ORIGINAL ARTICLE
Cognitive function, treatment response to lithium, and social functioning in Japanese patients with bipolar disorder
Satoshi Saito,
Kumiko Fujii,
Yuji Ozeki,
Kenichi Ohmori,
Gyo Honda,
Harunobu Mori,
Kazuko Kato,
Jinichi Kuroda, Akiko Aoki,
Haruhiko Asahi, Hayato Sato, Kazutaka Shimoda,
Kazufumi Akiyama,
Satoshi Saito
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorKumiko Fujii
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorYuji Ozeki
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorKenichi Ohmori
Shiseikai, Takizawa Hospital, Utsunomiya, Tochigi, Japan
Search for more papers by this authorGyo Honda
Seiseido Kohseikai, Mori Hospital, Utsunomiya, Tochigi, Japan
Search for more papers by this authorHarunobu Mori
Seiseido Kohseikai, Mori Hospital, Utsunomiya, Tochigi, Japan
Search for more papers by this authorKazuko Kato
Sakura La Mental Clinic, Utsunomiya, Tochigi, Japan
Search for more papers by this authorAkiko Aoki
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorKazutaka Shimoda
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorCorresponding Author
Kazufumi Akiyama
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Correspondence
Kazufumi Akiyama, Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
Email: [email protected]
Search for more papers by this authorSatoshi Saito,
Kumiko Fujii,
Yuji Ozeki,
Kenichi Ohmori,
Gyo Honda,
Harunobu Mori,
Kazuko Kato,
Jinichi Kuroda, Akiko Aoki,
Haruhiko Asahi, Hayato Sato, Kazutaka Shimoda,
Kazufumi Akiyama,
Satoshi Saito
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorKumiko Fujii
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorYuji Ozeki
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorKenichi Ohmori
Shiseikai, Takizawa Hospital, Utsunomiya, Tochigi, Japan
Search for more papers by this authorGyo Honda
Seiseido Kohseikai, Mori Hospital, Utsunomiya, Tochigi, Japan
Search for more papers by this authorHarunobu Mori
Seiseido Kohseikai, Mori Hospital, Utsunomiya, Tochigi, Japan
Search for more papers by this authorKazuko Kato
Sakura La Mental Clinic, Utsunomiya, Tochigi, Japan
Search for more papers by this authorAkiko Aoki
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorKazutaka Shimoda
Department of Psychiatry, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Search for more papers by this authorCorresponding Author
Kazufumi Akiyama
Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan
Correspondence
Kazufumi Akiyama, Department of Biological Psychiatry and Neuroscience, Dokkyo Medical University School of Medicine, Mibu, Tochigi, Japan.
Email: [email protected]
Search for more papers by this authorAbstract
Objectives
Patients with bipolar disorder often suffer from cognitive impairment that significantly influences their functional outcome. However, it remains unknown whether lithium has a central role in cognition and functional outcome. We examined whether cognition and functional outcome were predicted by demographic and clinical variables, including the response to lithium, in lithium-treated patients with bipolar disorder.
Methods
We evaluated 96 lithium-treated euthymic patients with bipolar disorder and 196 age- and-gender-matched healthy controls, using the Brief Assessment of Cognition in Schizophrenia (BACS). The patients were also assessed using the Social Functioning Scale (SFS) and “The Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” (Alda) scale, which was evaluated as either a continuous measure of the total scale or a dichotomous criterion.
Results
Multiple regression analysis revealed two key findings: first, that the premorbid intelligence quotient, age, and number of mood episodes were predictors of the BACS composite score; and, second, that the BACS composite score, negative symptoms, and continuous measure on the total Alda scale (but not its dichotomy) predicted the total SFS score. Structural equation modeling (SEM) was used to confirm these findings, and additionally revealed that the Alda scale was significantly associated with negative symptoms and also the number of mood episodes, regardless of how it was evaluated.
Conclusions
SEM delineated how demographic and clinical variables, cognitive performance, and response to lithium treatment were causally associated with, and converged on, social function. The putative role of the Alda scale for social function warrants further study.
REFERENCES
- 1Arts 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.
- 2Kurtz MM, Gerraty RT. A meta-analytic investigation of neurocognitive deficits in bipolar illness: profile and effects of clinical state. Neuropsychology. 2009; 23: 551-562.
- 3Mann-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: 334-342.
- 4Robinson LJ, Thompson JM, Gallagher P, et al. A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder. J Affect Disord. 2006; 93: 105-115.
- 5Antila M, Partonen T, Kieseppä T, et al. Cognitive functioning of bipolar I patients and relatives from families with or without schizophrenia or schizoaffective disorder. J Affect Disord. 2009; 116: 70-79.
- 6Bora E, Yucel 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.
- 7Frantom LV, Allen DN, Cross CL. Neurocognitive endophenotypes for bipolar disorder. Bipolar Disord. 2008; 10: 387-399.
- 8Doyle AE, Wozniak J, Wilens TE, et al. Neurocognitive impairment in unaffected siblings of youth with bipolar disorder. Psychol Med. 2009; 39: 1253-1263.
- 9Altshuler 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.
- 10Frangou S, Dakhil N, Landau S, Kumari V. Fronto-temporal function may distinguish bipolar disorder from schizophrenia. Bipolar Disord. 2006; 8: 47-55.
- 11Krabbendam L, Arts B, van Os J, Aleman A. Cognitive functioning in patients with schizophrenia and bipolar disorder: a quantitative review. Schizophr Res. 2005; 80: 137-149.
- 12Schretlen DJ, Cascella NG, Meyer SM, et al. Neuropsychological functioning in bipolar disorder and schizophrenia. Biol Psychiatry. 2007; 62: 179-186.
- 13Stefanopoulou E, Manoharan A, Landau S, Geddes JR, Goodwin G, Frangou S. Cognitive functioning in patients with affective disorders and schizophrenia: a meta-analysis. Int Rev Psychiatry. 2009; 21: 336-356.
- 14Harvey PD, Wingo AP, Burdick KE, Baldessarini RJ. Cognition and disability in bipolar disorder: lessons from schizophrenia research. Bipolar Disord. 2010; 12: 364-375.
- 15Hill SK, Reilly JL, Keefe RS, et al. Neuropsychological impairments in schizophrenia and psychotic bipolar disorder: findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) study. Am J Psychiatry. 2013; 170: 1275-1284.
- 16Seidman LJ, Kremen WS, Koren D, Faraone SV, Goldstein JM, Tsuang MT. A comparative profile analysis of neuropsychological functioning in patients with schizophrenia and bipolar psychoses. Schizophr Res. 2002; 53: 31-44.
- 17Dickerson F, Boronow JJ, Stallings C, Origoni AE, Cole SK, Yolken RH. Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the repeatable battery for the assessment of neuropsychological status. Psychiatry Res. 2004; 129: 45-53.
- 18Gray JD, McEwen BS. Lithium's role in neural plasticity and its implications for mood disorders. Acta Psychiatr Scand. 2013; 128: 347-361.
- 19Dell'Osso L, Del Grande C, Gesi C, Carmassi C, Musetti L. A new look at an old drug: neuroprotective effects and therapeutic potentials of lithium salts. Neuropsychiatr Dis Treat. 2016; 12: 1687-1703.
- 20de Sousa RT, van de Bilt MT, Diniz BS, et al. Lithium increases plasma brain-derived neurotrophic factor in acute bipolar mania: a preliminary 4-week study. Neurosci Lett. 2011; 494: 54-56.
- 21Rybakowski JK, Suwalska A. Excellent lithium responders have normal cognitive functions and plasma BDNF levels. Int J Neuropsychopharmacol. 2010; 13: 617-622.
- 22Hajek T, Bauer M, Simhandl C, et al. Neuroprotective effect of lithium on hippocampal volumes in bipolar disorder independent of long-term treatment response. Psychol Med. 2014; 44: 507-517.
- 23Dias VV, Balanzá-Martinez V, Soeiro-de-Souza MG, et al. Pharmacological approaches in bipolar disorders and the impact on cognition: a critical overview. Acta Psychiatr Scand. 2012; 126: 315-331.
- 24Goldberg JF, Chengappa KN. Identifying and treating cognitive impairment in bipolar disorder. Bipolar Disord. 2009; 11(Suppl 2): 123-137.
- 25Wingo AP, Wingo TS, Harvey PD, Baldessarini RJ. Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry. 2009; 70: 1588-1597.
- 26López-Jaramillo C, Lopera-Vásquez J, Ospina-Duque J, et al. Lithium treatment effects on the neuropsychological functioning of patients with bipolar I disorder. J Clin Psychiatry. 2010; 71: 1055-1060.
- 27Mur M, Portella MJ, Martínez-Arán A, Pifarré J, Vieta E. Persistent neuropsychological deficit in euthymic bipolar patients: executive function as a core deficit. J Clin Psychiatry. 2007; 68: 1078-1086.
- 28Torres IJ, DeFreitas VG, DeFreitas CM, et al. Neurocognitive functioning in patients with bipolar I disorder recently recovered from a first manic episode. J Clin Psychiatry. 2010; 71: 1234-1242.
- 29Sabater A, García-Blanco AC, Verdet HM, et al. Comparative neurocognitive effects of lithium and anticonvulsants in long-term stable bipolar patients. J Affect Disord. 2016; 190: 34-40.
- 30Daglas R, Cotton SM, Allott K, et al. A single-blind, randomised controlled trial on the effects of lithium and quetiapine monotherapy on the trajectory of cognitive functioning in first episode mania: a 12-month follow-up study. Eur Psychiatry. 2016; 31: 20-28.
- 31Rybakowski 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.
- 32Malhi GS, McAulay C, Gershon S, et al. The lithium battery: assessing the neurocognitive profile of lithium in bipolar disorder. Bipolar Disord. 2016; 18: 102-115.
- 33Zubieta JK, Huguelet P, O'Neil RL, Giordani BJ. Cognitive function in euthymic bipolar I disorder. Psychiatry Res. 2001; 102: 9-20.
- 34Cavanagh 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.
- 35Robinson LJ, Ferrier IN. Evolution of cognitive impairment in bipolar disorder: a systematic review of cross-sectional evidence. Bipolar Disord. 2006; 8: 103-116.
- 36Eric YW, Halari R, Cheng KM, Leung SK, Young AH. Cognitive performance is impaired in euthymic Chinese patients with Bipolar 1 Disorder. J Affect Disord. 2013; 151: 156-163.
- 37Garnham J, Munro A, Slaney C, et al. Prophylactic treatment response in bipolar disorder: results of a naturalistic observation study. J Affect Disord. 2007; 104: 185-190.
- 38Grof P, Duffy A, Cavazzoni P, et al. Is response to prophylactic lithium a familial trait? J Clin Psychiatry. 2002; 63: 942-947.
- 39Manchia M, Adli M, Akula N, et al. Assessment of response to lithium maintenance treatment in bipolar disorder: a Consortium on Lithium Genetics (ConLiGen) report. PLoS ONE. 2013; 8: e65636.
- 40Schulze TG, Alda M, Adli M, et al. The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment. Neuropsychobiology. 2010; 62: 72-78.
- 41Scott J, Geoffroy PA, Sportiche S, et al. Cross-validation of clinical characteristics and treatment patterns associated with phenotypes for lithium response defined by the Alda scale. J Affect Disord. 2017; 208: 62-67.
- 42Gallagher P, Gray JM, Watson S, Young AH, Ferrier IN. Neurocognitive functioning in bipolar depression: a component structure analysis. Psychol Med. 2014; 44: 961-974.
- 43Malhi GS, Ivanovski B, Hadzi-Pavlovic D, Mitchell PB, Vieta E, Sachdev P. Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia. Bipolar Disord. 2007; 9: 114-125.
- 44Solé B, Bonnin CM, Torrent C, et al. Neurocognitive impairment and psychosocial functioning in bipolar II disorder. Acta Psychiatr Scand. 2012; 125: 309-317.
- 45Bora E, Vahip S, Akdeniz F, et al. The effect of previous psychotic mood episodes on cognitive impairment in euthymic bipolar patients. Bipolar Disord. 2007; 9: 468-477.
- 46Glahn DC, Bearden CE, Barguil M, et al. The neurocognitive signature of psychotic bipolar disorder. Biol Psychiatry. 2007; 62: 910-916.
- 47Martinez-Aran A, Torrent C, Tabares-Seisdedos R, et al. Neurocognitive impairment in bipolar patients with and without history of psychosis. J Clin Psychiatry. 2008; 69: 233-239.
- 48Bora E, Yücel M, Pantelis C. Neurocognitive markers of psychosis in bipolar disorder: a meta-analytic study. J Affect Disord. 2010; 127: 1-9.
- 49Levy B, Weiss RD. Neurocognitive impairment and psychosis in bipolar I disorder during early remission from an acute episode of mood disturbance. J Clin Psychiatry. 2010; 71: 201-206.
- 50Simonsen C, Sundet K, Vaskinn A, et al. Neurocognitive dysfunction in bipolar and schizophrenia spectrum disorders depends on history of psychosis rather than diagnostic group. Schizophr Bull. 2011; 37: 73-83.
- 51Lewandowski KE, Cohen BM, Keshavan MS, Öngür D. Relationship of neurocognitive deficits to diagnosis and symptoms across affective and non-affective psychoses. Schizophr Res. 2011; 133: 212-217.
- 52Smith MJ, Barch DM, Csernansky JG. Bridging the gap between schizophrenia and psychotic mood disorders: relating neurocognitive deficits to psychopathology. Schizophr Res. 2009; 107: 69-75.
- 53Anaya C, Torrent C, Caballero FF, et al. Cognitive reserve in bipolar disorder: relation to cognition, psychosocial functioning and quality of life. Acta Psychiatr Scand. 2016; 133: 386-398.
- 54Bowie CR, Depp C, McGrath JA, et al. Prediction of real-world functional disability in chronic mental disorders: a comparison of schizophrenia and bipolar disorder. Am J Psychiatry. 2010; 167: 1116-1124.
- 55Burdick KE, Goldberg JF, Harrow M. Neurocognitive dysfunction and psychosocial outcome in patients with bipolar I disorder at 15-year follow-up. Acta Psychiatr Scand. 2010; 122: 499-506.
- 56Depp CA, Mausbach BT, Harmell AL, et al. Meta-analysis of the association between cognitive abilities and everyday functioning in bipolar disorder. Bipolar Disord. 2012; 14: 217-226.
- 57Martínez-Arán A, Vieta E, Colom F, et al. Cognitive impairment in euthymic bipolar patients: implications for clinical and functional outcome. Bipolar Disord. 2004; 6: 224-232.
- 58Martínez-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: 262-270.
- 59Wingo AP, Harvey PD, Baldessarini RJ. Neurocognitive impairment in bipolar disorder patients: functional implications. Bipolar Disord. 2009; 11: 113-125.
- 60Samalin L, de Chazeron I, Vieta E, Bellivier F, Llorca PM. Residual symptoms and specific functional impairments in euthymic patients with bipolar disorder. Bipolar Disord. 2016; 18: 164-173.
- 61Samalin L, Reinares M, de Chazeron I, et al. Course of residual symptoms according to the duration of euthymia in remitted bipolar patients. Acta Psychiatr Scand. 2016; 134: 57-64.
- 62Burdick KE, Goldberg TE, Cornblatt BA, et al. The MATRICS consensus cognitive battery in patients with bipolar I disorder. Neuropsychopharmacology. 2011; 36: 1587-1592.
- 63Cholet J, Sauvaget A, Vanelle JM, et al. Using the Brief Assessment of Cognition in Schizophrenia (BACS) to assess cognitive impairment in older patients with schizophrenia and bipolar disorder. Bipolar Disord. 2014; 16: 326-336.
- 64Poletti S, Sferrazza Papa G, Locatelli C, Colombo C, Benedetti F. Neuropsychological deficits in bipolar depression persist after successful antidepressant treatment. J Affect Disord. 2014; 156: 144-149.
- 65Chino B, Nemoto T, Fujii C, Mizuno M. Subjective assessments of the quality of life, well-being and self-efficacy in patients with schizophrenia. Psychiatry Clin Neurosci. 2009; 63: 521-528.
- 66Birchwood M, Smith J, Cochrane R, Wetton S, Copestake S. The Social Functioning Scale. The development and validation of a new scale of social adjustment for use in family intervention programmes with schizophrenic patients. Br J Psychiatry. 1990; 157: 853-859.
- 67Akiyama K, Saito S, Saito A, et al. Predictive value of premorbid IQ, negative symptoms, and age for cognitive and social functions in Japanese patients with schizophrenia: a study using the Japanese version of the Brief Assessment of Cognition in Schizophrenia. Psychiatry Res. 2016; 246: 663-671.
- 68Kaneda Y, Sumiyoshi T, Keefe R, Ishimoto Y, Numata S, Ohmori T. Brief assessment of cognition in schizophrenia: validation of the Japanese version. Psychiatry Clin Neurosci. 2007; 61: 602-609.
- 69Takei K, Yamasue H, Abe O, et al. Structural disruption of the dorsal cingulum bundle is associated with impaired Stroop performance in patients with schizophrenia. Schizophr Res. 2009; 114: 119-127.
- 70Uetsuki M, Matsuoka K, Kim Y, et al. Estimation of premorbid IQ by JART in schizophrenia. Seisin Igaku. 2006; 48: 15-22. (in Japanese).
- 71Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull. 1987; 13: 261-276.
- 72Kay SR, Opler LA, Spitzer RL, Williams JB, Fiszbein A, Gorelick A. SCID-PANSS: two-tier diagnostic system for psychotic disorders. Compr Psychiatry. 1991; 32: 355-361.
- 73Begemann M, Grube S, Papiol S, et al. Modification of cognitive performance in schizophrenia by complexin 2 gene polymorphisms. Arch Gen Psychiatry. 2010; 67: 879-888.
- 74Keefe RS, Goldberg TE, Harvey PD, Gold JM, Poe MP, Coughenour L. The brief assessment of cognition in schizophrenia: reliability, sensitivity, and comparison with a standard neurocognitive battery. Schizophr Res. 2004; 68: 283-297.
- 75Kleindienst N, Engel R, Greil W. Which clinical factors predict response to prophylactic lithium? A systematic review for bipolar disorders. Bipolar Disord. 2005; 7: 404-417.
- 76Alda M. Lithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics. Mol Psychiatry. 2015; 20: 661-670.
- 77Rybakowski JK, Chlopocka-Wozniak M, Suwalska A. The prophylactic effect of long-term lithium administration in bipolar patients entering treatment in the 1970s and 1980s. Bipolar Disord. 2001; 3: 63-67.
- 78Licht RW, Vestergaard P, Brodersen A. Long-term outcome of patients with bipolar disorder commenced on lithium prophylaxis during hospitalization: a complete 15-year register-based follow-up. Bipolar Disord. 2008; 10: 79-86.
- 79Gershon S, Chengappa KN, Malhi GS. Lithium specificity in bipolar illness: a classic agent for the classic disorder. Bipolar Disord. 2009; 11(Suppl 2): 34-44.
- 80Herbener ES, Harrow M. Longitudinal assessment of negative symptoms in schizophrenia/schizoaffective patients, other psychotic patients, and depressed patients. Schizophr Bull. 2001; 27: 527-537.
- 81Strauss GP, Vertinski M, Vogel SJ, Ringdahl EN, Allen DN. Negative symptoms in bipolar disorder and schizophrenia: a psychometric evaluation of the brief negative symptom scale across diagnostic categories. Schizophr Res. 2016; 170: 285-289.
- 82Marchese G, Scheggi S, Secci ME, De Montis MG, Gambarana C. Anti-anhedonic activity of long-term lithium treatment in rats exposed to repeated unavoidable stress. Int J Neuropsychopharmacol. 2013; 16: 1611-1621.
- 83Kessing LV, Vradi E, Andersen PK. Starting lithium prophylaxis early v. late in bipolar disorder. Br J Psychiatry. 2014; 205: 214-220.
- 84Arts B, Jabben N, Krabbendam L, van Os J. A 2-year naturalistic study on cognitive functioning in bipolar disorder. Acta Psychiatr Scand. 2011; 123: 190-205.
- 85Torrent C, Martinez-Arán A, Daban C, et al. Effects of atypical antipsychotics on neurocognition in euthymic bipolar patients. Compr Psychiatry. 2011; 52: 613-622.
- 86Demmo C, Lagerberg TV, Aminoff SR, et al. History of psychosis and previous episodes as potential explanatory factors for neurocognitive impairment in first-treatment bipolar I disorder. Bipolar Disord. 2016; 18: 136-147.
- 87Pålsson E, Figueras C, Johansson AG, et al. Neurocognitive function in bipolar disorder: a comparison between bipolar I and II disorder and matched controls. BMC Psychiatry. 2013; 13: 165.
- 88Savitz J, van der Merwe L, Stein DJ, Solms M, Ramesar R. Neuropsychological status of bipolar I disorder: impact of psychosis. Br J Psychiatry. 2009; 194: 243-251.
- 89Daban C, Martinez-Aran A, Torrent C, et al. Specificity of cognitive deficits in bipolar disorder versus schizophrenia. A systematic review. Psychother Psychosom. 2006; 75: 72-84.
- 90Torrent C, Bonnin Cdel M, Martinez-Arán A, et al. Efficacy of functional remediation in bipolar disorder: a multicenter randomized controlled study. Am J Psychiatry. 2013; 170: 852-859.
