Depressive Disorders

1. Depressive Disorders Chapter 71 PHARMACOTHERAPY A PATHOPHYSIOLOGIC APPROACH

2. Abbreviations APA: American Psychiatric Association DA: dopamine DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision ECT: electroconvulsive therapy 5-HT: serotonin HAMD: Hamilton depression scale MAOI: monoamine oxidase inhibitor MDD: major depressive disorder NE: norepinephrine NIH: National Institutes of Health REM: rapid eye movement SNRI: serotonin-norepinephrine reuptake inhibitor SSRI: serotonin-selective reuptake inhibitor STAR* D: Sequenced treatment alternatives to relieve depression TCA: tricyclic antidepressant TRD: treatment-resistant depression

3. Introduction American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000.  • Major depressive episode defined by Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision (DSM-IV-TR) criteria • Published by American Psychiatric Association • Depression associated with functional disability, morbidity and mortality • Newer antidepressants as effective and better tolerated than older agents

4. Epidemiology Kessler RC, Berglund P, Demler O. The epidemiology of major depressive disorders: Results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–3105. Burt VK, Stein K. Epidemiology of depression throughout the female life cycle. J Clin Psychol. 2002;63(Suppl 7):9–15.  • True prevalence unknown • The National Comorbidity Survey Replication • 16.2% of population studied had history of major depressive disorder • >6.6% had episode in past 12 months • Women at increased risk of depression from early adolescence until their mid-50s • Lifetime rate 1.7 to 2.7 times greater than for men

5. Epidemiology Kessler RC, Walters EE. Epidemiology of DSM-III-R major depression and minor depression among adolescents and young adults in the National Comorbidity Survey. Depress Anxiety. 1998;7:3–14. Kessler RC, Berglund P, Demler O. The epidemiology of major depressive disorders: Results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289:3095–3105. Steffens DC, Skoog I, Norton MC, et al. Prevalence of depression and its treatment in an elderly population. The Cache County study. Arch Gen Psychiatry. 2000;57:601–607. • Adults 18 to 29 years: highest rates of major depression • Estimated lifetime prevalence of MDD in individuals 65 to 80 years • 20.4% in women • 9.6% in men • Depressive disorders common during adolescence • Comorbid substance abuse • Suicide attempts

6. Epidemiology American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000. Weissman MM, Gershon ES, Kidd KK, et al. Psychiatric disorders in the relatives of probands with affective disorder. Arch Gen Psychiatry. 1984;41:13–21. Warner V, Weissman MM, Mufson L, Wickramaratne PJ. Grandparents, parents, and grandchildren at high risk for depression: A three-generation study. J Am Acad Child Adolesc Psychiatry. 1999;38:289–296.  • Depressive disorders and suicide tend to occur within families • ~8% to 18% of MDD patients have > one 1st-degree relative with history of depression, compared with 5.6% of 1st-degree relatives of those without depression • 1st-degree relatives of patients with depression 1.5 to 3 times more likely to develop depression than controls

7. Epidemiology Sullivan PF, Neale MC, Kendler KS. Genetic epidemiology of major depression: Review and meta-analysis. Am J Psychiatry. 2000;157:1552–1562. • Prevalence influenced by genetic and environmental factors • Heritability of liability for major depression 37% • 63% of variance in liability caused by individual-specific environment

8. Etiology Stahl SM. Blue genes and the mechanism of action of antidepressants. J Clin Psychiatry. 2000;61:164–165.  Hirschfield RM. History and the evolution of the monoamine hypothesis of depression. J Clin Psychiatry. 2000;61(Suppl 6):4–6.  Delgado PL. Depression: The case for a monoamine deficiency. J Clin Psychiatry. 2000;61(Suppl 6):7–11.  • Depressive disorder etiology too complex to be explained by single social, developmental, biologic theory • Several factors work together to cause/precipitate depressive disorders • Major depression symptoms consistently reflect changes in brain monoamine neurotransmitters • Norepinephrine (NE) • Serotonin (5-hydroxytryptamine [5-HT]) • Dopamine (DA)

9. Pathophysiology

10. Biogenic Amine Hypothesis Delgado PL, Moreno FA, Potter R, et al. Norepinephrine and serotonin in antidepressant action: Evidence from neurotransmitter depletion studies. In: Briley M, Montgomery SA, eds. Antidepressant Therapy at the Dawn of the Third Millennium. London: Marin Dunitz, 1997:141–163.  • Depression linked to decreased NE, 5-HT, DA in the brain • Actual cause unknown • Based on observations from early 1950s • Antihypertensive drug reserpine depletes neuronal storage granules of NE, 5-HT, DA • produces clinically significant depression >15% patients

11. Biogenic Amine Hypothesis Stahl SM. Blue genes and the monoamine hypothesis of depression. J Clin Psychiatry. 2000;61:77–78. Delgado PL. Depression: The case for a monoamine deficiency. J Clin Psychiatry. 2000;61(Suppl 6):7–11.  Baldessarini RJ. Drugs and the treatment of psychiatric disorders: Depression and anxiety disorders. In: Hardman JG, Limbrid LE, Goodman A, et al. eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill, 2000:447–484.  • Monoamine (e.g., NE, 5-HT) reuptake blockade occurs immediately on antidepressant administration • Antidepressant clinical effects generally not seen until after ~4 weeks • May be result of cascade of events from receptor occupancy to gene transcription • caused researchers to focus on adaptive changes induced by antidepressants

12. Theories of Postsynaptic Changes in Receptor Sensitivity Stahl SM. Blue genes and the mechanism of action of antidepressants. J Clin Psychiatry. 2000;61:164–165.  Discrepancy between timing of monoamine reuptake blockade (immediate) and measurable improvement in symptoms Some theories focus on adaptive/chronic changes in amine receptor systems compared with acute changes Mid-1970s: chronic (not acute) antidepressant administration to animals caused desensitization of NE-stimulated cyclic adenosine monophosphate synthesis

13. Theories of Postsynaptic Changes in Receptor Sensitivity Stahl SM. Blue genes and the mechanism of action of antidepressants. J Clin Psychiatry. 2000;61:164–165. Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60(Suppl 4):4–11.  Stahl SM. Basic psychopharmacology of antidepressants, part 1: Antidepressants have seven distinct mechanisms of action. J Clin Psychiatry. 1998;59(Suppl 4):5–14.  Downregulation of β-adrenergic receptors accompanies desensitization for most antidepressants Desensitization or downregulation of NE receptors corresponds to clinically relevant time course for antidepressant effects Other studies reveal desensitization of presynaptic 5-HT1A autoreceptors following chronic antidepressant administration

14. Dysregulation Hypothesis Bryant SG, Brown CS. Current concepts in clinical therapeutics: Major affective disorders, part 1. Clin Pharmacol. 1986;5:304–318. Siever LJ, Davis KL. Overview: Toward a dysregulation hypothesis of depression. Am J Psychiatry. 1985;142:1017–1031. Incorporates diversity of antidepressant activity with adaptive changes in receptor sensitization over several weeks Emphasizes failure of neurotransmitter system homeostatic regulation rather than absolute increases or decreases in activities Hypothesis: antidepressants restore efficient regulation to dysregulated neurotransmitter systems

15. 5-HT/NE Link Hypothesis Feighner JP. Mechanism of action of antidepressant medications. J Clin Psychiatry. 1999;60(Suppl 4):4–11.  • No single neurotransmitter theory adequate • Maintains serotonergic and noradrenergic systems both involved in antidepressant response • Consistent with rationale of postsynaptic alteration theory • Emphasizes importance of β-adrenergic receptor down regulation for antidepressant effect • Both serotonergic and noradrenergic medications downregulate β-adrenergic receptors • Link between 5-HT and NE

16. Role of DA in Depression Ordway GA, Klimek V, Mann JJ. Neurocircuitry of mood disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: The Fifth Generation of Progress. American College of Neuropsychopharmacology. Lippincott Williams and Wilkins: Philadelphia, 2002:1051–1064.  • Traditional explanations focused on NE and 5-HT • biogenic amine hypothesis does not distinguish between NE and DA • Evidence suggests decreased DA transmission in depression • agents that increase dopaminergic transmission are effective antidepressants • Studies suggest increased DA transmission in mesolimbic pathway accounts for part of antidepressant mechanism

17. Role of DA in Depression Ordway GA, Klimek V, Mann JJ. Neurocircuitry of mood disorders. In: Davis KL, Charney D, Coyle JT, Nemeroff C, eds. Neuropsychopharmacology: The Fifth Generation of Progress. American College of Neuropsychopharmacology. Lippincott Williams and Wilkins: Philadelphia, 2002:1051–1064.  • Mechanisms by which antidepressants alter DA transmission unclear • Can be mediated indirectly by actions at NE or 5-HT terminals • Complexity of interaction between 5-HT, NE, and possibly DA gaining greater appreciation • Precise mechanism not known

18. Biologic Markers Thase ME, Fasiczka AL, Berman SR, et al. Electroencephalographic sleep profiles before and after cognitive behavior therapy of depression. Arch Gen Psychiatry. 1998;55:138–144 • Search for biologic or pharmacodynamic markers to assist in MDD diagnosis and treatment • Although no biologic marker has been discovered, several biologic abnormalities are present in many depressed patients • Sleep studies in MDD patients identified several abnormalities • More pronounced with advancing age • Occur in other psychiatric disorders • Not diagnostic for major depression

19. Biologic Markers • ~45% to 60% of MDD patients have a neuroendocrine abnormality • Cortisol hypersecretion: lack of cortisol suppression after dexamethasone administration • Indicates hypothalamic-pituitary-adrenal axis overactivity or dysregulation • High rate of false-positive and false-negative results limits usefulness of testing • Relative lack of use in clinical practice • Abnormal/diminished response to thyroid-stimulating hormone 

20. Clinical Presentation Sofuoglu M, Dudish-Poulsen S, Poling J, et al. The effect of individual cocaine withdrawal symptoms on outcomes in cocaine users. Addict Behav. 2005;30:1125–1134. • Withdrawal from substances of abuse (e.g., cocaine) can cause depressive symptoms   • Rule out medical conditions or concomitant medication • Complete physical exam and medication review • Mental status examination • Laboratory workup • Complete blood count with differential • Thyroid function tests • Electrolytes

21. Medical Conditions Associated with Depressive Symptoms DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. 2008. http://www.accesspharmacy.com/.

22. Substance Use Disorders Associated with Depressive Symptoms DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. 2008. http://www.accesspharmacy.com/.

23. Medications Associated with Depressive Symptoms DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. 2008. http://www.accesspharmacy.com/.

24. Clinical Presentation American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revision. Washington, DC: American Psychiatric Association, 2000.  Stressors/life events trigger depression in some individuals Patients may have >1 recurrent episodes during lifetime

25. DSM-IV-TR Criteria for MDD DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. 2008. http://www.accesspharmacy.com/.

26. Emotional Symptoms McGirr A, Renaud J, Seguin M, et al. An examination of DSM-IV depressive symptoms and risk for suicide completion in major depressive disorder: A psychological autopsy study. J Affect Disord. 2007;97:203–209. • Persistent diminished ability to experience pleasure • Loss of interest/pleasure in usual activities, hobbies, work • Appear sad or depressed • Often pessimistic • Believe nothing will help them feel better • Feelings of worthlessness/inappropriate guilt • Identify patients at risk for suicide • ~90% of MDD patients have anxiety symptoms

27. Emotional Symptoms • Unrealistic guilt feelings • Can reach delusional proportions • Patients can feel they deserve punishment • View illness as punishment • MDD patients with psychotic features • May hear voices (auditory hallucinations) saying he/she is a bad person and should commit suicide • Can require hospitalization if patient becomes danger to self or others

28. Physical Symptoms • Often motivate patients to seek medical attention • Chronic fatigue • Often worse in morning; does not improve with rest • Pain (especially headache) often accompanies fatigue • Sleep disturbances • Frequent early morning awakening with difficulty returning to sleep • Difficulty falling asleep • Frequent nighttime awakening • Increased sleep (hypersomnia)

29. Physical Symptoms Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: Consensus statement update. JAMA. 1997;278:1186–1190. Trivedi MH. The link between depression and physical symptoms. Prim Care Companion J Clin Psychiatry. 2004;6(suppl 1):12–16. • Appetite disturbances • Decreased appetite • Can result in substantial weight loss, especially elderly patients • Other patients overeat/gain weight • Gastrointestinal complaints • Cardiovascular complaints • Palpitations • Loss of sexual interest/libido

30. Intellectual/Cognitive Symptoms Lebowitz BD, Pearson JL, Schneider LS, et al. Diagnosis and treatment of depression in late life: Consensus statement update. JAMA. 1997;278:1186–1190. Decreased ability to concentrate Slowed thinking Poor memory of recent events Confusion and indecisiveness Consider depression when elderly patientshave cognitive symptoms

31. Psychomotor Disturbances • Psychomotor retardation: noticeably slowed • Physical movements • Thought processes • Speech • Psychomotor agitation: purposeless, restless motion • Pacing • Wringing of hands • Shouting outbursts

32. Suicide Risk Evaluation/Management Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Suicide: Fact Sheet. 2006, http://www.cdc.gov/ncipc/factsheets/suifacts.htm.  • Center for Disease Control lists suicide as • 3rd leading cause of death in those aged 15 to 24 years • 2nd leading cause of death in those aged 25 to 34 years  • Widely held myths regarding suicide • People more likely to commit suicide if asked about it • People talking about suicide are looking for attention and are not serious • Suicidal people are crazy • Most suicides caused by sudden traumatic event

33. Suicide Risk Evaluation/Management Coryell WH. Clinical assessment of suicide risk in depressive disorder. CNS Spectr. 2006;11(6):137–142.  Claassen CA, Trivedi MH, Rush AJ, et al. Clinical differences among depressed patients with and without a history of suicide attempts: findings from the STAR*D trial. J Affect Disord. 2007;97:77–84. • Assess all MDD patients for suicidal potential • Factors increasing suicide risk • Suicidal plans/attempts • Male gender • Being single or living alone • Inpatient status • Feelings of hopelessness, relationship difficulties • General medical condition, alcohol/substance abuse • More work hours missed in past week

34. Suicide Risk Evaluation/Management • High suicide risk: detailed plan with intention and ability to carry it out • Hints of suicidal ideation used to assess severity of suicidal thoughts • Personality change • Sudden decision to make a will/give away possessions • Recent gun purchase; obtaining large supply of medications or other potentially toxic substances • Suicide risk can increase as MDD patients develop energy and capacity to act on a plan made earlier

35. Treatment

36. Treatment Goals • Reduce acute symptoms • Facilitate return to level of functioning before illness • Prevent further episodes • Decision to hospitalize based on • Suicide risk • Physical health • Social support system • Psychotic and/or catatonic symptoms

37. General Approach to Treatment American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4Suppl):1–45.  Mann JJ. The Medical Management of Depression. N Engl J Med. 2005;353:1819–1834. • Phases of treatment • Acute phase: 6 to 10 weeks; goal is remission (i.e., absence of symptoms) • Continuation phase: 4 to 9 months after remission achieved; goal to eliminate residual symptoms or prevent relapse (i.e., return of symptoms <6 months of remission) • Maintenance phase: >12 to 36 months; goal to prevent recurrence (i.e., separate episode of depression)  

38. General Approach to Treatment American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4Suppl):1–45.  • Risk of recurrence increases as number of past episodes increases • Duration of therapy depends on risk of recurrence • Some investigators recommend lifelong maintenance therapy for persons at greatest risk for recurrence • <40 years of age with >2 prior episodes • Any age with >3 prior episodes • Educate patient and his/her support system • Delay in antidepressant effects • Importance of adherence

39. Nonpharmacologic Therapy Blackburn IM, Moore RG. Controlled acute and follow-up trial of cognitive therapy and pharmacotherapy in outpatients with recurrent depression. Br J Psychiatry. 1997;171:328–334. Psychotherapy and antidepressant effects considered additive Mild to moderate depressive episode: psychotherapy can be 1st line therapy Severe and/or psychotic MDD: psychotherapy alone not recommended for acute treatment Maintenance psychotherapy generally not recommended as sole treatment to prevent recurrence

40. Nonpharmacologic Therapy Klapheke MM. Electroconvulsive therapy consultation: An update. Convuls Ther. 1997;13:227–241. • Electroconvulsive therapy (ECT): safe, effective treatment for certain severe mental illnesses including MDD • Candidates for ECT • Rapid response needed • Risks of other treatments outweigh potential benefits • History of poor antidepressant response • History of good ECT response • Patient prefers ECT

41. Nonpharmacologic Therapy • General ECT course • Unilateral or bilateral 2 to 3 times/week • 6 to 12 treatments • Rapid therapeutic response (10 to 14 days) • Conditions associated with increased risk • Increased intracranial pressure, cerebral lesions • Recent myocardial infarction • Recent intracerebral hemorrhage • Bleeding • Unstable vascular condition

42. Nonpharmacologic Therapy Klapheke MM. Electroconvulsive therapy consultation: An update. Convuls Ther. 1997;13:227–241. • Anesthetics and nondepolarizing neuromuscular blocking agents decrease ECT morbidity   • ECT adverse effects • Cognitive dysfunction • Cardiovascular dysfunction • Prolonged apnea • Treatment-emergent mania • Headache • Nausea • Muscle aches

43. Nonpharmacologic Therapy Klapheke MM. Electroconvulsive therapy consultation: An update. Convuls Ther. 1997;13:227–241. • Cognitive changes associated with ECT • Confusion • Memory disturbance • Most cognitive disturbances transient • Some patients report permanent memory loss for events months before, after, during treatment   • Relapse rates high during year following ECT unless maintenance antidepressant prescribed

44. Nonpharmacologic Therapy American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry. 2000;157(4Suppl):1–45.  Lafer B, Sachs GS, Labbate LA, et al. Side effects induced by bright light therapy. Am J Psychiatry. 1994;151:1081–1083. • Bright light therapy: patients gaze into 10,000-lux intensity light box ~30 minutes/day • Can use with antidepressants • Effective for seasonal affective disorder (SAD) and adjunctive use in MDD with seasonal exacerbations • Well tolerated • Most frequently reported adverse event: minor visual complaints • Baseline and periodic eye examinations recommended

45. Pharmacologic Therapy

46. Adult Dosagesa aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition: New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/

47. Adult Dosagesa aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/

48. Adult Dosagesa aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed. bParent drug plus metabolite. cIt has been suggested that combined imipramine + desipramine concentrations should fall between 150–240 ng/mL. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/

49. Adult Dosagesa aDoses listed are total daily doses; elderly patients are usually treated with approximately ½ of the dose listed. bTransdermal delivery system designed to deliver dose continuously over a 24-hour period. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: The McGraw-Hill Companies. http://www.accesspharmacy.com/

50. Pharmacologic Therapy Antidepressants are of equivalent efficacy when administered in comparable doses Initial choice made empirically Cannot predict which antidepressant will be most effective in a patient Failure to respond to 1 class or 1 drug in a class does not predict failed response to another drug class or another drug within the class