Abstract
Objective
The effect of benzodiazepine long-term administration (BLTA) in cognitive functioning of subjects with schizophrenia (SZ) has been partially explored to date. The objective was to assess BLTA-associated cognitive impairment with a comprehensive cognitive battery in a non-selected multicentric/national community-dwelling sample of stabilized SZ subjects.
Method
407 community-dwelling stabilized SZ subjects were consecutively included in the FondaMental Academic Centers of Expertise for Schizophrenia Cohort (FACE-SZ). Patients taking daily benzodiazepine were defined as BLTA+ as all patients examined by the Expert Center were clinically stabilized and under stable dose of treatment for at least 3 months. Each patient has been administered a 1-day long comprehensive cognitive battery (including The National Adult Reading Test, the Wechsler Adult Intelligence Scale, the Trail Making Test, the California Verbal Learning Test, the Doors test, and The Continuous Performance Test—Identical Pairs).
Results
In the multivariate analyses, results showed that BLTA was associated with impaired attention/working memory (OR 0.60, 95% confidence interval 0.42–0.86; p = 0.005) independently of socio-demographic variables and illness characteristics. Verbal and performance current IQ—[respectively, OR 0.98, 95% CI (0.96;0.99), p = 0.016 and 0.98, 95% CI(0.97;0.99), p = 0.034] but not premorbid IQ—(p > 0.05) have been associated with BLTA in a multivariate model including the same confounding variables.
Conclusion
BLTA is associated with impaired attention/working memory in schizophrenia. The BLTA benefit/risk ratio should be regularly reevaluated. Alternative pharmacological and non-pharmacological strategies for comorbid anxiety disorders and sleep disorders should be preferred when possible. It seems reasonable to withdraw BLTA before the start of cognitive remediation therapy, as soon as possible, to improve the effectiveness of this therapy. Limits: the delay between the last benzodiazepine intake and testing, as well as the specific class of benzodiazepines (long half-life vs. short half-life), and the number of benzodiazepine daily intakes have not been recorded in the present study. The precise motive for BLTA prescription and sleep disturbances have not been reported, which is a limit for the interpretation of the present results.
References
Achim AM, Maziade M, Raymond É, Olivier D, Mérette C, Roy M-A (2011) How prevalent are anxiety disorders in schizophrenia? A meta-analysis and critical review on a significant association. Schizophr Bull 37:811–821. doi:10.1093/schbul/sbp148
Addington D, Addington J, Maticka-Tyndale E, Joyce J (1992) Reliability and validity of a depression rating scale for schizophrenics. Schizophr Res 6:201–208
APA/CAPP Task Force on Serious Mental Illness and Severe Emotional Disturbance (2007) Training grid: best practices for recovery and improved outcomes for people with serious mental illness/serious emotional disturbance
Baandrup L, Fagerlund B, Glenthoj B (2016) Neurocognitive performance, subjective well-being, and psychosocial functioning after benzodiazepine withdrawal in patients with schizophrenia or bipolar disorder: a randomized clinical trial of add-on melatonin versus placebo. Eur Arch Psychiatry Clin Neurosci. doi:10.1007/s00406-016-0711-8
Baddeley AD, Emslie H, Nimmo-Smith I (1994) Doors and people: a test of visual and verbal recall and recognition. Thames Valley Test Company, Bury St Edmunds
Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Cognitive effects of long-term benzodiazepine use: a meta-analysis. CNS Drugs 18:37–48
Barker MJ, Greenwood KM, Jackson M, Crowe SF (2004) Persistence of cognitive effects after withdrawal from long-term benzodiazepine use: a meta-analysis. Arch Clin Neuropsychol 19:437–454. doi:10.1016/S0887-6177(03)00096-9
Bender R, Lange S (2001) Adjusting for multiple testing—when and how? J Clin Epidemiol 54:343–349. doi:10.1016/S0895-4356(00)00314-0
Berna F, Potheegadoo J, Aouadi I, Ricarte JJ, Allé MC, Coutelle R, Boyer L, Cuervo-Lombard CV, Danion J-M (2016) A meta-analysis of autobiographical memory studies in schizophrenia spectrum disorder. Schizophr Bull 42:56–66. doi:10.1093/schbul/sbv099
Cella M, Reeder C, Wykes T (2015) Cognitive remediation in schizophrenia—now it is really getting personal. Curr Opin Behav Sci 4:147–151
Chouinard S, Poulin J, Stip E, Godbout R (2004) Sleep in untreated patients with schizophrenia: a meta-analysis. Schizophr Bull 30:957–967
Curran HV (1991) Benzodiazepines, memory and mood: a review. Psychopharmacology (Berl) 105:1–8
Curran HV (1986) Tranquillising memories: a review of the effects of benzodiazepines on human memory. Biol Psychol 23:179–213
Delis DC, Kramer JH, Kaplan E, Ober BA (2000) California verbal learning test. The Psychological Corporation, Harcourt Assessment Company, San Antonio
Dold M, Li C, Gillies D, Leucht S (2013) Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: a meta-analysis and Cochrane review of randomized controlled trials. Eur Neuropsychopharmacol J Eur Coll Neuropsychopharmacol 23:1023–1033. doi:10.1016/j.euroneuro.2013.03.001
Elvevag B, Goldberg TE (2000) Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 14(1):1–21
Engin E, Liu J, Rudolph U (2012) α2-containing GABA(A) receptors: a target for the development of novel treatment strategies for CNS disorders. Pharmacol Ther 136:142–152. doi:10.1016/j.pharmthera.2012.08.006
Fatouros-Bergman H, Cervenka S, Flyckt L, Edman G, Farde L (2014) Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia. Schizophr Res 158:156–162. doi:10.1016/j.schres.2014.06.034
Fond G, Boukouaci W, Chevalier G, Regnault A, Eberl G, Hamdani N, Dickerson F, Macgregor A, Boyer L, Dargel A, Oliveira J, Tamouza R, Leboyer M (2014) The “psychomicrobiotic”: targeting microbiota in major psychiatric disorders: a systematic review. Pathol Biol (Paris). doi:10.1016/j.patbio.2014.10.003
Fond G, Boyer L, Favez M, Brunel L, Aouizerate B, Berna F, Capdevielle D, Chereau I, Dorey JM, Dubertret C, Dubreucq X, Faget C, Gabayet F, Laouamri H, Lancon C, Le Strat Y, Misdrahi D, Rey R, Passerieux C, Schandrin A, Schurhoff F, Tronche AM, Urbach M, Vidalhet P, Llorca PM, Pelissolo A, The FACE-SZ (FondaMental Academic Centers of Expertise for Schizophrenia) group* (2015) Medication and aggressiveness in real-world schizophrenia. Results from the FACE-SZ dataset. Psychopharmacology (Berl). doi:10.1007/s00213-015-4167-8
Gatt JM, Burton KLO, Williams LM, Schofield PR (2015) Specific and common genes implicated across major mental disorders: a review of meta-analysis studies. J Psychiatr Res 60:1–13. doi:10.1016/j.jpsychires.2014.09.014
Gillies D, Sampson S, Beck A, Rathbone J (2013) Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev 9:D003079
Green MF, Harvey PD (2014) Cognition in schizophrenia: past, present, and future. Schizophr Res Cogn 1:e1–e9. doi:10.1016/j.scog.2014.02.001
Haw C, Stubbs J (2007) Benzodiazepines—a necessary evil? A survey of prescribing at a specialist UK psychiatric hospital. J Psychopharmacol (Oxf) 21:645–649
Heinrichs RW, Zakzanis KK (1998) Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology 12:426
Holthausen EA, Wiersma D, Cahn W, Kahn RS, Dingemans PM, Schene AH, van den Bosch RJ (2007) Predictive value of cognition for different domains of outcome in recent-onset schizophrenia. Psychiatry Res 149:71–80
Kay SR, Fiszbein A, Opler LA (1987) The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 13:261–276
Kishi T, Moriwaki M, Kawashima K, Okochi T, Fukuo Y, Kitajima T, Furukawa O, Naitoh H, Fujita K, Iwata N (2010) Investigation of clinical factors influencing cognitive function in Japanese schizophrenia. Neurosci Res 66:340–344. doi:10.1016/j.neures.2009.12.007
Kitajima R, Miyamoto S, Tenjin T, Ojima K, Ogino S, Miyake N, Fujiwara K, Funamoto Y, Arai J, Tsukahara S, Ito Y, Tadokoro M, Anai K, Kaneda Y, Yamaguchi N (2012) Effects of tapering of long-term benzodiazepines on cognitive function in patients with schizophrenia receiving a second-generation antipsychotic. Prog Neuropsychopharmacol Biol Psychiatry 36:300–306. doi:10.1016/j.pnpbp.2011.11.008
Korpi ER, Gründer G, Lüddens H (2002) Drug interactions at GABA A receptors. Prog Neurobiol 67:113–159
Lister RG (1985) The amnesic action of benzodiazepines in man. Neurosci Biobehav Rev 9:87–94
Mackinnon A, Mulligan R (2005) The estimation of premorbid intelligence levels in French speakers. L’Encéphale 31:31–43
Matheson SL, Shepherd AM, Pinchbeck RM, Laurens KR, Carr VJ (2013) Childhood adversity in schizophrenia: a systematic meta-analysis. Psychol Med 43:225–238. doi:10.1017/S0033291712000785
Menzies L, Ooi C, Kamath S, Suckling J, McKenna P, Fletcher P, Bullmore E, Stephenson C (2007) Effects of gamma-aminobutyric acid-modulating drugs on working memory and brain function in patients with schizophrenia. Arch Gen Psychiatry 64:156–167. doi:10.1001/archpsyc.64.2.156
Nakazawa K, Zsiros V, Jiang Z, Nakao K, Kolata S, Zhang S, Belforte JE (2012) GABAergic interneuron origin of schizophrenia pathophysiology. Neuropharmacology 62:1574–1583. doi:10.1016/j.neuropharm.2011.01.022
Nelson HE, O’Connell A (1978) Dementia: the estimation of premorbid intelligence levels using the New Adult Reading Test. Cortex J Devoted Study Nerv Syst Behav 14:234–244
Nuechterlein KH, Green MF, Kern RS, Baade LE, Barch DM, Cohen JD, Essock S, Fenton WS, Frese FJ III, Gold JM (2008) The MATRICS Consensus Cognitive Battery, part 1: test selection, reliability, and validity. Am J Psychiatry 165:203–213
Page C et al. (2002) Integrated pharmacology, 2nd ed. C.V. Mosby, St. Louis
Paquette D, Laporte L, Bigras M, Zoccolillo M (2004) Validation of the French version of the CTQ and prevalence of the history of maltreatment. Santé Ment Au Qué 29:201–220
Poitrenaud J, Deweer B, Kalafat M, Van der Linden M (2007) Adaptation en langue française du California Verbal Learning Test. Éditions Cent. Psychol. Appliquée, Paris
Prouteau A, Verdoux H, Briand C, Lesage A, Lalonde P, Nicole L, Reinharz D, Stip E (2004) The crucial role of sustained attention in community functioning in outpatients with schizophrenia. Psychiatry Res 129:171–177
Reitan RM (1958) Validity of the trail making test as an indicator of organic brain damage. Percept Mot Skills 8:271–276
Ryan JJ, Ward LC (1999) Validity, reliability, and standard errors of measurement for two seven-subtest short forms of the Wechsler Adult Intelligence Scale—III. Psychol Assess 11:207
Schürhoff F, Fond G, Berna F, Bulzacka E, Vilain J, Capdevielle D, Misdrahi D, Leboyer M, Llorca P-M, FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) collaborators (2015) A National network of schizophrenia expert centres: an innovative tool to bridge the research-practice gap. Eur Psychiatry J Assoc Eur Psychiatr. doi:10.1016/j.eurpsy.2015.05.004
Tabachnick BG, Fidell LS (2001) Using multivariate statistics. Allyn and Bacon Pearson Education Company, Boston
Takahashi S, Ukai S, Kose A, Hashimoto T, Iwatani J, Okumura M, Tsuji T, Shinosaki K (2013) Reduction of cortical GABAergic inhibition correlates with working memory impairment in recent onset schizophrenia. Schizophr Res 146:238–243. doi:10.1016/j.schres.2013.02.033
Taylor SF, Demeter E, Phan KL, Tso IF, Welsh RC (2014) Abnormal GABAergic function and negative affect in schizophrenia. Neuropsychopharmacol 39:1000–1008. doi:10.1038/npp.2013.300
Tor P-C, Ng TP, Yong K-H, Sim K, Xiang Y-T, Wang C-Y, Lee EHM, Fujii S, Yang S-Y, Chong M-Y, Ungvari GS, Si T, He YL, Chung EK, Chee K-Y, Trivedi J, Udomratn P, Shinfuku N, Kua EH, Tan CH, Sartorius N, Baldessarini RJ (2011) Adjunctive benzodiazepine treatment of hospitalized schizophrenia patients in Asia from 2001 to 2008. Int J Neuropsychopharmacol 14:735–745. doi:10.1017/S146114571000163X
Wechsler D, 1997. WAIS-III: Wechsler Adult Intelligence Scale. Administration and Scoring Manual, Psychological Corporation, San Antonio
Wykes T, Huddy V, Cellard C, McGurk SR, Czobor P (2011) A meta-analysis of cognitive remediation for schizophrenia: methodology and effect sizes. Am J Psychiatry 168:472–485
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 133:429–435
Acknowledgements
Andrianarisoa Méjad,l, MD PhD, Aouizerate Brunoa,l, MD PhD, Berna Fabriceb,l, MD PhD, Blanc Olivierc,l, MSc, Brunel Lored,l, MSc, Bulzacka Ewad,l, MSc, Capdevielle Delphinee,l, MD PhD, Chéreau-Boudet Isabellec,l, MD, Chesnoy-Servanin Gabriellef,l, MSc, Danion Jean-Marieb,l, MD, D’Amato Thierryf,l, MD PhD, Deloge Arnaudg,l, MD PhD, Delorme Claireh,l, MSc, Denizot Hélènec,l, MD, Dorey Jean-Michelf,l, MD, Dubertret Carolinei,l, MD PhD, Dubreucq Julienh,l, MD, Faget Catherinej,l, MD, Fluttaz Cécileh,l, MSc, Fond Guillaumed,l, MD, Fonteneau Sandrinek,l, MSc, Gabayet Franckh,l, MSc, Giraud-Baro Elisabethh,l, MD, Hardy-Baylé Marie-Christinek,l, MD PhD, Lacelle Delphinec,l, MSc, Lançon Christophej,l, MD PhD, Laouamri Hakiml, MSc, Leboyer Mariond,l, MD PhD, Le Gloahec Tifennd,l, MSc, Le Strat Yanni,l, MD PhD, Llorca Pierre-Michelc,l, MD PhD, Mallet Jasminai,j, MD PhD, Metairie Emelinej,l, MSc, Misdrahi Davidg,l, MD, Offerlin-Meyer Isabelleb,l, PhD, Passerieux Christinek,l, MD PhD, Peri Paulinej,l, MSc, Pires Sylviec,l, MSc, Portalier Célinei,l, MSc, Rey Romainf,l, MD, Roman Célineh,l, MSc, Sebilleau Mathildek,l, MSc, Schandrin Auréliee,l, MD, Schurhoff Franckd,l, MD PhD, Tessier Arnaudg,l, MSc, Tronche Anne-Mariec,l, MD, Urbach Mathieuk,l, MD, Vaillant Florencej,l, MSc, Vehier Aurélief,l, MSc, Vidailhet Pierreb,l, MD PhD, Vilà Estelleg,l, MSc, Yazbek Hanane,l, PhD, Zinetti-Bertschy Annab,l, MSc. a Centre Hospitalier Charles Perrens, F-33076 Bordeaux, France; Université de Bordeaux, Inserm, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France; b Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, INSERM U1114, Fédération de Médecine Translationnelle de Strasbourg, Strasbourg, France; c CMP B, CHU, EA 7280 Faculté de Médecine, Université d’Auvergne, BP 69 63003 Clermont-Ferrand Cedex 1, France; d AP-HP, DHU Pe-PSY, Pôle de Psychiatrie et d’addictologie des Hôpitaux Universitaires H Mondor,INSERM U955, Eq. 15 Psychiatrie Translationelle, Université Paris Est-Créteil, Créteil, France; e Service Universitaire de Psychiatrie Adulte, Hôpital la Colombière, CHRU Montpellier, Université Montpellier 1, Inserm 1061, Montpellier, France; f Université Claude Bernard Lyon 1/Centre Hospitalier Le Vinatier Pole Est BP 300 39–95 bd Pinel-69678 BRON Cedex, France; g Centre Hospitalier Charles Perrens, F-33076 Bordeaux, France; Université de Bordeaux, CNRS UMR 5287-INCIA, France; h Centre Référent de Réhabilitation Psychosociale, CH Alpes Isère, Grenoble, France; i AP-HP, Department of Psychiatry, Louis Mourier Hospital, Colombes, Inserm U894 Université Paris Diderot, Sorbonne Paris Cité, Faculté de médecine, France; j Assistance Publique des Hôpitaux de Marseille (AP-HM), pôle universitaire de psychiatrie, Marseille, France; k Service de psychiatrie d’adulte, Centre Hospitalier de Versailles, Le Chesnay, EA 4047 HANDIReSP, UFR des Sciences de la Santé Simone Veil, Université Versailles Saint-Quentin en Yvelines, Versailles, France; l Fondation Fondamental.
Author information
Authors and Affiliations
Consortia
Corresponding author
Additional information
The members of the FACE-SCZ Group are listed in acknowledgements.
Rights and permissions
About this article
Cite this article
Fond, G., Berna, F., Boyer, L. et al. Benzodiazepine long-term administration is associated with impaired attention/working memory in schizophrenia: results from the national multicentre FACE-SZ data set. Eur Arch Psychiatry Clin Neurosci 268, 17–26 (2018). https://doi.org/10.1007/s00406-017-0787-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00406-017-0787-9