1 Introduction
Mirtazapine is a second-generation antidepressant that acts as an antagonist of α
2-adrenergic autoreceptors and serotonin (5-HT
2 and 5-HT
3) receptors, resulting in an antidepressant effect [
1]. Mirtazapine also acts as a potent antagonist of histamine (H
1) receptors, leading to predictable adverse effects such as sedation [
1]. Rates of sedation are greater for mirtazapine than all other second-generation antidepressants, including selective serotonin reuptake inhibitors (SSRIs) [
2]. Although mirtazapine may be useful in depression characterised by insomnia [
3], it can lead to unwanted daytime sedation [
4].
A meta-analysis of observational studies found that the risk of hip fracture is increased by use of antidepressants [
5], while another meta-analysis of observational studies found that the risk of hip fracture is increased by SSRIs and by tricyclic antidepressants (TCAs) [
6]. Subsequent studies have confirmed these findings across multiple observational study designs and databases [
7,
8]. Mirtazapine, which was first marketed in Australia in 2001, has been less well studied. One study of mirtazapine use and the risk of hip fracture was a cohort study conducted among 439,317 new users of antidepressants aged ≥ 65 years [
9]. This cohort study found that initiating mirtazapine was associated with a 34% lower rate of hip fracture than initiating the SSRI citalopram [
9]. No studies were located investigating mirtazapine use and the risk of hip fracture compared with no mirtazapine use. Mirtazapine use is increasing in Australia; the defined daily dose (DDD)/1000 people/day was 0.17 during 2010 and 0.24 during 2015 [
10‐
13].
In addition to studies which suggest an increased risk of hip fracture with antidepressants, pharmacological theory suggests that concomitant use of more than one antidepressant could elevate the risk of hip fracture beyond that of antidepressant monotherapy, potentially through pharmacodynamic or pharmacokinetic interactions [
14]. There are two main ways in which antidepressants are combined in clinical practice: switching and add-on therapy. It may be necessary to switch from an initial antidepressant to a new antidepressant when the initial antidepressant causes adverse effects or is ineffective [
15]. In the process of switching, medicines may be administered concurrently as one medicine is tapered and the other is introduced. Alternatively, multiple antidepressants can be used concurrently as add-on therapy when patients are resistant to treatment with antidepressant monotherapy [
15,
16].
In practice, the use of multiple antidepressants is infrequent [
17‐
19]. Two studies set in Australia estimated that two or more antidepressants were used by 5 and 3% of patients, respectively [
17,
18]. A Canadian study identified that, of 17,622 adults prescribed at least one antidepressant, 3842 (22%) were co-prescribed multiple antidepressants [
19]. Of the 3842 adults who were co-prescribed multiple antidepressants, 92% used agents from different classes and 46% used another antidepressant in combination with an SSRI [
19].
When switching from one antidepressant to another, there may be short-term overlap in use or effects of the two different antidepressants [
3]. This occurs because, in order to prevent withdrawal symptoms and serotonin syndrome, the dose of the initial antidepressant is gradually tapered [
3]. The new antidepressant may be added during or after the tapering period [
15]. The most appropriate approach to switching depends on the types of antidepressants involved in the switch and the reason for switching [
15]. The gradual introduction of a new antidepressant while tapering the initial antidepressant is referred to as cross-tapering [
15]. Cross-tapering needs to be performed cautiously due to the possibility of withdrawal symptoms as well as pharmacodynamic and pharmacokinetic interactions [
3,
15]. The dose of the initial antidepressant should be gradually reduced while a low dose of the new antidepressant is slowly titrated upwards [
15]. The Maudsley Prescribing Guidelines in Psychiatry and the Australian Medicines Handbook recommend the use of cross-tapering when switching between mirtazapine and TCAs, SSRIs, or serotonin and noradrenaline reuptake inhibitors (SNRIs) [
3,
15].
The second type of combined antidepressant exposure, namely add-on therapy, refers to the concurrent use of two antidepressants in the treatment of either refractory depression [
15,
20] or depression with comorbidities for which antidepressants are indicated (e.g. anxiety) [
19]. The two antidepressants used in add-on therapy typically have distinct yet complementary mechanisms of action [
16], with an example being the mirtazapine-SSRI combination [
15,
21]. In the treatment of refractory depression, one agent is employed to augment the effect of the other. While some international guidelines advocate antidepressant add-on therapy [
2,
15], the Australian Medicines Handbook and Australian Therapeutic Guidelines: Psychotropic caution against it due to a lack of supporting evidence and the potential for interactions between antidepressants [
3,
22]. Despite this guidance, psychiatrists prescribe antidepressant combinations in practice. In 2004, 76% of 1107 Australian psychiatrists who responded to a postal survey reported prescribing combination antidepressant therapy at some stage during their medical careers [
23]. Furthermore, 37% of respondents reported that they had combined mirtazapine with SSRIs sometime in the past [
23].
Patients who are prescribed two antidepressants for switching or add-on therapy may experience adverse drug interactions, including additive sedative or hypotensive effects, which in turn may lead to falls and fractures. No studies were located that assessed the risk of hip fracture due to concurrent use of multiple antidepressants related to switching or add-on therapy.
This study aimed to investigate the risk of hip fracture associated with mirtazapine use and to examine the risk of hip fracture in older people after switching between or concurrently using mirtazapine and other antidepressants.
3 Results
Overall, 8828 cases and 35,310 controls were included in this analysis. Cases and controls were similar for all baseline characteristics (Table
1).
Table 1
Characteristics of cases and controls
Female gender | 5592 (63%) | 22,368 (63%) |
Age (years)a
| 88 (85–91) | 88 (85–91) |
Number of co-morbiditiesa
| 4 (2–6) | 3 (0–6) |
Socioeconomic status |
Upper | 2537 (29%) | 9493 (27%) |
Middle-upper | 1559 (18%) | 6263 (18%) |
Middle | 1664 (19%) | 6941 (20%) |
Lower-middle | 1737 (20%) | 6925 (20%) |
Lower | 1320 (15%) | 5608 (16%) |
Unknown | 11 (0.1%) | 80 (0.2%) |
Residential status |
Community | 5668 (64%) | 23,170 (66%) |
Residential aged care | 3160 (36%) | 12,140 (34%) |
There were insufficient mirtazapine initiators to assess the effect, as the power was below 80%. Compared with non-users of mirtazapine, existing users of mirtazapine had 27% greater odds of hip fracture (Table
2). Initiation of TCAs was not found to be associated with hip fracture; however, existing users of TCAs had 38% greater odds of hip fracture (Table
2). The odds of hip fracture were increased by factors of 2.73 and 2.38 for new use of SSRIs and SNRIs, respectively, and by factors of 1.77 and 1.51 for continuous use of SSRIs and SNRIs, respectively (Table
2).
Table 2
Case-control study results for associations between individual use of antidepressants and the risk of hip fracture
Mirtazapine |
New | 35 (0.4) | 90 (0.3) | 1.59 (1.08–2.36) | 1.11 (0.74–1.66)b
|
Continuous | 375 (4.2) | 1026 (2.9) | 1.49 (1.32–1.68) | 1.27 (1.12–1.44) |
No | 8418 (95) | 34,194 (97) | 1.00 [Reference] | 1.00 [Reference] |
TCAs |
New (initiation) | 47 (0.5) | 109 (0.3) | 1.76 (1.25–2.48) | 1.40 (0.98–1.99) |
Continuous | 434 (4.9) | 1126 (3.2) | 1.58 (1.41–1.77) | 1.38 (1.23–1.55) |
No | 8347 (95) | 34,075 (97) | 1.00 [Reference] | 1.00 [Reference] |
SSRIs |
New (initiation) | 98 (1.1) | 122 (0.4) | 3.45 (2.64–4.50) | 2.73 (2.07–3.58) |
Continuous | 1232 (14) | 2598 (7.4) | 2.06 (1.92–2.22) | 1.77 (1.64–1.91) |
No | 7498 (85) | 32,590 (92) | 1.00 [Reference] | 1.00 [Reference] |
SNRIs |
New (initiation) | 27 (0.3) | 37 (0.1) | 2.99 (1.82–4.91) | 2.38 (1.43–3.96) |
Continuous | 256 (2.9) | 603 (1.7) | 1.72 (1.49–2.00) | 1.51 (1.29–1.75) |
No | 8545 (97) | 34,670 (98) | 1.00 [Reference] | 1.00 [Reference] |
In the assessment of mirtazapine–antidepressant combinations, the odds of hip fracture were elevated by a factor of 11 when an SSRI was added to continuous mirtazapine therapy, relative to no current use of either medicine (Table
3). The odds of hip fracture were also increased by a factor of 14 when a new TCA was added to continuous mirtazapine therapy (Table
3). Additive effects were identified for all antidepressant combinations that were used by both cases and controls (Table
4).
Table 3
Case-control study results for the joint effects of mirtazapine with each of three antidepressant groups
New | New | 0 | 1 | – | 4 | 2 | 4.8 (0.9–27)b
| 1 | 0 | – |
(Initiate mirtazapine and AD) | (0%) | (0.003%) | | (0.05%) | (0.01%) | | (0.01%) | (0%) | |
New | Continuous | 2 | 2 | 2.4 (0.3–19)b
| 2 | 7 | 0.9 (0.2–4.4)b
| 0 | 3 | – |
(Add mirtazapine to AD) | (0.02%) | (0.01%) | | (0.02%) | (0.02%) | | (0%) | (0.008%) | |
Continuous | New | 4 | 1 | 14 (1.4–132)b
| 7 | 2 | 11 (2.2–51) | 1 | 2 | 1.7 (0.1–19)b
|
(Add AD to mirtazapine) | (0.05%) | (0.003%) | | (0.1%) | (0.01%) | | (0.01%) | (0.005%) | |
Continuous | Continuous | 8 | 17 | 1.5 (0.6–3.5)b
| 22 | 33 | 2.4 (1.4–4.2) | 12 | 22 | 1.9 (0.95–4.0)b
|
(Cont. mirtazapine and AD) | (0.1%) | (0.05%) | | (0.2%) | (0.1%) | | (0.1%) | (0.06%) | |
New | No | 33 | 87 | 1.1 (0.7–1.7)b
| 29 | 81 | 1.2 (0.7–1.8)b
| 34 | 87 | 1.1 (0.8–1.7)b
|
(Initiate mirtazapine alone) | (0.4%) | (0.2%) | | (0.3%) | (0.2%) | | (0.4%) | (0.2%) | |
No | New | 43 | 107 | 1.3 (0.9–1.9)b
| 87 | 118 | 2.6 (1.9–3.4) | 25 | 35 | 2.4 (1.4–4.0) |
(Initiate AD alone) | (0.5%) | (0.3%) | | (1.0%) | (0.3%) | | (0.3%) | (0.1%) | |
Continuous | No | 363 | 1008 | 1.3 (1.1–1.43) | 346 | 991 | 1.3 (1.1–1.4) | 362 | 1002 | 1.3 (1.1–1.4) |
(Cont. mirtazapine alone) | (4.1%) | (2.9%) | | (3.9%) | (2.8%) | | (4.1%) | (2.8%) | |
No | Continuous | 424 | 1107 | 1.4 (1.2–1.6) | 1208 | 2558 | 1.8 (1.6–1.9) | 244 | 578 | 1.5 (1.3–1.8) |
(Cont. AD alone) | (4.8%) | (3.1%) | | (14%) | (7.2%) | | (2.8%) | (1.6%) | |
No | No | 7951 | 32,980 | 1.00 [Ref] | 7123 | 31,518 | 1.00 [Ref] | 8149 | 33,581 | 1.00 [Ref] |
(No mirtazapine or AD) | (90%) | (93%) | | (81%) | (89%) | | (92%) | (95%) | |
Table 4
Additive interaction assessment for concurrent use of mirtazapine and antidepressant groups
New | New | – | 2.1 (−6.3 to 11) | – |
(Initiation of mirtazapine with AD) | | | |
New | Continuous | 1.0 (−4.1 to 6.0) | −1.0 (−2.5 to 0.5) | – |
(Addition of mirtazapine to AD) | | | |
Continuous | New | 12 (−19 to 43) | 7.7 (−9.0 to 24) | −1.0 (−5.3 to 3.3) |
(Addition of AD to mirtazapine) | | | |
Continuous | Continuous | −0.2 (−1.4 to 1.1) | 0.4 (−0.9 to 1.7) | 0.2 (−1.3 to 1.6) |
(Continuous mirtazapine with AD) | | | |
When SSRIs were added to mirtazapine therapy in seven cases, the strength of mirtazapine dispensed before the SSRI did not appear to be subsequently reduced (Appendix 2, see ESM). The strength of mirtazapine appeared to be increased in three of the seven cases (Appendix 2). Similarly, when TCAs were added to mirtazapine therapy in all four cases and in one control, the strength of mirtazapine dispensed before the TCA was not subsequently reduced (Appendix 3, see ESM).
4 Discussion
This study found that continuous use of mirtazapine was associated with increased risk of hip fracture among older people. When SSRIs and TCAs were added to mirtazapine, the risk of hip fracture in older people relative to no current use of these antidepressants was increased by a factor of 11 and 14, respectively. The overlapping use of these medicines may reflect three situations in clinical practice: switching from mirtazapine to other antidepressants, add-on therapy, or the addition of other antidepressants to treat comorbidities (e.g. an SSRI for anxiety or a TCA for neuropathic pain) [
3]. The RERI did not reach significance, however, suggesting that combined use was not necessarily greater than the sum of the risk estimates for use of the antidepressants individually. The risk of hip fracture associated with continuously using both mirtazapine and an SSRI was also significant, although the magnitude of the risk estimate was lower than for the addition of an SSRI to mirtazapine therapy. This may be due to the greater potential for sedation and hypotension when antidepressants are initiated. Dosage may also play a role; however, a limitation of the study was inability to assess dosage as it was not available in the data source.
Despite clinical recommendations to gradually reduce mirtazapine dose when initiating a new antidepressant at a low dose [
3,
15], the strengths of mirtazapine in this study did not appear to be reduced upon introducing TCAs and SSRIs. Our study was limited by a lack of dose information in the dataset, so it was not possible to tell whether the mirtazapine 30-mg scored tablets were halved before use. Use of mirtazapine at strengths of 30–45 mg is not consistent with current clinical guidelines to switch between antidepressants via cross-tapering [
15].
Rather than switching from mirtazapine to the other antidepressants, patients may have been using mirtazapine together with SSRIs or TCAs in the treatment of refractory depression or comorbidities. Antidepressant add-on therapy in the treatment of refractory depression is controversial and potentially inappropriate [
22,
37]. The Maudsley Prescribing Guidelines in Psychiatry state that the concurrent use of an SSRI with mirtazapine (30–45 mg/day) is one of the first-choice drug treatments for refractory depression [
15]. The observed addition of an SSRI to mirtazapine is consistent with these guidelines because mirtazapine was used at strengths of 30–45 mg. However, this study was conducted in an older population and the Australian Medicines Handbook Drug Choice Companion: Aged Care suggests that prescribers should initiate mirtazapine in older patients at a dose of 15 mg/day and, due to a lack of evidence supporting a therapeutic benefit and the potential for interactions, avoid all antidepressant combinations [
37]. The results of this case–control study suggest that prescribers may not always be following the recommendations in the Australian Medicines Handbook Drug Choice Companion: Aged Care [
37].
To the best of our knowledge, this is the first study to investigate the risk of hip fracture due to concurrent use of mirtazapine with other antidepressants. The results of this study may help general practitioners and psychiatrists to weigh up the risks and benefits of prescribing add-on therapy in older populations and to be more cautious when switching therapies and tapering doses. A strength of this study was the classification of patients as new and continuous medicine users. This prevented the survivor bias that would have otherwise affected estimates of current medicine use [
38]. The use of administrative claims data precluded recall bias. Furthermore, as the median age of our subjects was 88 years and half of hip fractures among the elderly occur in those aged over 85 years, our results can be generalised from the study population to other older Australians over 65 years of age [
39].
This case–control study has several limitations. There was inadequate power to assess new use of mirtazapine individually as well as in combination with other antidepressants, mainly due to the low use of mirtazapine in the study population. This led to uncertainty in our conclusions of no effect. Larger datasets are required to further study the risk of hip fracture in older people following concurrent use of mirtazapine with other antidepressants. As in any observational study, unmeasured confounding factors could have biased the effect estimates towards or away from the null. In this case–control study, potential unmeasured confounders of the associations between antidepressant use and hip fracture include the severity of depression symptoms and ability to undertake activities of daily living (ADLs) [
40]. Since case-crossover studies have reported associations between antidepressants and hip fracture, it is likely that antidepressant use does indeed increase the risk of hip fracture independently of patient-specific, time-invariant confounders [
8,
41]. Since medicine use was inferred from dispensing records, a further limitation of this study is the potential misclassification of non-users of medicines as current users of medicines, and vice versa. However, a sensitivity analysis in which duration of use estimates were shortened by 50% found no impact of duration of exposure on effect estimates (results not shown). The use of the reference group of never users and past users is conservative and biases the result to the null. Thus, our study may have under-estimated risk. Furthermore, the lack of information on dosage prevented a rigorous assessment of the appropriateness of potential add-on therapy, switching or tapering.