Vortioxetina: evidenze sui sintomi cognitivi della depressione. Umberto Albert

Transcription

1 Vortioxetina: evidenze sui sintomi cognitivi della depressione Umberto Albert

2 Depression is a clinically heterogeneous disorder Sadness Anxiety Irritability Lack of enjoyment Suicidal ideation Hopelessness Inappropriate guilt Difficulties with: Attention and concentration Short- and long-term memory Decision making Planning and organisation Mental sharpness Word-finding Thinking speed Judgement Fatigue Eating / weight changes Insomnia / hypersomnia Sexual dysfunction Headaches Stomach problems Chest pain Psychomotor agitation 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Health Disorders. 5 th ed. Washington, DC: American Psychiatric Association; 2013; 2. Marazziti D, et al. Eur J Pharmacol. 2010;626(1): Hammar A, Ardal G. Front Hum Neurosci. 2009;3:26.

3 Presentation of the symptoms of major depressive disorder varies among individuals DSM-5 criteria lists the following symptoms of MDD Diagnosis of major depressive disorder must include: Depressed mood or irritability and / or Marked loss of interest/pleasure In addition, symptoms from the list below must be present during the same two-week period. A minimum of five symptoms (including the above) is required for diagnosis Increased appetite/weight Suicidal ideation Inappropriate guilt Impaired concentration/ decision-making capabilities Psychomotor retardation Hypersomnia Psychomotor agitation Decreased appetite/weight Insomnia Lack of energy DSM-5, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. MDD, major depressive disorder. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Health Disorders. 5 th ed. Washington, DC: American Psychiatric Association; 2013.

4

5 3) Sulla base della Sua esperienza, quali tra i seguenti sintomi ritiene che compromettano maggiormente il FUNZIONAMENTO DEL PAZIENTE con DDM? (Le chiediamo di metterli in ordine da quello che compromette maggiormente a quello che compromette meno). I sintomi che sono stati maggiormente inseriti nelle PRIME CINQUE posizioni sono: I sintomi che sono stati inseriti meno nelle PRIME CINQUE posizioni sono: 75,0% Umore depresso Sentimenti di autosvalutazione o di colpa 55,5% 74,2% Diminuzione di interesse o piacere Faticabilità o mancanza di energia 52,4% 73,4% 61,0% Ridotta capacità di pensare o di concentrarsi Pensieri ricorrenti di morte Insonnia o ipersonnia 35,9% 60,9% Agitazione o rallentamento psicomotorio Perdita di peso o aumento di peso 11,7%

6 4) Sulla base della Sua esperienza, quali tra i seguenti SINTOMI RESIDUI sono PIÙ FREQUENTI tra i suoi pazienti affetti da DDM? (Le chiediamo di metterli in ordine dal più frequente al meno frequente). I sintomi che sono stati maggiormente inseriti nelle PRIME CINQUE posizioni sono: I sintomi che sono stati inseriti meno nelle PRIME CINQUE posizioni sono: 86,7% Faticabilità o mancanza di energia Sentimenti di autosvalutazione o di colpa 53,1% 82,8% Ridotta capacità di pensare o di concentrarsi Agitazione o rallentamento psicomotorio 47,7% 71,9% 58,6% Diminuzione di interesse o piacere Insonnia o ipersonnia Perdita di peso o aumento di peso 29,7% 53,9% Umore depresso Pensieri ricorrenti di morte 15,6%

7 To what extend do you believe that residual cognitive symptoms could increase relapse risk? To what extend do you believe that addressing residual cognitive symptoms could improve patient functioning? Int J Psychiatry Clin Pract 2015

8 Disturbances in cognitive function are common during and between syndromal depressive episodes Affective remission versus cognitive remission Depressed patients Remitted patients Rock et al. Psychological Medicine (2014), 44,

9 Mean Proportion of Time DSM-IV Symptom Cluster Is Present Depressive symptoms persist during periods of remission and subsequent depressive episodes Mean proportion of time DSM-IV symptoms are present during 3-year follow-up period (n=267) Cognitive problems Core symptoms: depressed mood/diminished interest Lack of energy Sleeping problems Worthlessness/guilt Eating problems Psychomotor problems Death ideations Weeks of Follow-up Conradi HJ, et al. Psychol Med. 2011;41:

10 Lee et al. Journal of Affective Disorders 140 (2012)

11 Memory as a function of the number of depressive episodes Number of correct delayed recall responses Number of previous depressive episodes Gorwood et al. Toxic effects of depression on brain function: impairment of delayed recall and the cumulative length of depressive disorder in a large sample of depressed outpatinets. Am J Psychiatry 2008; 165: 731-9

12 Cumulative duration of depressive episodes Cumulative duration of depressive episodes with psychotic features -.14 lower CAMCOG score per month depressed -.18 lower CAMCOG score per month depressed R2adj = 0.31, P =.02 R2adj = 0.33, P =.01 Total number of depressive episodes with psychotic features -1.4 lower CAMCOG score per psychotic episode R2adj = 0.35, P =.006 CAMCOG=Cambridge Cognitive Examination Hasselbalch et al. European Psychiatry 28 (2013)

13 Cognitive impairment correlates with depressive severity but not for all cognitive domains Significant correlations between depression severity and cognitive performance were found in the domains of : episodic memory, executive function, and processing speed, but not for semantic memory or visuo-spatial memory. McDermott LM, Ebmeier KP. J Affect Disord 2009;119:1-8

14 Cognitive dysfunctions are not related to age Snyder Psychol Bull 2013

15 Depression symptoms Cognitive dysfunction as a partially separate illness dimension with its own evolution, prognosis and impact on psychosocial functioning Remission Normality I Symptom reduction Relapse New episode II Time Low III Acute phase Cognitive function I II III Does the cognitive impairment occur before the mood symptoms? Is the time course of cognitive normalisation delayed in relation to remission? Evidence that cognitive impairment may persist despite symptom reduction and remission Is the long-lasting cognitive impairment a predictor for higher relapse risk for new episodes? Hammar A, Ardal G. Front Hum Neurosci. 2009;3:26.

16 There are several ways to test cognitive function Neuropsychological tests = objective testing of patient performance on tests developed to assess function in cognitive domains known to be affected in MDD, for example: Executive function Psychomotor speed Attention Memory Rating scales = subjective rating of patient s function and symptoms by the physician (e.g., MADRS item 5, HAM-A item 6) Questionnaires = subjective self-rating of function and symptoms by the patient (e.g., CPFQ, PDQ) CPFQ=Cognitive and Physical Functioning Questionnaire; HAM-A=Hamilton Anxiety Rating Scale; MADRS=Montgomery Åsberg Depression Rating Scale; MDD=major depressive disorder; PDQ=Perceived Deficits Questionnaire

17 Cognitive function was assessed as part of the vortioxetine development programme DSST=Digit Symbol Substitution Test; RAVLT=Rey Auditory Verbal Learning Test Acquisition Learning Delayed recall (20 30 min) Memory DSST A measure of executive function, working memory, processing speed and visuospatial attention RAVLT A measure of verbal learning and memory Executive function Psychomotor speed Attention Memory

18 Trattamento dei sintomi cognitivi: focus su vortioxetina L'efficacia di vortioxetina (5-20 mg/die) sui sintomi cognitivi in pazienti con MDD è stata valutata in 2 studi su pazienti adulti (end point primario) 1 studio su pazienti anziani (endpoint secondario esplorativo predefinito)

19

20 Vortioxetine demonstrates efficacy in elderly patients with depression 8-week placebo-controlled study in patients aged 65 years Mean change from baseline in HAM-D 24 score by visit (FAS, MMRM; endpoint LOCF); **p<0.01, ***p<0.001 vs placebo; nominal p-values for MMRM Placebo (n=145) Vortioxetine 5 mg (n=155) Duloxetine 60 mg (n=148) Mean change from baseline (HAM-D 24 total score) Primary endpoint ** *** *** *** ** *** LOCF Duloxetine treatment arm included as an active reference. FAS, full analysis set; HAM-D 24, Hamilton Depression Rating Scale, 24-item version; LOCF, last observation carried forward; MMRM, mixed model for repeated measures. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):

21 Vortioxetine improved cognitive performance in elderly patients with depression Improvement from baseline compared with placebo at Week 8 in patients 65 years DSST and RAVLT exploratory endpoints FAS, ANCOVA, Cohen s d *p<0.05, **p<0.01 vs placebo; nominal p-values; n numbers are APTS Vortioxetine 5 mg Duloxetine 60 mg * ** * * * Duloxetine was included as active reference for study validation, not for comparison of effect sizes. ANCOVA, analysis of covariance; APTS, all patients treated set; DSST, Digit Symbol Substitution Test; FAS, full analysis set; RAVLT, Rey Auditory Verbal Learning Test. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):

22 Effect of vortioxetine on cognition is mainly direct and not mediated by improvement in mood symptoms in general Direct effect on DSST, RAVLT acquisition and RAVLT delayed recall in patients 65 years Path analysis: Direct effect of vortioxetine on DSST Vortioxetine 5 mg Direct effect 83% Duloxetine direct effect: 26% DSST Indirect effect 17% Duloxetine was included as active reference for study validation, not for comparison of effect sizes. DSST, Digit Symbol Substitution Test; HAM-D 24, Hamilton rating scale for Depression 24-item version; RAVLT, Rey Auditory Verbal Learning Test. HAM-D 24 Indirect effect 17% Duloxetine indirect effect: 74% RAVLT acquisition: Vortioxetine had a 71% direct effect (duloxetine 65%) RAVLT delayed recall: Vortioxetine had a 72% direct effect (duloxetine 66%) Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):

23 The FOCUS study

24 Endpoints dello studio: Endpoint primario variazione rispetto al basale dello z-score composito (DSST/RAVLTacq/RAVLTdelay) DSST RAVLT Funzioni esecutive Velocità Psicomotoria Attenzione Memoria Endpoint secondari STROOP Test Trail Making B Trail Making A Choice Reaction time task Simple Reaction time task DSST=Digit Symbol Substitution Test; RAVLT=Rey Auditory Verbal Learning Test McIntyre R et al. Int J Neuropsychopharmacol (2014), 17,

25 Mean difference from placebo in composite z-score Vortioxetine significantly improved cognitive performance in patients with depression: primary endpoint (composite z-score) FOCUS: Mean change from baseline, difference from placebo Composite z-score at Week 8 versus placebo DSST/RAVLT acq /RAVLT delay ; FAS, MMRM, *p<0.05, p>0.025, **p<0.01, ***p<0.001 vs placebo *** *** Secondary analyses Mean difference from placebo 10 mg 20 mg DSST 4.20*** 4.26*** RAVLT acq 1.02* 0.59 RAVLT delay 0.71** 0.65** Vortioxetine 10 mg (n=193) Vortioxetine 20 mg (n=204) acq, acquisition; delay, delayed recall; DSST, Digit Symbol Substitution Test; FAS, full analysis set; MMRM, mixed model for repeated measures; RAVLT, Rey Auditory Verbal Learning Test; VOR, vortioxetine. McIntyre RS, et al. Int J Neuropsychopharmacol. 2014;17(10):

26 Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. Protocol-specified path analysis Vortioxetina 10 mg Effetto diretto 64% (95% CI: 47 82%; p=0.0007) Effetto indiretto 36% Composite z- score MADRS Vortioxetina 20 mg Effetto indiretto 52% Effetto diretto 48% (95% CI: 23 73%; p=0.0246) Composite z- score The direct effect claim is a medical statement supported by published data CI=confidence interval; MADRS=Montgomery Åsberg Depression Rating Scale

27 Path and subgroup analyses indicate that the beneficial effect of vortioxetine on cognition is largely a direct treatment effect. Protocol-specified path analysis Subgroup analysis: Vortioxetina 10 mg Effetto diretto 64% (95% CI: 47 82%; p=0.0007) Effetto indiretto 36% Composite z- score Miglioramento Questi risultati performance dimostrano cognitive che di vortioxetina l effetto positivo vs placebo di vortioxetina in pazienti: sulle funzioni cognitive è indipendente non-responders dal miglioramento per il punteggio del della scala punteggio MADRS MADRS MADRS Effetto indiretto 52% non-remitters Questi risultati confermano i (MADRS risultati dello punteggio studio totale>10) di Katona et al.2012 Vortioxetina 20 mg Effetto diretto 48% Composite z- score (95% CI: 23 73%; p=0.0246) The direct effect claim is a medical statement supported by published data CI=confidence interval; MADRS=Montgomery Åsberg Depression Rating Scale

28

29 The CONNECT study Endpoint primario: variazione vs basale punteggio DSST dopo 8 settimane Endpoint secondari: PDQ CGI-I MADRS Valutazioni neuropsicologiche aggiuntive Every day functioning (UPSA)

30 Difference from placebo and standardized effect size vs placebo in DSST number of correct symbols at week 8 (ANCOVA, OC, LS means) p*<0,05 Mahableshwarkar et al Neuropsychopharmacology 1-

31 Path analysis of direct and indirect effects on cognitive function. Effetto diretto: Vortioxetina mg/die: 75,7% Duloxetina 60 mg/die : 48,7% *<0,05 Mahableshwarkar et al Neuropsychopharmacology 1-

32 Standardised effect size vs placebo Vortioxetine mediates an improvement in cognitive performance in depression in three clinical trials DSST Replication: Number of correct symbols, change from baseline at Week 8 (FAS, ANCOVA, LOCF, path analysis; *p<0.05, ***p<0.001) CONNECT 1 FOCUS 2 Elderly 3 *** *** Direct effect Indirect effect Path analysis mediated via MADRS total score * * The effect of vortioxetine on DSST performance is not mediated solely through an improvement in general depressive symptoms Duloxetine was included as active reference in the CONNECT and Elderly studies for study validation, not for comparison of effect sizes. DSST scores were assessed as predefined primary outcome of CONNECT, secondary outcome of FOCUS, and exploratory outcome of the Elderly study, with path analyses performed post hoc. 1. Mahableshwarkar AR, et al. Poster presented at CINP 2014; 2. McIntyre R, et al. Int J Neuropsychopharmacol. 2014;17(10): ; 3. Katona C, et al. Int Clin Psychopharmacol. 2012;27(4):

33 Risultati: Perceived Deficit Questionnaire (valutazione della percezione del paziente) Variazioni vs basale della scala PDQ Sia duloxetina che vortioxetina determinano un miglioramento nella variazione del punteggio della scala PDQ PDQ tot: (0-80, max 80 percezione negativa del proprio stato) *<0,05 Mahableshwarkar et al Neuropsychopharmacology 1-13

34 Change from baseline in UPSA composite score Vortioxetine significantly improves everyday functioning Change from baseline in UPSA composite score at Week 8 ANCOVA, LS means; ***p<0.001 vs placebo (nominal p-values, not adjusted for multiplicity) *** Placebo (n=167) Vortioxetine (n=175) Duloxetine (n=187) UPSA measures of everyday functioning Household chores Communication Finance Transportation Planning/recreational activities Duloxetine was included as active reference for study validation, not for comparison of effect sizes; UPSA data presented are a composite of UPSA and UPSA-B. ANCOVA, analysis of covariance; LS, least squares; UPSA, University of San Diego performance-based skill assessment; UPSA-B, UPSA-Brief. Mahableshwarkar et al Neuropsychopharmacology 1-13

35 Esistono altri farmaci con effetto pro-cognitivo? (nella Depressione Maggiore) McIntyre & Lee Curr Opin Psychiatry 2016, 29: 48-55

36 Bortolato et al. BMC Medicine (2016) 14:9

37 Bowie et al. J Nerv Ment Dis 2013;201:

38 Conclusioni 1. I sintomi cognitivi sono sintomi nucleari della depressione maggiore, ma dimensione indipendente e separata da quella affettiva 2. Possono facilmente essere misurati e monitorati nel tempo 3. Costituiscono una fonte rilevante di impairment funzionale durante l episodio depressivo maggiore e quindi devono essere oggetto di attenzione clinica 4. Frequentemente costituiscono sintomi residui e rappresentano un fattore di rischio per successive ricadute 5. Vortioxetina è un farmaco ad azione multimodale efficace che combina un azione antidepressiva e un effetto diretto sui sintomi cognitivi della depressione maggiore (almeno 3 studi indipendenti, 2 controllati verso comparatore attivo)