antidepressiva - hur gör man? · • Är en folksjukdom, med hög prevalens • Är episodisk, >...
TRANSCRIPT
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Antidepressiva - Hur gör man?
Mussie Msghina, docent överläkareOrdförande expertrådet för psykiatriska sjukdomarStudierektor för specialistläkarnaPsykiatri Sydväst, Karolinska Universitetssjukhuset
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Depression
• Är en folksjukdom, med hög prevalens
• Är episodisk, > 50% recidiverande
• Obehandlad kan den pågå i över 6 mån – med ökad risk för recidiv– Ökad risk för kontinuerligt funktionsförlust
• Medelålder vid debut kring 30 års åldern
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PresentatörPresentationsanteckningarThe study introduced a new metric – the disability-adjusted life year (DALY) – as a single measure to quantify the burden of diseases, injuries and risk factors. The DALY is based on years of life lost from premature death and years of life lived in less than full health. One DALY can be thought of as one lost year of “healthy” life
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Depression and Chronic Diseases: It Is Time for a Synergistic Mental Health and Primary Care
Approach
Voinov, Richie, Bailey. Prim Care Companion CNS Disord 2013;15(2):
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Farmakoterapi – antidepressiva läkemedel
• 38 olika anti-depressiva– SSRI (citalopram, escitalopram, sertralin, osv)– NRI (reboxetin / Edronax)– SNRI (venlafaxin, duloxetin, TCA)– NDRI (bupropion)– Receptorantagonister (mirtazapin, mianserin)– Multimodala
– Agomelatin: M1/M2 agonist & 5-HT2C antagonist– Vortioxetin: 5-HT återupttagshämmare, agonist på 5-HT1A, partiell agonist på
5-HT1B och antagonist på 5-HT3, 5-HT1D och 5-HT7)
– Enzymhämare (Nardil, Parnate, Aurorix)
PresentatörPresentationsanteckningarBrintellix har en multimodal verkningsmekanism, det vill säga verkar som en serotoninåterupptagshämmare samt har en agonist effekt på 5-HT1A, partiell agonist på 5-HT1B och en antagonist på 5-HT3-, 5-HT1D- och 5-HT7-receptorer.
Agomelatin är en agonist till melatoninreceptorerna M1 och M2 och en antagonist till serotoninreceptorn 5-HT2C
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Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58
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Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58
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Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58
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Diagram1
mirtazapin
escitalopram
venlafaxin
sertralin
citalopram
bupropion
milnacipran
paroxetin
fluoxetin
duloxetin
fluovoxamin
reboxetin
Odds Ratio
Response (Primary Outcome)
1.04
1
0.97
0.94
0.84
0.82
0.77
0.77
0.76
0.75
0.74
0.52
Blad1
quetiapin1.923.850.94methylfenidate3.13045
aripiprazol1.852.511.24thyroid hormone2.9414453
thyroid hormon1.840.740.36risperidone2.1722840
litium1.562.31.18quetiapin2.0832223
risperidon1.492.51.15buspirone1.8641417
olanzapin1.43.361.11aripiprazole1.83
methylfenidate1.373.341.06olanzapine1.79
bupropion1.291.10.85bupropion1.64
buspirone1.250.160.99lithium1.46
lamotrigen1.120.870.7lamotrigen1.37
placebo111pindolol1.26
pindolol0.960.550.36placebo1
Blad1
Tid (veckor)
MADRS
Blad2
Tid (veckor)
SUAS
Blad3
Remission (secondary outcome)
Response (primary outcome)
Odds Ratio
Response (primary outcome)
mirtazapin1.04escitalopram1
escitalopram1sertralin0.95
venlafaxin0.97bupropion0.94
sertralin0.94citalopram0.93
citalopram0.84fluoxetin0.84
bupropion0.82mirtazapin0.81
milnacipran0.77milnacipran0.81
paroxetin0.77venlafaxin0.78
fluoxetin0.76paroxetin0.76
duloxetin0.75duloxetin0.69
fluovoxamin0.74fluovoxamin0.69
reboxetin0.52reboxetin0.58
Odds Ratio
Response (Primary Outcome)
Odds Ratio
Acceptability
Diagram1
escitalopram
sertralin
bupropion
citalopram
fluoxetin
mirtazapin
milnacipran
venlafaxin
paroxetin
duloxetin
fluovoxamin
reboxetin
Odds Ratio
Acceptability
1
0.95
0.94
0.93
0.84
0.81
0.81
0.78
0.76
0.69
0.69
0.58
Blad1
quetiapin1.923.850.94methylfenidate3.13045
aripiprazol1.852.511.24thyroid hormone2.9414453
thyroid hormon1.840.740.36risperidone2.1722840
litium1.562.31.18quetiapin2.0832223
risperidon1.492.51.15buspirone1.8641417
olanzapin1.43.361.11aripiprazole1.83
methylfenidate1.373.341.06olanzapine1.79
bupropion1.291.10.85bupropion1.64
buspirone1.250.160.99lithium1.46
lamotrigen1.120.870.7lamotrigen1.37
placebo111pindolol1.26
pindolol0.960.550.36placebo1
Blad1
Tid (veckor)
MADRS
Blad2
Tid (veckor)
SUAS
Blad3
Remission (secondary outcome)
Response (primary outcome)
Odds Ratio
Response (primary outcome)
mirtazapin1.04escitalopram1
escitalopram1sertralin0.95
venlafaxin0.97bupropion0.94
sertralin0.94citalopram0.93
citalopram0.84fluoxetin0.84
bupropion0.82mirtazapin0.81
milnacipran0.77milnacipran0.81
paroxetin0.77venlafaxin0.78
fluoxetin0.76paroxetin0.76
duloxetin0.75duloxetin0.69
fluovoxamin0.74fluovoxamin0.69
reboxetin0.52reboxetin0.58
Odds Ratio
Response (Primary Outcome)
Odds Ratio
Acceptability
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Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58
• Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine, fluoxetine, fluvoxamine, paroxetine , and reboxetine . Reboxetine was significantly less efficacious than all the other antidepressants tested.
• Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine.
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Network Meta-Analysis and Cost-Effectiveness Analysis of New Generation Antidepressants. Khoo et al., CNS Drugs (2015) 29:695–712
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Comparative Efficacy, Acceptability, and Tolerability of Augmentation Agents in Treatment-Resistant Depression: Systemic Review and Network Analysis
Zhou et al., J Clin Psychiatry (2015) 76(4) e487-e498
Drug rank-ordered according to their overall probability of being the best treatment. Every drug was scored on a scale of 1-100 from the surface under the cumulative ranking curve (SUCAR) data
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Diagram1
quetiapin
aripiprazol
thyroid hormon
litium
risperidon
olanzapin
methylfenidate
bupropion
buspirone
lamotrigen
placebo
pindolol
Odds Ratio
Response (primary outcome)
1.92
1.85
1.84
1.56
1.49
1.4
1.37
1.29
1.25
1.12
1
0.96
Blad1
quetiapin1.923.850.94methylfenidate3.13045
aripiprazol1.852.511.24thyroid hormone2.9414453
thyroid hormon1.840.740.36risperidone2.1722840
litium1.562.31.18quetiapin2.0832223
risperidon1.492.51.15buspirone1.8641417
olanzapin1.43.361.11aripiprazole1.83
methylfenidate1.373.341.06olanzapine1.79
bupropion1.291.10.85bupropion1.64
buspirone1.250.160.99lithium1.46
lamotrigen1.120.870.7lamotrigen1.37
placebo111pindolol1.26
pindolol0.960.550.36placebo1
Blad1
Tid (veckor)
MADRS
Blad2
Tid (veckor)
SUAS
Blad3
Remission (secondary outcome)
Acceptability (primary outcome)
Odds Ratio
Response (primary outcome)
mirtazapin1.04escitalopram1
escitalopram1sertralin0.95
venlafaxin0.97bupropion0.94
sertralin0.94citalopram0.93
citalopram0.84fluoxetin0.84
bupropion0.82mirtazapin0.81
milnacipran0.77milnacipran0.81
paroxetin0.77venlafaxin0.78
fluoxetin0.76paroxetin0.76
duloxetin0.75duloxetin0.69
fluovoxamin0.74fluovoxamin0.69
reboxetin0.52reboxetin0.58
Odds Ratio
Response (Primary Outcome)
Odds Ratio
Acceptability
Diagram1
quetiapin
aripiprazol
thyroid hormon
litium
risperidon
olanzapin
methylfenidate
bupropion
buspirone
lamotrigen
placebo
pindolol
Probability of Being Best Treatment
1.92
1.85
1.84
1.56
1.49
1.4
1.37
1.29
1.25
1.12
1
0.96
Blad1
quetiapin1.923.850.94methylfenidate3.13045
aripiprazol1.852.511.24thyroid hormone2.9414453
thyroid hormon1.840.740.36risperidone2.1722840
litium1.562.31.18quetiapin2.0832223
risperidon1.492.51.15buspirone1.8641417
olanzapin1.43.361.11aripiprazole1.83
methylfenidate1.373.341.06olanzapine1.79
bupropion1.291.10.85bupropion1.64
buspirone1.250.160.99lithium1.46
lamotrigen1.120.870.7lamotrigen1.37
placebo111pindolol1.26
pindolol0.960.550.36placebo1
Blad1
Tid (veckor)
MADRS
Blad2
Tid (veckor)
SUAS
Blad3
Remission (secondary outcome)
Acceptability (primary outcome)
Odds Ratio
Response (primary outcome)
mirtazapin1.04escitalopram1
escitalopram1sertralin0.95
venlafaxin0.97bupropion0.94
sertralin0.94citalopram0.93
citalopram0.84fluoxetin0.84
bupropion0.82mirtazapin0.81
milnacipran0.77milnacipran0.81
paroxetin0.77venlafaxin0.78
fluoxetin0.76paroxetin0.76
duloxetin0.75duloxetin0.69
fluovoxamin0.74fluovoxamin0.69
reboxetin0.52reboxetin0.58
Odds Ratio
Response (Primary Outcome)
Odds Ratio
Acceptability
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Are ADs Effective? A debate on their efficacy for the treatment of major depression in adults
Bschor, Kilarski (2016) Expert Review of Neurotherapeutics
• The efficacy of AD has been studied in thousands of RCTs• AD are recommended in international guidelines• Large meta-analyses have concluded that AD have significant,
but modest effect when compared to placebo• 75% of improvement is assumed to be due to placebo and the
natural course of depression• AD efficacy is overestimated by selective publishing, patient
selection and insufficient blinding• The placebo effect is beneficial and should not be dismissed as
a disreputable mechanism of action of a given treatment.
PresentatörPresentationsanteckningarTotalt sett visade SSRI och SNRI en signifikant men liten effekt, jämfört med placebo (g=0,32). Effekten av SSRI och SNRI var lägst på depression (g=0,20), vilket kan förklaras av en större placeboeffekt vid just depression. Vid ångestsyndrom var effekten av SSRI, jämfört med placebo, relativt stor (g=0,71). Den enda studien på posttraumatiskt stressyndrom visade ingen effekt.
Locher, et al. Efficacy and safety of selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and placebo for common psychiatric disorders among children and adolescents: a systematic review and meta-analysis. JAMA Psychiatry. 2017 Aug 30. doi: 10.1001/jamapsychiatry.2017.2432. PubMed
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Behandlings mål
• Remission och fullständigt återkomst av funktion • Respons > 50% reduktion av symtom• Partiell respons > 20% reduktion av symtom• Icke-respons < 20% reduktion av symtom• A meta-analysis showed that early improvement (ie,
a 20% or greater improvement by week 2) is a highlysensitive predictor of remission at weeks 4 to 8.
Szegedi A, Jansen WT, van Willigenburg APP, et al. Early improvement in the first 2 weeks as a predictor oftreatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients. J Clin Psychiatry. 2009;70(3):344–353
Global patterns of workplace productivity for people with depression: absenteeism and presenteeism costs across eight diverse countries.Evans-Lacko S, Knapp M. Soc Psychiatry Psychiatr Epidemiol. 2016 Nov;51(11):1525-1537. Epub 2016 Sep 26.
https://www.ncbi.nlm.nih.gov/pubmed/27667656
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Underdiagnos - underbehandling
• Among people in the US who had MDD in the previous 12 months, half received health care for the disorder. Treatment was adequate in only 42%, meaning that, of all people with MDD, only 22% received adequate treatment. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major
depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095–3105
PresentatörPresentationsanteckningarFew patients who do receive a diagnosis of depression receive adequate treatment. An analysis by Kessler and colleagues4 published in 2003 showed that, among people in the US population who had MDD in the previous 12 months, half received health care for the disorder. Treatment was adequate in only 42% of those who received treatment, meaning that, of all people with MDD, only 22% received adequate treatment.
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Underdiagnos - underbehandling• Använd skattningsskalor för screening och
diagnostisk precision• Använd i första hand självskattningsskalor
såsom PHQ-9 alt MADRS-S, du sparar tid• Använd strukturerad strategi för att optimera
behandlingsutfall• Använd skattningsskalor (PHQ-9, MADRS-S) för
att följa upp behandlingsresultat och justera behandling för att uppnå remission
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Kloka listan 2017
I första hand escitalopram, sertralin
I andra hand mirtazapin
Specialiserad vård klomipramin
I tredje hand tillägg av litium
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Farmakologisk Behandling
• Vilka är de kritiska beslutsmoment?
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När Klinisk status S-skalor Plan
Vecka 0 Symtomatisk PHQ-9 > 10MADRS > 20
Initiera behandling, lägre dos inom det terapeutiska intervallet
Vecka 2 Remission PHQ-9 < 5MADRS < 12
Fortsätt med aktuell dos
Partiellrespons Gradvis öka dosen
Besvärliga biverkningar
Fortsätt med aktuell dos, hantera biverkningarnaMinska dosen, fortsätt i 2 veckor(Bytt till ett annat LM)
Ingen respons Gradvis öka dosen
Besvärliga biverkningar
Minska dosen, fortsätt i 2 veckor(Bytt till ett annat LM)
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När Klinisk status S-skalor Plan
Vecka 4 Remission +++ Fortsätt med aktuell dosPartiellrespons Höja dosen
Överväg att lägga till ett annatLM
Besvärliga biverkningar
Fortsätt med aktuell dos, försök att hantera biverknigarnaBytt till ett annat LM
Ingen respons Öka dosenBytt till ett annat LM
Besvärliga biverkningar
Bytt till ett annat LM
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När Klinisk status S-skalor Plan
Vecka 6 Remission +++ Fortsätt med aktuell dos
Partiellrespons Öka dosenLägg till ett annat LM
Besvärliga biverkningar
Fortsätt med aktuell dos, hantera biverknigarnaBytt till ett annat LM
Ingen respons Lägg till ett annat LMBytt till ett annat LM
Besvärliga biverkningar
Bytt till ett annat LM
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När Klinisk status S-skalor Plan
Vecka 9 Remission +++ Fortsätt med aktuell dos
Partiellrespons Öka dosenLägg till ett annat LMBytt till ett annat LM
Ingen responsel biverkningar
Bytt till ett annat LM
Vecka 12 Remission Gå till nästa fas i behandlingen
Partiellrespons Bytt till ett annat LM(Öka dosen, utvärdera om 2 v)
Ingen responsel biverkningar
Bytt till ett annat LM
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LM Startdos Titrering Måldos MaxdosBupropion 150 mg 150 mg / 2v 300 mg 450 mg
Citalopram 20 mg 10 mg / 2v 20-40 mg 40 mg
Duloxetin 30 - 60 mg 30 mg / 2v 60 mg 120 mg
Escitalopram 10 mg 10 mg / 2v 10-20 mg 20 mg
Fluoxetin 20 mg 10-20 mg/ 2v 20-40 mg 60 mg
Mirtazapin 15 mg 15 mg / 1-2 v 30 mg 45 mg
Sertralin 50 mg 50 mg / 1-2 v 100-150 mg 200 mg
Venlafaxin 37,5 mg 75 mg / 1 -2v 150 mg 375 mg
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Allvarliga biverkningar
• Serotonergt syndrom
• SIADH (SSRI)
• Krampanfall (bupropion, TCA)
• QTc förlängning (TCA, citalopram, escitalopram)
• Ökad blödningstid (SSRI)
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Utsättningsbesvär
• Yrsel• Illamående• Irritabilitet• Huvudvärk• Ångest• Influensa liknande symtombild
– Trappa ner med c:a 25% / vecka– Kan ta upp till 2-3 månader– Informera patienten noggrant om förväntade utsättningsbesvär
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SLUT
Antidepressiva - Hur gör man?DepressionMDD Diagnostic Criteria: DSM-5Bildnummer 4Bildnummer 5Bildnummer 6Depression and Chronic Diseases: It Is Time for a Synergistic Mental Health and Primary Care ApproachFarmakoterapi – antidepressiva läkemedelComparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Cipriani et al. Lancet 2009; 373: 746–58Network Meta-Analysis and Cost-Effectiveness Analysis of New Generation Antidepressants. Khoo et al., CNS Drugs (2015) 29:695–712Comparative Efficacy, Acceptability, and Tolerability of Augmentation Agents in Treatment-Resistant Depression: Systemic Review and Network Analysis�Zhou et al., J Clin Psychiatry (2015) 76(4) e487-e498Are ADs Effective? A debate on their efficacy for the treatment of major depression in adults�Bschor, Kilarski (2016) Expert Review of NeurotherapeuticsBehandlings målUnderdiagnos - underbehandlingUnderdiagnos - underbehandlingKloka listan 2017Farmakologisk BehandlingBildnummer 21Bildnummer 22Bildnummer 23Bildnummer 24Bildnummer 25Allvarliga biverkningarUtsättningsbesvär�Bildnummer 28