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DEPRESSION Diagnosis and treatment. TYPES of DEPRESSION.

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Presentation on theme: "DEPRESSION Diagnosis and treatment. TYPES of DEPRESSION."— Presentation transcript:

1 DEPRESSION Diagnosis and treatment

2 TYPES of DEPRESSION

3 Major Depressive Disorder Minor Depressive Disorder Recurrent Brief Depressive Disorder Bipolar Disorder – Depressive Episode Depressive Disorder NOS Premenstrual Dysphoric Disorder Mixed Anxiety-Depressive Disorder Postpsychotic Depressive Disorder of Schizophrenia Atypical Depression Depressive Disorder Due to a GMC Substance-Induced Depressive disorder Dysthymia

4 1. Insomnia or hypersomnia 2. Depressed mood or loss of interest or pleasure 3. Feelings of worthlessness 4. Fatigue 5. Diminished ability to think or make decisions 6. Weight change 7. Psychomotor retardation or agitation 8. Preoccupation with death,hopelessness DSM-IV Criteria for Major Depressive Episode 5 symptoms in the same 2-week period DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000.

5 Global burden of disease

6 Üstün and Sartorius (1995); Murray and Lopez (1996) Prevalence – 10%. Depression Recognised – 5%. Treated – 3%. World Health Organisations guideline for length of treatment for depression is 12 months. Actual length of treatment is 3-4 months.

7 Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19. Epidemiology of Depression Lifetime prevalence of a major depressive episode (MDE) 1 : 17% Male:13% Female:21% Trends Age at onset:younger Incidence:increasing Etiology:biologic vs psychologic

8 TREATMENT OF DEPRESSION Why is it important to be fast, effective and safe?

9 1.Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. AHCPR publication no April National Vital Statistics Reports. Vol 48, No. 11, July 24, Depression and Suicide Up to 15% of patients with MDD severe enough to require hospitalization eventually commit suicide 1 Suicide is the 8th leading cause of death in the U.S. 2

10 1.Frasure-Smith N, et al. JAMA. 1993;270: Penninx BW, et al. Arch Gen Psychiatry. 2001;58: Jiang W, et al. Arch Intern Med. 2001;161: Vaccarino V, et al. J Am Coll Cardiol. 2001;38: Rovner BW, et al. JAMA. 1991;265: Pohjasvaara T, et al. Eur J Neurol. 2001;8: Depression May Worsen Outcome of Many General Medical Conditions Depression may worsen morbidity and mortality after myocardial infarction 1,2 Depression increases morbidity and mortality in patients with CHF 3,4 Depression increases risk of mortality in patients in nursing homes 5 Depression worsens morbidity post-stroke 6

11 Lost productivity 55% Outpatient care 6% Suicide17% Inpatient care 19% Pharmaceuticals 3% Greenberg PE, et al. J Clin Psychiatry. 1993;54: Economics of Depression U.S.A. Data - Total Annual Cost ~$44 Billion U.S. data.

12 Depression in the old age

13 Lifetime prevalence of a major depressive episode (MDE) 1 : 17% Male:13% Female:21% Incidence of depression in ambulatory elderly patients (>65yrs) – 30% Epidemiology of Depression

14 Depression and Suicide 70% of suicides follow a depressive illness Most common risk factors: old age male gender Increasing age also an important risk factor in women

15 Depression and physical co-morbidity in older people Older patients diagnosed with major depression have a greater number of physical disorders Shows a high correlation with physical illness May worsen the course of physical illness May itself be modified by chronic ill health

16 Causes of death in depressed older patients The common causes of death in depressed older patients. Zubenko et al (1997) Disorders of digestive system 7% Neoplasms 14% Disorders of respiratory system 17% Disorders of circulatory system 46% Suicide 4% Others 12%

17 Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11. The goal of treatment in clinical practice should be remission of symptoms Treatment of Depression: Facing the Problem

18 Pharmacological treatment

19 Choosing Antidepressants Choose drugs according to side effect profile e.g., sedating drug for agitated depression Consider possible drug-drug interactions, P450 Iso enzymes Treatment of depression in the elderly Pharmacological treatment Tricyclic antidepressants - safety and tolerability SSRIs – Comparable efficacy: Improved safety and tolerability

20 1.Rush AJ, et al. Psychiatric Ann. 1995;25: Thase ME. J Clin Psychiatry. 1997;58: Frank E, et al. Arch Gen Psychiatry. 1991;48: Response Remission 50% decrease from baseline in HAM-D or MADRS scores CGI score of 1 or 2 HAM-D score 7 Minimally symptomatic or asymptomatic Psychosocial/occupational functioning restored Goals of Treatment in Major Depressive Disorder 1-3

21 Euthymia Symptoms Syndrome Treatment phases Progression to disorder Acute (6 to 12 wk) Continuation (4 to 9 mo) Maintenance ( 1 y) Time Increased severity Relapse Remission Recurrence Relapse Response Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5): Remission Is the Goal of Treatment in Major Depression

22 Up to 50% of responders do not achieve remission Residual symptoms are nearly as common as non-response Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11. The goal of treatment in clinical practice should be remission of symptoms Treatment of Depression: Facing the Problem

23 *P< Adapted from Paykel ES, et al. Psychol Med. 1995;25: Remission (HAM-D 17 7) Decreases Risk of Relapse Longitudinal follow-up study of patients treated with usual care by their physicians

24 Mean days of work missed per year * *P< Clinical depression status at 12-month assessment. Persistent=still meeting diagnostic criteria for MDD; response=HAM-D 8, but not meeting diagnostic criteria; remission=HAM-D 7. Simon GE, et al. Gen Hosp Psychiatry. 2000;22: Patients Treated to Remission Had Fewer Missed Workdays PersistentResponseRemission depression but not remission (n=118) (n=35)(n=137)

25 Treatment with Antidepressants

26 1950s 1960s 1970s 1980s 1990s Phenelzine Isocarboxazid Tranylcypromine Imipramine Clomipramine Nortriptyline Amitriptyline Desipramine Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram Nefazodone Mirtazapine Venlafaxine Duloxetine Milnacipran Reboxetine Moclobemide Escitalopram Maprotiline Amoxapine Mianserin The evolution of antidepressants

27 More serotonin selectiveMore noradrenaline selective 100 venlafaxine fluoxetine paroxetine sertraline fluvoxamine amitriptyline imipramine maprotiline nortriptyline protriptyline desipramine amoxapine Serotonin-noradrenaline spectrum of antidepressants noradrenaline uptake K i / serotonin K i serotonin K i / noradrenaline uptake K i

28 Different classes of antidepressant ClassExamples TCAs Clomipramine, imipramine, nortriptyline, desipramine, amitriptyline MAOIs Phenelzine, isocarboxazid RIMA Moclobemide SNRI Venlafaxine SSRIs Escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline Others Nefazodone, mianserin, reboxetine, tianeptine, bupropion, mirtazapine

29 First line Antidepressants Side effects Cost / availability Serotonin Selective Reuptake Inhibitors (SSRIs) The SSRI medications include fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram and escitalopram.fluoxetine paroxetinesertralinefluvoxaminecitalopramescitalopram Milnacipran

30 Second Line Antidepressant Newer Antidepressants A number of newer antidepressants including venlafaxine XR, nefazodone, bupropion SR, mirtazapine, and reboxetine have been recently approved for the treatment of MDD. These medications may be especially effective as "second-line" treatment in cases when a person has not responded that well to an SSRI venlafaxine XRnefazodonebupropion SR mirtazapinereboxetine

31 Forth line antidepressant Monoamine Oxidase Inhibitors (MAOIs) The MAOIs including phenelzine, tranylcypromine and isocarboxazid, are effective in treating depression. However, while effective, the MAOIs have side-effects that make them mostly a second- or third-line choice for treatment.phenelzine tranylcypromineisocarboxazid

32 SSRIs

33 General considerations about SSRIs Compared to TCAs, all SSRIs show a greater selectivity for inhibition of serotonin re-uptake than for norepinephrine re-uptake. SSRIs provide an advantageous safety profile. SSRIs lack TCA-like anticholinergic, cardiovascular, sedative and weight-increasing properties. SSRIs lack affinity for the various receptors implicated in TCA-induced adverse effects. Hale (1997); Leonard (1996)

34 References Honig A, Van Praag HM (eds)., Depression: Neurobiological, Psychopathological and Therapeutic Advances., 1997, New York: John Wiley & Sons, Unknown Leonard B., The comparative pharmacological properties of selective serotonin reuptake inhibitors in animals. In: Feighner JP, Boyer WF (eds.). Selective serotonin reuptake inhibitors: advances in basic research and clinical practice., 1996, 35–62., John Wiley & Sons Ltd, Unknown

35 General considerations about SSRIs Currently five drugs in this class with different structures, pharmacokinetic profiles and secondary pharmacology (Preskorn, 1996) Improved safety and tolerability profile compared with tricyclic antidepressants and MAOIs lack of anticholinergic, histaminergic and cardiovascular effects Clinically meaningful differences between the SSRIs efficacy in specific subgroups side-effect profile

36 References Preskorn SH., Clinical pharmacology of selective serotonin re- uptake inhibitors., 1996, Caddo, OK: Professional Communications Inc, Unknown

37 Comparative properties of SSRIs SSRIActive metabolite Fluoxetine Sertraline Paroxetine Elimination half-life Fluvoxamine Escitalopram Norfluoxetine Citalopram- Hale (1997); Sanchez et al (2002) ZimeldineNorzimeldine 1-3 days (parent drug) 1-3 weeks (metabolite) 26 hours 24 hours 15 hours 30 hours 8 hours (parent drug) 31 hours (metabolite) 33 hours

38 References Honig A, Van Praag HM (eds)., Depression: Neurobiological, Psychopathological and Therapeutic Advances., 1997, New York: John Wiley & Sons, Unknown

39 Comparative pharmacokinetic profiles of SSRIs SSRIMean half-life Steady-state plasma levels PK profile similar in adults & elderly Chirality Citalopram 33 hours a 7-14 days in adultsNo Yes s-enantiomer active r-enantiomer inactive Fluoxetine + norfluoxetine (active metabolite) 5 Days 15 days a 6-8 weeks, longer at higher doses and in the elderly No Yes s-r-fluoxetine & s-norfluoxetine potent SSRIs Fluvoxamine 15.6 hours7 daysYes No Paroxetine 21 hours 7 days, longer at higher doses and in the elderly No Sertraline 26 hours7 daysYes No a prolonged in the elderly; PK, pharmacokinetic Escitalopram 30 hours7-14 daysNo

40 References Benfield P, Ward A., Fluvoxamine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness., Drugs, 1986, 32: 313–34., Unknown Bjerkenstedt L, Flyckt L, Overo KF et al., Relationship between clinical effects, serum drug concentration and serotonin uptake in depressed patients treated with citalopram. A double-blind comparison of three dose levels., Eur J Clin Pharmacol, 1985, 28: 553– 7., Unknown Fuller RW, Snoddy HD, Krushinski JH., Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo., Neuropsychopharmacology, 1992, 31: 997–1000., Unknown Hrdina PD., Pharmacology of serotonin uptake inhibitors: focus on fluvoxamine., J Psychiatr Neurosci, 1991, 16 (Suppl 1): 10–18., Unknown Hyttel J, Bogeso KP, Perregaard J et al., The pharmacological effect of citalopram residues in the (s)-(+)- enantiomer., J Neural Transm Gen Sect, 1992, 88: 157–60., Unknown Kragh-Sorensen P et al., In: Usdin E, Dahl S, Gram LF et al. (eds). Clinical pharmacology in psychiatry: neuroleptics and antidepressant research., 1981, 351–8., London: Macmillan, Unknown Milne RJ, Goa KL., Citalopram: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in depressive illness., Drugs, 1991, 41: 450–77., Unknown Overmars H, Scherpenisse PM, Post LC., Fluvoxamine maleate: metabolism in man., Eur J Drug Metab Pharmacokinet, 1983, 8: 269–80., Unknown Overo KF., Preliminary studies of the kinetics of citalopram in man., Eur J Clin Pharmacol, 1978, 14: 69–73., Unknown Preskorn SH, Shad M, Alderman J et al., Fluoxetine: age and dose dependent pharmacokinetics and CYP 2C19 inhibition., Clin Pharmacol Therap, 1998, 63:166., Unknown Preskorn SH., Recent pharmacological advances in antidepressant therapy for the elderly., Am J Med, 1993, 94 (Suppl 5A): 2S– 12S., Unknown Preskorn SH., Pharmacokinetics of antidepressants: why and how are they relevant to treatment., J Clin Psychiatry, 1993, 54 (Suppl 9): 14–34., Unknown Ruijten HM, DeBree HD, Borst JM et al., Fluvoxamine: metabolic fate in animals., Drug Metab Dispos, 1984, 12: 82–92., Unknown Warrington SJ., Clinical implications of the pharmacology of the serotonin re-uptake inhibitors., Int Clin Psychopharmacol, 1992, 7 (Suppl 2): 13–19., Unknown

41 Relevance of drug half-life Long elimination half-life contributes to potential toxicity by promoting drug accumulation. Long elimination half-life increases the likelihood of drug- drug interactions. Half-life is important for the wash-out period. Longer half-life may be a protection against abrupt discontinuation symptoms. Preskorn (1997)

42 References Preskorn SH., Clinically relevant pharmacology of selective serotonin re-uptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism., Clin Pharmacokinet, 1997, 32 (1): 1–21., Unknown

43 Binding to plasma proteins Escitalopram and citalopram 50% van Harten (1993); Sanchez et al (2002) Fluvoxamine 77% Other SSRIsTCA over 90%

44 References van Harten, J., Clinical pharmacokinetics of selective serotonin reuptake inhibitors., Clin Pharmacokinet, 1993, 24 (3): 203–20., Unknown

45 Inhibitory effects of SSRIs on drug metabolising CYP450 isoenzymes Greenblatt et al (1998) Degrees of inhibition and the resultant potential for elevation of substrate plasma levels: minimal 10%; mild 10-50%; moderate %; substantial > 200%. a extrapolation from in vitro data; b at usually effective minimum dose. SSRICYP1A2CYP2C19CYP2D6CYP3A3/4Reference CitalopramMinimal a MinimalMild b MinimalPreskorn (1997) SertralineMinimalMinimalMildMinimalGreenblatt et al (1998) Fluoxetine and norfluoxetine Flu MinimalMildSubstantialMildLemberger et al (1988) Ozdemir et al (1998) FluvoxamineSubstantialSubstantialMildModerateKragh-Sorensen et al (1981) ParoxetineMildMildSubstantialMildPreskorn (1997) EscitalopramMinimalMinimalMildMinimalMoltke et al (2001)

46 Examples of drug metabolising cytochrome P450 – CYP1A2 Clomipramine Clozapine Propanolol Imipramine Paracetamol Theophylline Fluvoxamine Haloperidol Olanzapine Verapamil

47 Examples of drug metabolising cytochrome P450 – CYP2C19 Amitriptyline Diazepam Clomipramine Moclobemide Imipramine

48 Examples of drug metabolising cytochrome P450 – CYP2D6 Amitriptyline Clomipramine Desipramine Mianserine Propanolol Venlafaxine Antiarrhytmics Codeine Haloperidol Nortriptyline Risperidone Zuclopenthixol Nefazodone Trazodone Valproate

49 Examples of drug metabolising cytochrome P450 – CYP3A3/4 Clomipramine Imipramine Fluvoxamine Mirtazapine Nefazodone Verapamil Carbamazepine Clonazapam Alprazolam

50 References Greenblatt DJ, von Moltke LL, Harmatz JS, Shader RI., Drug interactions with newer antidepressants: role of human cytochromes P450., J Clin Psychiatry, 1998, 59 (Suppl 15): 19–27., Unknown Kragh-Sorensen P et al., In: Usdin E, Dahl S, Gram LF et al. (eds). Clinical pharmacology in psychiatry: neuroleptics and antidepressant research., 1981, 351– 8., London: Macmillan, Unknown Lemberger L, Rowe H, Bosomworth JC et al., The effect of fluoxetine on the pharmacokinetics and psychomotor responses of diazepam., Clin Pharmacol Therap, 1988, 43 :412–9., Unknown Ozdemir V, Naranjo CA, Herrmann N et al., The extent and determinants of change in CYP2D6 and CYP1A2 activities with therapeutic doses of sertraline., J Clin Psychopharmacol, 1998, 18: 55–61., Unknown Ozdemir V, Naranjo CA, Shulman RW et al., Determinants of interindividual variability and extent of CYP2D6 and CYP1A2 inhibition by paroxetine and fluvoxamine in vivo., J Clin Psychopharmacol, 1998, 18: 198–207., Unknown Preskorn SH., Clinically relevant pharmacology of selective serotonin re-uptake inhibitors: an overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism., Clin Pharmacokinet, 1997, 32 (1): 1–21., Unknown

51 Dosing regimen for SSRIs Drug Dosing regimen (mg/day) Comment Escitalopram Initial: 10Use lower doses in the elderly (10 mg) Range: 10-20T½ approx 40 hours in elderly Citalopram Initial: 20 Range: 20-60Recommended maximum in the elderly: 40 mg Fluoxetine Initial: 20 Range: Fluvoxamine Initial: Range: Paroxetine Initial: 20 Range: 20-50Recommended maximum in the elderly: 40 mg Sertraline Initial: 50 Range: Doses > 150 mg should not be used for longer than 8 weeks

52 References Dunner DL, Dunbar GC., Optimal dose regimen for paroxetine., J Clin Psychiatry, 1992, 53 (Suppl 2): 21–6., Unknown Fabre LF, Abuzzahab FS, Amin M et al., Sertraline safety and efficacy in major depression: a double-blind fixed dose comparison with placebo., Biol Psychiatry, 1995, 38: 592–602., Unknown Montgomery SA, Pedersen V, Tanghoj P, Rasmussen P, Rioux P., The optimal dosing regime for citalopram – a meta-analysis of nine placebo- controlled studies., Int Clin Psychopharmacol, 1994, 9S: 35–40., Unknown Wernicke JF, Dunlop SR, Dornseif BE et al., Fixed-dose fluoxetine therapy for depression., Psychopharmacol Bull, 1987, 23: 164–8., Unknown Wernicke JF, Dunlop SR, Dornseif BE., Low-dose fluoxetine therapy for depression., Psychopharmacol Bull, 1988, 24: 183–8., Unknown

53 Treatment of Depression: Facing the Problem Pharmacokinetics & Parmacodynamics alterations Drug-drug interactions Lower tolerance of side-effects Require simplicity of dosing

54 PSYCHOTHERAPY

55 AUGMENTATION

56 Augmantation Augmentations - Mood Stabelizers - Lithium - Lamotrigine - Pindolol - Buspirone - Tricyclic

57 Augmantation Antipsychotic Atypical - Risperdone - Olanzapine - Clozapine - Ziprazidone Typical - Metylphenidate - Tianeptine –increase serotonin reuptake

58 ECT

59

60 TMS

61 SLEEP DEPRIVATION

62 LIGHT THERAPY

63 Conclusions: Depression is under diagnosed and under treated Current therapies offer improved tolerability and efficacy These needs are fulfilled by Selective Serotonin Re- uptake inhibitors (SSRIs) SSRIs are recommended as the first drug of choice for MDD treatment


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