Long-term antipsychotic and benzodiazepine use. and brain volume changes in schizophrenia : The Northern Finland Birth Cohort 1966 study

High doses of antipsychotics have been associated with loss in cortical and total gray matter in schizophrenia. However, previous imaging studies have not taken benzodiazepine use into account, in spite of evidence suggesting adverse effects such as cognitive impairment and increased mortality. In this Northern Finland Birth Cohort 1966 study, 69 controls and 38 individuals with schizophrenia underwent brain MRI at the ages of 34 and 43 years. At baseline, the average illness duration was over 10 years. Brain structures were delineated using an automated volumetry system, volBrain, and medication data on cumulative antipsychotic and benzodiazepine doses were collected using medical records and interviews. We used linear regression with intracranial volume and sex as covariates; illness severity was also taken into account. Though both medication doses associated to volumetric changes in subcortical structures, after adjusting for each other and the average PANSS total score, higher scan-interval antipsychotic dose associated only to volume increase in lateral ventricles and higher benzodiazepine dose associated with volume decrease in the caudate nucleus. To our knowledge, there are no previous studies reporting associations between benzodiazepine dose and brain structural changes. Further studies should focus on how these observations correspond to cognition and functioning.Peer reviewe

Brain structural changes in women and men during midlife.

Brain development during childhood and adolescence differs between boys and girls. Structural changes continue during adulthood and old age, particularly in terms of brain volume reductions that accelerate beyond age 35 years. We investigated whether brain structural change in mid-life differs between men and women. 43 men and 28 women from the Northern Finland 1966 Birth Cohort underwent MRI brain scans at age 33-35 (SD=0.67) and then again at age 42-44 (SD=0.41). We examined sex differences in total percentage brain volume change (PBVC) and regional brain change with FSL SIENA software. Women showed significant PBVC reduction compared with men between the ages of 33-35 and 42-44 years (Mean=-3.21% in men, Mean=-4.03% in women, F (1, 68)=6.37, p<0.05). In regional analyses, women exhibited greater brain reduction than men in widespread areas. After controlling for total percent brain volume change, men show greater relative regional brain reduction than women in bilateral precentral gyri, bilateral paracingulate gyri, and bilateral supplementary motor cortices. The results indicate sex differences in brain changes in mid-life. Women have more total brain reduction, and more reduction on the outer brain surface than men, whereas men exhibit more brain reduction on the mid-line surface than women after co-varying for total brain volume loss. These changes could contribute to sex differences in midlife behaviour and health.The study was supported by the UK Medical Research Council (G0701911), the Academy of Finland, the Sigrid Juselius Foundation, the Stanley Foundation, and the Brain and Behavior Research Fund, and was conducted in part within the University of Cambridge Behavioural and Clinical Neuroscience Institute, supported by a joint award by the Medical Research Council (G1000183) and Wellcome Trust (093875/Z/10Z). The funding bodies did not participate in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. We are grateful to Marianne Haapea for assistance with analysis.This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neulet.2016.01.00

The association between antipsychotic and benzodiazepine use with brain morphology and its changes in schizophrenia

Abstract The association between antipsychotics and brain volume changes in schizophrenia is not clear. Previous imaging studies have not examined benzodiazepine use, though it has been linked to cognitive impairment. The aim of this thesis was to examine the association between long-term antipsychotic and benzodiazepine use and brain structures in schizophrenia. Based on a systematic review and meta-analysis of previous studies on long-term antipsychotic use and brain changes in schizophrenia, a higher antipsychotic exposure associated with parietal lobe decrease and basal ganglia increase. Previous data on the topic is very heterogenous and the overall number of studies is small (N=34). Most reported findings were non-significant. In the Northern Finland Birth Cohort 1966, 38 cases with schizophrenia spectrum disorder participated in the longitudinal study at the ages of 24 and 43. In the cross-sectional study, 44 cases with schizophrenia and 35 cases with affective psychoses participated at the age of 43. Structural brain MRI scans were acquired from all participants an data on antipsychotic and benzodiazepine dose was collected using medical records and interviews. Illness severity and antipsychotic/benzodiazepine dose were included as confounders in the analyses. Higher scan-interval antipsychotic dose associated to volume increase in lateral ventricles and higher benzodiazepine dose associated to volume decrease in the caudate nucleus during the 9-year follow-up. In the 43-year study, higher lifetime antipsychotic dose associated to smaller nucleus accumbens volume in schizophrenia. In comparison, higher lifetime benzodiazepine dose associated to larger volumes of total gray matter, cerebral gray matter, and thalamus in affective psychoses. In analyses without illness severity and other medication as confounders, there were several statistically significant associations. It seems that long-term antipsychotic use may associate to structural brain changes in schizophrenia and some associations may be confounded by symptoms and the use of benzodiazepines. These findings underline the importance of taking benzodiazepine use and other confounding factors into account when studying the effects of antipsychotics on the brain. Further studies should focus on how these findings relate to cognition and functioning.Tiivistelmä Psykoosilääkityksen yhteys skitsofreniassa tapahtuviin aivomuutoksiin on epäselvä. Aiemmat kuvantamistutkimukset eivät ole tutkineet bentsodiatsepiinien käyttöä, vaikka niiden käyttö on yhdistetty heikompaan kognititioon. Tämän tutkimuksen tarkoituksena oli selvittää pitkäaikaisen psykoosi- ja bentsodiatsepiinlääkityksen yhteyttä aivojen rakenteisiin skitsofreniassa. Systemaattisen katsauksen ja meta-analyysin perusteella suurempi psykoosilääkeannos liittyi päälakilohkon tilavuuden pienenemiseen sekä tyvitumakkeiden koon kasvuun skitsofreniassa pitkäaikaisseurannoissa. Aikaisempi kirjallisuus on erittäin heterogeenistä ja tutkimusten kokonaismäärä on pieni (N=34). Suurin osa löydöksistä ei ollut tilastollisesti merkitseviä. Pohjois-Suomen syntymäkohortti 1966 aineistossa 38 skitsofreniaspektrin psykoosia sairastavaa henkilöä osallistui pitkittäistutkimukseen 34 vuoden ja 43 vuoden iässä. Poikkileikkaustutkimuksessa 44 skitsofreniaa ja 24 mielialapsykoosia sairastavaa henkilöä osallistui tutkimukseen 43 vuoden iässä. Pään rakenteellinen magneettikuvaus tehtiin kaikille osallistujille. Tiedot psykoosilääkkeiden ja bentsodiatsepiinien annoksista kerättiin sairauskertomusmerkinnöistä ja haastatteluista. Taudin vakavuus ja psykoosilääkkeiden/bentosidatsepiinien annos huomioitiin sekoittavina tekijöinä. Korkeampi psykoosilääkeannos liittyi aivokammioiden koon kasvuun ja korkeampi bentsodiatsepiiniannos häntätumakkeen koon pienenemiseen 9 vuoden seurannassa. Poikkileikkaustutkimuksessa korkeampi elinaikainen psykoosilääkeannos liittyi pienempään makaavan tumakkeen tilavuuteen skitsofreniassa. Mielialapsykooseissa korkeampi elinaikainen bentsodiatsepiiniannos liittyi suurempaan koko aivojen harmaan aineen, isoaivojen harmaan aineen ja talamuksen tilavuuteen. Kun sekoittavia tekijöitä ei otettu huomioon, tilastollisesti merkitseviä yhteyksiä löytyi useammilta aivoalueilta Tutkimuksen perusteella psykoosilääkkeiden pitkäaikaiskäyttö saattaa liittyä aivojen rakenteellisiin muutoksiin skitsofreniassa. Bentsodiatsepiinien käyttö ja oireet voivat toimia sekoittavina tekijöinä. Löydökset korostavat sekoittavien tekijöiden huomioimisen tärkeyttä tutkittaessa psykoosilääkkeiden vaikutuksia aivoihin. Tulevaisuudessa tutkimusten tulisi selvittää, miten löydökset liittyvät kognitioon ja toimintakykyyn

Early Adversity and Emotion Processing From Faces: A Meta-analysis on Behavioral and Neurophysiological Responses

BACKGROUND: Although the link between early adversity (EA) and later-life psychiatric disorders is well established, it has yet to be elucidated whether EA is related to distortions in the processing of different facial expressions. We conducted a meta-analysis to investigate whether exposure to EA relates to distortions in responses to different facial emotions at three levels: 1) event-related potentials of the P100 and N170, 2) amygdala functional magnetic resonance imaging responses, and 3) accuracy rate or reaction time in behavioral data. METHODS: The systematic literature search (PubMed and Web of Science) up to April 2020 resulted in 29 behavioral studies (n = 8555), 32 functional magnetic resonance imaging studies (n = 2771), and 3 electroencephalography studies (n = 197) for random-effect meta-analyses. RESULTS: EA was related to heightened bilateral amygdala reactivity to sad faces (but not other facial emotions). Exposure to EA was related to faster reaction time but a normal accuracy rate in response to angry and sad faces. In response to fearful and happy faces, EA was related to a lower accuracy rate only in individuals with recent EA exposure. This effect was more pronounced in individuals with exposure to EA before (vs. after) the age of 3 years. These findings were independent of psychiatric diagnoses. Because of the low number of eligible electroencephalography studies, no conclusions could be reached regarding the effect of EA on the event-related potentials. CONCLUSIONS: EA relates to alterations in behavioral and neurophysiological processing of facial emotions. Our study stresses the importance of assessing age at exposure and time since EA because these factors mediate some EA-related perturbations

Lifetime use of psychiatric medications and cognition at 43 years of age in schizophrenia in the Northern Finland Birth Cohort 1966

Background: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. Methods: Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43 years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. Results: Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11 months) before the cognitive examination was associated with better cognitive performance (P = 0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P = 0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. Conclusions: Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia. (C) 2017 Elsevier Masson SAS. All rights reserved.Peer reviewe

Early adversity and emotion processing from faces:a meta-analysis on behavioral and neurophysiological responses

Abstract Background: Although the link between early adversity (EA) and later-life psychiatric disorders is well established, it has yet to be elucidated whether EA is related to distortions in the processing of different facial expressions. We conducted a meta-analysis to investigate whether exposure to EA relates to distortions in responses to different facial emotions at three levels: 1) event-related potentials of the P100 and N170, 2) amygdala functional magnetic resonance imaging responses, and 3) accuracy rate or reaction time in behavioral data. Methods: The systematic literature search (PubMed and Web of Science) up to April 2020 resulted in 29 behavioral studies (n = 8555), 32 functional magnetic resonance imaging studies (n = 2771), and 3 electroencephalography studies (n = 197) for random-effect meta-analyses. Results: EA was related to heightened bilateral amygdala reactivity to sad faces (but not other facial emotions). Exposure to EA was related to faster reaction time but a normal accuracy rate in response to angry and sad faces. In response to fearful and happy faces, EA was related to a lower accuracy rate only in individuals with recent EA exposure. This effect was more pronounced in individuals with exposure to EA before (vs. after) the age of 3 years. These findings were independent of psychiatric diagnoses. Because of the low number of eligible electroencephalography studies, no conclusions could be reached regarding the effect of EA on the event-related potentials. Conclusions: EA relates to alterations in behavioral and neurophysiological processing of facial emotions. Our study stresses the importance of assessing age at exposure and time since EA because these factors mediate some EA-related perturbations

Medication management of antipsychotic treatment in schizophrenia:a narrative review

Abstract Background/Objective: The risk-benefit ratio of antipsychotics in schizophrenia depends primarily on their effect on brain chemistry. An important factor influencing the efficacy of prescribed drugs is medication management, which can be defined as an ongoing process to manage and monitor the recommended use of antipsychotics to facilitate their cost-effective, adherent, and acceptable use. Materials: We reviewed narratively relevant literature that examined the medication management of antipsychotics in schizophrenia based on a search of PubMed, Scopus, Web of Science, PsycARTICLES, and Cochrane in May 2020. We also included controlled interventional studies with a follow-up period of at least 2 years. Results: Based on the previous literature, there is no unified approach for optimal medication management, but multiple useful strategies are presented for individual patients, prescribers, and organizations. Conclusions: Systematic medication management may improve the risk-benefit balance of antipsychotics by achieving the lowest effective dose, minimizing adverse effects, and improving adherence. There is a need for well-designed naturalistic studies and clinical trials to optimize management in schizophrenia

Psychiatric research in the Northern Finland Birth Cohort 1986:a systematic review

Abstract The Northern Finland Birth Cohort 1986 is a large population-based birth cohort, which aims to promote health and wellbeing of the population. In this paper, we systematically review the psychiatric research performed in the cohort until today, i.e. at the age of 32 years of the cohort (2018). We conducted a systematic literature search using the databases of PubMed and Scopus and complemented it with a manual search. We found a total of 94 articles, which were classified as examining ADHD, emotional and behavioural problems, psychosis risk or other studies relating to psychiatric subjects. The articles are mainly based on two large comprehensive follow-up studies of the cohort and several substudies. The studies have often used also nationwide register data. The studies have found several early predictors for the aforementioned psychiatric outcomes, such as problems at pregnancy and birth, family factors in childhood, physical inactivity and substance use in adolescence. There are also novel findings relating to brain imaging and cognition, for instance regarding familial risk of psychosis in relation to resting state functional MRI. The Northern Finland Birth Cohort 1986 has been utilised frequently in psychiatric research and future data collections are likely to lead to new scientifically important findings

Structural and functional alterations in the brain gray matter among first-degree relatives of schizophrenia patients:a multimodal meta-analysis of fMRI and VBM studies

Abstract Objective: We conducted a multimodal coordinate-based meta-analysis (CBMA) to investigate structural and functional brain alterations in first-degree relatives of schizophrenia patients (FRs). Methods: We conducted a systematic literature search from electronic databases to find studies that examined differences between FRs and healthy controls using whole-brain functional magnetic resonance imaging (fMRI) or voxel-based morphometry (VBM). A CBMA of 30 fMRI (754 FRs; 959 controls) and 11 VBM (885 FRs; 775 controls) datasets were conducted using the anisotropic effect-size version of signed differential mapping. Further, we conducted separate meta-analyses about functional alterations in different cognitive tasks: social cognition, executive functioning, working memory, and inhibitory control. Results: FRs showed higher fMRI activation in the right frontal gyrus during cognitive tasks than healthy controls. In VBM studies, there were no differences in gray matter density between FRs and healthy controls. Furthermore, multi-modal meta-analysis obtained no differences between FRs and healthy controls. By utilizing the BrainMap database, we showed that the brain region which showed functional alterations in FRs (i) overlapped only slightly with the brain regions that were affected in the meta-analysis of schizophrenia patients and (ii) correlated positively with the brain regions that exhibited increased activity during cognitive tasks in healthy individuals. Conclusions: Based on this meta-analysis, FRs may exhibit only minor functional alterations in the brain during cognitive tasks, and the alterations are much more restricted and only slightly overlapping with the regions that are affected in schizophrenia patients. The familial risk did not relate to structural alterations in the gray matter

Lifetime use of psychiatric medications and cognition at 43 years of age in schizophrenia in the Northern Finland Birth Cohort 1966

Abstract Background: Higher lifetime antipsychotic exposure has been associated with poorer cognition in schizophrenia. The cognitive effects of adjunctive psychiatric medications and lifetime trends of antipsychotic use remain largely unclear. We aimed to study how lifetime and current benzodiazepine and antidepressant medications, lifetime trends of antipsychotic use and antipsychotic polypharmacy are associated with cognitive performance in midlife schizophrenia. Methods: Sixty participants with DSM-IV schizophrenia from the Northern Finland Birth Cohort 1966 were examined at 43 years of age with an extensive cognitive test battery. Cumulative lifetime and current use of psychiatric medications were collected from medical records and interviews. The associations between medication and principal component analysis-based cognitive composite score were analysed using linear regression. Results: Lifetime cumulative DDD years of benzodiazepine and antidepressant medications were not significantly associated with global cognition. Being without antipsychotic medication (for minimum 11 months) before the cognitive examination was associated with better cognitive performance (P = 0.007) and higher lifetime cumulative DDD years of antipsychotics with poorer cognition (P = 0.020), when adjusted for gender, onset age and lifetime hospital treatment days. Other lifetime trends of antipsychotic use, such as a long antipsychotic-free period earlier in the treatment history, and antipsychotic polypharmacy, were not significantly associated with cognition. Conclusions: Based on these naturalistic data, low exposure to adjunctive benzodiazepine and antidepressant medications does not seem to affect cognition nor explain the possible negative effects of high dose long-term antipsychotic medication on cognition in schizophrenia