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Diagnosis and treatment

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Presentation on theme: "Diagnosis and treatment"— Presentation transcript:

1 Diagnosis and treatment
DEPRESSION Diagnosis and treatment

2 TYPES of DEPRESSION

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

5 Global burden of disease
Moderator Summary None Found User Notes

6 Depression Prevalence – 10%. Recognised – 5%. Treated – 3%.
World Health Organisation’s guideline for length of treatment for depression is 12 months. Actual length of treatment is 3-4 months. Moderator Summary Studies carried out in general health services have demonstrated that, on average, 10% of all contacts with general healthcare services occur because of the presence of a depressive disorder. These findings have been duplicated a number of times and in different parts of the world. A discrepancy exists between the prevalence of depression and the percentage of cases which are recognised. The World Health Organisation figures show the actual average length of treatment for depression is 3 to 4 months, compared with their recommendation of 12 months. User Notes None Found Üstün and Sartorius (1995); Murray and Lopez (1996)

7 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 Depression is a common and increasingly recognized disorder Depression is an increasingly important health problem, with an estimated lifetime prevalence of 17.1% in the United States.1 Lifetime prevalence is defined as the proportion of those sampled who have experienced a specific disorder at least once in their lifetime1 Depression is almost twice as common in women (21.3%) as in men (12.7%)1 A recent cross-national survey of epidemiologic studies showed that major depression occurs more often in women in every country studied2 According to a worldwide epidemiologic survey, the mean age of onset of depression ranges from 25 to 35 years2 The current model of depression has shifted from one based on maladaptive psychological processes to one based on biologic processes. This shift has increased the recognition of depression as a medical illness and has increased the emphasis on pharmacotherapy in its treatment The incidence of depression has been increasing, with a focus on younger age groups Sources: 1. Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19. 2. Weissman MM, et al. JAMA. 1996;276: Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19.

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

9 Depression and Suicide
Up to 15% of patients with MDD severe enough to require hospitalization eventually commit suicide1 Suicide is the 8th leading cause of death in the U.S.2 Suicide can be a significant risk among patients with depression Up to 15% of patients with MDD severe enough to require hospitalization eventually die of suicide1 According to the National Center for Health Statistics, suicide is the 8th leading cause of death in the United States and is responsible for more than 30,000 deaths annually2 This high mortality rate necessitates the accurate identification and immediate treatment of patients experiencing MDD Sources: 1. Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. AHCPR publication no April 1993. 2. National Vital Statistics Reports. Vol 48, No. 11, July 24, 2000. 1. Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. AHCPR publication no April 1993. 2. National Vital Statistics Reports. Vol 48, No. 11, July 24, 2000.

10 Depression May Worsen Outcome of Many General Medical Conditions
Depression may worsen morbidity and mortality after myocardial infarction1,2 Depression increases morbidity and mortality in patients with CHF3,4 Depression increases risk of mortality in patients in nursing homes5 Depression worsens morbidity post-stroke6 Depression may worsen the morbidity and mortality of many general medical conditions When depression is accompanied by certain nonpsychiatric medical conditions (eg, coronary artery disease, diabetes), the outcome of these concurrent medical disorders is likely to be worse than if depression were not present Specifically, depression has been shown to worsen outcomes after myocardial infarction and increase the risk of cardiac mortality1,2 Recent studies also have confirmed that the presence of major depression or depressive symptoms is associated with increased morbidity and mortality in patients with congestive heart failure (CHF)3,4 The presence of depression may increase the risk of mortality in patients in nursing homes5 Depression may worsen outcomes after stroke6 Sources: 1. Frasure-Smith N, et al. JAMA. 1993;270: 2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58: 3. Jiang W, et al. Arch Intern Med. 2001;161: 4. Vaccarino V, et al. J Am Coll Cardiol. 2001;38: 5. Rovner BW, et al. JAMA. 1991;265: 6. Pohjasvaara T, et al. Eur J Neurol. 2001;8: 1. Frasure-Smith N, et al. JAMA. 1993;270: 2. Penninx BW, et al. Arch Gen Psychiatry. 2001;58: 3. Jiang W, et al. Arch Intern Med. 2001;161: 4. Vaccarino V, et al. J Am Coll Cardiol. 2001;38: 5. Rovner BW, et al. JAMA. 1991;265: 6. Pohjasvaara T, et al. Eur J Neurol. 2001;8:

11 Economics of Depression — U.S.A. Data - Total Annual Cost ~$44 Billion
Lost productivity—55% Suicide—17% Depression can be associated with considerable direct and indirect costs Pharmaceuticals—3% Outpatient care—6% The morbidity costs associated with depression in the workplace are derived from traditional research, including costs arising from workplace absenteeism of depressed employees, as well as reductions in workplace productivity during the employees’ episodes of depression1 Up to 15% of patients with MDD severe enough to require hospitalization eventually die of suicide.2 This high mortality rate necessitates the accurate identification and immediate treatment of patients experiencing MDD Depression is associated with direct and indirect costs that place a significant burden on society1 MDD, if left untreated, significantly worsens health and functioning, giving rise to physical complaints and increased use of health care resources3 Sources: 1. Greenberg PE, et al. J Clin Psychiatry. 1993;54: 2. Depression Guideline Panel. Depression in Primary Care: Volume 1. Detection and Diagnosis. Clinical Practice Guideline, Number 5. AHCPR publication no April 1993. 3. Henk HJ, et al. Arch Gen Psychiatry. 1996;53: Inpatient care—19% Greenberg PE, et al. J Clin Psychiatry. 1993;54: U.S. data.

12 Depression in the old age

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

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. Others 12% Disorders of circulatory system 46% Suicide 4% Disorders of digestive system 7% Neoplasms 14% Disorders of respiratory system 17% Zubenko et al (1997)

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

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 Goals of Treatment in Major Depressive Disorder1-3
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 Attainment of remission is the best way to prevent depression-related morbidity1 The major health problem represented by recurrent depression mandates successful, long-term treatment.2 The minimum goal of acute treatment is to elicit a response to medication or psychotherapy, or both.2 Researchers have defined response as a 50% or greater decrease from baseline in Hamilton Rating Scale for Depression (HAM-D) and Montgomery-Asberg Depression Rating Scale (MADRS) total scores, and a Clinical Global Impressions (CGI) severity scale rating of 1 or 21,3 From a clinical perspective, the acute phase of treatment is most successful if it results in remission rather than merely response.1 Once the patient is minimally symptomatic or asymptomatic, remission is considered to have occurred.4 In subsequent maintenance treatment, the minimal goal is to prevent a recurrence (ie, a new episode of major depression), and preferably to sustain remission.1,2 A HAM-D score of <7 and a patient who is minimally symptomatic or asymptomatic, with psychosocial/occupational functioning restored, should be considered the goal3 Attaining remission is the best way to prevent depression-related morbidity1 Sources: 1. Rush AJ, Trivedi MH. Psychiatric Ann. 1995;25: 2. Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. 3. Thase ME. J Clin Psychiatry. 1997;58: 4. Frank E, et al. Arch Gen Psychiatry. 1991;48: 1. Rush AJ, et al. Psychiatric Ann. 1995;25: 2. Thase ME. J Clin Psychiatry. 1997;58: 3. Frank E, et al. Arch Gen Psychiatry. 1991;48:

21 Remission Is the Goal of Treatment in Major Depression
Relapse Recurrence Euthymia + Relapse Increased severity Response Symptoms Progression to disorder + Syndrome Remission is the goal of acute-phase treatment; prevention of relapse and recurrence is the goal of continuation and maintenance-phase treatment Treatment phases Acute (6 to 12 wk) Continuation (4 to 9 mo) Maintenance (1 y) The acute phase of treatment begins when the patient first presents with an episode of depression, and the minimal treatment goal is to elicit a response to medication or psychotherapy, or both. From a clinical perspective, this phase of treatment is most successful if it results in a remission rather than merely a response. Note that remission can occur beyond the acute phase, especially in chronic depression A goal during the continuation phase is to prevent relapse (a return of symptoms of the major depressive episode); once the patient is minimally symptomatic or asymptomatic, remission is considered to have occurred During maintenance treatment, the minimal goal is to prevent a recurrence (ie, a new episode of major depression), and preferably to provide continuing sustained remission Attainment of initial remission and then sustained remission is the best way to prevent depression-related morbidity Source: Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34. Time Adapted from: Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.

22 Treatment of Depression: Facing the Problem
The goal of treatment in clinical practice should be remission of symptoms Up to 50% of “responders” do not achieve remission Residual symptoms are nearly as common as non-response The goal of treatment in clinical practice should be remission of symptoms The dilemma facing clinicians is the fact that 40% to 50% of responders do not achieve remission Remission is the desired goal, to lower the probability of relapse as well as decrease distress and disability Incomplete remission is nearly as common as treatment failure Source: Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11. Nierenberg AA, et al. J Clin Psychiatry. 1999;60(suppl 22):7-11.

23 Remission (HAM-D17 7) Decreases Risk of Relapse
Longitudinal follow-up study of patients treated with usual care by their physicians Achievement of remission (ie, HAM-D17 score of 7 or less) decreases the risk of relapse by two thirds compared with a response without remission This prospective, longitudinal, naturalistic, follow-up study evaluated the impact of residual symptoms on relapse in psychiatric inpatients or outpatients (aged 18 to 65 years) with primary unipolar major depression. Patients were selected consecutively from treatment facilities in the United Kingdom. They were treated with usual care by their physicians and followed to the point of remission or until 15 months had elapsed without achievement of remission. Remission was defined as 2 consecutive months below the Research Diagnostic Criteria (RDC) for definite major depression. Those patients who remitted were subsequently followed for 12 to 15 months to identify relapse1 By 15 months, 60 patients no longer met the RDC for major depression. Response with residual symptoms (defined as an HAM-D17 score of 8 or more) occurred in 32% (n=19) of the 60 patients. The other 41 patients had achieved full remission with no residual symptoms (ie, they had HAM-D scores of 7 or less)1 The presence of residual symptoms, as quantified by HAM-D17 scores, was a strong predictor of subsequent early relapse (defined as a return to symptoms meeting the RDC for definite major depression for 1 month). Significantly more patients (P<0.001) with HAM-D17 scores of 8 or more (76%) relapsed compared with patients with HAM-D17 scores of 7 or less (25%)1 Insufficient dosing or duration of antidepressant treatment may be an important factor in failure to achieve remission2 Sources: 1. Paykel ES, et al. Psychol Med. 1995;25: 2. Ramana R, et al. Br J Psychiatry. 1999;174: *P<0.001. Adapted from Paykel ES, et al. Psychol Med. 1995;25:

24 Patients Treated to Remission Had Fewer Missed Workdays
18 16 14 12 Mean days of work missed per year 10 8 * 6 4 Clinical outcomes (Hamilton Rating Scale for Depression and depression module of the Structured Clinical Interview for DSM-III-R), employment status, and workdays missed due to illness were examined in 290 adults with major depression beginning antidepressant therapy via a retrospective analysis of data obtained from a randomized, multicenter trial Patients completed structured interviews at baseline, 1, 3, 6, 9, 12, 18, and 24 months. Patients were classified as remitters (41%), responders but not remitters (47%), and persistently depressed (12%) using data from the 12-month assessment As depicted in the graph, patients with better 12-month clinical outcomes reported fewer missed workdays per year due to illness (P<0.001) during the 2-year study period Also of note, patients with greater clinical improvement were more likely to maintain paid employment (P<0.007) and had marginally lower health care costs during the second year of follow-up (P=0.06) Remission from depression is associated with significant reductions in work disability and possible reductions in health care costs compared with patients who do not achieve remission Source: Simon GE, et al. Gen Hosp Psychiatry. 2000;22: 2 Persistent Response Remission† depression† but not remission† (n=118) (n=35) (n=137) *P<0.001. †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:

25 Treatment with Antidepressants
Moderator Summary None Found User Notes

26 The evolution of antidepressants
Phenelzine Isocarboxazid Tranylcypromine Imipramine Clomipramine Nortriptyline Amitriptyline Desipramine Maprotiline Amoxapine Mianserin Fluoxetine Sertraline Paroxetine Fluvoxamine Citalopram Nefazodone Mirtazapine Venlafaxine Duloxetine Milnacipran Reboxetine Moclobemide Escitalopram Since the introduction of antidepressants, the “pendulum” has swung from dual reuptake inhibitors (eg, TCAs) to selective agents (eg, SSRIs), and finally back to dual reuptake inhibitors with improved tolerability over TCAs (eg, venlafaxine) The modern era of psychopharmacology for depression began in the 1940s with the discovery of lithium. In the 1950s, monoamine oxidase inhibitors (MAOIs) began to be used as antidepressants. This was followed by the synthesis of the antipsychotic agent chlorpromazine and continued with the discovery of the tricyclic antidepressant (TCA) imipramine in 1957 The next major innovation was the availability of the first selective serotonin reuptake inhibitor (SSRI), fluoxetine, in The SSRIs lacked the dietary restrictions associated with MAOIs, and they offered safety and tolerability advantages over older tricyclic and heterocyclic agents.1,2 Other treatment options include psychotherapy, the combination of pharmacotherapy and psychotherapy, and electroconvulsive therapy (ECT). Psychotherapy alone may be effective in patients with mild-to-moderate depression. Psychotherapy alone or in combination with pharmacotherapy may be useful in patients who experience significant psychosocial stressors, intrapsychic conflict, or interpersonal difficulties. ECT is considered an option in patients with severe symptoms and functional impairment and in those with an urgent need for response (eg, suicidal patients); ECT may also be appropriate when comorbid medical illnesses restrict the use of an antidepressant3 Most recently, pharmacologic refinement has emphasized the combined role of norepinephrine and serotonin in depression, as evidenced by the mechanism of action of venlafaxine. Venlafaxine inhibits the reuptake of both serotonin and norepinephrine. It has a favorable side-effect profile similar to those of the SSRIs Source: 1. Schmitt JA, et al. J Psychopharmarcol. 2001; 15: 2. Bourin M, et al. CNS Drug Rev. 2001; 7:25-47 3. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depression. 2nd ed

27 Serotonin-noradrenaline spectrum of antidepressants
More serotonin selective More noradrenaline selective 100 80 60 40 20 20 40 60 100 300 500 venlafaxine imipramine fluoxetine amitriptyline paroxetine amoxapine sertraline protriptyline fluvoxamine nortriptyline desipramine maprotiline noradrenaline uptake Ki / serotonin Ki serotonin Ki / noradrenaline uptake Ki 5

28 Different classes of antidepressant
Class Examples 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 Moderator Summary None Found User Notes

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

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.

32 SSRIs Moderator Summary None Found User Notes

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. Moderator Summary An important breakthrough in the development of antidepressants that combine selectivity for one neurotransmitter with minimal or no effect on adrenergic, histaminergic and cholinergic receptors came with the synthesis of the SSRIs. User Notes None Found 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 Moderator Summary Cell bodies of 5-HT neurons are found predominantly in the raphe nucleus and brainstem but the major fibres innervate many regions of the brain including the hippocampus and frontal cortex. 5-HT, also known as serotonin, is synthesised in the pre-synaptic neuron from tryptophan, an essential amino acid. After manufacture, 5-HT is packaged into synaptic vesicles found in the nerve terminals. When stimulated by an action potential, these vesicles fuse with the membrane releasing 5-HT into the synaptic cleft. At least 15 distinct 5-HT receptors have been identified in the brain but this sequence will only focus on two of them. 5-HT1A receptors are most common in the hippocampus and raphe nucleus. 5-HT1A receptors are linked to the second messenger system consisting of a G protein negatively coupled to adenyl cyclase. Activation of the receptors causes the G protein to directly influence the ion channels, increasing conductance of calcium and potassium. Consequently levels of cyclic AMP decrease, while diacylglycerol and inositol phosphate increase. Because of this inhibitory effect, the action potential along the post-synaptic neuron is considerably weaker than along the pre-synaptic neuron. 5-HT2A receptors are concentrated in the medial prefrontal cortex of the brain, a region thought to become abnormal in schizophrenia. As with 5-HT1A receptors, 5-HT2A receptors are linked to G proteins. In contrast with 5-HT1A receptors, however, the G proteins linked to 5-HT2A transmission are excitatory, and activation of the receptor stimulates phospholipase C leading to the formation of diacylglycerol and inositol triphosphate. Phospholipase A2 is also activated releasing arachidonic acid. The increased formation of DAG and IP3 causes the intracellular levels of calcium to rise along with activation of protein kinase. Chloride and potassium travel through the membrane normally up to this point. Responding to the rise in calcium, calmodulin enters the post-synaptic neuron and begins to soak up the excess calcium. As a consequence, the efflux of potassium from the cell is slowed. Due to these stimulatory effects, the electrical impulse along the post-synaptic neuron is considerably stronger than in the pre-synaptic neuron. 5-HT is quickly removed from the synaptic cleft by a re-uptake mechanism. Inside the pre-synaptic neuron, metabolism by monoamine oxidase on the outer membrane of mitochondria renders 5-HT inactive. A deficiency in 5-HT neurotransmission is thought to be the underlying cause of many mood disorders such as depression, obsessive-compulsive disorder and mania. User Notes None Found

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

37 Comparative properties of SSRIs
Active metabolite Elimination half-life Fluoxetine Norfluoxetine 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 Sertraline - Paroxetine - Fluvoxamine - Escitalopram - Citalopram - Zimeldine Norzimeldine Hale (1997); Sanchez et al (2002) Moderator Summary None Found User Notes

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
Steady-state plasma levels PK profile similar in adults & elderly SSRI Mean half-life Chirality Escitalopram 30 hours 7-14 days No No Yes s-enantiomer active r-enantiomer inactive Citalopram 33 hoursa 7-14 days in adults No Fluoxetine + norfluoxetine (active metabolite) 5 Days 15 daysa 6-8 weeks, longer at higher doses and in the elderly Yes s-r-fluoxetine & s-norfluoxetine potent SSRIs No Fluvoxamine 15.6 hours 7 days Yes No 7 days, longer at higher doses and in the elderly No Paroxetine 21 hours No Sertraline 26 hours 7 days Yes No Moderator Summary Kinetic profiles vary considerably among the SSRIs There are significant differences in drug handling between adults and elderly for citalopram, fluoxetine/norfluoxetine and paroxetine Little is currently known about the kinetic profiles in children and adolescents, although there is an increasing emphasis on research in these patient populations User Notes None Found aprolonged in the elderly; PK, pharmacokinetic

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. Moderator Summary Most SSRIs have a half-life (t1/2) of approximately 1 day. Fluoxetine, however, has a longer t1/2 of 2–4 days, and its active metabolite, norfluoxetine, has an extended t1/2 of 7–15 days. Fluoxetine, paroxetine and, to a lesser extent, fluvoxamine inhibit their own metabolism. That is not the case for citalopram or sertraline. There are non-linear increases in paroxetine plasma concentrations with dosage increases, but proportional changes with citalopram and sertraline. Indirect data suggest that fluoxetine and fluvoxamine also have non-linear pharmacokinetics over their usual dosage range. Age-related increases in plasma drug concentrations for citalopram (approximately 130%) and paroxetine (approximately 50–100%) have been observed in healthy elderly (65–75 years) persons versus those who are younger. There is an age-gender interaction for sertraline, with its plasma concentrations being 35–40% lower in young men than in elderly or young females or elderly males. While there is no apparent change in fluvoxamine plasma levels as a function of age, plasma drug concentrations are 40–50% lower in males than in females. Limited data from clinical trials suggest that age-related differences with fluoxetine may be comparable to those of citalopram and paroxetine (Preskorn, 1997). User Notes None Found 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
Fluvoxamine 77% Escitalopram and citalopram 50% Other SSRIs TCA over 90% over 90% van Harten (1993); Sanchez et al (2002) Moderator Summary Plasma protein binding of fluoxetine, paroxetine and sertraline is > 95%; values for fluvoxamine (77%) and citalopram (50%) are much lower. For all compounds, however, protein binding interactions do not seem to be of great importance. Although many attempts were made, to date no convincing evidence exists of a relationship between plasma concentrations of any of the SSRIs and clinical efficacy (van Harten, 1993). User Notes None Found

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
CYP1A2 CYP2C19 CYP2D6 CYP3A3/4 Reference Escitalopram Minimal Minimal Mild Minimal Moltke et al (2001) Citalopram Minimala Minimal Mildb Minimal Preskorn (1997) Fluoxetine and norfluoxetine Flu Minimal Mild Substantial Mild Lemberger et al (1988) Fluvoxamine Substantial Substantial Mild Moderate Kragh-Sorensen et al (1981) Paroxetine Mild Mild Substantial Mild Preskorn (1997) Ozdemir et al (1998) Sertraline Minimal Minimal Mild Minimal 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%. aextrapolation from in vitro data; bat usually effective minimum dose. Moderator Summary Drug metabolism is usually a multi-step process that involves oxidation and conjugation of the oxidised metabolite. In the liver, the CYP450 system is broadly involved in the oxidation of many endogenous substances and detoxification of consumed substances (drugs, toxins, mutagens). Drugs such as the SSRIs can increase or decrease the functional activity of CYP enzymes. Drug-induced inhibition is usually competitive and occurs immediately, but the magnitude of the inhibition is a function of inhibitor concentration. The half-life of the inhibitor will determine the time taken to exert its full effect and, conversely, how long the inhibition will last after discontinuation. User Notes None Found Greenblatt et al (1998)

46 Examples of drug metabolising cytochrome P450 – CYP1A2
Clomipramine Clozapine Propanolol Imipramine Paracetamol Theophylline Fluvoxamine Haloperidol Olanzapine Verapamil Moderator Summary Drug metabolism is usually a multi-step process that involves oxidation and conjugation of the oxidised metabolite. In the liver, the CYP450 system is broadly involved in the oxidation of many endogenous substances and detoxification of consumed substances (drugs, toxins, mutagens). Drugs such as the SSRIs can increase or decrease the functional activity of CYP enzymes. Drug-induced inhibition is usually competitive and occurs immediately, but the magnitude of the inhibition is a function of inhibitor concentration. The half-life of the inhibitor will determine the time taken to exert its full effect and, conversely, how long the inhibition will last after discontinuation. User Notes None Found

47 Examples of drug metabolising cytochrome P450 – CYP2C19
Amitriptyline Diazepam Clomipramine Moclobemide Imipramine Moderator Summary Drug metabolism is usually a multi-step process that involves oxidation and conjugation of the oxidised metabolite. In the liver, the CYP450 system is broadly involved in the oxidation of many endogenous substances and detoxification of consumed substances (drugs, toxins, mutagens). Drugs such as the SSRIs can increase or decrease the functional activity of CYP enzymes. Drug-induced inhibition is usually competitive and occurs immediately, but the magnitude of the inhibition is a function of inhibitor concentration. The half-life of the inhibitor will determine the time taken to exert its full effect and, conversely, how long the inhibition will last after discontinuation. User Notes None Found

48 Examples of drug metabolising cytochrome P450 – CYP2D6
Amitriptyline Clomipramine Desipramine Mianserine Propanolol Venlafaxine Antiarrhytmics Codeine Haloperidol Nortriptyline Risperidone Zuclopenthixol Nefazodone Trazodone Valproate Moderator Summary Drug metabolism is usually a multi-step process that involves oxidation and conjugation of the oxidised metabolite. In the liver, the CYP450 system is broadly involved in the oxidation of many endogenous substances and detoxification of consumed substances (drugs, toxins, mutagens). Drugs such as the SSRIs can increase or decrease the functional activity of CYP enzymes. Drug-induced inhibition is usually competitive and occurs immediately, but the magnitude of the inhibition is a function of inhibitor concentration. The half-life of the inhibitor will determine the time taken to exert its full effect and, conversely, how long the inhibition will last after discontinuation. User Notes None Found

49 Examples of drug metabolising cytochrome P450 – CYP3A3/4
Clomipramine Imipramine Fluvoxamine Mirtazapine Nefazodone Verapamil Carbamazepine Clonazapam Alprazolam Moderator Summary Drug metabolism is usually a multi-step process that involves oxidation and conjugation of the oxidised metabolite. In the liver, the CYP450 system is broadly involved in the oxidation of many endogenous substances and detoxification of consumed substances (drugs, toxins, mutagens). Drugs such as the SSRIs can increase or decrease the functional activity of CYP enzymes. Drug-induced inhibition is usually competitive and occurs immediately, but the magnitude of the inhibition is a function of inhibitor concentration. The half-life of the inhibitor will determine the time taken to exert its full effect and, conversely, how long the inhibition will last after discontinuation. User Notes None Found

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: 10 Use lower doses in the elderly (10 mg) Range: T½ approx 40 hours in elderly Citalopram Initial: 20 Range: Recommended maximum in the elderly: 40 mg Fluoxetine Initial: 20 Range: 20-60 Fluvoxamine Initial: Range: Paroxetine Initial: 20 Range: Recommended maximum in the elderly: 40 mg Sertraline Initial: 50 Range: Doses > 150 mg should not be used for longer than 8 weeks Moderator Summary The dose–response curves for the SSRIs in acute 6-week treatment studies are generally flat across their recommended dose ranges (Wernicke et al, 1987; Dunner and Dunbar, 1992; Fabre et al, 1995). Studies are not powered to detect small differences between doses Increased doses are associated with increased side-effects Patients may respond preferentially to one SSRI User Notes None Found

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 ECT

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 (SSRI’s) SSRI’s are recommended as the first drug of choice for MDD treatment


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