4. Discussion
Our results showed that the risk of falling in older users of TCAs is
possibly associated with drug exposure, whereas no association was found
in users of SSRIs. These results need to be interpreted with caution
considering the small sample size and subsequently confinement to
unadjusted analysis for the TCA users.
To our knowledge, this is the first study to assess whether
antidepressant blood concentrations are associated with fall risk within
antidepressant users. Falls have been established to be an important ADE
in community-dwelling older persons. Previous studies have consistently
established the association between antidepressant use and falls4. However, literature linking antidepressant plasma
concentrations and falls is scarce. A first indication that measuring
antidepressant plasma concentrations might be of value in falls
prevention was demonstrated in a case series of patients with
drug-induced falls. This study suggested that TDM may help identify
patients with drug-induced falls and confirm clinical suspicion of an
ADE 21. The observed possible association between TCA
concentrations and fall risk is in line with earlier studies that
addressed the role of antidepressant plasma concentrations in
fall-related outcomes, e.g. orthostatic hypotension (OH)22. Significant correlations between serum
concentrations of amitriptyline and fluvoxamine and orthostatic blood
pressure drop have been demonstrated 22. OH is
considered an important fall risk factor and pathway in drug-related
falls 23. OH results in transient cerebral
hypoperfusion upon standing, which may result in a syncope and/or fall.
OH is a prevalent ADE in antidepressants, best known for TCAs, but also
seen with SSRIs 7. Furthermore, anticholinergic
activity, which can increase fall risk, by among others risk of delirium
and visual disturbances, increases with increasing plasma concentrations
of nortriptyline (even at therapeutic levels) 24.
We observed a possible increased fall risk for users with higher plasma
concentrations of TCA , which is in line with our hypothesis. However,
the sample size was small. Furthermore, especially for amitriptyline the
measured concentrations were below reference range for therapeutic
effect or in therapeutic range, thus we cannot generalize our findings
to potentially toxic concentrations. However, older adults are more at
risk for adverse events due to altered pharmacokinetics and – dynamics25. TDM for TCAs is well-established in clinical
practice, both for therapeutic effect and toxicity26-29. For SSRIs, the clinical use of TDM is less
frequently employed, especially in older adults 30.
For most SSRIs therapeutic reference ranges are wide, evidence for a
relationship between drug concentration and therapeutic outcome is weak
and risk for toxicity is relatively low compared to TCAs29, 31, 32. So in general, available data do not
suggest benefit for (routine) monitoring of SSRI plasma concentrations31. However, TDM for SSRIs is recommended in specific
populations like advanced age 13, 32. Since, studies
have shown higher exposure to antidepressant concentrations compared to
younger patients 33, 34. And also adequate use of TDM
has been shown to be cost effective in older adults 35,
36. Thus, the lack of applying TDM and lack of lower blood
concentrations as target, can possibly contribute to the risk of falls,
an important ADE.
An important strength of our study is the prospective nature, using fall
calendars. In falls research this method is considered the golden
standard to avoid recall bias 37. Also, data on
medication use was collected thoroughly, using both pharmacy
prescription data and self-reported medication lists. Our study also has
some important limitations. First, limited power was a problem. Despite
the large B-PROOF database, the remaining group of participants that met
the inclusion criteria was small as prevalence of antidepressant usage
was low. Due to small groups, we needed to pool the data and needed to
standardize and categorize the plasma concentrations. Second,
information about plasma concentrations during the fall incident was not
available, since such an unplanned event cannot be anticipated for. Thus
we only had blood samples from baseline and follow-up study visit.
Baseline or follow-up plasma concentrations might not be representative
for the plasma concentration at the time of the fall incidents. Also,
for some participants follow-up samples were missing. Thus it was unsure
whether they were an actual antidepressant user at the time of the fall
incident. However, this issue probably did not affect our results, since
when repeating the analyses in the participants with baseline and
follow-up samples, the results did not change significantly (data not
shown). Third, for the association between delta concentrations and fall
risk cannot be ruled out that concentrations changes did not reflect
clinical relevant differences. By coding them binary (either increase or
decrease) it could be that not relevant changes are mixed with clinical
relevant changes. Fourth, our cohort consisted of relatively healthy
community-dwelling older people. Frail older adults, can exhibit
different patient characteristics, different pharmacokinetics which
could lead to different results 25.