1. Real-World Pharmacologic Treatment of Depression B. Anthony Lindsey, MD Professor and Vice Chair UNC Department of Psychiatry

2. Antidepressants - History  1958Monoamine oxidase inhibitors (MAOIs)  1958 Tricyclics (TCA’s)  1982Trazodone (Deseryl)  1988Fluoxetine (Prozac)  1989Bupropion (Wellbutrin)  1994Nefazodone (Serzone)  1994Venlafaxine (Effexor)  1996 Mirtazapine (Remeron)

3. Treatment Response Categories STATE OBJECTIVE CRITERION CLINICAL STATUS PREVALENCE IN RCTS Remission HAM-D ≤ 7 No residual psychopathology ~ 40% Response ≥ 50% decrease in HAM-D without remission Substantially improved, but with residual sxs ~ 25% Partial response 25%-50% decrease in HAM-D Mild-moderate improvement ~ 10% Nonresponse < 25% decrease in HAM-D No clinically meaningful response ~ 25%

4. Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE): comparing patients with unipolar major depressive disorder who recovered from intake MDE with residual subsyndromal depressive symptoms vs. asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96; P<0.0001. Send feedback to ScienceDirect Software and compilation © 2001 ScienceDirect. All rights reserved. ScienceDirect® is an Elsevier Science B.V. registered trademark.feedback

5. Why Is Achieving Remission Important? Residual symptoms put patients at high risk of relapse and recurrence Residual symptoms put patients at high risk of relapse and recurrence –Patients with residual symptoms after medication treatment are 3.5 times more likely to relapse compared to those fully recovered (Judd et al, 1998) –This risk is greater than the risk associated with having ≥ 3 prior depressive episodes –Similar finding exists after response to cognitive therapy

6. What is the course of antidepressant response?

7. Why a temporal delay for maximal therapeutic benefit   -adrenergic receptor down- regulation  5-HT 2 receptor down-regulation

8. Antidepressant medications have essentially equivalent efficacy

9. Tricyclic Antidepressants (TCAs)  Characteristic three-ring nucleus  Clinical effects  Normalization of mood and resolution of neurovegetative symptoms  Biochemical effects  Inhibit monoamine uptake at nerve terminals  May potentiate action of drugs that cause neurotransmitter release  Temporal delay of weeks for clinical effects, although biochemical effects are immediate

10. Mechanism of action of TCAs “Tertiary” TCAs  Inhibit 5-HT uptake imipramine(weaker inhibition of NE uptake) amitriptyline clomipramine “Secondary” TCAs  Inhibit NE uptake desipramine (weaker inhibition of 5-HT uptake) nortriptyline

11. TCA Metabolism N CH 3 H 3 C N N CH 3 H 3 C N N CH 3 H N CH 3 H nortriptyline imipramine amitriptyline desipramine tertiary aminessecondary amines

12. In vivo action of TCAs If one administers a tertiary TCA  there is always both the tertiary and the secondary amine in the circulation If one administers a secondary TCA  there is only the secondary amine in the circulation.

13. Neuropharmacology of TCAs  Inhibit monoamine uptake (NE and 5- HT)  Muscarinic cholinergic antagonism  H 1 histamine antagonism   1 -adrenergic antagonism

14. Tricyclics- Contraindications QTc greater than 450 msec QTc greater than 450 msec Conditions worsened by muscarinic blockade (eg myasthenia gravis, BPH) Conditions worsened by muscarinic blockade (eg myasthenia gravis, BPH) pre-existing orthostatic hypotension pre-existing orthostatic hypotension Seizure disorder Seizure disorder

15. Side effect profile of TCAs  Dry mouth  Constipation  Dizziness  Tachycardia  Urinary retention  Impaired sexual funtion  Orthostatic hypotension

16. Low therapeutic index of TCAs  Cardiotoxicity: resulting from combination of:  Conduction defects, arrhythmias  Delirium Potentiation of effects of other sedating drugs Potentiation of effects of other sedating drugs  Consequences  suicide  requires care in prescribing  monitoring drugs that might have synergistic effects on monoamine function

17. Monoamine Oxidase Inhibitors (MAOIs)  Irreversibly inhibit monoamine oxidase enzymes  Effective for major depression, panic disorder, social phobia  Drug interactions and dietary restrictions limit use

18. Biochemistry of MAO  Occurs as two isoenzymes  MAO-A – Oxidizes norepinephrine, serotonin, tyramine Oxidizes norepinephrine, serotonin, tyramine  MAO-B selective for dopamine metabolism selective for dopamine metabolism

19. Dietary and Drug Interactions  Increased stores of catecholamines sensitize patients to effects of sympathomimetics  Accumulation of tyramine (sympathomimetic) = high risk of hypertensive reactions to dietary tyramine  requires dietary restrictions  Interactions with other sympathomimetic drugs  Antidepressants  OTC cold remedies phenylpropanolamine phenylpropanolamine  Meperidine  L-dopa

20. Examples of MAOIs  Irreversible, non-selective MAOIs  phenelzine  isocarboxazid  tranylcypromine  Selective MAO-B inhibitors  deprenyl (selegiline)  loses its specificity for MAO-B in antidepressant doses  Reversible monoamine oxidase inhibitors (RIMAs)  Moclobemide – not approved  Appears to be relatively free of food/drug interactions

21. Transdermal Selegiline (Emsam) Potentially effective antidepressant- effect size less than most other antidepressants Potentially effective antidepressant- effect size less than most other antidepressants Dietary restrictions are unnecessary at the 6 mg dose but probably required at the 9 and 12 mg doses Dietary restrictions are unnecessary at the 6 mg dose but probably required at the 9 and 12 mg doses Drug interactions are still a major issue Drug interactions are still a major issue VERY costly- ~$500/month VERY costly- ~$500/month

22. Serotonin syndrome  Evoked by interaction between serotonergic agents  e.g., SSRIs and MAOIs  Combination of increased stores plus inhibition of reuptake after release  Symptoms  Hyperthermia  Muscle rigidity  Myoclonus  Rapid changes in mental status and vital signs  Can be lethal

23. Selective Serotonin Uptake Inhibitors (SSRIs)  Currently marketed medications  fluoxetine (Prozac).  sertraline (Zoloft).  paroxetine (Paxil)  fluvoxamine (Luvox)  citalopram (Celexa)  escitalopram (Lexapro)  Selectively inhibit 5-HT (not NE) uptake  Differ from TCAs by having little affinity for muscarinic, as well as many other neuroreceptors

24. Selective Serotonin Reuptake Inhibitors (SSRIs)  Much higher therapeutic index than TCAs or MAO-I’s  Much better tolerated in early therapy  Equal or almost equal in efficacy to TCAs

25. Side effects associated with SSRIs  Nausea  Sexual dysfunction  Delayed ejaculation/anorgasmia  Anxiety  Insomnia  Hyponatremia

26. Selective Norepinephrine- Serotonin Reuptake Inhibitors  Venlafaxine (Effexor), Duloxetine (Cymbalta), Desvenlafaxine(Pristiq) :  relatively devoid of antihistaminergic, anticholinergic, and antiadrenergic properties  nonselective inhibitor of both NE and 5- HT uptake. Adverse effects: GI, Sexual dysfunction, hypertension (venlafaxine, desvenlafaxine), hyponatremia Adverse effects: GI, Sexual dysfunction, hypertension (venlafaxine, desvenlafaxine), hyponatremia

27. Other antidepressants  Trazodone  mixed 5-HT agonist/antagonist  1 antagonist  1 antagonist H 1 antagonist H 1 antagonist  Nefazodone (Serzone)  5 HT 2 antagonist  Bupropion (Wellbutrin; Zyban)  Inhibits uptake of DA and NE  antismoking properties probably involves parent molecule  Lacks sexual side effects  Seizure risk

28.  Mirtazapine (Remeron)   2 antagonist  5H 2 and 5HT 3 antagonist  Net effect selective increase in 5HT 1A function  H 1 antagonist advantages: sedation, no adverse sexual effects advantages: sedation, no adverse sexual effects

29. Antidepressants and drug interactions  Pharmacodynamic –Additive effects with alcohol and other sedating drugs –MAOI interactions  Pharmakokinetic –Cytochrome P450-2D6 inhibition Fluoxetine and paroxetine Fluoxetine and paroxetine Increased levels of TCAs, antipsychotics, warfarin Increased levels of TCAs, antipsychotics, warfarin –Cytochrome P450-3A4 inhibition Nefazodone and fluvoxamine Nefazodone and fluvoxamine Increased levels of terfenadine, astemizole, cisapride – can cause fatal arrhythmias Increased levels of terfenadine, astemizole, cisapride – can cause fatal arrhythmias

30. Other uses for antidepressants  Panic Disorder  Obsessive Compulsive Disorder  Only the ADs that inhibit serotonin reuptake  Social Phobia  Post Traumatic Stress Disorder  Premenstrual Dysphoric Disorder  Chronic pain syndromes

31. When Do You Characterize a Response As Treatment Resistant? After a patient has been on an antidepressant at for a reasonable amount of time at an adequate dose After a patient has been on an antidepressant at for a reasonable amount of time at an adequate dose No commonly accepted time point No commonly accepted time point –Most drug trial data comes from 8 week long studies –If no onset of response by weeks 4 or 6, there is a 73- 88% chance of not having onset of response by end of 8 wk trial (Nierenberg et al, 2000), so 4 weeks is a reasonable point to increase dose –An 8-12 week course is consistent with acute treatment framework and allows patients 8 weeks at a dose expected to produce response

32. A Working Definition of Treatment Resistant Depression 6-8 weeks of at least a middle range dose without remission

33. What Are the Clinical Features Associated With TRD? Incorrect primary diagnosis Incorrect primary diagnosis –Is there a secondary cause of the depressive symptoms (e.g., substance-induced mood disorder from prescription meds or ethanol, hypothyroidism, hypercalcemia ) –Is their primary psychiatric diagnosis wrong (?bipolar, schizoaffective, cluster B personality DO)? –Is there an unrecognized depressive subtype? Psychotic depression Psychotic depression

34. What Are the Clinical Features Associated With TRD? Patient factors Patient factors -acceptance of diagnosis -acceptance of diagnosis -compliance -compliance Physician factors Physician factors-Underdosing -Inadequate length of treatment

35. Electroconvulsive Therapy Electroconvulsive Therapy –Response rate in patients with inadequate medication trials: 86% inadequate medication trials: 86% adequate trials: 50% adequate trials: 50% –Probably treatment of choice for catatonic states

36. STARD http://www. star-d.org

37. STAR-D Level 1 Level 1 –Initial Treatment: Citalopram Level 2 Level 2 –Switch To: bupropion bupropion sertraline sertraline Venlafaxine Venlafaxine –Augment With: bupropion bupropion buspirone buspirone

38. Level 3 Level 3 –Switch To: mirtazapine or nortriptyline mirtazapine or nortriptyline –Augment With: Lithium or T3 Lithium or T3 Level 4 Level 4 –Switch To: Tranylcypromine or mirtazapine combined with venlafaxine Tranylcypromine or mirtazapine combined with venlafaxine

39. How Effective is an SSRI in Real World Practice? ~1/3 met criteria for remission (HAM-D ≤ 7) ~1/3 met criteria for remission (HAM-D ≤ 7) ~ 1/2 met criteria for response (≥ 50% decrease in depressive severity) ~ 1/2 met criteria for response (≥ 50% decrease in depressive severity) (Trivedi et al, Am J Psychiatry, 2006)

40. Treatment Outcomes (% Remission) (L-2 Switch) Rush et al., N Engl J Med 2006;354(12):1231-42

41. Treatment Outcomes (% Remission) (L-2 Augmentation) (n=279)(n=286) Trivedi et al., N Engl J Med 2006;354(12):1243-52

42. Remission Rates Through Levels 1 and 2

43. TREATMENT OUTCOMES L-3 Switch Remission (HAM- D) Remission (HAM- D) mirtazapine 12.3% mirtazapine 12.3% nortriptyline 19.8% nortriptyline 19.8%

44. TREATMENT OUTCOMES L-3 Augmentation Remission (HAM-D) Remission (HAM-D) Lithium 15.9% Lithium 15.9% T3 24.7% T3 24.7%

45. TREATMENT OUTCOMES L-4 Switch Remission (HAM-D) Remission (HAM-D) Tranylcypromine 6.9% Tranylcypromine 6.9% mirtazapine + venlafaxine 13.7% mirtazapine + venlafaxine 13.7%

46. STAR*D SUMMARY Patients suffering from major depression (primarily with chronic disease and multiple recurrences) in Primary and Specialty Care settings have a 30% chance of achieving full remission with an adequate dose of citalopram Patients suffering from major depression (primarily with chronic disease and multiple recurrences) in Primary and Specialty Care settings have a 30% chance of achieving full remission with an adequate dose of citalopram

47. STAR*D SUMMARY Patients who did not remit with citalopram had a 1 in 4 chance of achieving remission by switching to bupropion, sertraline or venlafaxine and a 1 in 3 chance of responding to augmentation of the citalopram with bupropion or buspirone Patients who did not remit with citalopram had a 1 in 4 chance of achieving remission by switching to bupropion, sertraline or venlafaxine and a 1 in 3 chance of responding to augmentation of the citalopram with bupropion or buspirone There was no clear advantage in switching antidepressant class There was no clear advantage in switching antidepressant class

48. STAR*D SUMMARY Depressed patients who fail to respond to two antidepressant trials are have a 12-20% remission rate with another single antidepressant agent and a 16- 25% remission rate with T3 or lithium augmentation Depressed patients who fail to respond to two antidepressant trials are have a 12-20% remission rate with another single antidepressant agent and a 16- 25% remission rate with T3 or lithium augmentation

49. STAR*D SUMMARY While there is indisputable evidence for real world effectiveness of available antidepressant medications, many patients do not achieve remission. While there is indisputable evidence for real world effectiveness of available antidepressant medications, many patients do not achieve remission. There is a pressing need to develop more effective treatments for depression and also to elucidate factors that may help us choose from our currently available treatments. There is a pressing need to develop more effective treatments for depression and also to elucidate factors that may help us choose from our currently available treatments.

50. References Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. Mar 23 2006;354(12):1231-1242. Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression. N Engl J Med. Mar 23 2006;354(12):1231-1242. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. Mar 23 2006;354(12):1243-1252. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. Mar 23 2006;354(12):1243-1252. Fava M, Rush AJ, Wisniewski SR, et al. A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report. Am J Psychiatry 2006; 163:1161-1172. Fava M, Rush AJ, Wisniewski SR, et al. A Comparison of Mirtazapine and Nortriptyline Following Two Consecutive Failed Medication Treatments for Depressed Outpatients: A STAR*D Report. Am J Psychiatry 2006; 163:1161-1172. Nierenberg AA, Fava M, Trivedi MH, et al. A Comparison of Lithium and T3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report. Am J Psychiatry 2006; 163:1519-1530. Nierenberg AA, Fava M, Trivedi MH, et al. A Comparison of Lithium and T3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report. Am J Psychiatry 2006; 163:1519-1530. www.ids-qids.org www.ids-qids.org