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  • 1.
    Alaie, Iman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Philipson, Anna
    Orebro Univ, Univ Hlth Care Res Ctr, Fac Med & Hlth, Orebro, Sweden.
    Ssegonja, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Hagberg, Lars
    Orebro Univ, Univ Hlth Care Res Ctr, Fac Med & Hlth, Orebro, Sweden.
    Feldman, Inna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Sampaio, Filipa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Social medicine/CHAP.
    Moller, Margareta
    Orebro Univ, Univ Hlth Care Res Ctr, Fac Med & Hlth, Orebro, Sweden.
    Arinell, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Ramklint, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Päären, Aivar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    von Knorring, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Olsson, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    von Knorring, Anne-Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Bohman, Hannes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Jonsson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry. Karolinska Inst, Karolinska Inst KIND, Dept Womens & Childrens Hlth, Ctr Neurodev Disorders,Pediat Neuropsychiat Unit, Stockholm, Sweden;Stockholm Cty Council, Stockholm Hlth Care Serv, Ctr Psychiat Res, Stockholm, Sweden.
    Uppsala Longitudinal Adolescent Depression Study (ULADS)2019In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 9, no 3, article id e024939Article in journal (Refereed)
    Abstract [en]

    Purpose: To present the Uppsala Longitudinal Adolescent Depression Study, initiated in Uppsala, Sweden, in the early 1990s. The initial aim of this epidemiological investigation was to study the prevalence, characteristics and correlates of adolescent depression, and has subsequently expanded to include a broad range of social, economic and health-related long-term outcomes and cost-of-illness analyses.

    Participants: The source population was first-year students (aged 16-17) in upper-secondary schools in Uppsala during 1991-1992, of which 2300 (93%) were screened for depression. Adolescents with positive screening and sex/age-matched peers were invited to a comprehensive assessment. A total of 631 adolescents (78% females) completed this assessment, and 409 subsequently completed a 15year follow-up assessment. At both occasions, extensive information was collected on mental disorders, personality and psychosocial situation. Detailed social, economic and health-related data from 1993 onwards have recently been obtained from the Swedish national registries for 576 of the original participants and an age-matched reference population (N=200 000).

    Findings to date: The adolescent lifetime prevalence of a major depressive episode was estimated to be 11.4%. Recurrence in young adulthood was reported by the majority, with a particularly poor prognosis for those with a persistent depressive disorder or multiple somatic symptoms. Adolescent depression was also associated with an increased risk of other adversities in adulthood, including additional mental health conditions, low educational attainment and problems related to intimate relationships.

    Future plans: Longitudinal studies of adolescent depression are rare and must be responsibly managed and utilised. We therefore intend to follow the cohort continuously by means of registries. Currently, the participants are approaching mid-adulthood. At this stage, we are focusing on the overall long-term burden of adolescent depression. For this purpose, the research group has incorporated expertise in health economics. We would also welcome extended collaboration with researchers managing similar datasets.

  • 2.
    Breedh, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comasco: Neuropsychopharmacology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Comasco, Erika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Comasco: Neuropsychopharmacology.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Papadopoulos, Fotios C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Hypothalamic-pituitary-adrenal axis responsiveness, startle response, and sensorimotor gating in late pregnancy2019In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 106, p. 1-8Article in journal (Refereed)
    Abstract [en]

    During pregnancy, the hypothalamic-pituitary-adrenal (HPA) axis, the main regulator of the stress response, undergoes dramatic changes. The acoustic startle response (ASR) and the prepulse inhibition (PPI) of the startle response are neurophysiological research tools and objective measures of an individual's response to an emotional context or stressor. The ASR and PPI are influenced by psychiatric diseases characterized by anxiety symptoms and are sensitive to cortisol. Hence, the ASR and the PPI can be used to investigate the effects of pregnancy-induced endocrine changes and their contribution to affective disorders. The present study sought to investigate the association between measures of HPA-axis responsiveness, startle reactivity and sensorimotor gating during pregnancy that to date remains unknown. The eye-blink component of the ASR, and its prepulse inhibition, were measured in 107 late third trimester pregnant women. Saliva samples were collected to assess the cortisol awakening response (CAR), a measure of HPA-axis activity. Blood was sampled to measure serum levels of cortisol, cortisone and the cortisone to cortisol ratio. Ongoing anxiety disorders, sleep duration, smoking, and age were considered as potential confounders in the statistical analyses. CAR reactivity, measured as area under the curve (AUC) increase and above baseline, was positively associated with baseline startle magnitude [Cohen's d = 0.27; F (1, 105) = 4.99; p = 0.028, and Cohen's d = 0.30; F (1, 105) = 6.25; p = 0.014, respectively] as well as PPI at 86 dB [Cohen's d = 0.29; F (1, 105) = 5.93; p = 0.017; and Cohen's d = 0.34; F (1, 105) = 8.38; p = 0.005, respectively]. The observed positive correlation between startle magnitude in pregnant women and greater increase in cortisol during the awakening response may be interpreted as heightened neurophysiological reactivity, likely associated with dysregulation of the stress system.

  • 3.
    Brenner, Philip
    et al.
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden.
    Brandt, Lena
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden.
    Li, Gang
    Janssen Res & Dev LLC, Titusville, NJ USA.
    DiBernardo, Allitia
    Janssen Res & Dev LLC, Titusville, NJ USA.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry. Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden.
    Reutfors, Johan
    Karolinska Inst, Dept Med Solna, Ctr Pharmacoepidemiol, Stockholm, Sweden.
    Treatment-resistant depression as risk factor for substance use disorders: a nation-wide register-based cohort study2019In: Addiction, ISSN 0965-2140, E-ISSN 1360-0443, Vol. 114, no 7, p. 1274-1282Article in journal (Refereed)
    Abstract [en]

    Background and aims Treatment-resistant depression (TRD) is common among patients with major depressive disorder (MDD). MDD may increase the risk for developing substance use disorders (SUD). The aim of this study was to investigate the risk for developing SUD among patients with TRD compared with other depressed patients.

    Design Observational cohort study.

    Setting Nation-wide governmental health registers in Sweden.

    Participants All patients aged 18-69 years with an MDD diagnosis in specialized health care who had received at least one antidepressant prescription during 2006-14 were identified. Patients with at least three treatment trials within a single depressive episode were classified with TRD.

    Measurements Patients with TRD were compared with the whole MDD cohort regarding risk for obtaining a SUD diagnosis or medication using survival analyses adjusted for socio-demographics and comorbidities.

    Findings Of 121 669 MDD patients, 13% were classified with TRD. Among the patients without any history of SUD, patients with TRD had a risk increase for any SUD both ≤ 1 and > 1 year after antidepressant initiation [> 1 year hazard ratio (HR) = 1.4; 95% confidence interval (CI) = 1.3-1.5]. Risks were elevated for the subcategories of opioid (HR = 1.9, 95% CI = 1.4-2.5) and sedative SUD (HR = 2.7, 95% CI = 2.2-3.2). Patients with a history of SUD had a risk increase for any SUD ≤ 1 year after start of treatment (HR = 1.2, 95% CI = 1.1-1.4), and both ≤ 1 year and > 1 year for sedative (> 1 year HR = 2.0, 95% CI = 1.3-3.0) and multiple substance SUD (HR = 1.9, 95% CI = 1.4-2.5).

    Conclusions Patients with treatment-resistant depression may be at greater risk for substance use disorders compared with other patients with major depressive disorder. Patterns may differ for patients with and without a history of substance use disorders, and for different categories of substance use disorder.

  • 4.
    Hensler, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry.
    Sveen, Josefin
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Solid State Electronics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Cernvall, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry.
    Arnberg, Filip
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, National Center for Disaster Psychiatry.
    PTSD Coach Sweden: A Self-Management App for Trauma-Related Symptoms: A RCT study protocol evaluating a self-help app for posttraumatic stress in a Swedish community sample2019In: European Journal of Psychotraumatology, ISSN 2000-8066, E-ISSN 2000-8066, Vol. 10, no S1, article id 4–010Article in journal (Other academic)
    Abstract [en]

    Background: Resources to administer evidence-based care for PTSD and trauma-related complications are scarce, especially in particular geographical areas, during mass casualty situations and for individuals with subclinical symptoms as clinics prioritize more severe cases. Effective interventions for PTSD through technical platforms could disseminate information and self-management strategies to decrease individual suffering and societal costs. Assessment at multiple time points can elucidate which aspects of an intervention that are effective, in addition to the evolution of intervention use and well-being over time. 

    Objective: Evaluate an app-administered self-help intervention (PTSD Coach Sweden) aiming to reduce and manage PTSD symptoms and other related complications. 

    Method: In this trial, 200 participants from Sweden who have experienced a traumatic event in the past two years and who report posttraumatic stress symptoms will be randomized to three months use of the app or waitlist. The primary endpoint is self-rated PTSD symptom severity at three months, with follow-up at six and nine months. Secondary outcomes include depressive symptoms, physical symptoms, functional impairment and health care use. Ecological momentary assessment of health status and use of strategies corresponding to app content is used for 21 days during the first three months.

    Results: Lessons learned and recommendations from the preparations of app-based intervention trials are presented. Available data from the primary endpoint are presented. 

    Conclusions: App-based interventions hold promise to increase outreach, but further trials are needed. Several challenges introduced when preparing an app-based intervention are discussed.

  • 5. Lööf, Måns
    et al.
    Meyer, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    Ramklint, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Isaksson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Child and Adolescent Psychiatry.
    SKILLS – A PSYCHOEDUCATIONAL GROUP PROGRAM FOR ADOLESCENTS WITH ADHD2018In: Journal of the American Academy of Child and Adolescent Psychiatry, 2018, Vol. 57Conference paper (Refereed)
  • 6.
    Persson, Jonas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Szalisznyo, Krisztina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET-MRI Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fällmar, David
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Zora, Hatice
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry.
    Phosphodiesterase 10A levels are related to striatal function in schizophrenia: a combined positron emission tomography and functional magnetic resonance imaging study2019In: European Archives of Psychiatry and Clinical Neuroscience, ISSN 0940-1334, E-ISSN 1433-8491Article in journal (Refereed)
    Abstract [en]

    Pharmacological inhibition of phosphodiesterase 10A (PDE10A) is being investigated as a treatment option in schizophrenia. PDE10A acts postsynaptically on striatal dopamine signaling by regulating neuronal excitability through its inhibition of cyclic adenosine monophosphate (cAMP), and we recently found it to be reduced in schizophrenia compared to controls. Here, this finding of reduced PDE10A in schizophrenia was followed up in the same sample to investigate the effect of reduced striatal PDE10A on the neural and behavioral function of striatal and downstream basal ganglia regions. A positron emission tomography (PET) scan with the PDE10A ligand [11C]Lu AE92686 was performed, followed by a 6 min resting-state magnetic resonance imaging (MRI) scan in ten patients with schizophrenia. To assess the relationship between striatal function and neurophysiological and behavioral functioning, salience processing was assessed using a mismatch negativity paradigm, an auditory event-related electroencephalographic measure, episodic memory was assessed using the Rey auditory verbal learning test (RAVLT) and executive functioning using trail-making test B. Reduced striatal PDE10A was associated with increased amplitude of low-frequency fluctuations (ALFF) within the putamen and substantia nigra, respectively. Higher ALFF in the substantia nigra, in turn, was associated with lower episodic memory performance. The findings are in line with a role for PDE10A in striatal functioning, and suggest that reduced striatal PDE10A may contribute to cognitive symptoms in schizophrenia.

  • 7.
    Pohlkamp, Lilian
    et al.
    Ersta Skondal Bracke Univ Coll, Palliat Res Ctr, Dept Hlth Care Sci, Stockholm, Sweden.
    Kreicbergs, Ulrika
    Ersta Skondal Bracke Univ Coll, Palliat Res Ctr, Dept Hlth Care Sci, Stockholm, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
    Sveen, Josefin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry. Ersta Skondal Bracke Univ Coll, Palliat Res Ctr, Dept Hlth Care Sci, Stockholm, Sweden.
    Bereaved mothers' and fathers' prolonged grief and psychological health 1 to 5 years after loss-A nationwide study2019In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 28, no 7, p. 1530-1536Article in journal (Refereed)
    Abstract [en]

    Objective To assess differences in prolonged grief, depression, posttraumatic stress, and sleep disturbances in bereaved parents across years since loss (1-5 years) and by gender and to assess potential interactive effects of time since loss and gender on bereavement outcomes. Methods This study examined symptom levels of prolonged grief disorder, depression, posttraumatic stress, and insomnia in bereaved parents. A sample, including 133 mothers and 92 fathers who had lost a child to cancer 1 to 5 years previously, subdivided to five subsamples, one for each year since loss. Analysis of variance (ANOVA) was used to assess differences in symptom levels, related to years since loss, and gender. Results Regardless of how many years had passed since the loss, symptom levels of prolonged grief, depression, posttraumatic stress symptoms, and insomnia were elevated in all subsamples. Mothers showed higher symptom levels of prolonged grief, depression, and posttraumatic stress than fathers. However, no significant interaction effects were found between years since loss and gender on any of the symptom levels. Conclusions Cancer-bereaved mothers and fathers are vulnerable to prolonged grief and psychological symptoms up to 5 years after the death of their child. Findings highlight that bereaved parents may need long-term support, and the results deserve further attention in research and clinical care.

  • 8.
    Szalisznyo, Krisztina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry. Hungarian Acad Sci Budapest, Computat Neurosci Grp, Wigner Res Inst, Budapest, Hungary.
    Silverstein, David
    KTH Royal Inst Technol, Dept Computat Sci & Technol, Stockholm, Sweden.
    Tóth, János
    Budapest Univ Technol & Econ, Dept Math Anal, Budapest, Hungary.
    Neural dynamics in co-morbid schizophrenia and OCD: A computational approach2019In: Journal of Theoretical Biology, ISSN 0022-5193, E-ISSN 1095-8541, Vol. 473, p. 80-94Article in journal (Refereed)
    Abstract [en]

    The co-morbidity of obsessive-compulsive disorder (OCD) and schizophrenia is higher than what would be expected by chance and the common underlying neuropathophysiology is not well understood. Repetitive stereotypes and routines can be caused by perseverative thoughts and motor sequences in both of these disorders. We extended a previously published computational model to investigate cortico-striatal network dynamics. Given the considerable overlap in symptom phenomenology and the high degree of co-morbidity between OCD and schizophrenia, we examined the dynamical consequences of functional connectivity variations in the overlapping network. This was achieved by focusing on the emergence of network oscillatory activity and examining parameter sensitivity. Opposing activity levels are present in orbitofrontal cortex (OFC) and anterior cingulate cortex (ACC) in schizophrenia and OCD. We found that with over-compensation of the primary pathology, emergence of the other disorder can occur. The oscillatory behavior is delicately modulated by connections between the OFC/ACC to the ventral and dorsal striatum and by the coupling between the ACC and dorsolateral prefrontal cortex (DLPFC). Modulation on cortical self-inhibition (e.g. serotonin reuptake inhibitor treatment) together with dopaminergic input to the striatum (e.g. anti-dopaminergic medication) has non-trivial complex effects on the network oscillatory behavior, with an optimal modulatory window. Additionally, there are several disruption mechanisms and compensatory processes in the cortico-striato-thalamic network which may contribute to the underlying neuropathophysiology and clinical heterogeneity in schizo-obsessive spectrum disorders. Our mechanistic model predicts that dynamic over-compensation of the primarily occuring neuropathophysiology can lead to the secondary co-morbid disease.

  • 9.
    Wingård, Louise
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Brandt, Lena
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Bodén, Robert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ekselius: Psychiatry. Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Kieler, Helle
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Andersen, Morten
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden;Univ Copenhagen, Fac Hlth & Med Sci, Dept Drug Design & Pharmacol, Copenhagen, Denmark.
    Reutfors, Johan
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Pharmacoepidemiol, T2, SE-17176 Stockholm, Sweden.
    Monotherapy vs. combination therapy for post mania maintenance treatment: A population based cohort study2019In: European Neuropsychopharmacology, ISSN 0924-977X, E-ISSN 1873-7862, Vol. 29, no 6, p. 691-700Article in journal (Refereed)
    Abstract [en]

    In recent years, the use of atypical antipsychotics and combination therapy for relapse prevention in bipolar disorder has increased substantially. However, real-world data on the comparative effectiveness of these treatment options are largely non-existent. We conducted a population-based cohort study, using data from Swedish national registers. All patients aged 18-75 years who were hospitalized for mania 2006-2014 and filled at least one prescription of lithium, valproate, olanzapine, quetiapine, aripiprazole or any combination of these drugs were included, and followed for up to one year after hospital discharge, generating follow-up data from 5 713 hospitalizations. We used Cox proportional hazard regression models to study time to treatment failure for each individual drug and combination therapy, using lithium as comparator. Treatment failure was defined as treatment discontinuation, switch, or rehospitalization, and the results were adjusted for clinical and sociodemographic factors. We found that treatment failure occurred in 85% of cases and that the majority of combination therapies were associated with lower risks of treatment failure compared to monotherapies. Patients combining lithium + valproate + quetiapine had the lowest risk of treatment failure (adjusted HR [AHR] 0.40, 95% CI 0.30-0.54), followed by patients on lithium + valproate + olanzapine (AHR 0.55, 95% CI 0.45-0.68). In contrast, monotherapies with antipsychotics were associated with significantly higher risks of treatment failure compared to single use of lithium. In conclusion, our results support experimental findings, suggesting that combination therapy is more effective than monotherapy after a manic episode.

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