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Schizophrenia, ketamine and cannabis: evidence of overlapping memory deficits Paul C. Fletcher and Garry D. Honey Box 189, University of Cambridge, Department of Psychiatry, Addenbrooke’s 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 understanding 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 impairment 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, delusions 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, moreover, 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 schizophrenia and compare them with deficits produced by these drugs. We explore the mnemonic effects of these drugs not Corresponding author: Fletcher, P.C. ([email protected]). Available online 10 March 2006

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 shortterm 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 information. 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 manipulation [9–11]. 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 [4,13–16] 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 engaging manipulation but not on those requiring maintenance 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).

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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 following ketamine are still unclear, research using THC might be complementary and informative. Like ketamine, acute THC administration induces symptoms of schizophrenia in healthy volunteers and it exacerbates symptoms 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 [20–22]. www.sciencedirect.com

Functional imaging of WM Functional neuroimaging studies have identified a ventral–dorsal PFC dissociation that supports the suggested distinction between manipulation and maintenance processes (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 observations 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

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Box 1. Limitations in drug models of schizophrenia Model validity

Model specificity

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 neurotransmitter 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.

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-naı¨ve 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.

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 manipulation 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 metabolism 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 neurotransmitter systems and it is likely that there is more to consider than solely a dopaminergic upregulation (downregulation 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 www.sciencedirect.com

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 manipulations have been used in an attempt to locate EM deficits with respect to encoding and retrieval stages. Although there are serious limitations in these manipulations in this respect (see Box 2), existing data, supplemented 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, attending to its meaning or organizing it according semantic attributes, improves memory performance. People with schizophrenia seem not to take advantage of this

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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 subject’s 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.

Study–test 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 [38–40]. 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 [38–40], (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. Ketamine’s 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 memoryoptimising 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 www.sciencedirect.com

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 pharmacological 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 encodingretrieval distinction is discussed in Box 2. In brief, the findings from in schizophrenia are inconsistent: although there is evidence of worsening performance with increasing delay in schizophrenia [44], this is not always seen [39,40]. Likewise, with ketamine some studies show worsening performance with increasing delay [45–47] but others do not [5,18,48–51]. 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

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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 [13,45–47] 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]. THC’s 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 www.sciencedirect.com

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 drug’s 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 [61–63] and MTL [64] activation and those which show

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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 neurophysiological 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 psychopathology? 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 characterize 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 underactivation solely during a deep encoding task, but this was anterior-medial to the areas characteristically activated 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 schizophrenia also implicate fronto-temporal systems. Reduced MTL activation is consistent [64,68,69] whereas retrievalrelated right PFC activation can be increased [66] or decreased [68]. More consistent is left lateral PFC underactivation at retrieval [61–63] 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 schizophrenia and in association with ketamine administration. Retrieval findings are the more consistent, with attenuations 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 www.sciencedirect.com

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 interpretations. 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 psychopharmacology 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 summarized 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 ketamine’s 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 provide 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 impairments 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 development 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.

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