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A PHARMACOLOGICAL UPDATE ON THE TREATMENT OF

A PHARMACOLOGICAL UPDATE ON THE TREATMENT OF. MAJOR DEPRESSIVE DISORDER. PRESENTED BY: . RICHARD A ELLISON, MD MEDICAL DIRECTOR WACCAMAW CENTER FOR MENTAL HEALTH CONWAY, SOUTH CAROLINA. OUR OBJECTIVES:. 1) REVIEW THE DIAGNOSTIC CRITERIA FOR MAJOR DEPRESSION

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A PHARMACOLOGICAL UPDATE ON THE TREATMENT OF

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  1. A PHARMACOLOGICAL UPDATE ON THE TREATMENT OF MAJOR DEPRESSIVE DISORDER

  2. PRESENTED BY: • RICHARD A ELLISON, MD MEDICAL DIRECTOR WACCAMAW CENTER FOR MENTAL HEALTH CONWAY, SOUTH CAROLINA

  3. OUR OBJECTIVES: • 1) REVIEW THE DIAGNOSTIC CRITERIA FOR MAJOR DEPRESSION • 2) REVIEW THE EPIDEMIOLOGY AND ASSOCIATED CONDITIONS OF DEPRESSION THAT EVIDENCE A NEED FOR TREATMENT • 3) REVIEW THE COMMON ANTIDEPREPRESSANT MEDICATIONS THAT ARE ON THE MARKET TODAY

  4. “Iceberg” Phenomenon Depressed Patients Seen By Psychiatrists Depressed Patients Seen in Primary Care Practice Watts, 1966 WPA/PTD Educational Program on Depressive Disorders

  5. AXIS I CLINICAL DISORDERS • SUBSTANCE RELATED DISORDERS • SCHIZOPHRENIA & PSYCHOTIC DISORDERS • MOOD DISORDERS • ANXIETY DISORDERS • SOMATOFORM DISORDERS • FACTITIOUS DISORDERS

  6. MAJOR DEPRESSIVE EPISODE • Depressed mood or anhedonia — at least 2 wks • At least 5 of the following • Depressed mood • Decreased interest or pleasure most of the time • Insomnia or hypersomnia • Anorexia or hyperphagia or 5% weight gain/loss in month • Psychomotor agitation or retardation • Fatigue • Decreased concentration or thinking, indecisiveness • Negative thinking — worthlessness, inappropriate guilt • Recurring thoughts of death or suicide • Not organically caused • Not uncomplicated bereavement

  7. RISK FACTORS FOR MAJOR DEPRESSION Risk Factor Association Gender Twice as likely in women Age Peak age of onset = 20–40 years Family history 1.5–3.0X higher risk Marital status Higher rates in separated, widowed, and divorced persons Married males < never married Married females > never married* *Highest risk: young mothers stuck at home with children

  8. OCCURRENCE OF DEPRESSION • Point prevalence 4–5% • Women 5–6% • Men 3% • 1 year prevalence 11.3% (major depression) • Lifetime relapse rate 65–80% • Lifetime incidence • Women ~20% • Men ~10%

  9. Prevalence of Depressive Disorders in Various Patient Populations* General population 5.8% Chronically ill 9.4% Hospitalized 33.0% Geriatric inpatients 36.0% Cancer outpatients 33.0% Cancer inpatients 42.0% Stroke 47.0% MI 45.0% Parkinson’s disease 39.0% 0% 10% 20% 30% 40% 50% Prevalence * There is a range of percentages depending on the study. Adapted from WPA/PTD Educational Program on Depressive Disorders

  10. DYSTHYMIC DISORDER • Depressed mood most of days, more days than not, for at least 2 years • Two or more: • Poor appetite or overeating • Insomnia or hypersomnia • Low energy or fatigue • Poor concentration, indecisiveness • Low self-esteem • Hopelessness • Not symptom-free for 2 or more months

  11. DYSTHYMIC DISORDER • 2.5% annual prevalence rate Equals or Exceeds Major Depression in: • Suicide rate • Loss of marriage or job secondary to depression • Overall impairment Kessler, 1994

  12. MOOD DISORDER WITH ATYPICAL FEATURES • 15–20% of depressive episodes have atypical features • Do not respond as well to TCAs (<50%) as to MAOIs or SSRIs (~70%) * ~80% are women

  13. MOOD DISORDER WITH ATYPICAL FEATURES • Atypical features often seen in seasonal affective disorder * ~80% of SAD are women • Seen frequently in PMD (premenstrual dysphoric disorder) • Seen frequently in bipolar depression • Particularly rapid cycling (85% women)

  14. Functional impairment <2 mo Fluctuating anhedonia Self-esteem preserved Functioning: “muddles through” Guilt not generalized: focuses on better care of deceased Passively suicidal or not at all GRIEF vs DEPRESSION Grief Depression Impairment >2 mo Relatively fixed anhedonia Self-esteem decreased Functioning severely impaired Generalized guilt Often actively suicidal

  15. Etiology and Pathogenesis of Depressive Disorders • Neurobiologic factors • Psychosocial factors • Developmental factors WPA/PTD Educational Program on Depressive Disorders

  16. Chronic Stress, Anxiety, and Depression • During chronic stress, synthesis of norepinephrine in the brain is increased • This leads to overactivity of the noradrenergic system, hyperarousal, and anxiety • The chronic hypersecretion of cortisol results in secondary changes in neuronal structure and function in the brain (eg, Cushing’s disease). This could provide a neurotransmitter basis for depression

  17. MAJOR DEPRESSIVE DISORDERNeurotransmitters • State but not trait markers • Norepinephrine and serotonin abnormalities normalize with Rx • Norepinephrine • First believed to be too low • Dysregulation frequently seen • Basal rate of firing of noradrenergic neurons high • Decreased response of noradrenergic neurons to stimulation

  18. MAJOR DEPRESSIVE DISORDERNeurotransmitters • Serotonin • First believed to be too low • May be low, but 5HT2 and/or 5HT1a appear to be main receptors involved • Other neurotransmitters (or their precursors) with reported abnormalities include: • GABA  • Phenylalanine  • Dopamine 

  19. 5-HT NE Anxiety Irritability Energy Interest Impulse Mood, Emotion, Cognitive Function Sex Appetite Motivation Aggression Drive DA

  20. SUICIDE RISK IN DEPRESSIONLifetime Rates • 10–15% risk in untreated: • Major depressive disorder • Dysthymic disorder

  21. Suicide Rates Due to Depressive Disorders Two-Thirds of Depressed Patients Exhibit Suicidal Ideation 10%-15% ofDepressed Patients Commit Suicide Kaplan & Sadock, 1991WPA/PTD Educational Program on Depressive Disorders

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

  23. Differential Diagnosis of Depression Mimicking Condition Symptoms Differentiators Depression Mood changes Apathy Loss of energy Withdrawal Depression Apathy Loss of energy Fatigue Apathy Depression Apathy Depression Depression Mood changes Loss of appetite Apathy • Substance abuse • Alcohol • Cocaine • CNS stimulants • Marijuana • Schizophrenia • Anemia • Hyperthyroidism/ • Hypothyroidism • Neoplasia Medical history Family history Blood screen Urine screen Difficult to differentiate depression from early schizophrenia Hemoglobin Hematocrit Thyroid function tests Medical history CT scan MRI Ultrasound DSM-IV

  24. Differential Diagnosis of Depression Symptoms Differentiators Mimicking Condition Medical history Medical history Laboratory findings Various imaging techniques Medical history CT scan MRI PET scan Medical history Neurologic exam CT scan MRI,EMG • Medications • Reserpine • Corticosteroids • Beta- blockers • Estrogen • Interferon • Benzodiazepines • Chronic illnesses • TB • Neoplasia • AIDS • Arthritis • Trauma • Brain injury • Left hemisphere • Injuries • CNS disease • Parkinson’s • Alzheimer’s Depression Fatigue Mania Depression Fatigue Loss of appetite Apathy Anxiety Major depression Loss of appetite Apathy Major depression Apathy DSM-IV

  25. CLUES TO MEDICAL CAUSE OF DEPRESSION • If there is no pain or discomfort, most medical conditions, unlike depression, have: • hypersomnia • energy better in a.m. • Almost no medical condition, unlike depression, has • energy better in p.m. • hyperphagia

  26. NATURAL COURSE OF UNTREATED DEPRESSION Normal Mood 40% Recovery 20% Dysthymia or Partial Recovery 40% Stay Depressed Depression 1 year

  27. Depressive Disorders:Treatment Goals Treatment Minimize Relapse/ Recurrence Risk Reduce/Remove Signs, Symptoms Restore Role/ Function Adapted from WPA/PTD Educational Program on Depressive Disorders

  28. THREE TREATMENT PHASES • Acute 6–12 weeks • Continuation 4–9 months • Maintenance 1 or more years

  29. Clinical Status And Treatment Phases Of Depression Recovery Recurrence Remission Relapse X X “Normalcy” Relapse Progression ¨ Severity X Response Treatment Phases Acute 6-12 wk Continuation 4-9 mo Maintenance ~1 yr

  30. Recurrence of Depressive Disorders 50% of Patients With aMajor Depressive Disorder Experience One Episode 30% of Patients Become Chronically Depressed 20% of Patients Exhibit a Recurrent Course Merikangas et al, 1994 WPA/PTD Educational Program on Depressive Disorders

  31. CONSIDERATIONS FOR MAINTENANCE TREATMENT • Very strongly recommended • 3 episodes of major depression • Strongly recommended • 2 episodes of major depression and • Positive family history of bipolar disorder • History of recurrence within 1 year after previously effective Rx discontinued • Early onset of first depressive episode (before age 20 years) • Both episodes severe, sudden, or life-threatening in the past 3 years

  32. Indications for Formal Psychotherapy as Monotherapy Psychotherapy only if • Mild disorder • Psychotic or melancholic features are absent • History of chronic psychosocial problems Adapted from WPA/PTD Educational Program on Depressive Disorders

  33. Response Rate Mild depression Placebo = medication Moderate depression – Cognitive-behavioral 70% – Interpersonal 70% – Antidepressants 70% Moderate-severe depression Antidepressant > psychotherapy PSYCHOTHERAPY OF DEPRESSION

  34. Response Rate After Pharmacologic Treatment Of Depression Normal Mood Medication Started 67% Responders 33% Nonresponders Depression 8 weeks

  35. MEDICATIONS USED IN THE TREATMENT OF DEPRESSION

  36. CLASSIFICATIONS OF ANTIDEPRESSANT MEDICATIONS • TRICYCLICS (TCAs) • Selective Serotonin Reuptake Inhibitors (SSRIs) • ATYPICAL ANTIDEPRESSANTS • Monoamine Oxidase Inhibitors (MAOIs)

  37. TRICYCLIC ANTIDEPRESSANTS(TCAs) • AMITRIPTYLINE-------------------------------------------ELAVIL* 25-75mg QHS--MAX OF 200-300mg/day • AMOXAPINE-------------------------------------------ASCENDIN* 50mg BID/TID—MAX OF 400-600mg/day • CLOMIPRAMINE-------------------------------------ANAFRANIL 25mg QD TO A MAX OF 250mg/day • DESIPRAMINE--------------------------------------NORPRAMIN 50-75mg QHS--MAX OF 200-300mg/day • DOXEPIN------------------------------------------------SINEQUAN 50-75mg QHS--MAX OF 200-300mg/day *no longer marketed—generic only

  38. TRICYCLIC ANTIDEPRESSANTS(TCAs) • IMIPRAMINE------------------------------------------TOFRANIL 25-50mg QHS TO A MAX OF 150mg/day • MAPROTILINE ------------------------------------LUDIOMIL* 25mg TID—MAC OF150-225mg/day • NORTRYPTILINE------------------------------------PAMELOR 25-50mg QHS TO A MAX OF 150mg/day • PROTRYPTILINE-------------------------------------VIVACTYL 5mg TID TO A MAX OF 60mg/day • TRIMIPRAMINE------------------------------------SURMONTIL 25mg BID TO A MAX OF 200mg/day *no longer marketed—generic only

  39. PREDICTORS OF TRICYCLIC RESPONSE • Increased response • insomnia • anorexia • psychomotor retardation • anhedonia • insidious onset • guilt • Decreased response (response to TCA £50% when one of the following symptoms is present) • hypersomnia* • hyperphagia* • mood worse in p.m.* • panic/severe anxiety (TCAs initially worsen this) *Atypical symptoms

  40. Adverse Effects Associated With Specific Neuroreceptors NE Tremors, tachycardia, augmentation of pressor effects of sympathomimetic amines, sexual dysfunction 5HT GI disturbances, increase or decrease inanxiety, sexual dysfunction D1 Psychomotor activation, antiparkinsonian effects, aggravation of psychosis D2 Extrapyramidal movement disorders, endocrine changes, sexual dysfunction (males) Richelson E. Mayo Clin Proc. 1994.

  41. Adverse Effects Associated WithSpecific Neuroreceptors (cont.) H1 Potentiation of central depressant drugs, drowsiness, sedation, weight gain, hypotension Musc Blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, memory dysfunction a1&2 Postural hypotension, dizziness, reflex tachycardia

  42. ADVANTAGES TO POST-TCA ANTIDEPRESSANTS • Lower side effects • Lower dropout rate • Very low toxicity in overdose

  43. SEROTONIN REUPTAKE INHIBITORS(SSRIs) • ATOMOXETINE----------------STRATTERA 40mg QD TO A MAX OF 100mg/day • CITALOPRAM-------------------------CELEXA 20mg QD TO A MAX OF 60mg/day • ESCITALOPRAM------------------LEXAPRO 10mg QD TO A MAX OF 20mg/day

  44. SEROTONIN REUPTAKE INHIBITORS (SSRIs) • FLUOXETINE-----------------------------PROZAC 20mg QD TO A MAX OF 80mg/day • FLUVOXAMINE----------------------------LUVOX 50mg QHS TO A MAX OF 300mg/day • PAROXETINE-------------------------------PAXIL* 10mg QD TO A MAX OF 50mg/day • SERTRALINE------------------------------ZOLOFT 50mg QD TO A MAX OF 200mg/day • *dosing varies for CR formulations

  45. PDR: ADVERSE EFFECT INCIDENCE Nervousness Headache Insomnia Drowsiness Nausea Sexual Anorexia Dizzy/LH Tremor Visual Diarrhea Constipation % AEs:

  46. DROPOUTS SECONDARY TO SIDE EFFECTS Paroxetine 21% Venlafaxine 19% mirtazapine 16% Nefazodone 16% Sertraline 15% Fluoxetine 15% Bupropion SR 9% TCAs 30% Tertiary >32% Secondary 26%

  47. SEROTONIN REUPTAKE INHIBITORS vs TCA • Typical depression: same • TCA possibly superior in geriatric/severe melancholic depression (still controversial) • SSRI superior in depression with • panic disorder • hypersomnia • hyperphagia • mood reactivity • mood worse in p.m. • profound anergy • delusions (?)

  48. SSRI DOSING • Fluoxetine 20mg; 40mg; 60mg • Sertraline 50mg; 100mg; 150mg • Paroxetine 20mg; 40mg; 50mg

  49. SSRISPros • Low side effects and dropout rates • Once a day dosing • Starting dose often sufficient • Very low toxicity in overdose • Very low mania induction • <3% in bipolars • Effective in atypical and typical depressions • Effective in broad spectrum of comorbid disorders • e.g., anxiety disorders, anger, impulsive, premenstrual dysphoric disorder

  50. SSRISCons • Significant sexual side effects • All with insomnia, diarrhea, sweating, and nausea risk • Significant drug interactions with other meds • Especially with fluoxetine, paroxetine, and fluvoxamine • Nervousness, agitation, and/or anorexia occasional problem with fluoxetine • Somnolence a problem with paroxetine and occasional problem with sertraline

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