INTRODUCTION

Cognitive dysfunctions can be seen at any stage of bipolar disorder (BD) (1-3), however become more evident at acute mood episodes (2,4-7). Emil Kraepelin said that there is improvement between the acute episodes and cognitive losses recover with clinical remission. In the last 20 years, new evidence cumulated that cognitive losses can also be detected in clinical remission (euthymia) periods (6,8). In this context, cognitive dysfunction cannot be entirely explained by the mood changes. Likewise, in a meta-analysis of studies which cognitive functions were evaluated in euthymic phase, most evident dysfunctions were found in executive and in verbal learning areas. However, areas like verbal memory, abstract thinking, attention processing, response inhibition and psychomotor speed were also found defective (9). In another meta-analysis, moderate dysfunction was found in verbal memory, attention, processing speed and executive function (10). In the meta-analysis of Arts et al. (11), which of these dysfunctions can be a candidate endophenotype was investigated. Verbal memory and executive dysfunction can be detected in milder forms in the families so that these were the best candidate endophenotypes . In their 2-years follow-up study, Mur et al. (12) found that neurocognitive test performance of euthymic bipolar patients were found to be lower compared to healthy volunteers (Table 1).

Current neuroscience models propose that cognitive processes are managed by neuronal networks scattered to various brain regions rather than a single brain region (13). In these networks, most popular approach was regional specialization in these networks, i.e. different levels of responsibility of different regions in data processing (14). According to this theory, specific brain regions (15) and even specific neuron groups (16, 17) may be related with a distinct cognitive process. Sub-cognitive domains which became foremost in current studies are executive functions, working memory, verbal learning, verbal memory, attention, vigilance and process speed.

Main Sub-Cognitive Domains in Bipolar Disorder

1. Executive Functions

Wisconsin card sorting test, block design, London tower test, verbal and non-verbal problem solving tasks, Stroop test, trail making tests, verbal fluency and figure fluency tests and various gambling tasks are some of the tests utilized for testing executive function. Problem solving and reasoning are also considered as executive function and (based on factor analysis) it was suggested that they can help to seperate working memory from executive functions (28). Studies which executive functions of bipolar patients were investigated was shown in Table 2.

Inconsistency of the findings was interpreted as not all but part of the executive functions were disturbed. Perseverative errors in Wisconsin card sorting test may be considered as reduced cognitive flexibility (6,22,30). Wisconsin card sorting test performance was disturbed before disease started in the high risk group of children (31). However, number of episodes (22) and duration of illness (6) also found to affect test performance.

2. Working Memory

Working memory can be defined as required and temporary storage possibilities, which are needed to increase the neuronal response between the real event and its mental representation. It builds the infrastructure of “higher” cognitive processes like judgement, planning, language and abstract thinking (32,33). Baddeley (34,35) suggested an organization for working memory having 3 components: Central executive component (provides the distribution of information retrieved in memory to the final process regions) and two slave systems, articulating cycle and visual-spatial note book (they provide maintenance of the mental representation of verbal and visual information). Rubinsztein et al. (24) found that euthymic patients poorly performed in remembering the geometric shapes and spatial locations in CANTAB computerized cognitive test battery. Thompson et al. (25) found deficits in spatial memory and disorder in relevant learning (episodical memory) with the same battery. Findings about the visual spatial memory are contradictory. Rubinsztein et al. (24) reported that there is a relationship between visual working memory and hospital days. Thompson et al. (25) found a relationship between total hospitalization numbers and spatial working memory. Similarly, Frangou et al. (29) reported that increased duration of illness also affects executive functions, however, there are also opposite data (36,37).

3. Verbal Learning and Memory

Most consistent findings about the cognitive deficits in bipolar disorder are the ones from the verbal memory tests (4,6,20,21,37-43). First degree relatives who were not affected by the disease were also performed badly at verbal memory tests (44,45). Executive functions are directly related to learning and memory problems and learning and memory problems in bipolar disorder can be related with this. Deckersbach et al. tested this (41) and concluded that impairment can be related with semantic clustering. However, in another study it was concluded that problem in the learning strategy can be related with coding (38). Bipolar patients performed badly in episodic memory tests in the acute episodes (46,47). Martinez-Arán et al. (48) suggested that delayed verbal recall is the best cognitive criterium to predict psychosocial functionality in the global evaluation of functionality. In the same study, verbal cognitive deterioration in areas like memory and executive functions are related with lower functionality.

4. Attention and Vigilance

Stroop, Dichotic Listening, Continous Performance Test (CPT) and SPAN are tests which can be used to investigate attention processes. It can easily be observed in routine clinical settings that bipolar patients can not concentrate for longer time periods and their attention can easily be reduced. There is a substantial number of studies showing that manic symptoms can affect Continous Performance Test (CPT) (49-55). Clark ve Goodwin (51) reported that manic patients make errors at discriminating target impulses at CPT and false alarms began to increase; however, euthymic bipolar patients make errors only at discriminating target impulses. This test was utilized in the studies published by other groups and similar results were reported (39, 51, 56). There are studies which showed that duration of illness and severity are inversely correlated with attention processes (51, 57, 58) and there are also studies which could not concluded at the same results (59). Reasons for these confusing results may be due to attention process deficits starting with or before the disease in a small proportion of patients.

5. Process Speed

Digit-symbol exchange, Trail Making and Stroop are among tests which can used for measuring process speed. If process speed is a parameter as the consequence of different brain regions working in coordination then cognitive slowing can be an important criterium for evaluating neuronal competence. Digit-symbol exchange (25) and trail making tests A and B (18, 27, 60) were found to be defective in euthymic patients. Cognitive slowing was found in bipolar disorder, depression (46, 61), hypomania and mania (39, 46, 61, 62). There are studies which found correlation between process speed (6, 25) and duration of illness (27). Clark et al. (8) found that process speed slows in patients who do not take medication (n=11) and for this reason suggested that reduction in process speed is not related with treatment in their small size study.

Relationship between Clinical Factors and Cognitive Functions

There is evidence showing cognitive deficits affect functionality more than sub-syndromal symptoms (6, 48). It was showed that number of previous episodes (especially mania), number of hospitalizations, presence of psychotic symptoms and total duration of illness affects cognitive functions (memory, attention, abstraction etc.) negatively (6, 22, 63). In a study done in early-onset bipolar patients, even though short time passed between illness onset and evaluation and not too many mood periods have been experienced, deficits detected in adults are also present in childhood bipolar disorder (64). Bora et al. (65) reviewed 45 studies and reported a correlation between age of onset and verbal memory deficit and psychomotor slowing. Joseph et al. (66) reviewed studies on cognitive functions in childhood bipolar disorders and reported that most consistent findings were at verbal memory, attention, executive functions and working memory like in adults. Martino et al. (67) compared 20 elderly euthymic patients whom have mean 28 years disease duration with age, gender, education and premorbid IQ matched 20 healthy volunteers. Significant differences were found in sub-tests in verbal memory, psychomotor speed and executive functions and results were not reported different from the young population. These findings are consistent with Young et al. (68).

Torrent et al. (69) investigated the presence of cognitive deficits in type II bipolar disorder. Cognitive deficits mainly in verbal learning and executive functions were found in type II which is less severe than type I. Authors noted this does not mean that type II disorder is not a milder disease.

In the study of Glahn et al. (36) done in euthymic and symptomatic mixed patient groups, presence of previous psychotic episodes found to negatively affect cognitive functions (working memory). Bora et al. (70) showed the relationship between the history of psychotic episode and memory and cognitive flexibility impairment in their relatively big sample and totally composed of euthymic patients.

In a study which investigated the impact of gender on cognitive functions in bipolar disorder, performance of male patients were found to be worse than female ones (46). There are few studies on the impact of comorbidity on cognitive dysfunction in bipolar disorder. Van Gorp et al. (71) reported that executive functions of the alcohol addicts were impaired compared to healthy controls. Impact of comorbid disorders (as attention deficit hyperactivity disorder, substance and alcohol addiction, anxiety disorders) with bipolar disorder on the cognitive deficits are subjects waiting to be evaluated.

Effects of Medications on Cognitive Functions

It was previously thought that mood stabilizers do not have any significant effect on cognitive performance (72). However, in the meta-analysis of Wingo et al. (73) which 12 studies in the literature were analysed, 276 lithium using and 263 non-lithium using patients were compared and it was found that verbal memory and verbal learning have been negatively affected in the lithium group. In a recent study, cognitive performances of 20 lithium-using, 20 non-lithium using and 20 healthy volunteers were compared (74). Verbal memory performances of all bipolar patients were found worse than healthy volunteers regardless of medication use. No difference was found between the medication using and non-using groups and this interpreted as lithium not negatively affecting cognitive functions. Rybakowski et al. (75) grouped patients as good responders (n=12), partly responders (n=26) and non-responders to lithium and compared them with patients’ first degree relatives and healthy volunteers. Non-responders to lithium performed worse in Wisconsin card sorting test compared to good responders, first degree relatives performed worse than healthy controls. In the meta-analysis of Wingo et al. patients were divided into two groups: lithium using and non-lithium using. It can be observed that non-lithium using patients were not without treatment. Şentürk et al. (76) compared verbal memory and executive functions of patients using lithium as monotherapy (n=17) and valproate as monotherapy (n=11) with healthy volunteers (n=29) by using Wechsler Memory Scale and Wisconsin card sorting test and found that performance of lithium and valproate groups were similar but both of their performance were lower than healthy controls. In the comprehensive review of Bora et al. (65), it was reported that medications are related with psychomotor slowing.

Information on the effects of first generation antipsychotics and benzodiazepines are based on clinical observations. In bipolar disorder which chronobiology is importantComparative studies needed considering the impact of treatment on cognitive functions. However, there are some ethical obstacles. In a recent review by Balanzá-Martinez et al. (77) a novel method was proposed by having medication sensitive patients investigated to obtain important data.

Difficulties of investigating the relatiosnship between medications and cognitive disorders can be listed as follows: There is a substantial amount of variation related with dose and type of treatment. Polypharmacy became like a rule rather than an exception in bipolar disorder. Data from medication-free or monotherahy subgroups of milder patients - should not be adjusted to the universe of more severe patients. Another methodological problem is successive accumulation of neurocognitive side effects of treatments or contribution of neurotoxicity of drug interactions from combination treatments to cognitive deficits and the impossibility of examining this currently. On the other hand Goldberg and Chengappa (78) proposed that cognitive dysfunction can be part of the disease or of iatrogenic origin.

A Candidate Endophenotype: Cognitive Loss

There is robust evidence from twin, adoption and family studies which shows that bipolar disorder has a strong genetic component and heritability of bipolar disorder was found 80% (79). However, due to its complex, polygenic nature and partial penetrance, its genetic inheritance has not been fully explained (80,81).

It was suggested that endophenotypes which mean endophenotypes are better indicators of genetic tendency. Gottesman ve Gould (82) proposed some criteria for symptoms and signs which can be suggested as endophenotypes. Two important criteria were added due to their relevance with the disease, heritability and co-segregating in families which the disease is clustered:

I. It should be independent from the clinical condition and can also be shown in clinically improved patients;

II. It should be observed in relatives whom were not affected compared to general population.

Determining endophenotypes is important due to following reasons:

i. They may make the genetic linkage stuides easier and accelerate them;

ii. They may make it possible to predict which individulas will develop bipolar disorder in the future;

iii. They may provide early diagnosis and intervention possibilities;

iv. They may be utilized to develop sub-types.

There are several convincing studies showing that cognitive dysfunctions are strong endophenotype candidates in schizophrenia (83-85). However, there is not enough evidence for bipolar disorder yet. In their recent publication of Bora et al. (65), they reviewed researches which evaluated euthymic patients (45 studies and 1423 patients) and their first-degree relatives (17 studies, 443 participants). It was reported that attention deficit, response inhibition, executive functions and verbal memory deficits were observed both in patients (medium-to-high impact magnitude) and relatives (small-to-medium impact magnitude), deterioration in process speed, visual memory and verbal fluency were only observed in patients.

Cognitive deficits in first-degree relatives whom were not affected by the disease suggest possible neurodevelopmental processes of genetic origin. Several studies were done in first-degree relatives of two-sided probands but inconsistent results were obtained (39,44,86). However, in a meta-analysis, statistically significant deficits with a medium-impact factor (Cohen’s db: 0.5) in executive functions and verbal memory were found (11). In their systematic review, Balanzá-Martínez et al. (87) found deficits in sub-cognitive domains of verbal learning and memory (6 out of 11 studies), working memory (3 out of 9 studies), psychomotor speed (2 out of 8 studies) and attention (2 put of 8 studies) and they concluded that there is not adequate data. Frantom et al. (88) reported that tests which are most sensitive to cognitive endophenotypes were digit-symbol and block design tests.

Relatively limited losses in patients’ relatives suggest that cognitive deficits seen in patients may be due to disease-related factors such as chronic course of the disease, mood episodes, side effects of the treatment and psychiatric comorbidity (89) and this shows that neurodevelopmental process has a little role in the etiopathogenesis of cognitive deficits.

There are several studies done with the relatives of the bipolar type I patients. There are few studies done with the relatives of the bipolar type II patients and when compared with the relatives of the type I bipolar patients, similar but less severe cognitive deficits were reported (44, 90, 91). This finding is in concordance with the presence of less severe cognitive deficits in type II bipolar patients compared to type I patients (69,92).

Determining endophenotypes is possible with combining information from research areas such as cognitive, neuroimaging and genetics (93-95). Tests which are sensitive to learning, memory and executive functions are similar from test functions point of view (93). Verbal learning, memory and working memory are processed in pre- and medial frontal areas and these regions are in close relation with bipolar pathophysiology (96, 97). Similar changes observed in non-affected relatives of patients (94, 95) show that there may be a tendency to emotional and cognitive disorders. Decrease in volume of white and grey matters of ventral striatum and anterior cingulate cortex were observed in patients’ relatives (98). Changes in the prefrontal cortex of patients which are independent of mood is thought to be an indicator of the sensitivity to continous pathology (99).

It has been suggested that cognitive impairment may be familial or has genetic origin (100). Cognitive losses may be due to genetic and environmental factors of various degrees. Familial similarity of cognitive loss may be an inheritance indicator of cognitive functions (101) and because of this; genetic should be considered in designing research. Heritability has been shown in some cognitive deficits (56,102) but has not been evaluated in bipolar disorder in detail(103). Investigating cognitive functions in families with bipolar patients by genetic transference methods is important to test whether cognitive functions can be endophenotypes or not.

CONCLUSION

Executive dysfunction is generally not fulminant in bipolar disorder and different functions were affected with various severity. However, determining the degree of impairment in different executive functions can be done by developing current tests, studies done with bigger samples and investigating the underlying neuroanatomy. Dysfunction of tracts between prefrontal areas and other brain regions can explain both executive dysfunctions and affective findings such as disinhibition, impulsivity and attention deficit.

The type and degree of cognitive impairment affected by mood episodes, what extent can this impairment be explained by the mood, , impact of the course of disease on cognitive functions, contribution of comorbidity and lastly the cognitive effects of the medications used are main topics that should comprehensively evaluated.

By the demonstration of functionality affected more by cognitive deficits than sub-threshold symptoms and signs, there is now a new symptom domain in bipolar disorder and therefore cognitive deficits should be added to therapeutic targets. Treatments with cholinergic, dopaminergic and glutamatergic properties may be efficacious as cognitive enhancing strategies. However, when developmental and structural impairment is considered, medications used to improve cognitive deficits in bipolar disorder can be of limited value.

According to current data, verbal learning, verbal memory and working memory are the most appropriate cognitive functions to be endophenotypical indicators. In order current data to reach adequate value of evidence, there is a need for longitudinal follow-up studies with greater samples. Evaluation of stability of deficits in patients’ relatives can be provided by longitudinal follow-up studies. Cognitive domains such as language, social cognition, planning and motor skills should also be investigated.

 REFERENCES

1. Bearden CE, Hoffman KM, Cannon TD. The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review. Bipolar Disord 2001; 3:106-150.

2. Quraishi S, Frangou S. Neuropsychology of bipolar disorder: a review. J Affect Disord 2002; 72:209–226.

3. Savitz J, Solms M, Ramesar R. Neuropsycholgical dysfunction in bipolar affective disorder: a critical opinion. Bipolar Disord 2005; 7:216-235.

4. Basso MR, Lowery N, Neel J, Purdie R, Bornstein RA. Neuropsychological impairment among manic, depressed, and mixed-episode inpatients with bipolar disorder. Neuropsychology 2002; 16:84–91.

5. Malhi GS, Lagopoulos J, Owen AM, Ivanovski B, Shnier R, Sachdev P. Reduced activation to implicit affect induction in euthymic bipolar patients: an fMRI study. J Affect Disord 2007; 97:109-122.

6. Martinez-Arán A, Vieta E, Reinares M, Colom F, Torrent C, Sánchez-Moreno J, Benabarre A, Goikolea JM, Comes M, Salamero M. Cognitive function across manic or hypomanic,depressed, and euthymic states in bipolar disorder. Am J Psychiatry 2004; 161:262-270.

7. Murphy FC, Sahakian BJ. Neuropsychology of bipolar disorder. Br J Psychiatry 2001; 178 (Suppl.41):120-127.

8. Clark L, Iversen SD, Goodwin GM. Sustained attention deficit in bipolar disorder. Br J Psychiatry 2002; 180:313-319.

9. Robinson LJ, Thompson JM, Gallagher P, Goswami U, Young AH, Ferrier IN, Moore PB. A metaanalysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord 2006; 93:105-115.

10. Torres IJ, Boudreau VG, Yatham LN. Neuropsychological functioning in euthymic bipolar disorder: a meta-analysis. Acta Psychiatr Scand Suppl 2007; 434:17-26.

11. Arts B, Jabben N, Krabbendam L, van Os J. Meta-analyses of cognitive functioning in euthymic bipolar patients and their first-degree relatives. Psychol Med 2008; 38:771-785.

12. Mur M, Portella MJ, Martinez-Arán A, Pifarré J, Vieta E. Neuropsychological profile in bipolar disorder: a preliminary study of monotherapy lithium-treated euthmic bipolar patients evaluated at a 2-year interval. Acta Psychiatr Scand 2008; 118:373-381.

13. Mesulam MM. From sensation to cognition. Brain 1998; 121:1013-1052.

14. O’Reilly RC, Braver TS, Cohen JD. A biologically based computational model of working memory: In Miyake A, Shah P (editors). Models of working memory: Mechanisms of active maintenance and executive control. NY, USA: Cambridge University Press, 1999, 375–411.

15. Price CJ, Friston KJ. Degeneracy and cognitive anatomy. Trends Cogn Sci 2002; 6:416–421.

16. Miller EK. The prefrontal cortex: complex neural properties for complex behavior. Neuron 1999; 22:15–17.

17. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001; 24:167–202.

18. Ferrier IN, Stanton BR, Kelly TP, Scott J. Neuropsychological function in euthymic patients with bipolar disorder. Br J Psychiatry 1999; 175:246–251.

19. El-Badri SM, Ashton CH, Moore PB, Marsh VR, Ferrier IN. Electrophysiological and cognitive function in young euthymic patients with bipolar affective disorder. Bipolar Disord 2001; 3:79–87.

20. van Gorp WG, Altshuler L, Theberge DC, Mintz J. Declarative and procedural memory in bipolar disorder. Biol Psychiatry 1999; 46:525–531.

21. Altshuler LL, Ventura J, van Gorp WG, Green MF, Theberge DC, Mintz J. Neurocognitive function in clinically stable men with bipolar I disorder or schizophrenia and normal control subjects. Biol Psychiatry 2004; 56:560-569.

22. Zubieta JK, Huguelet P, O’Neil RL, Giordani BJ. Cognitive function in euthymic bipolar I disorder. Psychiatry Res 2001; 102:9–20.

23. Wilder-Willis KE, Sax KW, Rosenberg HL, Fleck DE, Shear PK, Strakowski SM. Persistent attentional dysfunction in remitted bipolar disorder. Bipolar Disord 2001; 3:58–62.

24. Rubinsztein JS, Michael A, Paykel ES, Sahakian BJ. Cognitive impairment in remission in bipolar affective disorder. Psychol Med 2000; 30:1025–1036.

25. Thompson JM, Gallagher P, Hughes JH, Watson S, Gray JM, Ferrier IN, Young AH. Neurocognitive impairment in euthymic patients with bipolar affective disorder. Br J Psychiatry 2005; 186:32–40.

26. Scott J, Stanton B, Garland A, Ferrier IN. Cognitive vulnerability in patients with bipolar disorder. Psychol Med 2000; 30:467-472.

27. Tham A, Engelbrektson K, Mathe AA, Johnson L, Olsson E, Aberg-Wistedt A. Impaired neuropsychological performance in euthymic patients with recurring mood disorders. J Clin Psychiatry 1997; 58:26–29.

28. Baddeley A. The central executive: a concept and some misconceptions. J Int Neuropsychol Soc 1998; 4:523–526.

29. Frangou S, Haldane M, Roddy D, Kumari V. Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder. Biol Psychiatry 2005; 58:838–839.

30. Sapin LR, Berrettini WH, Nurnberger JI Jr, Rothblat LA. Mediational factors underlying cognitive changes and laterality in affective illness. Biol Psychiatry 1987; 22:979–986.

31. Meyer SE, Carlson GA, Wiggs EA, Martinez PE, ROnsaville DS, Klimes-Dougan B, Gold PW, Radke-Yarrow M. A prospective study of the association among impaired executive functioning, childhood attentional problems, and the development of bipolar disorder. Dev Psychopathol 2004; 16:461–476.

32. Fuster JM. Memory in the cerebral cortex: An empirical approach to neural networks in the human and nonhuman primate. Cambridge, MA, USA: The Mit Press, 1995.

33. Ericsson KA, Delaney PF. Long-term working memory as an alternative to capacity models of working memory in everyday skilled performance: In Miyake A, Shah P (editors). Models of working memory: Mechanisms of activemaintenance and executive control. NY, USA: Cambridge University Press, 1999, 257–297.

34. Baddeley A. Working memory. Science 1992; 255:556–559.

35. Baddeley A. The fractionation of working memory. Proc Natl Acad Sci USA 1996; 93:13468–13472.

36. Glahn DC, Bearden CE, Cakir S, Barret JA, Najt P, Serap Monkul E, Maples N, Velligan DI, Soares JC. Differential working memory impairment in bipolar disorder and schizophrenia: effects of lifetime history of psychosis. Bipolar Disord 2006; 8:117–123.

37. Donaldson S, Goldstein LH, Landau S, Raymont V, Frangou S. The Maudsley Bipolar Disorder Project: the effect of medication, family history, and duration of illness on IQ and memory in bipolar I disorder. J Clin Psychiatry 2003; 64:86–93.

38. Bearden CE, Glahn DC, Monkul ES, Barret J, Najt P, Kaur S, Sanches M, Villareal V, Bowden C, Soares JC. Sources of declarative memory impairment in bipolar disorder: Mnemonic processes and clinical features. J Psychiatr Res 2005; 40:47-58.

39. Clark L, Iversen SD, Goodwin GM. A neuropsychological investigation of prefrontal cortex involvement in acute mania. Am J Psychiatry 2001; 158:1605–1611.

40. Cavanagh JT, Van Beck M, Muir W, Blackwood DH. Case-control study of neurocognitive function in euthymic patients with bipolar disorder: an association with mania. Br J Psychiatry 2002; 180:320–326.

41. Deckersbach T, Savage CR, Reilly-Harrington N, Clark L, Sachs G, Rauch SL. Episodic memory impairment in bipolar disorder and obsessive-compulsive disorder: the role of memory strategies. Bipolar Disord 2004; 6:233–244.

42. Fleck DE, Shear PK, Zimmerman ME, Getz GE, Corey KB, Jak A, Lebowitz BK, Strakowski SM. Verbal memory in mania: effects of clinical state and task requirements. Bipolar Disord 2003; 5:375–380.

43. van Gorp WG, Altshuler L, Theberge DC, Wilkins J, DixonW. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Arch Gen Psychiatry 1998; 55:41–46.

44. Ferrier IN, Chowdhury R, Thompson JM, Watson S, Young AH. Neurocognitive function in unaffected first-degree relatives of patients with bipolar disorder: a preliminary report. Bipolar Disord 2004; 6:319–322.

45. Keri S, Kelemen O, Benedek G, Janka Z. Different trait markers for schizophrenia and bipolar disorder: a neurocognitive approach. Psychol Med 2001; 31:915–922.

46. Sweeney JA, Kmiec JA, Kupfer DJ. Neuropsychologic impairments in bipolar and unipolar mood disorders on the CANTAB neurocognitive battery. Biol Psychiatry 2000; 48:674–685.

47. Henry GM, Weingartner H, Murphy DL. Influence of affective states and psychoactive drugs on verbal learning and memory. Am J Psychiatry 1973; 130:966–971.

48. Martinez-Arán A, Vieta E, Torrent C, Sanchez-Moreno J, Goikolea JM, Salamero M, Malhi GS, Gonzalez-Pinto A, Daban C, Alvarez-Grandi S, Fountoulakis K, Kaprinis G, Tabares-Seisdedos R, Ayuso-Mateos JL. Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord 2007; 9:103-113.

49. Liu SK, Chiu CH, Chang CJ, Hwang TJ, Hwu HG, Chen WJ. Deficits in sustained attention in schizophrenia and affective disorders: stable versus state-dependent markers. Am J Psychiatry 2002; 159:975–982.

50. Addington J, Addington D. Attentional vulnerability indicators in schizophrenia and bipolar disorder. Schizophr Res 1997; 23:197–204.

51. Clark L, Goodwin GM. State- and trait-related deficits in sustained attention in bipolar disorder. Eur Arch Psychiatry Clin Neurosci 2004; 254:61–68.

52. Fleck DE, Sax KW, Strakowski SM. Reaction time measures of sustained attention differentiate bipolar disorder from schizophrenia. Schizophr Res 2001; 52:251–259.

53. Neuchterlein KH, Dawson ME, Ventura J, Miklowitz D, Konishi G. Information-processing anomalies in the early course of schizophrenia and bipolar disorder. Schizophr Res 1991; 5:195–196.

54. Sax KW, Strakowski SM, Keck PE Jr., McElroy SL, West SA, Stanton PA. Symptom correlates of attentional improvement following hospitalization for a first episode of affective psychosis. Biol Psychiatry 1998; 44:784–786.

55. Sax KW, Strakowski SM, Zimmerman ME, DelBello MP, Keck PE Jr, Hawkins JM. Frontosubcortical neuroanatomy and the continuous performance test in mania. Am J Psychiatry 1999; 156:139–141.

56. Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord 2004; 6:171-182.

57. Denicoff KD, Ali SO, Mirsky AF, et al. Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder. J Affect Disord 1999; 56:67–73.

58. Frangou S, Donaldson S, Hadjulis M, Landau S, Goldstein LH. The Maudsley Bipolar Disorder Project: executive dysfunction in bipolar disorder I and its clinical correlates. Biol Psychiatry 2005; 58:859–864.

59. Najt P, Glahn D, Bearden CE , Hatch JP, Monkul ES, Kaur S, Villarreal V, Bowden C, Soares JC. Attention deficits in bipolar disorder: a comparison based on the Continuous Performance Test. Neurosci Lett 2005; 379:22–126.

60. Hawkins KA, Hoffman RE, Quinlan DM, Rakfeldt J, Docherty NM, Sledge WH. Cognition, negative symptoms, and diagnosis: a comparison of schizophrenic, bipolar, and control samples. J Neuropsychiatry Clin Neurosci 1997; 9:81–89.

61. Murphy FC, Rubinsztein JS, Michael A, Rogers RD, Robbins TW, Paykel ES, Sahakian BJ. Decision-making cognition in mania and depression. Psychol Med 2001; 31:679–693.

62. Martinez-Aran A, Vieta E, Colom F, Reinares M, Benabarre A, Torrent C, Goikolea JM, Corbella B, Sánchez-Moreno J, Salamero M. Neuropsychological performance in depressed and euthymic bipolar patients. Neuropsychobiology 2002; 46 (Suppl.1):16–21.

63. McKay AP, Tarbuck AF, Shapleske J, McKenna PJ. Neuropsychological function in manic-depressive psychosis. Evidence for persistent deficits in patients with chronic, severe illness. Br J Psychiatry 1995;167:51-57

64. Doyle AE, Wilens TE, Kwon A, Seidman LJ, Faraone SV, Fried R, Swezey A, Snyder L, Biederman J. Neuropsychological functioning in youth with bipolar disorder. Biol Psychiatry 2005; 58: 540-548.

65. Bora E, Yücel M, Pantelis C. Cognitive endophenotypes of bipolar disorder: A meta-analysis of neuropsychological deficits in euthymic patients and their first-degree relatives. J Affect Disord 2009; 113:1–20.

66. Joseph MF, Frazier TW, Youngstrom EA, Soares JC. A quantitative and qualitative review of neurocognitive performance in pediatric bipolar disorder. J Child Adelosc Psychopharmacol 2008; 18:595-605.

67. Martino DJ, Igoa A, Marengo E, Scápola M, Ais ED, Strejilevich SA. Cognitive and motor features in elderly people with bipolar disorder. J Affect Disord 2008; 105:291-295.

68. Young RC, Murphy CF, Heo M, Schulberg HC, Alexopoulos GS. Cognitive impairment in bipolar disorder in oldu age: literature review and findings in manic patients. J Affect Disord 2006; 92:125-131.

69. Torrent C, Martinez-Arán A, Daban C, Sánchez-Moreno J, Comes M, Goikolea JM, Salamero M, Vieta E. Cognitive impairment in bipolar II disorder. Br J Psychiatry 2006; 189:254-259.

70. Bora E, Vahip S, Akdeniz F, Gonul AS, Eryavuz A, Ogut M, Alkan M. The effect of previous psychotic mood episodes on cognitive impairment in euthymic bipolar patients. Bipolar Disord 2007; 9:468-477.

71. Van Gorp WG, Altshuler L, Theberge DC, Wilkins J, DixonW. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence. A preliminary study. Arch Gen Psychiatry 1998; 55:41–46.

72. Joffe RT, MacDonald C, Kutcher SP. Lack of differential cognitive effects of lithium and carbamazepine in bipolar affective disoder. J Clin Psychopharmacol 1988; 8:425-428.

73. Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry 2009; 70:1588-1597.

74. López-Jaramillo C, Lopera-Vásquez J, Ospina-Duque J, Gallo A, Cortez V, Palacio C, Torrent C Martinez-Arán A, Vieta E. Lithium treatment effects on the neuropsychological functioning of patients with bipolar I disorder. J Clin Psychiatry 2010 (in press)

75. Rybakowski JK, Permoda-Osip A, Borkowska A. Response to prophylactic lithium in bipolar disorder may be associated with a preservation of executive cognitive functions. Eur Neuropsychopharmacol 2009; 19:791-795.

76. Senturk V, Goker C, Bilgic A, Olmez S, Tugcu H, Oncu B, Atbasoglu EC. Impaired verbal memory and otherwise spared cognition in remitted bipolar patients on monotherapy with lithium or valproate. Bipolar Disord 2007: 9 (Suppl.1):136–144.

77. Balanzá-Martinez V, Selva G, Martinez-Arán A, Prickaerts J, Salazar J, González-Pinto A, Vieta E, Tabarés-Seisdedos R. Neurocognition in bipolar disorders—A closer look at comorbidities and medications. Eur J Pharmacol 2010; 626:87-96.

78. Goldberg JF, Chengappa KN. Identifying and treating cognitive impairement in bipolar disorder. Biplar Disord 2009; 11 (Suppl.2):123-137.

79. Cardno AG, Marshall EJ, Coid B, Macdonald AM, Ribchester TR, Davies NJ, Venturi P, Jones LA, Lewis SW, Sham PC, Gottesman II, Farmer AE, McGuffin P, Reveley AM, Murray RM. Heritability estimates for psychotic disorders: the Maudsley twin psychosis series. Arch Gen Psychiatry 1999; 56:162–168.

80. Lenox H, Gould TD, Manji HF. Endophenotypes in bipolar disorder. Am J Med Genet 2002; 114:391–406.

81. MacQueen GM, Hajek T, Alda M. The phenotypes of bipolar disorder: relevance for genetic investigations. Mol Psychiatry 2005; 10:811-826.

82. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160:636-645.

83. Gur RE, Nimgaonkar VL, Almasy L, Calkins ME, Ragland JD, Pogue-Geile MF, Kanes S, Blangero J, Gur RC. Neurocognitive endophenotypes in a multiplex multigenerational study of schizophrenia. Am J Psychiatry 2007; 164:813-819.

84. Pantelis C, Yücel M, Bora E, Fornito A, Testa R, Brewer WJ, Velakoulis, Wood SJ. Neurobiological markers of illness onset in psychosis and schizophrenia: The search for moving target. Neuropsychol Rev 2009; 19:385-398.

85. Snitz BE, Macdonald AW 3rd, Carter CS. Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull 2006; 32:179-194.

86. McIntosh AM, Harrison LK, Forrester K, Lawrie SM, Johnstone EC. Neuropsychological impairments in people with schizophrenia or bipolar disorder and their unaffected relatives. Br J Psychiatry 2005; 186:378–385.

87. Balanzá-Martínez V, Rubio C, Selva-Vera G, Martinez-Aran A, Sánchez-Moreno J, Salazar-Fraile J, Vieta E, Tabarés-Seisdedos R. Neurocognitive endophenotypes (endophenocognitypes) from studies of relatives of bipolar disorder subjects: a systematic review. Neurosci Biobehav Rev 2008; 32:1426-1438.

88. Frantom LV, Allen DN, Cross CL. Neurocognitive endophenotypes for bipolar disorder. Bipolar Disord 2008; 10:387–399.

89. Kapczinski F, Vieta E, Andreazza AC, Frey BN, Gomes FA, Tramontina J, Kauer-Sant’anna M, Grassi-Oliveira R, Post RM. Allostatic load in bipolar disorder: implications for pathophysiology and treatment. Neurosci Biobehav Rev 2008; 32:675-692.

90. Sobczak S, Honig A, van Duinen MA, Maes M, Riedel WJ. Mood, prolactin and cortisol responses following intravenous L-tryptophan challenge: evidence for serotonergic vulnerability in first-degree relatives of bipolar patients. Int J Neuropsychopharmacol 2002; 5:249-254.

91. Sobczak S, Honig A, Nicolson NA, Riedel WJ. Effects of acute tryptophan depletion on mood and cortisol release in first-degree relatives of type I and type II bipolar patients and healthy matched controls. Neuropsychopharmacology 2002; 27:834-842.

92. Simonsen C, Sundet K, Vaskinn A, Birkenaes AB, Engh JA, Hansen CF, Jónsdóttir H, Ringen PA, Opjordsmoen S, Friis S, Andreassen OA. Neurocognitive profiles in bipolar I and bipolar II disorder: differences in pattern and magnitude of dysfunction. Bipolar Disord 2008; 10:245-255.

93. Tabarés-Seisdedos R, Escámez T, Martínez-Giménez JA, Balanzá V, Salazar J, Selva G, Rubio C, Vieta E, Geijó-Barrientos E, Martínez-Arán A, Reiner O, Martínez S. Variations in genes regulating neuronal migration predict reduced prefrontal cognition in schizophrenia and bipolar subjects from mediterranean Spain: a preliminary study. Neuroscience 2006; 139:1289-1300.

94. Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. Toward constructing an endophenotype strategy for bipolar disorders. Biol Psychiatry 2006; 60:93-105.

95. Phillips ML, Vieta E. Identifying functional neuroimaging biomarkers of bipolar disorder: toward DSM-V. Schizophr Bull 2007; 33:893-904.

96. Duff K, Schoenberg MR, Scott JG, Adams RL. The relationship between executive functioning and verbal and visual learning and memory. Arch Clin Neuropsychol 2005; 20:111-122.

97. Strakowski SM, DelBello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 2005; 10:105-116.

98. McDonald C, Bullmore E, Sham P, Chitnis X, Wickham H, Bramon E, Murray RM. Association of genetic risks for schizophrenia and bipolar disorder with specific and generic brain structural endophenotypes. Arch Gen Psychiatry 2004; 61:974–984.

99. Blumberg HP, Leung HC, Skudlarski P, Lacadie CM, Fredericks CA, Harris BC, Charney DS, Gore JC, Krystal JH, Peterson BS. A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices. Arch Gen Psychiatry 2003; 60:601–609.

100. Cornblatt BA, Malhotra AK. Impaired attention as an endophenotype for molecular genetic studies of schizophrenia. Am J Med Genet 2001; 105:11-15.

101. Szöke A, Schürhoff F, Golmard JL, Alter C, Roy I, Méary A, Etain B, Bellivier F, Leboyer M. Familial resemblance for executive functions in families of schizophrenic and bipolar patients. Psychiatry Res 2006; 144:131-138.

102. Kuntsi J, Rogers H, Swinard G, Börger N, van der Meere J, Rijsdijk F, Asherson P. Reaction time, inhibition, working memory and ‘delay aversion’ performance: genetic influences and their interpretation. Psychol Med 2006; 36:1613-1624.

103. Antila M, Tuulio-Henriksson A, Kieseppä T, Soronen P, Palo OM, Paunio T, Haukka J, Partonen T, Lönnqvist J. Heritability of cognitive functions in families with bipolar disorder. Am J Med Genet B Neuropsychiatr Genet 2007; 144B:802-808.