Should Schizophrenia Be Treated as a
Neurocognitive Disorder?
by Michael Foster Qreen and Keith H. Nuechterlein
Abstract
The search is on for meaningful psychopharmacologi-
cal and cognitive/behavioral interventions for neu-
rocognitive deficits in schizophrenia. Findings in this
area are emerging rapidly, and in the absence of inte-
grating frameworks, they are destined to emerge
chaotically. Clear guidelines for testing neurocognitive
interventions and interpreting results are critical at
this early stage. In this article, we present three mod-
els of increasing complexity that attempt to elucidate
the role of neurocognitive deficits in schizophrenia in
relation to treatment and outcome. Through discus-
sion of the models, we will consider methodological
issues and interpretive challenges facing this line of
investigation, including direct versus indirect neu-
rocognitive effects of antipsychotic medications, selec-
tion of particular neurocognitive constructs for inter-
vention, the importance of construct validity in
interpreting cognitive/behavioral studies, and the
expected durability of treatment effects. With a grow-
ing confidence that some neurocognitive deficits in
schizophrenia can be modified, questions that seemed
irrelevant only a few years ago are now fundamental.
The field will need to reconsider what constitutes a
successful intervention, what the relevant outcomes
are, and how to define treatment efficacy.
Keywords: Neurocognition, cognition, antipsy-
chotic medication, cognitive remediation, functional
outcome.
Schizophrenia Bulletin, 25(2):309-318,1999.
Although the presentation of schizophrenia has changed
minimally over time, our perceptions of the disorder have
changed dramatically, particularly over the past two
decades. During the 1980s, schizophrenia went from
being viewed as mainly a progressively deteriorating dis-
order to one of neurodevelopmental origin, partly because
it was discovered that very early events can influence risk
309
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for the disorder. Also during the 1980s, the predominant
view of the phenomenology of schizophrenia broadened
beyond a narrow focus on psychotic symptoms to include
negative symptoms as well. In the 1990s, another change
in our perception of schizophrenia occurred, which may
be even more fundamental. With this change, we have
expanded the phenomenology of schizophrenia even fur-
ther, beyond symptoms altogether, to include a strong
emphasis on neurocognitive aspects of schizophrenia.
The study of the neurocognition of schizophrenia is
not new; key deficits in attention, perception, and cogni-
tion were noted by very early descriptive psychopatholo-
gists (Bleuler 1950; Kraepelin 1913/1971), and experi-
mental psychopathologists have worked to identify the
core abnormalities for several decades (Shakow 1962;
Chapman and Chapman 1973; Goldstein 1978;
Nuechterlein and Dawson 1984; Braff 1993). But neu-
rocognitive studies of schizophrenia are now viewed as
having direct implications for treatment. Interest in the
topic has extended far beyond a rather small and dedi-
cated group of experimentalists. Practitioners now
believe that schizophrenia can legitimately be viewed, in
essence, as a disorder of neurocognition.
Articles in this theme issue represent the state of the
art in pharmacological and cognitive/behavioral treat-
ments for neurocognitive deficits in schizophrenia.
Findings in this area are emerging rapidly and in the
absence of integrating frameworks are destined to emerge
chaotically. In this article, we present three models of
increasing complexity that are designed to serve an orga-
nizing function. Through discussion of die models, we
will address methodological challenges inherent in
research on neurocognitive interventions, drawing from
the articles in this dieme issue to illustrate points. Let's
start with the simplest model.
Reprint requests should be sent to Dr. M.F. Green, UCLA-
Neuropsychiatric Institute, 760 Westwood Plaza, C9-420, Los Angeles,
CA 90024-1759.
Schizophrenia Bulletin, Vol. 25, No. 2, 1999
Simple Model
Figure 1 depicts a simple model based entirely on three
conclusions that can be drawn from the literature. First,
conventional neuroleptics are generally effective for psy-
chotic symptoms, but their effects on neurocognition are
relatively weak (Cassens et al. 1990; Strauss 1993).
Conventional neuroleptics sometimes have short-term
detrimental effects on tests of psychomotor speed, and
some studies have shown longer term benefits for vigi-
lance and early visual processing. However, the modal
finding across studies and neurocognitive constructs is
that of no significant effect.
Second, the cross-sectional relationships between neu-
rocognition and psychotic symptoms are usually minimal,
particularly for hallucinations and delusions. The relation-
ships are weak for most neurocognitive constructs, even
when they are statistically significant (Comblatt et al.
1985; Green and Walker 1985; Nuechterlein et al. 1986;
Green et al. 1992; Strauss 1993). In cross-sectional stud-
ies, it is unusual to find relationships between psychotic
symptoms and neurocognitive measures in which more
than 10 percent of the variance can be explained (Goldberg
et al. 1993). Nevertheless, it is possible that some very
specific neurocognitive processes underlie particular posi-
tive symptoms. For example, several rather comprehen-
sive theoretical models have proposed testable links
between particular types of psychotic symptoms and neu-
rocognitive deficits (Frith and Done 1988; Hemsley 1994).
In addition, some studies have linked formal thought disor-
der (sometimes considered to be on a disorganized symp-
tom dimension instead of a positive symptom dimension)
to performance on a highly specific laboratory measure of
Figure 1. Pathways from conventional antipsy-
chotic treatment to functional outcome
Neurocognition
Conventional I Functional
Antipsychotlcsl Outcome
Psychotic
Symptoms
Note.—This simple model represents a possible mismatch: the
aspect of illness most influenced by conventional antipsychotic
medications (psychotic symptoms) is not the aspect most associ-
ated with functional outcome.
310
M.F. Green and K.H. Nuechterlein
semantic priming (Spitzer 1997). While the possibility of
informative specific linkages remains, our position is that
models will have greater explanatory power when psy-
chotic symptoms and neurocognition are treated as sepa-
rate domains. While psychotic symptoms and neurocogni-
tive processes are not completely separate, they are
sufficiently separate. Further, we know that some neu-
rocognitive deficits are entirely separate in terms of time
course, because they remain unchanged when psychotic
symptoms improve (Comblatt et al. 1997) or even fully
remit (Nuechterlein et al. 1992).
Third, initial studies suggest that certain neurocogni-
tive deficits are rather good predictors or correlates of
functional outcome, whereas the relationships between
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psychotic symptoms and functional outcome are weak or
questionable. In a review of the literature (Green 1996),
mostly from 1990 to 1995, certain neurocognitive con-
structs such as verbal memory and vigilance emerged as
reliable correlates and predictors of several outcome areas
in chronic schizophrenia, including community function-
ing, social problem solving, and psychosocial skill acqui-
sition. Within these same studies, the relationships
between psychotic symptoms and functional outcome
were much weaker than those for neurocognitive vari-
ables. Data from Bellack et al. (1999, this issue), as well
as several recent studies published subsequent to this
review, lend support for these conclusions (Dickerson et
al. 1996; Brekke et al. 1997; Harvey et al. 1997; Velligan
etal. 1997).
A problematic mismatch is immediately apparent in
the simple model. Conventional neuroleptics have an
impact on symptoms but, in general, not on most areas of
neurocognition. However, functional outcome appears to
be more closely related to neurocognitive abilities than to
symptoms. When viewed within this model, common
treatment experiences that previously seemed paradoxical
no longer are. A treatment team should not be puzzled
when it successfully eliminates psychotic symptoms of a
patient only to find that the patient is unable to resume
social functioning. Likewise, parents should not be sur-
prised to discover that their son or daughter with schizo-
phrenia is able to return to work despite rather prominent
auditory hallucinations. These situations would be
expected when viewed within the simple model in figure 1.
Which Neurocognitive Deficits to Target If neurocog-
nitive deficits are more closely related to functional out-
come, then should neurocognitive deficits themselves
become a target of treatment? Improvement in neurocog-
nition suggests but does not logically guarantee improved
outcome, because we do not yet understand the causal
pathways. Most of the articles in this theme issue consider
Neurocognitive Deficits
the prerequisite question of whether it is possible to alter
neurocognition in schizophrenia, and the results are gener-
ally encouraging. Assuming we can improve neurocogni-
tive deficits, we are faced with a difficult decision: With
such a wide array of deficits to choose from, which ones
do we select for intervention efforts? The need for selec-
tion is particularly pronounced for cognitive/behavioral
interventions that focus on one neurocognitive deficit (and
maybe one cognitive construct) at a time. However, phar-
macological intervention studies are not immune to this
problem, because it is highly likely that certain agents will
influence some neurocognitive constructs more than others
(Meltzer and McGurk 1999, this issue). One way to
approach this question of construct selection is first to
determine which deficits are associated with outcome
areas of interest. For example, if the goal is to improve
skill acquisition, constructs that have reliable associations
with this outcome area, such as verbal memory and vigi-
lance, may be excellent candidates for interventions.
An alternative approach would be to target deficits
for which the neural substrates are known. This approach
might be particularly attractive for pharmacological inter-
vention studies, especially to the degree that certain neu-
rocognitive deficits may be linked to specific neurotrans-
Figure 2. Neurocognition and functional outcome: Individual factors
Novel
Antipsychotic
Medications
Neurocognition
Anticholinergic
Medications
Conventional
Antipsychotic
Medications
Psychotic
Symptoms
Note.—This more complex model includes boxes for novel as well as conventional antipsychotic medications, negative as well as positive
symptoms, and adjunctive anticholinergic medications. The model emphasizes individual factors as opposed to psychosocial, familial,
and community determinants.
311
Schizophrenia Bulletin, Vol. 25, No. 2, 1999
mitter systems in particular brain regions (Robbins and
Everitt 1995; Keefe et al. 1999). Working memory, for
example, has substantial current appeal as a target for
intervention, partially because of our understanding of its
neural circuitry and neurotransmitter mediation (Fuster
1989; Goldman-Rakic 1991).
More Complex Model
While the simple model in figure 1 has the advantage of
parsimony, it is woefully incomplete. A more complex
model, depicted in figure 2, has three additional compo-
nents: new antipsychotic agents, anticholinergic agents,
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and negative symptoms. Three types of arrows have been
added to convey the presumed strengths of the associa-
tions. While not based on a formal path analysis, the
model is intentionally presented in the style of a path dia-
gram. The neurocognition component is placed in an oval
for emphasis, not to indicate that it is a separate type of
variable.
Whereas the impact of conventional antipsychotic
medications on neurocognition has been unimpressive,
early indications are that the story for newer antipsychotic
Functional
Outcome
Associations
Negative
Strong
Symptoms Moderate
->• Potential
(+) Beneficial Effects
(•) Deleterious Effects
Schizophrenia Bulletin, Vol. 25, No. 2, 1999 M.F. Green and K.H. Nuechterlein

Figure 3. Neurocognition and functional outcome: Possible mediators

Individual Factors
Cognitive/Behavioral
Interventions
I Basic
Neurocognition
Adjunctive
Pharmacology Functional
Outcome
Novel - 7 ^^ • Social
Antipsychotic | — r ^ Aeconda^yX

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(+ • Occupational
Medications I M ( verbal Social
emory^^Executlve Cognition • Patient
Emotion Satisfaction

Antichohnergic Perception • Caregiver

Medications Social Burden
Schema
Coping
Conventional Skills
Antipsychotic Insight
Medications
Associations
Strong
Psychotic Negative > Moderate
Symptoms Symptoms >- Potential
Beneficial Effects
(•) Deleterious Effects
Note.—This complex model shows differentiated sub-components of basic neurocognition and functional outcome. It includes cognitive/
behavioral and adjunctive pharmacology as additional interventions, and social cognition as a possible mediator between basic neu-
rocognition and functional outcome.

medications is more encouraging (Hagger et al. 1993;
Green et al. 1997; Jeste et al. 1998). Because this field of
investigation is still young, the arrow in the model from
new antipsychotic medications to neurocognition indi-
cates a potential, instead of a known, effect. Three arti-
cles in this issue consider the role of new antipsychotic
agents for treatment of neurocognitive deficits (Keefe et
al. 1999; Kern et al. 1999, this issue; Meltzer and McGurk
1999, this issue). These articles contribute to an emerging
opinion that the new medications are better than the old
ones for neurocognition. If this is so, we need to consider
whether the beneficial effects of these medications are
direct or indirect.
Direct versus Indirect Psychopharmacological Effects.
A direct effect would involve an action of a particular
medication on a particular neurocognitive construct. An
indirect effect would mean that some aspect of treatment
other than a direct action of the agent itself is responsible
for a change in neurocognition. A possible mechanism for
an indirect effect is represented in figure 2. Consider the
situation in which a new antipsychotic agent is compared
with a conventional one. Conventional antipsychotic
medications involve a much greater coadministration of
anticholinergic medications (e.g., benztropine mesylate)
than do novel medications. Medications with strong anti-
cholinergic properties are known to have a negative effect
on certain aspects of neurocognition, particularly memory
(Spohn and Strauss 1989). Thus, it is unclear whether a
differential treatment effect is the result of something
good (from the new medication) or the absence of some-
thing bad (from the anticholinergic agent).
Although anticholinergic agents have a reputation for
disrupting neurocognition (Spohn and Strauss 1989), we

312
Neurocognitive Deficits
know surprisingly little about the degree and scope of the
detrimental effect. Data indicate a negative effect on
aspects of secondary verbal memory that may rely on
rehearsal strategies. In contrast, other aspects of memory,
such as immediate or working memory, are less affected
(Drachman and Leavitt 1974; Sweeney et al. 1991), and
the effects on other neurocognitive abilities, such as per-
ception, are relatively unknown. Hence, we do not know
if anticholinergic agents are the neurocognitive culprits
we often believe them to be. Nonetheless, these medica-
tions still represent the source of a possible indirect effect
One way to control for this possibility is demonstrated in
the article by Kem et al. (1999, this issue), in which anti-
cholinergic medication was entered as a covariate into the
statistical model. This made it possible to demonstrate
that the neurocognitive effects of the antipsychotic agent
were significant, over and above any effect of the anti-
cholinergic medication. The tentative conclusion is that
new antipsychotic medication may actually be good for
neurocognition, instead of merely not bad.
How does one address and interpret the role of symp-
tom changes and neurocognition? One variable in the
article by Kern et al. (1999, this issue), recall consistency,
showed a significant differential response to risperidone
compared with haloperidol. This beneficial effect
remained significant when anticholinergic medication was
entered into the model. However, the effect weakened
slightly and became a trend when changes in psychotic
and negative symptoms were entered. Do we conclude
that the neurocognitive effect of the medication is an indi-
rect effect of changes in clinical state? Not necessarily. It
depends on how we view the interrelationships between
symptoms and neurocognition. If neurocognitive changes
contributed to the symptom changes, statistical adjust-
ment for the presumed "effect" of symptom changes
would lead to the entirely incorrect interpretation that the
medication's impact on neurocognition is accounted for
by its impact on symptoms. Meehl (1971) describes simi-
lar interpretive errors that can arise when effects of a vari-
able X are used as covariates to examine the relationships
between X and Y. To disentangle such relationships, care-
ful examination of temporal sequence and of the interven-
tions impact on neurocognition in relatively asympto-
matic patients will likely be needed.
Alternative Causal Pathways for Negative Symptoms.
The addition of a component for negative symptoms, sep-
arate from psychotic symptoms, creates new pathways
and new challenges. One question is the degree of over-
lap between neurocognitive deficits and negative symp-
toms. Relationships tend to be stronger between neu-
rocognitive deficits and negative symptoms (Nuechterlein
313
Schizophrenia Bulletin, Vol. 25, No. 2, 1999
et al. 1986; Censits et al. 1997) or between neurocognitive
deficits and the more narrowly defined deficit syndrome
(Buchanan et al. 1997) than they are between neurocogni-
tive deficits and psychotic symptoms. However, since the
percent of variance explained is still relatively small
(10%—15%), we believe that negative symptoms and neu-
rocognitive deficits can be placed on different pathways.
Also, neurocognitive deficits appear to start earlier than
negative symptoms (Cornblatt et al. 1992). We have con-
servatively used a double-headed arrow between neu-
rocognition and negative symptoms in figure 2 to indicate
shared variance without making any assumptions about
causality, but it is entirely possible that the critical path-
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way runs from neurocognitive deficits to negative symp-
toms. In support of that view, Nuechterlein et al. (1986)
used longitudinal data to conclude that vigilance and per-
ceptual span deficits act as vulnerability factors for devel-
opment of negative symptoms rather than as secondary
effects of negative symptoms.
A single-headed arrow indicates a moderate relation-
ship between negative symptoms and functional outcome,
but the nature of this relationship is not yet clear. First,
the assessment of negative symptoms sometimes overlaps
with the assessment of social functioning, so it is not
always clear if relationships are due to associations
between separate constructs or to redundancy of assess-
ment. Assuming the constructs are moderately associated,
the relationships between negative symptoms and func-
tional outcome can have two quite different interpreta-
tions. It might be that negative symptoms have a direct,
causal impact on functional outcome, an interpretation
that is obvious, intuitive, and quite possibly wrong.
Instead, the moderate relationship may be explained by
(1) the shared variance between negative symptoms and
neurocognition and (2) the strong associations between
neurocognition and functional outcome. In other words,
the causal pathways from negative symptoms to func-
tional outcome may be due to a common neurocognitive
intersection. Indeed, two recent studies based on statisti-
cal models (Harvey et al. 1997; Velligan et al. 1997) have
arrived at exactly this conclusion.
Complex Model
The second model is also incomplete, so we introduce
three new components in a third and final model: cogni-
tive/behavioral interventions, adjunctive pharmacology,
and social cognition (see figure 3). To distinguish the
neurocognitive oval from the box on social cognition, the
oval was relabeled as "basic" neurocognition. This model
also depicts some of the subcomponents of the complex,
Schizophrenia Bulletin, Vol. 25, No. 2, 1999
multifactorial domains of neurocognition and functional
outcome.
Three articles in this theme issue address cognitive/
behavioral interventions for neurocognitive deficits
(Bellack et al. 1999, this issue; Spaulding et al. 1999, this
issue; Wykes et al. 1999, this issue). One key interpretive
challenge for many cognitive/behavioral studies is con-
struct validity.
Construct Validity. To understand construct validity,
one needs to distinguish between a construct (or latent
variable) and an indicator (Loehlin 1987; Nunnally 1978).
In the study of neurocognition, we are inevitably inter-
ested in constructs that cannot be directly observed.
Instead we measure performance on an indicator that pre-
sumably reflects a particular construct. For example, per-
formance on a continuous performance test is an indica-
tor; vigilance is the underlying construct. The
neurocognitive function, vigilance, has numerous perfor-
mance and psychophysiological indicators (Davies and
Parasuraman 1982; Nuechterlein 1991).
This distinction between the construct and the indica-
tor creates difficulties in the context of remediation stud-
ies. Consider a training method for performance on the
continuous performance test: if subjects' performance on
one task improves following training, it is difficult to
know if the intervention affected the underlying construct
(vigilance) or some aspect of the task unrelated to vigi-
lance (perhaps skill in initiating a button press). One way
to test for construct validity is to use multiple indicators
of the same construct. When it comes to training schizo-
phrenia patients on a continuous performance task, the
results have been mixed (Benedict et al. 1994; Medalia et
al. 1998). Training on one task can bring about clear
improvement, but the benefits do not always extend to
another measure of the same construct. This situation
could arise if training improved the underlying construct
but the second test was not a good indicator of that con-
struct. However, it is also possible that the training
brought about improvement at the level of the indicator,
but not at the level of the construct.
Construct validity is somewhat less of a concern for
pharmacological studies than it is for cognitive/behavioral
interventions that focus training on particular tasks.
Certainly, there is still the inherent separation of the con-
struct from the measure, but with pharmacological inter-
ventions, there is no training task. If a drug improves per-
formance on a test of verbal working memory in a
controlled trial, it is often reasonable to conclude that the
drug helped verbal working memory. But without differ-
ent indicators of verbal working memory, it remains pos-
sible that the improvement is due to a pharmacological
314
M.F. Green and K.H. Nuechterlein
effect on an isolated component of the verbal working
memory task (e.g., oral fluency) rather than on functions
that are considered to be more central to the construct.
The complex model includes two other components
that represent largely unexplored territory. One is adjunc-
tive pharmacology; the other includes hypothesized medi-
ators between neurocognition and functional outcome.
Adjunctive Psychopharmacology. The use of adjunc-
tive pharmacology for neurocognitive deficits has only
recently received serious consideration (Davidson and
Keefe 1995). Some of this emerging interest in adjunc-
tive medications undoubtedly stems from recent develop-
ments in the pharmacological treatment of cognitive
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decline in dementia. The medications for dementia act on
the cholinergic system, which is related to memory func-
tioning. It is not yet known whether this system is also
critical to the pathophysiology of schizophrenia. Perhaps
more relevant to schizophrenia is the glutamate system. It
has been suggested diat hypofunction of the A^-methyl-r>
aspartate subtype of glutamate receptor may be a key dis-
ease mechanism for schizophrenia (Olney and Farber
1995). This receptor is modulated by glycine, which has
led to interest in using glycinergic agents to treat schizo-
phrenia. Preliminary data on a small sample of patients
showed improvement in choice reaction time when d-
clycloserine, a partial glycine agonist, was added to con-
ventional antipsychotic medications (Goff et al. 1995). If
adjunctive agents are found to improve neurocognition,
schizophrenia patients may start receiving one medication
for each major domain of illness: symptoms and neu-
rocognitive deficits.
Social Cognition as Mediator. Between basic neu-
rocognition and functional outcome are a cluster of medi-
ating variables labeled as social cognition. In the model,
components of social cognition include emotion percep-
tion, social schema, insight into illness, and coping/attri-
butional strategies. Our intention is to distinguish these
variables, which have substantial social or emotional
components, from basic neurocognition, although the pre-
cise boundaries between basic and social cognition are not
clear-cut.
One key aspect of social cognition is the ability to
perceive emotion in others. Perception of emotion in
schizophrenia is associated with basic neurocognition
(Schneider et al. 1995; Bryson et al. 1997), suggesting
that intact basic neurocognition is necessary for accurate
perception of emotion. It is reasonable to expect that a
reduced ability to perceive emotion in others would result
in misinterpretation and compromised social interactions.
Indeed, perception of emotion appears to be closely
Neurocognitive Deficits
related to social competence in schizophrenia inpatients
(Mueser et al. 1996; Perm et al. 1996).
In this model, we have also included insight and cop-
ing in the "social cognition" box even though they are not
generally considered to be prototypic features of social
cognition. A subsequent model may place them in a sepa-
rate box for "attributional" or "metacognitive" constructs.
The relationship between insight and neurocognition is
not at all clear. Most studies have reported that insight is
related to better neurocognitive performance, particularly
on measures of executive functioning (Silverstein and
Zenvic 1985; Young et al. 1993; Lysaker and Bell 1994).
However, other studies have not found such relationships
(Cuesta and Peralta 1994; Dickerson et al. 1997).
Disparity in these findings may stem from differences in
the definition and measurement of insight.
By placing social cognition between basic neurocog-
nition and functional outcome, this model may help to
illuminate an issue that has preoccupied investigators:
whether deficits in social cognition are general rather than
specific (reviewed in Penn et al. 1997). For example, sev-
eral studies have evaluated whether emotion perception
deficits in schizophrenia are specific to emotional stimuli
or whether they are part of general perception deficits.
While this question remains scientifically interesting, the
distinction between a specific emotion perception deficit
and a general nonemotion perception deficit is not entirely
relevant to the complex model. In this model, basic and
social cognition are closely related but not identical com-
ponents. Basic neurocognition is a prerequisite for social
cognition, and social cognition, in turn, is a prerequisite
for social functioning.
Overarching Questions
The models described here help to isolate components
that serve as intersections between treatment and out-
come. Stepping back from the components, several broad
questions emerge. The questions are rather basic, which
is understandable given their recency. Pondering interpre-
tation and implications of neurocognitive interventions
will be pointless until there is some agreement that inter-
vention in this domain works. Now that there is growing
confidence that at least some neurocognitive deficits in
schizophrenia can be modified, we are forced to confront
seemingly simple definitional matters. Only a few years
ago these questions seemed irrelevant; now they seem
fundamental.
What Constitutes a Successful Intervention? Some
neurocognitive deficits in schizophrenia are rather stable
over time (Nuechterlein et al. 1992, 1994; Cornblatt et al.
315
Schizophrenia Bulletin, Vol. 25, No. 2, 1999
1997), and it would be unreasonable to expect long-stand-
ing deficits to improve permanently with a short-lived
treatment. So, how long should an effect last for an inter-
vention to be considered successful? The answer seems
to depend on whether the intervention is psychopharma-
cological or cognitive/behavioral. If a medication
improves neurocognition while it is administered but not
after it is stopped, it is usually considered a success. If a
cognitive/behavioral intervention improves neurocogni-
tive performance while the training is administered but
not after the intervention is stopped, it is usually consid-
ered a failure. As Wykes et al. point out (1999, this
issue), this double standard complicates notions of what
constitutes successful treatment Whether an intervention
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is a success depends on both implicit and explicit goals.
The goal of psychopharmacological interventions is to
treat; the goal of cognitive/behavioral interventions is to
retrain. The complementarity of these two related but
separate goals provides a rationale for combining the
approaches. To the extent that psychopharmacological
treatments are successful, they are likely to open the door
for effective retraining.
It is possible that the dichotomy is not absolute
between the treating and retraining approaches to neu-
rocognitive deficits in schizophrenia. Behavioral studies
make it clear that learned skills can deteriorate over time
and that booster sessions are often called for. For psy-
chopharmacological treatments, it is entirely possible that
a short-term treatment could reregulate a dysregulated
neurochemical system and not require ongoing adminis-
tration, or at least not at the same dosage. Hence, the
effects of retraining are not necessarily durable, and the
effects of medications are not necessarily transient.
What Are the Relevant Outcomes? When a reason-
able intervention for a neurocognitive deficit is achieved,
the question shifts to the selection of a relevant outcome.
Specifically, what benefits do we expect to see? Fre-
quently, the goal of clinically based cognitive intervention
programs is symptomatic improvement. Although this
seems like a reasonable goal, it presents an interpretive
challenge. The model in figure 3 shows no direct mecha-
nism-for an effect on psychotic symptoms.- Instead, neu-
rocognitive interventions might be more beneficial for
nonpsychotic symptoms such as blunted affect and hostil-
ity. This, in fact, may be the case (Brenner et al. 1990).
However, it is likely that neurocognitive interventions
will have their greatest impact outside the domain of
symptoms. The rather strong relationships between neu-
rocognitive deficits and functional outcome indicates that
we might expect to see an effect here. One notion is that
these deficits act as "neurocognitive rate limiting factors"
Schizophrenia Bulletin, Vol. 25, No. 2, 1999
and restrict the functional adaptation of the patient (Green
1996). Following intervention for neurocognitive deficits,
this limitation is eased, allowing for more complete skill
acquisition and functioning. If new learning is required to
achieve the functional gains, we should expect a time lag
between any improvement in neurocognitive functioning
and measurable improvement in outcome.
The Delta Question. A key question, which we refer to
as the "delta" question, is whether changes in neurocogni-
tion translate into changes in functional outcome. Given
the associations between neurocognition and functional
outcome, it is reasonable to expect that changes in the two
domains would be associated. However, most studies
have examined whether level of neurocognitive perfor-
mance is associated with functional outcome, not whether
changes in neurocognitive functioning are directly linked
to changes in functional outcome.
Some data bearing on this point suggest that changes
in the two domains may be linked. For example,
Buchanan et al. (1994) found that changes in memory
over 1 year were correlated with changes in quality of life
in schizophrenia patients. Wykes et al. (1999, this issue)
report that change in cognitive flexibility was related to
improvement in social functioning in a relatively short
treatment trial (8 weeks). Spaulding et al. (1999, this
issue) report that improvement in card sorting was associ-
ated with improved social competence, and that improve-
ment in verbal memory was associated with increased
psychosocial skill acquisition over the course of a 6-
month intervention study. These studies provide very pre-
liminary, but encouraging, support for the hypothesis that
changes in the neurocognitive domain will result in
changes in functional outcome.
It may be even more informative to phrase the delta
question in quantitative terms: How much of a change in
neurocognition is needed to bring about a meaningful
change in an outcome area? In this way, the question can
be answered with cost/benefit considerations in mind.
Knowing the amount of neurocognitive improvement
required to make a clinically meaningful improvement in
daily functioning for a given domain would enable us to
better evaluate the practical utility of neurocognitive gains
that may be possible through psychopharmacological or
cognitive/behavioral intervention. Clearly, a key chal-
lenge facing this entire area of investigation will be to
understand the process through which short-term perfor-
mance gains can be converted into long-term functional
benefits.
How to Define Efficacy. Several articles in this theme
issue strongly suggest that the new generation of antipsy-
chotic agents acts on more than one domain of illness. If
316
M.F. Green and K.H. Nuechterlein
so, then we are confronted with the problem of how to
define efficacy. Traditionally, efficacy has been defined in
terms of reduction of psychotic symptoms, but more
recently, the reduction of negative symptoms has been
added to the definition. However, if the new medications
act on multiple domains of illness, then symptom reduc-
tion is simply too narrow a definition of efficacy (Green et
al. 1997). Even our language betrays us; the very term
"antipsychotic" may prove to be too narrow for the new
generation of medications.
To the extent that new medications and innovative
cognitive/behavioral interventions act in the neurocogni-
tive domain, it may be more accurate to describe an inter-
mediate goal of treatment as impairment reduction. And
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if psychopharmacological and cognitive/behavioral neu-
rocognitive interventions translate into functional gains
for patients, then even impairment reduction may be too
narrow. In this case it may be more accurate to describe
the eventual goal of treatment as disability reduction. The
articles in this theme issue can be viewed as concerted
efforts toward these goals of impairment and disability
reduction.
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Acknowledgment
The authors thank Mary Jane Robertson for her help with
the graphics for this article.
The Authors
Michael Foster Green, Ph.D., is Professor, Department of
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Psychiatry and Biobehavioral Sciences, University of
California Los Angeles, and Health Sciences Specialist,
Department of Veterans Affairs VISN 22 Mental Illness
Research Education and Clinical Center, Los Angeles,
CA. Keith H. Nuechterlein, Ph.D., is Professor,
Department of Psychiatry and Biobehavioral Sciences,
University of California Los Angeles.
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