265 medical outpatients evaluated for depression Assessment made by Diagnostic Interview Schedule(DIS) Of 70 patients diagnosed as depressed, only

Transcription

1 의학적상태에따른 항우울제치료 이상열원광의대신경정신과 Depression in Physical Illness High prevalence Often unrecognized Often underdiagnosed Often untreated Often inadequately treated 1

2 Underrecognition of Depression in Medical Outpatients A Study of in Primary Care 265 medical outpatients evaluated for depression Assessment made by Diagnostic Interview Schedule(DIS) Of 70 patients diagnosed as depressed, only 25(36%) were recognized by primary care physician Of the 25 recognized as depressed, 8(32%) were prescribed medication Arch Intern Med 1990 :150 Primary Care Current Conditions-Depression Current Conditions Depressive disorder 10.4% Dysthymia 2.1% Subthreshold depressive disorder 17.9% Total 30.4% Arch Gen Psychiatry 1993;50:819 2

3 Physical illness and Depression 파킨슨병 51% 암 42% 당뇨병 심근경색 뇌졸중 23% 25% 27% 관상동맥질환 17% AIDS 알쯔하이머치매 12% 11% Reasons for Underdiagnosis and Undertreatment of Depression in Medically Ill Patients Emphasis on somatic rather than cognitive and mood condition Reluctance to stigmatize patient with psychiatric diagnosis Mild or nonspecific symptoms of depression Fear of antidepressants side effects Mistaken notion that reactive depression are not pathological( She should be depressed, she has cancer) Time limitations in primary care Inadequate training in psychiatry among primary care physicians Inaccurate coding for purpose of reimbursement improvement 3

4 Diagnostic Issues of depression in Medical Illness Inclusive -> false positive Exclusive pure culture of depressed patients -> false negative (i.e., anorexia and fatigue from depressed symptoms in cancer patients) Etiological not caused by the primary illness Substitutive(Endicott 1984) change in appetite or weight -> tearfulness or depressed appearance sleep disturbance -> Social withdrawal indecisiveness ->lack of reactivity to events loss of energy or fatigue -> brooding pessimism Importance of Treating Depression in Medically Ill(I) Untreated or inadequately treated depression increases mortality in medically ill patients Major depression is an independent risk factors for mortality in patients - admitted to a nursing home - hospitalized post-mi JAMA 1991; 265: 993 JAMA 1993; 270:

5 Importance of Treating Depression in Medically Ill(II) Depressive symptoms that are severe, persistent, or unresponsive to simple psychosocial interventions Depressive symptoms that interfere with medical intervention Depressed mood, loss of interest, or demoralization that is not alleviated by improvement of the medical illness Antidepressants for Depression in Physical Ill 5

6 Antidepressants in Medical Illness? Meta analysis of randomized trials of patients with cancer, diabetes, head injury, heart disease, HIV disease, multiple sclerosis, renal disease and stroke Antidepressants significantly > placebo BMJ 2002;325: Pharmacological and psychotherapeutic interventions are more effective for the treatment than psychopharmacological intervention alone!!! Antidepressants for Depressed Patients in Medically Ill Consider safety and efficacy Consider physical side effect profile of antidepressant drugs Consider kinetic effects of physical disease Consider psychiatric side effects of drugs for physical illness Consider drug-drug interaction 6

7 Cardiovascular Disorder and Antidepressants 7

8 Antidepressants TCAs SSRIs Novel antidepressants Psychostimulants Tricyclics: Most Common Side Effects Cardiovascular Anticholinergic - orthostatic hypotension - dry mouth - conduction defect - urinary retention - negative inotrophic effect - blurred vision - EKG changes - constipation - congestive heart failure - increased intraocular pressure * Orthostatic hypotension - occurs in up to 20% of patients taking TCAs - not consistently dose related - increased risk hip fractures 8

9 TCAs Orthostatic hypotension Increased Slowing of cardiac conduction 2:1 artrioventricular block in patients with preexisting bundle branch block Do not adversely affect left ventricular function Type 1A antiarrythmic agents such as qunidine and moricizine (Cardiac Arrythmica Suppression Trial II study) - mortality 2.6% in morocizine VS 0.5% in placebo Decrease all component measures of heart rate variability and increase QT variability Heart Rate Variability (HRV) Note that the time (ms) between R-R R intervals is continuously changing. Reflect the autonomic control over the cardiac cycle HRV analysis is an inexpensive, noninvasive technique for studying cardiac autonomic tone 9

10 HRV in patients with Paroxetine & amitriptyline Major depressive disorder (N=28) Randomized trials of paroxetine (N=14) or amitriptyline (N=14) for 35 days HRV measurement at baseline & endpoint Paroxetine: no effects Amitriptyline standard deviation of all normal R-R R intervals (SDNN) standard deviations of averages of the N-N N intervals (SDANN) Heart rate.lederbogen F et al (2001). J Clin Psychopharmacology 21: Patient Population (N) Mean ± SD Age (yrs) Treatment Length of Trial Clinical End Points Mean ± SD Daily Dose (mg) Results Raskind 1998 Recent MI, CABG (12) 56.1 ± 8.6 Imipramine 4 wks CV effects 125 ± st degree AVB, arrow up Q Tc, arrow down PVCs, arrow up HR, statistically significant orthostatic hypotension compared with baseline (p<0.05). Veith 1982 Recent MI, CABG; prosthetic valve, conduction disease (24) 55 ± 9 Imipramine Doxepin Placebo 4 wks CV effects Imipramine 129 ± 57 Doxepin 153 ± 72 Imipramine : no change in ECG, arrow down PVCs, arrow up HR, orthostatic hypotension (33.3%). Doxepin: arrow up HR, orthostatic hypotension (12.5%). Glassman 1983 Heart failure (15) 70 Imipramine 3 wks Change in EF, CV effects ± 34.4 No change in EF, orthostatic hypotension (47%). Roose 1986 Heart failure (21) 68 ± 9 Nortriptyline 3 wks Change in EF, CV effects 76 ± 29 mg No change in EF, orthostatic hypotension (5%). Roose 1987 Conduction disease (196) 56 ± 15 Imipramine Nortriptyline 10 days CV effects Imipramine 288 ± 109 Nortriptyline 89 ± 33 Imipramine: 2:1 AVB, orthostatic hypotension (13%). Nortriptyline: sinus arrest, orthostatic hypotension (1.8%). Hummel 1984 Conduction disease (10) 84.3 Nortriptyline 7-10 da ys CV effects 58g No change in HR, ECG; no orthostatic hypotension. Cohn 1993 Mild heart disease (22) 54 Trimipramine 3 wks CV effects 92.7 No change in HR, ECG; no orthostatic hypotension. 10

11 SSRIs First line treatment because of tolerability and relative safety Randomized controlled study - cardiac disease, stroke, cancer, HIV infection, Alzeheimer s disease, MS, diabetes Open trial - Parkinson s s disease, renal failure SSRIs and Cardiac Disease Do not slow cardiac conduction or cause orthostatic hypotension Slightly decreased heart rate(1-3 beats/min), but the clinical significance is not known No effect on heart rate variability or QT variability measures Antiplatelet effect -> decrease mortality rate - interfere with serotonin accumulation in platelets - normalizes elevated indices of platelet activation and aggregation in depressed patients with IHD - not associated with the antidepressant effect of medication - the effect occurred with low doses of SSRIs 11

12 Patient Population (N) Mean ± SD Age (yrs) Treatment Length of Trial Clinical End Points Mean ± SD Daily Dose (mg) Results Roose 1998 IHD (81) 58 ± 13 Paroxetine (41) Nortriptyline (40) 6 wks Antidepress ant efficacy, CV effects Paroxetine 22 ± 5 Nortriptylin e 74 ± 30 No difference in antidepressant efficacy. Nortriptyline: high frequency of CV side effects (25%), statistically significant in HR (p<0.001). Roose 1998 HF (EF </= 50%), conduction disease(87) 73.3 ± 9 Fluoxetine (27) Nortriptyline (60) 7 wks CV effects NR No statistically significant differences between the 2 groups. Nortriptyline:HR, orthostatic hypotension, PVCs. Stikk 2000 Recent MI (54) 54.1 ± 11.3 Fluoxetine (27) Placebo (27) 25 wks Antidepress ant- antihostility efficacy, CV effects 47.3 ±19.1 No difference in antidepressant efficacy compared with placebo. Fluoxetine: no change in BP, HR, ECG, or EF compared with baseline. Shapiro 1999 Recent MI (EF >/= 35%)(26) Sertraline 16 wks CV effects 79.8 ±38.7 No change in HR, ECG, BP, EF, or PVCs compared with baseline. Glassm an 2002 Recent MI or unstable angina (369) 56.8 ± 11.1 Sertraline (186) Placebo (183) 24 wks Change in EF, CV adverse effects 68.8 ±40.1 Sertraline: no statistically significant change in EF, no statistically significant change in HR, BP, PR, QRS duration or SDNN compared with placebo. McFarl ance 2001 Recent MI (38) 62 ± 11 Sertraline (12) Placebo (15) 6 mo Heart rate variability NR Sertraline: statistically significant difference in SDNN at 22 wks compared with placebo (p<0.04). IHD = ischemic heart disease; CV = cardiovascular; HR = heart rate; HF = heart failure; EF = ejection fraction; NR = not reported; PVCs = premature ventricular contractions; MI = myocardial infarction; BP = blood pressure; ECG = electrocardiogram; SDNN = standard deviation of all normal-to-normal intervals. Venlafaxine : Side Effects (serotonin-norepinephrine norepinephrine reuptake inhibitor) Nausea Headache, sweating Dry mouth Burst of dizziness Insomnia, fatigue Mild increase Bp Advantage - similar side-effects effects to SSRIs - onset of action possibly more rapid 12

13 The National Institute for Clinical Excellence (NICE), U.K. The CSM has additionally considered the balance of risks and benefits of Efexor because of concerns about cardiotoxicity and toxicity in overdose. CSM recommended that treatment with Efexor should only be initiated by specialist mental health practitioners, including GPs with a special interest, and there should be arrangements in place for continuing supervision of the patient. Efexor should not be used in patients with heart disease, (e.g. cardiac failure, coronary artery disease, ECG abnormalities including pre-existing existing QT prolongation), patients with electrolyte imbalance or in patients who are hypertensive. Patients currently doing well on treatment with venlafaxine can continue to the end of their course. Antidepressant Drug Class Aminoketone Orthostatic Hypotension Conduction Abnormalities Hypertension Tachycardi a Bradycardia Bupropion 0 +/ Monoamine oxidase inhibitors Phenelzine Tranylcypromine a 0 0 Selective serotonin reuptake inhibitors Citalopram Escitalopram Fluoxetine Fluvoxamine /0 Paroxetine /0 Sertraline Serotonin-norepinephrine norepinephrine reuptake inhibitor Venlafaxine /+++b ++ 0 a 2 antagonist-specific specific serotonergic antagonist Mirtazapine Selective norepinephrine reuptake inhibitor Reboxetine = high; +++ = moderate; ++ = low; += very low; 0 = none. a Frequency of hypertension increases when taken with tyramine-containing foods. b Frequency of hypertension increases with dosages greater than 225 mg/day. 13

14 SSRIs and Rare Side Effects Inappropriate antidiuretic hormone secretion Unpredictable impact on homeostasis - blockade of serotonin uptake into platelets can inhibit platelet function and cause bleeding Hyponatremia ( venlafaxine also) - retrospective study of 199 inpatients : 74 taking SSRI or venlafxaine : controlled for other factors causing hyponatremia( medical illness, diuretics, age, sex) => 5.6 times have hyponatremia SSRIs: Common Side Effects Similarities > differences Class Profile - Nausea - Headache - Sexual dysfunction(50-70%) ; caution in patients with medical problems associated with sexual dysfunction (diabetes or vascular disease) - Withdrawal syndrome(except fluoxetine) All better tolerated than TCAs * Should not be used with a MAOI or within 14 days of taking a MAOI 14

15 Mirtazapine: Side Effects (antagonist at central presynaptic alpha 2-adrenergic) autoreceptor, potent antagonist of 5-HT2 A, 5-HT 2C, 5-HT 3, and H1 receptors Somnolence Dry Mouth Increased appetite => weight gain Agranulocytosis (rapid recovery when mirtazapine is discontinued) Advantage - no nausea, gastrointestinal complaint including diarrhea, headache(5-ht 3 blocking) - appetite (H1 blocking and 5-HT 2C blocking) - Nutcracker Esophagus and Mirtzapine (Sang-Yeol Lee, 2001) Functional Dyspepsia and Mirtazapine (Sang-Yeol Lee and Min- Cheol Park, 2001) Bupropion (blockade of presynaptic dopamine reuptake) Smocking cessation Agitation or provoke psychotic episodes Association with seizure - head trauma, withdrawal Lack of cardiovascualr toxicity 15

16 Cancer and Depression Evidence of Antidepressants for Cancer SSRIs Venlafaxine Mirtazapine Mianserin Amitryptyline Desipramine Psychostimulants 16

17 Controlled Trials of AD Useful Guide for Caner SSRIs : effective, few sedative and autonomic side effects and few drug interaction - transient weight loss - anorexic properties : cancer anorexic-cachectic cachectic cancer patient - hepatic insufficiency -> consider half life - consider serotonin syndrome in caner Mirtazapine - advantageous in anorexic-cachetic cachetic cancer patients - disadvanteous in those who are gaining weight from steroids or from chemotherapy 17

18 SSRIs and Venlafaxine - reduce both the number and intensity of hot flashes and night sweat in nondepressed women who become menopausal after chemotherapy for breast cancer Psychostimulants - low dose (dextroamphetamine and methylpenidate initiated 2.5mg at 8 AM and noon) - promote sense of well-being, decrease fatigue, stimulate appetite - maintained for 1-2 months and tapering Gastrointestinal Disorder and Depression 18

19 Response to Antidepressants in Patients with FGID TCAs, Trazodone, SSRIs, Mianserine, Mirtazapine Antidepressants for Functional GI Disorders: A meta-analysisanalysis 14 RTCs, IBS, 5 NCCP, 4 NUD, 1 functional abdominal pain 849 patients 19 TCAs; 4 other Effective for primary, global, and pain outcome measures(p<0.001) OR for benefit of global outcome = 4.4 (95% CI: ) OR for benefit of pain = 8.0( ) Conclusions have benefits for functional GI disorders(fgids) benefits might not be restricted to pain Clouse, Gastroenterology 2001; 120: A642 19

20 국내정신과의사가중요시하는항우울제의부작용 Risk of CV disease Sedation Sexual dysfunction Weight gain 7 37 GI trouble 7 37 Nausea st+2nd 1st Paroxetine CR in IBS : Response by week Paxil CR Placebo Masand et al(2005) Maximum dose of paroxetine CR (50 mg/d) reached by week 6. Dropouts =6 in drug group & 8 in placebo group IBS is not approved indication 20

21 Respiratory Disorder and Antidepressants Choose on the basis of side effect profile COPD or sleep apnea : less sedating AD Considering possible synergistic effects with other sedating drugs : antianxiety and sedative-hypnotics SSRIs, bupropion, venlafaxine : safe - fluoxetine : increase arterial oxygen concentration - sertraline : antidyspenic effect With BZ -> smaller dose of AD 21

22 결론 신체질환과우울은밀접한연관이있으나, 임상특히타과에서우울이잘인식되지못하고있고치료역시부적절하게받고있다. 정신약물치료에는 SSRIs, venlafaxine, mirtazapine, bupropione등이주로선택되어지고, TCA는주의가필요하며, 중추신경자극제는비교적유용하게사용할수있다. 항우울제의사용은신체질환의약력학및현재복용중인약물과상호작용에대한고려가필요하다. 정신약물치료와함께정신치료가동반되면우울의치료가더효과적이다 22