old female who has major depression, panic attacks, and significant anxiety. Which medication(s) would you use and how?

30 PREVALENCE OF MAJOR DEPRESSION IN PATIENTS WITH ANXIETY 67% (OCD + MD) 34-70% (SAD + MD) 42% (GAD + MD) 65% (Panic + MD) 48% (PTSD + MD) 42% (phobia +MD) GAD Panic Specific Phobia PTSD SAD OCD Depression Kessler, Arch Gen Psych 1995

31 COMORBID ANXIETY DISORDERS Educate patient: SSRIs have efficacy but increase anxiety in short-term Start with low dose SSRI, titrate slowly Consider adjunctive meds for sleep or ‘escape’ (trazodone/hydroxyzine/benzodiazepine) Consider buspirone for GAD (not panic) Bupropion is not effective for Rx Of anxiety Consider monotherapy –venlafaxine/mirtazapine/paroxetine

32 x x x venlafaxine PDD x Adult and children x x sertraline x x x Adult x paroxetine x fluvoxamine BN PDD x x Adult and children fluoxetine x x escitalopram x citalopram PTSDGADSADOCDPanicDep DEP=major depression; OCD= Obsessive-compulsive disorder; SAD=social anxiety disorder; GAD=generalized anxiety disorder; PTSD=post-traumatic stress disorder; BN=bulemia nervosa; PDD=premenstrual dysphoric disorder 5-HT DRUGS-OTHER APPROVED INDICATIONS x xXxX PDD

33 CASE #6 POINTS TO CONSIDER Many antidepressants approved for the treatment of anxiety disorders may increase anxiety in the short term Use low doses and increase slowly Educate/warn patients Consider use of “escape” medication

34 CASE #7 Two weeks ago, you started a 60-year-old female with diabetes on nortriptyline (e.g. Pamelor) 50 mg h.s. She now complains of lightheadedness when she stands up. What should you do?

35 CASE #7 POINTS TO CONSIDER Dizziness does not = postural BP changes Nortriptyline (NTP) causes the least postural BP change of all the TCAs Starting dose of NTP should be 10-25mg Best predictor of postural BP change with TCA is prior postural BP changes Postural BP changes secondary to TCA do not resolve with time

36 CASE #8 This 46 year old female has had diabetes for 20 years and now has depression and painful peripheral neuropathy. She was tried on amitriptylene which caused severe constipation and sedation. What do you do now for the depression and the pain?

37 CASE #8 POINTS TO CONSIDER Dual action tricyclics (amitriptyline, nortriptyline, imipramine) useful for pain TCA risk of hypotension, gastroparesis Consider duloxetine (has indication for depression and diabetic neuropathy) Consider venlafaxine or desvenlafaxine (dual action)

38 ANTIDEPRESSANTS IN DIABETES Tricyclics –useful for diabetic neuropathy –watch for postural hypotension & gastroparesis –may impair glycemic control SSRIs shown to improve depression/GHb Evidence of efficacy of new dual agents for neuropathic pain

39 CASE #9 This 66 year old male has depression and unstable angina. He had been treated with sertraline several years ago and it didn’t work. Which antidepressant do you choose now?

40 CASE #9 POINTS TO CONSIDER Sertraline is a good choice for post-MI patients because of safety data and probable anti-platelet aggregation activity Review doses used previously (if inadequate doses, repeat trial is reasonable) Other antidepressants studied post-MI include citalopram and mirtazepine

41 ANTIDEPRESSANTS IN CAD / CVD Tricyclics –prolong conduction –cause postural hypotension SADHART ( Glassman et al, JAMA 2002) –Sertraline is safe & effective –Sertraline inhibits platelet aggregation ENRICHD ( Taylor et al, Arch Gen Psychiatry 2005)  –Patients on SSRIs have  death &  repeat MI (OD=.53-.59)

42 TREATMENT RESISTANCE: What To Do When the First Drug Does Not Work

43 CASE #10 A 43 y.o. male 20 mg citalopram for 4 weeks, then 40 mg for 4 weeks PHQ-9 11%

44 QUESTIONS TO ALWAYS ASK Is Depression the right / only diagnosis? Are there psychosocial stressors? Is this treatment failure? If adequate dose If adequate adherence If adequate duration If inadequate response (PHQ-9)

45 OPTIONS Adjust medication –Maximally tolerated dose Change medications –If PHQ-9 does not drop ≥ 5 points after four to six weeks at adequate dose Add medications –If partial response Add psychological counseling –CBT –IPT –PST –Office Counseling Psychological issues Available Willing

46 Case # 10 POINTS TO CONSIDER Patient has experienced change in PHQ9 of > 5 points With partial response, continue increasing dose to maximal dose Increase dose of citalopram to 60 mg

47 CASE #11 A 37 y.o. female escitalopram 10 mg for 4 weeks then escitalopram 20 mg for 8 weeks otherwise healthy PHQ-9 24%38%

48 PRINCIPLES OF COMBINATION ANTIDEPRESSANT TREATMENT Combine mechanisms, not just drugs Pharmacologic synergies may promote efficacy Opposing side-effect profiles may promote tolerability

49 Pre-Synaptic Neurotransmitter Effects Oxman, 2005

50 Possible BP; cost for 1 / day XR Anxiety dx; less P450 37.5 - 75mg 75 - 375 mg Venlafaxine XR Serotonin and Norepinephrine Reuptake Inhibitor Stimulating; cost; Bid unless XL; not for hx of seizures Stimulating; less sex dysfunction 150 mg q. a.m. 300- 450 mg Bupropion SR Norepinephrine and Dopamine Reuptake Inhibitor Sedation at low dose; increased appetite Few interactions; less sex dys; sedation; appetite 7.5 - 15 mg h.s. 15 - 45 mg mirtazapine Serotonin and Norepinephrine Antagonist Dis- Advantages Advantages Starting Dose Dose Range Drug NON-SSRIs

51 TCA Norepinephrine Reuptake Inhibitors Dis- Advantages AdvantagesStarting Dose Dose Range Drug Anti- cholinergic; Not for cardiac disease Less orthostatic BP; generic; blood levels 10 -25 mg 25 - 150 mg nortriptyline Anti- cholinergic; Not for cardiac disease Less sedating, generic 50 mg100 - 300 mg desipramine

52 SIMULTANEOUS ACTIONS NE  2- mirtazapine bupropion venlafaxine SSRI DANE reuptk 5- HT2- 5- HT1 5-HT reuptk activatingsedating at low doses Oxman, 2005

53 AUGMENTATION OPTIONS Lithium (600-800 mg/d) T3 (25-50  g/d) Bupropion Pindolol Buspirone Stimulants (methylphenidate) Anticonvulsants (lamotrigine) Antipsychotics

54 WHEN TO COMBINE OR AUGMENT Partial response (rather than No response) Tolerating current antidepressant Current antidepressant at maximal dose More severe illness –Time urgency –Willingness to take multiple medications

55 DUAL ACTION MEDICATIONS? SSRI’S VS. TCA’S: HEAD TO HEAD (META-ANALYSES) All studies 101(10,496) Inpatients25 (1,377) Outpatients58 (7,834) High HAM-D38 (3,336) Low HAM-D39 (4,045) Serotonergic TCAs48 (5,317) Noradrenergic TCAs53 (5,179) Relative Effect Size N (Patients) Favors TCAs Favors SSRIs P<0.02 P<0.04 -0.40-0.20.2 Anderson IM. Depress Anxiety. 1989;7(suppl 1):11-17.

56 STAR*D Sequenced Treatment Alternatives to Relieve Depression Rush J et al… Summary of studies prepared by Steven Cole, MD

57 Publications 46 publications to date Primary and secondary outcomes Trivedi et al: Am J Psychiatry, January 2006 Rush et al: NEJM, March 2006 Trivedi et al: NEJM, March 2006 Fava et al: Am J Psychiatry, July 2006 Nierenberg et al: Am J Psychiatry, September 2006 McGrath et al: Am J Psychiatry, September 2006

58 Study Design 4000 patients 23 psychiatric settings 18 primary care settings 3 sequenced levels of randomization for non- responders to first level treatment

59 Levels Level One Treatment –Citalopram (up to 60 mg) Level Two Treatment –Switch bupropion SR, venlafaxine ER, sertraline, or CBT –Augment bupropion SR, buspirone, or CBT Level Three Treatment –Switch mirtazapine or nortriptyline –Augment Lithium or T3 (with bupropion SR, sertraline, or venlafaxine XR Level Four Treatment –Switch Tranylcypromine or (mirtazapine + venlafaxine XR)

60 Remission (Ham-D); Response (QIDS) Level One (N=2876; 80% chronic or recurrent depression) citalopram (28%,47%; mean dose = 42 mg.) Level Two (N=727) Switch strategy bupropion SR (21%,26%; mean dose = 283 mg) sertraline (18%,27%; mean dose = 136mg) venlafaxine XR (25%,28%; mean dose = 194; 33% > 225 mg) no significant differences among groups Augmentation (mean dose = 55mg citalopram) buproprion SR (30%,32%; mean dose = 267 mg) buspirone (30%,27%; mean dose = 41 mg) no significant differences between groups on primary outcome measure, but bupropion group had greater reductions in QIDS and lower attrition due to intolerance

61 Remission (HAM-D); Response (QIDS) Level Three (N=235) Switch strategy Mirtazapine (12%,13%; mean dose = 42 mg) Nortriptyline (20%;17%; mean dose = 97 mg) no significant differences between groups Augmentation strategy (with bupropion SR, sertraline, or venlafaxine XR) Li (16% remission; mean dose = 860 mg) T3 (25% remission; mean dose = 45 micrograms) no significant differences between groups on primary outcome measure, but Li was associated with more frequent side-effects and more attrition due to intolerance Level Four (N = 109) Tranylcypromine: (7%,12%; mean dose = 37 mg) Ven + Mir: (12%,24%; mean dose 210 mg/36 mg) no significant differences between groups on primary outcome measure, but (ven + mir) had greater symptom reduction and less attrition due to intolerance


63 CASE #12 A 40-year-old male with good response to paroxetine 20 mg a day for depression and panic disorder reports that he missed several doses and feels extremely anxious, with nausea, and tingling sensations in arms and legs. What do you do next?

64 CASE #12 POINTS TO CONSIDER Discontinuation/withdrawal effects can occur with all antidepressants, but seem more common with shorter half life medications (e.g. paroxetine and venlafaxine)

65 CASE #13 A 40-year-old female is back to baseline functioning after 3 months on desipramine (e.g. Norpramin) 150 mg a day. She has no side effects and has started to decrease the dose because she feels fine. What should you do?

66 CASE #13 POINTS TO CONSIDER Patients who attain remission should remain (continuation phase of treatment) on full active dose of antidepressant medication for at least 6-12 months after they reach remission The end of an episode of depression is not reached until after the continuation phase of treatment is complete

67 THREE PHASES OF TREATMENT Time Symptom Severity Normal Acute Phase (3 months+) Continuation Phase (4-9 months) Maintenance Phase (years) Response Remission Relapse Recurrence > 50% STOP Rx 65 to 70% STOP Rx Recovery Oxman, 2001

68 RISK FACTORS FOR RECURRENCE & THUS MAINTENANCE RX Maintain dose 6-12 months after remission Chance of relapse –50% if 1 prior episode –75% if 2 prior episodes –90% if 3 prior episodes Dysthymia Severe episode with suicidality Patient may need lifetime therapy Maintenance should be full dose

69 CASE #14 An 80 year old male regained full functioning after taking citalopram (Celexa) 20mg each morning. After 6 months, he is complaining of insomnia and depressive feelings again. What do you do now?

70 CASE #14 POINTS TO CONSIDER “poop-out” or tachyphylaxis is now a well- recognized, but little studied phenomenon thought to occur more commonly with the SSRIs than other antidepressant medications “poop-out” seems to respond well to a one-time increase in dosage (or augmentation/switch of medication if already at maximum dose)

71 RESIDUAL SYMPTOMS IN MAJOR DEPRESSION PREDISPOSE TO…. Greater risk of relapse Continued psychosocial limitations Continued impairments at work Worsens prognosis of Axis III disorders Increased utilization of medical services Sustained elevation of suicide and substance abuse risks Thase. J Clin Psych. 1999. Hirschfeld et al. JAMA. 1997.


73 Use T.A.C.C.T. T ell – provide basic information about illness T ell – provide basic information about illness A sk – about concerns/beliefs A sk – about concerns/beliefs (cognitive/emotional) (cognitive/emotional) C are – develop rapport; respond to emotions C are – develop rapport; respond to emotions C ounsel – provide information relevant to concerns and explanatory model C ounsel – provide information relevant to concerns and explanatory model T ailor – develop plan collaboratively T ailor – develop plan collaboratively

74 “C are” Reflection: Reflection: –“I can see you’re upset about this diagnosis.” Legitimation (validation): Legitimation (validation): – “I can understand why this would be upsetting… –“You came in with stomach pain and come out with a diagnosis about depression…that’s upsetting” –“Many of my patients feel the same way...”

75 C are (con’t) Support: Support: –“I want to do what I can…” Partnership: Partnership: –“Together, we…” Respect: Respect: –“I am really impressed by how well you are coping under the circumstances...”

76 UB-PAP Ultra-Brief Personal Action Planning Three question framework: 1. “Is there anything you would like to do for your health before we talk again?” (what, when, where, how often?) (Ask patient to restate plan.) 2. “We all have trouble meeting our goals, what is your level of confidence you will be able to carry out this plan?” (if <7, help patient problem-solve) 3. “When would you like to come back to discuss how the plan has gone?” Cole, unpublished document, 2005

77 OFFICE COUNSELING: USE “BATHE” B Background: “What is going on …” A Affect: “How do you feel about…” T Trouble: “What’s troubling you …” H Handling: “How are you handling..” E Empathy: “That must be difficult...” Stuart M, Lieberman J: The Fifteen-Minute Hour, 2002

78 OFFICE COUNSELING: USE “SPEAK” S schedule regular activities P plan pleasant events E exercise A assertiveness K kind thoughts about yourself Cole S, Christensen J. Depression. In Behavioral Medicine in Primary Care, 2008

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