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3. Genome-wide association analyses of symptom severity among clozapine-treated patients with schizophrenia spectrum disorders

Author

Okhuijsen-Pfeifer, C., van der Horst, M. Z., Bousman, C. A., Lin, B., van Eijk, K. R., Ripke, S., Ayhan, Y., Babaoglu, M. O., Bak, M., Alink, W., van Beek, H., Beld, E., Bouhuis, A., Edlinger, M., Erdogan, I. M., Ertuğrul, A., Yoca, G., Everall, I. P., Görlitz, T., Grootens, K. P., Gutwinski, S., Hallikainen, T., Jeger-Land, E., de Koning, M., Lähteenvuo, M., Legge, S. E., Leucht, S., Morgenroth, C., Müderrisoğlu, A., Narang, A., Pantelis, C., Pardiñas, A. F., Oviedo-Salcedo, T., Schneider-Thoma, J., Schreiter, S., Repo-Tiihonen, E., Tuppurainen, H., Veereschild, M., Veerman, S., de Vos, M., Wagner, E., Cohen, D., Bogers, J. P. A. M., Walters, J. T. R., Yağcıoğlu, A. E. Anil, Tiihonen, J., Hasan, A., and Luykx, J. J.

Published
2022
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6. Cohort profile:SUPER-Finland – the Finnish study for hereditary mechanisms of psychotic disorders

Author

Lähteenvuo, M. (Markku), Ahola-Olli, A. (Ari), Suokas, K. (Kimmo), Holm, M. (Minna), Misiewicz, Z. (Zuzanna), Jukuri, T. (Tuomas), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Kajanne, R. (Risto), Kyttälä, A. (Aija), Tuulio-Henriksson, A. (Annamari), Lahdensuo, K. (Kaisla), Häkkinen, K. (Katja), Hietala, J. (Jarmo), Paunio, T. (Tiina), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Kampman, O. (Olli), Tiihonen, J. (Jari), Hyman, S. (Steven), Neale, B. (Benjamin), Daly, M. (Mark), Suvisaari, J. (Jaana), Palotie, A. (Aarno), Lähteenvuo, M. (Markku), Ahola-Olli, A. (Ari), Suokas, K. (Kimmo), Holm, M. (Minna), Misiewicz, Z. (Zuzanna), Jukuri, T. (Tuomas), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Kajanne, R. (Risto), Kyttälä, A. (Aija), Tuulio-Henriksson, A. (Annamari), Lahdensuo, K. (Kaisla), Häkkinen, K. (Katja), Hietala, J. (Jarmo), Paunio, T. (Tiina), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Kampman, O. (Olli), Tiihonen, J. (Jari), Hyman, S. (Steven), Neale, B. (Benjamin), Daly, M. (Mark), Suvisaari, J. (Jaana), and Palotie, A. (Aarno)

Abstract

Purpose: SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland. Participants: 10 474 individuals aged 18 years or older were recruited throughout the country. The subjects have been genotyped with a genome-wide genotyping chip and exome sequenced. A subset of 897 individuals selected from known population sub-isolates were selected for whole-genome sequencing. Recruitment was done between November 2015 and December 2018. Findings to date: 5757 (55.2%) had a diagnosis of schizophrenia, 944 (9.1%) schizoaffective disorder, 1612 (15.5%) type I or type II bipolar disorder, 532 (5.1 %) psychotic depression, 1047 (10.0%) other psychosis and for 530 (5.1%) self-reported psychosis at recruitment could not be confirmed from register data. Mean duration of schizophrenia was 22.0 years at the time of the recruitment. By the end of the year 2018, 204 of the recruited individuals had died. The most common cause of death was cardiovascular disease (n=61) followed by neoplasms (n=40). Ten subjects had psychiatric morbidity as the primary cause of death. Future plans: Compare the effects of common variants, rare variants and copy number variations (CNVs) on severity of psychotic illness. In addition, we aim to track longitudinal course of illness based on nation-wide register data to estimate how phenotypic and genetic differences alter it.

Published
2023

7. Associations between polygenic risk score loading, psychosis liability, and clozapine use among individuals with schizophrenia

Author

Lin, B.D., Pinzón-Espinosa, J., Blouzard, E., Van Der Horst, M.Z., Okhuijsen-pfeifer, C., Van Eijk, K.R., Guloksuz, S., Peyrot, W.J., Luykx, J.J., Hasan, A., Wagner, E., Pantelis, C., Everall, I.P., Ayhan, Y., Babaoğlu, M.O., Bak, M., Alink, W., Beld, E, Bouhuis, A., Edlinger, M., Erdoğan, I.M., Gutwinski, S., Hallikainen, T., Jeger-land, E., Lähteenvuo, M., De Koning, M.B., Morgenroth, C., Müderrisoğlu, A., Oviedo-salcedo, T., Schreiter, S., Repo-tiihonen, E., Tuppurainen, H., Veereschild, M., Veerman, S.R.T., Cohen, D., de Vos, M., Bogers, J.P.A.M., Anıl Yağcıoğlu, A.E., Tiihonen, J., Ripke, S., Bousman, C.A., Van Beek, H, van der Horst, M., Van Eijk, K., Ertuğrul, A., Yoca, G., Görlitz, T., Grootens, K., Leucht, S., Narang, A., Schneider-thoma, J., Kahn, R.S., Bekema, E., Kleymann, P., Alizadeh, B.Z., van Amelsvoort, T., Cahn, W., de Haan, L., Schirmbeck, F., Simons, C.J.P., van Os, J., Rutten, B., van Winkel, R., Lin, B.D., Pinzón-Espinosa, J., Blouzard, E., Van Der Horst, M.Z., Okhuijsen-pfeifer, C., Van Eijk, K.R., Guloksuz, S., Peyrot, W.J., Luykx, J.J., Hasan, A., Wagner, E., Pantelis, C., Everall, I.P., Ayhan, Y., Babaoğlu, M.O., Bak, M., Alink, W., Beld, E, Bouhuis, A., Edlinger, M., Erdoğan, I.M., Gutwinski, S., Hallikainen, T., Jeger-land, E., Lähteenvuo, M., De Koning, M.B., Morgenroth, C., Müderrisoğlu, A., Oviedo-salcedo, T., Schreiter, S., Repo-tiihonen, E., Tuppurainen, H., Veereschild, M., Veerman, S.R.T., Cohen, D., de Vos, M., Bogers, J.P.A.M., Anıl Yağcıoğlu, A.E., Tiihonen, J., Ripke, S., Bousman, C.A., Van Beek, H, van der Horst, M., Van Eijk, K., Ertuğrul, A., Yoca, G., Görlitz, T., Grootens, K., Leucht, S., Narang, A., Schneider-thoma, J., Kahn, R.S., Bekema, E., Kleymann, P., Alizadeh, B.Z., van Amelsvoort, T., Cahn, W., de Haan, L., Schirmbeck, F., Simons, C.J.P., van Os, J., Rutten, B., and van Winkel, R.

Abstract

Importance: Predictors consistently associated with psychosis liability and course of illness in schizophrenia (SCZ) spectrum disorders (SSD), including the need for clozapine treatment, are lacking. Longitudinally ascertained medication use may empower studies examining associations between polygenic risk scores (PRSs) and pharmacotherapy choices. Objective: To examine associations between PRS-SCZ loading and groups with different liabilities to SSD (individuals with SSD taking clozapine, individuals with SSD taking other antipsychotics, their parents and siblings, and unrelated healthy controls) and between PRS-SCZ and the likelihood of receiving a prescription of clozapine relative to other antipsychotics. Design, Setting, and Participants: This genetic association study was a multicenter, observational cohort study with 6 years of follow-up. Included were individuals diagnosed with SSD who were taking clozapine or other antipsychotics, their parents and siblings, and unrelated healthy controls. Data were collected from 2004 until 2021 and analyzed between October 2021 and September 2022. Exposures: Polygenic risk scores for SCZ. Main Outcomes and Measures: Multinomial logistic regression was used to examine possible differences between groups by computing risk ratios (RRs), ie, ratios of the probability of pertaining to a particular group divided by the probability of healthy control status. We also computed PRS-informed odd ratios (ORs) for clozapine use relative to other antipsychotics. Results: Polygenic risk scores for SCZ were generated for 2344 participants (mean [SD] age, 36.95 years [14.38]; 994 female individuals [42.4%]) who remained after quality control screening (557 individuals with SSD taking clozapine, 350 individuals with SSD taking other antipsychotics during the 6-year follow-up, 542 parents and 574 siblings of individuals with SSD, and 321 unrelated healthy controls). All RR

Published
2023

8. Patterns of risk—Using machine learning and structural neuroimaging to identify pedophilic offenders

Author

Popovic, D., Wertz, M., Geisler, C., Kaufmann, J., Lähteenvuo, M., Lieslehto, J., Witzel, J., Bogerts, B., Walter, M., Falkai, P., Koutsouleris, N., and Schiltz, K.

Subjects
Psychiatry and Mental health
Abstract

BackgroundChild sexual abuse (CSA) has become a focal point for lawmakers, law enforcement, and mental health professionals. With high prevalence rates around the world and far-reaching, often chronic, individual, and societal implications, CSA and its leading risk factor, pedophilia, have been well investigated. This has led to a wide range of clinical tools and actuarial instruments for diagnosis and risk assessment regarding CSA. However, the neurobiological underpinnings of pedosexual behavior, specifically regarding hands-on pedophilic offenders (PO), remain elusive. Such biomarkers for PO individuals could potentially improve the early detection of high-risk PO individuals and enhance efforts to prevent future CSA.AimTo use machine learning and MRI data to identify PO individuals.MethodsFrom a single-center male cohort of 14 PO individuals and 15 matched healthy control (HC) individuals, we acquired diffusion tensor imaging data (anisotropy, diffusivity, and fiber tracking) in literature-based regions of interest (prefrontal cortex, anterior cingulate cortex, amygdala, and corpus callosum). We trained a linear support vector machine to discriminate between PO and HC individuals using these WM microstructure data. Post hoc, we investigated the PO model decision scores with respect to sociodemographic (age, education, and IQ) and forensic characteristics (psychopathy, sexual deviance, and future risk of sexual violence) in the PO subpopulation. We assessed model specificity in an external cohort of 53 HC individuals.ResultsThe classifier discriminated PO from HC individuals with a balanced accuracy of 75.5% (sensitivity = 64.3%, specificity = 86.7%, P5000 = 0.018) and an out-of-sample specificity to correctly identify HC individuals of 94.3%. The predictive brain pattern contained bilateral fractional anisotropy in the anterior cingulate cortex, diffusivity in the left amygdala, and structural prefrontal cortex-amygdala connectivity in both hemispheres. This brain pattern was associated with the number of previous child victims, the current stance on sexuality, and the professionally assessed risk of future sexual violent reoffending.ConclusionAberrant white matter microstructure in the prefronto-temporo-limbic circuit could be a potential neurobiological correlate for PO individuals at high-risk of reoffending with CSA. Although preliminary and exploratory at this point, our findings highlight the general potential of MRI-based biomarkers and particularly WM microstructure patterns for future CSA risk assessment and preventive efforts.

Published
2023

16. Substance use and sleep problems in patients with psychotic disorders

Author

Cederlöf, E. (Erik), Holm, M. (Minna), Ahti, J. (Johan), Lähteenvuo, M. (Markku), Hietala, J. (Jarmo), Häkkinen, K. (Katja), Isometsä, E. (Erkki), Kampman, O. (Olli), Lahdensuo, K. (Kaisla), Lönnqvist, J. (Jouko), Suvisaari, J. (Jaana), Tiihonen, J. (Jari), Wegelius, A. (Asko), Veijola, J. (Juha), Palotie, A. (Aarno), Kieseppä, T. (Tuula), Niemelä, S. (Solja), Paunio, T. (Tiina), Cederlöf, E. (Erik), Holm, M. (Minna), Ahti, J. (Johan), Lähteenvuo, M. (Markku), Hietala, J. (Jarmo), Häkkinen, K. (Katja), Isometsä, E. (Erkki), Kampman, O. (Olli), Lahdensuo, K. (Kaisla), Lönnqvist, J. (Jouko), Suvisaari, J. (Jaana), Tiihonen, J. (Jari), Wegelius, A. (Asko), Veijola, J. (Juha), Palotie, A. (Aarno), Kieseppä, T. (Tuula), Niemelä, S. (Solja), and Paunio, T. (Tiina)

Abstract

Background: Substance use and sleep problems are common in patients with psychotic disorders, but their associations in these patients have not been evaluated. We aimed to investigate associations between substance use and sleep problems in a large nationwide cohort of patients with a psychotic disorder. Study Design: This study is part of the Finnish SUPER study, which belongs to the Stanley Global Neuropsychiatric Genomics Initiative. In this cross-sectional, multicenter study, participants (N = 8616) were recruited from primary and specialized healthcare. Patients with schizophrenia, schizoaffective disorder, bipolar disorder, and psychotic depression were included. Information on current alcohol (Alcohol Use Disorders Identification Test-Concise) and cigarette use as well as on lifetime illicit drug use, including cannabis, benzodiazepines, amphetamines, and opioids, was collected using questionnaires. The sleep outcomes in our logistic regression analysis were short (≤6 h) and long sleep (≥10 h) duration, difficulties initiating asleep, early morning awakenings, fatigue, and poor sleep quality (SQ). Results: Self-reported substance use was associated with a higher prevalence of sleep problems. After adjustments with age, gender, diagnostic group, and living status, hazardous alcohol use (eg, poor SQ odds ratio [OR] = 1.80, 95% CI: 1.49 to 2.16, P < .001), current smoking (short sleep duration OR = 1.28, 95% CI: 1.08 to 1.52, P = .005), and lifetime benzodiazepine misuse (difficulties initiating sleep OR = 2.00, 95% CI: 1.55 to 2.48, P < .001) were associated with sleep problems. Conclusions: Substance use was associated with sleep problems. Our findings underline the potential benefits of screening substance use when treating sleep problems in patients with psychotic disorders.

Published
2022

17. Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Author

Häkkinen, K. (Katja), Kiiski, J. I. (Johanna I.), Lähteenvuo, M. (Markku), Jukuri, T. (Tuomas), Suokas, K. (Kimmo), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Lahdensuo, K. (Kaisla), Kajanne, R. (Risto), Kaunisto, M. A. (Mari A.), Tuulio-Henriksson, A. (Annamari), Kampman, O. (Olli), Hietala, J. (Jarmo), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Paunio, T. (Tiina), Suvisaari, J. (Jaana), Kalso, E. (Eija), Niemi, M. (Mikko), Tiihonen, J. (Jari), Daly, M. (Mark), Palotie, A. (Aarno), Ahola-Olli, A. V. (Ari V.), Häkkinen, K. (Katja), Kiiski, J. I. (Johanna I.), Lähteenvuo, M. (Markku), Jukuri, T. (Tuomas), Suokas, K. (Kimmo), Niemi-Pynttäri, J. (Jussi), Kieseppä, T. (Tuula), Männynsalo, T. (Teemu), Wegelius, A. (Asko), Haaki, W. (Willehard), Lahdensuo, K. (Kaisla), Kajanne, R. (Risto), Kaunisto, M. A. (Mari A.), Tuulio-Henriksson, A. (Annamari), Kampman, O. (Olli), Hietala, J. (Jarmo), Veijola, J. (Juha), Lönnqvist, J. (Jouko), Isometsä, E. (Erkki), Paunio, T. (Tiina), Suvisaari, J. (Jaana), Kalso, E. (Eija), Niemi, M. (Mikko), Tiihonen, J. (Jari), Daly, M. (Mark), Palotie, A. (Aarno), and Ahola-Olli, A. V. (Ari V.)

Abstract

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genetics study to construct an imputation panel (n = 902) for CYP2D6 CNV. The resulting data set was used as a CYP2D6 CNV imputation panel in 9262 non-related individuals from the SUPER-Finland study. Based on imputation of 9262 individuals we confirm the higher frequency of CYP2D6 ultrarapid metabolizers and a 22-fold enrichment of the UGT1A1 decreased function variant rs4148323 (UGT1A1*6) in Finland compared with non-Finnish Europeans. Similarly, the NUDT15 variant rs116855232 was highly enriched in Finland. We demonstrate that imputation of CYP2D6 CNV is possible and the methodology enables studying CYP2D6 in large biobanks with genome-wide data.

Published
2022

18. Sleep in psychotic disorders:results from nationwide SUPER Finland study

Author

Cederlöf, E. (Erik), Holm, M. (Minna), Lähteenvuo, M. (Markku), Haaki, W. (Willehard), Hietala, J. (Jarmo), Häkkinen, K. (Katja), Isometsä, E. (Erkki), Jukuri, T. (Tuomas), Kajanne, R. (Risto), Kampman, O. (Olli), Kieseppä, T. (Tuula), Lahdensuo, K. (Kaisla), Lönnqvist, J. (Jouko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Suvisaari, J. (Jaana), Tiihonen, J. (Jari), Turunen, H. (Hannu), Wegelius, A. (Asko), Veijola, J. (Juha), Palotie, A. (Aarno), Paunio, T. (Tiina), Cederlöf, E. (Erik), Holm, M. (Minna), Lähteenvuo, M. (Markku), Haaki, W. (Willehard), Hietala, J. (Jarmo), Häkkinen, K. (Katja), Isometsä, E. (Erkki), Jukuri, T. (Tuomas), Kajanne, R. (Risto), Kampman, O. (Olli), Kieseppä, T. (Tuula), Lahdensuo, K. (Kaisla), Lönnqvist, J. (Jouko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Suvisaari, J. (Jaana), Tiihonen, J. (Jari), Turunen, H. (Hannu), Wegelius, A. (Asko), Veijola, J. (Juha), Palotie, A. (Aarno), and Paunio, T. (Tiina)

Abstract

Objective: Characterizing sleep in patients with schizophrenia, schizoaffective disorder, bipolar disorder, and psychotic depression. Methods: This cross-sectional questionnaire study is based on the SUPER study sample, which is part of the Stanley Global Neuropsychiatric Genomics Initiative. The study is a multicentre, nationwide Finnish study consisting of patients (N = 8 623) both in primary and specialized health care. The main measurements were sleep duration, difficulties initiating sleep, early morning awakenings, and fatigue. These results were compared with a nationally representative sample of the Finnish population from the Health 2000 survey (N = 7 167) with frequency and logistic regression analyses. Results: Patients had more sleep problems compared with the general population, especially young and middle-aged patients (Difficulties initiating sleep in young patients odds ratio = 12.3, 95% CI 9.8–15.4). Long sleep duration was the most deviating property of the sleep characteristics, being particularly common among young patients with schizophrenia (odds ratio = 27.9, 95% CI 22.1–35.2, 47.4% vs 3.3% prevalence). All sleep problems were associated with worse subjective health. We also conducted a latent class analysis, resulting in a cluster relatively free of sleep problems (58% of patients), an insomnia symptom cluster (26%), and a hypersomnia symptom cluster (15%). Conclusions: In our sample, patients with psychotic disorders have more sleep problems—especially long sleep duration but also insomnia symptoms—compared with the general population. The patients can in a latent class analysis of their sleep symptoms be divided into groups with differing sleep profiles.

Published
2022

25. Reaction time and visual memory in connection to alcohol use in persons with bipolar disorder

Author

Mazumder, A. H. (Atiqul Haq), Barnett, J. (Jennifer), Isometsä, E. T. (Erkki Tapio), Lindberg, N. (Nina), Torniainen-Holm, M. (Minna), Lähteenvuo, M. (Markku), Lahdensuo, K. (Kaisla), Kerkelä, M. (Martta), Ahola-Olli, A. (Ari), Hietala, J. (Jarmo), Kampman, O. (Olli), Kieseppä, T. (Tuula), Jukuri, T. (Tuomas), Häkkinen, K. (Katja), Cederlöf, E. (Erik), Haaki, W. (Willehard), Kajanne, R. (Risto), Wegelius, A. (Asko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Lönnqvist, J. (Jouko), Tiihonen, J. (Jari), Paunio, T. (Tiina), Vainio, S. J. (Seppo Juhani), Palotie, A. (Aarno), Niemelä, S. (Solja), Suvisaari, J. (Jaana), Veijola, J. (Juha), Mazumder, A. H. (Atiqul Haq), Barnett, J. (Jennifer), Isometsä, E. T. (Erkki Tapio), Lindberg, N. (Nina), Torniainen-Holm, M. (Minna), Lähteenvuo, M. (Markku), Lahdensuo, K. (Kaisla), Kerkelä, M. (Martta), Ahola-Olli, A. (Ari), Hietala, J. (Jarmo), Kampman, O. (Olli), Kieseppä, T. (Tuula), Jukuri, T. (Tuomas), Häkkinen, K. (Katja), Cederlöf, E. (Erik), Haaki, W. (Willehard), Kajanne, R. (Risto), Wegelius, A. (Asko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Lönnqvist, J. (Jouko), Tiihonen, J. (Jari), Paunio, T. (Tiina), Vainio, S. J. (Seppo Juhani), Palotie, A. (Aarno), Niemelä, S. (Solja), Suvisaari, J. (Jaana), and Veijola, J. (Juha)

Abstract

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol-related disorder in persons with bipolar disorder (BD). The study population included 1268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol-related disorder including alcohol use disorder (AUD). Hazardous drinking was screened with the Alcohol Use Disorders Identification Test for Consumption (AUDIT-C) screening tool. Alcohol-related disorder diagnoses were obtained from the national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on A tablet computer: the 5-choice serial reaction time task, or reaction time (RT) test and the Paired Associative Learning (PAL) test. Depressive symptoms were assessed with the Mental Health Inventory with five items (MHI-5). However, no assessment of current manic symptoms was available. Association between RT-test and alcohol use was analyzed with log-linear regression, and eβ with 95% confidence intervals (CI) are reported. PAL first trial memory score was analyzed with linear regression, and β with 95% CI are reported. PAL total errors adjusted was analyzed with logistic regression and odds ratios (OR) with 95% CI are reported. After adjustment of age, education, housing status and depression, hazardous drinking was associated with lower median and less variable RT in females while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores in females. Our findings of positive associations between alcohol use and cognition in persons with bipolar disorder are difficult to explain because of the methodological flaw of not being able to separately assess only participants in euthymic phase.

Published
2021

26. Reaction time and visual memory in connection to hazardous drinking polygenic scores in schizophrenia, schizoaffective disorder and bipolar disorder

Author

Mazumder, A. H. (Atiqul Haq), Barnett, J. (Jennifer), Isometsä, E. T. (Erkki Tapio), Lindberg, N. (Nina), Torniainen-Holm, M. (Minna), Lähteenvuo, M. (Markku), Lahdensuo, K. (Kaisla), Kerkelä, M. (Martta), Ahola-Olli, A. (Ari), Hietala, J. (Jarmo), Kampman, O. (Olli), Kieseppä, T. (Tuula), Jukuri, T. (Tuomas), Häkkinen, K. (Katja), Cederlöf, E. (Erik), Haaki, W. (Willehard), Kajanne, R. (Risto), Wegelius, A. (Asko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Lönnqvist, J. (Jouko), Tiihonen, J. (Jari), Paunio, T. (Tiina), Vainio, S. J. (Seppo Juhani), Palotie, A. (Aarno), Niemelä, S. (Solja), Suvisaari, J. (Jaana), Veijola, J. (Juha), Mazumder, A. H. (Atiqul Haq), Barnett, J. (Jennifer), Isometsä, E. T. (Erkki Tapio), Lindberg, N. (Nina), Torniainen-Holm, M. (Minna), Lähteenvuo, M. (Markku), Lahdensuo, K. (Kaisla), Kerkelä, M. (Martta), Ahola-Olli, A. (Ari), Hietala, J. (Jarmo), Kampman, O. (Olli), Kieseppä, T. (Tuula), Jukuri, T. (Tuomas), Häkkinen, K. (Katja), Cederlöf, E. (Erik), Haaki, W. (Willehard), Kajanne, R. (Risto), Wegelius, A. (Asko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Lönnqvist, J. (Jouko), Tiihonen, J. (Jari), Paunio, T. (Tiina), Vainio, S. J. (Seppo Juhani), Palotie, A. (Aarno), Niemelä, S. (Solja), Suvisaari, J. (Jaana), and Veijola, J. (Juha)

Abstract

The purpose of this study was to explore the association of cognition with hazardous drinking Polygenic Scores (PGS) in 2649 schizophrenia, 558 schizoaffective disorder, and 1125 bipolar disorder patients in Finland. Hazardous drinking PGS was computed using the LDPred program. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: the 5-choice serial reaction time task, or Reaction Time (RT) test, and the Paired Associative Learning (PAL) test. The association between hazardous drinking PGS and cognition was measured using four cognition variables. Log-linear regression was used in Reaction Time (RT) assessment, and logistic regression was used in PAL assessment. All analyses were conducted separately for males and females. After adjustment of age, age of onset, education, household pattern, and depressive symptoms, hazardous drinking PGS was not associated with reaction time or visual memory in male or female patients with schizophrenia, schizoaffective, and bipolar disorder.

Published
2021

27. Reaction time and visual memory in connection with alcohol use in schizophrenia and schizoaffective disorder

Author

Mazumder, A. H. (Atiqul Haq), Barnett, J. (Jennifer), Lindberg, N. (Nina), Torniainen-Holm, M. (Minna), Lähteenvuo, M. (Markku), Lahdensuo, K. (Kaisla), Kerkelä, M. (Martta), Hietala, J. (Jarmo), Isometsä, E. T. (Erkki Tapio), Kampman, O. (Olli), Kieseppä, T. (Tuula), Jukuri, T. (Tuomas), Häkkinen, K. (Katja), Cederlöf, E. (Erik), Haaki, W. (Willehard), Kajanne, R. (Risto), Wegelius, A. (Asko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Lönnqvist, J. (Jouko), Niemelä, S. (Solja), Tiihonen, J. (Jari), Paunio, T. (Tiina), Palotie, A. (Aarno), Suvisaari, J. (Jaana), Veijola, J. (Juha), Mazumder, A. H. (Atiqul Haq), Barnett, J. (Jennifer), Lindberg, N. (Nina), Torniainen-Holm, M. (Minna), Lähteenvuo, M. (Markku), Lahdensuo, K. (Kaisla), Kerkelä, M. (Martta), Hietala, J. (Jarmo), Isometsä, E. T. (Erkki Tapio), Kampman, O. (Olli), Kieseppä, T. (Tuula), Jukuri, T. (Tuomas), Häkkinen, K. (Katja), Cederlöf, E. (Erik), Haaki, W. (Willehard), Kajanne, R. (Risto), Wegelius, A. (Asko), Männynsalo, T. (Teemu), Niemi-Pynttäri, J. (Jussi), Suokas, K. (Kimmo), Lönnqvist, J. (Jouko), Niemelä, S. (Solja), Tiihonen, J. (Jari), Paunio, T. (Tiina), Palotie, A. (Aarno), Suvisaari, J. (Jaana), and Veijola, J. (Juha)

Abstract

The purpose of this study was to explore the association between cognition and hazardous drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognition is more or less compromised in schizophrenia, and schizoaffective disorder and alcohol use might aggravate this phenomenon. The study population included 3362 individuals from Finland with diagnoses of schizophrenia or schizoaffective disorder. Hazardous drinking was screened with the AUDIT-C (Alcohol Use Disorders Identification Test for Consumption) screening tool. Alcohol use disorder (AUD) diagnoses were obtained from national registrar data. Participants performed two computerized tasks from the Cambridge Automated Neuropsychological Test Battery (CANTAB) on a tablet computer: The Five-Choice Serial Reaction Time Task (5-CSRTT) or the reaction time (RT) test and the Paired Associative Learning (PAL) test. The association between alcohol use and the RT and PAL tests was analyzed with log-linear regression and logistic regression, respectively. After adjustment for age, education, housing status, and the age at which the respondents had their first psychotic episodes, hazardous drinking was associated with a lower median RT in females and less variable RT in males, while AUD was associated with a poorer PAL test performance in terms of the total errors adjusted scores (TEASs) in females. Our findings of positive associations between alcohol and cognition in schizophrenia and schizoaffective disorder are unique.

Published
2021

31. Implementation of CYP2D6 copy-number imputation panel and frequency of key pharmacogenetic variants in Finnish individuals with a psychotic disorder

Author

Häkkinen, K., primary, Kiiski, JI., additional, Lähteenvuo, M., additional, Jukuri, T., additional, Suokas, K., additional, Niemi-Pynttäri, J., additional, Kieseppä, T., additional, Männynsalo, T., additional, Wegelius, A., additional, Haaki, W., additional, Lahdensuo, K., additional, Kajanne, R., additional, Kaunisto, MA., additional, Tuulio-Henriksson, A., additional, Kampman, O., additional, Hietala, J., additional, Veijola, J., additional, Lönnqvist, J., additional, Isometsä, E., additional, Paunio, T., additional, Suvisaari, J., additional, Kalso, E., additional, Niemi, M., additional, Tiihonen, J., additional, Daly, M., additional, Palotie, A., additional, and Ahola-Olli, AV., additional

Published
2020
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34. P.186 Molecular pathways underlying schizophrenia

Author

Tiihonen, J., primary, Koskuvi, M., additional, Lähteenvuo, M., additional, Trontti, K., additional, Ojansuu, I., additional, Vaurio, O., additional, Cannon, T.D., additional, Lönnqvist, J., additional, Therman, S., additional, Suvisaari, J., additional, Cheng, L., additional, Tanskanen, A., additional, Taipale, H., additional, Lehtonen, Š., additional, and Koistinaho, J., additional

Published
2020
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36. Sex-specific transcriptional and proteomic signatures in schizophrenia.

Author

Tiihonen, J, Koskuvi, M, Storvik, M, Hyötyläinen, I, Gao, Y, Puttonen, KA, Giniatullina, R, Poguzhelskaya, E, Ojansuu, I, Vaurio, O, Cannon, TD, Lönnqvist, J, Therman, S, Suvisaari, J, Kaprio, J, Cheng, L, Hill, AF, Lähteenvuo, M, Tohka, J, Giniatullin, R, Lehtonen, Š, Koistinaho, J, Tiihonen, J, Koskuvi, M, Storvik, M, Hyötyläinen, I, Gao, Y, Puttonen, KA, Giniatullina, R, Poguzhelskaya, E, Ojansuu, I, Vaurio, O, Cannon, TD, Lönnqvist, J, Therman, S, Suvisaari, J, Kaprio, J, Cheng, L, Hill, AF, Lähteenvuo, M, Tohka, J, Giniatullin, R, Lehtonen, Š, and Koistinaho, J

Abstract

It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific signal by minimizing genetic heterogeneity. In proteomic and pathway analyses, clinical illness is associated especially with altered glycosaminoglycan, GABAergic synapse, sialylation, and purine metabolism pathways. Although only 12% of all 19,462 genes are expressed differentially between healthy males and females, up to 61% of the illness-related genes are sex specific. These results on sex-specific genes are replicated in another dataset. This implies that the pathophysiology differs between males and females, and may explain why symptoms appear after adolescence when the expression of many sex-specific genes change, and suggests the need for sex-specific treatments.

Published
2019

41. Antegrade in situ fenestration of aortic stent graft: in-vivo experiments using a pig model.

Author

Saari P, Lähteenvuo M, Honkonen K, Manninen H, Saari, Petri, Lähteenvuo, Markku, Honkonen, Krista, and Manninen, Hannu

Subjects
*SURGICAL stents, *AORTIC aneurysms, *ABDOMINAL aorta, *RENAL artery, *REVASCULARIZATION (Surgery), *ISCHEMIA, *DISEASES
Abstract

Background: Short proximal neck of an abdominal aortic aneurysm is associated with risk of treatment failure during abdominal aortic repair. Important side branches, such as renal arteries, cannot be covered without serious consequences. Purpose: To test the feasibility of preoperative fenestration of abdominal aortic stent grafts with a re-entry catheter and steerable sheath to preserve the patency of renal arteries in an animal model. Material and Methods: Three domestic pigs were anesthetised and a stent graft placed in the abdominal aorta, covering the renal arteries. An attempt was made to fenestrate the renal arteries through the prosthesis using the Outback re-entry catheter supported by the Channel Steerable sheath. The hole that was created was dilated and stented. The specimens were visually analyzed after sacrifice. Results: In one pig, the graft material was successfully traversed and a guide wire advanced in the renal arteries. Due to insufficient guide wire support and a poor balloon profile, dilatation of the fenestration failed. In another pig, the procedure was technically successful, but a long warm ischemia time for the left kidney caused infarction. In the third experiment, the procedure had to be discontinued due to a technical failure of the Outback device. Conclusion: Fenestration of a stent graft with a re-entry device through a steerable sheath is technically feasible in vivo. However, without further refinement of the instrumentation, the technique cannot be recommended in elective cases of abdominal aortic repair, but if the renal arteries are covered accidentally during endovascular treatment, the technique may be a valuable salvage option if surgical revascularization is not considered as an option. [ABSTRACT FROM AUTHOR]

Published
2012
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42. Molecular signaling pathways underlying schizophrenia

Author

Tiihonen, J, Koskuvi, M, Lähteenvuo, M, Trontti, K, Ojansuu, I, Vaurio, O, Cannon, TD, Lönnqvist, J, Therman, S, Suvisaari, J, Sim, Lesley, Tanskanen, A, Taipale, H, Lehtonen, Š, and Koistinaho, J

Subjects
3. Good health, Uncategorized
Abstract

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were observed for glutamate receptor signaling, hepatic fibrosis, and glycoprotein 6 (GP6) pathways in the Finnish dataset, and GP6 and hepatic fibrosis pathways in the US dataset. In data-driven causal pathways, ADCYAP1, ADAMTS, and CACNA genes were involved in the majority of the top 10 pathways differentiating patients and controls in both Finnish and US datasets. Results from a Finnish nation-wide database showed that the risk of schizophrenia relapse was 41% lower among first-episode patients during the use of losartan, the master regulator of an ADCYAP1, ADAMTS, and CACNA–related pathway, compared to those time periods when the same individual did not use the drug. The results from the two independent datasets suggest that the GP6 signaling pathway, and the ADCYAP1, ADAMTS, and CACNA-related purine, oxidative stress, and glutamatergic signaling pathways are among primary pathophysiological alterations in schizophrenia among patients with European ancestry. While no reproducible dopaminergic alterations were observed, the results imply that agents such as losartan, and ADCYAP1/PACAP -deficit alleviators, such as metabotropic glutamate 2/3 agonist MGS0028 and 5-HT7 antagonists – which have shown beneficial effects in an experimental Adcyap1−/− mouse model for schizophrenia – could be potential treatments even before the full manifestation of illness involving dopaminergic abnormalities.

43. Repurposing Semaglutide and Liraglutide for Alcohol Use Disorder.

Author

Lähteenvuo M, Tiihonen J, Solismaa A, Tanskanen A, Mittendorfer-Rutz E, and Taipale H

Abstract

Importance: Preliminary studies suggest that glucagon-like peptide-1 receptor (GLP-1) agonists, used to treat type 2 diabetes and obesity, may decrease alcohol consumption., Objective: To test whether the risk of hospitalization due to alcohol use disorder (AUD) is decreased during the use of GLP-1 agonists compared with periods of nonuse for the same individual., Design, Setting, and Participants: This cohort study was an observational study conducted nationwide in Sweden using data from January 2006 to December 2023. The population-based cohort was identified from registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. Participants were all residents aged 16 to 64 years who had a diagnosis of AUD., Exposures: The primary exposure was use of individual GLP-1 agonists (compared with nonuse of GLP-1 agonists), and the secondary exposure was medications with indication for AUD., Main Outcomes and Measures: The primary outcome was AUD hospitalization analyzed in a Cox regression within-individual model. Secondary outcomes were any substance use disorder (SUD)-related hospitalization, somatic hospitalization, and suicide attempt., Results: The cohort included 227 866 individuals with AUD; 144 714 (63.5%) were male and 83 154 (36.5%) were female, with a mean (SD) age of 40.0 (15.7) years. Median (IQR) follow-up time was 8.8 (4.0-13.3) years. A total of 133 210 individuals (58.5%) experienced AUD hospitalization. Semaglutide (4321 users) was associated with the lowest risk (AUD: adjusted hazard ratio [aHR], 0.64; 95% CI, 0.50-0.83; any SUD: aHR, 0.68; 95% CI, 0.54-0.85) and use of liraglutide (2509 users) with the second lowest risk (AUD: aHR, 0.72; 95% CI, 0.57-0.92; any SUD: aHR, 0.78; 95% CI, 0.64-0.97) of both AUD and SUD hospitalization. Use of any AUD medication was associated with a modestly decreased risk (aHR, 0.98; 95% CI, 0.96-1.00). Semaglutide (aHR, 0.78; 95% CI, 0.68-0.90) and liraglutide (aHR, 0.79; 95% CI, 0.69-0.91) use were also associated with decreased risk of somatic hospitalizations but not associated with suicide attempts (semaglutide: aHR, 0.55; 95% CI, 0.23-1.30; liraglutide: aHR, 1.08; 95% CI, 0.55-2.15)., Conclusions and Relevance: Among patients with AUD and comorbid obesity/type 2 diabetes, the use of semaglutide and liraglutide were associated with a substantially decreased risk of hospitalization due to AUD. This risk was lower than that of officially approved AUD medications. Semaglutide and liraglutide may be effective in the treatment of AUD, and clinical trials are urgently needed to confirm these findings.

Published
2024
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44. Antipsychotic Use and Risk of Breast Cancer in Women With Severe Mental Illness: Replication of a Nationwide Nested Case-Control Database Study.

Author

Solmi M, Lähteenvuo M, Tanskanen A, Corbeil O, Mittendorfer-Rutz E, Correll CU, Tiihonen J, and Taipale H

Subjects
Humans, Female, Middle Aged, Case-Control Studies, Sweden epidemiology, Adult, Aged, Young Adult, Adolescent, Aged, 80 and over, Bipolar Disorder epidemiology, Bipolar Disorder drug therapy, Comorbidity, Breast Neoplasms epidemiology, Antipsychotic Agents adverse effects, Antipsychotic Agents pharmacology, Psychotic Disorders epidemiology, Psychotic Disorders drug therapy, Schizophrenia epidemiology, Schizophrenia drug therapy, Registries statistics & numerical data
Abstract

Background and Hypothesis: Breast cancer is more prevalent in women with severe mental illness than in the general population, and use of prolactin-increasing antipsychotics may be a contributing factor., Study Design: A nested case-control study was conducted using the Swedish nationwide registers (inpatient/outpatient care, sickness absence, disability pension, prescribed drugs, cancers). All women aged 18-85 years with schizophrenia/schizoaffective/other nonaffective psychotic disorder/bipolar disorder and breast cancer (cases) were matched for age, primary psychiatric diagnosis, and disease duration with five women without cancer (controls). The association between cumulative exposure to prolactin-increasing/prolactin-sparing antipsychotics and breast cancer was analyzed using conditional logistic regression, adjusted for comorbidities and co-medications., Study Results: Among 132 061 women, 1642 (1.24%) developed breast cancer between 2010 and 2021, at a mean age of 63.3 ± 11.8 years. Compared with 8173 matched controls, the odds of breast cancer increased in women with prior exposure to prolactin-increasing antipsychotics for 1-4 years (adjusted odds ratio [aOR] = 1.20, 95% confidence interval [CI] = 1.03-1.41), and for ≥ 5 years (aOR = 1.47, 95%CI = 1.26-1.71). There were no increased or decreased odds of breast cancer with exposure to prolactin-sparing antipsychotics of either 1-4 years (aOR = 1.17, 95%CI = 0.98-1.40) or ≥5 years (aOR = 0.99, 95%CI = 0.78-1.26). The results were consistent across all sensitivity analyses (ie, according to different age groups, cancer types, and primary psychiatric diagnosis)., Conclusions: Although causality remains uncertain, exposure to prolactin-elevating antipsychotics for ≥ 1 year was associated with increased odds of breast cancer in women with severe mental illness. When prescribing antipsychotics, a shared decision-making process should consider individual risk factors for breast cancer., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Published
2024
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45. Dosing levels of antipsychotics and mood stabilizers in bipolar disorder: A Nationwide cohort study on relapse risk and treatment safety.

Author

Lintunen J, Hamina A, Lähteenvuo M, Paljärvi T, Tanskanen A, Tiihonen J, and Taipale H

Abstract

Background: Finding effective treatment regimens for bipolar disorder is challenging, as many patients suffer from significant symptoms despite treatment. This study investigated the risk of relapse (psychiatric hospitalization) and treatment safety (non-psychiatric hospitalization) associated with different doses of antipsychotics and mood stabilizers in persons with bipolar disorder., Methods: Individuals aged 15-65 with bipolar disorder were identified from Finnish national health registers in 1996-2018. Studied antipsychotics included olanzapine, risperidone, quetiapine, aripiprazole; mood stabilizers lithium, valproic acid, lamotrigine, and carbamazepine. Medication use was divided into three time-varying dose categories: low, standard, and high. The studied outcomes were risk of psychiatric hospitalization (relapse) and the risk of non-psychiatric hospitalization (treatment safety). Stratified Cox regression in within-individual design was used., Results: The cohort included 60,045 individuals (mean age 41.7 years, SD 15.8; 56.4% female). Mean follow-up was 8.3 years (SD 5.8). Of antipsychotics, olanzapine and aripiprazole were associated with a decreased risk of relapse in low and standard doses, and risperidone in low dose. The lowest adjusted hazard ratio (aHR) was observed for standard dose aripiprazole (aHR 0.68, 95% CI 0.57-0.82). Quetiapine was not associated with a decreased risk of relapse at any dose. Mood stabilizers were associated with a decreased risk of relapse in low and standard doses; lowest aHR was observed for standard dose lithium (aHR 0.61, 95% CI 0.56-0.65). Apart from lithium, high doses of antipsychotics and mood stabilizers were associated with an increased risk of non-psychiatric hospitalization. Lithium was associated with a decreased risk of non-psychiatric hospitalization in low (aHR 0.88, 95% CI 0.84-0.93) and standard doses (aHR 0.81, 95% CI 0.74-0.88)., Conclusions: Standard doses of lithium and aripiprazole were associated with the lowest risk of relapse, and standard dose of lithium with the lowest risk of non-psychiatric hospitalization. Quetiapine was not associated with decreased risk of relapse at any dose., (© 2024 The Author(s). Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Published
2024
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46. Comparative Effectiveness of Antipsychotics in Patients With Schizophrenia Spectrum Disorder.

Author

Hamina A, Taipale H, Lieslehto J, Lähteenvuo M, Tanskanen A, Mittendorfer-Rutz E, and Tiihonen J

Subjects
Humans, Male, Female, Middle Aged, Adult, Sweden, Adolescent, Young Adult, Aged, Treatment Outcome, Cohort Studies, Hospitalization statistics & numerical data, Recurrence, Clozapine therapeutic use, Antipsychotic Agents therapeutic use, Schizophrenia drug therapy, Olanzapine therapeutic use, Comparative Effectiveness Research
Abstract

Importance: Antipsychotics are the cornerstone of maintenance treatment in schizophrenia spectrum disorders, but it is unclear which agents should be prioritized by prescribers., Objective: To investigate the clinical effectiveness of antipsychotics, including recent market entries, in comparison with oral olanzapine in relapse and treatment failure prevention among individuals with schizophrenia spectrum disorder., Design, Setting, and Participants: This comparative effectiveness research study with a within-individual analysis included data from Swedish health care registers of inpatient and specialized outpatient care, sickness absence, and disability pensions among all individuals aged 16 to 65 years who were diagnosed with schizophrenia spectrum disorder from January 1, 2006, to December 31, 2021, including an incident cohort and a prevalent cohort., Exposures: Specific antipsychotics., Main Outcomes and Measures: The risks for psychosis relapse hospitalization and treatment failure (psychiatric hospitalization, death, or change in an antipsychotic medication) were adjusted for the temporal order of treatments, time since cohort entry, and concomitant drugs. Comparisons of all antipsychotics with oral olanzapine, the most commonly used antipsychotic, were investigated., Results: Among the full cohort of 131 476 individuals, the mean (SD) age of the study cohort was 45.7 (16.2) years (70 054 men [53.3%]). During a median follow-up of 12.0 years [IQR, 5.2-16.0 years], 48.5% of patients (N = 63 730) experienced relapse and 71.1% (N = 93 464) underwent treatment failure at least once. Compared with oral olanzapine, paliperidone 3-month long-acting injectable (LAI) was associated with the lowest adjusted hazard ratio (AHR) in the prevention of relapses (AHR, 0.66; 95% CI, 0.51-0.86), followed by aripiprazole LAI (AHR, 0.77 [95% CI, 0.70-0.84]), olanzapine LAI (AHR, 0.79 [95% CI, 0.73-0.86]), and clozapine (AHR, 0.82 [95% CI, 0.79-0.86]). Quetiapine was associated with the highest risk of relapse (AHR, 1.44 [95% CI, 1.38-1.51]). For prevention of treatment failure, paliperidone 3-month LAI was associated with the lowest AHR (AHR, 0.36 [95% CI, 0.31-0.42]), followed by aripiprazole LAI (AHR, 0.60 [95% CI, 0.57-0.63]), olanzapine LAI (AHR, 0.67 [95% CI, 0.63-0.72]), and paliperidone 1-month LAI (AHR, 0.71 [95% CI, 0.68-0.74])., Conclusions and Relevance: This comparative effectiveness research study demonstrated large differences in the risk of relapse and treatment failure among specific antipsychotic treatments. The findings contradict the widely held conception that all antipsychotics are equally effective in relapse prevention.

Published
2024
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47. High Burden of Ileus and Pneumonia in Clozapine-Treated Individuals With Schizophrenia: A Finnish 25-Year Follow-Up Register Study.

Author

Partanen JJ, Häppölä P, Kämpe A, Ahola-Olli A, Hellsten A, Rask SM, Haaki W, Hietala J, Kampman O, Tiihonen J, Tanskanen AJ, Daly MJ, Ripatti S, Palotie A, Taipale H, Lähteenvuo M, and Koskela JT

Subjects
Humans, Male, Female, Middle Aged, Follow-Up Studies, Adult, Finland epidemiology, Incidence, Cytochrome P-450 CYP1A2 genetics, Longitudinal Studies, Clozapine adverse effects, Clozapine therapeutic use, Schizophrenia drug therapy, Antipsychotic Agents adverse effects, Antipsychotic Agents therapeutic use, Ileus chemically induced, Ileus epidemiology, Pneumonia epidemiology, Pneumonia chemically induced, Registries
Abstract

Objective: The authors used longitudinal biobank data with up to 25 years of follow-up on over 2,600 clozapine users to derive reliable estimates of the real-world burden of clozapine adverse drug events (ADEs)., Methods: A total of 2,659 participants in the FinnGen biobank project had a schizophrenia diagnosis and clozapine purchases with longitudinal electronic health record follow-up for up to 25 years after clozapine initiation. Diseases and health-related events enriched during clozapine use were identified, adjusting for disease severity. The incidence and recurrence of ADEs over years of clozapine use, their effect on clozapine discontinuation and deaths, and their pharmacogenetics were studied., Results: Median follow-up time after clozapine initiation was 12.7 years. Across 2,157 diseases and health-related events, 27 were enriched during clozapine use, falling into five disease categories: gastrointestinal hypomotility, seizures, pneumonia, other acute respiratory tract infections, and tachycardia, along with a heterogeneous group including neutropenia and type 2 diabetes, among others. Cumulative incidence estimates for ileus (severe gastrointestinal hypomotility) and pneumonia were 5.3% and 29.5%, respectively, 20 years after clozapine initiation. Both events were significantly associated with increased mortality among clozapine users (ileus: odds ratio=4.5; pneumonia: odds ratio=2.8). Decreased genotype-predicted CYP2C19 and CYP1A2 activities were associated with higher pneumonia risk., Conclusions: Clozapine-induced ileus and pneumonia were notably more frequent than has previously been reported and were associated with increased mortality. Two CYP genes influenced pneumonia risk. Pneumonia and ileus call for improved utilization of available preventive measures.

Published
2024
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48. Integrative metabolomics-genomics analysis identifies key networks in a stem cell-based model of schizophrenia.

Author

Spathopoulou A, Sauerwein GA, Marteau V, Podlesnic M, Lindlbauer T, Kipura T, Hotze M, Gabassi E, Kruszewski K, Koskuvi M, Réthelyi JM, Apáti Á, Conti L, Ku M, Koal T, Müller U, Talmazan RA, Ojansuu I, Vaurio O, Lähteenvuo M, Lehtonen Š, Mertens J, Kwiatkowski M, Günther K, Tiihonen J, Koistinaho J, Trajanoski Z, and Edenhofer F

Subjects
Humans, Transcriptome genetics, Genomics methods, Cell Differentiation physiology, Glutamate Decarboxylase metabolism, Glutamate Decarboxylase genetics, Metabolome, Schizophrenia metabolism, Schizophrenia genetics, Induced Pluripotent Stem Cells metabolism, Metabolomics methods, gamma-Aminobutyric Acid metabolism, Neurons metabolism
Abstract

Schizophrenia (SCZ) is a neuropsychiatric disorder, caused by a combination of genetic and environmental factors. The etiology behind the disorder remains elusive although it is hypothesized to be associated with the aberrant response to neurotransmitters, such as dopamine and glutamate. Therefore, investigating the link between dysregulated metabolites and distorted neurodevelopment holds promise to offer valuable insights into the underlying mechanism of this complex disorder. In this study, we aimed to explore a presumed correlation between the transcriptome and the metabolome in a SCZ model based on patient-derived induced pluripotent stem cells (iPSCs). For this, iPSCs were differentiated towards cortical neurons and samples were collected longitudinally at various developmental stages, reflecting neuroepithelial-like cells, radial glia, young and mature neurons. The samples were analyzed by both RNA-sequencing and targeted metabolomics and the two modalities were used to construct integrative networks in silico. This multi-omics analysis revealed significant perturbations in the polyamine and gamma-aminobutyric acid (GABA) biosynthetic pathways during rosette maturation in SCZ lines. We particularly observed the downregulation of the glutamate decarboxylase encoding genes GAD1 and GAD2, as well as their protein product GAD65/67 and their biochemical product GABA in SCZ samples. Inhibition of ornithine decarboxylase resulted in further decrease of GABA levels suggesting a compensatory activation of the ornithine/putrescine pathway as an alternative route for GABA production. These findings indicate an imbalance of cortical excitatory/inhibitory dynamics occurring during early neurodevelopmental stages in SCZ. Our study supports the hypothesis of disruption of inhibitory circuits to be causative for SCZ and establishes a novel in silico approach that enables for integrative correlation of metabolic and transcriptomic data of psychiatric disease models., (© 2024. The Author(s).)

Published
2024
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49. Genetic contribution to disease-course severity and progression in the SUPER-Finland study, a cohort of 10,403 individuals with psychotic disorders.

Author

Kämpe A, Suvisaari J, Lähteenvuo M, Singh T, Ahola-Olli A, Urpa L, Haaki W, Hietala J, Isometsä E, Jukuri T, Kampman O, Kieseppä T, Lahdensuo K, Lönnqvist J, Männynsalo T, Paunio T, Niemi-Pynttäri J, Suokas K, Tuulio-Henriksson A, Veijola J, Wegelius A, Daly M, Taylor J, Kendler KS, Palotie A, and Pietiläinen O

Subjects
Humans, Male, Female, Finland epidemiology, Adult, Middle Aged, Cohort Studies, Longitudinal Studies, Genotype, Registries, Psychotic Disorders genetics, Psychotic Disorders epidemiology, Schizophrenia genetics, Schizophrenia epidemiology, Disease Progression, Hospitalization, Multifactorial Inheritance genetics, Severity of Illness Index, Genetic Predisposition to Disease genetics
Abstract

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic shifts in the SUPER-Finland study, encompassing 10 403 genotyped individuals with a psychotic disorder. To longitudinally track the study participants' past disease-course severity, we created a psychiatric hospitalization burden metric using the full-coverage and nation-wide Finnish in-hospital registry (data from 1969 and onwards). Using a hierarchical model, ranking the psychotic diagnoses according to clinical severity, we show that high schizophrenia PGS (SZ-PGS) was associated with progression from lower ranked psychotic disorders to schizophrenia (OR = 1.32 [1.23-1.43], p = 1.26e-12). This development manifested already at psychotic illness onset as a higher psychiatric hospitalization burden, the proxy for disease-course severity. In schizophrenia (n = 5 479), both a high SZ-PGS and a low educational attainment PGS (EA-PGS) were associated with increased psychiatric hospitalization burden (p = 1.00e-04 and p = 4.53e-10). The SZ-PGS and the EA-PGS associated with distinct patterns of hospital usage. In individuals with high SZ-PGS, the increased hospitalization burden was composed of longer individual hospital stays, while low EA-PGS associated with shorter but more frequent hospital visits. The negative effect of a low EA-PGS was found to be partly mediated via substance use disorder, a major risk factor for hospitalizations. In conclusion, we show that high SZ-PGS and low EA-PGS both impacted psychotic disease-course development negatively but resulted in different disease-course trajectories., (© 2024. The Author(s).)

Published
2024
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50. Dopamine D2 receptor antagonism of antipsychotics and the risk of death due to choking.

Author

Luykx JJ, Tanskanen A, Lähteenvuo M, Manu P, Correll CU, Hasan A, Lieslehto J, Taipale H, and Tiihonen J

Subjects
Humans, Male, Female, Middle Aged, Adult, Aged, Cohort Studies, Receptors, Dopamine D2 metabolism, Young Adult, Antipsychotic Agents adverse effects, Schizophrenia drug therapy, Schizophrenia mortality, Dopamine D2 Receptor Antagonists adverse effects
Abstract

The risk of fatal choking for people with schizophrenia and associations with antipsychotic medication are largely unknown. Therefore, we calculated the choking-related standardized mortality ratio for schizophrenia relative to the general population (SMR choking ). We also computed adjusted hazard ratios (aHR) of choking-related mortality for antipsychotics in a nationwide cohort of patients with schizophrenia (N = 59,916). SMR choking was 20.5 (95 % confidence interval (CI)=17.1-23.9). The aHR was 1.74 (95 %CI=1.19-2.55) for strong dopamine 2-antagonists. For other antipsychotics, CIs included 1. Importantly, aHRs were particularly high for high dose categories of strong dopamine D2 receptor (D2R) antagonists. In conclusion, a schizophrenia diagnosis is associated with a 20-fold risk of death due to choking. This risk is elevated during use of strong D2R antagonist antipsychotics, particularly when prescribed in high dosages., Competing Interests: Declaration of competing interest AT, HT, and JT have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their employing institution. JT has been a consultant to HLS Therapeutics, Janssen, Orion and WebMed Global and received lecture fees from Janssen and Otsuka. HT has received lecture fees Gedeon Richter, Janssen, Lundbeck and Otsuka. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Adock Ingram, Alkermes, Allergan, Angelini, Aristo, Biogen, Boehringer-Ingelheim, Bristol-Meyers Squibb, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Delpor, Denovo, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Jamjoom Pharma, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Maplight, Mylan, Neumora, Neurocrine, Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Sage, Seqirus, SK Life Science, Sumitomo Pharma America, Sunovion, Sun Pharma, Supernus, Tabuk, Takeda, Teva, Tolmar, Vertex, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Compass Pathways, Denovo, Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Kuleon Biosciences, LB Pharma, Mindpax, and Quantic. AH: editor of the German (DGPPN) schizophrenia treatment guidelines, first author of the WFSBP schizophrenia treatment guidelines; on advisory boards of and speaker fees from AbbVie (speaker fees only), Advanz (speaker fees only), Janssen-Cilag, Lundbeck, Recordati, Rovi, and Otsuka. ML has received honoraria from Janssen, Janssen-Cilag, Lundbeck, Otsuka, Recordati and Sunovion. The other authors report no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2024
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