Review TRENDS in Cognitive Sciences
4 April 2006
Schizophrenia, ketamine and cannabis:
evidence of overlapping memory
deficits
Paul C. Fletcher and Garry D. Honey
Box 189, University of Cambridge, Department of Psychiatry, Addenbrookes Hospital, Hills Road, Cambridge CB2 2QQ, UK
Drug models of mental illness are considered useful if
they provoke its characteristic symptoms. In this
respect, ketamine and tetrahydrocannabinol (cannabis)
are coming under increasing scrutiny as models for
schizophrenia. However, although both undoubtedly
produce psychotic symptoms characteristic of the
disorder, we argue here that, because schizophrenia is
also accompanied by cognitive deficits, a full under-
standing of the impact of these drugs on cognition will
be crucial in taking these models further. Memory
deficits are pronounced in schizophrenia and we focus
upon patterns of working and episodic memory impair-
ment produced by ketamine and cannabis, identifying
overlaps between drug and illness. We suggest that
close attention to these deficits can offer insights into
core pathophysiology of schizophrenia.
Introduction
Drug models of schizophrenia are considered useful if they
provoke its characteristic symptoms, for example, delu-
sions and hallucinations. Yet there is increasing evidence
that cognitive deficits are a core feature of the disease,
preceding the emergence of psychopathology, correlating
with incapacity and predicting outcome [1,2]. A close
examination of such deficits could therefore aid early
diagnosis, intervention and treatment. We suggest, more-
over, that drug models should be examined with respect to
their cognitive effects as well as their provocation of
psychotic symptoms.
Because a full exploration of the cognitive effects of
drugs is vital to the assessment and refinement of models
of schizophrenia, we evaluate here two emerging drug
models with respect to their effects on memory. Both
drugs, ketamine and delta-9-tetrahydrocannabinol (THC),
reproduce symptoms that characterize schizophrenia [3
7] and thus represent a closer model than drugs producing
only a limited range of psychopathology (e.g. psilocybin) or
requiring repeated or prolonged use (e.g.amphetamine).
We focus on working memory (WM) and episodic memory
(EM) impairment, both prominent in schizophrenia. We
will consider memory deficits characteristic of schizo-
phrenia and compare them with deficits produced by these
drugs. We explore the mnemonic effects of these drugs not
Corresponding author: Fletcher, P.C. (pcf22@cam.ac.uk).
Available online 10 March 2006
www.sciencedirect.com 1364-6613/$ - see front matter Q 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tics.2006.02.008
Vol.10 No.
just in terms of behavioural change but of memory-evoked
brain responses assessed using functional neuroimaging,
identifying functional anatomical overlap between disease
and drug-induced states.
Working memory in schizophrenia
WM describes a system that has evolved for the short-
term maintenance and manipulation of information
necessary for the performance of such complex tasks as
learning, comprehension and reasoning [8]. It is central to
cognitive function and its disruption can result in
impaired processing across cognitive domains. A greater
understanding of the mechanisms by which WM is
disrupted in schizophrenia is therefore likely to be useful
in characterizing the syndrome more fully. We focus upon
the distinction between the maintenance of material
temporarily stored in WM, and the manipulation, or
reorganization, of that material. Maintenance tasks
emphasize the storage of verbal and non-verbal infor-
mation. Manipulating the stored material requires, in
addition, strategic updating and temporal coding, thereby
more directly involving the central executive system.
Maintenance versus manipulation impairments
Schizophrenia. This distinction between maintenance and
manipulation processes is relevant to WM dysfunction in
schizophrenia where deficits appear greater for manipu-
lation [911]. Furthermore, using a series of WM tasks
graded with respect to manipulation demands, Conklin
and colleagues [12] recently reported that non-psychotic
first-degree relatives of patients with schizophrenia show
increasing impairment as the requirement to manipulate
information in WM increased (Figure 1a).
Ketamine and THC: Studies exploring the effects of
ketamine on verbal WM in healthy volunteers have
largely reported impaired performance [4,1316] or a
trend towards impairment [17]. This is not always found
[18], discrepancies perhaps relating to doses and/or
sample sizes. As observed in schizophrenia (and their
relatives), ketamine impairs performance on tasks enga-
ging manipulation but not on those requiring mainten-
ance only (Figure 1b) [15], an effect not easily attributable
to simple difficulty, because no effect was observed in other
more difficult tasks (see Box 1).
168 Review TRENDS in Cognitive Sciences Vol.10 No.4 April 2006

(a) Schizophrenia and non-psychotic familial relatives

0.5

(mean +/ SEM)

0.5
Z score

1.5

2.5 DRT DRT Spatial span Digit span Letter number Self-ordered
with delay with interference backwards backwards span pointing
Working memory task

Key:
Schizophrenia Relative Control

(b) Sub-psychotic doses of ketamine

10

7
Mean score

0
Forward span Backward span VWM maintenance VWM manipulation

Key:
Placebo Lower ketamine Higher ketamine

TRENDS in Cognitive Sciences

Figure 1. Maintenance and manipulation in working memory. (a) Performance of people with schizophrenia and of non-psychotic first-degree relatives on WM tasks. There is
a putative increase in demand on central executive processes going from left to right. Note that the greater the manipulation demands, the more evident the performance
deficit in relatives of people with schizophrenia compared with controls, who performed at ceiling on all tasks. Data redrawn from [12], with kind permission of the authors
and publisher. (b) Effects of ketamine on WM performance. Note specific impairment on tasks requiring manipulation (Backward span and verbal WM manipulation) Data
redrawn from [15], with kind permission of the authors and publisher.

Although mechanisms underlying the WM disruption Functional imaging of WM

following ketamine are still unclear, research using THC
might be complementary and informative. Like ketamine,
acute THC administration induces symptoms of schizo-
phrenia in healthy volunteers and it exacerbates symp-
toms in schizophrenic patients [6,7]. Several studies have
examined the effects of THC on verbal WM. As with
ketamine, there is emerging evidence that working
memory manipulation can be preferentially disrupted.
Backward, but not forward, digit span was reduced under
THC administration [19], and tests of simple maintenance
of verbal material did not elicit impairment [2022].
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Functional neuroimaging studies have identified a ven-
traldorsal PFC dissociation that supports the suggested
distinction between manipulation and maintenance pro-
cesses (for review, see [23]). In this respect, Conklin and
colleagues suggest that their observed manipulation
deficit might arise from dorsolateral PFC (DLPFC)
dysfunction [12], a suggestion in accordance with obser-
vations of DLPFC disturbance in schizophrenia in a WM
manipulation task [24]. Moreover, fMRI findings suggest
that the impact of ketamine on WM manipulation is
mediated by DLPFC [25] and is consistent with patterns
 Review TRENDS in Cognitive Sciences
Box 1. Limitations in drug models of schizophrenia
Model validity
Clinical validity: To what extent does the psychopathology
induced by drug exposure overlap with that seen typically in
schizophrenia? No drug model is complete in this respect. For
example ketamine does not convincingly produce auditory
hallucinations, a primary symptom of schizophrenia. Perhaps the
different profiles of symptoms produced by different neurotrans-
mitter perturbations carry information pertinent to schizophrenic
sub-syndromes.
Contextual validity: The symptoms of schizophrenia are often marked
by a lack of insight. They are durable and reflect the reality
experienced by the sufferer. Drug studies produce transient symptoms
that are often experienced with full insight about their nature and
cause. In this respect, perhaps the cognitive deficits induced by drugs
more closely mirror those seen in the illness than does
the psychopathology.
Model reliability
It is fair to say that that the psychotomimetic effects of the drugs
under scrutiny are well-replicated. The cognitive effects that we
focus on here, however, are not. Some of the findings are isolated
and must be interpreted cautiously in light of this. This is
particularly so with respect to THC effects, where investigation is
at an early stage.
seen in schizophrenia and non-psychotic relatives: an
exaggerated frontal response under low-load manipu-
lation demands and a reduced frontal response under
higher demands, perhaps consistent with an inverted U
model of function [24,26,27].
In summary, given the initial evidence suggesting
comparable effects of ketamine and THC on WM, we
might consider overlapping neurophysiological effects of
these drugs as the basis for the disruption, effects that
might be related to those occurring in schizophrenia. WM
dysfunction in schizophrenia is likely to be related to
abnormalities in the dopaminergic innervation of PFC
[28]. Egan and colleagues [29] link cognitive performance
and DLPFC response to polymorphisms in the catechol
O-methyltransferase (COMT) gene, important for metab-
olism of synaptically-released dopamine in PFC. A
potential mechanism for the effects of both disease and
drug on WM could be the dysregulation of dopaminergic
innervation of prefrontal cortex via the mesocortical
dopaminergic system [30,31]. Administration of both
THC and phencyclidine (PCP; an analogue of ketamine)
markedly increase dopamine transmission in PFC in rats
[32]. Furthermore, administration of a selective NMDA
agonist prevents the increase associated with THC, and
ameliorates disruption of WM [31]. Similarly, clonidine
(an a2 noradrenergic agonist) blocks the increase in
prefrontal dopamine following both THC and PCP [33],
and prevents working memory deficits associated with
PCP [34]. Interestingly, Clonidine also improves memory
function in schizophrenia [35]. Of course, this is a
simplistic view of the interaction of these major neuro-
transmitter systems and it is likely that there is more to
consider than solely a dopaminergic upregulation (down-
regulation might also have a deleterious impact on WM).
Nevertheless, the overlap between WM effects seen across
ketamine, THC and schizophrenia could reflect a common
disturbance in the functional integrity of DLPFC, with a
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Vol.10 No.4 April 2006 169
Model specificity
Clinical specificity: in addition to considering the changes induced by
drugs that are comparable to schizophrenia, we must take into account
those that are not. For example, acute administration of ketamine
produces euphoria, which is not characteristic of the illness.
Cognitive specificity: Many of the memory impairments reported here,
although characteristic of schizophrenia, are not unique to it. Are we
modelling the disease or rather some deficit expressing a final
common pathway also seen in other conditions. Related to this,
apparently specific deficits must always be considered in light of more
parsimonious explanations. Might the manipulation-specific effects
on WM and the retrieval-cueing effects on EM be more simply
explained in terms of levels of difficulty?
Transmitter specificity: Psychotomimetic drug produces changes in
more than one transmitter system. Although we consider this with
respect to dopamine, a full consideration and exploration must take
into account other systems and other putative neurotransmitter
abnormalities in schizophrenia.
Experimental specificity: At present there are many variations in
experimental design that could explain differences across drug
studies. Different choices of subjects (drug-nave subjects versus
regular drug users) and different doses, regimens and routes of
administration combine to obfuscate the literature as a whole. All
differences, ultimately, will have to be taken into account.
consequent executive deficit, manifest as an impairment
in the ability to manipulate information stored in WM.
Episodic memory and schizophrenia
Encoding versus retrieval
Episodic memory (EM) refers to memory for events or
episodes. It has an autobiographical character [36] and is
distinct from memory for factual information (semantic
memory), although these systems are intrinsically linked.
It is of considerable theoretical interest in schizophrenia,
in which it is demonstrably abnormal [37].
Here, we distinguish primarily between the encoding or
learning stage and the retrieval stage of EM. In
considering task manipulations made at these stages, we
focus on whether crucial deficits in schizophrenia (and in
the drug models under scrutiny) occur in the encoding of
new memories or in their retrieval (bearing in mind, of
course, that encoding and retrieval deficits are not
mutually exclusive).
Identification of stage-specific deficits is problematic
because a performance deficit could reflect impaired
encoding or retrieval (or both). Various cognitive manip-
ulations have been used in an attempt to locate EM
deficits with respect to encoding and retrieval stages.
Although there are serious limitations in these manipula-
tions in this respect (see Box 2), existing data, sup-
plemented with functional neuroimaging and
pharmacological studies, might offer clues to stage and
process-specific impairments.
Distinguishing encoding from retrieval deficits using task
manipulations
(a) Encoding task manipulations
Semantic processing of material, for example, attend-
ing to its meaning or organizing it according semantic
attributes, improves memory performance. People with
schizophrenia seem not to take advantage of this
170 Review TRENDS in Cognitive Sciences
Box 2. Dissociating episodic memory encoding and retrieval: methodological approaches
Encoding material/task manipulation (See Figure 1, next
page)
Material manipulation: Material is presented that is organizable or
non-organizable. An alternative manipulation is to present material
that is either already organized (i.e. presented in category blocks) or
requires organizing.
Task manipulation: Deep and shallow encoding tasks typically
involve meaning-based and form-based judgements. The task draws
the subjects attention either towards or away from semantic attributes.
Encoding-retrieval dissociation?
Theory: If subjects fail to take advantage of semantic attributes
(including potential organizational structures) the deficit is likely to be
encoding-specific.
Limitations: This would be consistent with an encoding deficit but
does not rule out a retrieval deficit, particularly if explicit instruction or
external provision of an organizational structure does not completely
remove the deficit.
Studytest delay
Encoding-retrieval dissociation?
Theory: A deficit in immediate recall arises from a failure to encode
material. Impaired performance following delay indicates a
retrieval deficit.
Limitations: Retrieval processes are required irrespective of whether
recall is delayed or immediate. Poorly encoded material might well be
more susceptible to longer delays. This manipulation is therefore
ambiguous with respect to an encoding-retrieval dissociation.
Retrieval cueing
Retrieval manipulations using differing degrees of cueing: minimal
(free recall), partial (word stem-cued), maximal (recognition).
A recognition task might require a subsequent source memory
judgement (e.g. which task did I perform on this word?) or, perhaps,
agency source memory, involving a requirement to remember whether
the operation carried out was done by the subject or the experimenter.
Another retrieval task requires subjects to distinguish remembering
possibility [3840]. However, when already organized lists
are presented [38,40,41], or when semantic processing is
encouraged [42], memory is improved. This might favour
an encoding deficit. However, because (i) the provision of
an organizational structure ameliorates but does not
remove the deficit [3840], (ii) full improvement might
only be seen when retrieval cueing is also provided [41],
and (iii) even for non-semantically based encoding,
subsequent retrieval is impaired [39], the findings overall
do not refute the possibility of a retrieval deficit.
Ketamines effects too can be sensitive to encoding
processes, being seen when semantic attributes but not
emotional or alphabetical attributes of material are
emphasized [43]. However, a comparable study did not
find such distinction [16]. Clearly, this area requires
further exploration, particularly with respect to THC,
which has not been used in encoding manipulation
studies.
In brief, there appears to be a failure to adopt memory-
optimising strategies in people with schizophrenia. The
fact that explicit instructions or external help can improve
memory suggests that the deficit is at encoding, however,
the deficit that persists even after these changes does not
rule out a retrieval deficit. Data from the ketamine and
THC studies are currently too rudimentary to draw firm
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Vol.10 No.4 April 2006
from knowing. Remember responses are made in association with
rich recollection. Know responses are made when the stimulus feel
strongly familiar but is not accompanied by recollection.
Encoding-retrieval dissociation?
Theory: If material is not freely recalled, but is recognized, this
indicates a retrieval deficit. Conversely, impairment in both recall and
recognition suggest an encoding deficit.
Limitations: A deficit in cued recall with preserved recognition could
also indicate an encoding deficit: the impoverished memory trace
might engender a feeling of familiarity, resulting in preserved
recognition, but be insufficient when cueing is reduced or demands
are increased. Failures in both recognition and recall could equally
well indicate encoding and retrieval deficits.
Timing of drug administration
Encoding-retrieval dissociation?
Theory: Recall deficits following drug administration post-encoding
are not attributable to an encoding deficit. Likewise, if a drug can be
given before encoding but stopped before retrieval, the deficit is not
retrieval-related.
Limitations: The success of this approach depends upon pharmaco-
logical characteristics of the drug. It might be difficult to give a drug
before encoding and ensure that there is no trace of it at retrieval.
Functional imaging
Encoding-retrieval dissociation?
Theory: Functional imaging data is acquired during encoding or
during retrieval and can therefore dissociate them in terms of
brain responses.
Limitations The dissociation can be difficult. Encoding provokes
retrieval (e.g. encoding words might incidentally prompt semantic
retrieval); retrieval provokes encoding (if I make a recognition decision
on a word, then I might encode this operation). Further, if encoding is
affected by drug or disease, measurement of retrieval-related brain
response will be indirectly affected.
conclusions although there is a suggestion that the effects
of the former might be specific to the encoding task used.
(b) Study-test delay
The relevance of study-test delay to the encoding-
retrieval distinction is discussed in Box 2. In brief, the
findings from in schizophrenia are inconsistent: although
there is evidence of worsening performance with increas-
ing delay in schizophrenia [44], this is not always seen
[39,40]. Likewise, with ketamine some studies show
worsening performance with increasing delay [4547]
but others do not [5,18,4851]. THC is associated with
both immediate and delayed retrieval deficits [6,22,52]
with delay having no impact.
Thus, manipulation of the study-test interval has not
produced consistent results in either schizophrenia or
these drug models. Moreover, we criticize the idea that
even a consistent finding would provide evidence for a
stage-specific deficit (Box 2).
(c) Retrieval task manipulations
Reviews of memory studies (e.g. [37]) have established
that tasks requiring simple recognition memory are less
impaired than those requiring richer recollection of
studied material, for example, source memory [53] (Box
2). Although this could imply a retrieval specific deficit, we
suggest that it could equally well signify an encoding
 Review TRENDS in Cognitive Sciences Vol.10 No.4 April 2006 171

SOURCE MEMORY REMEMBER/KNOW

TASK MANIPULATION AGENCY MANIPULATION

OR ? Re
Pleasant? m
em
be
Animate? r
Kn
ow
Used for?
DEEP OR SHALLOW?
DEEP

Italics?
Rhymes?
Capitals?
SELF- OTHER- RECOLLECTION
SHALLOW GENERATED GENERATED

Stem cue "CHI . . ."

Copy cue "CHISEL?"

te
dia
me
Im

RECOGNITION
Delayed
ENCODING RETRIEVAL
FREE RECALL

MATERIAL MANIPULATION
Explicit Implicit No STRUCTURED RETRIEVAL
structure structure Structure
CHISEL TOOLS

SHIRT BEFORE BEFORE CLOTHING

ENCODING RETRIEVAL

DRUG
OREGANO
ADMINISTRATION SPICES

Figure I (Box 2). Task manipulations in the study of episodic memory (see text for details).

problem or some general memory decline to which a recall
test is simply more sensitive.
The pattern is comparable to that seen with
ketamine. As with schizophrenia, it might be crucial to
consider tasks dissociating basic familiarity from richer
recollection. Free recall [13,4547] and paired associate
recall [54] are impaired by ketamine. Recognition
memory can be impaired by the drug [13,16,43,50,55],
but this is not consistent [49,56]. Source memory also
appears to be more sensitive to ketamine than are
recognition tasks [16,50]. Recent work has suggested
that the source memory deficit is apparent whether
subjects are distinguishing between external sources
[43] or between internal and external sources [54].
Finally, performance on the remember/know paradigm
also used to make the dissociation between familiarity
and recollection, is worsened by ketamine [56].
THCs impact upon retrieval task manipulations,
however, is not yet well studied. Free recall is clearly
impaired by the drug [6,20,22,52] although not without
exception [19,57]. Associate cued recall [6] and recognition
[58] can also be impaired although the latter is frequently
preserved [6,19,57].
In summary, when memory is tested using tasks that
provide sparser cueing or require richer recollection,
people with schizophrenia show greater impairment an
impairment that both ketamine and THC replicate
convincingly. Whether this is evidence of a process- or
stage-specific deficit has yet to be proven and we must be
wary of over-interpreting a finding that could actually
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arise because of differences in overall difficulty of
the tasks.
Distinguishing encoding from retrieval effects using
timed drug administration
In contrast to a disease state, the timing of a drugs effects
can be manipulated. Thus, we can dissociate its effects on
encoding from those on retrieval. Its effects on retrieval
can be assessed by giving it before the retrieval stage but
after encoding has been accomplished. Similarly, when the
drug is present at encoding but terminated before
retrieval, effects can be attributed to encoding. This
strategy has been used with ketamine, suggesting
evidence of an encoding-specific deficit for recognition
memory [43,55] but not for free recall, in which its effects
occur post-encoding [59].
Distinguishing encoding from retrieval using functional
neuroimaging
Functional neuroimaging allows us to explore encoding
and retrieval separately (although see Box 2) and much
has been achieved in dissecting contributions of key areas
in prefrontal cortex (PFC) and medial temporal lobes
(MTL) with respect to the encoding-retrieval distinction
(for review see [23,60]).
With respect to encoding processes in schizophrenia,
numerous studies have identified functional disturbances
in both PFC and MTL. However, these are fairly equally
divided between those that show relative failures in PFC
[6163] and MTL [64] activation and those which show
172 Review TRENDS in Cognitive Sciences
Box 3. Questions for future research
Many of the observations discussed here arise from isolated
observations and small studies. Can they be replicated?
Work reviewed here has focussed on behavioural and neurophysio-
logical overlap between drug and disease effects. Can further work use
these approaches to compare directly competing models allowing us
to test and refine them?
Can we identify links between cognitive deficits and psychopathol-
ogy? Within-subject studies using drug manipulations will allow us to
produce, delineate and quantify (both in terms of behavioural
performance and of neurophysiological response) cognitive deficits
at lower doses of the drug and to evaluate the extent to which these
are predictive of the characteristic psychopathology emergent at
higher doses. Specific questions in this regard are:
(i) Do WM deficits seen in schizophrenia relate to the negative
(withdrawn, avolitional) symptoms of the condition?
(ii) Can we relate subtle deficits in associative learning at lower
doses to the emergence of delusional beliefs?
(iii) Changes in internal/external attributional biases might charac-
terize certain key symptoms of schizophrenia (e.g. auditory
hallucinations might arise from an inappropriate external attribution
PFC [65] or MTL [62,66] over-activation. Several design
features might explain these apparent inconsistencies.
For example, studies making a levels-of-processing
manipulation [65,66] do not show under-activation of
PFC, in contrast to studies in which no such manipulation
was made [61,62]. One study showed PFC under-
activation solely during a deep encoding task, but this
was anterior-medial to the areas characteristically acti-
vated during normal encoding [63]. A single study has
evaluated encoding-related activation under ketamine,
showing a PFC increase [67].
Patterns of retrieval-related activation in schizo-
phrenia also implicate fronto-temporal systems. Reduced
MTL activation is consistent [64,68,69] whereas retrieval-
related right PFC activation can be increased [66] or
decreased [68]. More consistent is left lateral PFC under-
activation at retrieval [6163] although this can depend
upon the contrast conditions used [69]. Interestingly, left
PFC under-activation is seen when subjects are retrieving
words that have been encoded according to semantic
attributes and should therefore be more richly recollected.
This could suggest that, in schizophrenia, there is a failure
of such recollection, in keeping with behavioural studies.
Interestingly, a fMRI study using timed administration of
ketamine to dissociate encoding from retrieval, shows that
there is a compellingly similar left PFC attenuation that is
clearly related to the retrieval stage [67].
In summary, PFC and MTL are disrupted in schizo-
phrenia and in association with ketamine administration.
Retrieval findings are the more consistent, with attenu-
ations of MTL and left PFC response, both perhaps
signalling a relative failure of recollective processes in
association with both disease and drug.
Conclusions
The central theme of this article is that a good drug model
of schizophrenia is one that replicates the core cognitive
deficits as well as the signs and symptoms of psychosis. At
this stage, we can assert that both ketamine and THC
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Vol.10 No.4 April 2006
of internal speech). Does drug administration reproduce such biases
in cognitive processing and, if so, does this predispose to such
symptoms?
Can we establish the neurobiological specificity of effects induced by
the drugs? To what extent, for example, is the effect of ketamine on
frontal responses to memory tasks mediated by dopamine? In this
respect, it will probably prove very useful to use combined drug
manipulations in pursuit of more specific neurochemical interpret-
ations. In this regard, convergent effects of pharmacologically distinct
drugs might constrain interpretations of their mechanism of action on
cognitive function. For example, both ketamine and THC have indirect
effects on dopaminergic transmission: if pre-treatment with dopamine
antagonists was shown to prevent the effects of both drugs on WM
and/or EM, this would provide compelling data for the centrality of
dopamine. Important too will be the integration of these findings with
models and theories including other neurotransmitter systems.
Perhaps one of the biggest challenges in taking cognitive psycho-
pharmacology further will be in understanding how relatively specific
drug manipulations exert their effects through indirect modulation of
multiple interactive systems.
show promise in reproducing characteristic memory
deficits of schizophrenia, which can presently be summar-
ized as (i) difficulties in manipulating the contents of WM,
(ii) failure to use semantic processing and organization to
optimize EM encoding, and (iii) impaired retrieval
performance when retrieval tasks provide sparser cueing
or demand richer recollection of material. Furthermore,
functional neuroimaging has suggested promising overlap
between ketamines effects on frontal mediation of both
WM manipulation processes and recollection processes
in EM.
It is still rather early to speculate, given the need for a
more precise cognitive neuropsychology of memory
impairment in schizophrenia and the fact that many key
experimental manipulations have yet to be made in
association with the drugs (see also Box 3). Nevertheless,
we believe that cognitive psychopharmacology will pro-
vide important insights into the nature of schizophrenia in
several ways. First, it offers ways of exploring links
between the drug- and the disease-state in terms of both
cognitive deficits and of symptoms. Second, controlled
manipulation, using ketamine/THC effects of cognition
and psychopathology within subjects might provide
unique information in linking subtle cognitive impair-
ments to the emergence of more complex psychopathology,
thus allowing evaluation of cognitive models of psychotic
symptoms (e.g. [70]). Third, observations that a given drug
produces some but not other impairments and that
different drugs provoke different symptoms will strongly
influence development and refinement of nosology
(disease classification). Finally, such studies might offer
clues to the nature of neurotransmitter disturbance in
schizophrenia, preceding the identification and develop-
ment of new therapeutic approaches. These advances will
ultimately depend upon the refinement of cognitive
models and on the application, through appropriately
specific cognitive tasks, of these models to disease and
drug states.
 Review TRENDS in Cognitive Sciences
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