European Neuropsychopharmacology (2015) 25, 158–168

www.elsevier.com/locate/euroneuro

Developmental trajectory of cognitive impairment in bipolar disorder: Comparison with schizophrenia Emre Boran Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne and Melbourne Health, VIC, Australia Received 15 May 2014; received in revised form 12 August 2014; accepted 3 September 2014

1.

KEYWORDS

Abstract

Bipolar disorder; Mania; Psychosis; Schizophrenia; Cognition; Development

Both schizophrenia and bipolar disorder (BP) are associated with neurocognitive deficits. However, it has been suggested that schizophrenia, but not BP, is characterised by premorbid cognitive impairments and neurodevelopmental abnormalities. In this paper, studies investigating neurocognitive deficits in premorbid, high-risk and first-episode BP were reviewed and these findings were compared with outcome of studies in schizophrenia. Available evidence suggests that cognitive deficits are evident in first-episode BP and such deficits can be evident even years before the onset of the illness in some patients. Trajectory of cognitive deficits from childhood to adulthood can be very similar in schizophrenia and many patients with BP. Developmental lag in acquisition of cognitive skills is a risk factor for both disorders. However, unlike schizophrenia, not only impaired cognition but also supranormal premorbid cognitive/scholastic performance predict BP. Neurodevelopmental cognitive impairment is evident in some but not all patients with BP. A model suggesting that only BP patients who share common genetic risk factors with schizophrenia have premorbid neurodevelopmental cognitive deficits is proposed. In this model, combination of absence of neurodevelopmental abnormalities and BP-related temperamental characteristics explains the relationship between supranormal cognition and risk for BP. & 2014 Elsevier B.V. and ECNP. All rights reserved.

Introduction

Cognitive dysfunction is a common and robust feature of schizophrenia (Gold and Harvey, 1993; Heinrrichs and n

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Zakzanis, 1998; Bora et al., 2010a). Bipolar disorder is also associated with cognitive deficits in a number of domains including executive functions, attention and memory that persists in remission (Bora et al., 2009a). The pattern of these cognitive deficits overlaps in schizophrenia and BP, but cognitive dysfunction is less severe in BP (Bora et al., 2009b; Krabbendam et al., 2005). It is argued that cognitive deficits in BP and schizophrenia might have very different trajectories. In schizophrenia,

Developmental trajectory of cognitive impairment in bipolar disorder: Comparison with schizophrenia there is a consensus that neurodevelopmental factors play an important role in cognitive deficits. A number of studies have provided evidence indicating that cognitive and intellectual deficits are evident early in neurodevelopment, including childhood, well before the onset of psychosis (Fuller et al., 2002; Kahn and Keefe, 2013; Reichenberg et al., 2010). It seems that cognitive development is abnormal in children and adolescents who develop adult schizophrenia. In addition to cognitive deficits, findings such as increased prevalence of neurological soft signs, childhood motor and language impairments, and prenatal and obstetric complications are among evidence supporting neurodevelopmental abnormality in schizophrenia (Murray and Lewis, 1987: Weinberger, 1986). Some authors also suggested that premorbid cognitive deficits in schizophrenia are not only related to problems in development of cognitive abilities but also to loss of acquired cognitive abilities before or around the onset of first-episode (Kahn and Keefe, 2013). In contrast to findings in schizophrenia, a number of studies have suggested normal, at times superior, cognitive abilities and school achievement in children and adolescents who develop adult BP (Kumar and Frangou, 2010). There is also good evidence suggesting a relationship between BP and creativity in adulthood (Kyaga et al., 2011). Therefore, it has been suggested that developmental cognitive abnormalities might be specific to schizophrenia (Kahn and Keefe, 2013; Murray et al., 2004). Patients with BP only develop cognitive deficits during the course of illness; whereas in schizophrenia cognition is impaired before the onset of the illness and at first-episode. On the other hand, another evidence suggests that abnormalities in neurodevelopment can play a role not only in schizophrenia but also in BP. A number of potential common susceptibility genes for schizophrenia and BP have a role in neurodevelopment (Craddock and Owen, 2010). There is also evidence suggesting that neurological soft signs might be more common in BP than healthy controls (Zhao et al., 2013). Some studies also suggested a link between prenatal and perinatal abnormalities and BP. A recent study showed a four-fold increase in risk for BP in adult offspring of mothers who had gestational influenza (Parboosing et al., 2013). Some evidence suggests that cognitive impairment in BP can be associated with abnormalities in genes that have role in brain development (Tabarés-Seisdedos et al., 2008). Further studies have reported cognitive abnormalities in first-episode of BP and unaffected healthy relatives of BP patients (Bora et al., 2009a; Torres et al., 2010). It is also important to note that longitudinal studies in chronic patients with BP and few available studies in first-episode BP (Bombin et al., 2013; Torres et al., 2014) have not so far supported evidence for progressive cognitive decline in BP. These findings are rather similar to outcome of longitudinal studies in schizophrenia (Bora and Murray 2013; Szöke et al., 2008) which suggest that neurodevelopmental factors might play an important role in major psychoses. Therefore, it is important to revisit the question of specificity of neurodevelopmental cognitive deficits to schizophrenia and offer an explanation to reconcile the seemingly contradicting findings in BP. The aim of the current paper is to review the studies investigating cognitive deficits in premorbid and early BP, compare these findings to schizophrenia and explore the

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relationship between premorbid cognitive functioning and BP risk. In the first part of the paper, neurocognitive studies in first-episode and high-risk samples were reviewed. In the second part of the paper, studies investigating premorbid cognitive deficits in BP and schizophrenia and course of these deficits were explored. In the final part, a proposal to explain the dual nature of relationship between cognitive/ scholastic performance and risk for BP is introduced.

2. Cognitive impairment in early “phases” of schizophrenia and BP 2.1.

Cognitive impairment in first-episode

It is well established that robust cognitive deficits are already evident in first-episode schizophrenia (FES) (Bora and Pantelis, 2013; Mesholam-Gately et al., 2009). However, in BP, it was suggested that cognitive deficits develop after the onset of the illness (Goodwin et al., 2008). It was argued that cognitive deficits should be absent or very modest in first-episode BP (FEBP) (Demjaha et al., 2012). It was also suggested that this might be a key difference between BP and schizophrenia. Recently, a number of neuropsychological studies have been conducted in FEBP and the bulk of these studies have not supported the preserved cognition argument in FEBP. In Table 1, findings of FEBP studies are summarised. These studies were selected through a literature search in the databases Pubmed, PsycINFO, ProQuest and Scopus to identify the relevant studies (January 1990–July 2014). Inclusion criterion investigated cognitive functions in FEBP in comparison to healthy controls. Any study that did not examine cognitive functions within 2 years after the onset of firstepisode was excluded. In the case of overlapping samples only studies with largest sample sizes selected with the exception of studies investigated different cognitive domains or different symptomatic state in comparison to larger study. Most of these cross-sectional studies suggest that neurocognitive deficits are already evident in FEBP, including euthymic patients, which is also confirmed in a recent meta-analysis (Lee et al., 2014). Another metaanalysis (Bora and Pantelis, unpublished data) suggest that the deficits with medium to large effect sizes are evident in all cognitive domains investigated (verbal memory, processing speed, sustained attention, problem solving and reasoning, working memory, fluency and visual memory) (d=0.36–0.83). Magnitude and pattern of such deficits in FEBP are very similar to findings in chronic BP patients (Bora et al., 2009a). Findings of these meta-analyses also suggest that cognitive deficits in FEBP cannot be explained by mood symptoms.

2.2. Cognitive impairment in high risk schizophrenia and BP While FE studies fail to support specificity of early cognitive deficits to schizophrenia, it might be argued that effects of recent illness and treatment might cause emergence of cognitive impairment in BP which might not be evident before the onset of the illness. Therefore, studies investigating cognitive deficits in at-risk subjects before the first-episode

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Table 1

E. Bora Cognitive deficits in first-episode bipolar disorder (BP).

Studies

Sample Characteristics

Cognitive tasks

Outcome

Ayres et al., 2007

41 State: not clear FEBP 383 HC BP history of psychotic symptoms 98 FES 13–22% patients have drug use disorder 32 State: subacute FEBP 67 HC BP history of psychotic

Verbal fluency, digit span

BP impaired in digit span backwards

Barrett et al., 2009

Bücker et al., 2014, Torres et al. 2010 Chan et al., 2013

Similar impairment in FEBP and FES in memory and executive functions. Verbal fluency, response inhibition, general intelligence better in BP than FES. 46 FES symptoms Brixton, Semantic fluency, Cognitive performances of IQ matched FES NART, Short WASI and FEBP are similar 74 State: mildly symptomatic Premorbid IQ, Letter fluency, BP impaired in working memory, attention, FEBP but smaller sample of Torres list euthymic 98 HC Learning, SOC, CPT, SWM, IED Fluency, verbal memory and executive functions

40 FEBP 38 FES 37 HC 16 Daros et al., FEBP 2014 24 FES 32 HC Dickerson 60 et al., FEBP 2011 312 HC 56 FES 21 Fleck et al., FEBP 48 HC 2008, Lebowitz et al., 2001, Larson et al. 2005 Gruber et al., 2008

Hellvin et al., 2012

FES impaired in all 3

26 FEBP 20 HC

34 FEBP

State: Euthymic

IQ

Substance abuse excluded-lifetime State: Symptomatic

Prospective memory IQ, premorbid IQ

BP history of psychotic symptoms State: Symptomatic

Reaction time Face emotion recognition RBANS, WCST

BP history of State:Manic or mixed but Larrson Euthymic Substance abuse excludedrecent psychotic symptoms

State: not clear Within 2 weeks of manic admission Substance abuse Excluded State: Some symptomatic

110 HC Hill et al., 22 2009 FEBP

Digit span, Corsi blocks, paired Associates, ROCF, Hayling,

State:Symptomatic

41 HC BP history of psychotic 30 FES Symptoms Substance abuse

WCST (Fleck)

Both patient groups impaired in prospective memory but relatively more in FES

BP impaired in emotion recognition

BP significantly impaired in memory, attention, executive functions and language. Schizophrenia more impaired in language than BP FEBP impaired in executive functions and inhibitory control

Letter and semantic fluency (Lebowitz) DRT, OA (Larson)

TMT, Stroop, WCST, letter fluency

BP significantly impaired in executive functions, Processing speed, response inhibition and Fluency Executive functions and verbal memory more Impaired in FES BP impaired in verbal memory, processing speed,

LM, CVLT, ROCF, DS, D-KEFS interference, letter and category fluency Digit span, LNS, n-back, WCST, Response inhibition, working memory IQ, premorbid TMT, letter and semantic BP impaired in working memory fluency, Set shifting, PCET, CVLT, face Memory, SWM, digit span, spatial span

Developmental trajectory of cognitive impairment in bipolar disorder: Comparison with schizophrenia

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Table 1 (continued ) Studies

Sample Characteristics

Hirayasu et al., 2000

24 FEBP 20 FES 22 HC 16 FEBP 20 HC

Nehra et al., 2006 Thomas et al., 1996 Zabala et al., 2010

Zanelli et al., 2010

Excluded-recent State: Manic Substance abuse Excluded-lifetime State: Euthymic Substance abuse Excluded State: acute manic

11 FEBP 38 FES No substance abuse 16 HC 19 State: Symptomatic FEBP 98 HC Early-onset 36 FES 37 BP State: Symptomatic 177 HC BP history of psychotic 65 FES symptoms

Cognitive tasks

Outcome

Digit span

Impaired working memory in patients No difference between FEBP and FES

WCST, TMT, Letter and semantic Fluency, IQ

BP significantly impaired in processing speed, fluency,

Digit span backwards

FEBP and FES impaired in sustained attention No differences between patients

Shape cancelling test Digits span, TMT, Stroop, CPT, LNS, WCST, list Learning, letter fluency, Category fluency List learning, visual memory, TMT, vocabulary,LNS, Digit symbol, letter and category Fluency, Raven, BD

Significant impairment in executive functions, verbal memory, attention and working memory in BP No difference with FES BP impaired only in semantic fluency and delayed recall Better performance than schizophrenia

FEBP=first-episode Bipolar disorder; HC=Healthy controls; FES= First-episode schizophrenia; SOC=Stockings of Cambridge; PRM=pattern recognition memory; LNS =Letter number sequencing; TMT=Trail making test; WCST=Wisconsin cart sorting test; SWM=Spatial working memory; IDED= Intradimensional/Extradimensional Shift test CPT=Continous performance test NART= National adult reading test; CANTAB =Cambridge automatic;BD=Block design; PA =Paired associates; PCET=Penn conditional exclusion test; RBANS= Repeatable Battery for the Assessment of Neuropsychological Status.

are important to test the hypothesis of specificity of early cognitive deficits to schizophrenia. Clinical and familial high risk paradigms are the most important methods used to study cognitive abilities prior to first-episode mania or psychosis. 2.2.1. Clinical-high risk studies Recent meta-analyses in youth with clinical high risk to psychosis clearly showed that cognitive impairment is already evident before the onset of psychotic symptoms in schizophrenia (Bora et al., 2014; Fusar-Poli et al., 2012). Clinical high risk paradigms were rarely used to investigate cognitive deficits in BP. However, the ultra-high-risk to psychosis (UHR) paradigm, which was initially developed to detect early phases of schizophrenia, suggested that UHR is a nonspecific risk paradigm of psychosis and a subset of UHR subjects develop BP at follow-up. Two recent studies in ultra-high risk to psychosis samples found that premorbid cognitive deficits are evident in at-risk subjects who develop BP at follow-up. Olvet et al. (2010) found that global cognition is significantly impaired in FEBP and Ratheesh et al. (2013) reported deficits in general intelligence, processing speed and executive functions in FEBP in comparison to healthy controls. 2.2.2. Familial high-risk studies Modest cognitive impairment is evident in healthy firstdegree relatives of both schizophrenia and BP (Bora et al., 2009a; Snitz et al., 2006). Such deficits are milder in magnitude in comparison to FE patients. Like in FE and

chronic samples, such cognitive deficits are relatively more severe in schizophrenia than BP but are not specific to schizophrenia. However, unlike UHR studies, most of these studies include middle-aged relatives who have limited risk of developing psychosis and therefore can fail to reveal schizophrenia-specific cognitive deficits before the onset of psychosis. Therefore, it is important to investigate cognitive deficits in young relatives of BP separately. Importantly, a number of studies investigated cognitive deficits in youth with familial high risk to psychosis, who were similar in age to the UHR samples. A recent meta-analysis of these studies has suggested that youth with familial risk to psychosis have cognitive deficits which are comparable to UHR subjects in severity (Bora et al., 2014). While there are relatively less studies in youth with familial high risk to BP, available evidence also suggests that cognitive deficits are evident in young relatives of BP (Balanzá-Martínez et al., 2008; Doyle et al., 2009; Klimes-Dougan et al., 2006; Maziade et al., 2009). In another study investigating a longitudinal sample of subjects at risk for major affective disorder, Meyer and Blechert (2005) found that executive functions were already evident in adolescence (Mean age=14.8) among those who developed BP in young adulthood (in comparison to subjects who developed unipolar disorder or remain well). 2.2.3. Comparison cognitive abilities in schizophrenia and BP in early “phases” of the illness In chronic samples, two meta-analyses compared cognitive abnormalities in schizophrenia and BP (Krabbendam et al., 2005;

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E. Bora

Bora et al., 2009a). Both meta-analyses found that cognitive impairment is significantly more severe in schizophrenia but between-group differences were modest, suggesting that there is a significant overlap between schizophrenia and BP. Our recent meta-analysis suggested that this is also true for first-episode (Bora and Pantelis, unpublished data). Moreover, findings of this meta-analysis do not suggest that between-group differences (schizophrenia vs BP) for cognitive impairment is more pronounced in FE (d=0.25–0.67) than in chronic samples (Bora et al.). A study suggested that premorbid deficits in UHR subjects that develop schizophrenia and BP might be similar to each other (Olvet et al., 2010).

2.3.

Summary

As a summary, cognitive impairment is evident in chronic, FE and high-risk subjects with both schizophrenia and BP. In all these groups of subjects, cognitive impairment is significantly but modestly more severe in schizophrenia than BP. Current evidence does not support the idea of normal cognitive abilities before and around the onset of BP.

3. Neurodevelopment and cognitive impairment in BP and schizophrenia Evidence showing that cognitive deficits are already evident at first-episode schizophrenia and BP in high-risk subjects suggests that neurodevelopmental factors play an important role in the development of cognitive deficits in schizophrenia and BP. Neurodevelopmental theory has been mainly proposed in the context of schizophrenia but was extended to BP by some (Arango et al., 2014; Roybal et al., 2012; Sanches et al., 2008; Sigurdsson et al., 1999). This theory suggests that schizophrenia (and BP) is related to genetic and nongenetic risk factors leading to abnormal development of the brain that can be associated with problems in acquiring cognitive abilities throughout development. Earlier accounts of neurodevelopmental theory regarded schizophrenia as the outcome of a developmental fixed “lesion” occurring most commonly in the second trimester of intrauterine life (Weinberger, 1986). Cognitive deficits were considered a consequence of this “static encephalopathy”. However, neurodevelopment is an extended process. Some aspects of normal cortical development, such as proliferation and migration, occur mostly during the prenatal life; other developmental processes (arborisation and myelination) continue at least through the first two postnatal decades (Catts et al., 2013). In accordance with neurodevelopment, some basic cognitive functions, mostly crystallised skills, typically develop during the early years of postnatal life, and the development of complex executive functions and other fluid skills is the outcome of protracted development well through early adulthood (Levin et al., 1991; Anderson et al., 2001; Brocki and Bohlin, 2004). According to neurodevelopmental theory, cognitive dysfunction in schizophrenia and BP can be better conceptualised as the outcome of aberrant neurodevelopment continuing throughout the first two to three decades of life. The level of severity of underlying neurodevelopmental impairment should be expected to influence the degree of cognitive deficits and the time range when cognitive

dysfunction can be detected with traditional neuropsychological batteries (Bora, 2014b). In individuals who have more severe underlying neurodevelopmental abnormality, cognitive dysfunction would be apparent from early childhood and such individuals would more likely present with intellectual disabilities, borderline intelligence and other developmental syndromes. In most others, premorbid cognitive deficits would be limited to abnormalities in more advanced skills and would become evident later in neurodevelopment. It is also important to note that severity of neurodevelopmental cognitive abnormality is an important determinant of individual's susceptibility to negative effects of aging and medical factors (cognitive reserve) in postonset adult life (please see Bora (2014b) for further discussion).

3.1.

Intellectual disabilities in schizophrenia and BP

Individuals with the most severe developmental abnormalities are likely to have mental retardation. In schizophrenia, there is good evidence suggesting that such abnormalities are present in a subset of patients. Childhood onset intellectual disabilities are overrepresented in schizophrenia samples compared to controls and psychosis is more prevalent than the general population in people with mental retardation (Doody et al., 1998; Morgan et al., 2008). In their population based study, Morgan et al. (2008) estimated the prevalence of intellectual disability in schizophrenia as 4.9%. In the same study, the prevalence of schizophrenia in intellectual disability was 4.4%. In BP, there is less evidence for severe childhood onset neurodevelopmental cognitive deficits. Some studies have not found significantly increased risk for BP in mental retardation (Morgan et al., 2008). However, some other evidence suggests that there might be some association between intellectual disabilities and BP. In a recent study, intellectual disabilities were thrice more common in children of mothers with schizophrenia and BP (Morgan et al., 2012). Of note, in BP, the risk of intellectual disability was significantly increased only if onset of maternal illness predated the index birth, suggesting that non-hereditary factors such as medication use and stress can also contribute to these findings. Also, there is some evidence suggesting an association between intellectual disability and rapid-cycling BP (Vanstraelen and Tyrer, 1999). Evidence suggests that there might be a relationship between BP and less severe forms of developmental abnormalities such as autism spectrum disorders and ADHD (Duffy, 2012; Joshi et al., 2013). Also, some syndromes characterised by intellectual deficits might be associated with not only schizophrenia but also BP (Yang et al., 2013).

3.2. Premorbid cognitive deficits in childhood and adolescence Individuals with less severe developmental abnormalities are expected to present with premorbid cognitive deficits which become evident later in neurodevelopment. The existence of premorbid cognitive deficits in people with schizophrenia (Dickson et al., 2012; Khandaker et al., 2011; Reichenberg et al., 2010; Schulz et al., 2014) is well

Developmental trajectory of cognitive impairment in bipolar disorder: Comparison with schizophrenia established. Premorbid intelligence quotient (IQ) deficits and learning difficulties in childhood and adolescence precede adult schizophrenia. Current evidence suggests that individuals who develop adult schizophrenia exhibit IQ deficit in their childhood (approximately 0.5 standard deviation, 33% non-overlap with controls) (Dickson et al., 2012; Khandaker et al., 2011). Evidence suggesting that premorbid cognitive impairment which precedes BP is more modest. A number of studies have not found any evidence of premorbid cognitive impairment in BP (Cannon et al., 2002; Goldberg et al., 1993; Reichenberg et al., 2002). However, these studies might have inadequate power to detect such abnormalities as the number of subjects who developed BP in most studies was small. Two of three conscript studies (MacCabe et al., 2010; Tiihonen et al., 2005; Zammit et al., 2004) which had at least 100 subjects with BP found a relationship between poor scholar achievement/cognitive function and risk for BP. In a population-based large national study from Sweden (over 700,000 individuals), MacCabe et al. (2010) investigated the relationship between scholastic achievement at age 15–16 and later hospital admissions for BP (280 individuals). The students with the poorest grades had nearly two-fold increased risk for bipolar disorder (Hazard ratio = 1.9). In a large cohort of male subjects conscripted into the Finnish defence forces (nearly 200,000 individuals; mean age=19.9), Tiihonen et al. (2005) investigated the relationship between cognitive assessment and later hospital admission for BP (mean follow-up 7 years; 100 individuals). In this study, cognitive impairment in visuospatial abilities was associated with increase risk for BP at follow-up. Premorbid cognitive deficits in BP might be evident in childhood as well. Seidman et al. (2013) showed that children (mean age = 7) who will develop BP or schizoaffective, bipolar type in adulthood have cognitive deficits. Effect size of this cognitive deficit was d= 0.3 and 23% children had significant neuropsychological impairment. In the same study, effect size for cognitive deficits in the schizophrenia group was moderately larger d= 0.57 and 42% of children had significant neuropsychological impairment.

3.3. Course of premorbid cognitive deficits: Is there a cognitive decline prior to onset of illness? Neurodevelopment is an extended process. Aberrant early neurodevelopment has a negative impact on later phases of cognitive maturation, as more advanced cognitive skills depend on the integrity of basic cognitive processes and the negative impact of many genetic abnormalities does not need to be restricted to early childhood as they do play a role in neurodevelopment throughout the life. Under neurodevelopmental conditions such as schizophrenia, problems in acquisition of cognitive abilities (developmental lag or arrest) during development are expected (Pantelis et al., 2009). Premorbid cognitive abnormalities under neurodevelopmental conditions most likely reach their maximum when cognitive development approaches near completion in adolescence and young adulthood. However, under neurodegenerative conditions, loss in acquired cognitive skills is expected. Therefore, longitudinal studies during

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development are critical to reveal the developmental trajectory and nature of premorbid cognitive deficits in schizophrenia and BP. Number of well-conducted follow-up studies suggested that there are continuing abnormalities in acquisition of cognitive abilities in individuals who will develop schizophrenia in adulthood (MacCabe et al., 2013; Reichenberg et al., 2010). This “relative decline” was a reflection of slower gain (developmental lag or arrest) in schizophrenia patients in comparison to their healthy peers whose cognitive functions continue to develop. There is no consistent evidence for real decline in raw scores, as previous longitudinal studies test at follow-up were age-corrected or included more challenging items (Bora, 2014a). These findings do not support the idea of premorbid cognitive decline in schizophrenia (Bora, 2014b). Unlike schizophrenia, the developmental trajectory of such premorbid abnormalities has not been investigated much in longitudinal studies in BP. However, available evidence suggests that developmental lag is also evident in BP. Two studies (Bombin et al., 2013; Pavuluri et al., 2009) have reported post-onset developmental lag during adolescence in early onset patients with BP.

3.4.

Normal and superior cognitive function in BP

A minority of patients with schizophrenia, and many patients with BP, have normal or supranormal cognitive functioning. Also, most individuals who have neurodevelopmental cognitive deficits would never develop psychosis or mania. Premobid cognitive impairment is neither necessary nor sufficient to develop major psychoses. However, it is clear that premorbid cognitive impairment has a strong association with risk of psychosis. People with above average cognitive abilities are less likely to develop schizophrenia. As discussed above, premorbid cognitive impairment is also (but less strongly) associated with risk for BP. However, the relationship between cognitive development and BP is much more complicated as there is some evidence suggesting that above average cognitive/scholastic abilities are also a risk factor to develop BP. This is an apparent striking difference with schizophrenia. It is important to note that there have been conflicting results in studies investigating the relationship between above average scholar achievement/intellectual abilities and risk for BP (Kumar and Frangou, 2010). After an early observation suggesting an association between better general intellectual function and higher risk for BD (Mason, 1956), a number of subsequent studies with better design found no relationship between premorbid cognition and risk for BP (David et al., 1997; Mortensen et al., 2005; Reichenberg et al., 2002; Zammit et al., 2004). In the Dunedin study, children who developed BP (n=20) in adulthood had no cognitive impairment (Cannon et al., 2002). In a subsequent analysis of the Dunedin study at age 32, higher childhood IQ predicted increased risk of mania (Koenen et al., 2009); however the number of patients with BP was very small in this report (n=8). However, two large conscript studies provided good evidence for association between above average premorbid cognition and risk for BP and both premorbid poor and

164 superior cognitive abilities and scholastic achievement. Tiihonen et al. (2005) clearly showed that highest performance in arithmetic abilities was associated with significantly increased risk for BP. MacCabe et al. (2010) reported the students with the best grades had nearly four-fold increased risk for BP (Hazard ratio = 3.8). Interestingly, as discussed above, both these studies also provided evidence for association between premorbid cognitive impairment and risk for BP. Overall these findings suggest an inverted U shaped relationship between premorbid cognitive impairment and risk for BP in which both poor and good premorbid cognitive/scholar functioning predict BP in adulthood.

4. A proposal to explain the dual nature of association between cognitive functioning and risk for BP Molecular genetic and family studies showed evidence that schizophrenia and BP partly share a common genetic cause. In a very large population-based study in Swedish families, Lichtenstein et al. (2009) found that first-degree relatives of probands with either schizophrenia or BP were at increased risk of both these disorders. Genetic studies suggested that there are susceptibility genes common to both disorders. It is important to note that familial and genetic studies also suggest that there is also schizophrenia and BP specific genetic susceptibility. Evidence has also suggested that candidate-shared susceptibility genes can impair neurodevelopment and cognition (Hall et al., 2006; Singh et al., 2011). These findings suggest that there is a large subgroup of schizophrenia and BP patients associated with genetic risk factors that are common to both disorders and expected to have neurodevelopmental abnormalities. These patients are likely to present with a mixture of affective and psychotic symptoms (mixed psychoses) and some would be diagnosed with BP (with psychotic features). Others would meet the diagnostic criteria of schizoaffective disorder (mostly bipolar type), schizophrenia (and co-morbid manic symptoms, BP NOS). Therefore, it can be hypothesised that robust neurodevelopmental abnormalities are evident only in BP patients within the mixed psychosis group who also have genetic risk to schizophrenia. Studies investigating the effect of personal or familial history of psychosis on cognitive impairment in BP have provided partial support to this theory. These studies generally have found a significant but modest relationship between cognitive impairment and history of psychosis (during mood episodes or in family members) (Bora et al., 2010b, 2008b; Martínez-Arán et al., 2008; Tabarés-Seisdedos et al., 2003). However, it is unlikely that the sole presence of a history of psychosis will serve as a robust marker of the shared neurobiological risk factors of schizophrenia and BP. The familial overlap rate of schizophrenia and bipolar disorder is much lower than the prevalence of the history of psychosis in bipolar I (approximately 2/3 of the patients had at least one single episode with psychotic features). It can be hypothesised that only a subgroup of psychotic BP cases lies in a continuum with schizophrenia and that the content (i.e. Schneiderian symptoms, paranoid delusions, mood incongruent delusions, and hallucinations) and nature (i.e. temporal

E. Bora relationship with mood symptoms), of psychotic symptoms, rather than their mere presence, might be important clinical markers of genetic susceptibility for mixed psychoses (Bora et al., 2008a; Bora and Berk, 2011). Effects of such characteristics on cognitive impairment in BP have been very rarely investigated. However, based on few available studies, it can be argued that the presence of subtle psychotic symptoms before the onset of affective disorder is associated with significant cognitive impairment in BP. Attenuated psychotic symptoms before the onset of firstepisode mania and high schizotypy scores in BP were reported to be associated with cognitive impairment in BP (Hori et al., 2012; Olvet et al., 2010; Ratheesh et al., 2013; Savitz et al., 2009). Importantly, one of these studies compared premorbid cognitive impairments in clinical high-risk individuals (i.e. presenting with attenuated psychotic symptoms) who will develop BP or schizophrenia, and found no between-group differences (Olvet et al., 2010). As discussed in the introduction, there is evidence suggesting that other neurodevelopmental markers of schizophrenia such as obstetric complications, soft signs, and minor physical anomalies can be evident in some patients with BP. Studies investigating the relationship between these markers, cognitive deficits and shared genetic susceptibility to schizophrenia in BP can further test the proposed model. On the contrary, many BP patients have no neurodevelopmental cognitive abnormalities; proposed model suggests that BP in these patients is associated with only mood disorder specific genetic susceptibility factors. It can be hypothesised that a subgroup of these BP patients would outperform many healthy controls in scholar achievement thanks to the advantage of some temperamental characteristics related to BP (i.e. goal directed, positive, approach). A combination of such temperamental characteristics and the absence of neurodevelopmental cognitive deficits can explain the association between artistic/scientific achievement and creativity and bipolar diathesis (Andreasen, 1987; Kyaga et al., 2011).

5.

Conclusion

The relationship between premorbid cognitive impairment and BP, as defined in current classification systems, is a complex one. On the one hand, neurodevelopmental abnormalities partly separate BP from schizophrenia. Many BP patients have no shared neurodevelopmental abnormality with schizophrenia. These patients have no premorbid cognitive deficits and they can function at supranormal level more often than healthy controls due to the positive effects of temperamental characteristics seen in BP. On the other hand, premorbid cognitive impairment is not specific to schizophrenia. Available evidence suggests that developmental trajectories of cognitive deficits in many other BP patients are similar to schizophrenia. Current evidence also suggests that premorbid cognitive deficits in these patients are the result of problems in acquisition of cognitive abilities rather than cognitive decline. The model proposed in this paper suggests that developmental lag in acquisition of cognitive abilities is not only a robust risk factor for schizophrenia but also for “mixed psychoses” that are diagnosed as BP and schizoaffective

Developmental trajectory of cognitive impairment in bipolar disorder: Comparison with schizophrenia disorder in current diagnostic systems. These BP patients share genetic risk factors with schizophrenia and are more likely to present with schizophreniform psychotic symptoms in addition to mood symptoms. A combination of the absence of neurodevelopmental abnormalities and positive temperamental characteristics increases the likelihood of supranormal scholar, cognitive and artistic skill in other patients with BP.

Role of funding source No funding source is involved in preparation of the paper.

Contributors N/A.

Conflict of interest I have no conflict of interests to declare.

Acknowledgements None.

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Developmental trajectory of cognitive impairment in bipolar disorder: comparison with schizophrenia.

Both schizophrenia and bipolar disorder (BP) are associated with neurocognitive deficits. However, it has been suggested that schizophrenia, but not B...
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