Case Studies in Depression Care: Treatment Non-Response, Medication Side-Effects and Office Counseling* PHARMACOTHERAPY. Initial Acute Phase Treatment

Transcription

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 Oman, MD Professor of Psychiatry Dartmouth School of Medicine PHARMACOTHERAPY Effective Major depression Dysthymia (chronic depression) Possibly effective Minor depression 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 1

2 CHOOSING AGENTS:GENERIC SSRIs Citalopram (Celea)/sertraline (Zoloft) effective for aniety ( in short term) may need to increase dose (60 mg/200 mg) for efficacy low-moderate drug interactions Fluoetine (Prozac) long half-life P450 inhibition at low doses effective for aniety (but aniety in short term) Possible insomnia (short term) Paroetine (Pail) possibly sedating effective for aniety possible weight gain P450 inhibition at low doses more frequent withdrawal symptoms measurable anti-cholinergic activity 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 seual side-effects once day dosing available (XL) Mirtazapine (Remeron) frequent appetite / weight gain very sedating at low dose few drug interactions Sol-tabs available CASE #1 A 40-year-old male reports a little (but not marked) improvement after 2 weeks on escitalopram (Leapro) 10 mg a day. What do you do net? 2

3 CASE #1 POINTS TO CONSIDER Usually takes 3-4 weeks to attain maimal clinical effects from one dosage of an antidepressant Probably because of prolonged time needed to effect receptor architecture or function SYNAPSE Post-Synaptic Signal Transduction Effects 5-HT 1C, 2 5-HT 4 5-HT 1A,1D 5-HT 3 G s G i Gq Ion Channel Adenyl Cylcase Phospholipase C CYTOPLASM camp Protein kinase A DAG Protein kinase C IP 3 Oman, 2005 NUCLEUS Ca 2+ calmodulindependent kinase neurogenesis TIME COURSE OF BIOLOGICAL CHANGES WITH ANTIDEPRESSANTS Hours Days Days Weeks Months Years Synaptic Signaling Receptor/ Transporter Regulation Intracellular Signaling & Posttranslational Modification Gene Neuroplasticity/ Epression Neurogenesis Oman,

4 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. 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? 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 eperience a 50% or greater response) are at greater risk for relapse and continued functional impairment 4

5 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 SIDE EFFECTS, DRUG INTERACTIONS, AND COMORBIDITIES CASE #3 A 30-year-old female complains of anorgasmia on citalopram (Celea) 40 mg/day What should you do and when? 5

6 CASE #3 POINTS TO CONSIDER Seual 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 seual problems Consider lower dose, switch medications, add bupropion (limited, inconsistent data) CASE #4 After three days of treatment, this 30 yearold female on fluoetine (Prozac) 20mg a day complains of agitation and insomnia. What do you do? CASE #4 POINTS TO CONSIDER Fluoetine (and other SSRIs) often cause increased aniety 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 aniety Consider prescribing escape medicine 6

7 SIDE EFFECTS (SSRIs) Agitation/insomnia GI distress Seual dysfunction SIDE EFFECTS (OTHER NEW AGENTS) bupropion - agitation; seizure risk duloetine - nausea (up to 40%) mirtazapine - sedation; weight gain venlafaine - SSRI effects; 1-3% BP 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 7

8 MANAGING SIDE EFFECTS (con t) Insomnia/agitation Use adjunctive sedating agent Switch to mirtazapine Seual dysfunction Switch to bupropion, mirtazapine Consider bupropion, sildenafil, yohimbine, cyproheptadine 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 paroetine (Pail) Patient has AF, aniety, migaine HA S/p MI, breast cancer Current meds Tamoifen Aspirin Risperidone Metoprolol, Sumatriptan In view of past history, should paroetine be prescribed? Paroetine Drug Interactions Paroetine inhibits P450 All SSRIs inhibit platelet function All SSRIs are highly protein-bound All SSRIs have warning about triptans and serotonin syndrome 8

9 Paroetine Drug Interactions Tamoifen pro drug requires P450 paroetine lowers drug levels of active metabolite Risperdal paroetine increases blood levels of most psychotropics 2-4 (eg atomoetine) adjust dose of psychotropic Metoprolol paroetine may increase blood level (no data) observe SSRI Drug Interactions Sumatriptan Potential risk of serotonin syndrome - observe Aspirin concern about increased bleeding; consider PPI 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 venlafaine (and desvenlafaine) 9

10 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 CASE #6 You decide to start antidepressants for a 30-year-old female who has major depression, panic attacks, and significant aniety. Which medication(s) would you use and how? PREVALENCE OF MAJOR DEPRESSION IN PATIENTS WITH ANXIETY 65% (Panic + MD) 42% (phobia +MD) Specific Phobia Panic PTSD 48% (PTSD + MD) 42% (GAD + MD) GAD Depression OCD SAD 34-70% (SAD + MD) Kessler, Arch Gen Psych % (OCD + MD) 10

11 COMORBID ANXIETY DISORDERS Educate patient: SSRIs have efficacy but increase aniety in short-term Start with low dose SSRI, titrate slowly Consider adjunctive meds for sleep or escape (trazodone/hydroyzine/benzodiazepine) Consider buspirone for GAD (not panic) Bupropion is not effective for R Of aniety Consider monotherapy venlafaine/mirtazapine/paroetine 5-HT DRUGS-OTHER APPROVED INDICATIONS citalopram escitalopram fluoetine fluvoamine paroetine sertraline venlafaine Dep Adult and children Adult Panic OCD Adult Adult and children SAD GAD X PTSD BN PDD PDD DEP=major depression; OCD= Obsessive-compulsive disorder; SAD=social aniety disorder; GAD=generalized aniety disorder; PTSD=post-traumatic stress disorder; BN=bulemia nervosa; PDD=premenstrual dysphoric disorder PDD CASE #6 POINTS TO CONSIDER Many antidepressants approved for the treatment of aniety disorders may increase aniety in the short term Use low doses and increase slowly Educate/warn patients Consider use of escape medication 11

12 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? 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 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? 12

13 CASE #8 POINTS TO CONSIDER Dual action tricyclics (amitriptyline, nortriptyline, imipramine) useful for pain TCA risk of hypotension, gastroparesis Consider duloetine (has indication for depression and diabetic neuropathy) Consider venlafaine or desvenlafaine (dual action) 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 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? 13

14 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 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= ) TREATMENT RESISTANCE: What To Do When the First Drug Does Not Work 14

15 CASE #10 A 43 y.o. male PHQ-9 11% 20 mg citalopram for 4 weeks, then 40 mg for 4 weeks Baseline 4 Weeks 8 Weeks 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) OPTIONS Adjust medication Maimally tolerated dose Change medications If PHQ-9 does not drop 5 points after four to si weeks at adequate dose Add medications If partial response Add psychological counseling CBT IPT PST Office Counseling Psychological issues Available Willing 15

16 Case # 10 POINTS TO CONSIDER Patient has eperienced change in PHQ9 of > 5 points With partial response, continue increasing dose to maimal dose Increase dose of citalopram to 60 mg 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% 0 Baseline 4 Wks 12 Wks PRINCIPLES OF COMBINATION ANTIDEPRESSANT TREATMENT Combine mechanisms, not just drugs Pharmacologic synergies may promote efficacy Opposing side-effect profiles may promote tolerability 16

17 Pre-Synaptic Neurotransmitter Effects Oman, 2005 Drug Bupropion SR Venlafaine XR Dose Range Serotonin and Norepinephrine Antagonist mg Few interactions; less Sedation at low mirtazapine mg h.s. se dys; dose; increased sedation; appetite appetite Norepinephrine and Dopamine Reuptake Inhibitor mg Serotonin and Norepinephrine Reuptake Inhibitor mg NON-SSRIs Starting Dose 150 mg q. a.m mg Advantages Stimulating; less se dysfunction Aniety d; less P450 Dis- Advantages Stimulating; cost; Bid unless XL; not for h of seizures Possible BP; cost for 1 / day XR Drug Dose Range Starting Dose Advantages Dis- Advantages desipramine nortriptyline TCA Norepinephrine Reuptake Inhibitors mg mg 50 mg mg Less sedating, generic Less orthostatic BP; generic; blood levels Anticholinergic; Not for cardiac disease Anticholinergic; Not for cardiac disease 17

18 SIMULTANEOUS ACTIONS 5-HT reuptk 5- HT1 5- HT2- NE reuptk NE α2- DA SSRI venlafaine bupropion mirtazapine activating sedating at low doses Oman, 2005 AUGMENTATION OPTIONS Lithium ( mg/d) T3 (25-50 µg/d) Bupropion Pindolol Buspirone Stimulants (methylphenidate) Anticonvulsants (lamotrigine) Antipsychotics WHEN TO COMBINE OR AUGMENT Partial response (rather than No response) Tolerating current antidepressant Current antidepressant at maimal dose More severe illness Time urgency Willingness to take multiple medications 18

19 DUAL ACTION MEDICATIONS? SSRI S VS. TCA S: HEAD TO HEAD (META-ANALYSES) All studies 101(10,496) Relative Effect Size N (Patients) Favors TCAs Favors SSRIs Inpatients 25 (1,377) Outpatients 58 (7,834) P<0.02 High HAM-D 38 (3,336) Low HAM-D 39 (4,045) Serotonergic TCAs 48 (5,317) Noradrenergic TCAs 53 (5,179) P<0.04 Anderson IM. Depress Aniety ;7(suppl 1): STAR*D Sequenced Treatment Alternatives to Relieve Depression Rush J et al Summary of studies prepared by Steven Cole, MD 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

20 Study Design 4000 patients 23 psychiatric settings 18 primary care settings 3 sequenced levels of randomization for nonresponders to first level treatment Level One Treatment Citalopram (up to 60 mg) Levels Level Two Treatment Switch bupropion SR, venlafaine 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 venlafaine XR Level Four Treatment Switch Tranylcypromine or (mirtazapine + venlafaine XR) 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) venlafaine 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 20

21 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 venlafaine 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 CONTINUATION & MAINTENANCE PHASE TREATMENT CASE #12 A 40-year-old male with good response to paroetine 20 mg a day for depression and panic disorder reports that he missed several doses and feels etremely anious, with nausea, and tingling sensations in arms and legs. What do you do net? 21

22 CASE #12 POINTS TO CONSIDER Discontinuation/withdrawal effects can occur with all antidepressants, but seem more common with shorter half life medications (e.g. paroetine and venlafaine) 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? 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 22

23 THREE PHASES OF TREATMENT Normal Remission Recovery Response > 50% STOP R Relapse Relapse 65 to 70% STOP R Recurrence Acute Continuation Phase (3 months+) Phase (4-9 months) Time Maintenance Phase (years) Oman, 2001 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 CASE #14 An 80 year old male regained full functioning after taking citalopram (Celea) 20mg each morning. After 6 months, he is complaining of insomnia and depressive feelings again. What do you do now? 23

24 CASE #14 POINTS TO CONSIDER poop-out or tachyphylais is now a wellrecognized, 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 maimum dose) RESIDUAL SYMPTOMS IN MAJOR DEPRESSION PREDISPOSE TO. Greater risk of relapse Continued psychosocial limitations Continued impairments at work Worsens prognosis of Ais III disorders Increased utilization of medical services Sustained elevation of suicide and substance abuse risks Thase. J Clin Psych Hirschfeld et al. JAMA OFFICE COUNSELING Use TACCT SELF-MANAGEMENT SUPPORT UB-PAP (ultra-brief personal action planning) OFFICE PSYCHOTHERAPY BATHE SPEAK 24

25 Use T.A.C.C.T. T ell provide basic information about illness A sk about concerns/beliefs (cognitive/emotional) C are develop rapport; respond to emotions C ounsel provide information relevant to concerns and eplanatory model T ailor develop plan collaboratively Reflection: C are Reflection: I can see you re upset about this diagnosis. 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... Support: C are (con t) Support: I want to do what I can Partnership: Together, we Partnership: Respect: I am really impressed by how well you are coping under the circumstances... 25

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