Browsing by Subject "Antidepressant"

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  • Komulainen, Emma; Heikkila, Roope; Meskanen, Katarina; Raij, Tuukka T.; Nummenmaa, Lauri; Lahti, Jari; Jylhä, Pekka; Melartin, Tarja; Harmer, Catherine J.; Isometsa, Erkki; Ekelund, Jesper (2016)
    Increased self-focus is a core factor in the psychopathology of depression. Cortical midline structures (CMS) are implicated in the neurobiology of self, depression and antidepressant treatment response. Mirtazapine, an antidepressant that increases serotonin and norepinephrine release, enhances processing of positive and attenuates processing of negative emotional information in healthy volunteers after a single dose. These early changes, which are opposite to the negative information bias in depression, may be important for the therapeutic effect of mirtazapine. It nevertheless remains unresolved whether/how mirtazapine specifically influences processing of self-referential emotional information. Half of the healthy volunteers (n=15/30) received a single dose of mirtazapine, in an open-label design, two hours before functional magnetic resonance imaging (fMRI), and the other half was scanned as a control group without medication. During fMRI the participants categorized positive and negative self-referential adjectives. Mirtazapine attenuated responses to self-referential processing in the medial prefrontal cortex and the anterior cingulate cortex. Mirtazapine further decreased responses to positive self-referential processing in the posterior cingulate cortex and parietal cortex. These decreased responses of the CMS suggest that mirtazapine may rapidly improve the ability of the CMS to down-regulate self-referential processing. In depressed patients, this could lead to decreased self-focus and rumination, contributing to the antidepressant effect.
  • Komulainen, Emma; Heikkila, Roope; Meskanen, Katarina; Raij, Tuukka T.; Nummenmaa, Lauri; Lahti, Jari; Jylhä, Pekka; Melartin, Tarja; Harmer, Catherine J.; Isometsa, Erkki; Ekelund, Jesper (SAGE SCIENCE PRESS (UK), 2016)
    Increased self-focus is a core factor in the psychopathology of depression. Cortical midline structures (CMS) are implicated in the neurobiology of self, depression and antidepressant treatment response. Mirtazapine, an antidepressant that increases serotonin and norepinephrine release, enhances processing of positive and attenuates processing of negative emotional information in healthy volunteers after a single dose. These early changes, which are opposite to the negative information bias in depression, may be important for the therapeutic effect of mirtazapine. It nevertheless remains unresolved whether/how mirtazapine specifically influences processing of self-referential emotional information. Half of the healthy volunteers (n=15/30) received a single dose of mirtazapine, in an open-label design, two hours before functional magnetic resonance imaging (fMRI), and the other half was scanned as a control group without medication. During fMRI the participants categorized positive and negative self-referential adjectives. Mirtazapine attenuated responses to self-referential processing in the medial prefrontal cortex and the anterior cingulate cortex. Mirtazapine further decreased responses to positive self-referential processing in the posterior cingulate cortex and parietal cortex. These decreased responses of the CMS suggest that mirtazapine may rapidly improve the ability of the CMS to down-regulate self-referential processing. In depressed patients, this could lead to decreased self-focus and rumination, contributing to the antidepressant effect.
  • Theilmann, Wiebke; Alitalo, Okko August; Yorke, Iris; Rantamäki, Tomi Pentti Johannes (2019)
    Objectives: Deep burst-suppressing isoflurane anesthesia regulates signaling pathways connected with antidepressant responses in the rodent brain: activation of TrkB neurotrophin receptor and inhibition of GSK3 beta kinase (glycogen synthase kinase 3 beta). The main objective of this study was to investigate whether EEG (electroencephalogram) burst suppression correlates with these intriguing molecular alterations induced by isoflurane. Methods: Adult male mice pre-implanted with EEG recording electrodes were subjected to varying concentrations of isoflurane (1.0-2.0% ad 20 min) after which medial prefrontal cortex samples were collected for molecular analyses, and the data retrospectively correlated to EEG ( + /- burst suppression). Results: Isoflurane dose-dependently increased phosphorylation of TrkB(Y816), CREBS133 (cAMP response element binding protein), GSK3 beta(S9) and p70S6k(T412/S424). The time spent in burst suppression mode varied considerably between individual animals. Notably, a subset of animals subjected to 1.0-1.5% isoflurane showed no burst suppression. While p-GSK3 beta(S9), p-CREBS133 and p-p70S6k(T412/S424) levels were increased in the samples obtained also from these animals, p-TrkB(Y816) levels remained unaltered. Conclusions: Isoflurane dose-dependently regulates TrkB and GSK3 beta signaling and dosing associated with therapeutic outcomes in depressed patients produces most prominent effects.
  • Kohtala, Henrik Samuel; Theilmann, Wiebke; Rosenholm, Marko Petteri; Müller, Heidi K.; Kiuru, Paula Sinikka; Wegener, Gregers; Yli-Kauhaluoma, Jari Tapani; Rantamäki, Tomi Pentti Johannes (2019)
    Subanesthetic rather than anesthetic doses are thought to bring the rapid antidepressant effects of the NMDAR (N-methyl-D-aspartate receptor) antagonist ketamine. Among molecular mechanisms, activation of BDNF receptor TrkB along with the inhibition of GSK3 beta (glycogen synthase kinase 3 beta) are considered as critical molecular level determinants for ketamine's antidepressant effects. Hydroxynorketamines (2R,6R)-HNK and (2S,6S) HNK), non-anesthetic metabolites of ketamine, have been proposed to govern the therapeutic effects of ketamine through a mechanism not involving NMDARs. However, we have shown that nitrous oxide, another NMDAR blocking anesthetic and a putative rapid-acting antidepressant, evokes TrkB-GSK3 beta signaling alterations during rebound slow EEG (electroencephalogram) oscillations. We investigated here the acute effects of ketamine, 6,6-d(2)-ketamine (a ketamine analogue resistant to metabolism) and cis-HNK that contains (2R,6R) and (2S,6S) enantiomers in 1:1 ratio, on TrkB-GSK3 beta signaling and concomitant electroencephalographic (EEG) alterations in the adult mouse cortex. Ketamine dose-dependently increased slow oscillations and phosphorylations of TrkB(Y816) and GSK3 beta(59) in crude brain homogenates (i.e. sedative/anesthetic doses ( > 50 mg/kg, i.p.) produced more prominent effects than a subanesthetic dose (10 mg/kg, i.p.)). Similar, albeit less obvious, effects were seen in crude synaptosomes. A sedative dose of 6,6-d(2)-ketamine (100 mg/kg, i.p.) recapitulated the effects of ketamine on TrkB and GSK3 beta phosphorylation while cis-HNK at a dose of 20 mg/kg produced negligible acute effects on TrkB-GSK3 beta signaling or slow oscillations. These findings suggest that the acute effects of ketamine on TrkB-GSK3 beta signaling are by no means restricted to subanesthetic (i.e. antidepressant) doses and that cis-HNK is not responsible for these effects.
  • Hulkko, A. P.; Murray, G. K.; Moilanen, J.; Haapea, M.; Rannikko, I.; Jones, P. B.; Barnett, J. H.; Huhtaniska, S.; Isohanni, M. K.; Koponen, H.; Jaaskelainen, E.; Miettunen, J. (2017)
    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.
  • Halonen, Jaana I.; Koskinen, Aki; Varje, Pekka; Kouvonen, Anne; Hakanen, Jari J.; Väänänen, Ari (2018)
    Background: We defined gender-specific profiles of mental ill-health for the main occupational groups using three outcomes; antidepressant use, sickness absence (SA) due to depression, and suicides. We also examined which occupational groups had the highest risk of the outcomes, and compared the importance of their predictors. Methods: From a random register cohort of Finnish working age population, individuals in the six largest occupational groups in 2004 for men and women were included (N = 414 357). We used register data to define the first antidepressant purchase (i.e. use), the first long-term SA spell for depression, and suicide between Jan 1st 2005 and Dec 31st 2014. We assessed the risk of each outcome by occupational group with logistic regression models, and used dominance analysis to compare the relative importance of predictors. Results: In all six occupational groups for women, the prevalence of antidepressant use and SA for depression was higher than in the men's occupational groups. The opposite was observed for suicides. The risk of antidepressant use was lower, but the risk of suicide was 2-times higher among men in low vs. high-skilled occupations. Among women, a lower skill-level was associated with a higher risk of SA due to depression. Gender was the most important predictor of all outcomes. Limitations: We lacked information on history of medication use or health problems prior to follow-up. Conclusions: Gendered occupational status was an underlying factor explaining distinctive mental health profiles in the working population. Occupational class-dependent behavioural patterns related to mental health existed among men.
  • Lille, Lotta (Helsingin yliopisto, 2021)
    Tutkielmassa kerättiin ja analysoitiin aineistoa psykoosilääkkeiden ja masennuslääkkeiden aiheuttamista myrkytyskuolemista vuosina 2016–2018 Suomessa. Tutkielmassa tarkastellut lääkeaineet valittiin siksi, että oikeuskemialliset tutkimukset ovat osoittaneet niiden lukeutuvan myrkytyskuolemien merkittävimpien aiheuttajien joukkoon. Eri psykoosi- ja masennuslääkkeiden aiheuttamia myrkytyskuolemia arvioitiin Fatal Toxicity Index (FTI) – käsitteen perusteella. FTI laskettiin jokaiselle tutkitulle lääkeaineelle jakamalla lääkeaineen aiheuttamien myrkytyskuolemien lukumäärä kyseisen lääkeaineen kulutuksella. Lääkeaineen kulutus ilmoitettiin WHO:n kansainvälisesti määrittelemän vuorokausiannoksen (DDD, Defined Daily Dose) avulla. Lääkeaineiden aiheuttamien myrkytyskuolemien suhde niiden kulutukseen antaa tärkeää tietoa lääkeaineisiin liittyvästä myrkytyskuoleman riskistä. Tutkimusaineiston myrkytyskuolemien lukumäärät sekä luokitellut kuolinsyyt vuositasolla saatiin oikeuslääketieteellisen kuolemansyyn selvittämisen yhteydessä Terveyden ja hyvinvoinnin laitoksen oikeustoksikologiayksikön tietokantaan tallennetuista tiedoista. Tiedot eri lääkeaineiden keskimääräisestä kulutuksesta vuositasolla saatiin Lääkealan turvallisuus- ja kehittämiskeskus Fimean sivuilta. Tiedot Suomen asukasluvusta eri vuosina ovat peräisin Tilastokeskukselta. Aineistossa oli tarkasteltavana 13 psykoosilääkettä ja 18 masennuslääkettä. Psykoosilääkkeiden aiheuttamia myrkytyskuolemia kirjattiin yhteensä 136 ja masennuslääkkeiden aiheuttamia myrkytyskuolemia 152 vuosina 2016–2018. Myrkytyskuolemat jakautuivat kolmeen eri kuolemanluokkaan: tapaturma, itsemurha ja epäselvä. Suurin osa myrkytyskuolemista oli itsemurhia. Tutkielmassa tarkastellulla aikavälillä 2016–2018 suurimmat FTI-arvot havaittiin seuraavilla lääkeaineilla: psykoosilääkkeissä levomepromatsiini, sulpiridi ja klooriprotikseeni, masennuslääkkeissä klomipramiini, doksepiini ja trimipramiini. Laskettujen FTI-arvojen pohjalta voidaan arvioida lääkeaineiden myrkyllisyyttä saman lääkeryhmän sisällä sekä eri lääkeryhmien välillä. Tutkielman tuloksilla on merkitystä arvioitaessa potilaalle sopivaa psykoosi- tai masennuslääkitystä sekä määritettäessä mahdollista seuraavaa saman lääkeaineryhmän lääkettä, kun potilaan lääkitystä vaihdetaan.
  • Taipale, Heidi; Koponen, Marjaana; Tanskanen, Antti; Lavikainen, Piia; Sund, Reijo; Tiihonen, Jari; Hartikainen, Sirpa; Tolppanen, Anna-Maija (BioMed Central, 2017)
    Abstract Background Antidepressant use has been associated with an increased risk of falling, but no studies have been conducted on whether antidepressant use is associated with an increased risk of head injuries which often result from falling among older persons. The objective of this study was to investigate the risk of head and brain injuries associated with antidepressant use among community-dwelling persons with Alzheimer’s disease. Methods A matched cohort study was conducted by comparing new antidepressant users (n = 10,910) with two matched nonusers (n = 21,820) in the MEDALZ study cohort. The MEDALZ cohort includes all community-dwelling persons newly diagnosed with Alzheimer’s disease between 2005 and 2011 in Finland. Incident antidepressant users were identified based on register-based dispensing data from the Prescription register with a 1-year washout period for antidepressant use. Nonusers were matched with users based on age, gender, and time since Alzheimer’s disease diagnosis. The outcome events were defined as any head injuries and traumatic brain injuries based on diagnoses in Hospital Discharge and Causes of Death registers. Propensity score adjusted Cox proportional hazard models were utilized. Sensitivity analyses with case-crossover design were conducted. All registers are linkable with unique personal identification numbers assigned for each resident. Results Antidepressant use was associated with an increased risk of head injuries (age-adjusted event rate per 100 person-years 2.98 (95% confidence interval (CI) 2.49–3.06) during use and 2.43 (95% CI 2.06–2.35) during nonuse, adjusted hazard ratio (HR) 1.35, 95% CI 1.20–1.52) and traumatic brain injuries (age-adjusted event rate per 100 person-years 1.33 (95% CI 1.13–1.53) during use and 1.10 (95% CI 1.00–1.20) during nonuse, adjusted HR 1.26, 95% CI 1.06–1.50). The risk was highest during the first 30 days of use (HR 1.71, 95% CI 1.10–2.66 for head injuries; HR 2.06, 95% CI 1.12–3.82 for traumatic brain injuries) and remained at an elevated level for head injuries for over 2 years of use. In case-crossover analyses, antidepressant use was consistently associated with a higher risk of head injuries. Conclusions Antidepressant use was associated with an increased risk of the most severe outcomes, head and brain injuries, in persons with Alzheimer’s disease. Antidepressant use should be carefully considered and the association confirmed in future studies.
  • Komulainen, Emma; Heikkilä, Roope; Nummenmaa, Lauri; Raij, Tuukka T.; Harmer, Catherine J.; Isometsä, Erkki; Ekelund, Jesper (2018)
    Background: Increased self-focus and negative self-concept play an important role in depression. Antidepressants influence self-referential processing in healthy volunteers, but their function in self-processing of depressed patients remains unknown. Methods: Thirty-two depressed patients were randomly allocated to receive either escitalopram 10 mg or placebo for one week. After one week, neural responses to positive and negative self-referential adjectives and neutral control stimuli were assessed with functional magnetic resonance imaging. A group of matched healthy volunteers served as a control group. Results: Escitalopram decreased responses of medial fronto-parietal regions to self-referential words relative to non-emotional control stimuli, driven by increased responses to the control condition. Escitalopram also increased responses in the pre-defined region of the medial prefrontal cortex (MPFC) and the anterior cingulate cortex (ACC) to positive relative to negative words. Importantly, the changes in neural responses occurred before any effect on depressive symptoms, implying a direct effect of escitalopram. Furthermore, the placebo group had decreased responses of the MPFC and the ACC to positive self-referential processing relative to the matched healthy controls. However, neural responses of the escitalopram group and the healthy unmedicated controls were similar. Limitations: Differences between the groups in self-reported depression symptoms and personality traits may have influenced the results. Conclusion: One-week treatment with escitalopram normalized aberrant self-referential processing in depressed patients, shifting the focus from the self to the external environment and potentiating positive self-referential processing. This may be an important factor in mechanism of action of antidepressants.
  • Komulainen, Emma; Glerean, Enrico; Meskanen, Katarina; Heikkila, Roope; Nummenmaa, Lauri; Raij, Tuukka; Lahti, Jari; Jylhä, Pekka; Melartin, Tarja; Isometsa, Erkki; Ekelund, Jesper (2017)
    The link between neurotransmitter-level effects of antidepressants and their clinical effect remain poorly understood. A single dose of mirtazapine decreases limbic responses to fearful faces in healthy subjects, but it is unknown whether this effect applies to complex emotional situations and dynamic connectivity between brain regions. Thirty healthy volunteers listened to spoken emotional narratives during functional magnetic resonance imaging (fMRI). In an open-label design, 15 subjects received 15 mg of mirtazapine two hours prior to fMRI while 15 subjects served as a control group. We assessed the effects of mirtazapine on regional neural responses and dynamic functional connectivity associated with valence and arousal. Mirtazapine attenuated responses to unpleasant events in the right fronto-insular cortex, while modulating responses to arousing events in the core limbic regions and the cortical midline structures (CMS). Mirtazapine decreased responses to unpleasant and arousing events in sensorimotor areas and the anterior CMS implicated in self-referential processing and formation of subjective feelings. Mirtazapine increased functional connectivity associated with positive valence in the CMS and limbic regions. Mirtazapine triggers large-scale changes in regional responses and functional connectivity during naturalistic, emotional stimuli. These span limbic, sensorimotor, and midline brain structures, and may be relevant to the clinical effectiveness of mirtazapine.
  • Kriikku, Pirkko; Ojanpera, Ilkka (2016)
    We reviewed the 33 727 postmortem toxicology investigations performed in Finland over a period of 5 years (2009-2013) and identified those in which the antidepressant bupropion was detected. Cases positive for other antidepressant drugs were reviewed for comparison. The postmortem toxicological examination included, in all cases, the routine screening and quantification of hundreds of drugs and poisons using quality-controlled methods. Bupropion was detected in 65 cases. A large proportion of the bupropion-positive deaths resulted from suicide (55%). In fatal poisoning cases found positive for bupropion, the proportion of suicide was even higher (77%). The measured median bupropion postmortem blood concentration (0.69 mg/L) was markedly higher than the normal therapeutic range in plasma in the treatment of depression (up to 0.1 mg/L) and even higher in fatal bupropion poisonings (13 mg/L). Only 14% of the deceased positive for bupropion were estimated to be drug abusers. However, nearly all of the drug abuse cases were from the last year of the study (2013), indicating a recent increase of the use of bupropion among drug abusers and possibly even abuse of bupropion itself. Suicide victims positive for bupropion were younger than those who died with other antidepressant drugs in their blood. In addition, the percentage of fatal poisonings among bupropion-positive postmortem cases was higher than among the users of other antidepressant drugs. Suicide was significantly more common among the deceased positive for bupropion than among users of other antidepressant drugs. An unknown degree of bupropion degradation before the assay and post-mortem redistribution of bupropion may have impacted the measured levels. Nonetheless, all post-mortem concentrations of bupropion were elevated and especially high concentrations were detected in suicides. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Ruckenstein, Minna (2019)
    This article is inspired by the social life of methods approach, joining a movement among social scientists engaging with ‘big data’ to contribute to methodological innovation and conceptual development in research and knowledge translation. It explores human-drug associations using a computational tool, Medicine Radar, meanwhile raising questions about the ways a digital device pushes us to rethink how drugs are known in the everyday. Medicine Radar is an apparatus for exploring human-drug associations by means of Suomi24 (Finland24) data, containing 19 million health-related online posts spanning a period of 16 years. Using defined markers, Medicine Radar sorts the medicine talk in health-related discussions, thereby assisting us to ‘see’ the actions of the drug and human responses to them. This kind of approach distances the drug from the illness experience, drawing attention to the private details of the human-drug relationship. The empirical analysis separates three areas of antidepressant use: articulations of reactions, stabilizing the life effects of drugs and coming to terms with antidepressants. Together, the online posts urge us to think of everyday experience where the effects of drugs – intended or unintended – are always lived. The side effects of antidepressants, including drowsiness, ravenous hunger, loss of sexual desire and emotional numbness, become life effects. As will be demonstrated, the move from conceptualizing such fallout as side effects to understanding them as life effects has political ramifications. The computation tool adds collective weight to antidepressant experiences and calls for politicizing their effects on life.
  • Rantamaki, Tomi (2019)
    The role of brain-derived neurotrophic factor (BDNF) and its receptor TrkB has been studied in the context of mood disorders and their treatments for a couple of decades. Pharmacologically diverse antidepressant drugs increase the synthesis of BDNF in the cortex (and some subcortical structures) and this effect accounts for their ability to facilitate neurotrophic processes eventually leading into heightened plasticity within the cortex. Induction of BDNF-TrkB signaling has also been associated with the mechanism of action of ketamine and more recently with some other anesthetics, even with ones not thought to possess antidepressant potential. Notably, both ketamine and conventional antidepressants activate TrkB receptor and its downstream signaling rapidly within the same time scale in the brain while electroconvulsive therapy (ECT), among the most potent inducers of BDNF, has not been unequivocally shown to produce such acute effects on TrkB. The ability of antidepressants to regulate TrkB signaling is developmentally regulated and requires an intact central nervous system. The purpose of this review is to highlight and discuss some of these peculiarities associated with the effects of ketamine and classical antidepressants and BDNF on TrkB signaling.