Major Depressive Disordered I

1. Mood Disorder Major Depressive Disordered I Jawza F. Al-Sabhan, Msc. College of Pharmacy Clinical Pharmacy Department

2. Introduction • Everyone experiences variations in mood, blues that come and go, disappointments, the normal grief that accompanies the loss of someone you love. But a severe or prolonged depression that interferes with the ability to function or feel pleasure is not a mere case of the blues. It is an illness. • Depression affects many people of all ages. • It is the 8th leading cause of death for males, and 19th leading cause of death for females.

3. Epidemiology • Lifetime incidence of depression is 13-20%. • Life time incidence of depression in KSA 17%. • Life time prevalence 5-12%(US,Europe) • Most common age is late 20s.

4. Pathophysiology

5. Pathophysiology hypotheses Biogenic amine 1. Central nervous system (CNS) deficiency in dopamine, norepinephrine, and/or serotonin 2. Based on knowledge that antidepressants increase monoamine neurotransmission Permissive An underlying deficiency of serotonin accompanied by decreased noradrenergic transmission

6. Pathophysiology hypotheses Neuroendocrine finding • Pituitary and adrenal glands are enlarged in depressed patients, and hypothalamic function may be abnormal. • Serotonin exerts a strong influence on HPA axis. • Approximately 45% to 60% of patients with major depression have a neuroendocrine abnormality, including hypersecretion of cortisol

7. NORADRENERGIC TRACTS Noradrenaline, a key neurotransmitter involved in the control of mood and emotional behavior, is believed to inhibit or stimulate a variety of emotional responses such as anxiety, aggression, stress, and sleep

8. SEROTONERGIC TRACTS Serotonin is involved in the regulation of pain, pleasure, anxiety, panic, appetite , and sleep behavior (the sleep-wake cycle).

9. Risk factors 1. Family history of depression a. 1st degree relative of patients with depression are 1.5 to 3 times more likely to develop depression b. Twin studies • Monozygotic twins have a 65% concordance rate for depression • Dizygotic twins have a 14% concordance rate for depression 2. Female gender 3. Previous depressive episode 4. Chronic medical illness 5. Substance abuse

11. Diagnostic Criteria (DSM-IV)for MDD • At least 5 symptoms present for 2 weeks most of day nearly every day • Represents change from previous functioning a. Depressed mood* b. Loss of interest or pleasure* c. Appetite or weight change d. Sleep disturbance e. Psychomotor agitation/retardation f. Fatigue/loss of energy g. Feelings of worthlessness/guilt h. Decreased concentration/indecisiveness i. Recurrent thoughts of death/suicidal ideation/suicide attempt 3. Symptoms cause social or occupational impairment 4. Symptoms are not due to substance abuse or medical condition 5. Symptoms are not due to gereavement

12. A-Melancholia (endogenous) Weight loss Early morning awakening Extreme listlessness Intense guilt Inability to cheer up even for a moment B- Psychotic (or delusional) Mood congruent Poverty, physical illness, moral transgressions Occur in 10–25% C-Atypical depression (exogenous) Increased appetite Weight gain Excessive sleep Leaden sensation in the arms and legs Mood reactive D-Postpartum Depression Onset of depression within 4 weeks occurs in 10% to 26% Depression Sub-classification

13. Specific features of diagnosis 1) Mild a) Minimum requirement to make diagnosis b) Minor functional impairment 2) Moderate • Greater degree of functional impairment 3) Severe a) Marked interference with social and/or occupational functioning b) Suicidal ideation

14. Assessing Depression

15. Target symptoms • D — depressed mood • S — sleep • I — interest • G — guilt • E — energy • C — concentration • A — appetite • P — psychomotor • S — suicide

16. Laboratory studies • There are no diagnostic lab tests for depression, although the following should be obtained to rule out other medical illnesses which mimic depression a. Complete blood count (CBC; i.e., anemia) b. Thyroid function tests (TFTs; i.e., hypothyroidism) c. Rapid plasma reagin (RPR; i.e., syphilis) d. Urine drug screen (i.e., substance abuse)

17. Prognosis • 70% of patients are responsive to antidepressant therapy 2. Relapse a. Following 1st episode, 50% experience another episode b. Following 2nd episode70% experience another episode c. Following 3nd episode 90% experience another episode

18. Hospitalization • Patients who lack capacity to cooperate with treatment • Patients at risk for suicide or other violent behavior • Patients who lack psychosocial supports • Patients who have other psychiatric or general medical problems.

19. Rating scales • General purpose a. Brief Psychiatric Rating Scale (BPRS), investigator-rated b. Hopkins Symptom Checklist (SCL-90), patient-rated • Disease-specific rating scales (depression) a. Investigator-rated 1) Hamilton Rating Scale for Depression (Ham-D, HRSD) 2) Montgomery-Asburg Depression Rating Scale (MADRS) b. Patient-rated 1) Beck Depression Inventory (BDI) 2) Zung Self Rating Scale

20. TREATMENT

21. Treatment Goals

22. Treatment

23. Psychotherapy a. Less severe b. Less chronic c. No psychotic d. Past positive response e. Medical contraindication to medications Medication a. More severe b. Chronic c. Recurrent d. Psychotic e. Melancholic f. Past positive response g. Family history h. Failure to respond to psychotherapy Choices of Treatment

24. Medication and psychotherapy a. More severe b. Chronic c. Partial response to either therapy alone d. Personality disorder Electroconvulsive therapy a. Psychotic b. Severe or extremely severe c. Past positive response d. Failure of several medications or combined treatment trials e. Need for rapid response f. Medical contraindications to medications Choices of Treatment

25. Antidepressant therapy • Initiation of therapy • Initiate therapy with divided doses to minimize adverse drug reactions • Consider age of patient and adjust accordingly • Target dose should be achieved as quickly as tolerated • Improvement in 3–4 weeks of therapy • Maximal response in 8 weeks of therapy

26. Phases of Treatment

27. Duration usually 6–12 weeks Response (symptom remission) a) Definition i) Complete (> 50% reduction) ii) Partial (> 20% but < 50%) iii) No response (< 20%) b) Rate of response i) First week • Decreased anxiety • Improvement in sleep • Improvement in appetite ii) 1–3 weeks • ↑ Activity, sex drive, self-care, memory • Thinking and movements normalize • Sleeping and eating patterns normalize iii) 2–4 weeks • Relief of depressed mood • Less hopeless/helpless • Thoughts of suicide subside Acute treatment

28. Continuation treatment • To prevent relapse • Continue antidepressant 6–9 months after 1st episode at same dose • Continue with the same treatment and the same dose in acute phase.

29. Maintenance treatment • 1 year duration • Use full therapeutic doses • Goal is to prevent new episode (recurrence) • Potential candidates a) Three episodes of MDD or b) Two episodes of MDD and: i) Family history of borderline personality disorder/recurrent MDD in 1st degree relative ii) Recurrence within 1 year after medicine discontinued iii) Onset before age 20 or after age 60 iv) Severe, sudden or life threatening depression

30. Factors to be consider on Selection of an antidepressant • Neurotransmitter profile family history • Side effect profile potential drug interactions • Patient age • cost • ease of administration (compliance) • Safety profile

32. ANTIDEPRESSANT MEDICATION: REVIEW

34. ANTIDEPRESSANT MEDICATION • Antidepressants can be classified in several ways, including by chemical structure and the presumed mechanism of antidepressant activity. • All antidepressants are potentially effective in the treatment of depression, they show similar efficacy when used in adequate dosages.

35. Antidepressants • TCA = Tricyclic Antidepressants • MAOI = Mono- Amines Oxides Inhibitor • SSRI = Selective Serotonin Reuptake Inhibitor • SNRI = Serotonin Reuptake Inhibitor

36. ANTIDEPRESSANT MEDICATION

37. ANTIDEPRESSANT MEDICATION Tricyclics “TCAs” • Amitriptyline 50 –300 mg/day • Clomipramine 50 –250 mg/day • Doxepin 25 –300 mg/day • Trimipramine 50 –300 mg/day • Imipramine 50 –300 mg/day • Desipramine 50 –300 mg/day • Nortriptyline 25 –150 mg/day • Protriptyline 10 – 60 mg/day Tertiaryamines Secondary amines

38. Mechanism Of Tricyclic Antidepressants TCA

39. ANTIDEPRESSANT MEDICATION Tricyclics • Block the reuptake of both norepinephrine(NE) , serotonin (5HT),muscarinic, alpha1 adrenergic, and histaminic receptors. • The extent of these effects vary with each agent resulting in differing side effect profiles. • TCA have effects on cardiac action potentials typical of class IA antiarrhythmics

40. Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*

41. Possible Adverse Effects of Reuptake Blocking of Antidepressant Drugs*

42. Possible Adverse Effects of Receptor Blocking of Antidepressant Drugs*

43. Tricyclic Antidepressants Managements of Anticholinergic side effects. • Impaired visual accommodation may be counteracted through the use of pilocarpine eye drops. • Urinary hesitation may be treated by prescribing bethanechol, 200 mg/day • Dry mouth may be counteracted by advising the patient to use sugarless gum or candy or by prescribing an oral rinse of 1% pilocarpine used three or four times daily. • Constipation is best dealt with through adequate hydration and the use of bulk laxatives.

44. Tricyclic Antidepressants Sedation • TCAs also have affinity for histaminergic receptors and produce varying degrees of sedation. • In general, tertiary amines cause greater sedation, whereas secondary amines cause less. • Patients with major depressive disorder with insomnia may benefit from sedation when their medication is given as a single dose before bedtime.

45. Tricyclic Antidepressants Weight gain. • TCAs have the capacity to induce weight gain possibly through their histaminergic properties. • The degree of weight gain appears to vary by agent (e.g., greater weight gain with amitriptyline and less with desipramine), be dose dependent, and be reversible with cessation of tricyclic antidepressant therapy.

46. Tricyclic Antidepressants Neurological effects. • TCAs can induce mild myoclonus, this may be a sign of toxicity. • Amoxapine, a TCA with antipsychotic properties, can also cause extrapyramidal side effects and tardive dyskinesia. • In overdoses, tricyclic antidepressants can precipitate seizures especially (Maprotiline).

47. ANTIDEPRESSANT MEDICATION Monoamine oxidase irreversible, non selective inhibitors “MAO Is” • Phenelzine 15 –90 mg/day • Tranylcypromine 10 – 60 mg/day • Inhibit the enzymatic breakdown of 5HT and NE. • They are usually reserved for atypical or resistant depression due to their toxicityprofile.

48. ANTIDEPRESSANT MEDICATION Reversible monoamine oxidase inhibitors ”RIMA” • Moclobemide • This unique mechanism results in a good tolerability profile and unlike traditional MAOIs, there is no need to restrict dietary tyramine.

49. Monoamine oxidase inhibitors Hypertensive crises. • A hypertensive crisis can occur when a patient taking an MAOI ingests large amounts of tyramine or other pressor amines in foods or medications. • This reaction is characterized by the acute onset of severe headache, nausea, neck stiffness, palpitations, profuse perspiration, and confusion, possibly leading to stroke and death.

50. Monoamine oxidase inhibitors Hypertensive crises. • Dietary restrictions include avoiding such foods as aged cheeses or meats, fermented products, yeast extracts • The list of medications that must be avoided includes all sympathomimetic and stimulant drugs as well as over-the-counter decongestants and cold remedies.