Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling *

1. Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling* Steven Cole, MDProfessor 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 www.ahrq.gov; www.depression-primarycare.org; APA

4. CHOOSING AGENTS:GENERIC SSRIs • Citalopram(Celexa)/sertraline (Zoloft) • 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 anxiety (but  anxiety in short term) • 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. TIME COURSE OF BIOLOGICAL CHANGES WITH ANTIDEPRESSANTS Hours Days Days Weeks Months Years Neuroplasticity/ Neurogenesis Synaptic Signaling Receptor/ Transporter Regulation Intracellular Signaling & Posttranslational Modification Gene Expression 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

14. SIDE EFFECTS, DRUG INTERACTIONS, ANDCOMORBIDITIES

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

25. Paroxetine Drug Interactions • 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 • Sumatriptan • 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 65% (Panic + MD) 48% (PTSD + MD) Panic Specific Phobia 42% (phobia +MD) PTSD SAD 42% (GAD + MD) GAD Depression 34-70% (SAD + MD) OCD 67% (OCD + MD) 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. Dep Panic OCD SAD GAD PTSD citalopram x escitalopram x x fluoxetine Adult and children x x BN PDD fluvoxamine x paroxetine Adult x Adult x x x sertraline x x Adult and children x PDD venlafaxine x x x 5-HT DRUGS-OTHER APPROVED INDICATIONS xX PDD x 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

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 PHQ-9 • A 43 y.o. male • 20 mg citalopram for 4 weeks, then 40 mg for 4 weeks 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 PHQ-9 • A 37 y.o. female • escitalopram 10 mg for 4 weeks • then escitalopram 20 mg for 8 weeks • otherwise healthy 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. Drug Dose Range Starting Dose Advantages Dis-Advantages Serotonin and Norepinephrine Antagonist mirtazapine 15 - 45 mg 7.5 - 15 mg h.s. Few interactions; less sex dys; sedation; appetite Sedation at low dose; increased appetite Norepinephrine and Dopamine Reuptake Inhibitor Bupropion SR 300- 450 mg 150 mg q. a.m. Stimulating; less sex dysfunction Stimulating; cost; Bid unless XL; not for hx of seizures Serotonin and Norepinephrine Reuptake Inhibitor Venlafaxine XR 75 - 375 mg 37.5 - 75mg Anxiety dx; less P450 Possible BP; cost for 1 / day XR NON-SSRIs