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depression

1. Depression Major Depressive Disorder ( MDD ) 1

2. Definition The essential feature of MDD is a clinical course that is characterized by one or more major depressive episodes without a history of manic, mixed, or hypomanic episodes. Dysthymic disorder is a chronic disturbance of mood involving depressed mood and at least two other symptoms, and it is generally less severe than major depressive disorder . This chapter focuses exclusively on the diagnosis and treatment of major depressive disorder.

3. Types of Depression Dysthymia Low grade but associated w/significant impairment Chronic Not reversed spontaneously (unlike MD) Tends to appear earlier Age of onset…………….. Often develops <15 y.o . If not addressed leads to MDD Seasonal Affective Disorder Occurs in Winter but gets improved in other seasons Occurs at least for 2 consecutive years More frequent in women Occurs at least for 2 consecutive years Light therapy ……..effective in 85% of patients 3

4. Postpartum Depression Up to 85% incidence New mothers affected the most Usually resolve spontaneously 5-20 % may last over 6 mo 5-20 % may last over 6 mo SSRIs are drug of choice (safe in pregnancy & breast feeding ) Melancholia extreme depression characterized by tearful sadness and irrational fears Atypical Depression 4

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6. PATHOPHYSIOLOGY Biogenic amine hypothesis. Depression may be caused by decreased brain levels of the neurotransmitters norepinephrine (NE), serotonin (5- HT ), and dopamine (DA ). Postsynaptic changes in receptor sensitivity. Studies of many antidepressants have demonstrated that desensitization or down regulation of NE or 5HT1A receptors may relate to onset of antidepressant effects . Dysregulation hypothesis. This theory emphasizes a failure of homeostatic regulation of neurotransmitter systems, rather than absolute increases or decreases in their activities. Effective antidepressants are theorized to restore efficient regulation to these systems . 6

7. 5- HT /NE link hypothesis. This theory suggests that there is a link between 5- HT and NE activity, and that both the serotonergic and noradrenergic systems are involved in the antidepressant response. The role of DA. Several reviews suggest that increased DA neurotransmission in the mesolimbic pathway may be related to the mechanism of action of antidepressants. 7

8. Epidemiology Major Depressive Disorder is the “ Common Cold ” of Mental Disorders As many as 12% of men and 21% of women may experience major depressive disorder during their lifetimes. Most patients with MDD are women . Prior to adolescence, boys and girls – Prior to adolescence, boys and girls are equally likely to experience depression . In adults, about 2/3 of patients with depression are female. Most patients experience 5–6 episodes during their lifetimes. About 33% of all depressed patients attempt… suicide - About half of them succeed 31,000 death per year in the US 8

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14. Risk Factors 14 • Genetic predisposition …. Family History 2.5x greater: 1 st degree relative twins : 65% increases incidence Gender difference……….. F 25%; M 15% Age …………Elderly higher incidence Race…Whites >Native Americans >African Americans Age …………Elderly higher incidence Co morbidity……. Marital status……….Single>Divorced>Widow Substance abuse

15. Risk Factors Stress: Abnormalities in glucocorticoids (highly elevated plasma cortisl is demonstrated in Depressed >> psychiatric > normal pnts ) Sleep Patterns Depressed people: enter REM earlier. spend little time in Stage 3 or 4. awaken frequently. 15

16. CLINICAL PRESENTATION DSM-IV- TR Criteria for Major Depressive Episode Diagnostic Criteria: 4 Criteria Clinical Symptoms Duration of illness Duration of illness Impact of quality of life Absence of other organic diseases 16

17. Diagnostic Criteria I . Five or more of the following symptoms for at least two week period . One of the symptoms is either : Depressed mood Loss of interest in pleasurable activities II. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. III . Cannot be established that an organic factor initiated or maintained the disturbance 17

18. Diagnostic Criteria A SAD FACE A – Appetite (Poor; 5-10 lb gain if atypical) S – Sleep (insomnia) A – Anhedonia (loss of interest in life) D - Depressed Mood F - Fatigue D - Depressed Mood A - Agitation C – Concentration (Lack of) E – Esteem (low self-esteem) S - Suicide thought (still remains high) 18

19. DESIRED OUTCOME The goals of treatment of the acute depressive episode are to eliminate or reduce the symptoms of depression, minimize adverse effects, ensure compliance with the therapeutic regimen, facilitate a return to a premorbid level of functioning, and prevent further episodes of depression. 19

20. TREATMENT NONPHARMACOLOGIC TREATMENT The efficacy of psychotherapy and antidepressants is considered to be additive . Psychotherapy alone is not recommended for the acute treatment of patients with severe and/or psychotic major depressive disorders. For uncomplicated nonchronic major depressive disorder, combined treatment may provide no unique advantage. Cognitive therapy, behavioral therapy, and interpersonal psychotherapy appear to be equal in efficacy. 20

21. Electroconvulsive therapy ( ECT ) is a safe and effective treatment for major depressive disorder. It is considered when a rapid response is needed, risks of other treatments outweigh potential benefits, there has been a poor response to drugs, and the patient expresses a preference for ECT . A rapid therapeutic response (10 to 14 days) has been reported. Relative contrain-dications include increased intracranial pressure, cerebral lesions, recent myocardial infarction, recent intracerebral hemorrhage, bleeding, and otherwise unstable vascular conditions. Adverse effects of ECT include confusion , memory impairment (retrograde and anterograde), prolonged 21

22. apnea, treatment emergent mania, headache, nausea, muscle aches, and cardiovascular dysfunction. Relapse rates during the year following ECT are high unless maintenance antidepressants are prescribed. • Bright light therapy (i.e., the patient looking into a 10,000-lux intensity light box for about 30 min/day) may be used for patients with seasonal affective disorder and as adjunctive use for major depression. 22

23. PHARMACOLOGIC THERAPY—General Therapeutic Principles In general, antidepressants are equal in efficacy in groups of patients when administered in comparable doses. Between 65% and 70% of patients with major depression improve with drug therapy. Psychotically depressed individuals generally require either ECT or combination therapy with an antidepressant and an antipsychotic agent . 23

24. General Treatment Rules Often takes………. 4-6 weeks for response Monitor for ……response versus remission Vegetative symptoms ……….. tend to improve first, cognitive symptoms take –longer SSRI’s are …………. the first line of treatment for most MDD’s Address biopsychosocial needs and maintain meds for 6-12 months 24

25. 25 Educating patients and supportrs regarding the delay in antidepressant effects (typically 2 to 4 weeks) and the importance of adherence should occur before therapy is started and throughout treatment.

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27. General principles…phases of Treatment ( Tx ) Acute phase of Tx : lasts 6 to 10 weeks, and the goal is remission (i.e., absence of symptoms). Continuation phase lasts 4 to 9 months after remission. The goal is to eliminate residual symptoms or prevent relapse. Maintenance phase lasts at least 12 to 36 months, and the goal is to prevent recurrence of a separate episode of depression. Some clinicians recommend lifelong maintenance therapy for persons at greatest risk for recurrence (i.e., persons younger than 40 years with two or more prior episodes and persons of any age with three or more prior episodes ). 27

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29. General Principles….factors in choice Factors in the choice of antidepressant include: patient’s or familial history of response-Use it if it works in the past concurrent medical conditions , MAOI – Atypical features Mood stablizers – Mania Avoid Bupropione / TCA – Seizure d/o Bupropirone – Parkinsons ’ Disease TCA – Migraine presenting symptoms, potential for drug–drug interactions, comparative side-effect profiles of various drugs , E.g . Drugs that are associated with wt gain (young vs. old) Patient desire – direct to patient ad. 30% placebo effect & drug cost 29

30. DOSING The usual initial adult dose of most TCAs is 50 mg at bedtime, and the dose may be ↑ ed by 25 to 50 mg every third day. Bupropion is usually initiated at 100 mg twice daily, and this dose may be ↑ ed to 100 mg three times daily after 3 days. An ↑ to 450 mg / day (the ceiling dose), given as 150 mg three times daily, may be considered in patients with no clinical response after several weeks at 300 mg/day . A 6-week antidepressant trial at a maximum dosage is considered an adequate trial. Patients must be told about the expected lag time of 2 to 4 weeks before the onset of antidepressant effect. Elderly patients should receive one-half the initial dose given to younger adults , and the dose is increased at a slower rate. The elderly may require 6 to 12 weeks of treatment to achieve the desired antidepressant response. To prevent relapse, antidepressants should be continued at full therapeutic doses for 4 to 9 months after remission. 30

31. DRUG CLASSIFICATION 31

32. Selective Serotonin Reuptake Inhibitors ( SSRIs ) SSRIs inhibit the reuptake of 5- HT into the presynaptic neuron. They are generally chosen as first line antidepressants because of their safety in overdose and improved tolerability compared to earlier agents . The SSRIs , with the possible exception of citalopram & sertraline , may have a nonlinear pattern of drug accumulation with chronic dosing. 32

33. Citalopram ( Celexa ): 20 mg initially; maintenance 40 mg per day; maximum dose 60 mg per day. Escitalopram (Lexapro, Cipralex ): 10 mg and shown to be as effective as 20 mg in most cases. Maximum dose 20 mg. Also helps with anxiety. Paroxetine (Paxil, Seroxat ): Also used to treat panic disorder, OCD , social anxiety disorder, generalized anxiety disorder and PTSD . Usual dose 25 mg per day; may be increased to 40 mg per day . Available in controlled release 12.5 to 37.5 mg per day; controlled release dose maximum 50 mg per day. Less cycling in patients who are bipolar . 33

34. Fluoxetine (Prozac): Also used to treat OCD , bulimia, and panic disorder ( PD ). Long half-life; less withdrawal when medication is stopped. Dosing is 20 mg to a maximum of 80 mg. Fluvoxamine ( Luvox ): Although primarily used in OCD , it can be used for depression . Initial dose is 50 mg, If daily dose is greater than 100 mg give in equally divided doses or give larger dose at bedtime not to exceed 300 mg per day. Sertraline (Zoloft, Lustral ): Also used to treat PD , OCD , PTSD , SAD, premenstrual dysphoric disorder. Dosing is 50-200 mg per day and should be titrated upward 34

35. A patient with MDD was started with Zoloft ® 100 mg q.d . for 4-6 weeks with minimum or no change in his symptoms. Your recommendation is: A . switch to another SSRI (Prozac®) B . increase the dose of Zoloft® C . wait for another week D . none of the above 35

36. SSRIs Dosage Fluoxetine [Prozac] 10-80 mg/d Paroxetine [Paxil] 10-50 mg/d Sertraline [Zoloft] 25-200 mg/d Fluvoxamine [ Luvox ] 50-300 mg/d Citalopram[ Celexa ] 20-50 mg/d Initial response 2-4 wks If there is a response but not adequate response after 3-4 wks increase dose . If no response at all, switch . One SSRI failure should not dictate class switch 36

37.   5-HT DA NE Half-life Fluoxetine +++ + + 45 (24-144) Norfluoxetine 200 hrs Sertraline +++ ++ 26 (23-26) Desomethylsertraline 71 Paroxetine +++ + ++ 18 (7-65) Fluvoxamine +++ + 15 (9-28) Citalopram ++++ 33 (23-45) 37 Which SSRI does not need tapering before discontinuation of therapy?

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39. SSRIs …. Adverse effects Fewer sedative, anticholinergic, and cardiovascular adverse effects than the TCAs and are less likely to cause weight gain than the TCAs . The primary adverse effects include: GI: N/V/diarrhea (Fluoxetine/sertraline); Constipation (paroxetine) CNS: headache ( paroxetine ), insomnia (Fluoxetine) fatigue , and sexual dysfunction. A few patients have anxiety symptoms early in treatment. 39

40. SSRIs and Sexual Dysfunction Common ………..class effect (All, except fluoxetine ) Affects both……….men and women Reduced libido Orgasmic dysfunction delayed ejaculation anorgasmia Erection difficulties …….. Minimal Associated with anxiety/depression 40

41. SSRIs Late onset side effect Weight gain ( Paroxetine >> Fluoxetine> sertraline) Patients on SSRIs gain 10 pounds year … Weight gain antidotes---- Weight loss ( Phen -Pro) Add: Stimulants, / H2 Blockers, / Topiramate Switch to: Bupropion / Nafazodone Increase exercise ( Regular exercise ) Nutritional consult ( nutritionally balanced, low calorie diet ) 1,200 to 1,500 calories per day: 60 % carbohydrate , 30 % fat , & 10 % protein . Tiredness (Weakness, Fatigue, Asthenia) and Apathy (blunting of emotion, amotivation , lack of excitement by anything) 41

42. SSRI – Serotonin Syndrome may occur, where mental status changes along with …… Agitation sweating Shivering tremors Shivering tremors Diarrhea uncoordination fever may develop This syndrome may be life-threatening . SSRIs should not be used with any drug that increases serotonin concentrations, including…. 42 Tramadol Sibutramine MAO inhibitors Meperidine Lithium St. John's wort Sumatriptan Some anti-psychotics Ginkgo biloba .

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45. Tricyclic antidepressants ( TCAs ) Chemical structure with characteristic three -ring nucleus Originally developed as antipsychotic s (1949), but were found to have no effect in this indication. TCAs are effective for all depressive subtypes , but less used because of the availability of equally effective but safer on overdose and better tolerated therpies . Principal mechanism of action: blockade of re-uptake of NA and 5- HT by competition for binding site of the carrier protein. in most TCA , other receptors (incl. those outside the CNS) are also affected: blockade of H1 -receptor, a-receptors, M-receptors 45

46. TCA depression dosing Tertiary amines – amitriptyline (Elavil) = 50-300 mg – imipramine ( Tofranil ) = 50-300 mg – doxepine ( Sinequan ) = 50-300 mg – doxepine ( Sinequan ) = 50-300 mg Secondary amines – nortriptyline ( Aventyl ) = 50-150 mg – desipramine ( Norpramine ) = 50-300 mg – protryptline ( Vivactil ) = 15-60 mg TCA Other Indications Anxiety (Panic); Chronic pain; Migraine; Neuropathy; Easting Disorder 46

47. Adverse effects of TCAs Anticholinergic side effects ( e.g., dry mouth, blurred vision, constipation , urinary retention, tachycardia, memory impairment, and delirium ) & sedation are more likely to occur with tertiary amine s than with secondary amine TCAs . Orthostatic hypotension (& resultant syncope), a common and potentially serious adverse effect of the TCAs , occurs as a result of a-adrenergic antagonism . Additional side effects include cardiac conduction delays and heart block, especially in patients with preexisting conduction disease. Other side effects that may lead to noncompliance include weight gain and sexual dysfunction. Abrupt withdrawal of TCAs (especially high doses) may result in symptoms of cholinergic rebound (e.g., dizziness, nausea, diarrhea, insomnia , restlessness). 47

48. TCA Overdose & Acute Intoxication Unfortunately TCA have…… a low therapeutic index: Target systems (toxicity) – the CNS and heart Initially excitement, hallucinations and deliriumis observed , may be accompanied with convulsions. Coma and respiratory depression may follow. Cardiac dysr rhythmias are very common – tachycardia QRS complex widening, QT interval elongation. Ventricular fibrillation and sudden death may occur. Hypotension Treatment- diazepam ( for seizures ), No effect of haemodialysis & hemoperfusion is-practically ineffective 48

49. MonoAmine Oxidase Inhibitors ( MAOI ) The first compounds ( iproniazid derivatives) were originally developed as antimycobacterial drugs bychemical modification of isoniazid molecule ( 1950s ). ADR ……hypertensive crisis, hepatotoxicity, insomnia 49 Agents Initial Dose (mg/day) Dose (mg/day) Selegiline (Eldepryl) 5 mg 10-30 Isocarboxazide (Marplan) 10 mg 30-60 Phenelzine (Nardil) 15 mg 45-90 Tranylcypromine (Parnate) 10 mg 20-40

50. monoamine oxidase inhibitors ( MAOIs ) MOA: increase the concentrations of NE, 5- HT , and DA within the neuronal synapse through inhibition of the MAO enzyme system. phenelzine and tranylcypromine: Both are nonselective inhibitors of MAO-A & MAO-B . Selegiline is available as a transdermal patch for treatment of major depression. It inhibits MAO-A and MAO-B in the brain, but has reduced effects on MAO-A in the gut . Oral selegiline is selective for MAO-B at lowdose used for Parkinson's... but it's nonselective at higher doses needed for depression . 50

51. Adverse effect (AE) of MAOIs Most common AE of MAOIs is postural hypotension ( more likely with phenelzine than tranylcypromine), minimized by divided-daily dosing. Anticholinergic side effects are common but less severe than with the TCAs . Phenelzine causes mild to moderate sedating effects, but tranylcypromine is often stimulating, and the last dose of the day is administered in early afternoon. Sexual dysfunction in both genders is common . Phenelzine has been associated with hepatocellular damage and weight gain . 51

52. AE of MAOIs …. Hypertensive crisis is a potentially fatal adverse reaction if taken concurrently with certain foods, especially high in tyramine , and with certain drugs. Symptoms: occipital headache, stiff neck, nausea, vomiting, sweating, and sharply elevated blood pressure. Managemet Can be treated with agents, such as captopril . Education of patients taking MAOIs regarding dietary and medication restrictions is critical. 52

53. MOAI …. Interaction with foods The most serious problem of this class of drugs Tyramine „cheese and wine“ reaction some kind of foods contain high amounts of tyramine (natural indirect sympathomimetic produced during fermentation), which is however normally metabolized by MAO in the gut and liver. is however normally metabolized by MAO in the gut and liver. In depressed patients treated with MAO , these enzymes are also inhibited →bioavailability of tyramine is significantly higher which together with pharmacodynamic synergism → strikingly increased noradrenaline transmission results in hypertensive crisis , severe headache and potentially fatal intracranial hemorrhage or other organ damage. Dietary precautions: restriction in the consumption of some maturing cheeses, wine, beer, yogurts, bananas etc. 53

54. MOAI …….. Interaction with drugs Hypertension & hypertensive crisis TCA wash-out period (2 weeks) when switching these antidepressants ! Lower risk in RIMA. levodopa (catecholamine precursor), sympathomimetics Serotonin syndrome ( SSRI , TCA , opioids e.g. Pethidin ) confusion , agitation and excitation, tremor, fever, sweating, nausea , diarrhea, sleep disruption Prolongs and profound the effect of: benzodiazepines, antihistamines , alcohol (inhibition of liver enzymes – low specificity ) 54

55. Triazolopyridines ( Serotonin antagonist and reuptake inhibitors ( SARIs ) ) The triazolopyridines are antagonists at the 5HT 2 receptor and inhibit the reuptake of 5-HT. They can also enhance 5HT 1A neurotransmission . They have negligible affinity for cholinergic and histaminergic receptors . Etoperidone ( Axiomin , Etonin ) Lubazodone ( YM -992, YM -35,995) Nefazodone ( Serzone , Nefadar )….in many countries banned from sale because of Liver failure and injury Trazodone ( Desyrel ) 55

56. Triazolopyridines Adverse effect Trazodone and nefazodone cause minimal anticholinergic effects. Seda tion , dizziness, and orthostatic hypotension are the most frequent dose limiting side effects. Priapism occurs rarely with trazodone use (1 in 6,000 male patients). Surgical intervention may be required, and impotence may result. A black box warning for life-threatening liver failure was added to the prescribing information for nefazodone . Treatment with nefazodone should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases 56

57. Aminoketone ( Norepinephrine-dopamine reuptake inhibitors ( NDRIs )……Bupropion ) Bupropion’s most potent blockade of DA reuptake ; it blocks the reuptake of NE to a lesser extent . Brand names: Wellbutrin SR Half-life : 10-21 hours Dosage : Initiate with 100 mg bid Maintenance dose: 300-450 mg/day (divided doses) Notes : max dose 150 mg/dose Last daily dose no later 5 pm 57

58. Bupropion … side effects Side effect: proven efficacy and clinical safety profile Seizure: Most common, dose related and increase by predisposing factors (e.g., history of head trauma or CNS tumor). At the ceiling dose (450 mg/day), the incidence of seizures is 0.4%. Other side effects include nausea, vomiting, tremor, insomnia, dry mouth, and skin reactions. Rash Different dyes used for 100 mg and 150 mg SR Rash with one does not mean rash with the other Low incidence of sexual side effects and weight gain Contraindicated: bulimia or anorexia nervosa . 58

59. Questions A patient called for a refill prescription of his bupropione medication (150 mg bid). Upon discussing with him he told you that he has been itching for the entire month. Your recommendation is: A. to stop medication immediately B. to dispense a 100 mg dose and instruct him to take 1 ½ dose and to report if the itching continues. C. tell the patient that the allergy may be something else because bupropione never reported to cause allergic reaction. 59

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61. Serotonin-Norepinephrine Reuptake Inhibitors ( SNRIs ) Venlafaxine (Effexor): inhibitor of 5- HT & NE reuptake & weak inhibitor of DA reuptake . Also for generalized anxiety (GAD) & social anxiety disorder. Dose 37.5 mg …..Maximum dose 375 mg in XL form. BP should be monitored as this medication can increase it. Desvenlafaxine ( Pristiq ); recently approved by FDA ….Similar to Venlafaxine The dose is 50 mg once daily . Duloxetine (Cymbalta)…………. Dosing 40 mg two X daily or 60 mg once daily. Milnacipran ( Ixel , Savella ): ….. Manufactured in France by Pierre Fabre. 61

62. Venlafaxine: cause a dose-related increase in diastolic BP…Especially in men Dosage reduction or discontinuation may be necessary if sustained hypertension occurs. Other side effects are similar to those with the SSRIs usually mild - often get milder or disappear after the first couple of weeks of treatment. (e.g., N & V…Worse after switching from 2D6 inhibitor (e.g. Fluoxetine) Dizziness sexual dysfunction ( don't improve with time )). About 1 in 7 people stop taking venlafaxine because of side effects . 62

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64. SNRIs … Desvenlafaxine succinate ( Pristiq ®) approve in…………2008 Is an extended release of active metabolite of venlafaxine …. like Effexor XR It has………a lower recommended dose ie , 50 mg daily vs 75-225 mg daily because of the greater bioavailability of the succinate salt Pristiq doses over 50 mg don't work better ...& increase side effects. Pristiq and Effexor XR to cause …… similar side effects...nausea, dry mouth, sexual dysfunction , insomnia, etc. Pristiq and other SNRIs …………. can increase blood pressure by affecting norepinephrine . monitoring BP is recommended. 64

65. Duloxetine Good for emotional and physical symptoms of depression and for Diabetic peripheral neuropathy Therapeutic dosage range is 60-120 mg/day The most common side effects are nausea , dry mouth, constipation, decreased appetite, insomnia, and increased sweating. 65

66. Question The antidepressant drug of choice for patients with cardiac disease includes: – A. amitriptyline – B. Paxil® – A. amitriptyline – C. Cymbalta® – D. all of the above 66

67. SNRIs ( Venlafaxine , Duloxetine , etc.) and Worsening of Heart Failure • There are reports of …heart failure exacerbations in patients shortly after starting venlafaxine ( Effexor®) or duloxetine. Not well proven – Depression itself can also worsen heart failure. To be safe ……….suggest using an SSRI (sertraline, etc ) for initial treatment of depression in heart failure patients. Counsel heart failure patients to report ………… right away any fatigue, edema, trouble breathing, etc after starting an SNRI . 67

68. SNRIs and Worsening of HF ….. All serotonin norepinephrine reuptake inhibitors can increase heart rate and blood pressure... which can cause problems for patients with advanced or unstable heart failure . Heart failure patients have …….. high circulating levels of NE to compensate for poor cardiac output. NE helps to make the heart pump faster and more forcefully. However , this sustained response increases demand on an already damaged heart... eventually leading to further deterioration of heart function. It makes sense that drugs that increase norepinephrine MIGHT lead to worsening heart failure. 68

69. Tetracyclic antidepressants ( TeCAs ) Mirtazapine ( Remeron ) Amoxapine ( Asendin ) Maprotiline ( Ludiomil ) Mianserin ( Bolvidon , Norval , Tolvon )• Mianserin ( Bolvidon , Norval , Tolvon ) 69

70. Mirtazapine : Has Mixed Serotonin-Norepinephrine Effects…complex mechanism of action …not reuptake inhibitor enhances central noradrenergic and serotonergic activity through the antagonism of central presynaptic a2 -adrenergic autoreceptors and heteroreceptors . It also antagonizes 5- HT2 and 5- HT3 receptors. It also blocks histamine receptors . Therapeutic dose range 15-60 mg/day Most common adverse effects: somnolence , weight gain , dry mouth, and constipation. 70

71. Mirtazapine Side Effects Sjogren’s ( sho 'grənz ) Syndrome (rare) Minimal sexual dysfunction Increased appetite and weight gain: The weird thing about mirtazapine ( Remeron ) is in Europe people do not gain weight. ……..but ………In the placebo-controlled trials in the US …………the rates of weight gain was around 10% Sedation: goes down as you increase the dose because the effects on norepinephrine relative to the antihistaminergic effects start to go up. 71

72. Other Heterocyclics Maprotiline and amoxapine inhibitors of NE reuptake, with less effect on 5- HT reuptake. Amoxapine is a demethylated metabolite of loxapine and, as a result of its postsynaptic receptor DA-blocking effects, may be associated with extra-pyramidal side effects. Maprotiline , a tetracyclic drug, causes seizures at a higher incidence than do standard TCAs and is contraindicated in patients with a history of seizure disorder. The ceiling dose is considered to be 225 mg/day . 72

73. • St. John’s wort , an herbal nonprescription medication containing hypericum , may be effective for mild to moderate depression, but it is associated with several drug–drug interactions. Its potency, purity, and manufacture are not regulated by the FDA. As depression is a potentially life-threatening disease, all antidepressant treatments should be overseen by a trained healthcare professional. 73

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75. SPECIAL POPULATIONS--- Elderly Patients SSRIs : first-choice antidepressants in elderly patients . In healthy elderly patients, cautious use of a secondary amine TCA ( desipramine or nortriptyline ) may be appropriate because of their defined therapeutic plasma concentration ranges, well-established efficacy, and well known adverse-effect profiles. Bupropion and venlafaxine may also be chosen because of their milder anticholinergic and less frequent cardiovascular side effects. 75

76. Children and Adolescents Data supporting efficacy of antidepressants in children and adolescents are sparse . Fluoxetine is the only antidepressant that is FDA approved for age less than 18 years of age. Antidepressant use and suicidality ( suicidal thinking and behaviors) in children, adolescents, & young adults 18 to 24 years old. All antidepressants carry a black box warning. A baseline CG is recommended before initiating a TCA in children and adolescents, and an additional ECG is advised when steady-state plasma concentrations are achieved. TCA plasma concentration monitoring is critical to ensure safety. 76

77. Pregnancy As a general rule, if effective, nondrug approaches are preferred when treating depressed pregnant patients . The risks of untreated depression in pregnancy should be considered. One study showed that pregnant women who discontinued antidepressants were five times more likely to relapse during their pregnancy than were women who continued treatment. No major teratogenic effects have been identified with the SSRIs or TCAs . 77

78. REFRACTORY PATIENTS Most “treatment-resistant” depressed patients have received inadequate therapy. Issues to be considered in non respondents: ( 1) Is the diagnosis correct? ( 2) Does the patient have a psychotic depression ? ( 3) Has patient received adequate dose & duration of treatment? ( 4) Do adverse effects preclude adequate dosing ? (5) Has the patient been compliant with the prescribed regimen? ( 6) Was treatment outcome measured adequately? ( 7) coexisting or preexisting medical or psychiatric disorder? ( 8) Was a stepwise approach to treatment used ? ( 9) Are there other factors that interfere with treatment ? 78

79. The STAR*D study showed that one in three depressed patients who previously did not achieve remission with an antidepressant became symptom-free with the help of an additional medication (e.g., bupropion sustained release), and one in four achieved remission after switching to a different antidepressant (e.g., venlafaxine XR ). 79

80. after 6 to 8 weeks of antidepressant treatment, partial responders changing the dose, augmenting the antidepressant, or adding psychotherapy or ECT . T hose with no response , changing to another antidepressant or the addition of psychotherapy or ECT . 80

81. EVALUATION OF THERAPEUTIC OUTCOMES Several monitoring parameters, in addition to plasma concentrations, are useful in managing patients. Patients must be monitored for adverse effects , remission of previously documented target symptoms, and changes in social or occupational functioning. Regular monitoring should be assured for several months after antidepressant therapy is discontinued. 81

82. Patients given venlafaxine should have blood pressure monitored regularly. Patients older than age 40 years should receive a pretreatment ECG before starting TCA therapy, and follow-up ECGs should be performed periodically. Patients should be monitored for emergence of suicidal ideation after initiation of any antidepressant, especially in the first few weeks of treatment. In addition to the clinical interview, psychometric rating instruments allow for rapid and reliable measurement of the nature and severity of depressive and associated symptoms 82