Cognition in Euthymic Patients with Bipolar Disorder: Do Not Forget to | NDT

Introduction

Bipolar Disorder (BD) is a chronic, highly disabling condition, characterized by severe mood instability. This disorder is accompanied by cognitive deficits, which vary in severity, and are present in the majority of patients, even before illness onset and despite being in euthymia.^1–3 The importance of recognizing their presence lies in their link to functional and other well-being outcomes: cognitive variables are associated with functioning scores as evidenced by transversal as well as longitudinal studies.^4–9

Several factors are related to these deficits, likely in a two-direction relationship, and are therefore systematically evaluated when studying cognitive symptoms in this population. Such is the case of age, illness duration, number and type of affective episodes and history of psychotic symptoms as all have been linked to differential cognitive performance.^10–13 Furthermore, depressive and manic symptoms have such high correlation with these deficits that studies on cognition must not only state the affective state of participants but also report the severity of residual symptoms, as important differences have been documented between performance in euthymia and performance in active episodes.^12,14 Also, as comorbid substance use disorder also affects cognitive performance and is so common in BD, participants with active substance use are systematically excluded from studies on cognition in BD (for example, see exclusion criteria of).^1,9,12,14,15

On the other hand, anxious symptoms, whether part of a comorbid anxiety disorder or independent, are highly prevalent in persons with BD and are risk factors of various poor outcome measures, such as relapse, hospitalizations, suicidal behavior, functioning and lower quality of life.^16–23 Also, anxiety, as a general construct, is related to diminished performance on cognitive tasks, particularly with attentional control aspects of the central executive.²⁴ Thus, it would be expected that the presence of anxious symptoms (whether or not sufficient to fulfill criteria for a comorbid anxiety disorder) would worsen cognitive performance of patients with BD. A few studies have addressed this question: Wu et al compared performance on memory, attention, psychomotor speed, and frontal executive function between euthymic patients with type II BD (BD-II) with and without comorbid anxiety, and non-bipolar controls.²⁵ Only participants from the BD group with anxiety performed worse than controls, with a more significant difference in verbal memory. Chang et al compared type I (BD-I) and BD-II patients with and without comorbid anxiety, and found that cognitive performance was poorer in those with comorbid anxiety, although the affected cognitive domains varied between BD-I and BD-II.²⁶ Lu et al looked at the possible interaction between cognitive performance in BD-II patients with and without comorbid anxiety and the aldehyde dehydrogenase 2 polymorphism involved in the metabolism of dopamine.²⁷ Cognitive performance was not affected by comorbid anxiety in their sample. Finally, Huang et al evaluated cognitive performance in BDI and II with and without comorbid anxiety across different mood states, namely depressed, (hypo)manic, mixed and euthymic. The presence of anxiety tended to worsen the performance in all mood states, reaching significance for executive tasks in the mania and depressed subgroups.²⁸

Yet, despite the high prevalence of anxiety in BD and the evidence of its possible impact on cognitive performance, the assessment of anxious symptoms is not part of the recommended evaluations to perform when screening for cognitive deficits in patients with BD (see recommendations of the International Society for Bipolar Disorders (ISBD) cognition task force for assessing and addressing cognitive impairment).²⁹ Also, although the ISBD recommendations for clinical trials on cognition do state that patients with comorbid anxiety should not be excluded and anxiety should be evaluated and monitored, the presence and severity of anxious symptoms is not systematically evaluated in studies on cognition in bipolar disorder (for example, see measurements on important studies on cognition such as).^1,30–32 Furthermore, to the best of our knowledge, the relationship between anxious symptoms and perceived cognitive deficits (ie subjective cognition) has not been addressed (as an example, in the relevant study addressing the possible reasons for discrepancies between subjective and objective cognition in anxiety performed by Miskowiak et al, neither comorbid anxiety nor anxious symptoms were considered among the possible factors).³³

Consequently, our objective was to determine, in a Mexican sample of euthymic BD-I patients, if the severity of anxious symptoms would affect attention and/or inhibition of cognitive interference, while accounting for other possible contributors of diminished performance on these tasks, such as age, years of schooling, residual affective symptoms and perception of cognitive deficits.

Materials and Methods

The present was a cross-sectional correlational study performed with a convenience sampling approach. All study procedures comply with the declaration of Helsinki and were approved by the Ethics and Research Committee of the Ramón de la Fuente Muñiz National Institute of Psychiatry (INPRFM), approval number CONBIOETICA-09-CEI-010-20170316.

Participants

Euthymic patients with a diagnosis of type I BD attending the outpatient service of the National Institute of Psychiatry “Ramón de la Fuente Muñiz” at Mexico City were invited to participate. BD diagnosis was established through the following procedure: the medical records of willing participants were retrieved. Only those who had undergone at least one evaluation by the Affective Disorders’ Clinic confirming that BD was the primary psychiatric diagnosis were retained: in this clinic, a semi-structured interview following DSM-5 criteria is performed by a senior psychiatrist with more than 15-year experience in the diagnosis and treatment of patients with BD. Psychiatric comorbidities were also retrieved from this evaluation, and all participants with psychiatric comorbidities other than generalized anxiety disorder (GAD) or panic disorder (PD) were excluded. Also, patients had to be in euthymia for the past two months (six months if the last episode had been severe enough to require hospitalization or involved a suicide attempt), confirmed on the day of evaluation with a score 34 Those who accepted and signed an informed consent were evaluated for socio-demographic characteristics, variables related to the evolution of their BD, residual affective symptoms, presence and severity of anxious symptoms, subjective and objective cognition.

Assessment Procedure

All possible candidates who met the selection criteria received an explanation of the aims and procedures of the study and read the written informed consent. Once doubts about any procedure were answered and verbal consent was given, all participants signed the consent, and the clinical assessment was performed.

Demographic characteristics (age, current occupation, years of schooling) were assessed during a face-to-face interview with the patient. Clinical characteristics, such as the age of illness onset, previous hospitalizations, and the total number of hospitalizations were obtained from the clinical records, to avoid memory bias.

Residual symptoms of mania and depression were assessed with the Hamilton Depression 17-item scale (HAMD) and the Young Mania Rating Scale (YMRS), respectively. Both are clinician-rated instruments used for the objective evaluation of symptom severity of depression and mania. Concurrent validity of the HAMD in Mexican out-patients with depression was of 0.77.^35,36 Test-retest reliability and Cronbach´s alpha for the translation and adaptation of the YMRS in the Mexican population were high (0.93 and 0.84, respectively).³⁷

Anxious symptoms were assessed with the Brief Inventory of Anxious Responses and Situations (ISRA-B) which is composed by two subscales: the first one assesses the frequency of presentation of different types of anxious symptoms (cognitive, motor or physiologic anxious responses) in a 5-point Likert scale (0 = hardly ever to 4 = almost always), thus representing state anxiety and the second assesses the type of situations able to trigger such symptoms (situations of performance evaluation, interpersonal situations, phobic, every-day situations), thus evaluating trait anxiety.^38–40 For the present study, only state anxiety is reported.

Subjective cognitive complaints were evaluated with the COBRA scale. This scale comprises 16 self-administered items rated on a 4-point Likert frequency scale (0 = never to 3 = always) which assesses subjective cognitive complaints including memory, attention, executive functions, and processing speed. A total score is obtained by the sum of the item scores, with higher scores reflecting more subjective cognitive complaints. Its internal consistency for its use in Mexican patients with type I BD was high (0.91) with an adequate construct validity (one-factor explaining 45.5% of the total variance).⁴¹

For objective cognitive performance, we centered on two cognitive domains: attention and inhibition of cognitive interference. Attention is a lower-order cognitive task that can be affected by a spectrum of factors; its integrity is necessary for more intricate functions. On the other hand, inhibition of cognitive interference is an executive function, thus more complex, and requiring the integrity of various lower order abilities.

Attention was measured with the Digit Span forward task, which consists of strings of digits of increasing length (3 to 9), which are read out loud by the examinator at a speed of one word per second, and that the participant must repeat orally in the correct sequence. When the subject repeats correctly, a larger string is read, continuing in this way until the subjects fails to repeat two consecutive trials or correctly repeats twice the largest string. It involves auditory attention as well as short-term retention, although it is more an indicator of attention than memory.⁴²

Inhibition of cognitive interference was measured with the interference index of the Stroop test, an executive functioning measure of selective attention, cognitive flexibility, cognitive inhibition, and information processing speed.⁴³ This test consists of three pages, each with 100 components randomly organized into five columns. The individual has 45 seconds to read aloud, as quickly as possible, the columns from left to right. The sheet on words is formed by the words “Red”, “Green”, and “Blue” in black ink, and the score is the number of words read correctly (W score). For the sheet on colors, there are groups of four X’s (“XXXX”) printed in blue, green, and red. The score is the number of elements properly named (C score). Finally, the last list consists of the three words of the first printed page in the colors of the second, with words being incongruent with the color of the ink. The task is to name the ink color, inhibiting the reading of the word, and the score is the number of correctly named elements (WC score). Finally, an Interference Index is calculated with the formula: WC – [(WxC) /(P + W)], and indicates the degree to which a person is able to inhibit the interference produced by the incongruence of the reading task (automatic process that must be inhibited) and color naming (a task which must be voluntarily controlled). It is therefore an indicator of resistance to cognitive interference and of inhibitory control processes.⁴⁴ For the present study, all analyses were performed using raw scores.

Statistical Analyses

All analyses were conducted using IBM SPSS statistics V. 21 for PC and were deemed significant with a p-value ≤0.05. Frequencies and percentages for categorical variables and means with standard deviations (S.D) for continuous variables were used to summarize the demographic and clinical features of the sample.

Selection of Variables

Given the sample size (n = 87), a significance level of 0.05, and a power of at least 0.80, six associated variables were allowed in a linear regression model to be able to detect a small effect size. Therefore, we selected the most important sociodemographic variables, ie age and years of schooling, given the fact that raw —and not standardized scores— were used; for clinical variables, we selected those which could reflect the impact of affective symptoms and mood instability on cognition, but with the least collinearity, thus retaining residual affective symptoms over the number of affective episodes or the chronicity of the disorder (which would highly depend on the age of the subject). We also decided to include subjective cognition as a measure reflecting the individual’s experience with cognitive deficits. Finally, the severity of anxious symptoms was included to test the main hypothesis.

Linear Regression Models

Assumptions of normality, homoscedasticity and absence of multicollinearity were determined. The distribution of the variables exhibited acceptable values of skewness (range −0.82–1.62) and kurtosis (range −0.32–1.98). Homoscedasticity assumption was obtained by plotting the predicted values and residuals on a scatterplot (which were randomly distributed) and determining the Levene’s test for each variable. The p-values obtained were >0.05 (range 0.07–0.96) indicative of homogeneity of variances. The variance inflation factor (VIF) values measuring multicollinearity were determined and the obtained values were between 1.06 and 1.31, indicative of lack of multicollinearity. After these assumptions were determined, stepwise backward conditional linear regression models were performed to determine the association of current anxious symptoms with attention and inhibition of cognitive interference considering demographics (age and years of schooling) and clinical features (residual manic and depressive symptoms, and subjective cognitive complaints) as variables considered to be related to diminished cognitive performance in patients with BD. Unstandardized regression coefficients (β) reflect the change in cognitive scores associated with the score changes in the associated variables. We chose a stepwise backward conditional model as it has the advantage of initially considering the effects of all variables simultaneously and removes non-significant variables until reaching those who are clearly related to the dependent variable included in the model.

Results

Demographic and Clinical Characteristics of Patients with BP in Euthymia

Eighty-seven patients were included in the study. Most of them were women (81.6%, n = 71) with a mean age of 43.5 years (S.D.=10.3), and 14.4 (S.D.=3.2) mean years of schooling. Most patients had a remunerated activity.

The age of onset was mostly in the middle of the third decade of life, and a high percentage of patients had had at least one psychiatric hospitalization. Thirty-nine patients (45%) had an additional diagnosis of GAD. No patient from our sample was diagnosed with comorbid PD. Demographics, clinical characteristics, and cognitive assessment scores are exhibited in Table 1.

The Digit Span forward task exhibited an indirect association with age and the YMRS total score and a direct association with years of schooling in the first regression model. After the backward conditional method, age and the total score of the YMRS remained significant. Anxious symptoms were not related to attention in this regression modeling (see Tables 2 and 3).

Table 2 Association of Anxious Symptoms with Attention– Regression Models (n = 87)

Table 3 Association of Anxious Symptoms with Inhibition of Cognitive Interference– Regression Models (n=87)

In the first linear regression model, years of schooling and cognitive complaints were related to higher interference scores assessed by the Stroop test. At this moment, anxious symptoms only show a trend towards significance. However, after the backward conditional method, years of schooling and cognitive complaints remain significant, while more severe anxious symptoms were negatively related to cognitive interference score. These results show that a better performance in inhibiting cognitive interference is seen in patients with higher schooling, higher subjective cognitive complaints, and lower anxious symptoms, as assessed by the Stroop cognitive interference index.

Discussion

Impaired cognition has been largely recognized as a central component of BD, although the source of these deficits remain elusive, with evidence indicating neurodevelopmental origins and also showing a possible scar left by previous affective episodes, although this is still a controversial topic as a meta-analysis on longitudinal course of cognitive performance found no significant differences.45–47 Furthermore, many factors, present in a vast majority of patients, can affect performance on cognitive testing, as is the case of residual affective symptoms and anxious symptoms.

Anxiety as a construct can be divided in at least two dimensions: worry and arousal. Worry in a severe form would correspond to DSM-5’s conceptualization of GAD, whereas arousal would be closer to PD, although both symptoms can be present without other necessary criteria to establish a diagnosis of a formal anxiety disorder.²⁴ Nonetheless, their presence can be sufficient to affect cognitive performance: according to the processing efficiency theory and the attentional control theory worry gives rise to competition between anxiety-related processes and task-related processes and affects specific executive processes such as inhibition.⁴⁸

Our results illustrate the possibility that the severity of anxious symptoms does not affect simple cognitive processes, as attention; however, when faced with complex tasks, anxiety starts to play a role. This is in line with the findings of Wu et al who found greater differences in working memory, psychomotor speed and executive functions in BD-II with comorbid anxiety.²⁵ Also, in the subgroup of BD-I patients, Chang et al found differences only in working memory when comparing those with and without comorbid anxiety.²⁶

Another interesting finding is the interaction between perception of cognitive deficits, years of schooling and anxiety: more years of schooling, greater subjective cognitive complaints, and less anxiety were associated with a better inhibition of cognitive interference. One possible explanation is that patients who perceive cognitive deficits but do not have severe anxiety might be attentive to the task to a sufficient degree to improve their concentration on the task without reaching a threshold where hyper-arousal and worry shifts the attention towards their performance. This is congruent with studies on emotional acceptance, and its effect on executive control where meditators had a better performance on the Stroop test than did non meditators, an effect accounted for by heightened emotional acceptance.⁴⁹

The limitations of this study must be mentioned and include the following: a relatively small sample impeded interesting additional analysis, such as the interaction of trait-state anxiety. Indeed, the chronicity of anxious symptoms (versus current anxiety) has a significant effect on the many clinical factors affecting cognition, for example, lifetime anxiety was associated with a two-fold increase in recurrence rate of depressive episodes, whereas current anxiety did not —unless lifetime anxiety was also present—, among other relevant outcomes, such as time spent in episodes, maximum period of continuous euthymia, presence of psychosis and response to mood stabilizers.^50,51 As well, the inclusion of other neuropsychological tests would have been interesting, but their inclusion would need correction for multiple correlations thus highly increasing type-II error. Also, we only included BD-I patients, thus cannot generalize to all types of BD. Additionally, we did not include controls; it would be interesting to determine in future research if the impact of anxiety and subjective cognitive deficits is also present in the general population.

Despite these deficits, these findings bring to light the importance of anxious symptoms, whether or not part of a formal comorbid anxiety disorder, suggesting that future research on cognition in BD would benefit from systematically measuring the presence and severity of anxious symptoms, as a possible factor contributing to deficiencies, at least when evaluating cognitive inhibition; furthermore, they remind us of the importance of considering the high prevalence and importance of anxiety in patients with BD as well as the possible interaction between anxiety and cognitive complaints, which might also be a contributing factor for the discrepancies seen in subjective vs objective cognitive measures.

Conclusion

Beyond residual affective symptoms, anxiety might affect some cognitive processes. We recommend routine testing of anxiety when considering cognitive evaluations, especially when screening for cognitive deficits.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Lima F, Rabelo-da-Ponte FD, Bücker J, et al. Identifying cognitive subgroups in bipolar disorder: a cluster analysis. J Affect Disord. 2019;246:252–261. doi:10.1016/j.jad.2018.12.044

2. Bortolato B, Miskowiak KW, Köhler CA, Vieta E, Carvalho AF. Cognitive dysfunction in bipolar disorder and schizophrenia: a systematic review of meta-analyses. Neuropsychiatr Dis Treat. 2015;11:3111–3125. doi:10.2147/NDT.S76700

3. Martino DJ, Samamé C, Ibañez A, Strejilevich SA. Neurocognitive functioning in the premorbid stage and in the first episode of bipolar disorder: a systematic review. Psychiatry Res. 2015;226(1):23–30. doi:10.1016/j.psychres.2014.12.044

4. Lahera G, Ruiz-Murugarren S, Iglesias P, et al. Social cognition and global functioning in bipolar disorder. J Nerv Ment Dis. 2012;200(2):135. doi:10.1097/NMD.0b013e3182438eae

5. Martinez-Aran A, Vieta E, Torrent C, et al. Functional outcome in bipolar disorder: the role of clinical and cognitive factors. Bipolar Disord. 2007;9(1–2):103–113. doi:10.1111/j.1399-5618.2007.00327.x

6. Martino DJ, Marengo E, Igoa A, et al. Neurocognitive and symptomatic predictors of functional outcome in bipolar disorders: a prospective 1 year follow-up study. J Affect Disord. 2009;116(1–2):37–42. doi:10.1016/j.jad.2008.10.023

7. Martino DJ, Igoa A, Marengo E, Scápola M, Strejilevich SA. Neurocognitive impairments and their relationship with psychosocial functioning in euthymic bipolar II disorder. J Nerv Ment Dis. 2011;199(7):459–464. doi:10.1097/NMD.0b013e3182214190

8. Bonnín CM, Martínez-Arán A, Torrent C, et al. Clinical and neurocognitive predictors of functional outcome in bipolar euthymic patients: a long-term, follow-up study. J Affect Disord. 2010;121(1):156–160. doi:10.1016/j.jad.2009.05.014

9. Mora E, Portella MJ, Forcada I, Vieta E, Mur M. Persistence of cognitive impairment and its negative impact on psychosocial functioning in lithium-treated, euthymic bipolar patients: a 6-year follow-up study. Psychol Med. 2013;43(6):1187–1196. doi:10.1017/S0033291712001948

10. Kessing LV. Cognitive impairment in the euthymic phase of affective disorder. Psychol Med. 1998;28(5):1027–1038. doi:10.1017/s0033291798006862

11. Mann-Wrobel MC, Carreno JT, Dickinson D. Meta-analysis of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables. Bipolar Disord. 2011;13(4):334–342. doi:10.1111/j.1399-5618.2011.00935.x

12. Martínez-Arán A, Vieta E, Reinares M, et al. Cognitive function across manic or hypomanic, depressed, and euthymic states in bipolar disorder. Am J Psychiatry. 2004;161(2):262–270. doi:10.1176/appi.ajp.161.2.262

13. Zubieta JK, Huguelet P, O’Neil RL, Giordani BJ. Cognitive function in euthymic bipolar I disorder. Psychiatry Res. 2001;102(1):9–20.

14. Burdick KE, Ketter TA, Goldberg JF, Calabrese JR. Assessing cognitive function in bipolar disorder: challenges and recommendations for clinical trial design. J Clin Psychiatry. 2015;76(3):e342–e350. doi:10.4088/JCP.14cs09399

15. Benaiges I, Prat G, Adan A. Neuropsychological aspects of dual diagnosis. Curr Drug Abuse Rev. 2010;3(3):175–188. doi:10.2174/1874473711003030175

16. Albert U, Rosso G, Maina G, Bogetto F. Impact of anxiety disorder comorbidity on quality of life in euthymic bipolar disorder patients: differences between bipolar I and II subtypes. J Affect Disord. 2008;105(1–3):297–303. doi:10.1016/j.jad.2007.05.020

17. Gaudiano BA, Miller IW. Anxiety disorder comorbidity in Bipolar I Disorder: relationship to depression severity and treatment outcome. Depress Anxiety. 2005;21(2):71–77. doi:10.1002/da.20053

18. Keller MB. Prevalence and impact of comorbid anxiety and bipolar disorder. J Clin Psychiatry. 2006;67(Suppl 1):5–7.

19. Kinrys G, Bowden CL, Nierenberg AA, et al. Comorbid anxiety in bipolar CHOICE: insights from the bipolar inventory of symptoms scale. J Affect Disord. 2019;246:126–131. doi:10.1016/j.jad.2018.12.039

20. Otto MW, Simon NM, Wisniewski SR, et al. Prospective 12-month course of bipolar disorder in out-patients with and without comorbid anxiety disorders. Br J Psychiatry. 2006;189(01):20–25. doi:10.1192/bjp.bp.104.007773

21. Simon NM, Otto MW, Wisniewski SR, et al. Anxiety disorder comorbidity in bipolar disorder patients: data from the first 500 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Am J Psychiatry. 2004;161(12):2222–2229. doi:10.1176/appi.ajp.161.12.2222

22. Toprak E, Yavuz B. Anxiety disorders comorbidity in bipolar disorder patients and quality of life. J Mood Disord. 2011;1(2):55. doi:10.5455/jmood.20110619122123

23. Yoldi-Negrete M, Morera D, Palacios-Cruz L, et al. Subsyndromal anxiety: does it affect the quality of life? A study on euthymic patients with bipolar disorder. Eur J Psychiatr. 2019;33(4):159–164. doi:10.1016/j.ejpsy.2019.06.005

24. Moran TP. Anxiety and working memory capacity: a meta-analysis and narrative review. Psychol Bull. 2016;142(8):831–864. doi:10.1037/bul0000051

25. Wu HI, Chang YH, Lai CC, et al. The effect of comorbid anxiety disorder on neuropsychological function in bipolar II disorder. Prog Neuropsychopharmacol Biol Psychiatr. 2011;35(8):1841–1845. doi:10.1016/j.pnpbp.2011.07.013

26. Chang CT, Chang YH, Yung-Wei Wu J, et al. Neuropsychological functions impairment in different subtypes of bipolar disorder with or without comorbid anxiety disorders. Psychiatry Res. 2012;200(2–3):246–251. doi:10.1016/j.psychres.2012.06.012

27. Lu RB, Chang YH, Wang TY, Lee SY, Chen PS, Yang YK. The aldehyde dehydrogenase 2 polymorphisms on neuropsychological performance in bipolar II disorder with or without comorbid anxiety disorder. PLoS One. 2018;13(2):e0192229. doi:10.1371/journal.pone.0192229

28. Huang CJ, Lin CH, Wu JI, Yang WC. The relationship between depression symptoms and anxiety symptoms during acute ECT for patients with major depressive disorder. Int J Neuropsychopharmacol. 2019;22(10):609–615. doi:10.1093/ijnp/pyz038

29. Miskowiak K, Burdick K, Martinez-Aran A, et al. Assessing and addressing cognitive impairment in bipolar disorder: the international society for bipolar disorders targeting cognition task force recommendations for clinicians. Bipolar Disord. 2018;20(3):184–194. doi:10.1111/bdi.12595

30. Groves SJ, Douglas KM, Moot W, et al. Relationship between baseline cognition and 18-month treatment response in bipolar disorder. J Affect Disord. 2022;318:224–230. doi:10.1016/j.jad.2022.08.112

31. Kjærstad HL, Mistarz N, Coello K, et al. Aberrant cognition in newly diagnosed patients with bipolar disorder and their unaffected relatives. Psychol Med. 2020;50(11):1808–1819. doi:10.1017/S0033291719001867

32. Miskowiak K, Burdick K, Martinez-Aran A, et al. Methodological recommendations for cognition trials in bipolar disorder by the international society for bipolar disorders targeting cognition task force. Bipolar Disord. 2017;19(8):614–626. doi:10.1111/bdi.12534

33. Miskowiak KW, Petersen JZ, Ott CV, et al. Predictors of the discrepancy between objective and subjective cognition in bipolar disorder: a novel methodology. Acta Psychiatr Scand. 2016;134(6):511–521. doi:10.1111/acps.12649

34. Tohen M, Frank E, Bowden CCL, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on the nomenclature of course and outcome in bipolar disorders. Bipolar Disord. 2009;11(5):453–473. doi:10.1111/j.1399-5618.2009.00726.x

35. Berlanga C, Cortés J, Bauer J. Adaptación y validación de la Escala de Depresión de Carroll en español [Adaptation and validation of the Carroll depression scale in spanish]. Salud Ment. 1992;15(4):36–40. Spanish.

36. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatr. 1960;23:56–62.

37. Apiquian R, Péez F, Tapia RO, Fresán A, Vallejo G, Nicolini H. Validez y confiabilidad de la Escala para la Evaluacion de la Mania [Validity and reliability of the evaluation of mania scale]. Salud Ment. 1997;20(3):23–29. Spanish.

38. Cano-Vindel A, Muñoz-Navarro R, Moretti LS, Medrano LA. Propiedades psicométricas del Inventario de Situaciones y Respuestas de Ansiedad Breve (ISRA-B) [Psychometric properties of the brief inventory of situations and responses of anxiety (ISRA-B)]. Ansiedad Estrés. 2020;26(2):155–166. Spanish. doi:10.1016/j.anyes.2020.07.004

39. Cano-Vindel A, Miguel-Tobal JJ. Evaluación de la ansiedad desde un enfoque interactivo y multidimensional: el Inventario de Situaciones y Respuestas de Ansiedad (ISRA) [Evaluation of anxiety from an interactive and multidimensional focus: the Inventory of Situations and Responses of Anxiety (ISRA).]. Psicol Contemp. 1999;6(1):14–21. Spanish.

40. González-Ramírez MT, Del C Q-BL, Díaz-Rodríguez CL, Cano-Vindel A. Adaptación para México y estructura factorial del Inventario de Situaciones y Respuestas de Ansiedad Breve (ISRA-B) | [Adaptation to Mexico and factor structure of the Brief Inventory of Situations and Responses of Anxiety (ISRA-B)]. Ansiedad Estrés. 2014;20(1):89–100. Spanish.

41. Yoldi-Negrete M, Fresán-Orellana A, Martínez-Camarillo S, et al. Psychometric properties and cross-cultural comparison of the cognitive complaints in bipolar disorder rating assessment (COBRA) in Mexican patients with bipolar disorder. Psychiatry Res. 2018;269:536–541. doi:10.1016/j.psychres.2018.08.098

42. Lezak M. Neuropsychological Assessment. Oxford University Press; 2012. Available from: https://global.oup.com/academic/product/neuropsychological-assessment-9780195395525?cc=us&lang=en&. Accessed May 24, 2017.

43. Rivera D, Perrin PB, Stevens LF, et al. Stroop color-word interference test: normative data for the Latin American Spanish speaking adult population. NeuroRehabilitation. 2015;37(4):591–624. doi:10.3233/NRE-151281

44. Stroop GCJ. Test de Colores y Palabras – Edición Revisada. TEA Ediciones; 2020.

45. 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(6):771–785. doi:10.1017/S0033291707001675

46. López-Jaramillo C, Lopera-Vásquez J, Gallo A, et al. Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence. Bipolar Disord. 2010;12(5):557–567. doi:10.1111/j.1399-5618.2010.00835.x

47. Samamé C, Martino D, Strejilevich S. Longitudinal course of cognitive deficits in bipolar disorder: a meta-analytic study. J Affect Disord. 2014;164:130–138. doi:10.1016/j.jad.2014.04.028

48. Eysenck MW, Derakshan N, Santos R, Calvo MG. Anxiety and cognitive performance: attentional control theory. Emot Wash DC. 2007;7(2):336–353. doi:10.1037/1528-3542.7.2.336

49. Teper R, Inzlicht M. Meditation, mindfulness and executive control: the importance of emotional acceptance and brain-based performance monitoring. Soc Cogn Affect Neurosci. 2013;8(1):85–92. doi:10.1093/scan/nss045

50. Shah S, Kim JP, Park DY, et al. Lifetime anxiety disorder and current anxiety symptoms associated with hastened depressive recurrence in bipolar disorder. J Affect Disord. 2017;219:165–171. doi:10.1016/j.jad.2017.05.007

51. Zutshi A, Reddy YCJ, Thennarasu K, Chandrashekhar CR. Comorbidity of anxiety disorders in patients with remitted bipolar disorder. Eur Arch Psychiatry Clin Neurosci. 2006;256(7):428–436. doi:10.1007/s00406-006-0658-2