2 - Sheffield et al. (2018) Cognitive deficits in psychotic disorders
Introduction
• Psychosis refers to the experience of delusions, hallucinations, and thought disorder. Psychotic symptoms are significant
enough to cause distress or functional impairment. However, psychotic experiences occur on a spectrum.
• Although not a symptom of psychotic disorders, cognitive dysfunction is a core feature of illnesses that include psychotic
symptoms. Despite the co-occurence of cognitive deficits with psychosis, antipsychotic medications do not improve cognitive
impairment.
● In fact, antipsychotics demonstrate minimal efficacy in improving daily functioning, and research suggests that
functional impairment is most strongly associated with cognitive impairment, not severity of psychotic symptoms.
Therefore, cognitive deficits represent an important target for improving the lives of patients suffering from psychotic
disorders.
• The relevance of understanding cognitive impairment is further highlighted when considering its presence early in the
disease course. While psychotic symptoms typically emerge between ages 18 and 25, cognitive deficits are observed much
earlier on in the lifespan of those who go on to develop schizophrenia. This suggests that cognitive deficits are a marker of
abnormal neurodevelopment, especially within the context of genetic risk and early developmental insults.
Cognitive functioning in schizophrenia
Premorbid cognitive function in schizophrenia
• There is a general consensus that children and adolescents exhibit premorbid cognitive impairments prior to the onset of
schizophrenia.
• Consistent with premorbid impairments, first-degree relatives also show cognitive impairments, and the presence of
psychosis in a first-degree relative increases the severity of childhood premorbid impairment in schizophrenia.
General cognitive impairments
• Children and adolescents who later develop schizophrenia show deficits in general
cognitive abilities. Consist IQ deficits are observed among individuals who
subsequently develop schizophrenia.
● In terms of the relationship between premorbid school achievement and
schizophrenia, poor premorbid school achievement and schizophrenia, poor
premorbid school performance is generally associated with increased risk for
schizophrenia.
Specific cognitive impairments
• Premorbid impairments are present in the domains: attention, memory, reasoning, and executive functioning.
• There is also considerable support for premorbid impairments in processing speed.
● In the premorbid state of schizophrenia, processing speed impairments are multifaceted, both relying on other areas
of cognition that are impaired and potentially contributing to, or interacting with, deficit development of the host of
cognitive impairments seen in later stages of the disorder, such as verbal abilities
• Verbal abilities are consistently associated with premorbid impairments, particularly receptive language.
Neurodevelopment model of cognitive impairments
• Premorbid cognitive deficits support the neurodevelopmental model of schizophrenia, which posits that the earliest signs
of the disorder are mild abnormalities in cognitive development.
• This model conceptualizes cognitive dysfunction in schizophrenia as aberrant neurodevelopment during the first two
decades of life, with deficits in the acquisition of cognitive abilities compared to normative individuals.
• The presence of cognitive deficits years prior to the onset of psychotic symptoms suggests that cognitive dysfunction is at
the core of schizophrenia, with abnormal neurodevelopment manifesting through performative lag as early as preschool age.
• Multiple lines of evidence converge on the notion that schizophrenia is a cognitive illness that is neurodevelopmental in
nature:cognitive deficits exist prior to psychosis onset, cognitive ability is influenced by genetics, and cognition is an
independent predictor of functional outcome.
,• There is some evidence for static deficits, including in attention and verbal abilities. Yet the majority of research shows
increasing cognitive deficits prior to the onset of schizophrenia, especially immediately prior to the onset of the disorder.
• Schizophrenia is largely associated with premorbid deficits in the acquisition of cognitive abilities during
neurodevelopment, as opposed to the loss of previously acquired cognitive abilities, indicating these deficits increase in
severity throughout development.
Schizophrenia: Ultra-high risk
• Prior to first-episode psychosis, prediction of who will develop a primary psychotic disorder remains elusive. However,
researchers have identified markers of increased risk. These individuals, often referred to as ultra-high risk, clinical high risk,
or prodromal, are identified through dimensions of attenuated psychotic symptoms and/or familial risk.
● Approximately 13 - 23% of individuals meeting these ultra-high risk criteria convert to psychosis within two years.
Ultra-high risk compared to healthy control
• There is evidence that ultra-high risk individuals are globally cognitively impaired when compared to a normative sample.
• At risk participants demonstrate deficits in working memory, executive function, verbal fluency, attention, and memory.
Ultra-high risk compared to first-episode schizophrenia
• Cognitive ability in individuals at-risk for schizophrenia is globally impaired compared to healthy controls, but the
magnitude of impairment is less than can be seen in patients who have recently experienced their first-episode of psychosis.
● However, there may be domains that are impaired to the same degree as first-episode psychosis, even during the
prodromal state, particularly in the domains of memory and attention.
Ultra-high risk+ compared to ultra-high risk-
• Research suggests that ultra-high risk+ subjects (ie.e those who convert) demonstrate greater cognitive impairment than
ultra-high risk- subjects (i.e. those who do not convert), which some evidence of ultra-high risk+ subjects having cognitive
deficits similar to first-episode participants, and ultra-high risk- subjects looking similar to healthy controls.
• Meta-analysis has found that ultra-high risk+ individuals have significantly lower general intelligence, poorer verbal fluency,
verbal and visual memory, and working memory compared to ultra-high risk- individuals.
• Conversion to psychosis is associated with poor verbal memory and sustained attention.
More specific impairments in ultra-high risk schizophrenia
• Unpacking executive dysfunction into “cold” (e.g. working memory) and “hot” (e.g. decision making) functions, there are
specific relationships between “hot” executive functioning and psychotic severity, suggesting that certain aspects of these
broad cognitive domains are more critical for understanding relationships with current and impending psychotic experiences.
• Specific analysis of latent inhibition, a learning process dependent on both attentional and perceptual resources, identified
a deficit in latent inhibition in ultra-high risk individuals, indicating impaired ability to learn from past experiences to adjust
expectations for future experiences.
Schizophrenia: First-episode
• Although definitions of “first-episode” are variable, the phrase refers to the identification of individuals who have recently
transitioned to a primary psychotic disorder.
First-episode compared to chronic schizophrenia
• Chronic subjects had greater illness chronicity, and had substantially longer duration of medication exposure, yet their
impairments were similar to those observed in first-episode subjects. Verbal memory also represented the greatest deficit in
chronic schizophrenia subjects, suggesting a stable profile of impairment across the illness course.
Longitudinal analysis of first-episode schizophrenia
• In general, studies point to a stable cognitive profile in the years following a patient’s first break.
● Duration of untreated psychosis was unrelated to cognitive performance.
,• Global cognitive ability measured at first-episode therefore appears to reflect a patient’s cognitive capacity during the
chronic course, arguing against neurotoxic effects of schizophrenia.
Additional cognitive abnormalities in first-episode schizophrenia
• Data suggest that cognitive impairment contributes to a cognitive bias, which is associated with more severe psychotic
symptoms in early stages of psychosis.
Summary
• First-episode schizophrenia is characterized by large deficits in overall cognitive ability. Analysis of specific cognitive
domains reveals a similar pattern of impairment as seen in chronic schizophrenia, with comparable magnitude. Verbal
memory and processing speed were most robustly impaired in first-episode patients, consistent with findings in both
ultra-high risk and chronic stages (discussed below). These deficits are observed even in the absence of neuroleptics and
prior to chronicity of illness, and therefore are not a byproduct of anti-psychotics or a result of degeneration as the illness
progresses. Longitudinal studies suggest a stable cognitive profile following one’s first break. Data therefore suggests that
global cognitive deficits are a core feature of schizophrenia that are present in close to their final form at the first-episode of
psychosis.
Chronic schizophrenia
Generalized deficit
• It appears that at the start of the illness a general cognitive deficit is present, without strong evidence for a steep decline in
the context of aging. The generalized deficit is therefore a stable feature of schizophrenia.
Specific deficits
• Processing speed and social cognition have been found to best distinguish patients from controls beyond the generalized
deficit.
● Processing speed, and even more specifically digit symbol coding, has been found to be particularly sensitive to
impairments in schizophrenia, leading some to suggest that processing speed represents a specific deficit in
schizophrenia that contributes to the generalized deficit.
• Furthermore, processing speed, visual learning, and attention or vigilance best distinguish patients with and without
competitive employment, suggesting that impairments in these areas contribute to functional disability.
Impact of medications on cognition
• Small, but positive influence of anti-psychotic use on global cognition has been observed in early psychosis patients taking
either haloperidol or second-generation antipsychotics over six months.
● While there is some suggestion that first-generation anti-psychotics have negligible if not adverse impact on cognitive
performance with second-generation anti-psychotics having a more positive impact, a recent meta-analysis found no
global differences in cognition for first- versus second-generation anti-psychotics.
Summary
• Together, findings across the lifespan of schizophrenia widely suggest cognitive deficits that can be observed as early as
childhood, are robust in ultra-high risk individuals who develop the disorder, and are stable and severe from the first-episode
of psychosis throughout the remainder of the life course. While deficits in verbal memory and attention
may be early markers of abnormal psychiatric development, there is less specificity at the chronic stage, with the strongest
evidence pointing to particularly robust deficits in processing speed. Cognitive deficits are minimally impacted by
antipsychotics and, as will be discussed in more detail below, contribute to the functional disability that takes such a large toll
on this patient population.
, Bipolar disorder
Premorbid cognitive functioning in bipolar disorder
• In terms of research examining bipolar disorder in general (i.e. including bipolar disorder with and without psychotic
features), studies largely fail to find evidence of significant premorbid cognitive impairments. Furthermore, there is evidence
that higher cognitive functioning is associated with the development of bipolar disorder.
• In contrast to premorbid cognitive function in bipolar disorder generally, a mild global cognitive impairment exists in
individuals with bipolar disorder with psychotic features, including evidence that the presence of psychotic features may
worsen IQ deficits.
• In early onset bipolar disorder with psychotic features, research demonstrates premorbid IQ deficits. Similarly, individuals at
high-risk for schizophrenia who later develop bipolar disorder show global cognitive deficits, and medium-sized impairments
in processing speed and executive functioning are observed in the premorbid phase.
• Taken together, research more consistently points to mild premorbid global cognitive impairments in bipolar disorder with
psychotic features in comparison to premorbid cognitive function in bipolar disorder generally.
Comparison with premorbid cognitive function in schizophrenia
• Research indicates that schizophrenia and bipolar disorder with psychotic features are distinguished by the degree of
premorbid impairment, with schizophrenia showing more severe premorbid cognitive impairments than bipolar disorder.
• Thus, while bipolar disorder with psychotic features is more consistently associated with premorbid impairments than in
bipolar disorder generally, these impairments are generally less severe than premorbid cognitive deficits in schizophrenia.
First-episode bipolar disorder
• Deficits occur across the spectrum of cognitive domains early after the onset of bipolar disorder with psychotic features,
including in samples of first-episode bipolar disorder with psychotic features (FEBP+) and recent onset psychosis diagnosed
with bipolar disorder.
● These cognitive impairments have generally been localized to attention, processing speed, verbal learning or
memory, and executive functioning.
Bipolar disorder with and without psychotic features
• While research consistently indicates that FEBP+ is associated with cognitive impairments, there is a lack of consensus
regarding the relative severity of FEBP+ impairments compared to other forms of bipolar disorder.
● There is also mixed evidence regarding whether FEBP+ exhibits significantly greater impairments compared to bipolar
disorder without psychotic features (FEBP-), with some studies demonstrating similar severity of neuropsychological
deficits.
• Thus, FEBP+, if anything, appears to be intermediate in severity between FEBP- and chronic bipolar disorder, although
additional research should attempt to resolve disparities in these findings.
Bipolar disorder compared to schizophrenia
• The majority of research indicates that first-episode schizophrenia shows greater cognitive impairments than FEBP+.
Specific deficits
• Impaired semantic verbal fluency has been observed in first episode psychotic bipolar patients in the context of intact
cognitive functioning over a wide range of cognitive domains.
• Cognitive flexibility is an area of particular deficit in first episode psychotic bipolar disorder patients compared to bipolar
patients without a history of psychosis.
Chronic bipolar disorder
• Similar to FEBP+, chronic bipolar disorder with psychotic features (CBP+) is associated with impairments across the gamut
of cognitive domains, especially in attention, executive functioning, and memory.
Introduction
• Psychosis refers to the experience of delusions, hallucinations, and thought disorder. Psychotic symptoms are significant
enough to cause distress or functional impairment. However, psychotic experiences occur on a spectrum.
• Although not a symptom of psychotic disorders, cognitive dysfunction is a core feature of illnesses that include psychotic
symptoms. Despite the co-occurence of cognitive deficits with psychosis, antipsychotic medications do not improve cognitive
impairment.
● In fact, antipsychotics demonstrate minimal efficacy in improving daily functioning, and research suggests that
functional impairment is most strongly associated with cognitive impairment, not severity of psychotic symptoms.
Therefore, cognitive deficits represent an important target for improving the lives of patients suffering from psychotic
disorders.
• The relevance of understanding cognitive impairment is further highlighted when considering its presence early in the
disease course. While psychotic symptoms typically emerge between ages 18 and 25, cognitive deficits are observed much
earlier on in the lifespan of those who go on to develop schizophrenia. This suggests that cognitive deficits are a marker of
abnormal neurodevelopment, especially within the context of genetic risk and early developmental insults.
Cognitive functioning in schizophrenia
Premorbid cognitive function in schizophrenia
• There is a general consensus that children and adolescents exhibit premorbid cognitive impairments prior to the onset of
schizophrenia.
• Consistent with premorbid impairments, first-degree relatives also show cognitive impairments, and the presence of
psychosis in a first-degree relative increases the severity of childhood premorbid impairment in schizophrenia.
General cognitive impairments
• Children and adolescents who later develop schizophrenia show deficits in general
cognitive abilities. Consist IQ deficits are observed among individuals who
subsequently develop schizophrenia.
● In terms of the relationship between premorbid school achievement and
schizophrenia, poor premorbid school achievement and schizophrenia, poor
premorbid school performance is generally associated with increased risk for
schizophrenia.
Specific cognitive impairments
• Premorbid impairments are present in the domains: attention, memory, reasoning, and executive functioning.
• There is also considerable support for premorbid impairments in processing speed.
● In the premorbid state of schizophrenia, processing speed impairments are multifaceted, both relying on other areas
of cognition that are impaired and potentially contributing to, or interacting with, deficit development of the host of
cognitive impairments seen in later stages of the disorder, such as verbal abilities
• Verbal abilities are consistently associated with premorbid impairments, particularly receptive language.
Neurodevelopment model of cognitive impairments
• Premorbid cognitive deficits support the neurodevelopmental model of schizophrenia, which posits that the earliest signs
of the disorder are mild abnormalities in cognitive development.
• This model conceptualizes cognitive dysfunction in schizophrenia as aberrant neurodevelopment during the first two
decades of life, with deficits in the acquisition of cognitive abilities compared to normative individuals.
• The presence of cognitive deficits years prior to the onset of psychotic symptoms suggests that cognitive dysfunction is at
the core of schizophrenia, with abnormal neurodevelopment manifesting through performative lag as early as preschool age.
• Multiple lines of evidence converge on the notion that schizophrenia is a cognitive illness that is neurodevelopmental in
nature:cognitive deficits exist prior to psychosis onset, cognitive ability is influenced by genetics, and cognition is an
independent predictor of functional outcome.
,• There is some evidence for static deficits, including in attention and verbal abilities. Yet the majority of research shows
increasing cognitive deficits prior to the onset of schizophrenia, especially immediately prior to the onset of the disorder.
• Schizophrenia is largely associated with premorbid deficits in the acquisition of cognitive abilities during
neurodevelopment, as opposed to the loss of previously acquired cognitive abilities, indicating these deficits increase in
severity throughout development.
Schizophrenia: Ultra-high risk
• Prior to first-episode psychosis, prediction of who will develop a primary psychotic disorder remains elusive. However,
researchers have identified markers of increased risk. These individuals, often referred to as ultra-high risk, clinical high risk,
or prodromal, are identified through dimensions of attenuated psychotic symptoms and/or familial risk.
● Approximately 13 - 23% of individuals meeting these ultra-high risk criteria convert to psychosis within two years.
Ultra-high risk compared to healthy control
• There is evidence that ultra-high risk individuals are globally cognitively impaired when compared to a normative sample.
• At risk participants demonstrate deficits in working memory, executive function, verbal fluency, attention, and memory.
Ultra-high risk compared to first-episode schizophrenia
• Cognitive ability in individuals at-risk for schizophrenia is globally impaired compared to healthy controls, but the
magnitude of impairment is less than can be seen in patients who have recently experienced their first-episode of psychosis.
● However, there may be domains that are impaired to the same degree as first-episode psychosis, even during the
prodromal state, particularly in the domains of memory and attention.
Ultra-high risk+ compared to ultra-high risk-
• Research suggests that ultra-high risk+ subjects (ie.e those who convert) demonstrate greater cognitive impairment than
ultra-high risk- subjects (i.e. those who do not convert), which some evidence of ultra-high risk+ subjects having cognitive
deficits similar to first-episode participants, and ultra-high risk- subjects looking similar to healthy controls.
• Meta-analysis has found that ultra-high risk+ individuals have significantly lower general intelligence, poorer verbal fluency,
verbal and visual memory, and working memory compared to ultra-high risk- individuals.
• Conversion to psychosis is associated with poor verbal memory and sustained attention.
More specific impairments in ultra-high risk schizophrenia
• Unpacking executive dysfunction into “cold” (e.g. working memory) and “hot” (e.g. decision making) functions, there are
specific relationships between “hot” executive functioning and psychotic severity, suggesting that certain aspects of these
broad cognitive domains are more critical for understanding relationships with current and impending psychotic experiences.
• Specific analysis of latent inhibition, a learning process dependent on both attentional and perceptual resources, identified
a deficit in latent inhibition in ultra-high risk individuals, indicating impaired ability to learn from past experiences to adjust
expectations for future experiences.
Schizophrenia: First-episode
• Although definitions of “first-episode” are variable, the phrase refers to the identification of individuals who have recently
transitioned to a primary psychotic disorder.
First-episode compared to chronic schizophrenia
• Chronic subjects had greater illness chronicity, and had substantially longer duration of medication exposure, yet their
impairments were similar to those observed in first-episode subjects. Verbal memory also represented the greatest deficit in
chronic schizophrenia subjects, suggesting a stable profile of impairment across the illness course.
Longitudinal analysis of first-episode schizophrenia
• In general, studies point to a stable cognitive profile in the years following a patient’s first break.
● Duration of untreated psychosis was unrelated to cognitive performance.
,• Global cognitive ability measured at first-episode therefore appears to reflect a patient’s cognitive capacity during the
chronic course, arguing against neurotoxic effects of schizophrenia.
Additional cognitive abnormalities in first-episode schizophrenia
• Data suggest that cognitive impairment contributes to a cognitive bias, which is associated with more severe psychotic
symptoms in early stages of psychosis.
Summary
• First-episode schizophrenia is characterized by large deficits in overall cognitive ability. Analysis of specific cognitive
domains reveals a similar pattern of impairment as seen in chronic schizophrenia, with comparable magnitude. Verbal
memory and processing speed were most robustly impaired in first-episode patients, consistent with findings in both
ultra-high risk and chronic stages (discussed below). These deficits are observed even in the absence of neuroleptics and
prior to chronicity of illness, and therefore are not a byproduct of anti-psychotics or a result of degeneration as the illness
progresses. Longitudinal studies suggest a stable cognitive profile following one’s first break. Data therefore suggests that
global cognitive deficits are a core feature of schizophrenia that are present in close to their final form at the first-episode of
psychosis.
Chronic schizophrenia
Generalized deficit
• It appears that at the start of the illness a general cognitive deficit is present, without strong evidence for a steep decline in
the context of aging. The generalized deficit is therefore a stable feature of schizophrenia.
Specific deficits
• Processing speed and social cognition have been found to best distinguish patients from controls beyond the generalized
deficit.
● Processing speed, and even more specifically digit symbol coding, has been found to be particularly sensitive to
impairments in schizophrenia, leading some to suggest that processing speed represents a specific deficit in
schizophrenia that contributes to the generalized deficit.
• Furthermore, processing speed, visual learning, and attention or vigilance best distinguish patients with and without
competitive employment, suggesting that impairments in these areas contribute to functional disability.
Impact of medications on cognition
• Small, but positive influence of anti-psychotic use on global cognition has been observed in early psychosis patients taking
either haloperidol or second-generation antipsychotics over six months.
● While there is some suggestion that first-generation anti-psychotics have negligible if not adverse impact on cognitive
performance with second-generation anti-psychotics having a more positive impact, a recent meta-analysis found no
global differences in cognition for first- versus second-generation anti-psychotics.
Summary
• Together, findings across the lifespan of schizophrenia widely suggest cognitive deficits that can be observed as early as
childhood, are robust in ultra-high risk individuals who develop the disorder, and are stable and severe from the first-episode
of psychosis throughout the remainder of the life course. While deficits in verbal memory and attention
may be early markers of abnormal psychiatric development, there is less specificity at the chronic stage, with the strongest
evidence pointing to particularly robust deficits in processing speed. Cognitive deficits are minimally impacted by
antipsychotics and, as will be discussed in more detail below, contribute to the functional disability that takes such a large toll
on this patient population.
, Bipolar disorder
Premorbid cognitive functioning in bipolar disorder
• In terms of research examining bipolar disorder in general (i.e. including bipolar disorder with and without psychotic
features), studies largely fail to find evidence of significant premorbid cognitive impairments. Furthermore, there is evidence
that higher cognitive functioning is associated with the development of bipolar disorder.
• In contrast to premorbid cognitive function in bipolar disorder generally, a mild global cognitive impairment exists in
individuals with bipolar disorder with psychotic features, including evidence that the presence of psychotic features may
worsen IQ deficits.
• In early onset bipolar disorder with psychotic features, research demonstrates premorbid IQ deficits. Similarly, individuals at
high-risk for schizophrenia who later develop bipolar disorder show global cognitive deficits, and medium-sized impairments
in processing speed and executive functioning are observed in the premorbid phase.
• Taken together, research more consistently points to mild premorbid global cognitive impairments in bipolar disorder with
psychotic features in comparison to premorbid cognitive function in bipolar disorder generally.
Comparison with premorbid cognitive function in schizophrenia
• Research indicates that schizophrenia and bipolar disorder with psychotic features are distinguished by the degree of
premorbid impairment, with schizophrenia showing more severe premorbid cognitive impairments than bipolar disorder.
• Thus, while bipolar disorder with psychotic features is more consistently associated with premorbid impairments than in
bipolar disorder generally, these impairments are generally less severe than premorbid cognitive deficits in schizophrenia.
First-episode bipolar disorder
• Deficits occur across the spectrum of cognitive domains early after the onset of bipolar disorder with psychotic features,
including in samples of first-episode bipolar disorder with psychotic features (FEBP+) and recent onset psychosis diagnosed
with bipolar disorder.
● These cognitive impairments have generally been localized to attention, processing speed, verbal learning or
memory, and executive functioning.
Bipolar disorder with and without psychotic features
• While research consistently indicates that FEBP+ is associated with cognitive impairments, there is a lack of consensus
regarding the relative severity of FEBP+ impairments compared to other forms of bipolar disorder.
● There is also mixed evidence regarding whether FEBP+ exhibits significantly greater impairments compared to bipolar
disorder without psychotic features (FEBP-), with some studies demonstrating similar severity of neuropsychological
deficits.
• Thus, FEBP+, if anything, appears to be intermediate in severity between FEBP- and chronic bipolar disorder, although
additional research should attempt to resolve disparities in these findings.
Bipolar disorder compared to schizophrenia
• The majority of research indicates that first-episode schizophrenia shows greater cognitive impairments than FEBP+.
Specific deficits
• Impaired semantic verbal fluency has been observed in first episode psychotic bipolar patients in the context of intact
cognitive functioning over a wide range of cognitive domains.
• Cognitive flexibility is an area of particular deficit in first episode psychotic bipolar disorder patients compared to bipolar
patients without a history of psychosis.
Chronic bipolar disorder
• Similar to FEBP+, chronic bipolar disorder with psychotic features (CBP+) is associated with impairments across the gamut
of cognitive domains, especially in attention, executive functioning, and memory.
