Summary Neuropsychology & Psychiatric Disorders
Bora, Yalincetin, Akdede, & Alptekin (2018) – Duration of untreated psychosis and
neurocognition in first-episode psychosis: A meta-analysis
Schizofrenie wordt geassocieerd met cognitieve beperkingen, ook al na het hebben van een eerste
episode.
− Neurodevelopment = het zou komen door verstoorde acquisitie van cognitieve vaardigheden
in de ontwikkeling
− Neurotoxicity = komt door het niet-behandelen van psychotische symptomen in de eerste jaren
van de stoornis
Duration of untreated psychosis (DUP) = de tijd tussen het eerste symptoom en de eerste effectieve
interventie → in dit onderzoek in weken. Lange DUP kan leiden tot structurele breinverandering en
cognitieve beperkingen in first-episode psychosis (FEP). Andere studies spreken dit tegen.
Hypotheses:
1. DUP heeft een significant effect op cognitieve beperkingen in FEP.
2. De relatie wordt vooral duidelijk in de complexe cognitieve vaardigheden die ontwikkelen in
de late adolescentie en vroege volwassenheid.
Methode
Literatuuronderzoek van 27 studies in een meta-analyse.
Resultaten
Er is geen significante relatie tussen zowel DUP- als FEP t.o.v. globale cognitie. Ook correleert DUP
niet met IQ, behalve met probleem-oplossend vermogen. Dit wordt slechter naarmate de DUP langer
is. Individuele metingen lieten zien dat een lange DUP voor slechte prestaties op de WCST zorgde,
maar niet op de andere neuropsychologische taken. Daarnaast is er geen effect van leeftijd, geslacht,
percentage schizofreniepatiënten in de studie, kwalitatieve score en opleidingsniveau op de sterkte van
de relatie tussen globale cognitie en DUP.
Bovenstaande resultaten geven (op probleem-oplossend vermogen na) geen bewijs voor een relatie
tussen lange DUP en daarmee beperkingen in neurocognitie. Resultaten zijn consistent met de
neurodevelopmental hypothese (en dus niet met de neurotoxicity hypothese) dat cognitieve
beperkingen vaak op neuro-ontwikkeling gericht zijn en er zijn voorafgaand aan het ontstaan van de
stoornis. Er is echter wel bewijs voor verslechtering van de hogere orde EF tijdens de prodromale
periode. Dit is bijv. te zien aan de resultaten van de WCST. De duur van DUP is een marker voor een
slechte prognose, maar niet de oorzaak.
De neurodevelopmental theorie geeft ook een verklaring voor de relatie tussen DUP en
planningsvaardigheden: deze ontwikkelen zich vaak pas in of na het 20e levensjaar en zijn daarom het
duidelijkst zichtbaar in de jaren voorafgaand aan een eerste episode.
Ook zijn er in sommige studies patiënten meegenomen die niet enkel een schizofrenie stoornis hebben,
maar soms ook schizo-affectief. De correlaties zijn dan soms anders.
De zwakke relatie tussen DUP en neurocognitie in DUP kan ook verklaard worden door etiologische
heterogeniteit van de stoornis. Er is verder onderzoek nodig voor deze subgroepen.
Het reduceren van DUP helpt niet om cognitieve beperkingen te verminderen.
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,Meer kanttekeningen van de studie:
− Te weinig studies in de analyse (27)
− Heterogeniteit van de cognitieve taken waarmee gemeten wordt
− Limitaties door subjectieve ervaringen van patiënten en families
− Het was cross-sectioneel. De DUP moet ook onderzocht worden op andere neurobiologische
markers, er zijn namelijk studies die aantonen dat ook andere factoren van belang zijn
− Gebrek aan info over sommige variabelen, zoals premorbide functioneren, SES,
familiegeschiedenis etc.
Green, Nuechterlein, Gold, Barch, Cohen, Essock, Fenton, Frese, Goldberg, Heaton, Keefe,
Kern, Kraemer, Stover, Weinberger, Zalcman & Marder (2004) – Approaching a consensus
cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select
cognitive domains and test criteria
To stimulate the development of new drugs for cognitive deficits in schizophrenia, the National
Institute of Mental Health (NIMH) established measurement and treatment research to improve
cognition in schizophrenia (MATRICS) initiative. The goals of the meeting were to (1) identify the
cognitive domains that should be represented in a consensus cognitive battery and (2) prioritize key
criteria for selection of tests for the battery.
− 7 cognitive domains: working memory, attention/vigilance, verbal learning and memory,
visual learning and memory, reasoning and problem solving, speed of processing, and social
cognition
− 5 criteria were considered essential for test selection: good test-retest reliability, high utility as
a repeated measure, relationship to functional outcome, potential response to pharmacologic
agents, and practicality/tolerability
A key reason that there is a rapid growth in public rate is that cognitive deficits in schizophrenia are
increasingly viewed as influencing functional outcome and, hence targets for interventions are now
viewed as potential treatment targets for psychopharmacology. However, there is no standard for
evaluating drugs to treat the cognitive deficits in schizophrenia, and no drug has been approved for
this purpose.
The absence of a standardized set of measures for cognitive deficits has been 1 of the obstacles to
receiving regulatory acceptance (the FDA does not want 1 company to have an advantage as they
prefer that a clinical end point for drug approval and labelling be widely accepted by the scientific
community).
Cognitive deficits in this context refer to a wide range of performance deficits in areas such as
attention memory, speeded responses, or problem solving. A cognitive deficit reflects a disturbance in
1 of these underlying processes.
The MATRICS contract has 4 main goals:
1. To promote development of novel compounds to enhance cognition in schizophrenia
2. To catalyze regulatory acceptance of cognition in schizophrenia as a target for drug approval
3. To help focus the economic research power of industry on a neglected clinical target
4. To identify promising compounds and support proof of concept trials for cognition in
schizophrenia
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,The rationale for the psychopharmacologic treatment of cognition in schizophrenia rests on a few
premises that have received substantial empirical support:
1. Cognitive deficits of schizophrenia are a core feature of the illness (that the cognitive deficits
are not simply the result of symptoms, nor the current treatment but instead they represent a
fundamental aspect of the illness). Evidence of this premise:
− Many patients demonstrate clear cognitive impairments before the onset of psychotic
symptoms and before the start of other clinical features
− A subgroup of the first-degree relatives of schizophrenic patients who have no
evidence of psychosis also demonstrate a pattern of cognitive impairments that is
similar to that found in schizophrenia (genetic vulnerability)
− The level of impairment shown by patients during a psychotic episode is similar to
that seen in the same patients when their symptoms are under control (independently
and even in the absence of clinical symptoms)
− The correlations between psychotic symptom severity and measures of cognitive
performance are typically near zero as cognitive performance tend to be more related
to negative symptoms
− The types of cognitive deficits seen in schizophrenia, tend to fit a typical profile that
differs from the pattern of deficits seen in dementia, bipolar disorder and depression
− Both first- and second-generation antipsychotic treatments have marked effects on the
psychotic symptoms of the illness (but the effects on cognition much smaller, with the
second-generation showing cognitive advantages) antipsychotic might act on different
neural systems than those that underlie the cognitive impairments
2. Cognitive deficits are relatively common in schizophrenia (75-90%)
− Almost all schizophrenia patients are performing at a level below that would be
expected in the absence of illness
3. Cognitive deficits are related to the daily functioning of patients, and these relationships are
generally stronger than those between psychotic symptoms and functional outcome
4. Patients’ performance on cognitive tasks can be improved through psychopharmacologic
treatment
− Newer antipsychotic medications have cognitive benefits when compared with
conventional antipsychotic medications (may depend on dosage of the conventional
medication)
− Novel intervention approaches (e.g. glutamatergic, serotonergic, and dopaminergic
agents) that have shown promise for cognitive enhancement in schizophrenia
To maximize the utility of examining various cognitive domains within clinical trials in schizophrenia,
the subgroup sought to identify dimensions of cognitive performance that have been implicated in
schizophrenia and are relatively independent of each other → factor analysis of well-established
instruments such as WAIS-III and WMS-III were examined.
− The 6 separable factors: working memory, attention/vigilance, verbal learning and memory.
visual learning and memory, reasoning and problem solving, speed of processing. Several
participants of the convention were concerned that social cognition was not on the list of
domains (mental operations underlying social and emotional interactions, including the human
ability and capacity to perceive the intentions and disposition of others)
Social cognition is fairly new and has not yet achieved standardization across investigation groups.
Initial data does suggest that social cognition is closely related to functional outcome and may be an
intervening variable between (nonsocial) cognition and outcome. Neuroimaging studies suggest that
certain measures of social cognition (such as perception of affect expressed in faces) may have a
distinctive neural substrate from at least some of the system that support the cognitive domains
described, so social cognition became number 7.
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, 5 criteria were prioritized for the selection of tests:
1. Test-retest reliability: highest rated test criterion. Critical for detecting changes with treatment
→ translates directly into statistical power: as test-retest reliability decreases for any given
measure, a larger sample size is required to detect the same amount of change
2. High utility as a repeated measure: includes 2 separate considerations: (1) select measures that
do not have substantial practice effect, and (2) if measures do show a practice effect, it is
important that the improvement in performance with repeated administrations not be so large
that the mean performance at follow-up approaches ceiling and has reduced variability,
because this situation makes it difficult to detect treatment effects → tests with potentially
large practice effects: memory tests and problem-solving tests (sometimes use alternative
forms, which generally prevent from reaching the ceiling, but are not perfectly equivalent →
form-to-form variability and potential drop in test-retest reliability)
3. Relationship to functional outcome: for the purpose of evaluating cognitive tests for the
consensus battery, priority will be given to tests that have demonstrated a relationship to some
aspect of functional outcome. It might be that the relationship between cognition and
functional outcome may vary across situations, so the committee did not specify a particular
type of functional outcome. The possibility that a cognitively enhancing drug may be required
to demonstrate change on a functional outcome measure presents a dilemma: (1) perhaps
changes in functional outcome are an indirect and unreliable index of improvements in
cognition, (2) any such changes in functioning would heavily depend on factors that are
typically beyond the control of clinical trial studies (including availability of psychosocial
rehabilitation, social support networks, and local school and vocational opportunities).
Solution? → using standardized tests of ‘functional capacity’, assesses whether an individual
has the capacity for performing key tasks of daily living
4. Potential response to pharmacologic agents: perhaps tests that are otherwise useful may assess
constructs that are unlikely to change with drug treatments (verbal ability). As there is no
clearly successful drug to normalize cognitive deficits in schizophrenia, we do not know
which cognitive abilities will change with future pro-cognitive agents, so the priority now will
lie with abilities that have shown to be sensitive to differences between first-and second-
generation antipsychotic medications that have shown a response with novel agents (d-
cycloserine, d-serine, tandospirone)
5. Tolerability and practicality: with 7 domains, the battery might be very long. Tolerability
refers to both the length of the test and to any feature of a test that would make it more or less
pleasant for patients. Practicality includes consideration of any particular difficulties in set-up,
staff training, administration, and scoring that would create a burden for an experimenter
Halverson, Orleans-Pobee, Merritt, Sheeran, Fett & Penn (2019) – Pathways to functional
outcomes in schizophrenia spectrum disorders: Meta-analysis of social cognitive and
neurocognitive predictors
Overall, associations between social cognition and neurocognition, and functional outcomes
demonstrated significant small-to medium effect sizes. Social cognition explained more unique
variance in functioning than neurocognition. Social cognition also mediated the relationship between
neurocognition and functional outcomes. However, a significant proportion of variance remained
unexplained.
There is a strong link between functional outcomes in schizophrenia and impairments in both social
cognition (SC) and neurocognition (NC). Although both NC and SC exhibit some overlap, they are
demonstrably separate constructs that differentially relate to functional outcomes.
− SC has incremental validity in explaining the variance in functional outcomes beyond NC in
both first-episode and chronic schizophrenia populations, possibly as a mediator between NC
and functional outcomes. Despite this, most interventions target either NC or SC impairments
This article is a meta-analysis of the relationship between functional outcomes in schizophrenia and
social cognition and neurocognition.
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