the drugs don't work in psychopharmacology
TRANSCRIPT
Microsoft PowerPoint - ESSEM Pharmacology UE.pptx"The Drugs Don't
Work" Eye Movements as Biomarkers in Psychopharmacology
ESSEM, 11.9.2014
Ulrich Ettinger
Biomarkers and Model Systems
• What is a biomarker?
• How can eye movements be used in this work?
Cognition in Schizophrenia • Cognitive deficits in schizophrenia (see Reilly & Sweeney
2014) – Core features of schizophrenia – Present at illness onset – Relatively stable over the course of the illness – Not treated effectively by antipsychotics – Cause functional disability – Not explained by reduction in general intellect
• Current pharmacological treatments of schizophrenia (Carpenter & Koenig 2008 NPP) – alleviate positive symptoms in most but not all patients – do not satisfactorily reduce negative or cognitive symptoms – produce many unwanted side effects
Treatment of Cognitive Deficits • Treatment of cognitive deficits in schizophrenia: unmet clinical need for
successful new compounds
• Problem in drug development: high attrition rate of new compounds in surrogate patient populations in phase II and III studies (Kola & Landis 2004 Nat Rev Drug Discov)
• Importance of good biomarkers and experimental model systems
Kola & Landis 2004 Nat Rev Drug Discov
Biomarkers
evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" (National Institutes of Health Biomarkers Definitions Working Group)
• Similarities and differences between endophenotypes and biomarkers (Glahn et al 2014 Am J Med Genet)? – "heritability and co-segregation requirements differentiate
an endophenotype from a biomarker" – "endophenotypes are that subset of biomarkers that are
influenced by the same genetic factors that confer risk for the illness"
Top Models in Psychiatry
• What is a model? – A smaller or larger physical copy of an object – A replica or prototype of an object
• Numerous experimental medicine models available for development of antipsychotics … – including amphetamine, ketamine, PCP, lesions, isolation
rearing, schizotypy – modelling (aspects of) the schizophrenia illness phenotype
• Importance in drug development undisputed (especially in combination with well validated, translational biomarkers)
Top Models in Psychiatry
• Criticisms (e.g. Carhart-Harris et al 2013 J Psychopharmacol; Geyer et al 2012 TIPS) – phenomenological incompleteness – lack of cross-species translation – "receptor tautology" (e.g. amphetamine and D2
antagonists)
• "need to develop experimental medicine paradigms that are more predictive of outcomes and to carry out such proof-of-concept clinical trials much earlier in development" (Kola & Landis 2004 Nat Rev Drug Discov)
Human Model Systems of Schizophrenia:
Schizotypy, Ketamine, Sleep Deprivation
Schizotypy • Schizotypy: a cluster of personality traits that resemble, in
attenuated form, the symptoms of schizophrenia
• Phenotype – three dimensions (e.g. Raine 2006 Annu Rev Clin Psychol) – Cognitive-perceptual – Interpersonal – Disorganized
• Can high schizotypy act as model system of schizophrenia? (Dawson et al 2011 Biochem Pharmacol)
• Biomarkers – Antisaccade (AS) eye movements – Smooth pursuit eye movements (SPEM)
Model: Schizotypy Biomarker: Antisaccades
• Question – Using antisaccades as biomarker, does level of schizotypy
predict the response to (1) clinically effective antipsychotics and (2) the established cognitive enhancer nicotine?
• Hypotheses – High schizotypals show antisaccade impairments under placebo – High but not medium schizotypals benefit from risperidone, which
is known to improve antisaccades in schizophrenia (Burke & Reveley 2002 JNNP; Harris et al 2006 Psychol Med) but impair performance in controls (Barrett et al 2004 J Psychopharmacol)
– Both groups benefit from nicotine (Dépatie et al 2002 NPP; Ettinger et al 2009 NeuroImage)
Schmechtig et al (2013) Psychopharmacology
Method
Schmechtig et al (2013) Psychopharmacology
Results • Antisaccade error rate:
– Main effect of Drug (F[3,219]=5.99, p<0.01) – Drug-by-Group interaction (F[3,219]=2.77, p=0.04) – Post-hoc
• Effect of nicotine vs. placebo independent of Group (F(1,111)=5.87, p=0.02) • Effect of antipsychotics vs. placebo depends on Group (F(2,163)=4.15, p=0.02)
Schmechtig et al (2013)
• Ketamine model of schizophrenia – Ketamine produces positive, negative and
disorganised symptoms (Krystal et al 1994) and thought disorder (Adler et al 1999) in healthy volunteers
– Ketamine increases symptoms of schizophrenia patients (Lahti et al 1995)
• Ketamine as experimental model system with smooth pursuit eye movements as biomarker
Model: Ketamine Biomarker: Smooth Pursuit
Method • Aims of our study
– To replicate effects of ketamine – To investigate whether pre-dosing with risperidone counteracts
effects of ketamine
• N=72 in Between-subjects design (placebo-controlled, double- blind, randomised) – Arm1: Placebo capsule and saline infusion (PLA_SAL) – Arm2: Placebo capsule and ketamine infusion (PLA_KET) – Arm3: Risperidone capsule and saline infusion (RIS_SAL) – Arm4: Risperidone capsule and ketamine infusion (RIS_KET)
• Doses – 2mg risperidone – 100ng/ml ketamine
Schmechtig et al (2013) Transl Psychiatry
Results
• Significant increases following ketamine (all p<.001) – Total score – Amnesia – Derealisation
• No effects on CADSS depersonalization
• No modulatory effects of risperidone
Schmechtig et al (2013) Transl Psychiatry
Results
Reduced pursuit gain with ketamine (F[1,64]=28.84, p<0.01)
Increased saccadic frequency with ketamine (F[1,64]=28.84, p<0.01)
No modulatory effects of risperidone (all p>.26)
Sleep Deprivation
Early to bed and early to rise, makes a man healthy, wealthy and wise
Effects of Sleep Deprivation
• Single-handed cross-Atlantic yacht race, very little sleep and not for long periods
• "Most competitors woke themselves at intervals to ensure that they were heading in the right direction and that the sails were trimmed and gear functioning correctly. Five managed to sleep for not more than 1 hour at a time for practically the entire crossing (lasting 24-52 days), and the most rigorous of these (a lawyer) woke himself every half-hour, day and night, for 38 days."
Effects of Sleep Deprivation
• "My mind was completely separated from my body, I just used my body to get me around the boat."
• "Eventually there was no difference between sleeping and waking. You went about in a kind of 'sleep-wake'"
• "Mentally numb. Took hours to do everything, then you find you've hoisted the sail upside down"
• "Almost like being drunk or high on pot".
Effects of Sleep Deprivation
• "T was setting his twin foresails for the first time in the race at about noon on day 33 in good visibility when he saw an object in the water. "A baby elephant", he thought: "A funny place to put a baby elephant." A little later, looking at the same object: "A funny place to put a Ford Popular." He accepted these observations without question until on closer inspection he realised that the object was a whale."
Background
Model: Sleep Deprivation Biomarker: Prepulse Inhibition
Sleep deprivation causes schizophrenia- like reductions in PPI in rats – these are alleviated by antipsychotics but not diazepam or citalopram (Frau et al 2008 Int J Neuropsychopharmacol)
Research Question and Method
• Research Question: What are the effects of sleep deprivation on PPI and subjective ratings in healthy humans?
Petrovsky et al (2014) J Neurosci
Results
Petrovsky et al (2014) J Neurosci
Results
-20
-10
0
10
20
30
40
50
60
70
80
P re
p u
ls e
in h
ib it
io n
Summary and Discussion
Summary • High schizotypes…
– "tolerated" risperidone (unlike controls, who deteriorated) but did not improve significantly
• Ketamine… – induced dissociative symptoms – impaired smooth pursuit – but neither effect was reversed by risperidone
• Sleep deprivation… – induced perceptual, cognitive and negative symptoms – reduced PPI, replicating evidence from animal work – (impaired smooth pursuit and antisaccade performance)
Discussion
• Partial support for the validity of the proposed models and biomarkers
• Open questions – Impaired PPI / eye movements as product of
multiple aetiological pathways: "Any jackass can kick down a barn, but it takes a good carpenter to build one" (Sam Rayburn)
– Why did we not see more pronounced phenomenological changes? What to expect of a good model? A little bit of everything? A lot of some aspect of it?
Discussion
ESSEM, 11.9.2014
Ulrich Ettinger
Biomarkers and Model Systems
• What is a biomarker?
• How can eye movements be used in this work?
Cognition in Schizophrenia • Cognitive deficits in schizophrenia (see Reilly & Sweeney
2014) – Core features of schizophrenia – Present at illness onset – Relatively stable over the course of the illness – Not treated effectively by antipsychotics – Cause functional disability – Not explained by reduction in general intellect
• Current pharmacological treatments of schizophrenia (Carpenter & Koenig 2008 NPP) – alleviate positive symptoms in most but not all patients – do not satisfactorily reduce negative or cognitive symptoms – produce many unwanted side effects
Treatment of Cognitive Deficits • Treatment of cognitive deficits in schizophrenia: unmet clinical need for
successful new compounds
• Problem in drug development: high attrition rate of new compounds in surrogate patient populations in phase II and III studies (Kola & Landis 2004 Nat Rev Drug Discov)
• Importance of good biomarkers and experimental model systems
Kola & Landis 2004 Nat Rev Drug Discov
Biomarkers
evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention" (National Institutes of Health Biomarkers Definitions Working Group)
• Similarities and differences between endophenotypes and biomarkers (Glahn et al 2014 Am J Med Genet)? – "heritability and co-segregation requirements differentiate
an endophenotype from a biomarker" – "endophenotypes are that subset of biomarkers that are
influenced by the same genetic factors that confer risk for the illness"
Top Models in Psychiatry
• What is a model? – A smaller or larger physical copy of an object – A replica or prototype of an object
• Numerous experimental medicine models available for development of antipsychotics … – including amphetamine, ketamine, PCP, lesions, isolation
rearing, schizotypy – modelling (aspects of) the schizophrenia illness phenotype
• Importance in drug development undisputed (especially in combination with well validated, translational biomarkers)
Top Models in Psychiatry
• Criticisms (e.g. Carhart-Harris et al 2013 J Psychopharmacol; Geyer et al 2012 TIPS) – phenomenological incompleteness – lack of cross-species translation – "receptor tautology" (e.g. amphetamine and D2
antagonists)
• "need to develop experimental medicine paradigms that are more predictive of outcomes and to carry out such proof-of-concept clinical trials much earlier in development" (Kola & Landis 2004 Nat Rev Drug Discov)
Human Model Systems of Schizophrenia:
Schizotypy, Ketamine, Sleep Deprivation
Schizotypy • Schizotypy: a cluster of personality traits that resemble, in
attenuated form, the symptoms of schizophrenia
• Phenotype – three dimensions (e.g. Raine 2006 Annu Rev Clin Psychol) – Cognitive-perceptual – Interpersonal – Disorganized
• Can high schizotypy act as model system of schizophrenia? (Dawson et al 2011 Biochem Pharmacol)
• Biomarkers – Antisaccade (AS) eye movements – Smooth pursuit eye movements (SPEM)
Model: Schizotypy Biomarker: Antisaccades
• Question – Using antisaccades as biomarker, does level of schizotypy
predict the response to (1) clinically effective antipsychotics and (2) the established cognitive enhancer nicotine?
• Hypotheses – High schizotypals show antisaccade impairments under placebo – High but not medium schizotypals benefit from risperidone, which
is known to improve antisaccades in schizophrenia (Burke & Reveley 2002 JNNP; Harris et al 2006 Psychol Med) but impair performance in controls (Barrett et al 2004 J Psychopharmacol)
– Both groups benefit from nicotine (Dépatie et al 2002 NPP; Ettinger et al 2009 NeuroImage)
Schmechtig et al (2013) Psychopharmacology
Method
Schmechtig et al (2013) Psychopharmacology
Results • Antisaccade error rate:
– Main effect of Drug (F[3,219]=5.99, p<0.01) – Drug-by-Group interaction (F[3,219]=2.77, p=0.04) – Post-hoc
• Effect of nicotine vs. placebo independent of Group (F(1,111)=5.87, p=0.02) • Effect of antipsychotics vs. placebo depends on Group (F(2,163)=4.15, p=0.02)
Schmechtig et al (2013)
• Ketamine model of schizophrenia – Ketamine produces positive, negative and
disorganised symptoms (Krystal et al 1994) and thought disorder (Adler et al 1999) in healthy volunteers
– Ketamine increases symptoms of schizophrenia patients (Lahti et al 1995)
• Ketamine as experimental model system with smooth pursuit eye movements as biomarker
Model: Ketamine Biomarker: Smooth Pursuit
Method • Aims of our study
– To replicate effects of ketamine – To investigate whether pre-dosing with risperidone counteracts
effects of ketamine
• N=72 in Between-subjects design (placebo-controlled, double- blind, randomised) – Arm1: Placebo capsule and saline infusion (PLA_SAL) – Arm2: Placebo capsule and ketamine infusion (PLA_KET) – Arm3: Risperidone capsule and saline infusion (RIS_SAL) – Arm4: Risperidone capsule and ketamine infusion (RIS_KET)
• Doses – 2mg risperidone – 100ng/ml ketamine
Schmechtig et al (2013) Transl Psychiatry
Results
• Significant increases following ketamine (all p<.001) – Total score – Amnesia – Derealisation
• No effects on CADSS depersonalization
• No modulatory effects of risperidone
Schmechtig et al (2013) Transl Psychiatry
Results
Reduced pursuit gain with ketamine (F[1,64]=28.84, p<0.01)
Increased saccadic frequency with ketamine (F[1,64]=28.84, p<0.01)
No modulatory effects of risperidone (all p>.26)
Sleep Deprivation
Early to bed and early to rise, makes a man healthy, wealthy and wise
Effects of Sleep Deprivation
• Single-handed cross-Atlantic yacht race, very little sleep and not for long periods
• "Most competitors woke themselves at intervals to ensure that they were heading in the right direction and that the sails were trimmed and gear functioning correctly. Five managed to sleep for not more than 1 hour at a time for practically the entire crossing (lasting 24-52 days), and the most rigorous of these (a lawyer) woke himself every half-hour, day and night, for 38 days."
Effects of Sleep Deprivation
• "My mind was completely separated from my body, I just used my body to get me around the boat."
• "Eventually there was no difference between sleeping and waking. You went about in a kind of 'sleep-wake'"
• "Mentally numb. Took hours to do everything, then you find you've hoisted the sail upside down"
• "Almost like being drunk or high on pot".
Effects of Sleep Deprivation
• "T was setting his twin foresails for the first time in the race at about noon on day 33 in good visibility when he saw an object in the water. "A baby elephant", he thought: "A funny place to put a baby elephant." A little later, looking at the same object: "A funny place to put a Ford Popular." He accepted these observations without question until on closer inspection he realised that the object was a whale."
Background
Model: Sleep Deprivation Biomarker: Prepulse Inhibition
Sleep deprivation causes schizophrenia- like reductions in PPI in rats – these are alleviated by antipsychotics but not diazepam or citalopram (Frau et al 2008 Int J Neuropsychopharmacol)
Research Question and Method
• Research Question: What are the effects of sleep deprivation on PPI and subjective ratings in healthy humans?
Petrovsky et al (2014) J Neurosci
Results
Petrovsky et al (2014) J Neurosci
Results
-20
-10
0
10
20
30
40
50
60
70
80
P re
p u
ls e
in h
ib it
io n
Summary and Discussion
Summary • High schizotypes…
– "tolerated" risperidone (unlike controls, who deteriorated) but did not improve significantly
• Ketamine… – induced dissociative symptoms – impaired smooth pursuit – but neither effect was reversed by risperidone
• Sleep deprivation… – induced perceptual, cognitive and negative symptoms – reduced PPI, replicating evidence from animal work – (impaired smooth pursuit and antisaccade performance)
Discussion
• Partial support for the validity of the proposed models and biomarkers
• Open questions – Impaired PPI / eye movements as product of
multiple aetiological pathways: "Any jackass can kick down a barn, but it takes a good carpenter to build one" (Sam Rayburn)
– Why did we not see more pronounced phenomenological changes? What to expect of a good model? A little bit of everything? A lot of some aspect of it?
Discussion