Figures
Abstract
Methods
We analyzed data on age, sex and dispensed drugs for individuals aged ≥65 years registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1 347 564; 81% of the total population aged ≥65 years in Sweden). Main outcome measures were dopaminergic (enhancing and/or lowering) and serotonergic (enhancing and/or lowering) drugs and combinations of these.
Results
Dopaminergic and serotonergic drugs were used by 5.6% and 13.2% the participants, respectively. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old. The occurrence of combinations of dopaminergic and serotonergic drugs was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%). Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, whereas age showed a mixed pattern.
Conclusion
Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.
Citation: Johnell K, Fischer H (2011) Dopaminergic and Serotonergic Drug Use: A Nationwide Register-Based Study of Over 1 300 000 Older People. PLoS ONE 6(8): e23750. https://doi.org/10.1371/journal.pone.0023750
Editor: Stefan Kiechl, Innsbruck Medical University, Austria
Received: June 7, 2011; Accepted: July 23, 2011; Published: August 15, 2011
Copyright: © 2011 Johnell, Fischer. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was supported financially by a grant from the Swedish Research Council (dnr 2007-5870) and from Konung Gustav V:s och Drottning Victorias Frimurarstiftelse (HF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Introduction
The use of pharmaceutical drugs in today's society is unevenly distributed across different age cohorts. Over 90% of older people (≥70 years) use drugs compared to less than 65% in younger age groups (<50 years) [1]. Many drugs affect one or more of the monoaminergic transmitter systems that have important roles in different cognitive and emotional processes. This could, in turn, result in hampered function in these cognitive and affective domains, as side effects of the drug [2]. Given that age-related changes in cognition and emotion are in part a consequence of age-related changes in the brain, it is of interest to investigate how frequent the use of drugs is that alter dopaminergic and serotonergic function in older adults brains.
Two monoaminergic systems that have important roles in cognitive and affective processing are the dopaminergic and the serotonergic transmitter systems. Many studies have shown that dopamine is strongly involved in higher cognitive function [3], [4] and that aging is associated with a loss of striatal and extrastriatal biomarkers [5], [6]. Some studies have even indicated a curvelinear trajectory with accelerated dopamine losses from young-old to very old age [7]–[9] and that these age-related dopamine losses are related to age-related deficits in several different cognitive abilities [10]. Experimental data now support this latter claim [11]. Studies in humans have also shown significant decline in the serotonergic system in normal aging, important for both emotional function [12], [13] and dyfunction [14], [15], that are independent of disease state [16], [17]. Recent research also implicate a role for serotonin in the NMDA receptor antagonist models of cognitive impairment [18]. The importance of balance between the dopaminergic and the serotonergic systems for working memory function gives further evidence for involvement of the serotonin system also in cognitive function [19].
Little is known about the extent of use of dopaminergic and serotonergic drugs in the general elderly population. However, the prevalence of use of certain types of dopaminergic and serotonergic drugs has been estimated. For instance, recent studies have reported prevalences of 12–20% for antidepressant [20]–[23], 5–12% for antipsychotic [20], [21], [24] and 2% for L-dopa [21] use in older people.
The aim of the present study was to investigate dopaminergic and serotonergic drug use in a very large population of elderly people in a typical modern industrial society (Sweden). These data will demonstrate how many elderly persons who are potentially cognitively and emotionally affected by drugs that either enhance or decrease function in the dopaminergic or serotonergic system.
Methods
Ethics Statement
This study was approved by the ethical board at the Karolinska Institutet in Stockholm (dnr 2009/477-31/3) and we only analyzed de-identified data.
Study population
The Swedish Prescribed Drug Register contains individual-based data for all prescriptions dispensed to the whole population of Sweden (about 9 million inhabitants) [25]. We analyzed non-identifiable data from individuals aged ≥65 years who were registered in the Swedish Prescribed Drug Register from July to September 2008 (n = 1 347 564), with information on every individual's age, sex and dispensed drugs (amount of prescribed drug, when the prescription was filled, and prescribed dosage according to the prescriptions written by the prescribers).
Information from the 3 month period about when the prescription was filled, the amount of drug and the prescribed dosage was processed to calculate the duration of drug exposure [26]–[28]. The time period of 3 months was chosen based on the fact that drugs are prescribed for use for at most 90 days in Sweden. When prescribed dosage was incomplete or missing, we based our calculations of drug exposure on defined daily doses (DDDs) [29]. For each drug, the mean prescribed daily dose (PDD) [29] for regular use was calculated. In the few cases where the PDD could not be calculated, we assumed 0.9 DDDs for regularly used drugs (based on calculations of the total mean value for regularly used drugs among the elderly in the study population). For drugs prescribed as needed, 0.45 DDDs (50% of 0.9) was employed. For dermatological and eye preparations, 1 DDD was assumed [27], [28]. A list of current prescriptions was constructed based on the calculations of the duration of drug exposures for every individual on the arbitrarily chosen date 30 September 2008. If a patient was dispensed the same drug in different doses during the study period, this was counted as one dispensed drug.
Definitions
Drugs were classified according to the Anatomical Therapeutic Chemical (ATC) classification system [29], as recommended by the World Health Organization. The classification of dopaminergic (i.e. enhancing and/or lowering) and serotonergic (i.e. enhancing and/or lowering) drugs [30], [31] is shown in Table 1.
Age was categorized into six groups: 65–69, 70–74, 75–79, 80–84, 85–89 and ≥90 years.
Statistical analysis
We analyzed the occurrence of dopaminergic and serotonergic drug use in relation to age and sex. We also investigated the occurrence of the following combinations of dopaminergic and serotonergic drugs: dopamine enhancing + dopamine lowering drug, serotonin enhancing + serotonin lowering drug, dopamine enhancing + serotonin enhancing drug and dopamine lowering + serotonin lowering drug.
Logistic regression analysis was used to analyze whether age and sex were associated with use of dopaminergic and serotonergic drugs and combinations of these. The results are expressed as odds ratios (ORs) with 95% confidence intervals (CIs). PASW Statistics 18 for Windows was used for the analyses.
Results
In the study population, mean age was 76.2 years (range 65–109 years), 58% were women and 4.5 drugs were on average used per person (Table 2).
Dopaminergic drugs were used by 5.6% of the participants and they were most commonly used by the oldest old (Table 3). The most frequently used dopaminergic drugs were antipsychotics (2.8%) and anti-Parkinson dopaminergic drugs (1.8%). Use of dopamine enhancing drugs were about as common as use of dopamine lowering drugs. Use of ≥2 dopamine enhancing (0.6%) or ≥2 dopamine lowering drugs (0.3%) was uncommon. Serotonergic drugs were used by 13.2% of the elderly. The most frequently used serotonergic drugs were antidepressants (12.3%) and atypical antipsychotics (1.2%). Use of serotonergic drugs increased with age and 23.0% of people aged ≥90 years used these drugs. Serotonin enhancing drugs were more commonly used than serotonin lowering drugs, particularly in women. Use of ≥2 serotonin enhancing (1.7%) or ≥2 serotonin lowering drugs (0%) was also uncommon.
Table 4 shows the results of the logistic regression analysis of whether age and sex were associated with use of dopaminergic and serotonergic drugs. Female gender was related to use of both dopaminergic and, particularly, serotonergic drugs, after adjustment for age. Higher age was associated with use of dopamine lowering drugs and serotonergic drugs, whereas the association with use of dopamine enhancing drugs declined in the oldest old.
Table 5 shows combinations of dopaminergic and serotonergic drugs. The occurrence of these combinations was generally low, with dopamine lowering + serotonin lowering drug the most common combination (1.6%). The combinations of dopaminergic and serotonergic drugs were more common in women than in men. However, the relationship with age showed a mixed pattern. The prevalence of combinations of serotonin enhancing + serotonin lowering drug and dopamine lowering + serotonin lowering drug increased with age, whereas the combinations dopamine enhancing + dopamine lowering drug and dopamine enhancing + serotonin enhancing drug showed no clear relationship with age.
Table 6 shows the results of the logistic regression analysis of whether age and sex were associated with combinations of dopaminergic and serotonergic drugs. Female gender was associated with all of the combinations of dopaminergic and serotonergic drugs, after adjustment for age. Older age was associated with use of serotonin enhancing + serotonin lowering drug and dopamine lowering + serotonin lowering drug, after adjustment for sex. However, age did not show a clear association with the combinations of dopamine enhancing + dopamine lowering drug and dopamine enhancing + serotonin enhancing drug.
Discussion
Main findings
In our large nationwide study, dopaminergic drugs were used by 6% and serotonergic drugs by 13% of the elderly population (≥ 65 years). Use of these drugs was associated with female gender and higher age. Drugs that affect the dopaminergic and serotonergic systems are used for a wide range of different medical conditions in older adults. The frequent use of these drugs calls for awareness of cognitive and emotional side-effects in elderly people. This needs to be taken into account when making different clinical evaluations on elderly persons that are based on cognitive or affective deficits.
One important finding in our study is that the use of dopaminergic and serotonergic drugs increases with age. Given what is known about accelerated dopamine losses in the brain from young-old to very-old age [7]–[9], these two opposing trajectories suggest a potential increase of dopaminergic side effect in the older age cohort. This could also be true for serotonergic drugs, even though there are still too few studies on age related decline in the serotonergic system [16], [17].
Previous studies on young women and men have demonstrated a sexual dimorphism in neurotransmission, particularly in the dopamine system [32], [33], related to sex differences in cognitive function [34]. However, given age-related changes in sex hormones levels, the implications of our gender- related findings are difficult to evaluate because of the lack of studies on gender differences in the dopaminergic and serotonergic systems in old age.
Use of dopaminergic and serotonergic drugs can also cause severe somatic side effects in older people. Both dopaminergic and serotonergic drugs have been associated with an increased risk of fractures [35], [36]. In particular, the combination of dopamine enhancing and serotonin enhancing drugs has been associated with increased hip fracture risk [35]. This drug combination was related to female gender in our study, which may be problematic as women are at greatest risk of fractures [37]. Further, advanced age and use of serotonergic drugs have previously been associated with an increased risk of bleeding [31]. In our study, advanced age was correlated to use of these drugs.
However, dopaminergic and serotonergic drug therapy may also be efficacious for treatment of depression, psychotic disorders and Parkinson's disease in old age [38]–[41]. Nonetheless, older people are often underrepresented in clinical trials [42] and, therefore, there is a lack of high-level evidence for treatment with dopaminergic and serotonergic drugs in this population.
Limitations
We analysed data on 1 347 564 elderly people registered in the Swedish Prescribed Drug Register from July to September 2008, which corresponded to about 81% of the total population aged ≥65 years in Sweden (according to Statistics Sweden's census data from 30 September 2008). Hence, about 19% of the of the total Swedish population aged ≥65 years did not fill a prescription at a Swedish pharmacy during the study period. The generalizability of our results to other similar countries is postulated to be high given that we have analyzed an unselected population. The Swedish Prescribed Drug Register does not include information about diagnoses or over-the-counter drugs. In 2008, some antimigraine selective serotonin (5HT1) agonists were available over the counter in Sweden, which may lead to an underestimation of the use of these drugs in our study. Also, the register does not include drugs used in hospitals or from drug storerooms, which may lead to an underestimation of drug use in the institutional setting.
Moreover, our method is built on an assumption that all current drugs were dispensed during the observed 3 month period, due to the fact that drugs are prescribed for use during at most 90 days in Sweden. Therefore, we might have disregarded drugs that were dispensed before the three month period and used at a slower rate than intended. At the same time, we might have included drugs that were dispensed during the three month period but discontinued prematurely. In addition, our method is based on interpretations of the dispensed drugs' dosages written by the prescribers, as well as assumptions about DDDs when information about dosage was incomplete or missing [26], [27]. Finally, a general limitation of studies on drug registers is that data may not adequately reflect actual drug use given that adherence to treatment can be low [43].
Conclusion
Approximately one out of ten older patients uses serotonergic drugs and one out of twenty dopaminergic drugs. The frequent use of dopaminergic and serotonergic drugs in the elderly patients is a potential problem due to the fact that aging is associated with a down-regulation of both these monoaminergic systems. Future studies are needed for evaluation of the impact of these drugs on different cognitive and emotional functions in old age.
Acknowledgments
We thank the National Board of Health and Welfare for providing data. We also wish to thank Johan Fastbom for initial processing of the data and Marianne Kristiansson for help with the dopaminergic and serotonergic drug classification.
Author Contributions
Conceived and designed the experiments: KJ HF. Analyzed the data: KJ. Wrote the paper: KJ HF.
References
- 1. Hovstadius B, Astrand B, Petersson G (2009) Dispensed drugs and multiple medications in the Swedish population: an individual-based register study. BMC Clin Pharmacol 9: 11.
- 2. Lotrich FE, Pollock BG (2005) Aging and clinical pharmacology: implications for antidepressants. J Clin Pharmacol 45: 1106–1122.
- 3. Backman L, Robins-Wahlin TB, Lundin A, Ginovart N, Farde L (1997) Cognitive deficits in Huntington's disease are predicted by dopaminergic PET markers and brain volumes. Brain 120: 2207–2217.
- 4. Glickstein SB, Desteno DA, Hof PR, Schmauss C (2005) Mice lacking dopamine D2 and D3 receptors exhibit differential activation of prefrontal cortical neurons during tasks requiring attention. Cereb Cortex 15: 1016–1024.
- 5. Kaasinen V, Vilkman H, Hietala J, Nagren K, Helenius H, et al. (2000) Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain. Neurobiol Aging 21: 683–688.
- 6. Wang Y, Chan GL, Holden JE, Dobko T, Mak E, et al. (1998) Age-dependent decline of dopamine D1 receptors in human brain: a PET study. Synapse 30: 56–61.
- 7. Rinne JO, Lonnberg P, Marjamaki P (1990) Age-dependent decline in human brain dopamine D1 and D2 receptors. Brain Res 508: 349–352.
- 8. Antonini A, Leenders KL, Reist H, Thomann R, Beer HF, et al. (1993) Effect of age on D2 dopamine receptors in normal human brain measured by positron emission tomography and 11C-raclopride. Arch Neurol 50: 474–480.
- 9. Bannon MJ, Whitty CJ (1997) Age-related and regional differences in dopamine transporter mRNA expression in human midbrain. Neurology 48: 969–977.
- 10. Backman L, Lindenberger U, Li SC, Nyberg L (2010) Linking cognitive aging to alterations in dopamine neurotransmitter functioning: recent data and future avenues. Neurosci Biobehav Rev 34: 670–677.
- 11. Fischer H, Nyberg L, Karlsson S, Karlsson P, Brehmer Y, et al. (2010) Simulating neurocognitive aging: effects of a dopaminergic antagonist on brain activity during working memory. Biol Psychiatry 67: 575–580.
- 12. Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38: 1083–1152.
- 13. Munafo MR, Brown SM, Hariri AR (2008) Serotonin transporter (5-HTTLPR) genotype and amygdala activation: a meta-analysis. Biol Psychiatry 63: 852–857.
- 14. Stein M, Steckler T, Lightfoot JD, Hay E, Goddard AW (2010) Pharmacologic treatment of panic disorder. Curr Top Behav Neurosci 2: 469–485.
- 15. Treit D, Engin E, McEown K (2010) Animal models of anxiety and anxiolytic drug action. Curr Top Behav Neurosci 2: 121–160.
- 16. Blin J, Baron JC, Dubois B, Crouzel C, Fiorelli M, et al. (1993) Loss of brain 5-HT2 receptors in Alzheimer's disease. In vivo assessment with positron emission tomography and [18F]setoperone. Brain 116: 497–510.
- 17. Verhoeff NP, Meyer JH, Kecojevic A, Hussey D, Lewis R, et al. (2000) A voxel-by-voxel analysis of [18F]setoperone PET data shows no substantial serotonin 5-HT(2A) receptor changes in schizophrenia. Psychiatry Res 99: 123–135.
- 18. Meltzer HY, Horiguchi M, Massey BW (2011) The role of serotonin in the NMDA receptor antagonist models of psychosis and cognitive impairment. Psychopharmacology (Berl) 213: 289–305.
- 19. Luciana M, Collins PF, Depue RA (1998) Opposing roles for dopamine and serotonin in the modulation of human spatial working memory functions. Cereb Cortex 8: 218–226.
- 20.
Desplenter F, Caenen C, Meelberghs J, Hartikainen S, Sulkava R, et al. Change in psychotropic drug use among community-dwelling people aged 75 years and older in Finland: repeated cross-sectional population studies. Int Psychogeriatr. (in press).
- 21. Lovheim H, Karlsson S, Gustafson Y (2008) The use of central nervous system drugs and analgesics among very old people with and without dementia. Pharmacoepidemiol Drug Saf 17: 912–918.
- 22.
Parabiaghi A, Franchi C, Tettamanti M, Barbato A, D'Avanzo B, et al. Antidepressants utilization among elderly in Lombardy from 2000 to 2007: dispensing trends and appropriateness. Eur J Clin Pharmacol. (in press).
- 23. Haider SI, Johnell K, Thorslund M, Fastbom J (2008) Analysis of the association between polypharmacy and socioeconomic position among elderly aged >/ = 77 years in Sweden. Clin Ther 30: 419–427.
- 24.
Jedenius E, Johnell K, Fastbom J, Stromqvist J, Winblad B, et al. Dementia management programme in a community setting and the use of psychotropic drugs in the elderly population. Scand J Prim Health Care. (in press).
- 25. Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, et al. (2007) The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf 16: 726–735.
- 26. Lau HS, de Boer A, Beuning KS, Porsius A (1997) Validation of pharmacy records in drug exposure assessment. J Clin Epidemiol 50: 619–625.
- 27. Johnell K, Fastbom J, Rosen M, Leimanis A (2007) Inappropriate drug use in the elderly: a nationwide register-based study. Ann Pharmacother 41: 1243–1248.
- 28.
Johnell K, Fastbom JAntiepileptic drug use in community-dwelling and institutionalized elderly: a nationwide study of over 1 300 000 older people. Eur J Clin Pharmacol.
- 29. WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway. (2011) http://www.whocc.no/. Accessed 24 May.
- 30. Arbouw ME, Movig KL, van Staa TP, Egberts AC, Souverein PC, et al. (2011) Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study. Osteoporos Int 22: 2197–2204.
- 31. Verdel BM, Souverein PC, Meenks SD, Heerdink ER, Leufkens HG, et al. (2011) Use of serotonergic drugs and the risk of bleeding. Clin Pharmacol Ther 89: 89–96.
- 32. Cosgrove KP, Mazure CM, Staley JK (2007) Evolving knowledge of sex differences in brain structure, function, and chemistry. Biol Psychiatry 62: 847–855.
- 33. Gillies GE, McArthur S (2010) Estrogen actions in the brain and the basis for differential action in men and women: a case for sex-specific medicines. Pharmacol Rev 62: 155–198.
- 34. Mozley LH, Gur RC, Mozley PD, Gur RE (2001) Striatal dopamine transporters and cognitive functioning in healthy men and women. Am J Psychiatry 158: 1492–1499.
- 35.
Arbouw ME, Movig KL, van Staa TP, Egberts AC, Souverein PC, et al. (2010) Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study. Osteoporos Int.
- 36. Ginzburg R, Rosero E (2009) Risk of fractures with selective serotonin-reuptake inhibitors or tricyclic antidepressants. Ann Pharmacother 43: 98–103.
- 37. Johnell O, Kanis J (2005) Epidemiology of osteoporotic fractures. Osteoporos Int 16: Suppl 2S3–7.
- 38. Rajji TK, Mulsant BH, Lotrich FE, Lokker C, Reynolds CF, 3rd (2008) Use of antidepressants in late-life depression. Drugs Aging 25: 841–853.
- 39. Chan DK, Cordato DJ, O'Rourke F (2008) Management for motor and non-motor complications in late Parkinson's disease. Geriatrics 63: 22–27.
- 40. Hasnain M, Vieweg WV, Baron MS, Beatty-Brooks M, Fernandez A, et al. (2009) Pharmacological management of psychosis in elderly patients with parkinsonism. Am J Med 122: 614–622.
- 41.
Mottram P, Wilson K, Strobl J (2006) Antidepressants for depressed elderly. Cochrane Database Syst Rev. CD003491 p.
- 42. Giron MS, Fastbom J, Winblad B (2005) Clinical trials of potential antidepressants: to what extent are the elderly represented: a review. Int J Geriatr Psychiatry 20: 201–217.
- 43. Haukka J, Suvisaari J, Tuulio-Henriksson A, Lonnqvist J (2007) High concordance between self-reported medication and official prescription database information. Eur J Clin Pharmacol 63: 1069–1074.