Aging & Mental Health
ISSN: 1360-7863 (Print) 1364-6915 (Online) Journal homepage: http://www.tandfonline.com/loi/camh20
New antidepressant use in older adults: a Canadian population-based study (1997–2013) Christine Leong, Murray W. Enns, Jitender Sareen, Silvia Alessi-Severini, James Bolton, Heather J. Prior & Dan Chateau To cite this article: Christine Leong, Murray W. Enns, Jitender Sareen, Silvia Alessi-Severini, James Bolton, Heather J. Prior & Dan Chateau (2016): New antidepressant use in older adults: a Canadian population-based study (1997–2013), Aging & Mental Health, DOI: 10.1080/13607863.2016.1154014 To link to this article: http://dx.doi.org/10.1080/13607863.2016.1154014
Published online: 29 Feb 2016.
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Date: 01 March 2016, At: 12:34
AGING & MENTAL HEALTH, 2016 http://dx.doi.org/10.1080/13607863.2016.1154014
New antidepressant use in older adults: a Canadian population-based study (1997 2013) Christine Leonga, Murray W. Ennsb, Jitender Sareenb, Silvia Alessi-Severinia, James Boltonb, Heather J. Priorc and Dan Chateauc
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a College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; bDepartment of Psychiatry, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; cDepartment of Community Health Sciences, Manitoba Centre for Health Policy, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
ABSTRACT
ARTICLE HISTORY
Objective: There has been much attention on appropriate prescribing in older adults in recent years. Recent guidelines favor the use of newer antidepressants over older agents based on their safety profile in this population. This study aimed to examine whether there has been a decline in older antidepressants and an increase in newer antidepressants used by older adults. Method: A retrospective cross-sectional study using administrative databases examined the annual incidence of antidepressant use (per 1000) of community-dwelling adults 60 years old between 1997/1998 and 2012/2013 in Manitoba, Canada. Results: The population of Manitoba 60 years increased by 25.6% from 188,296 to 236,569 from 1997/1998 to 2012/2013. New antidepressant use peaked to 45.9 per 1000 in 1999/2000, and then decreased steadily to 30.5 per 1000 in 2012/2013 (p < 0.0001). Incident amitriptyline use was high but declined from 15.5 to 7.4 per 1000 (p < 0.001). An increase in incident trazodone, mirtazapine, and venlafaxine use was observed (p < 0.001). Conclusions: There has been an overall decrease in the annual incidence of antidepressant users in older adults over the last 16 years, with a marked decline in new amitriptyline use and an increase in the incidence of newer agents.
Received 21 September 2015 Accepted 4 February 2016
Introduction Antidepressants are widely prescribed in North America primarily for the treatment of mood and anxiety disorders (Akincigil et al., 2011; Gelenberg et al., 2010; IMS Health, 2012; Lam, Kennedy, & Grigoriadis, 2009; Marcus & Olfson, 2010; Olfson & Marcus, 2009; Principles of Diagnosis and Management of Anxiety Disorders, 2006; Special Populations, 2006). They have a modest effect over placebo in reducing the signs and symptoms of depression (Cipriani, Furukawa, & Salanti, 2009; Gelenberg, 2010; Lam et al., 2009; Turner, Matthews, Linardatos, Tell, & Rosenthal, 2008), and are recommended first-line by clinical practice guidelines for the long-term treatment of mood and anxiety (Principles of Diagnosis and Management of Anxiety Disorders, 2006; Special Populations, 2006). However, older adults are frequently underrepresented in clinical trials (Fick et al., 2012; Barry, Gallagher, & Ryan, 2007; Gallagher & O’Mahony, 2008; Ryynanen, Kivela, & Honkanen, 1993; Special Populations, 2006). While there is accumulating evidence supporting the efficacy and safety of antidepressants in older patients (Alexopoulos et al., 2009; Hunkeler et al., 2006; Stone et al. 2009; Unutzer et al., 2002), the proper use of these agents to ensure their effectiveness and safety in this population has not been fully established. Past research has suggested that all antidepressants are similar in efficacy but not safety (Cipriani et al., 2009; Gelenberg, 2010; Lam et al., 2009; Turner et al., 2008). Accordingly, the safety profile of an agent has largely been the guiding principle
CONTACT Christine Leong © 2016 Taylor & Francis
[email protected]
KEYWORDS
Antidepressants; drug utilization; older adults; cross-sectional study
for treatment choice for older adults in clinical practice (Cipriani et al., 2009; Gelenberg, 2010; Lam et al., 2009; Turner et al., 2008). Most practice guidelines prefer the use of selective serotonin reuptake inhibitors (SSRIs) and other new generation antidepressants over tricyclic antidepressants (TCAs) due to their lower risk of central nervous system, anticholinergic, and cardiovascular effects (Gelenberg, 2010; Lam et al., 2009). Older patients also tend to have multiple comorbidities, medications, and may be more susceptible to side effects than younger patients. Choosing a medication with a favorable side effect profile is therefore important for effective long-term therapy. Previous studies on antidepressant utilization showed conflicting trends in use (Aarts, Noordam, & Hofman, 2014; Aguglia, Ravasio, & Simonetti, 2012; Akincigil et al., 2011; Bolton, Dahl, & Sareen, 2012; Marcus & Olfson, 2010; Noordam, Aarts, & Vernamme, 2015; Olfson & Marcus, 2009; Parabiaghi, Franchi, & Tettamanti, 2011; Raymond, Morgan, & Caetano, 2007; Rojas-Fernandez, Thomas, & Carver, 1999). A decline in the incident use of antidepressants could be a reflection of patients or clinicians less likely to use pharmacotherapy versus non-drug alternatives to manage their condition. In contrast, an increase in new antidepressant use could be an indication that patients and clinicians are more accepting of drug treatment in this population, and an increase in certain antidepressants could be a result of their known safety profile or effective marketing. Understanding the prescribing trends of new antidepressant therapy in older adults will provide the
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basis for future research that aims to examine the potential impact of these changing trends on health outcomes, such as relapse in depression, hospitalization, emergency room visits, and risk of overdose. In light of this, we aim to examine the extent of new antidepressant utilization for older adults in Manitoba, Canada. Based on the introduction of practice recommendations over the past 16 years, it is hypothesized that there will be a decline in the new use of older antidepressants and an increase in the incident use of newer antidepressants.
Methods
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Design We conducted a population-based retrospective time series analysis study between 1 April 1997 and 31 March 2013. This study was conducted in full compliance with the Privacy of Health Information Act of Manitoba and approved by the Research Ethics Board of the University of Manitoba and the Manitoba Health Information Privacy Committee.
In Canada, universal health coverage is provided to all residents for medically necessary services including hospital care and physician visits. However, each province may differ in the provision of prescription drug coverage for their residents. In Manitoba, all residents who are not covered by other plans (e.g. federal or private) are eligible for Manitoba drug coverage in which 100 % of their prescription costs are covered after an income-based deductible has been paid by the resident (Manitoba Health, Health Living and Seniors, 2015). The deductible rate may change from year to year, but ranged from 2.97 % to 6.73 % of the patient’s adjusted total family income category (e.g. $75,000) in the 2015/16 fiscal year (Manitoba Health, Health Living and Seniors, 2015). As a result, drug-dispensing patterns would not be largely influenced by cost unless the drug is not included in the formulary. It is important to note that regardless of coverage status (out-of-pocket, private insurance, federal plan, provincial coverage, etc.), the patient’s drug dispensing information gets captured on to DPIN.
Antidepressant agents Data sources Data was obtained from the administrative Population Health Research Data Repository located at the Manitoba Centre for Health Policy (MCHP). These databases have been used extensively for research and MCHP has developed a framework for establishing data quality assurance. The Drug Program Information Network (DPIN) database captures the prescription dispensing record of all individuals living in Manitoba with the exception of medications received in hospital and by First Nations (indigenous peoples of Canada) receiving care from nursing stations. Of note, more than 90 % of all prescriptions that are filled in the community are captured in DPIN regardless of coverage. Diagnoses were obtained from medical services and hospitalization files and identified using International Classification of Diseases, Clinical Modification (ICD-9-CM and ICD-10-CA) codes. Patient records were stored using an encrypted personal health identification number. Individual prescription data was linked with specific diagnoses from their health service contacts. The Manitoba Health Insurance Registry provided the number of residents in Manitoba, and demographic information at the beginning of each threemonth interval. Income quintile was obtained through data from Statistics Canada and it is an area-based measure determined by dividing the urban and rural populations into fifths based on the average household income of the neighborhood.
Patient population Community dwelling individuals receiving at least one prescription of an antidepressant in any of the index years from 1 April to 31 March were included. New users were defined as people who have not received a prescription for any antidepressant in the year before receiving their first prescription. Individuals may be included more than once if there is a period of at least one year or greater in which no prescription for an antidepressant was dispensed. Only participants aged 60 years and older at the time of the first antidepressant prescription were included.
All oral antidepressants (ATC code N06A) available in Canada were included in the analysis. These include tricyclic antidepressants: amitriptyline, clomipramine, desipramine, doxepin, imipramine, imipramine oxide, maprotiline, nortriptyline, and trimipramine; SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; SNRIs: venlafaxine, desvenlafaxine, duloxetine; non-selective monoamine oxidase inhibitors (MAOIs): phenelzine, tranylcypromine; monoamine oxidase A inhibitors: moclobemide; norepinephrine dopamine reuptake inhibitors (NDRIs): bupropion; other antidepressants: trazodone; mirtazapine.
Statistical analysis The primary analysis examined the annual incidence rates of antidepressant use over the study period. Incident use was calculated by dividing the number of individuals filling a new prescription for an antidepressant in a given interval by the total number of individuals who were 60 years and older and alive in Manitoba at the beginning of the given interval and multiplied by 1000 to estimate the incidence rate per 1000 individuals. Secondary analyses examined the annual incident use of specific antidepressants at each interval. The annual incident use of antidepressants was also described by 10-year age group, sex, region of residence, income quintile, and resource utilization. Patient demographics were summarized based on the earliest (1997/1998) and the most recent year (2012/2013) for new antidepressant users. Demographic information that was reported includes age, sex, region of residence, income quintile, resource utilization band, and prescriber. The type of antidepressant medications used among new antidepressant users was also summarized based on data from the most recent year. Summary statistics was used to describe prescription data using the SAS software package for Windows, Version 9.3 (SAS Institute, Inc., Cary, NC, USA). The Poisson distribution was chosen to model the count of new users per annual population count as the most appropriate distribution based on model fit. This was then applied for age group (10-year age groups), sex, region of residence,
AGING & MENTAL HEALTH
income quintile, and Johns Hopkins Adjusted Clinical Group® Resource Utilization Bands (Reid, Roos, MacWilliam, Frohlich, & Black, 2002; Weiner, Starfield, & Lieberman, 1992) to determine whether the trend in new antidepressant use will differ based on these factors.
The total population of Manitoba residents 60 years and older increased by 25.6 % from 188,296 to 236,569 from 1997/1998 to 2012/2013. The number of individuals who were new users of an antidepressant remained steady from 7045 to 7214 during the study period. However, the incidence of new antidepressant use peaked to 45.9 per 1000 in 1999/2000 and remained at similar levels until 2004/2005, and then decreased steadily to 30.5 per 1000 in 2012/2013 (p < 0.0001). The population demographics for the most recent fiscal year are shown in Table 1. Incident antidepressant use by 10-year age group is shown in Figure 1. New antidepressant user rates were higher for females compared to males over all years (Figure 2; mean 43.5 per 1000 and 30.3 per 1000, respectively, p < 0.0001). The lowest-income urban dwellers represented the highest rate of new antidepressant users (mean 43.1 per 1.000, SE 5.3) compared to the highest-income urban dwellers (mean 33.6 per 1000, SE 4.8; p < 0.0001), but the disparity decreased over time (Figure 3). Individuals with very high morbidity represented the highest incident users of an antidepressant with a decreasing trend over the study period (Figure 4; 74.3 56.6 per 1000, p < 0.0001; 82.4 62.4 per 1000, p < 0.0001, respectively). Among the TCA class, there was a marked twofold decrease in new amitriptyline use among older individuals from 15.5 per 1000 in 1997/1998 to 7.4 per 1000 in 2012/2013 (Figure 5; p < 0.001). New use of nortriptyline was the second most common TCA used and its incidence remained relatively stable at a mean of 1.5 per 1000 (SE 0.2) over the study period. New use of citalopram was the highest among SSRIs used and the incident rates increased by 325 % from 2.0 to 8.5 per 1000 from when it was first introduced in 1999/2000 to 2003/ 2004 (p < 0.0001), after which the incident use of citalopram fluctuated from 7.5 to 9.3 per 1000 between 2004/2005 and 2012/2013 (Figure 6). In contrast, new paroxetine use peaked
Table 1. Characteristics of new users of antidepressants among Manitoba residents aged 60 years or more in 1997/1998 and 2012/2013. Characteristic Population 60 years and older Incident antidepressant prescription in fiscal year Age (n, %) 60 69 70 79 80 89 90C Female sex (n, %) Urban resident (n, %) Income quintile (urban only) U1 (lowest income) U2 U3 U4 U5 (highest income) Unknown Resource utilization band (n, %) Very high morbidity High morbidity Moderate morbidity Low morbidity Healthy user Non user Prescriber (n, %) General practitioner Specialist Missing
1997/1998 188,296 7035
2012/2013 236,569 7214
2743 (39.0) 2613 (37.1) 1466 (20.8) 213 (3.0) 4784 (68.0) 4393 (62.4)
3260 (45.2) 2045 (28.3) 1534 (21.3) 375 (5.2) 4494 (62.3) 4432 (61.4)
1096 (15.6) 976 (13.9) 858 (12.2) 644 (9.2) 632 (9.0) 204 (2.9)
939 (13.0) 860 (11.9) 906 (12.6) 826 (11.4) 764 (10.6) 166 (2.3)
659 (9.4) 1305 (18.6) 4204 (59.8) 587 (8.3) 158 (2.2) 122 (1.7)
717 (9.9) 1465 (20.3) 4273 (59.2) 538 (7.5) 102 (1.4) 119 (1.6)
5680 (80.7) 962 (13.7) 393 (5.6)
6403 (88.8) 652 (9.0) 159 (2.2)
to 6.9 per 1000 in 2000/2001, and then decreased by more than fivefold to 1.3 per 1000 in 2012/2013 (p < 0.0001). The new use of sertraline also declined by threefold from 4.2 to 1.3 per 1000 (p < 0.0001). New use of fluoxetine and fluvoxamine showed a similar trend in decline over the study period (1.8 0.4 per 1000, p < 0.0001; and 2.2 0.1 per 1000, p < 0.0001, respectively), while new use of escitalopram increased gradually from when it was introduced in 2005/2006 to 2012/ 2013 (0.4 0.5 per 1000, p < 0.0001). The new use of trazodone, mirtazapine, venlafaxine, and duloxetine increased in this population. The incidence of trazodone increased by more than 30 % from 2.7 to 3.6 per 1000 over the study period (Figure 7; p < 0.001). The new use of mirtazapine increased more than threefold from 0.6 to 1.9 per 1000 between 2001/2002 and 2012/2013 (p < 0.001). The new use of venlafaxine peaked from 1.0 to 4.1 per 1000 between 1997/1998 and 2002/2003 (p < 0.0001), then declined to 2.4 per 1000 in 2012/2013 (p < 0.001), while
60
50
Users per 1000
40
30
Age 60-69 Age 70-79
20
Age 80-89 Age 90+
10
Fiscal Year
Figure 1. Annual incidence of antidepressant use by age.
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
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0 1997/98
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Results
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60
50
Users per 1000
40
30 Male Female 20
0
Year
Figure 2. Annual incidence of antidepressant use by sex.
duloxetine increased steadily from 0.1 per 1000 in 2008/2009 to 0.7 per 1000 in 2012/2013 (p < 0.001). The incidence of bupropion peaked at 7.2 per 1000 in 1999/2000 and decreased by more than eightfold to 0.9 per 1000 in 2012/ 2013 (p < 0.0001).
Discussion There has been a decrease in the incidence of antidepressant use among older adults over the last 16 years, with a noticeable decline in the incidence of amitriptyline, bupropion, and all SSRIs, with the exception of citalopram. An increase in the new use of trazodone, mirtazapine, duloxetine, and venlafaxine was observed in this population. This was the longest study that observed a decreasing trend in new antidepressant use in the older adult population
in a Canadian province. The decreasing trend in new antidepressant use observed in our study was consistent with more recent findings from previous studies in Europe and Canada (Aarts et al., 2014; Aguglia et al. 2012; Bolton et al., 2012; Noordam et al. 2015; Parabiaghi et al., 2011; Raymond et al., 2007; Rojas-Fernandez et al. 1999), but contrasted to a few studies in the United States (Akincigil et al., 2011; Marcus & Olfson, 2010; Olfson & Marcus, 2009). Previous studies differed in the definition of new use, reported only prevalence or adjusted rate ratios over time, and often had a short study period. The decrease in the incident use of antidepressants observed in previous studies could be attributed to the uptake of guidelines cautioning the use of psychotropic medications in older adults (Fick et al., 2012; Barry et al., 2007; Gallagher & O’Mahony, 2008; van Marwijk et al., 2003). For instance, Noordam et al. referenced guidelines in 2003
55 50 45 40 Users per 1000
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35 30 25 20 15 10 5 0 1997/98 1998/99 1999/00 2000/01 2001/02 2002/03 2003/04 2004/05 2005/06 2006/07 2007/08 2008/09 2009/10 2010/11 2011/12 2012/13 Fiscal Year Andepressant (Urban 1)
Andepressant (Urban 2)
Andepressant (Urban 3)
Andepressant (Urban 4)
Andepressant (Urban 5)
Figure 3. Annual incidence of antidepressant use by income quintile in urban Manitoba. Urban 1 D lowest income; Urban 5 D highest income. Note Income quintile is an area-based measure determined by dividing the urban and rural populations into fifths based on the average household income of the neighborhood.
5
Figure 4. Annual incidence of antidepressant use by resource utilization band.
recommending non-pharmacological interventions as firstline prior to pharmacotherapy, which may explain the decline in incident antidepressant use (Noordam et al. 2015; van Marwijk et al., 2003). The increase in antidepressant use observed in the United States could be a result of a greater recognition and acceptance of depression and anxiety treatment and increased coverage for mental health conditions in the United States (Blumner et al., 2009; Kessler et al. 2003). The decreased incidence in antidepressant use in the population that was observed in our study could be a result of raised awareness and practice guidelines encouraging appropriate prescribing in older adults (Fick et al., 2012; Barry et al., 2007; Gallagher & O’Mahony, 2008). For instance, antidepressants associated with strong anticholinergic properties, such as tricyclic antidepressants and
paroxetine, are considered potentially inappropriate in the older adult population and may be less likely to be prescribed in recent years (Fick et al., 2012; Barry et al., 2007; Gallagher & O’Mahony, 2008). Other antidepressants are recommended to be used only with caution (Fick et al., 2012). Although decreasing in incident use, amitriptyline was the most common antidepressant used in this population. However, this could be explained by its use for other indications such as neuropathic pain, anxiety disorder, insomnia, irritable bowel syndrome, and behavioral and psychological symptoms in dementia (Cyclic Antidepressants, 2012). The decline in new amitriptyline use could be a reflection of newer agents for neuropathic pain (e.g. gabapentin and pregabalin) and sleep (e.g. zolpidem and zopiclone).
18 16 14 12 Users per 1,000
Desipramine
10
Imipramine Clomipramine
8
Trimipramine 6
Amitriptyline Nortriptyline
4
Doxepin
2
Fiscal Year
Figure 5. Annual incidence of tricyclic antidepressant use by drug.
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
2000/01
1999/00
1998/99
0 1997/98
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10 9 8
Users per 1,000
7 6 Fluoxetine 5
Citalopram Paroxetine
4
Sertraline Fluvoxamine
3
Escitalopram 2
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
2000/01
1999/00
1998/99
1997/98
0
Fiscal Year
Figure 6. Annual incidence of selective serotonin reuptake inhibitor use by drug.
The marked rise in citalopram over the study period was an interesting finding, but a decline in the new use of citalopram could be expected given recent Health Canada notice on the risk of QT prolongation associated with its use in higher doses (Health Canada, 2012). QT prolongation is an abnormal finding on an electrocardiogram (EKG) that may increase the risk of Torsades de Pointes, which is a rare but potentially fatal type of cardiac arrhythmia (Health Canada, 2012). Citalopram and escitalopram are the newest agents of the SSRI class (citalopram was introduced in 1999 and escitalopram in 2005; Table 2) and have been associated with fewer drug interactions and a relatively mild side effect profile compared to the other SSRIs (Health Canada, 2015; Solai, Mulsant, & Pollock,
2001). Escitalopram was only recently included in the provincial formulary for drug coverage, which may explain the low incidence in use of this agent relative to the other SSRIs (Manitoba Health, 2015). The decline in the new use of the other SSRIs occurred after the introduction of citalopram into the market. Paroxetine was introduced in 1993, with the lowest strength (10 mg) made available in Canada in 1997 and the controlled-release formulation made available in 2004 (Health Canada, 2015). Paroxetine has been reported to be the most anticholinergic among the SSRI class, which makes this agent less ideal for the older adult population or in patients with cognitive impairment (Solai et al., 2001). Sertraline (introduced in 1992), fluvoxamine (introduced in 1991), and
8
7
6
Users per 1,000
5 Trazodone 4
Mirtazapine Bupropion Venlafaxine
3
Duloxetine Desvenlafaxine
2
1
Fiscal Year
Figure 7. Annual incidence of other antidepressant use by drug.
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
2000/01
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1998/99
0 1997/98
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Table 2. Antidepressants by year of availability in Canada, Health Canada Approved Indication, Off-Label Use, and Drug Coverage in Manitoba. Active date Drug name Tricylcic antidepressant 1965 Nortriptyline
1970
Major depressive disorder
1975
Major depressive disorder Insomnia Clomipramine Major depressive disorder Obsessive compulsive disorder Amitriptyline Major depressive disorder
1975
Imipramine
Major depressive disorder
1987 1996
Trimipramine Desipramine
Major depressive disorder Major depressive disorder
1973
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Health Canada-approved indication
Doxepin
Selective serotonin reuptake inhibitors 1989 Fluoxetine Major depressive disorder Bulimia nervosa Obsessive compulsive disorder
1991
Fluvoxamine
Major depressive disorder Obsessive compulsive disorder
1992
Sertraline
Major depressive disorder Panic disorder Obsessive compulsive disorder
1993
Paroxetine
1999
Citalopram
Major depressive disorder Obsessive compulsive disorder Panic disorder Social anxiety disorder Generalized anxiety disorder Post-traumatic stress disorder Major depressive disorder
2004
Paroxetine CR Major depressive disorder Panic disorder Social anxiety disorder Premenstrual dysphoric disorder Escitalopram Major depressive disorder Generalized anxiety disorder Obsessive compulsive disorder
2005
Manitoba drug coverage
Off-label use Chronic pain Irritable bowel syndrome Myofascial pain Orofacial pain Postherpetic neuralgia Smoking cessation Chronic urticaria
Yes
Panic attack
Yes
Anxiety disorder Attention-deficit hyperactivity disorder Behavioral/psychological symptoms in dementia Bulimia nervosa Insomnia Interstitial cystitis Irritable bowel syndrome Migraine prophylaxis Premature ejaculation Smoking cessation Fibromyalgia Irritable bowel syndrome Neuropathic pain Post-traumatic stress disorder Sialorrhea Attention-deficit hyperactivity disorder Bulimia nervosa Neuropathic pain Panic disorder Post-traumatic stress disorder N/A Bulimia nervosa Chronic pain Irritable bowel syndrome Neuropathic pain Postherpetic neuralgia
Yes
Borderline personality disorder Fibromyalgia Post-traumatic stress disorder Raynaud phenomenon Selective mutism Social anxiety disorder Bulimia nervosa Panic disorder Post-traumatic stress disorder Social anxiety disorder Binge eating disorder Bulimia nervosa Generalized anxiety disorder Panic disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Social anxiety disorder Premenstrual dysphoric disorder Vasomotor symptoms of menopause Irritable bowel syndrome
Yes
Binge eating disorder Generalized anxiety disorder Hot flashes Obsessive-compulsive disorder Panic disorder Pathologic gambling Vasomotor symptoms of menopause Irritable bowel syndrome Panic disorder Post-traumatic stress disorder Hot flashes
Yes
Yes
Yes Yes
Yes
Yes
Yes
Yes
No
Yes
(continued)
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Table 2. (Continued ) Active date Drug name Other antidepressants 1993 Trazodone 1998
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1993 1995
Bupropion
Health Canada-approved indication Major depressive disorder Major depressive disorder Smoking cessation
2004 Venlafaxine Major depressive disorder Venlafaxine XR Major depressive disorder Generalized anxiety disorder Social anxiety disorder Panic disorder
2001
Mirtazapine
2003
Mirtazapine RD Major depressive disorder
2008
Duloxetine
2009
Major depressive disorder
Major depressive disorder Generalized anxiety disorder Neuropathic pain associated with diabetic peripheral neuropathy Fibromyalgia Chronic low back pain Osteoarthritis of the knee Desvenlafaxine Major depressive disorder
fluoxetine (introduced in 1989) have been associated with more gastrointestinal side effects compared to the other SSRI agents (Health Canada, 2015; Solai et al., 2001). Fluoxetine, fluvoxamine, and paroxetine are also more likely to contribute to drug interactions compared to the other SSRIs (Solai et al., 2001). The rise in new trazodone and mirtazapine use could be a reflection of their dual use in this population. Trazodone is commonly prescribed in patients with insomnia and concurrent depression (Trazodone, 2012). Mirtazapine is known to cause sedation and weight gain, with minimal anticholinergic effects. As a result, this agent may be beneficial in older adults with insomnia, depression, and who could benefit from appetite stimulation (Remeron®, 2015). Bupropion was introduced in 1998 and was marketed under two different brand names for the management of depression (Wellbutrin®) and smoking cessation (Zyban®). The peak in new bupropion use during this time period is likely the result of this agent being prescribed to patients for either or both indications. The decline in use of this agent in this population may have been influenced by post-marketing surveillance of seizures and cardiovascular adverse effects associated with its use (Health Canada, 2015). Duloxetine is an antidepressant with an approved indication for neuropathic pain, fibromyalgia, chronic low back pain, osteoarthritis of the knee, generalized anxiety disorder, and major depressive disorder (Cymbalta®, 2015); but no generic version of this agent is yet available and is only covered by the provincial drug plan under certain criteria (Table 2). This may be influencing the low incident use of duloxetine in this population. Venlafaxine has an approved indication for the management of major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder (Effexor XR®, 2015), but off-label use for neuropathic pain and hot flashes have been reported. Venlafaxine is associated with few drug interactions, but has been associated with hypertension, higher risk of fatal overdose, and self-harm (Deshauer, 2007; Wyeth Medical Information & Pharmacovigilance, 2004).
Manitoba drug coverage
Off-label use Insomnia Bulimia nervosa Attention-deficit hyperactivity disorder Bipolar disorder Weight loss promotion Seasonal affective disorder N/A Attention-deficit/hyperactivity disorder Diabetic neuropathy Episodic migraine prevention Hot flashes Obsessive compulsive disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Insomnia Weight gain Insomnia Weight gain Stress urinary incontinence (women)
Hot flashes
Yes Yes (2006 present)
N/A Yes
Yes (2006 present) Yes Covered for diabetic peripheral neuropathic pain or depression after adequate trial of two less expensive alternative agents
No
Strengths of this study include the length of the study period, and the comprehensiveness of the administrative databases, which capture nearly all residents of Manitoba who contact the health care system regardless of age, socioeconomic status, and reimbursement plans. The Manitoba DPIN database allows for a complete real-world examination of drug utilization unaffected by sampling errors or restrictions based on health coverage. Drug-dispensing patterns would not be largely influenced by cost unless the drug is not included in the formulary. Moreover, the majority of antidepressants studied are listed on the provincial formulary, and therefore, access to these agents is unrestricted to the study population with the exception of duloxetine, which is covered if patients meet specific criteria for diabetic peripheral neuropathy or depressive not responsive or intolerant to other therapy. However, some limitations of our study merit emphasis, such as the lack of clinical information and identification of actual indication for antidepressant therapy, which may explain the high incidence in use for certain agents (e.g. amitriptyline may be used for depression, neuropathic pain, and sleep). The trend in the new use of antidepressants in this population may only be generalizable to older adult populations residing in a similar jurisdiction in which drug coverage is provided to all eligible residents. Only incidence, and not prevalence, was reported in this study. It is also important to note that the trend in new antidepressant use is based on the prescription dispensing records of DPIN and may not be a true representation of actual consumption of these agents. A decrease in the incident use of antidepressant agents in the past 16 years was observed. Understanding the annual trend in new antidepressant utilization will provide foundational information for studying their potential impact on health and economic outcomes. The overall decline in incident antidepressant use could be a reflection of preferences for non-drug alternatives over pharmacotherapy in this patient population. An increased incidence in some of the newer antidepressants could be a reflection of their overall
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known safety profile in older adults or a result of effective marketing. How these changes in incident use affect relapse in depression, hospitalization, emergency room visits, and risk of overdose warrants future study.
Acknowledgments
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The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Population Health Research Data Repository under project # 2013/2014 (HIPC# 2013/2014 39). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, or other data providers is intended or should be inferred. Data used in this study are from the Population Health Research Data Repository housed at the Manitoba Centre for Health Policy, University of Manitoba and were derived from data provided by Manitoba Health and (name other data providers). The authors would like to thank pharmacy student, Lindsay Baum, for her contribution as research assistant during the preparation of this manuscript.
Disclosure statement The authors declare no conflicts of interest.
Funding This study was funded by the University of Manitoba start-up fund [#315359].
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Gallagher, P., & O’Mahony, D. (2008). STOPP (Screening Tool of Older Persons’ potentially inappropriate Prescriptions): Application to acutely ill elderly patients and comparison with Beers’ criteria. Age Ageing, 37, 673 679. Gelenberg, A.J., Freeman, M.P., Markowitz, J.C., Rosenbaum, J.F., Thase, M. E., Trivedi, M.H., & Van Rhoads, R.S. (2010). Practice guideline for the treatment of patients with major depression disorder, 3rd ed. American Psychiatric Association. November . Retrieved May 25, 2015, from http://psychiatryonline.org/pb/assets/raw/sitewide/practice_guide lines/guidelines/mdd.pdf. Health Canada. (2012). Public communication health Canada endorsed important safety information on celexa. Last updated January 30,. Retrieved May 25, 2015, from http://www.healthycanadians.gc.ca/ recall-alert-rappel-avis/hc-sc/2012/16887a-eng.php. Health Canada. (2015). Drug product database online query. Last updated July 17,. Retrieved December 22, 2015, from http://webprod5.hc-sc.gc. ca/dpd-bdpp/index-eng.jsp Hunkeler, E.M., Katon, W., Tang, L., Williams, J.W., Kroenke, K., Lin, E.H.B., ... Unutzer, J. (2006). Long term outcomes from the IMPACT randomized trial for depressed patients in primary care. BMJ, 332, 259 263. IMS Health. (2012). Top 20 therapeutic classes by U.S. dispensed prescriptions [IMS Health Web site]. February 3,. Retrieved May 25, 2015, from http://www.imshealth.com/deployedfiles/imshealth/Global/Content/ Corporate/Press%20Room/Top_line_data/Top_Therapy_Classes_by_ RX.pdf Kessler, R.C., Berglund, P., Demler, O., Jim, R., Koretz, D., Merikangas, K.R., ... Wang, P.S. Replication, National Comorbidity Survey. (2003). The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA, 289, 3092 3105. Lam, R.W., Kennedy, S., & Grigoriadis, McIntyre, R.S., Milev, R., Ramasubbu, R., …Ravindran, A.V. (2009). Canadian network for mood and anxiety treatments (canmat) clinical guidelines for the management of major depressive disorder in adults. iii. pharmacotherapy. Journal of Affective Disorders, 117, S26 S43. Manitoba Health. (2015). Bulletin #82 Manitoba drug benefits and interchangeability formulary amendments. Last updated April 20,. Retrieved December 22, 2015, from http://webprod5.hc-sc.gc.ca/dpdbdpp/index-eng.jsp Marcus, S.C., & Olfson, M. (2010). National trends in the treatment for depression from 1998 to 2007. Archives of General Psychiatry, 67, 1265 1273. Manitoba Health, Health Living and Seniors. (2015). Manitoba pharmacare program. Pharmacare Deductible Estimator. Retrieved January 7, 2016, from http://www.gov.mb.ca/health/pharmacare/estimator.html. Noordam, R., Aarts, N., & Vernamme, K.M., Sturkenboom, M.C.M., Stricker, B.H., & Visser, L.E. (2015). Prescription and indication trends of antidepressant drugs in the Netherlands between 1996 and 2012: A dynamic population-based study. European Journal of Clinical Pharmacology, 71, 369 375. Olfson, M., & Marcus, S.C. (2009). National patterns in antidepressant medication treatment. Archives of General Psychiatry, 66, 848 856. Parabiaghi, A., Franchi, C., & Tettamanti, M., Barbato, A., D’Avanzo, B., Fortino, I., … Nobili, A. (2011). Antidepressants utilization among elderly in Lombardy from 2000 to 2007: Dispensing trends and appropriateness. European Journal of Clinical Pharmacology, 67, 1077 1083. Principles of Diagnosis and Management of Anxiety Disorders. (2006). Management of anxiety disorders: Clinical practice guidelines. Canadian Journal of Psychiatry, 51, 9S 22S. Raymond, C.B., Morgan, S.G., & Caetano, P.A.. (2007). Antidepressant utilization in british columbia from 1996 to 2004: Increasing prevalence but not incidence. Psychiatric Services, 58, 79 84. Reid, R.J., Roos, N.P., MacWilliam, L., Frohlich, N., & Black, C. (2002). Assessing population health care need using a claims-based ACG morbidity measure: A validation analysis in the province of Manitoba. Health Services Research journal, 37, 1345 1364. Remeron®. (2015). CPhA Product Monograph. Last updated March 16, 2015. Retrieved May 25, 2015, from http://www.e-therapeutics.ca Rojas-Fernandez, C., Thomas, V.S., & Carver, D., & Tonks, R. (1999). Suboptimal use of antidepressants in the elderly: A population-based study in Nova Scotia. Clinical Therapeutics, 22, 1937 1950. Ryynanen, O.P., Kivela, S.L., Honkanen, R.., Laippala, P., & Saano, V. (1993). Medications and chronic diseases as risk factors for falling injuries in the elderly. Scandinavian Journal of Social Medicine, 21, 264 271. Solai, L.K., Mulsant, B.H., & Pollock, B.G. (2001). Selective serotonin reuptake inhibitors for late-life depression: A comparative review. Drugs & Aging, 18, 355 368.
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Unutzer, J., Katon, W., Callahan, C.M., Jr, Williams, J.W., Hunkeler, E., Harpole, L., … Langston, C. (2002). Collaborative care management of late-life depression in the primary care setting: A randomized controlled trial. JAMA, 288, 2836 2845. Weiner, J.P., Starfield, B.H., & Lieberman, R.N. (1992). Johns Hopkins ambulatory care groups (ACGs). A case-mix system for UR, QA and capitation adjustment. HMO Practice, 6, 13 19. Wyeth Medical Information & Pharmacovigilance. (2004). Important drug safety information for EFFEXOR®: Warning for SSRIs and other newer anti-depressants regarding the potential for behavioural and emotional changes, including risk of self-harm. Last updated January 1, 2004. Retrieved December 22, 2015, from http://www.healthycana dians.gc.ca/recall-alert-rappel-avis/hc-sc/2004/14256a-eng.php
ISSN: 1360-7863 (Print) 1364-6915 (Online) Journal homepage: http://www.tandfonline.com/loi/camh20
New antidepressant use in older adults: a Canadian population-based study (1997–2013) Christine Leong, Murray W. Enns, Jitender Sareen, Silvia Alessi-Severini, James Bolton, Heather J. Prior & Dan Chateau To cite this article: Christine Leong, Murray W. Enns, Jitender Sareen, Silvia Alessi-Severini, James Bolton, Heather J. Prior & Dan Chateau (2016): New antidepressant use in older adults: a Canadian population-based study (1997–2013), Aging & Mental Health, DOI: 10.1080/13607863.2016.1154014 To link to this article: http://dx.doi.org/10.1080/13607863.2016.1154014
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AGING & MENTAL HEALTH, 2016 http://dx.doi.org/10.1080/13607863.2016.1154014
New antidepressant use in older adults: a Canadian population-based study (1997 2013) Christine Leonga, Murray W. Ennsb, Jitender Sareenb, Silvia Alessi-Severinia, James Boltonb, Heather J. Priorc and Dan Chateauc
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a College of Pharmacy, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; bDepartment of Psychiatry, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; cDepartment of Community Health Sciences, Manitoba Centre for Health Policy, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada
ABSTRACT
ARTICLE HISTORY
Objective: There has been much attention on appropriate prescribing in older adults in recent years. Recent guidelines favor the use of newer antidepressants over older agents based on their safety profile in this population. This study aimed to examine whether there has been a decline in older antidepressants and an increase in newer antidepressants used by older adults. Method: A retrospective cross-sectional study using administrative databases examined the annual incidence of antidepressant use (per 1000) of community-dwelling adults 60 years old between 1997/1998 and 2012/2013 in Manitoba, Canada. Results: The population of Manitoba 60 years increased by 25.6% from 188,296 to 236,569 from 1997/1998 to 2012/2013. New antidepressant use peaked to 45.9 per 1000 in 1999/2000, and then decreased steadily to 30.5 per 1000 in 2012/2013 (p < 0.0001). Incident amitriptyline use was high but declined from 15.5 to 7.4 per 1000 (p < 0.001). An increase in incident trazodone, mirtazapine, and venlafaxine use was observed (p < 0.001). Conclusions: There has been an overall decrease in the annual incidence of antidepressant users in older adults over the last 16 years, with a marked decline in new amitriptyline use and an increase in the incidence of newer agents.
Received 21 September 2015 Accepted 4 February 2016
Introduction Antidepressants are widely prescribed in North America primarily for the treatment of mood and anxiety disorders (Akincigil et al., 2011; Gelenberg et al., 2010; IMS Health, 2012; Lam, Kennedy, & Grigoriadis, 2009; Marcus & Olfson, 2010; Olfson & Marcus, 2009; Principles of Diagnosis and Management of Anxiety Disorders, 2006; Special Populations, 2006). They have a modest effect over placebo in reducing the signs and symptoms of depression (Cipriani, Furukawa, & Salanti, 2009; Gelenberg, 2010; Lam et al., 2009; Turner, Matthews, Linardatos, Tell, & Rosenthal, 2008), and are recommended first-line by clinical practice guidelines for the long-term treatment of mood and anxiety (Principles of Diagnosis and Management of Anxiety Disorders, 2006; Special Populations, 2006). However, older adults are frequently underrepresented in clinical trials (Fick et al., 2012; Barry, Gallagher, & Ryan, 2007; Gallagher & O’Mahony, 2008; Ryynanen, Kivela, & Honkanen, 1993; Special Populations, 2006). While there is accumulating evidence supporting the efficacy and safety of antidepressants in older patients (Alexopoulos et al., 2009; Hunkeler et al., 2006; Stone et al. 2009; Unutzer et al., 2002), the proper use of these agents to ensure their effectiveness and safety in this population has not been fully established. Past research has suggested that all antidepressants are similar in efficacy but not safety (Cipriani et al., 2009; Gelenberg, 2010; Lam et al., 2009; Turner et al., 2008). Accordingly, the safety profile of an agent has largely been the guiding principle
CONTACT Christine Leong © 2016 Taylor & Francis
[email protected]
KEYWORDS
Antidepressants; drug utilization; older adults; cross-sectional study
for treatment choice for older adults in clinical practice (Cipriani et al., 2009; Gelenberg, 2010; Lam et al., 2009; Turner et al., 2008). Most practice guidelines prefer the use of selective serotonin reuptake inhibitors (SSRIs) and other new generation antidepressants over tricyclic antidepressants (TCAs) due to their lower risk of central nervous system, anticholinergic, and cardiovascular effects (Gelenberg, 2010; Lam et al., 2009). Older patients also tend to have multiple comorbidities, medications, and may be more susceptible to side effects than younger patients. Choosing a medication with a favorable side effect profile is therefore important for effective long-term therapy. Previous studies on antidepressant utilization showed conflicting trends in use (Aarts, Noordam, & Hofman, 2014; Aguglia, Ravasio, & Simonetti, 2012; Akincigil et al., 2011; Bolton, Dahl, & Sareen, 2012; Marcus & Olfson, 2010; Noordam, Aarts, & Vernamme, 2015; Olfson & Marcus, 2009; Parabiaghi, Franchi, & Tettamanti, 2011; Raymond, Morgan, & Caetano, 2007; Rojas-Fernandez, Thomas, & Carver, 1999). A decline in the incident use of antidepressants could be a reflection of patients or clinicians less likely to use pharmacotherapy versus non-drug alternatives to manage their condition. In contrast, an increase in new antidepressant use could be an indication that patients and clinicians are more accepting of drug treatment in this population, and an increase in certain antidepressants could be a result of their known safety profile or effective marketing. Understanding the prescribing trends of new antidepressant therapy in older adults will provide the
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basis for future research that aims to examine the potential impact of these changing trends on health outcomes, such as relapse in depression, hospitalization, emergency room visits, and risk of overdose. In light of this, we aim to examine the extent of new antidepressant utilization for older adults in Manitoba, Canada. Based on the introduction of practice recommendations over the past 16 years, it is hypothesized that there will be a decline in the new use of older antidepressants and an increase in the incident use of newer antidepressants.
Methods
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Design We conducted a population-based retrospective time series analysis study between 1 April 1997 and 31 March 2013. This study was conducted in full compliance with the Privacy of Health Information Act of Manitoba and approved by the Research Ethics Board of the University of Manitoba and the Manitoba Health Information Privacy Committee.
In Canada, universal health coverage is provided to all residents for medically necessary services including hospital care and physician visits. However, each province may differ in the provision of prescription drug coverage for their residents. In Manitoba, all residents who are not covered by other plans (e.g. federal or private) are eligible for Manitoba drug coverage in which 100 % of their prescription costs are covered after an income-based deductible has been paid by the resident (Manitoba Health, Health Living and Seniors, 2015). The deductible rate may change from year to year, but ranged from 2.97 % to 6.73 % of the patient’s adjusted total family income category (e.g. $75,000) in the 2015/16 fiscal year (Manitoba Health, Health Living and Seniors, 2015). As a result, drug-dispensing patterns would not be largely influenced by cost unless the drug is not included in the formulary. It is important to note that regardless of coverage status (out-of-pocket, private insurance, federal plan, provincial coverage, etc.), the patient’s drug dispensing information gets captured on to DPIN.
Antidepressant agents Data sources Data was obtained from the administrative Population Health Research Data Repository located at the Manitoba Centre for Health Policy (MCHP). These databases have been used extensively for research and MCHP has developed a framework for establishing data quality assurance. The Drug Program Information Network (DPIN) database captures the prescription dispensing record of all individuals living in Manitoba with the exception of medications received in hospital and by First Nations (indigenous peoples of Canada) receiving care from nursing stations. Of note, more than 90 % of all prescriptions that are filled in the community are captured in DPIN regardless of coverage. Diagnoses were obtained from medical services and hospitalization files and identified using International Classification of Diseases, Clinical Modification (ICD-9-CM and ICD-10-CA) codes. Patient records were stored using an encrypted personal health identification number. Individual prescription data was linked with specific diagnoses from their health service contacts. The Manitoba Health Insurance Registry provided the number of residents in Manitoba, and demographic information at the beginning of each threemonth interval. Income quintile was obtained through data from Statistics Canada and it is an area-based measure determined by dividing the urban and rural populations into fifths based on the average household income of the neighborhood.
Patient population Community dwelling individuals receiving at least one prescription of an antidepressant in any of the index years from 1 April to 31 March were included. New users were defined as people who have not received a prescription for any antidepressant in the year before receiving their first prescription. Individuals may be included more than once if there is a period of at least one year or greater in which no prescription for an antidepressant was dispensed. Only participants aged 60 years and older at the time of the first antidepressant prescription were included.
All oral antidepressants (ATC code N06A) available in Canada were included in the analysis. These include tricyclic antidepressants: amitriptyline, clomipramine, desipramine, doxepin, imipramine, imipramine oxide, maprotiline, nortriptyline, and trimipramine; SSRIs: citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline; SNRIs: venlafaxine, desvenlafaxine, duloxetine; non-selective monoamine oxidase inhibitors (MAOIs): phenelzine, tranylcypromine; monoamine oxidase A inhibitors: moclobemide; norepinephrine dopamine reuptake inhibitors (NDRIs): bupropion; other antidepressants: trazodone; mirtazapine.
Statistical analysis The primary analysis examined the annual incidence rates of antidepressant use over the study period. Incident use was calculated by dividing the number of individuals filling a new prescription for an antidepressant in a given interval by the total number of individuals who were 60 years and older and alive in Manitoba at the beginning of the given interval and multiplied by 1000 to estimate the incidence rate per 1000 individuals. Secondary analyses examined the annual incident use of specific antidepressants at each interval. The annual incident use of antidepressants was also described by 10-year age group, sex, region of residence, income quintile, and resource utilization. Patient demographics were summarized based on the earliest (1997/1998) and the most recent year (2012/2013) for new antidepressant users. Demographic information that was reported includes age, sex, region of residence, income quintile, resource utilization band, and prescriber. The type of antidepressant medications used among new antidepressant users was also summarized based on data from the most recent year. Summary statistics was used to describe prescription data using the SAS software package for Windows, Version 9.3 (SAS Institute, Inc., Cary, NC, USA). The Poisson distribution was chosen to model the count of new users per annual population count as the most appropriate distribution based on model fit. This was then applied for age group (10-year age groups), sex, region of residence,
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income quintile, and Johns Hopkins Adjusted Clinical Group® Resource Utilization Bands (Reid, Roos, MacWilliam, Frohlich, & Black, 2002; Weiner, Starfield, & Lieberman, 1992) to determine whether the trend in new antidepressant use will differ based on these factors.
The total population of Manitoba residents 60 years and older increased by 25.6 % from 188,296 to 236,569 from 1997/1998 to 2012/2013. The number of individuals who were new users of an antidepressant remained steady from 7045 to 7214 during the study period. However, the incidence of new antidepressant use peaked to 45.9 per 1000 in 1999/2000 and remained at similar levels until 2004/2005, and then decreased steadily to 30.5 per 1000 in 2012/2013 (p < 0.0001). The population demographics for the most recent fiscal year are shown in Table 1. Incident antidepressant use by 10-year age group is shown in Figure 1. New antidepressant user rates were higher for females compared to males over all years (Figure 2; mean 43.5 per 1000 and 30.3 per 1000, respectively, p < 0.0001). The lowest-income urban dwellers represented the highest rate of new antidepressant users (mean 43.1 per 1.000, SE 5.3) compared to the highest-income urban dwellers (mean 33.6 per 1000, SE 4.8; p < 0.0001), but the disparity decreased over time (Figure 3). Individuals with very high morbidity represented the highest incident users of an antidepressant with a decreasing trend over the study period (Figure 4; 74.3 56.6 per 1000, p < 0.0001; 82.4 62.4 per 1000, p < 0.0001, respectively). Among the TCA class, there was a marked twofold decrease in new amitriptyline use among older individuals from 15.5 per 1000 in 1997/1998 to 7.4 per 1000 in 2012/2013 (Figure 5; p < 0.001). New use of nortriptyline was the second most common TCA used and its incidence remained relatively stable at a mean of 1.5 per 1000 (SE 0.2) over the study period. New use of citalopram was the highest among SSRIs used and the incident rates increased by 325 % from 2.0 to 8.5 per 1000 from when it was first introduced in 1999/2000 to 2003/ 2004 (p < 0.0001), after which the incident use of citalopram fluctuated from 7.5 to 9.3 per 1000 between 2004/2005 and 2012/2013 (Figure 6). In contrast, new paroxetine use peaked
Table 1. Characteristics of new users of antidepressants among Manitoba residents aged 60 years or more in 1997/1998 and 2012/2013. Characteristic Population 60 years and older Incident antidepressant prescription in fiscal year Age (n, %) 60 69 70 79 80 89 90C Female sex (n, %) Urban resident (n, %) Income quintile (urban only) U1 (lowest income) U2 U3 U4 U5 (highest income) Unknown Resource utilization band (n, %) Very high morbidity High morbidity Moderate morbidity Low morbidity Healthy user Non user Prescriber (n, %) General practitioner Specialist Missing
1997/1998 188,296 7035
2012/2013 236,569 7214
2743 (39.0) 2613 (37.1) 1466 (20.8) 213 (3.0) 4784 (68.0) 4393 (62.4)
3260 (45.2) 2045 (28.3) 1534 (21.3) 375 (5.2) 4494 (62.3) 4432 (61.4)
1096 (15.6) 976 (13.9) 858 (12.2) 644 (9.2) 632 (9.0) 204 (2.9)
939 (13.0) 860 (11.9) 906 (12.6) 826 (11.4) 764 (10.6) 166 (2.3)
659 (9.4) 1305 (18.6) 4204 (59.8) 587 (8.3) 158 (2.2) 122 (1.7)
717 (9.9) 1465 (20.3) 4273 (59.2) 538 (7.5) 102 (1.4) 119 (1.6)
5680 (80.7) 962 (13.7) 393 (5.6)
6403 (88.8) 652 (9.0) 159 (2.2)
to 6.9 per 1000 in 2000/2001, and then decreased by more than fivefold to 1.3 per 1000 in 2012/2013 (p < 0.0001). The new use of sertraline also declined by threefold from 4.2 to 1.3 per 1000 (p < 0.0001). New use of fluoxetine and fluvoxamine showed a similar trend in decline over the study period (1.8 0.4 per 1000, p < 0.0001; and 2.2 0.1 per 1000, p < 0.0001, respectively), while new use of escitalopram increased gradually from when it was introduced in 2005/2006 to 2012/ 2013 (0.4 0.5 per 1000, p < 0.0001). The new use of trazodone, mirtazapine, venlafaxine, and duloxetine increased in this population. The incidence of trazodone increased by more than 30 % from 2.7 to 3.6 per 1000 over the study period (Figure 7; p < 0.001). The new use of mirtazapine increased more than threefold from 0.6 to 1.9 per 1000 between 2001/2002 and 2012/2013 (p < 0.001). The new use of venlafaxine peaked from 1.0 to 4.1 per 1000 between 1997/1998 and 2002/2003 (p < 0.0001), then declined to 2.4 per 1000 in 2012/2013 (p < 0.001), while
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Figure 1. Annual incidence of antidepressant use by age.
2012/13
2011/12
2010/11
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Results
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60
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40
30 Male Female 20
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Figure 2. Annual incidence of antidepressant use by sex.
duloxetine increased steadily from 0.1 per 1000 in 2008/2009 to 0.7 per 1000 in 2012/2013 (p < 0.001). The incidence of bupropion peaked at 7.2 per 1000 in 1999/2000 and decreased by more than eightfold to 0.9 per 1000 in 2012/ 2013 (p < 0.0001).
Discussion There has been a decrease in the incidence of antidepressant use among older adults over the last 16 years, with a noticeable decline in the incidence of amitriptyline, bupropion, and all SSRIs, with the exception of citalopram. An increase in the new use of trazodone, mirtazapine, duloxetine, and venlafaxine was observed in this population. This was the longest study that observed a decreasing trend in new antidepressant use in the older adult population
in a Canadian province. The decreasing trend in new antidepressant use observed in our study was consistent with more recent findings from previous studies in Europe and Canada (Aarts et al., 2014; Aguglia et al. 2012; Bolton et al., 2012; Noordam et al. 2015; Parabiaghi et al., 2011; Raymond et al., 2007; Rojas-Fernandez et al. 1999), but contrasted to a few studies in the United States (Akincigil et al., 2011; Marcus & Olfson, 2010; Olfson & Marcus, 2009). Previous studies differed in the definition of new use, reported only prevalence or adjusted rate ratios over time, and often had a short study period. The decrease in the incident use of antidepressants observed in previous studies could be attributed to the uptake of guidelines cautioning the use of psychotropic medications in older adults (Fick et al., 2012; Barry et al., 2007; Gallagher & O’Mahony, 2008; van Marwijk et al., 2003). For instance, Noordam et al. referenced guidelines in 2003
55 50 45 40 Users per 1000
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35 30 25 20 15 10 5 0 1997/98 1998/99 1999/00 2000/01 2001/02 2002/03 2003/04 2004/05 2005/06 2006/07 2007/08 2008/09 2009/10 2010/11 2011/12 2012/13 Fiscal Year Andepressant (Urban 1)
Andepressant (Urban 2)
Andepressant (Urban 3)
Andepressant (Urban 4)
Andepressant (Urban 5)
Figure 3. Annual incidence of antidepressant use by income quintile in urban Manitoba. Urban 1 D lowest income; Urban 5 D highest income. Note Income quintile is an area-based measure determined by dividing the urban and rural populations into fifths based on the average household income of the neighborhood.
5
Figure 4. Annual incidence of antidepressant use by resource utilization band.
recommending non-pharmacological interventions as firstline prior to pharmacotherapy, which may explain the decline in incident antidepressant use (Noordam et al. 2015; van Marwijk et al., 2003). The increase in antidepressant use observed in the United States could be a result of a greater recognition and acceptance of depression and anxiety treatment and increased coverage for mental health conditions in the United States (Blumner et al., 2009; Kessler et al. 2003). The decreased incidence in antidepressant use in the population that was observed in our study could be a result of raised awareness and practice guidelines encouraging appropriate prescribing in older adults (Fick et al., 2012; Barry et al., 2007; Gallagher & O’Mahony, 2008). For instance, antidepressants associated with strong anticholinergic properties, such as tricyclic antidepressants and
paroxetine, are considered potentially inappropriate in the older adult population and may be less likely to be prescribed in recent years (Fick et al., 2012; Barry et al., 2007; Gallagher & O’Mahony, 2008). Other antidepressants are recommended to be used only with caution (Fick et al., 2012). Although decreasing in incident use, amitriptyline was the most common antidepressant used in this population. However, this could be explained by its use for other indications such as neuropathic pain, anxiety disorder, insomnia, irritable bowel syndrome, and behavioral and psychological symptoms in dementia (Cyclic Antidepressants, 2012). The decline in new amitriptyline use could be a reflection of newer agents for neuropathic pain (e.g. gabapentin and pregabalin) and sleep (e.g. zolpidem and zopiclone).
18 16 14 12 Users per 1,000
Desipramine
10
Imipramine Clomipramine
8
Trimipramine 6
Amitriptyline Nortriptyline
4
Doxepin
2
Fiscal Year
Figure 5. Annual incidence of tricyclic antidepressant use by drug.
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
2000/01
1999/00
1998/99
0 1997/98
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AGING & MENTAL HEALTH
6
C. LEONG ET AL.
10 9 8
Users per 1,000
7 6 Fluoxetine 5
Citalopram Paroxetine
4
Sertraline Fluvoxamine
3
Escitalopram 2
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
2000/01
1999/00
1998/99
1997/98
0
Fiscal Year
Figure 6. Annual incidence of selective serotonin reuptake inhibitor use by drug.
The marked rise in citalopram over the study period was an interesting finding, but a decline in the new use of citalopram could be expected given recent Health Canada notice on the risk of QT prolongation associated with its use in higher doses (Health Canada, 2012). QT prolongation is an abnormal finding on an electrocardiogram (EKG) that may increase the risk of Torsades de Pointes, which is a rare but potentially fatal type of cardiac arrhythmia (Health Canada, 2012). Citalopram and escitalopram are the newest agents of the SSRI class (citalopram was introduced in 1999 and escitalopram in 2005; Table 2) and have been associated with fewer drug interactions and a relatively mild side effect profile compared to the other SSRIs (Health Canada, 2015; Solai, Mulsant, & Pollock,
2001). Escitalopram was only recently included in the provincial formulary for drug coverage, which may explain the low incidence in use of this agent relative to the other SSRIs (Manitoba Health, 2015). The decline in the new use of the other SSRIs occurred after the introduction of citalopram into the market. Paroxetine was introduced in 1993, with the lowest strength (10 mg) made available in Canada in 1997 and the controlled-release formulation made available in 2004 (Health Canada, 2015). Paroxetine has been reported to be the most anticholinergic among the SSRI class, which makes this agent less ideal for the older adult population or in patients with cognitive impairment (Solai et al., 2001). Sertraline (introduced in 1992), fluvoxamine (introduced in 1991), and
8
7
6
Users per 1,000
5 Trazodone 4
Mirtazapine Bupropion Venlafaxine
3
Duloxetine Desvenlafaxine
2
1
Fiscal Year
Figure 7. Annual incidence of other antidepressant use by drug.
2012/13
2011/12
2010/11
2009/10
2008/09
2007/08
2006/07
2005/06
2004/05
2003/04
2002/03
2001/02
2000/01
1999/00
1998/99
0 1997/98
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7
Table 2. Antidepressants by year of availability in Canada, Health Canada Approved Indication, Off-Label Use, and Drug Coverage in Manitoba. Active date Drug name Tricylcic antidepressant 1965 Nortriptyline
1970
Major depressive disorder
1975
Major depressive disorder Insomnia Clomipramine Major depressive disorder Obsessive compulsive disorder Amitriptyline Major depressive disorder
1975
Imipramine
Major depressive disorder
1987 1996
Trimipramine Desipramine
Major depressive disorder Major depressive disorder
1973
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Health Canada-approved indication
Doxepin
Selective serotonin reuptake inhibitors 1989 Fluoxetine Major depressive disorder Bulimia nervosa Obsessive compulsive disorder
1991
Fluvoxamine
Major depressive disorder Obsessive compulsive disorder
1992
Sertraline
Major depressive disorder Panic disorder Obsessive compulsive disorder
1993
Paroxetine
1999
Citalopram
Major depressive disorder Obsessive compulsive disorder Panic disorder Social anxiety disorder Generalized anxiety disorder Post-traumatic stress disorder Major depressive disorder
2004
Paroxetine CR Major depressive disorder Panic disorder Social anxiety disorder Premenstrual dysphoric disorder Escitalopram Major depressive disorder Generalized anxiety disorder Obsessive compulsive disorder
2005
Manitoba drug coverage
Off-label use Chronic pain Irritable bowel syndrome Myofascial pain Orofacial pain Postherpetic neuralgia Smoking cessation Chronic urticaria
Yes
Panic attack
Yes
Anxiety disorder Attention-deficit hyperactivity disorder Behavioral/psychological symptoms in dementia Bulimia nervosa Insomnia Interstitial cystitis Irritable bowel syndrome Migraine prophylaxis Premature ejaculation Smoking cessation Fibromyalgia Irritable bowel syndrome Neuropathic pain Post-traumatic stress disorder Sialorrhea Attention-deficit hyperactivity disorder Bulimia nervosa Neuropathic pain Panic disorder Post-traumatic stress disorder N/A Bulimia nervosa Chronic pain Irritable bowel syndrome Neuropathic pain Postherpetic neuralgia
Yes
Borderline personality disorder Fibromyalgia Post-traumatic stress disorder Raynaud phenomenon Selective mutism Social anxiety disorder Bulimia nervosa Panic disorder Post-traumatic stress disorder Social anxiety disorder Binge eating disorder Bulimia nervosa Generalized anxiety disorder Panic disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Social anxiety disorder Premenstrual dysphoric disorder Vasomotor symptoms of menopause Irritable bowel syndrome
Yes
Binge eating disorder Generalized anxiety disorder Hot flashes Obsessive-compulsive disorder Panic disorder Pathologic gambling Vasomotor symptoms of menopause Irritable bowel syndrome Panic disorder Post-traumatic stress disorder Hot flashes
Yes
Yes
Yes Yes
Yes
Yes
Yes
Yes
No
Yes
(continued)
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C. LEONG ET AL.
Table 2. (Continued ) Active date Drug name Other antidepressants 1993 Trazodone 1998
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1993 1995
Bupropion
Health Canada-approved indication Major depressive disorder Major depressive disorder Smoking cessation
2004 Venlafaxine Major depressive disorder Venlafaxine XR Major depressive disorder Generalized anxiety disorder Social anxiety disorder Panic disorder
2001
Mirtazapine
2003
Mirtazapine RD Major depressive disorder
2008
Duloxetine
2009
Major depressive disorder
Major depressive disorder Generalized anxiety disorder Neuropathic pain associated with diabetic peripheral neuropathy Fibromyalgia Chronic low back pain Osteoarthritis of the knee Desvenlafaxine Major depressive disorder
fluoxetine (introduced in 1989) have been associated with more gastrointestinal side effects compared to the other SSRI agents (Health Canada, 2015; Solai et al., 2001). Fluoxetine, fluvoxamine, and paroxetine are also more likely to contribute to drug interactions compared to the other SSRIs (Solai et al., 2001). The rise in new trazodone and mirtazapine use could be a reflection of their dual use in this population. Trazodone is commonly prescribed in patients with insomnia and concurrent depression (Trazodone, 2012). Mirtazapine is known to cause sedation and weight gain, with minimal anticholinergic effects. As a result, this agent may be beneficial in older adults with insomnia, depression, and who could benefit from appetite stimulation (Remeron®, 2015). Bupropion was introduced in 1998 and was marketed under two different brand names for the management of depression (Wellbutrin®) and smoking cessation (Zyban®). The peak in new bupropion use during this time period is likely the result of this agent being prescribed to patients for either or both indications. The decline in use of this agent in this population may have been influenced by post-marketing surveillance of seizures and cardiovascular adverse effects associated with its use (Health Canada, 2015). Duloxetine is an antidepressant with an approved indication for neuropathic pain, fibromyalgia, chronic low back pain, osteoarthritis of the knee, generalized anxiety disorder, and major depressive disorder (Cymbalta®, 2015); but no generic version of this agent is yet available and is only covered by the provincial drug plan under certain criteria (Table 2). This may be influencing the low incident use of duloxetine in this population. Venlafaxine has an approved indication for the management of major depressive disorder, generalized anxiety disorder, social anxiety disorder, and panic disorder (Effexor XR®, 2015), but off-label use for neuropathic pain and hot flashes have been reported. Venlafaxine is associated with few drug interactions, but has been associated with hypertension, higher risk of fatal overdose, and self-harm (Deshauer, 2007; Wyeth Medical Information & Pharmacovigilance, 2004).
Manitoba drug coverage
Off-label use Insomnia Bulimia nervosa Attention-deficit hyperactivity disorder Bipolar disorder Weight loss promotion Seasonal affective disorder N/A Attention-deficit/hyperactivity disorder Diabetic neuropathy Episodic migraine prevention Hot flashes Obsessive compulsive disorder Post-traumatic stress disorder Premenstrual dysphoric disorder Insomnia Weight gain Insomnia Weight gain Stress urinary incontinence (women)
Hot flashes
Yes Yes (2006 present)
N/A Yes
Yes (2006 present) Yes Covered for diabetic peripheral neuropathic pain or depression after adequate trial of two less expensive alternative agents
No
Strengths of this study include the length of the study period, and the comprehensiveness of the administrative databases, which capture nearly all residents of Manitoba who contact the health care system regardless of age, socioeconomic status, and reimbursement plans. The Manitoba DPIN database allows for a complete real-world examination of drug utilization unaffected by sampling errors or restrictions based on health coverage. Drug-dispensing patterns would not be largely influenced by cost unless the drug is not included in the formulary. Moreover, the majority of antidepressants studied are listed on the provincial formulary, and therefore, access to these agents is unrestricted to the study population with the exception of duloxetine, which is covered if patients meet specific criteria for diabetic peripheral neuropathy or depressive not responsive or intolerant to other therapy. However, some limitations of our study merit emphasis, such as the lack of clinical information and identification of actual indication for antidepressant therapy, which may explain the high incidence in use for certain agents (e.g. amitriptyline may be used for depression, neuropathic pain, and sleep). The trend in the new use of antidepressants in this population may only be generalizable to older adult populations residing in a similar jurisdiction in which drug coverage is provided to all eligible residents. Only incidence, and not prevalence, was reported in this study. It is also important to note that the trend in new antidepressant use is based on the prescription dispensing records of DPIN and may not be a true representation of actual consumption of these agents. A decrease in the incident use of antidepressant agents in the past 16 years was observed. Understanding the annual trend in new antidepressant utilization will provide foundational information for studying their potential impact on health and economic outcomes. The overall decline in incident antidepressant use could be a reflection of preferences for non-drug alternatives over pharmacotherapy in this patient population. An increased incidence in some of the newer antidepressants could be a reflection of their overall
AGING & MENTAL HEALTH
known safety profile in older adults or a result of effective marketing. How these changes in incident use affect relapse in depression, hospitalization, emergency room visits, and risk of overdose warrants future study.
Acknowledgments
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The authors acknowledge the Manitoba Centre for Health Policy for use of data contained in the Population Health Research Data Repository under project # 2013/2014 (HIPC# 2013/2014 39). The results and conclusions are those of the authors and no official endorsement by the Manitoba Centre for Health Policy, Manitoba Health, or other data providers is intended or should be inferred. Data used in this study are from the Population Health Research Data Repository housed at the Manitoba Centre for Health Policy, University of Manitoba and were derived from data provided by Manitoba Health and (name other data providers). The authors would like to thank pharmacy student, Lindsay Baum, for her contribution as research assistant during the preparation of this manuscript.
Disclosure statement The authors declare no conflicts of interest.
Funding This study was funded by the University of Manitoba start-up fund [#315359].
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