Depression in Medicine

1. 1 Depression in Medicine David Schilling, M.D. August 2, 2007

2. 2 * Major Teaching Points of this Lecture Remind you that depression is common in your patients. Convince you that depression is an important issue for your patients. Enable you to diagnose depressive disorders accurately according to the DSM-IV criteria. Give antidepressants adequate time to work.

3. 3 “Iceberg” Phenomenon "Iceberg" Phenomenon The overwhelming majority of patients with depressive disorders are seen by primary care physicians (Watts, 1966). In some countries, specialists treat less than 5% of all patients with depressive disorders (Madianos & Stefanis, 1992). WPA/PTD Educational Program on Depressive Disorders "Iceberg" Phenomenon The overwhelming majority of patients with depressive disorders are seen by primary care physicians (Watts, 1966). In some countries, specialists treat less than 5% of all patients with depressive disorders (Madianos & Stefanis, 1992). WPA/PTD Educational Program on Depressive Disorders

4. 4 Prevalence Of Major Depression

5. 5 RATES OF MAJOR DEPRESSION Point prevalence 4–5% Women 5–6% Men 3% 1 year prevalence 11.3% Lifetime incidence Women 20% Men 10%

6. 6 Prevalence of Depressive Disorders in Various Patient Populations* Results of various studies demonstrate that depressive disorders occur in up to 33% of hospitalized patients (Katon & Sullivan, 1990). This slide shows the prevalence of depression in several categories of patients studied, including geriatric patients (Magni et al, 1986) and those with cancer (Bukberg et al, 1984), stroke (Robinson et al, 1983), myocardial infarction (MI) during the days immediately following the event and 3 to 4 months later (Schleifer et al, 1989), and Parkinson's disease (Mayeux et al, 1984). WPA/PTD Educational Program on Depressive DisordersResults of various studies demonstrate that depressive disorders occur in up to 33% of hospitalized patients (Katon & Sullivan, 1990). This slide shows the prevalence of depression in several categories of patients studied, including geriatric patients (Magni et al, 1986) and those with cancer (Bukberg et al, 1984), stroke (Robinson et al, 1983), myocardial infarction (MI) during the days immediately following the event and 3 to 4 months later (Schleifer et al, 1989), and Parkinson's disease (Mayeux et al, 1984). WPA/PTD Educational Program on Depressive Disorders

7. 7 Major Depression Prevalence:Chronic Medical Illness Heart disease 15 to 23% Diabetes 11 to 12% Chronic obstructive pulmonary disease (COPD) 10 to 20%

8. 8 RISK FACTORS FOR MAJOR DEPRESSION

9. 9 Depression Prevalence Is Especially High in Neurological Illness Lifetime prevalence Parkinson’s disease: 40-50% lifetime prevalence Huntington’s disease: 40% lifetime prevalence. Depression may antedate chorea by years Multiple sclerosis: 10-50% lifetime prevalence Alzheimer’s disease: 15-55% prevalence CVAs: 30-50% lifetime prevalence

10. 10 * MAJOR DEPRESSIVE EPISODE Depressed mood or anhedonia — either 1. or 2. below At least 5 of the following 1. Depressed mood most of the day nearly every day 2. Decreased interest or pleasure most of the day/every day 3. Insomnia* or hypersomnia 4. Anorexia or hyperphagia or 5% weight gain/loss in month 5. Psychomotor agitation or retardation 6. Fatigue* 7. Decreased concentration* or thinking, indecisiveness 8. Negative thinking — worthlessness, inappropriate guilt 9. Recurring thoughts of death or suicide Not organically caused Not uncomplicated bereavement

11. 11 MAJOR DEPRESSIVE DISORDERCommon Presenting Complaint in Medical Settings Anxiety: >50% will have depression Insomnia* Fatigue* Chronic pain e.g., tension headaches, back pain, etc. Somatization e.g., increase in all “medical” complaints Cognitive impairment* in elderly (pseudodementia)

12. 12 “Not Organically Caused” DDx of Depression The differential diagnosis of depression includes substance abuse, schizophrenia, anemia, hyper- and hypothyroidism, cancer, medications, chronic illnesses, trauma, and CNS disease. The majority of these conditions feature depressive symptoms such as mood changes, apathy, and loss of energy. Usually these conditions can be ruled out by medical history, blood and urine screens, or imaging studies. The differential diagnosis of depression includes substance abuse, schizophrenia, anemia, hyper- and hypothyroidism, cancer, medications, chronic illnesses, trauma, and CNS disease. The majority of these conditions feature depressive symptoms such as mood changes, apathy, and loss of energy. Usually these conditions can be ruled out by medical history, blood and urine screens, or imaging studies.

13. 13 “Not Organically Caused” DDx of Depression The differential diagnosis of depression includes substance abuse, schizophrenia, anemia, hyper- and hypothyroidism, cancer, medications, chronic illnesses, trauma, and CNS disease. The majority of these condition feature depressive symptoms such as mood changes, apathy, and loss of energy. Usually these conditions can be ruled out by medical history,blood and urine screens, or imaging studies. The differential diagnosis of depression includes substance abuse, schizophrenia, anemia, hyper- and hypothyroidism, cancer, medications, chronic illnesses, trauma, and CNS disease. The majority of these condition feature depressive symptoms such as mood changes, apathy, and loss of energy. Usually these conditions can be ruled out by medical history,blood and urine screens, or imaging studies.

14. 14 SUBSTANCE INDUCED DEPRESSIONMany Abused Substance Have Been Proven to Cause Depression Alcohol Cocaine Heroin Marijuana Amphetamines Look for evidence of dependence, abuse, intoxication or withdrawal

15. 15 MEDICATION INDUCED DEPRESSIONVery Few Medications Have Been Proven to Cause Depression Many cases reported of a med “associated” depression, but causality harder to prove Often a proper assessment for depression is not made before the drug is started many cases may have already had depression

16. 16 “Not Uncomplicated Bereavement”

17. 17 MAJOR DEPRESSIVE DISORDER Presence of major depressive episode Not attributable to: separate psychotic disorder or bipolar disorder or medical disorder or substance abuse disorder or uncomplicated bereavement

18. 18 Impact Of Depression In Chronic Medical Illness

19. 19 Economic Impact Of Mental Disorders High Utilizers Of General Medical Care

20. 20 Economic Impact Of Mental Disorders Medical Inpatients With Psychiatric Comorbidity Length of stay Use of medical services Medical costs ER costs Rehospitalization rates for at least 4 years after discharge

21. 21 Impact Of Depression In Chronic Medical Illness

22. 22 Depression Decreases Adherenceto Medical Regimens Depression may affect adherence by Adversely influencing expectations and benefits about efficacy of treatment Increasing withdrawal and social isolation Reducing cognitive functioningand memory Influencing dietary choices and reducing energy to exercise and follow self-management regimens (ie, checking blood glucose)

23. 23 Meta-Analysis of the Adverse Effect of Depression on Patient Adherence Compared to nondepressed patients, the odds are 3 times greater that depressed patients would be nonadherent with medical treatment recommendations

24. 24 Depression Adversely Impacts Self-Management of Chronic Medical Illness Depressed patients with MI are more likely to drop out of exercise programs1 Smokers with history of depression are 40% less likely to succeed in quitting smoking over a 9-year period compared to nondepressed smokers2 Patients with major depression and coronary artery disease are less likely to adhere to low-dose aspirin therapy than nondepressed controls3 Patients with history of depression compared to nondepressed are more likely to develop depression with smoking cessation4

25. 25 Depression Decreases Medication Adherence in Patients With Diabetes

26. 26 Depression Is Associated With an Increased Percent of Smoking

27. 27 Depression is Associated with an increased BMI >30 kg/m2 by

28. 28 Depression Is Associated With Higher Percentage with HbA1c > 8% The % of patients with HbA1c >8 increased as the level of depression increased. e.g. The % of patients with HbA1c >8 increased as the level of depression increased. e.g.

29. 29 Depression Is Associated With a Higher Number of Cardiac Risk Factors

30. 30 Impact Of Depression In Chronic Medical Illness

31. 31 Depression Is Associated With Increased Diabetes Complications Meta-analysis of 27 studies showed a significant association between depression and a range of diabetes complications with effect sizes in the small to moderate range (95% CI 0.17 to 0.32)

32. 32 Depression: Effect on Risk of Diabetic Complications Incidence of coronary artery disease was 3 times as common over a 10-year period in diabetics who were initially depressed vs nondepressed1 In a prospective study of children with type 1 diabetes, the risk of development of retinopathy was associated with duration of diabetes, time spent in poor glucose control, and time spent in major depression2

33. Depression Associated With Increased Mortality Post-Myocardial Infarction The impact of depression on post-myocardial infarction (MI) cardiac mortality was assessed prospectively among 222 patients in a large, university hospital over the first 6 months after discharge. Consenting patients were enrolled who met the established criteria for MI between August 1991 and July 1992 and survived to be discharged from the hospital. Patients were followed for up for 6 months. The mean age was 60 years (range, 24 to 88 years), and 78% were male. At approximately 7 days post-MI, patients were interviewed in the hospital by a research assistant using the National Institute of Mental Health Diagnostic Interview Schedule (DIS), which provided sufficient data for a diagnosis of depression according to DSM-III-R criteria. Based on the DIS results, 35 patients (16%) were diagnosed with major depressive disorder. Only 3 patients were prescribed antidepressant therapy. A total of 12 patients had died at 6 months, including 6 depressed patients (17%) and 6 nondepressed patients (3%). All deaths were due to cardiac causes. The Kaplan-Meier cumulative mortality curve for depressed and nondepressed patients is depicted in the graph. Major depression was a significant predictor of mortality at 6 months (Cox model hazard ratio, 5.74; 95% confidence interval, 4.61 to 6.87; P=0.0006). The increase in risk among depressed patients remained after controlling for other clinical variables such as left ventricular dysfunction (Killip class) and previous MI. Source: Frasure-Smith N, et al. JAMA. 1993;270:1819-1825. The impact of depression on post-myocardial infarction (MI) cardiac mortality was assessed prospectively among 222 patients in a large, university hospital over the first 6 months after discharge. Consenting patients were enrolled who met the established criteria for MI between August 1991 and July 1992 and survived to be discharged from the hospital. Patients were followed for up for 6 months. The mean age was 60 years (range, 24 to 88 years), and 78% were male. At approximately 7 days post-MI, patients were interviewed in the hospital by a research assistant using the National Institute of Mental Health Diagnostic Interview Schedule (DIS), which provided sufficient data for a diagnosis of depression according to DSM-III-R criteria. Based on the DIS results, 35 patients (16%) were diagnosed with major depressive disorder. Only 3 patients were prescribed antidepressant therapy. A total of 12 patients had died at 6 months, including 6 depressed patients (17%) and 6 nondepressed patients (3%). All deaths were due to cardiac causes. The Kaplan-Meier cumulative mortality curve for depressed and nondepressed patients is depicted in the graph. Major depression was a significant predictor of mortality at 6 months (Cox model hazard ratio, 5.74; 95% confidence interval, 4.61 to 6.87; P=0.0006). The increase in risk among depressed patients remained after controlling for other clinical variables such as left ventricular dysfunction (Killip class) and previous MI. Source: Frasure-Smith N, et al. JAMA. 1993;270:1819-1825.

34. 34 Adverse Bidirectional Interaction Smoking Sedentary lifestyle Obesity Lack of adherenceto medical regimens Medical illnessat earlier age Poor symptom control Increased functional impairment Increased complications of medical illness

35. 35 Depressive Disorders:Treatment Goals Once depressive disorders are diagnosed, the initial objectives of treatment, in order of priority, are to: - Reduce and ultimately remove all signs and symptoms of the  depressive disorder - Restore occupational and psychosocial roles/functions to the  asymptomatic state - Minimize the risk of relapse and recurrence WPA/PTD Educational Program on Depressive Disorders Once depressive disorders are diagnosed, the initial objectives of treatment, in order of priority, are to: - Reduce and ultimately remove all signs and symptoms of the depressive disorder - Restore occupational and psychosocial roles/functions to the asymptomatic state - Minimize the risk of relapse and recurrence WPA/PTD Educational Program on Depressive Disorders

36. 36 Consider for Medication Referral: Patient preference Previous positive response to medications Moderate to severe vegetative symptoms Significant residual symptoms after 6 weeks of psychotherapy 2 or more episodes

37. 37 PHARMACOTHERAPY:THREE TREATMENT PHASES Acute 6–12 weeks Continuation 4–9 months Maintenance 1 or more years

38. 38 Treatment with Antidepressant: Acute Phase As shown in the scheme on the slide, adequate treatment should be used long enough to establish whether it is effective. Once treatment with antidepressant medication is initiated, the patient is seen every 1 to 2 weeks, and more often if the patient has severe depression or requires titration of a tricyclic antidepressant (TCA). Response to therapy (clearly better, not better) is assessed at 6 weeks, although a patient may respond earlier. WPA/PTD Educational Program on Depressive Disorders As shown in the scheme on the slide, adequate treatment should be used long enough to establish whether it is effective. Once treatment with antidepressant medication is initiated, the patient is seen every 1 to 2 weeks, and more often if the patient has severe depression or requires titration of a tricyclic antidepressant (TCA). Response to therapy (clearly better, not better) is assessed at 6 weeks, although a patient may respond earlier. WPA/PTD Educational Program on Depressive Disorders

39. 39 * Selecting a Safe and Effective Antidepressant Medication 1) Efficacy 2) Side effect profile relative to your patient’s needs 3) Dosing

40. 40 All Antidepressants Are Efficacious 70 - 80% efficacy with any marketed antidepressant SRI’s or Bupropion are excellent first line choices TCA’s may be superior for some “severe” depressions MAO-I’s may be preferred for some atypical depressions

41. 41 SSRIs (Selective SRIs) Citalopram (Celexa) Escitalopram (Lexapro) Fluoxetine (Prozac) Fluvoxamine (Luvox) Paroxetine (Paxil) Sertraline (Zoloft)

42. 42 * Serotonin Reuptake Inhibitors: A First Line Choice for Treatment of Depression and Various Anxiety Disorders Similar efficacy to earlier agents More acceptable side effect profile Relative medical safety/ease of use Reduced lethality with overdose

43. 43 * PHARMACOLOGY OF SSRI ANTIDEPRESSANTS

44. 44 * “Common” SRI Adverse Effects GI disturbances Headache changes Sleep disturbances Appetite changes Sexual function changes Anxiety level changes Allergic reactions

45. 45 * Unusual SRI Adverse Effects Withdrawal reactions Electrolyte disturbances Bruxism/myoclonus Hypotension/bradycardia Word-finding difficulties Photosensitivity Blunted emotional reactivity Paradoxical/unusual sexual effects Suicidal risk (a subject of controversy)

46. 46 * LOW TOXICITY IN OVERDOSE Fluoxetine Sertraline Paroxetine Trazodone Venlafaxine

47. 47 * General Dosing Strategy Avoid frequent dose increases but make contact with patient every 1-2 weeks Wait 2-4 weeks with total non-response (or partial response that has plateaued) before increasing. Change if no response after 4 weeks. When clinically necessary, may have to make above changes earlier than 4 weeks. Wait 8-12 weeks if gradual response that has not plateaued

48. 48 * Fluoxetine Dosing Begin 10-20 mg/morning, 5-10 mg for age > 60 or if hx of unprecipitated panic attacks, or to avoid side effects. Increase to 20 mg after 1 week. Continue with 20 for 4 weeks. If no response, increase in 20 mg increments every 4 weeks as tolerated (Fava M et al. J Clin Psychopharmacol 2002; 22:379-387) No improvement after 4 weeks at 60 mg/d? Stop trial. Partial response? Difficult to interpret. Get consult

49. 49 * Citalopram Dosing Begin 20 mg in AM, 10 mg for elderly, unprecipitated panic attacks, etc. Increase to 40 mg after 1 week. Continue 40 mg for 4 weeks if tolerated. If no/partial response after 4 weeks, increase to 60 mg. Change if no response to 60 mg in 4 weeks.

50. 50 * Sertraline Dosing Start with 50 mg in AM (25 mg for elderly, and those with panic disorder) Maintain 50 mg/day for 2-4 weeks before increasing. If no/partial response increase in 50 mg increments every 4 weeks. Change if no response at 200 mg for 4 weeks. Licht RW, Ovitzau S. Treatment strategies in patients with major depression not responding to first-line sertraline treatment. A randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology (Berl). 2002 May;161(2):143-51. Another study showed comparable efficacy when treating with 50 mg for 8 weeks compared with increasing to 150 mg after 3 weeks when there was no response. There may not be a dose response relationship with sertraline. Schweitzer E et al. Int Clin Psychopharmacol. 2001 May;16(3):137-43 The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial. Licht RW, Ovitzau S. Treatment strategies in patients with major depression not responding to first-line sertraline treatment. A randomised study of extended duration of treatment, dose increase or mianserin augmentation. Psychopharmacology (Berl). 2002 May;161(2):143-51. Another study showed comparable efficacy when treating with 50 mg for 8 weeks compared with increasing to 150 mg after 3 weeks when there was no response. There may not be a dose response relationship with sertraline. Schweitzer E et al. Int Clin Psychopharmacol. 2001 May;16(3):137-43 The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial.

51. 51 * Bupropion (Wellbutrin) NDRI with comparable antidepressant efficacy Seizure risk up to 0.44/1,000 at higher doses Equally effective as SSRIs for the non-specific anxiety symptoms that typically are present in depressed patients. (Rush AJ et al. Neuropsychopharmacol 2001;25:131-138) But, probably not effective for panic disorder. Contraindicated in patients with history of bulimia or anorexia nervosa because of increased seizure risk

52. 52 * Bupropion II More costly than SSRIs even in generic SR form (e.g. $42 for 30 day supply at 300 mg/d) Minimal sedation May enhance sexual functioning Weight neutral or slight weight loss on average Minimal cardiac or other medical effects

53. 53 * DOSING OF BUPROPION SR associated with lower seizure risk than regular release (0.1/1,000) in 150 mg bid dose. XL used when single daily dose administration is needed. Begin: 100–150 mg qAM X 4+ days Increase to 100–150 mg BID (at least 8 hours between doses) In patients with liver disease ~ 50% increase in T1/2 of hydroxybupropion No effect on bupropion and other metabolites Start with 100 mg qAM

54. 54 * Bupropion: Adverse Effects More frequent Tremors Dry mouth Constipation Sweating Dizziness Insomnia Nausea

55. 55 Bupropion Dosing Caution with concurrent medications that lower seizure threshold Avoid if history of seizure disorder IR dosage: Do not exceed 450 mg/d, 150 mg/dose SR dosage: Do not exceed 400 mg/d, 200 mg/dose XR dosage: Do not exceed 450 mg/d, single dose Avoid rapid dose increase

56. 56 Impact Of Depression In Chronic Medical Illness

57. 57 Antidepressant Treatment Trials In Patients With Chronic Medical IllnessMajor depression is responsive to antidepressant treatment in patients with: Cancer Chronic tinnitus COPD Diabetes Inpatient rehabilitation needs Ischemic heart disease Parkinson’s disease Rheumatoid arthritis Stroke HIV+

58. 58 Antidepressant Analgesia In Chronic, Nonmalignant Pain Summary of 28 studies: More effective than placebo A median of 58% of patients reported at least 50% pain reduction Response is greater when a specific pain diagnosis is made Greater response for pain in the head region ***Response not dependent on presence of depression*** Doses similar to those used for depression

59. 59 SSRIs In Chronic Pain Tricyclics > heterocyclics Mixed drugs (venlafaxine, duloxetine) are more effective than selective drugs - further study warranted Both pure serotonergic and pure noradrenergic drugs may have less effect size than drugs with mixed effects

60. 60 Suicide Rates Due to Depressive Disorders 10% to 15% of all depressed patients commit suicide, and two-thirds have suicidal ideation (Kaplan & Sadock, 1991). Patients at high risk for suicide include those who have: - a biological predisposition (eg, low levels of serotonin) - a previous history of suicide attempts or a current plan - an emotional situation of social isolation, estrangement, and  hopelessness - comorbid substance abuse and/or personality disorder - psychotic features - serious concomitant physical illness Adapted from WPA/PTD Educational Program on Depressive Disorders10% to 15% of all depressed patients commit suicide, and two-thirds have suicidal ideation (Kaplan & Sadock, 1991). Patients at high risk for suicide include those who have: - a biological predisposition (eg, low levels of serotonin) - a previous history of suicide attempts or a current plan - an emotional situation of social isolation, estrangement, and hopelessness - comorbid substance abuse and/or personality disorder - psychotic features - serious concomitant physical illness Adapted from WPA/PTD Educational Program on Depressive Disorders

61. 61 Depression and Chronic Medical Illness Increased prevalence of major depression in the medically ill Depression amplifies physical symptoms associated with medical illness Comorbidity increases impairment in functioning Depression decreases adherence to prescribed regimens Depression is associated with adverse health behaviors (diet, exercise, smoking) Depression increases mortality