Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety.

Review

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Introduction

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Age-related pharmacokinetic and pharmacodynamic

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Monash University on 03/07/15 For personal use only.

changes Drug--drug interactions

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AD-associated ADRs in elderly

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Conclusion

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Expert opinion

Janet Sultana, Edoardo Spina & Gianluca Trifiro`† †

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persons

Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety University of Messina, Policlinico Universitario G. Martino, Department of Clinical and Experimental Medicine, Messina, Italy

Introduction: Antidepressants (ADs) are widely used among elderly persons, making AD-related safety an important issue. Areas covered: This review highlights safety considerations related to AD use including risks associated with inappropriate and off-label use. The agerelated pharmacokinetic and pharmacodynamic changes underlying safety concerns connected to ADs are outlined. Drug--drug interactions as a cause of AD-related adverse drug reactions (ADRs) are also discussed. We reviewed scientific evidence concerning three important safety outcomes related to ADs in elderly persons: cardiac arrhythmias, hyponatraemia and falls/ fractures. Expert opinion: Several AD-related ADRs in elderly people are likely to be preventable. Current evidence suggests that selective serotonin re-uptake inhibitors (SSRIs) are best avoided particularly in persons with kidney disease due to the risk of hyponatraemia. The use of tricyclic antidepressants (TCAs) should be limited in the elderly due to anticholinergic adverse effects. TCAs should also be avoided in elderly persons at high risk of cardiovascular events due to a risk of cardiac arrhythmia. Emerging evidence suggests that SSRIs also have arrhythmogenic potential. Both TCAs and SSRIs should be used cautiously in elderly persons at risk of falls. Future research in this area should aim to investigate the lowest effective dose of AD possible, the relationship between AD dose and adverse effects, and which elderly subgroups are most prone to develop severe ADRs. Keywords: adverse drug reaction, antidepressants, drug safety, elderly Expert Opin. Drug Metab. Toxicol. [Early Online]

1.

Introduction

The antidepressant (AD) drugs, including monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs), were first used in the 1950s. They were the main AD drugs used during the 1960s through 1980s. Fluvoxamine was launched in the European market in 1983 and in the US market in 1994. Fluoxetine was marketed in 1988, but the other commonly used selective serotonin re-uptake inhibitors (SSRIs) were marketed in the 1990s and later. Trazodone was introduced in 1981 and bupropion in 1986. The 1970s through the 1990s saw the launch of other SSRIs and the broadening of AD indications (e.g., anxiety and pain) beyond depressive disorders. The final wave of new AD launches occurred between the 1990s and 2003, when selective noradrenaline re-uptake inhibitors (SNRIs) such as venlafaxine, duloxetine as well as mirtazapine, bupropion and nefazodone were made available [1]. Since then, ADs have been increasingly used, predominantly in the treatment of depressive disorder and anxiety disorder [2,3]. ADs, in particular 10.1517/17425255.2015.1021684 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. . .

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Antidepressants (ADs), particularly selective serotonin re-uptake inhibitors, are widely used in the elderly. Although most ADs are generally considered to be safe, AD use in the elderly is more likely to result in adverse effects because of age-related pharmacokinetic and pharmacodynamic changes, polypharmacy and an increase in co-morbidities. The risk of AD-related ADRs may be reduced by minimising the use of concomitantly administered interacting drugs. Currently available evidence tends to report risk for AD drug classes rather than for individual drugs. Future research should focus more on individual, and particularly newer AD drugs in the elderly, given that every AD has a unique pharmacological profile.

This box summarises key points contained in the article.

TCAs, are also prescribed for the treatment of other indications such as neuropathic pain [4], headache and insomnia [5]. Due to their higher tolerability, especially when compared to traditional TCAs, SSRIs tend to be the most commonly prescribed class of ADs, particularly in the treatment of depressive disorders in elderly persons [3,6,7]. The prevalence of major depression in the elderly has been reported to vary between 4.6 and 9.3%, whereas the prevalence of subthreshold depressive disorder is much greater, varying from 4.5 to 37.4% in patients over 75 [8]. The symptoms in late-life depression differ somewhat from those of depression in younger adults [9], possibly confounding diagnosis. It is therefore not surprising that late-life depression may be misdiagnosed or go undiagnosed [10]. ADs in the elderly may be underused, overused or inappropriately used. The potentially inappropriate use of ADs may be due to the overlooked risk of drug--drug interactions, drug--disease interactions as well as incorrect dose and duration of use [11]. The off-label use of ADs in elderly patients is another common issue in the geriatric population. A survey of old age psychiatrists’ prescribing practices in the UK reported that ADs are considered a therapeutic option for the management of behavioural and psychological symptoms in dementia, mainly agitation, wandering and aggression, even though UK NICE guidance does not recommend the use of ADs for non-cognitive symptoms of dementia [12]. 2. Age-related pharmacokinetic and pharmacodynamic changes

The process of aging is accompanied by a progressive reduction in the function of various organ systems, subsequently leading to changes in pharmacokinetics and pharmacodynamics. Such changes in drug handling involve differences in drug absorption, distribution, metabolism and 2

excretion. Not all age-related changes in pharmacokinetics and pharmacodynamics are likely to be significant. For example, drug absorption does not change significantly with age. Changes in fat and muscle composition, mainly a decrease in total body mass and resulting increase in body fat are more likely to affect drug distribution in a critical manner, increasing the distribution and accumulation of lipid-soluble ADs. Nevertheless, the most significant age-related pharmacokinetic changes involve drug elimination, either through hepatic metabolism and/or renal excretion. Hepatic metabolism and renal function decline progressively with age, thus reducing the elimination of several drugs. The decline in hepatic metabolism is mainly due to changes in hepatic blood flow and liver mass. Age-related pharmacodynamic changes may arguably be more important than age-related pharmacokinetic changes. Older patients may require a lower AD drug dosage due to an increase in pharmacodynamic sensitivity, for example, due to structural and physiological changes in neurons and neurotransmission [13,14]. Although the mechanisms underlying such changes are not fully understood, it is hypothesised that changes in neurotransmission systems, changes in hormone levels, impaired glucose metabolism and reduced cerebrovascular circulation all contribute to increased pharmacodynamic sensitivity to centrally acting drugs [13]. In general, elderly patients are likely to require lower drug doses compared to their younger counterparts; however, studies investigating the effect of age-related changes on drug response are fraught with limitations such as small study population size, lack of differentiation between chronological and biological age and lack of differentiation between physiological and pathological [15,16] characteristics. In addition, the inter-individual variability in drug responses may be accented in elderly patients, making the drug efficacy and safety profile difficult to predict [17]. The increased risk of AD-related adverse drug reactions (ADRs) in elderly patients, even at lower doses, is partly related to the above-mentioned changes in pharmacodynamics [18]. For example, anticholinergic effects such as urinary retention, constipation, glaucoma, xerostomia and confusion are commonly reported in elderly patients prescribed ADs with anticholinergic properties such as TCAs but also some SSRIs such as paroxetine [19]. These effects may be due to an age-related attenuation in cholinergic transmission systems, leading to an increased sensitivity to anticholinergic effects. Similarly, attenuated dopaminergic transmission systems in the elderly are likely to be associated with drug-induced extrapyramidal symptoms which, although rarely encountered in elderly patients, are still more commonly reported in this population compared to younger patients [20]. Elderly patients also have an increased risk of gastrointestinal bleeding when taking SSRIs, a risk partly related to the antiplatelet effect of SSRIs to which elderly persons may be more susceptible [21].

Expert Opin. Drug Metab. Toxicol. (2015) 11(5)

Antidepressant use in the elderly: the role of pharmacodynamics and pharmacokinetics in drug safety


3.

Drug--drug interactions

Drug interactions are of significant relevance to AD safety because of the increased risk of polypharmacy with advancing age, particularly in the treatment of psychiatric, neurological or somatic disorders [22]. The rates of polypharmacy reported in scientific literature vary greatly depending on the type of population sampled and the definition of polypharmacy used, but have been reported to vary between 5 and 78% [23]. Drug interactions are often divided into two categories based on their mechanism of action, that is, pharmacokinetics and pharmacodynamics [24]. Drug use can give rise to pharmacokinetic drug interactions, such as changes in the absorption, distribution, metabolism or excretion of a drug and/or its metabolite(s), which occur due to the use of an additional drug. Most pharmacokinetic drug interactions with ADs occur at a metabolic level, often at the level of the hepatic CYP system and, to a lesser extent, the uridine diphosphate glucuronosyltransferase system. The prediction of metabolic drug interactions has improved significantly due to an ever-increasing knowledge of the in vitro activity of major drug-metabolising enzymes, in particular the CYP system. This has proved to be invaluable in helping clinicians predict and prevent potential drug interactions, which are more likely to take place with the concomitant use of drugs metabolised by the same isoenzyme or drugs, which inhibit or induce the metabolism of the another drug. The potential occurrence and clinical significance of a metabolic drug interaction will then depend on a variety of drug-related (i.e., potency and concentration/dose of the inhibitor/inducer, therapeutic index of the substrate, extent of metabolism of the substrate through the affected enzyme and presence of active metabolites), patient-related (i.e., age, genetic predisposition) and environmental factors (i.e., smoking). Protein binding displacement interactions may theoretically occur with ADs, as many of these agents, namely TCAs, fluoxetine, paroxetine, sertraline, duloxetine, vilazodone and vortioxetine, are highly bound to plasma proteins (> 90%) [25]. Competition between two drugs for binding sites on plasma proteins may cause a rise in the free fraction of the displaced drug in plasma or tissue, thereby potentially increasing its pharmacological effects. However, unless additional mechanisms are at work, these interactions are usually not clinically relevant, because the free drug is rapidly cleared from the plasma. Pharmacokinetic drug interactions with ADs can also involve drug transporters, in particular P-glycoprotein (P-gp), which play a central role in the absorption, distribution and excretion of a wide variety of drugs. P-gp is a multi-drug efflux transporter, encoded by the MDR1 gene (or ABCB1), and is highly expressed in the intestine, brain, liver and kidney. It acts as a natural barrier to several of its substrates by significantly limiting their

absorption from the gastrointestinal tract and their penetration across the blood brain barrier, as well as enhancing their elimination in the bile and urine. Like metabolising enzymes, the activity of P-gp can be inhibited or induced by other agents, altering the concentration of substrate drug in circulation. In vitro studies have indicated that some SSRIs, namely paroxetine and sertraline, may inhibit P-gp. Concerning newer ADs, preliminary results from in vitro studies suggest that venlafaxine, but not its active metabolite desvenlafaxine, is an inducer of P-gp. In theory, as many drug substrates for P-gp have a narrow therapeutic range (e.g., digoxin, cyclosporine and various chemotherapeutic agents) and are widely used in the elderly, co-administration with ADs may result in clinically relevant drug interactions. Additional experimental and clinical studies will be necessary to better evaluate the clinical effects of this possible interaction via P-gp in routine care [22]. Pharmacodynamic interactions take place when two drugs act on the same molecular target (e.g., receptors, ion channels, transporters, enzymes, etc.). This generally results in additive, synergistic or antagonistic effects. The potential for pharmacodynamic interactions differs markedly between the various classes of ADs depending on the mechanism of action and molecular targets involved. In general, older drugs, such as TCAs or MAOIs, which have a large range of receptor or enzyme target, are associated with a corresponding higher risk of pharmacodynamic interaction with other drugs targeting the same system(s) compared to newer agents having a more specific mechanism. AD drugs currently available differ in their potential for drug interactions, as summarised in Table 1. Monoamine oxidase inhibitors The use of MAOIs in the management of depression has declined significantly, largely due to their high potential for severe pharmacodynamic interactions [24,26]. Potentially fatal hypertensive crises may occur when non-selective MAOIs are co-administered with foods containing tyramine or other pressor amines, sympathomimetic agents and TCAs [24]. In addition, a serious and life-threatening toxic reaction, known as ‘serotonin syndrome’, has been reported in patients receiving non-selective MAOIs in combination with highly serotonergic drugs such as an SSRI or SNRI. Serotonin syndrome may arise with the concomitant administration of other drugs potentiating the central serotonergic system such as SSRIs, SNRIs and even non-AD drugs such as triptans [27]; it can present with agitation, tachycardia, hallucinations, hyperthermia and nausea/vomiting. 3.1

Tricyclic antidepressants Despite proven efficacy, TCAs are generally reserved as alternative agents for treating late-life depression [28]. The clinical use of TCAs in the elderly may be particularly problematic due to their anticholinergic, sedative and cardiovascular side effects. TCAs have a relatively narrow therapeutic 3.2


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Table 1. Comparison of the potential for drug interactions among various classes of antidepressants in the elderly. Antidepressant drug class Monoamine oxidase inhibitors Tricyclic antidepressants


Selective serotonin re-uptake inhibitors

Serotonin and noradrenaline re-uptake inhibitors

Other newer antidepressants

Potential for drug interactions in the elderly Increased risk of potentially fatal pharmacodynamic interactions, particularly with tyramine-rich foods, sympathomimetic drugs and other antidepressants Metabolism of these drugs is susceptible to enzyme inhibition by CYP2D6 inhibitors (associated with hydroxylation primarily) and by CYP1A2, CYP2C19 and CYP3A4 inhibitors (associated with demethylation primarily) and to enzyme induction by various anticonvulsant drugs High risk of pharmacodynamic interactions, particularly with anticholinergic drugs and drug acting on the CNS and the cardiovascular system Varying potency in the inhibition of CYP isoenzymes, for example: Fluoxetine is a potent inhibitor of CYP2D6 and moderate inhibitor of CYP2C9 and CYP3A4 Paroxetine is a potent inhibitor of CYP2D6 Fluvoxamine is a potent inhibitor of CYP1A2 and CYP2C19 and a moderate inhibitor of CYP2C9 and CYP3A4 Sertraline is a weak to moderate inhibitor of CYP2D6 Citalopram and escitalopram are weak inhibitors of CYP isoenzymes The potential for pharmacodynamic interactions is low, but pharmacodynamic interactions may arise when these drugs are used with other drugs which increase serotonin levels (serotonin syndrome). There is also an increased risk of bleeding when SSRIs are used with NSAIDs, corticosteroids, oral anticoagulants and antiplatelet drugs (including low-dose aspirin) Venlafaxine, desvenlafaxine, milnacipran and levomilnacipran are weak inhibitors of CYP isoenzymes Duloxetine is a moderate inhibitor of CYP2D6 Overall, this has only a low potential for pharmacodynamic interactions, but possible involvement in pharmacodynamic interactions with other serotonergic drugs (serotonin syndrome) Bupropion is a moderate inhibitor of CYP2D6 Nefazodone is a potent inhibitor of CYP3A4 Mirtazapine, trazodone, vilazodone and vortioxetine are weak inhibitors of CYP isoenzymes

Modified with permission from [24].

index and are known to cause significant dose- and concentration-dependent CNS and cardiac side effects. In addition to tolerability and safety problems, the use of these agents in geriatric patients is further complicated by a relatively high potential for drug interactions with a variety of concomitantly prescribed medications. TCAs have a variety of pharmacological actions and may therefore interact pharmacodynamically with compounds acting on the same target(s). TCAs inhibit the neuronal re-uptake of noradrenaline and serotonin, bind to multiple receptor types (M1 cholinergic receptors, H1-histamine receptors and a1-adrenoceptors) and inhibit fast sodium channels. Based on this, TCAs should not be used or used with extreme caution in elderly patients treated with anticholinergic drugs and with drugs affecting the CNS and the cardiovascular system [24]. Concomitant administration of TCAs with other medications possessing antimuscarinic activity, such as phenothiazines and antiparkinsonian agents, may induce additive central and peripheral anticholinergic effects, including memory impairment, dry mouth, blurred vision and constipation. In geriatric patients, this interaction could also precipitate confusional states, acute glaucoma, paralytic ileus and urinary retention. TCAs may potentiate the sedative effects of alcohol and other CNS depressants such as barbiturates, benzodiazepines, antihistamines and antipsychotics, thereby impairing psychomotor and cognitive function, particularly dangerous in an elderly population. Undesirable interactions may also 4

occur when TCAs are used in combination with a variety of cardiovascular drugs (e.g., antiarrhythmics, antihypertensives and oral anticoagulants). In this respect, TCAs may prolong the QT interval of the electrocardiogram, which is associated with an increased risk of arrhythmias and sudden death [29]. Therefore, the combination of TCAs with other drugs known to cause QT prolongation, such as class I and class III antiarrhythmics and other non-cardiac drugs, may increase the mechanistic risk of arrhythmogenesis. TCAs can also give rise to clinically relevant pharmacokinetic interactions when used with significant inhibitors of CYP enzymes involved in their biotransformation [24]. These include CYP1A2 inhibitors such as fluvoxamine and ciprofloxacin, CYP2D6 inhibitors such as quinidine, fluoxetine, paroxetine and bupropion, and CYP3A4 inhibitors such as nefazodone, some azole antifungals and some macrolide antibiotics. Inhibition of CYP enzymes may cause an increase in plasma concentrations of TCAs, possibly resulting in serious adverse reactions, such as anticholinergic effects, orthostatic hypotension, QT-prolongation with subsequent risk of arrhythmias, convulsions and delirium. These effects are presumably more common and more serious in elderly patients because of age-related changes in pharmacokinetics and pharmacodynamics. In contrast, co-administration of enzyme inducers, namely various anticonvulsants, may lead to decreased concentrations of TCAs and, therefore, attenuate their effects.




3.3

Selective serotonin re-uptake inhibitors

Owing to their efficacy, good tolerability and relative safety, the SSRIs have become the most frequently prescribed ADs. The published clinical evidence suggests that SSRIs are firstline agents for treating geriatric depression [30]. The use of SSRIs in the elderly is associated with the risk of clinically relevant pharmacokinetic interactions with other drugs due to their inhibitory effect on CYP enzymes. The differential effects of various SSRIs on CYPs are well-known in vitro [31]. The various SSRIs available differ considerably in their propensity to inhibit CYP enzymes in vitro and this should guide the selection of an appropriate drug for a patient in the context of pre-existing drug regimens. It appears that the in vitro potential for individual SSRIs to interact with other drugs is greater for fluvoxamine, fluoxetine and paroxetine and lower for sertraline, citalopram and escitalopram. In view of these considerations, caution is required when adding an SSRI to a multi-drug regimen in the elderly. In fact, as the inhibitory effect on CYPs is concentration-dependent, the potential for drug interactions is likely to be higher in the elderly, especially for compounds whose elimination depends on mechanisms susceptible to age-related changes, such as citalopram and paroxetine, and for those which exhibit non-linear kinetics, such as fluoxetine and paroxetine [24]. For drugs with long half-lifes, for example, fluoxetine and its active metabolite, the potential for interaction may persist for weeks after treatment discontinuation. Concomitant administration of SSRIs with novel antipsychotics is relatively common, but may occasionally result in clinically important interactions [25]. Paroxetine and fluoxetine have been reported to produce a clinically relevant increase in plasma concentrations of risperidone, presumably through inhibition of CYP2D6, whereas fluvoxamine may cause a significant elevation of plasma concentrations of clozapine and, to a lesser extent, olanzapine which are both substrates of CYP1A2 [25]. Clinically relevant pharmacokinetic drug interactions between SSRIs and drugs used to treat concomitant cardiovascular disorders, in particular b-blockers and digoxin, have been occasionally documented in elderly patients. Co-administration of fluoxetine with metoprolol or propranolol has occasionally resulted in serious adverse events such as bradycardia or heart block [32,33]. Inhibition of CYP2D6-mediated oxidative metabolism of b-blockers by fluoxetine is the most likely explanation for this interaction. Isolated case reports have described a remarkable elevation of serum digoxin concentrations along with signs of toxicity in elderly patients after co-administration of fluoxetine or paroxetine [34,35]. This interaction has been attributed to inhibition of P-gp by SSRIs. However, a recent population-based assessment of the potential interaction between SSRIs and digoxin in elderly patients has indicated that this mechanism is unlikely to be of major clinical significance [36]. SSRIs may also affect the pharmacokinetics of some chemotherapeutic agents. In this respect, paroxetine and fluoxetine are potent

inhibitors of CYP2D6 and administration of these SSRIs may reduce the clinical benefit of the anticancer tamoxifen, by reducing the formation of its active metabolite [37]. Women with breast cancer who receive paroxetine in combination with tamoxifen are at increased risk for death. Other SSRIs, such as citalopram and escitalopram, are weak or negligible CYP2D6 inhibitors. These drugs are therefore much less likely to interact with anticancer drugs. Sertraline inhibits this isoform significantly only at high plasma levels. Due to their selective mechanism of action, SSRIs are usually considered at relatively low risk for pharmacodynamically mediated interaction. However, SSRIs may interact adversely with other drugs affecting serotonergic transmission, such as MAOIs, TCAs and tryptophan, with possible occurrence of a potentially fatal serotonin syndrome [27]. According to post-mortem forensic investigation, elderly patients, particularly those with atherosclerotic cardiovascular disease or preexisting heart disease, are at high risk for this syndrome [38]. In addition, recent epidemiological evidence suggests that SSRI use is associated with an increased incidence of upper gastrointestinal bleeding. The risk of bleeding with SSRIs is relatively low when these drugs are used alone but increases markedly when used concomitantly with drugs such as NSAIDs, oral anticoagulant and antiplatelet drugs (including low-dose aspirin), which also increase the risk of bleeding [39]. Paradoxically, one study combining seven population-based databases reported that the risk of bleeding was also relatively high when COX inhibitors, which are indicated particularly in patients at risk of bleeding, were combined with SSRIs (incidence rate ratio [IRR] = 5.82 [95% CI: 4.45 -- 7.62]) compared to when NSAIDs were co-prescribed with SSRIs (IRR = 6.95 [95% CI: 5.97 -- 8.08]) [40]. This study also reported a risk of bleeding even when low-dose aspirin was used with SSRIs (IRR = 4.60 [95% CI: 4.09 -- 5.17]). The interaction between SSRIs and warfarin has also been associated with an increased risk of bleeding. A case--control study in a population of coumarin users found that the concomitant use of SSRIs was associated with non-gastric bleeding [41]. At least two studies confirmed an increased risk of bleeding when SSRIs were prescribed in warfarin users: a case--control study reported an increased 3.5-fold risk of bleeding in a small sample of nine patients [42], whereas a retrospective study reported approximately a 2.5-fold risk of any bleeding event [43]. In addition, the following caveat regarding warfarin-related interactions should be noted: the pharmacological mechanism underlying such interactions may differ. Warfarin interactions may be due to an additive effect (the independent bleeding effects of an AD in addition to those of warfarin), protein-binding displacement of warfarin or hepatic inhibition of the CYP2D6-mediated oxidative metabolism of the S-enantiomer of warfarin by SSRIs, in particular fluvoxamine and fluoxetine [22]. This may influence the extent and severity of the drug interaction.


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3.4

Other newer ADs

Several newer ADs with a heterogeneous mechanism of action were marketed in the past few years. Bupropion inhibits the reuptake of dopamine and noradrenaline in neurons [22]. It is a moderate CYP2D6 inhibitor and interacts pharmacokinetically with some ADs, such as venlafaxine, leading to increased plasma levels of the latter. In fact, suboptimal response to venlafaxine in major depression may be approached adding on bupropion, although this may lead to adverse effects caused by elevated serotonin levels. Nefazodone, which is not currently on the market, inhibits the re-uptake of serotonin, acts as a serotonin 5-HT2-receptor antagonist and also inhibits the re-uptake of noradrenaline [44]. It is a potent inhibitor of CYP3A4 and is known to interact with drugs having a narrow therapeutic index such as cyclosporine, tacrolimus, carbamazepine, terfenadine and loratadine. Mirtazapine, trazodone, vilazodone and vortioxetine are weak inhibitors of CYP isoenzymes and are less likely to give rise to drug interactions. 4.

AD-associated ADRs in elderly persons

Cardiovascular effects TCAs such as amitriptyline, clomipramine, trimipramine, doxepin and imipramine have been associated with a risk of tachycardia and atrioventricular block due to their anticholinergic profile [45]. Despite the known cardiovascular risk associated with TCAs, a case--control study in the UK showed that SSRIs at any dose were also associated with a higher risk of sudden cardiac death (SCD) (odds ratio [OR] = 1.89 [95% CI: 1.34 -- 2.69]) than TCAs at any dose (OR = 1.41 [95% CI: 0.93 -- 2.13]) [46], although the latter was not statistically significant. Similarly, another study investigating the risk of SCD and ventricular arrhythmia (VA) using Medicaid beneficiaries’ data found no difference in the risk between individual TCAs and paroxetine, whereas mirtazapine (IRR = 2.06 [95% CI: 1.84 -- 2.30]), citalopram (IRR = 1.14 [95% CI: 1.02 -- 1.28]) and sertraline (IRR = 1.12 [95% CI: 1.01 -- 1.24]) had a statistically significant risk of SCD/VA compared to paroxetine [47]. The dose--effect relationship between AD dose and cardiac arrhythmia was not always clear. Jolly et al. failed to demonstrate a statistically significant dose--effect response for TCAs and SSRIs use and the risk of torsades de pointes [46]. Ray et al. found no dose--effect response for TCA use and the risk of SCD but observed a difference in risk when the overall TCA dosage was divided in < 100 mg amitriptyline equivalents and ‡ 100mg amitriptyline equivalents [48]. When out-of-hospital cardiac arrest was investigated in a Danish case--time--control study, the highest risk was found for nortriptyline (OR = 5.14 [95% CI: 2.17 -- 12.2]), followed by mirtazapine (OR = 1.37 [95% CI: 0.95 -- 1.95]), amitriptyline (OR = 1.36 [95% CI: 0.83 -- 2.32]), citalopram (OR = 1.29 [95% CI: 1.02 -- 1.63]) and escitalopram (OR = 1.10 [95% CI: 0.64 -- 1.87]) [49]. An FDA alert in 4.1

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2011, updated in 2012 [50], warned about the risk of cardiac arrhythmia associated with the use of citalopram at high doses. At the pharmacological level, SSRIs are likely to mediate the increased risk of arrhythmia via inhibition of cardiac voltage-gated ion channels [51]. SNRIs, mainly duloxetine and venlafaxine, were found to be relatively safe within therapeutic doses with respect to cardiovascular effects such as arrhythmias, QTc interval prolongation or SCD [52-54]. Nevertheless, the summary of product characteristics for duloxetine and venlafaxine cautions about the risk of elevated blood pressure. Hyponatraemia Hyponatraemia is defined by abnormally low blood sodium concentrations and may be asymptomatic, mild (e.g., leading to nausea and muscle cramps) or severe (e.g., leading to seizures and/or coma) [55]. The risk factors for hyponatraemia were investigated in a case--control study by Siegler et al., who reported that hyponatraemia was more likely in patients prescribed fluoxetine and TCAs [56]. A Dutch case--control study by Movig et al. also explored the risk of hyponatraemia with any SSRI compared to other AD drugs, however, in the context of a psychiatric in- and out-patient setting [57]. This study found that the risk of hyponatraemia with SSRI use in the general population (OR = 3.9 [95% CI: 1.2 -- 13.1]) was much lower than that in patients 65 and over (OR = 6.2 [95% CI: 0.4 -- 97]). The risk of hyponatraemia in this elderly population increased with the concomitant use of SSRIs and diuretics. Paroxetine was associated with the highest risk of hyponatraemia in the general population (OR = 5.1 [95% CI; 1.5 -- 17.2]) [57]. Another Dutch case--control study reported that the main clinical risk factors for hyponatraemia were hypothyroidism (OR = 18.00 [95% CI: 2.17 -- 149]) and congestive heart failure (OR = 4.46 [95% CI: 2.47 -- 8.05]) [58]. 4.2

Falls and fractures Falls are a common source of injury in elderly persons and a significant number of hospitalisations in this population are due to fractures leading to falls [59]. There are several known risk factors for falls, such as poor vision, postural hypotension, confusion and declining neuromuscular and cerebellar function. Drugs which may cause orthostatic hypotension or impair balance contribute to the risk of falling. Sedating drugs may also increase the risk of falls. One such AD drug, trazodone, is commonly prescribed at subtherapeutic doses in the management of insomnia in elderly persons [60]. In addition, the anticholinergic properties of drugs such as TCAs may lead to a confusional state, which may also impact the risk of falls in elderly patients [61]. In the case of TCAs, a-1 receptors inhibition may underlie orthostatic hypotension, particularly in patients with a medical history of congestive heart failure [45]. Elderly women and nursing home residents are particularly prone to falls, suggesting that these populations may be at 4.3




even higher risk if using ADs [62]. AD use has been associated with falls in general [63] and outdoor falls in particular among community-dwelling elderly people [64]. SSRIs and TCAs have both been associated with falls. A meta-analysis of 28 observational studies and one randomised controlled trial comparing the risk of falls with TCA or SSRI use found a slightly higher risk with SSRIs [65]. The studies considered in the meta-analysis did not include elderly persons specifically, however, so it is not clear if this applies to geriatric patients. It is important to note that, although observational studies are useful in the detection of an association between an exposure and an outcome, they cannot provide evidence of causality and they give no indication as to why an association may have come about. As with other study designs, the results of several studies need to be consistent in order to increase the likelihood of a valid association. Findings from the systematic review above suggest that, even though the risk of falls was higher for SSRIs than for TCAs, the confidence intervals for the risk associated with SSRIs were wider than those for TCAs [65]. Despite the limitations associated with observational studies, it can be said that the risk estimates presented in this systematic review appear to be consistent. However, the lack of a biological explanation for the increased risk with one class rather than another remains a limitation as far as the ‘certainty’ of the causality is concerned, but this does not necessarily preclude an association. The risk of falls in elderly persons is important considering that these may lead to fractures. Some observational studies have highlighted the association between ADs and hip fractures [66-68]. SSRIs were found to have a slightly stronger association with hip fracture (standardised incidence ratio [SIR] = 1.8 [95% CI: 1.7 -- 1.8]) than TCAs (SIR = 1.4 [95% CI: 1.3 -- 1.5]) or other ADs (SIR = 1.6 [96% CI: 1.5 -- 1.7]) in elderly people [69]. In addition, it was found that ADs with higher serotonergic activity are associated more strongly with the risk of fracture (SIR = 1.7 [95% CI: 1.7 -- 1.8]).

5.

Conclusion

Newer ADs, especially SSRIs, are generally considered to be relatively safe drugs when used in the adult population. However, elderly persons may be particularly prone to developing ADRs when using ADs, including SSRIs. Risks associated with AD use in older persons may be minimised by preventing the concomitant use of potentially interacting drugs and using ADs more cautiously and with dose-titration in patients with hepatic or renal impairment. The safety profile of individual AD drug is heterogeneous. However, most of the available scientific evidence is reported by AD class rather than for individual ADs. The risk of adverse reactions for individual ADs, especially the newer drugs, in the elderly population is often not well described.

6.

Expert opinion

ADs are widely used in elderly persons, making AD safety an important public health issue in this population. Age-related changes in pharmacokinetics and pharmacodynamics influence the risk of clinically significant ADRs with the use of all ADs, including SSRIs, in the elderly population. Several potential AD-related ADRs may be prevented by avoiding the use of potentially interacting drugs. More research on drug interactions associated with ADs should be carried out specifically in elderly persons because this is a potentially modifiable source of risk. Further risk minimisation measures can be implemented by the use of the lowest effective dose of AD possible. It is also important to review the need for AD drugs and gradually discontinue them if they are not needed. Currently available evidence suggests that although SSRIs are generally considered safe first-line agents, these drugs are best avoided in persons with kidney disease as this may lead to hyponatraemia. SSRIs should also be used with caution in persons at risk of cardiovascular adverse events as this class of drugs has been associated with an increased risk of SCD. Due to their arrhythmogenic potential, TCAs should be avoided in persons with a medical history of cardiac arrhythmia. Both TCAs and SSRIs should be used with caution in elderly persons at risk of falls. Future research should focus more on the dose--effect relationship between AD dose and unwanted effects. In addition, more information is needed about the safety profile of individual ADs when used in the elderly population, as well as risk factors predisposing elderly persons to various ADRs as these may have clinically relevant consequences in this population. The increasing availability of electronic patient records and electronic prescription data, even at the national level, expands the possibilities for AD drug utilisation research [3,70-74]. Such studies have several strengths: healthcare databases have large population sizes and often reflect routine clinical practice (e.g., if they are general practice databases). Such databases are ideal to study AD safety post-marketing, in particular as they permit the study of polypharmacy and outcomes thereof. Nevertheless, the limitations of investigating AD drug safety using this approach should be borne in mind: although observational studies are useful in the detection of an association between an exposure and an outcome, they cannot provide definitive evidence of causality and they give no indication why an association may have come about. As with other study designs, the results of several studies need to be consistent in order to increase the likelihood of a valid association. Ideally, a study design used to investigate AD drug safety in patients, particularly the occurrence of lesser known adverse effects, should be carried out in parallel with in silico predictions of drug-drug interactions and pharmacokinetic parameters (absorption, distribution, metabolism and elimination). The study


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of AD safety must continuously evolve with the expanding indications for drugs that were initially marketed with other primary indications. For example, although the MAOI selegiline was originally marketed for the management of Parkinson’s disease [75], a transdermal formulation is available which is indicated for major depressive disorder [76]. Other drugs, such as vortioxetine, levomilnacipran, vilazodone, desvenlafaxine and desvenlafaxine, were already approved for major depression in adults but much more information on the safety of these newer ADs in elderly Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Affiliation Janet Sultana1 MSc, Edoardo Spina2 MD PhD & Gianluca Trifiro`†3 MD PhD † Author for correspondence 1 PhD Student, University of Messina, Policlinico Universitario G. Martino, Department of Clinical and Experimental Medicine, Via Consolare Valeria, 98125 Messina, Italy 2 Professor of Pharmacology, University of Messina, Policlinico Universitario G. Martino, Department of Clinical and Experimental Medicine, Via Consolare Valeria, 98125 Messina, Italy 3 Associate Professor of Pharmacology, University of Messina, Policlinico Universitario G. Martino, Department of Clinical and Experimental Medicine, Via Consolare Valeria, 98125 Messina, Italy E-mail: [email protected]

Pharmacokinetics and pharmacodynamics of terfenadine and chlorpheniramine in the elderly.

Alprazolam in the elderly: pharmacokinetics and pharmacodynamics during multiple dosing.

The pharmacokinetics of tricyclic antidepressant drugs in the elderly.

Ticagrelor: pharmacokinetics, pharmacodynamics, clinical efficacy, and safety.

Pharmacokinetics and pharmacodynamics of edrophonium in elderly surgical patients.

Pharmacokinetics and pharmacodynamics of the ace inhibitor benazepril hydrochloride in the elderly.

Risk-benefit analysis of antidepressant drug treatment in the elderly.

Role of antimicrobial pharmacokinetics and pharmacodynamics in surgical prophylaxis.

Evaluation of the Pharmacokinetics and Pharmacodynamics of Prasugrel in Japanese Elderly Subjects.

Preclinical Pharmacokinetics, Pharmacodynamics and Safety of Sucroferric Oxyhydroxide.

Nonclinical analysis of the safety, pharmacodynamics, and pharmacokinetics of plasma-derived human FXIII concentrate in animals.

2 inhibitor, in healthy volunteers.

Pharmacokinetics and pharmacodynamics of bambuterol, a long-acting bronchodilator pro-drug of terbutaline, in young and elderly patients with asthma.

The pharmacokinetics and pharmacodynamics of furosemide in the anaesthetized dog.

[Integration of pharmacokinetics and pharmacodynamics based on the in vivo analysis of drug-receptor binding].

Pharmacokinetics and pharmacodynamics in the design of controlled-release beads with acetaminophen as model drug.

Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers .

Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient.

Pharmacodynamics and pharmacokinetics of flunixin in the cat.

Pharmacodynamics and pharmacokinetics of miloxicam in the horse.

Pharmacokinetics and pharmacodynamics of doxacurium in young and elderly patients during isoflurane anesthesia.

Antifungal pharmacokinetics and pharmacodynamics.

Heparin pharmacokinetics and pharmacodynamics.

Predicting drug-drug interactions through drug structural similarities and interaction networks incorporating pharmacokinetics and pharmacodynamics knowledge.