An Investigation of the Acute and Chronic Effects of Ketamine on Cognition

324 Pages·2013·9.83 MB·English

An Investigation of the Acute and
Chronic Effects of Ketamine on
Cognition
Celia J.A. Morgan
University College London
Submitted for the degree of Doctor of Philosophy
University of London
May 2005
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UMI Number: U593077
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Abstract
The work presented in this thesis aimed to investigate the consequences and causes of
ketamine abuse and compare them with the acute effects of the drug. Seven
experimental chapters report the findings of a total of 9 studies: 5 with ketamine users,
3 administering ketamine to healthy volunteers and 1 with psychosis-prone individuals.
Acute studies with volunteers demonstrated ketamine-induced impairments to item
recognition, source memory, controlled semantic processing, working memory and
procedural learning. There was also a suggestion of a disruption in self-monitoring but
perceptual priming and executive functioning were largely preserved. Ketamine was
subjectively reinforcing in healthy volunteers. Suggested chronic effects of ketamine in
drug users included deficits in source memory and controlled semantic processing
indicative of a degraded semantic store. Following substantial reduction in ketamine
use, semantic function appeared to recover whilst episodic and attentional impairments
appeared persistent. Overall, this thesis suggested that ketamine, both acutely and
chronically, produces selective cognitive impairments, particularly to those functions
that require integration of contextual information. The implications of this thesis are
drawn out for an acute versus ‘chronic’ model of psychosis. Chronic deficits in
ketamine users may reflect neurological changes associated with repeated NMDA-
receptor antagonism and hence may be more similar to changes observed in the later
stages of schizophrenia, whereas acute ketamine may better model the acute phase.
Persisting cognitive impairments are of concern in light of the burgeoning population of
ketamine users.
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Acknowledgments
I could not have completed this thesis without the help of so many colleagues and
friends. Most of all, I will be forever indebted to my supervisor Professor Val Curran
for her wisdom and insight. She has been a true inspiration and her encouragement,
confidence in my abilities, and above all patience and good humour throughout the
completion of this work has been astonishing. Thankyou, Val, I will always be proud to
have been a member of ‘the Unit’! I also was incredibly lucky to have shared an office
with the other notable member of the Unit, Rosa Hoshi, who kept me from the vortex
and is the best ‘Pi’ mate anyone could ever wish to have. To Sally Zlotowitz, a big high
five, thankyou for always so skilfully separating the ‘wheat from the chaff. Thankyou
also to Lee Rowland, Dr. Mat Whalley and Robin Hayman , the other members of the
Marlborough Army. I feel truly fortunate to have met such an amazing group of
individuals to share all the high’s and low’s of this process with; you are all the ‘Proof
I need that it was worthwhile.
I would also like to thank the Centre for Anaesthesia in particular Brigitta Brandner, Ali
Mofeez and James Smart for their time and dedication. For their help with data
collection my thanks go to Fiona Pepper, Jake Bird , Charlie Maitland, Grazia Pac,
Marcio Ricelli and Rachael Lippett. I am also grateful to Dr. Susan Rossell and
Professor John Krystal, Professor Chris Frith, Professor Judith Ford and Professor Cyril
D’Souza for valuable discussions. My grateful thanks to Leslie Muetzelfeldt for helping
me with many computer and administrative issues. Thankyou also to my family for
their kindness and sense of humour. To Dr. Nick Jones, even though you don’t agree
with acknowledgments, thanks for everything, you will always be the better scientist.
Finally, I would like to thank all the people who enthusiastically participated in these
experiments.
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The work presented in this thesis has also been published in the following journal
articles:
Morgan CJA, Mofeez A, Brandner B, Bromley L, Curran HV (2004a) Acute effects of
ketamine on memory systems and psychotic symptoms in healthy volunteers.
Neuropsychopharmacology 29: 208-218
Morgan CJA, Mofeez A, Brandner B, Bromley L, Curran HV (2004b) Ketamine
impairs response inhibition and is positively reinforcing in healthy volunteers: a dose
response study. Psychopharmacology 172: 298-308
Morgan CJA, Monaghan L, Curran HV (2004c) Beyond the K-hole: A 3-year
longitudinal investigation of the cognitive and subjective effects of ketamine, in
recreational users who have substantially reduced their use of the drug. Addiction
99:1450-61.
Morgan CJA, Ricelli M, Maitland CH, Curran HV (2004d) Long-term effects of
ketamine: evidence for a persisting impairment of source memory in recreational users.
Drug and Alcohol Dependence 75: 301-308
Morgan, CJA, Rossell SL, Peppr, F, Smart, J, Blackburn, J, Brandner, B, Curran HV
(submitted) Semantic priming after ketamine acutely in healthy volunteers and
following chronic self-administration in substance users.
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Abstract...................................................................................................................................2
Acknowledgments.................................................................................................................3
List of Tables........................................................................................................................15
List of Figures.......................................................................................................................18
Selected Abbreviations and Acronyms...............................................................................21
Chapter 1: Introduction........................................................................................................22
1.1. History of the use of ketamine and related compounds in anaesthesia............22
1.2 History the abuse of ketamine and PCP by recreational users..............................23
1.3 Basic pharmacology of ketamine, PCP and dizocilipine........................................25
1.4 The chemical mechanism of the arylcyclohexylamines.........................................26
1.5 Glutamate, the NMDA -receptor complex and Long-Term Potentiation...........27
1.6. Effects on other neurotransmitter systems............................................................28
1.7 PET and BOLD fMRI studies with ketamine and PCP..........................................29
1.8 Summary....................................................................................................................31
LITERATURE REVIEW....................................................................................................32
PART I: ACUTE EFFECTS OF NMDA-R ANTAGONISM ON COGNITIVE
FUNCTION..........................................................................................................................33
1.9.1 Animal studies of cognitive function after acute administration of NMDA-R
antagonists........................................................................................................................33
1.9.2 Memory Systems and NMDA-R Hypofunction..................................................34
1.9.3 Episodic Memory..................................................................................................35
1.9.4 Working Memory, Attention and Executive functioning...................................38
1.9.5. Semantic Memory...............................................................................................43
1.9.6 Procedural Memory and Perceptual Representation System (PRS)................43
1.9.7.Summary of acute cognitive effects.....................................................................44
PART II: SCHIZOPHRENIC SYMPTOMS AND NMDA-R ANTAGONISTS 44
1.10.1 Background to theories of cognitive dysfunction in schizophrenia................45
1.10.2 Schizophrenia and NMDA-R Antagonists.........................................................46
1.10.3 Animal models of other psychotic symptoms...................................................48
1.10.4. Human studies of psychotic symptoms following NMDA-R antagonism 49
1.10.5. Administration of NMDA-R antagonists to schizophrenic patients.................52
1.10.6. Interactive effects of ketamine with other drugs..............................................53
1.10.7. Summary of acute psychotomimetic effects......................................................56
PART III: CHRONIC EFFECTS OF NMDA-R ANTAGONISTS................................58
1.11.1 NMDA-R antagonist associated neurotoxicity studies......................................58
1.11.2. Studies of the behavioural and cognitive effects of chronic NMDA-R
antagonists in animals......................................................................................................60
1.11.3 Chronic behavioural and cognitive effects of NMDA-R antagonists in humans
61
1.11.4 PCP, ketamine and dependence...........................................................................63
1.11.5. Summary of Chronic Effects............................................................................64
1.12 Overview and Research Questions........................................................................65
Chapter 2: Ketamine and Memory Systems......................................................................68
Acute effects of ketamine on memory systems and psychotic symptoms in healthy
volunteers..............................................................................................................................68
2.1 Overview...................................................................................................................68
2.2 Introduction...............................................................................................................69
2.3 Methods.....................................................................................................................70
2.3.1 Participants and Design.....................................................................................70
2.3.2 Drug Administration..........................................................................................72
2.3.3 Procedure............................................................................................................72
2.3.4 Assessments........................................................................................................73
2.3.5 Statistical Analyses............................................................................................76
2.4 Results........................................................................................................................77
2.4.1 Trait Scores, Demographics and Drug dosage................................................77
2.4.2 Cognitive Tasks..................................................................................................78
2.4.2.1 Source Memory:.........................................................................................78
2.4.2.2 Speed of Comprehension............................................................................81
2.4.2.3 N-Back Working Memory Task................................................................81
2.4.2.4 LOP Retrieval Intentionality.....................................................................83
2.4.2.5 Serial Reaction Time Task........................................................................83
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2.4.2.6 Trailmaking..............................................................................................85
2.4.3 Subjective Effects............................................................................................86
2.4.3.1 Schizotypal Symptomatology....................................................................86
2.4.3.2 Adapted Dissociative States Scale.............................................................87
2.4.3.3 Subjective Drowsiness................................................................................87
2.4.4. Correlations.....................................................................................................87
2.5 Discussion................................................................................................................88
Chapter 3: Source memory in ketamine users...................................................................94
Chronic effects of ketamine abuse: evidence for a persisting impairment of source
memory in recreational users..............................................................................................94
3.1 Overview...................................................................................................................94
3.2 Introduction...............................................................................................................95
3.3 Methods.....................................................................................................................97
3.3.1 Participants and design......................................................................................97
3.3.2 Procedure............................................................................................................97
3.3.3 Assessments on day 0 and day 3 ......................................................................98
3.3.4 Subjective Ratings.............................................................................................99
3.3.5 Statistical Analysis..........................................................................................100
3.4 Results......................................................................................................................100
3.4.1 Demographics and Drug Use...........................................................................100
3.4.2 Cognitive Tasks................................................................................................102
3.4.2.1 Source Memory........................................................................................102
3.4.3 Subjective Ratings...........................................................................................103
3.4.3.1 Schizotypal symptomatology..................................................................103
3.4.3.2 Adapted Dissociative States Scale...........................................................104
3.4.3.3 Visual Analogue scales.............................................................................104
3.4.4 Correlations......................................................................................................104
3.5 Discussion................................................................................................................106
Chapter 4 : Semantic priming and ketamine...................................................................Ill
Semantic priming after ketamine acutely in healthy volunteers and following chronic
self-administration in substance users..............................................................................111
4.1 Overview..................................................................................................................Ill
4.2 Introduction.............................................................................................................112
Experiment 1 - Acute effects of ketamine on semantic priming in healthy volunteers
.........................................................................................................................................115
4.3 Methods and Materials............................................................................................115
4.3.1 Design...............................................................................................................115
4.3.2 Participants.......................................................................................................115
4.3.3 Drug Administration........................................................................................115
4.3.4 Procedure..........................................................................................................116
4.3.5 Assessments......................................................................................................116
4.3.6 Statistical Analyses..........................................................................................118
4.4 Results......................................................................................................................118
4.4.1 Trait Scores, Demographics and Drug dosage..............................................118
4.4.2 Semantic Priming Data....................................................................................119
4.4.3 Subjective Effects.............................................................................................122
4.4.3.1 SSQ............................................................................................................122
4.4.3.2 ADDS........................................................................................................123
4.4.4 Correlations......................................................................................................123
Experiment 2 - Semantic priming in recreational ketamine users............................123
4.5 Methods and Materials............................................................................................123
4.5.1 Participants and Design...................................................................................123
4.5.2 Procedure..........................................................................................................124
4.5.3 Statistical Analysis..........................................................................................124
4.6 Results......................................................................................................................124
4.6.1 Demographics and Drug Use...........................................................................124
4.6.2 Semantic Priming Task....................................................................................125
4.6.3 Subjective Ratings............................................................................................127
4.6.4 Correlations......................................................................................................127
4.7 Discussion................................................................................................................127
4.7.1 Acute ketamine.................................................................................................128
4.7.2 Chronic Ketamine.............................................................................................130
Chapter 5: Beyond the K-hole...........................................................................................134
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A 3 year longitudinal investigation of the cognitive and subjective effects of ketamine,
in recreational users who have substantially reduced their use of the drug...................134
5.1 Overview..................................................................................................................134
5.2 Introduction..............................................................................................................136
5.3 Method......................................................................................................................139
5.3.1 Design................................................................................................................139
5.3.2 Procedure..........................................................................................................140
5.3.3 Test Battery.......................................................................................................140
5.3.4 Statistical Analysis..........................................................................................142
5.4 Results......................................................................................................................142
5.4.1 Demographics...................................................................................................142
5.4.2 Drug Use...........................................................................................................143
5.4.3 Cognitive Tasks................................................................................................144
5.4.3.1 Category generation..................................................................................144
5.3.4.2 Speed of Comprehension Task................................................................145
5.4.3.3 Prose Recall...............................................................................................146
5.4.3.4 Digit Cancellation.....................................................................................146
5.4.3.5 Serial Seven’s and Verbal fluency...........................................................148
5.4.4.1 Schizotypal Symptomatology Questionnaire.........................................148
5.4.4.2 Adapted Dissociative States Scale...........................................................149
5.4.4.3 Mood Rating Scale...................................................................................149
5.4.4.4 Subjective Effects Scale...........................................................................149
5.4.5 Correlations......................................................................................................149
5.5 Discussion.................................................................................................................150
Chapter 6: Special K?........................................................................................................158
Ketamine impairs response inhibition and is positively reinforcing in healthy
volunteers: a dose response study.....................................................................................158
6.1 Overview..................................................................................................................158
6.2 Introduction.............................................................................................................159
6.3 Method......................................................................................................................161
6.3.1 Design, Procedure and Participants................................................................161
6.3.2 Assessments......................................................................................................161
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