Update on neurochemistry: Decision-making for Clinicians

Transcription

1 Update on neurochemistry: Decision-making for Clinicians Pierre Blier, MD, Ph.D Professor, Psychiatry and Cellular & Molecular Medicine University of Ottawa Endowed Chair and Director Mood Disorders Research Institute of Mental Health Research Canada Research Chair, Psychopharmacology

2 Objectives of the Presentation Provide a summary of the mechanism of action of antidepressant strategies on the serotonin system Describe the functional connectivity between monoaminergic systems from a clinical viewpoint Emphasize target engagement when using psychotropic agents Describe the receptor profile of atypical antipsychotics that makes them useful in MDD

3 5-HT transmission and 5-HT reuptake inhibition normal acute treatment with a SSRI (and SNRIs) long-term treatment with a SSRI (and SNRIs)

4 Average occupancy of the 5-HTT transporter based on striatal binding Meyer et al, Am J Psychiatry 2004

5 Treatments Cell body 5-HT 1A autoreceptor responsiveness Terminal 5-HT 1B autoreceptor responsiveness Terminal a 2- adrenoceptor responsiveness on 5-HT terminals Postsynaptic 5-HT 1A receptor responsiveness Net effect net on 5-HT transmission SSRI SNRI MAOI 5-HT 1A agonists or Tricyclics ECS Mirtazapine* Bupropion* Vagus Nerve St* n.d n.d Agomelatine* n.d n.d Lamotrigine n.d n.d n.d *These treatments increase the firing rate of 5-HT neurons Blier et al,

6 The Serotonin (5-HT) System MAO X Serotonin Syndrome: Increased heart rate & blood pressure Myoclonus, increased CPK Hyperthermia Abdominal cramps/diarrhea Increased tendon reflexes (+ve Babinski) Agitation and/or Confusion Death X Courtesy of ST Szabo, MD,PhD

7 Vortioxetine: pharmacological profile Vortioxetine SERT HT 1A 5-HT 1B 5-HT 1D 5-HT 3 5-HT 7 Uptake inhibitor Agonist Partial agonist Antagonist SERT, serotonin transporter; 5-HT, serotonin

8 Dose-dependent occupancy of the 5-HT transporter by Vortioxetine (LU AA21004) 11 C-MADAM binding Vortioxetine ~20 mg Vortioxetine 5-10 mg Stenkrona et al, Eur Neuropsychopharmacol 2013; Areberg et al, 2012

9 Incidence of TESD based on ASEX scoring (%) Sexual dysfunction Sexual dysfunction, reported as TEAEs during treatment with vortioxetine, was low (1.6%) and similar to the placebo group (0.9%) 1 Sexual dysfunction, assessed using the ASEX scale No difference from placebo for 5 mg to 15 mg doses of vortioxetine 2 Increase in TESD from 5 mg to 20 mg vortioxetine, but there was no clear dose response relationship 1 Vortioxetine 20 mg was associated with an increase in TESD (46%) 1 Placebo 5 mg 10 mg 15 mg 20 mg 60 mg Vortioxetine Duloxetine TEAEs, treatment-emergent adverse events; TESD, treatment-emergent sexual dysfunction; ASEX, Arizona Sexual Experiences Scale 1. Vortioxetine EPAR;2. Vortioxetine Summary of Product Characteristics, 2013

10 Symptom severity Approximate occupancy of the 5-HTT (%) Evolution of approximate 5-HT transporter occupancy with antidepressants Consider a crossover of 2 weeks when switching to Vortioxetine Possibility of discontinuation problems Fluoxetine Vortioxetine 20 Venlafaxine Escitalopram Days

11 RAPHE SSRI? 5-HT (-) (-) LOCUS COERULEUS 5-HT (-) (+) 1 5-HT POSTSYNAPTIC NEURON

12 SSRIs decrease NE transmission (Szabo and Blier, 2000; Kawahara et al, 2007) Spikes/sec Fmoles/sample Normal : Norepinephrine (NE) Long-term treatment with a SSRI Locus coeruleus Amygdala * Cont Citalopram Cont * Citalopram

13 Decrease in CSF noradrenergic metabolite by SSRIs (fluoxetine, fluvoxamine) N = 24 Sheline et al, J Clin Psychopharmacol 1997

14 Functional Overlap Between Aminergic Systems: Features of Depression NE Energy Interest Motivation Anxiety Irritability Mood, emotion, cognitive function Sex Appetite Aggression Impulsivity 5-HT Drive Dopamine Courtesy of S. Stahl

15 RAPHE SSRI? 5-HT DA (-) (-) VENTRAL TEGMENTAL AREA 5-HT (-) (+) 2 5-HT POSTSYNAPTIC NEURON

16 Inhibitory Effect of Escitalopram (X 14 days) on VTA Dopamine Neuronal Firing * Control Escitalopram * * * Rate (Hz) Bursts/10 sec Spikes/Bursts % Spikes Occurring in Bursts (x10) Dremencov et al, J Psychiat Neurosci 34: , 2009

17 SSRIs Decrease Hedonic Tone fmri study of neural response in healthy participants to reward after 7 days of citalopram (20mg), reboxetine (4mg b.i.d) or placebo (n=15 per group) Sight of Chocolate p<.001, Citalopram vs. Placebo Sight + Taste of Chocolate Citalopram resulted in decreased neural response to the sight and taste of chocolate in the ventral striatum and orbitofrontal cortex (sight + taste) compared to placebo Reboxetine had an enhanced response to the sight and taste of chocolate in the OFC compared to placebo Suggests dampening of reward response with SSRIs p=.05, Reboxetine vs. Placebo McCabe et al, 2010

18 Common Residual Symptoms Despite Remission, or Iatrogenic Symptoms? Fatigue (mental and physical) Concentration Decreased interest or pleasure Cognitive impairment Target engagement!!! Nutt D, et al. Journal of Psychopharmacology 2007; 21(5): Trivedi MH, Hollander E, Nutt D, Blier P. J Clin Psychiatry 2008; 69:

19 The SNRI myth! RAPHE 5-HT (-) (-) LOCUS COERULEUS 5-HT (-) (+) 1 5-HT POSTSYNAPTIC NEURON

20 Control Situation TYR MAO MHPG NE NE Blood Pressure mm of Hg Time

21 Following NE Reuptake Blockade (nortriptyline, desipramine, reboxetine) TYR MAO NE X Venlafaxine? Duloxetine? Desvenlafaxine? MHPG 200 NE Blood Pressure mm of Hg Time

22 Pressor response to tyramine in healthy volunteers Systolic blood pressure change (mm Hg) Placebo Nortriptyline (50 mg BID) * Baseline Day Tyramine dose (mg i.v.) Gobbi et al, J Clin Psychopharmacol 2001

23 NE Reuptake Inhibiting Action of Atomoxetine on NE Reuptake in Depressed Patients 3 mg 4 mg 6 mg * Baseline 25 mg 43 mg 60 mg 80 mg Blier et al, Int J Neuropsychopharmacol 24 (Suppl 3): 143S, 2010

24 Similarities between the NE and the DA systems (transporters and receptors)

25 Lack of Inhibitory Action of Paroxetine on NE Reuptake in Depressed Patients 3 mg 4 mg 6 mg Baseline 20 mg 30 mg 40 mg 50 mg Blier et al, Int J Neuropsychopharmacol 24 (Suppl 3): 143S, 2010

26 Dose-Dependent Inhibition of NE Reuptake by Venlafaxine in Depressed Patients * Blier et al, Int J Neuropsychopharmacol 24 (Suppl 3): 143S, 2010

27 ED 30 Values (mg of Tyramine ± SEM) Pressor Response to Intravenous Tyramine 10 High dose Low dose * 375 mg/day * mg/day 6 75 mg/day 4 0 Baseline 7 14 Day ED 30 = Dose of tyramine (iv) required to induce a 30 mm Hg increase in systolic BP Debonnel et al, Int J Neuropsychopharmacol 2007

28 CIT (n = 2876) BUS (n = 286) BUP-SR (n = 279) VEN-XR (n= 250) BUP-SR (n = 239) SERT (n = 238) T3 (n = 73) Li (n = 69) NTP (n = 121) MIRT (n = 114) VEN-XR + MIRT (n = 51) TCP (n = 58) Remission Rates (%) STAR*D Remission Rates at Treatment Exit (n = 943) 32.9 (n = 94) 39.0 (n = 108) Venlafaxine = Augmentation (SNRI) Mean dose: 190 mg/day Level 1 (n = 2876) Level 2 (Augment) (n= 565) Level 2 (Switch) (n = 727) Level 3 (Augment) (n = 142) Level 3 (Switch) (n = 235) Level 4 (Switch) (n = 109) (n = 62) 25.5 (n = 61) 26.6 (n = 63) 24.7 (n = 18) (n = 9) 12.4 (n = 15) 8.0 (n = 9) 15.7 (n = 8) 13.8 (n = 8) 0 Adapted from Warden D, et al. Curr Psychiatry Rep 2007: 9:

29 Proportion of Patients With Remission P = 0.01 P = 0.02 Venlafaxine: 272 mg Paroxetine: 36 mg Patients (%) (n=124) 0 Observed Cases LOCF Poirier MF, Boyer P. Br J Psychiatry. 1999;175:12-16.

30 Increase in in systolic blood pressure (mmhg) Tyramine Pressor Response with ODV and Plasma Levels *** * 4 mg 6 mg * 5 0 Baseline Daily dose of ODV (mg) Pristiq Effexor Plasma level of ODV (ng/ml) (75) (225) (375) Plasma level of VEN + ODV in ng/ml (daily dose in mg)

31 INCREASE IN SYSTOLIC BLOOD PRESSURE (mm Hg) Pressor Response to 6 mg of IV Tyramine in Healthy Volunteers 40 BASELINE DAY 7 DAY * * 0 6 PLACEBO 5 CLOMIPRAMINE 100 mg/day 8 6 DULOXETINE 20 mg/day DULOXETINE 40 then 60 mg/day Turcotte et al, Neuropsychopharmacology 2001

32 ED 30 mm Hg- Tyramine (mg) Daily Regimens of Duloxetine Necessary to Inhibit NE Reuptake in Healthy Volunteers 20 ** 16 ** 12 8 * ** 4 0 Vincent et al, Circulation 109:3205, Duloxetine Dose (mg)

33 Enhanced response to duloxetine in SSRI non-responders (open labelled) 60 mg/day 120 mg/day 60 mg/day 60 mg/day Sagman et al, Int J Psychiat Clin Pract 2011

34 Reciprocal interactions between monoaminergic neurons (-)5-HT? (-) 5-HT a1 (+) Svensson et al, 1975; Mongeau et al, 1998 NE

35 5-HT2A antagonism reverses the inhibition of NE neurons by escitalopram 150 # Control SB Haldol SALINE MDL 100,907 * * * Haldol SB Cont ESCITALOPRAM MDL 100,907 Dremencov, El Mansari, Blier, Biological Psychiatry 2007

36 Reciprocal interactions between monoaminergic neurons DOPAMINE D2 (-) (-) 5-HT? (-) 5-HT (-) 5-HT2A a1 (+) NE

37 5-HT 2C antagonism reverses the inhibition of dopamine neurons by an SSRI Escitalopram Escitalopram + SB mg/kg/day Escitalopram + SB mg/kg/day # # *** *# *** * * *** * 20 0 Firing rate, spikes/sec *p<0.05; ***p<0.001 vs vehicle; #p<0.05 vs escitalopram alone SEM, standard error of mean; SSRI, selective serotonin reuptake inhibitor Number of bursts/10 sec Number of spikes/burst Proportion of spikes occurring in bursts Dremencov E et al. J Psychiatry Neurosci 2009;34:223-9

38 Reciprocal interactions between monoaminergic neurons DOPAMINE D2 (-) (-) 5-HT2C (-) 5-HT (-) 5-HT2A a1 (+) NE

39 Pharmacology of Mirtazapine: a 1 Target engagement!!! Mirtazapine a H M HT 2A HT 2C HT HT : Decreased 5-HT action : Antidepressant effect : Sedation * The larger the number, the greater is the affinity (pki ) : Restoration of sleep architecture and anxiolytic/antidep. effect : Anti-nausea effect : Antidepressant effect?

40 5-HT Locus Coeruleus Raphe (-) (-) mirtazapine 5-HT (-) ( + ) 1 mirtazapine mirtazapine Postsynaptic Neuron

41 HAMD 17 scores (+ SEM) Effectiveness of drug combinations Fluoxetine (n = 28) Fluoxetine + Mirtazapine30 mg (n = 25) Bupropion + Mirtazapine 30 mg (n = 26) Venlafaxine 225 mg+ Mirtazapine 30 mg (n = 26) Dropout: 15% Day of treatment * P = when comparing the combination groups with fluoxetine * Blier et al, Am J Psychiat 167:281-8,2010

42 Patients (%) achieving remission Remission rates in monotherapy vs combination from treatment initiation SSRI mg Mirtazapine 30 mg Blier et al, Eur Neuropsychopharmacol 2009 Blier et al, Am J Psychiat 2010; * Paroxetine 20-30, Fluoxetine SSRI Bupropion Venlafaxine mg* 150 mg 225 mg + Mirtazapine 30 mg

43 CO-MED Study: open and single-blinded (TRIAL DESIGN) 17 mg/day (Not blinded) 288 mg/day +13 mg/day 192 mg/day +20 mg/day Rush et al, Am J Psychiat 168:689, 2011

44 Functional connectivity: (-) (-) (-)

45 Why Use Antipsychotics to Treat MDD? Historically, the typical antipsychotic haloperidol, which predominately acts as a potent D2/3 antagonist, is not effective in the treatment of MDD Atypical antipsychotics, however, are effective as adjunctive therapies for MDD at lower doses than are effective in schizophrenia Therefore, properties other than D2/3 receptor blockade accounts for the therapeutic action of atypical antipsychotics in MDD

46 Receptor Pharmacology of Antipsychotic Medications Affinity K i [nm] for D2 and 5-HT receptors D2 2A 2C 1A 1D Haloperidol Clozapine Olanzapine Quetiapine Risperidone Paliperidone Ziprasidone Aripiprazole NS NS NS 200 NS NS NS 800 NS ND An important metabolite of quetiapine, norquetiapine is a potent 5-HT2C antagonist Aripiprazole is a partial D2 agonist

47 Placebo-controlled trials of atypicals as adjuncts in unipolar depression Cariprazine + SSRI/SNRI 1 (trials) 819 (patients) Olanzapine + fluoxetine Risperidone + SSRI/SNRI Quetiapine XR + SSRI/SNRI Aripiprazole + SSRI and SNRI Ziprasidone + SSRI/SNRI Brexpiprazole + SSRI/SNRI Adapted from Shelton RC, Papakostas GI., Acta Psychiatr Scand. 2008;117(4): ; Kamijima et al, J Affect Dis, 2013 ; Lenze et al, Lancet 2015; Papakostas et al, Am J Psychiat 2015; Thase et al, J Clin Psychiat, 2015a,b; Durgam et al. 2016

48 Detailed receptor pharmacology of atypical antipsychotics Atypical antipsychotic 5-HT 2A/C antagonism a 2 antagonism 5-HT 1A partial agonism 5-HT 7 antagonism 5-HT 1B/D antagonism D2/3 partial agonism Clozapine O Risperidone + + O + + Olanzapine + O O + O Quetiapine O O Brexpiprazole O Ziprasidone + O Aripiprazole + O + + O Asenapine Lurasidone +/O O Iloperidone + O + O O O O O O + O + O O O Amisulpiride O O O + O O* Cariprazine O/+ O + O O + O indicates no activity; + indicates significant activity

49 Firing rate of NE neurons Atypical antipsychotics reverse the inhibition of NE neurons produced by SSRIs # * # * *

50 DA D 2 Postsynaptic Neurons D2 5-HT (-) NE All

51 Atypicals and specific receptor affinities & depressive symptoms Atypicals 5-HT2A/C antagonism a2 antagonism 5-HT1A agonism D2 agonism NE reuptake inhibition Aripiprazole + O + + O Asenapine O O Lurasidone +/O + + O O Olanzapine + O O O O Paliperidone + + O O O Quetiapine O + Risperidone + + O O O Ziprasidone + O + O O O: indicates no activity and (+) significant activity

52 Clinical evidence for an antidepressant effect of 5-HT1A receptor agonism Three double-blind studies showed the efficacy of the selective 5-HT1A agonist gepirone ER in MDD 1-3 Bupropion and the 5-HT1A agonist buspirone augmentation of citalopram: equal effectiveness in STAR*D 2 1. Feiger et al, Psychopharmacol Bull 32: , Feiger et al, J Clin Psychiat 64: , Bielsky et al, J Clin Psychiat 69: , Trivedi et al, NEJM 2007

53 DA D 2 Postsynaptic Neurons D2 5-HT X (-) NE

54 Atypicals and specific receptor affinities & depressive symptoms Atypicals 5-HT2A/C antagonism a2 antagonism 5-HT1A agonism D2 agonism NE reuptake inhibition Aripiprazole + O + + O Asenapine O O Lurasidone +/O + + O O Olanzapine + O O O O Paliperidone + + O O O Quetiapine O + Risperidone + + O O O Ziprasidone + O + O O O: indicates no activity and (+) significant activity

55 DA D 2 Postsynaptic neurons Ari D2 5-HT (-) NE

56 Clinical evidence for an antidepressant effect of D2 receptor agonism A double-blind, placebo- and fluoxetine-controlled study showed the efficacy of the D2 receptor agonist pramipexole in MDD 1 A double-blind, placebo-controlled positive trial of pramipexole augmentation in MDD was recently reported 2 1. Corrigan et al, Depression Anxiety 11:58-65, Cusin et al, J Clin Psychiat 74: e636-41, 2013

57 Mean Change in MADRS total score Aripiprazole as Adjunctive Antidepressant: Study in Japan (ADMIRE) Week *** *** *** *** * *** * *** ** ** ** ** ** *** ** *** ** ** *** *** placebo Placebo (n=195) mg/d mg/d (n=197) (n=194) mg/d mg/d (n=197) (n=194) ** ** *** *** *: p<0.05, **: p<0.01, ***: p<0.001 vs. adjunctive placebo (ANCOVA) Mean baseline MADRS total scores: aripiprazole 3-15 mg/day 25.3; 3 mg/day 25.2; placebo Kamijima, K.,et al., J. Affective Disorders, 2013

58 Conclusions We have new drugs with novel mechanisms of action since the late 1950 s, we have made progress! Remission rates in MDD are low in large part because of inadequate implementation of treatment protocols Unfortunately, we have no reliable predictors of response

59 Conclusions Antidepressants in real life are often more effective than they appear in controlled trials because of the constraints of the studies (i.e. suicidal patients) Use the neurobiological algorithm: never do the same thing twice! Avoid irrational polypharmacy (Rx with the same properties) Hopelessness is good predictor of suicide: the physician must convince him/herself and the patient of the depth of the tool box