Q&A 369.2
What is the first choice antidepressant for patients with renal impairment?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
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Date prepared: Oct 2014
Background
Depression is a common psychiatric disorder which can be caused and exacerbated by chronic physical health problems [1-2]. Patients with chronic kidney disease, especially severe renal impairment (RI) have been shown to be at higher risk of depression [2]. It has been shown that antidepressant prescribing rates are lower in patients on dialysis despite the increased prevalence of depression [3]. There is a lack of controlled trial data for the treatment of depression in RI and this together with concern over antidepressant side effects may contribute to reduced prescribing of antidepressants in RI [3]. The use of antidepressants in renal replacement therapies is not discussed here.
Answer
Most antidepressants can be used with caution in RI [3-9] since the majority are hepatically metabolised and do not significantly accumulate, even in severe RI [3-9]. The main issues surrounding prescribing antidepressants for patients with RI are therefore much the same as for those patients with normal renal function, where the effects of age, comorbidities and the potential effects of other medications taken concurrently need to be considered. In addition patients with renal impairment have specific increased risks including gastrointestinal bleeding, cardiovascular disease and cerebral sensitivity to sedating medications which also need to be considered.
In line with NICE guidance [1-2], the most appropriate antidepressant should be chosen based on:
¨ Any anticipated adverse events, for example side effects and discontinuation symptoms and potential interactions with concomitant medication or physical health problems
¨ The patient’s perception of the efficacy and tolerability of any antidepressants they have previously taken.
NICE guidelines state that there is no evidence as yet supporting the use of specific antidepressants for patients with particular chronic physical health problems [1-2]. They recommend that when an antidepressant is to be prescribed, a SSRI is usually chosen first line as they are equally effective as other antidepressants but have a favourable side effect profile; citalopram and sertraline are particularly recommended as they also have less propensity to interact compared with other SSRIs [1-2].This advice is not specific to RI.
Table 1 contains a summary of the information from the manufacturer’s product information, Renal Drug Handbook and The Maudsley Prescribing Guidelines for a range of antidepressants.
The Maudsley Prescribing Guidelines state that no agent is clearly preferred over another in RI however citalopram and sertraline may be reasonable choices [5].
The Psychotropic Drug Directory assesses antidepressants in terms of risk in RI as follows [6]:
¨ Lower risk – agomelatine, mianserin, moclobemide, TCA’s, trazodone, tryptophan
¨ Moderate risk – duloxetine, MAOIs, mirtazapine, reboxetine, SSRIs (except sertraline)
¨ Higher risk – venlafaxine, fluoxetine, sertraline
Both The Psychotropic Drug Directory and The Maudsley Prescribing Guidelines provide information on individual drugs where available [5,6]. The Psychotropic Drug Directory considers sertraline a higher risk antidepressant, compared with the recommendation in The Maudsley Guidelines. This view is based on a study of 12 patients with end stage renal disease who were on maintenance haemodialysis and were taking 25mg/day sertraline. All 12 showed signs of serotonin syndrome and 11 discontinued within 3 weeks. The Renal Drug Handbook [4] suggests no dose reduction is required with sertraline in various stages of RI whereas Nagler et al [9] suggest dosage reduction of sertraline is required in patients with severe RI (eGFR <30mL/min).
The majority of information regarding the use of antidepressants relates to pharmacokinetic studies or to patients undergoing dialysis and there is limited data on clinical use in RI prior to dialysis. Reviews by Hedayati et al [3] and Nagler et al [9] provide information on most antidepressants in RI, including pharmacokinetic data, where available, and both reviews suggest that SSRIs be considered as a first choice although specific agents are not mentioned. Raymond et al [8] and Nagler et al [9], highlight that few studies have evaluated the clinical efficacy of antidepressants in RI but state that there is most evidence for the use of SSRI’s. Raymond et al., apply the principles of prescribing antidepressants for the general population to those with renal disease and suggest that newer drugs such as SSRIs, venlafaxine and mirtazapine are generally favoured over TCA’s and MAOIs due to their safety profiles, with choice of a particular agent based on adverse effects and interactions [8].
Hyponatraemia has been associated with all antidepressants, although it has been reported more frequently with SSRIs; reduced renal function is a risk factor for developing hyponatraemia [10-11].
Particular caution may be required when switching between antidepressants as half lives of individual agents may be increased in RI [4,6,7]. Wash out periods, where advised, may need to be extended to take this into account.
The Maudsley Guidelines specifically recommend vigilance in monitoring for serotonin syndrome in patients with RI prescribed antidepressants [5].
Selective Serotonin Reuptake Inhibitors (SSRIs)
SSRIs are often recommended as the agents of choice in RI [3, 5, 9] although there is a lack of robust evidence to support this recommendation and therefore it is mainly based on pharmacokinetic data and clinical experience [3, 7, 9]. Reviews by Nagler et al [9] and the Cochrane Collaboration [12] have demonstrated the paucity of information available on the use of antidepressants, including SSRIS, in RI and renal replacement therapies.
SSRIs are predominantly hepatically metabolised and some SSRIs alter the kinetics of CYP450 enzymes [13-19]. In general SSRIs do not require a dose adjustment in RI, however as some metabolites are renally excreted, caution is required [4,13-18]. The half life and plasma concentration of paroxetine have been shown to increase as renal function declines and lower starting doses are recommended by most sources [4,5,7,8,16] Drug interactions may be a problem with the SSRIs that affect CYP450 enzymes. Fluoxetine, fluvoxamine and paroxetine in particular may interact with other medicines via this mechanism [1, 8]. Fluoxetine has been shown to be efficacious and well tolerated in in dialysis patients [7]; however it may not be the most appropriate first-line agent due to its extended half-life and interaction potential [1, 5, 7-8].(See notes above regarding citalopram and sertraline).
SSRIs are associated with an increased bleeding risk which may be a concern in RI [3, 8,11].
Tricyclic Antidepressants (TCAs)
Historically TCAs were the agents of choice in RI due to more experience of their use, but they have been superseded by the SSRIs due to safety concerns and adverse effects with TCAs [3, 8]. Amitriptyline and dosulepin are effective but they are particularly dangerous in overdose and NICE [1- dosulepin only] and the BNF do not recommend their use in the treatment of depression [11]. Although most TCAs can be used cautiously in RI, as in patients with normal renal function, they are generally not recommended as first-line antidepressants.
The majority of TCAs are hepatically metabolised and most do not alter the kinetics of enzymes in the CYP450 pathway [18-19, 20-26]. Interactions with other medicines metabolised via the CYP450 pathway are therefore less likely than with the SSRIs, but numerous other interactions occur [11, 18-19, 20-26]. Lofepramine, of which approximately 50% is renally excreted, is contraindicated by its manufacturer in severe RI [6, 24].
TCAs’ antimuscarinic adverse effects may be more pronounced in RI, and all patients given TCAs should be monitored for urinary retention, confusion, sedation and postural hypotension [5]. Cardiac adverse effects, e.g. hypotension and arrhythmias, may also be a problem in patients with RI and co-existing cardiovascular disease [3, 8].
Miscellaneous Antidepressants
As Duloxetine is a relatively new antidepressant there is only limited experience of its use in RI. Duloxetine is contra-indicated in patients with creatinine clearance (CrCl) of less than 30mL/min [5,27]. Duloxetine is extensively metabolised by the CYP450 pathway to mainly inactive metabolites and it has been shown to accumulate in dialysis patients [7, 27]. Duloxetine has also been associated with increases in blood pressure, and patients with known hypertension or other cardiac disease or whose condition may be affected by an increase in blood pressure should have their blood pressure monitored [10].
Mirtazapine is extensively metabolised via the CYP450 pathway to active and inactive metabolites which are mainly excreted in the urine [18, 28]. Clearance of mirtazapine is reduced in moderate to severe RI (CrCl <40mL/min) and the manufacturers advise that this should be taken into account when prescribing mirtazapine [28]. Mirtazapine exhibits weak antimuscarinic effects [11, 28].
Moclobemide is extensively metabolised by the liver, in part by CYP450 enzymes, to mainly inactive metabolites, which are renally excreted [18, 29]. No dose alteration is required in RI as RI has not been shown to alter the elimination of moclobemide [29]. Moclobemide is claimed to have a reduced risk of interactions and to cause less potentiation of the pressor effect of tyramine than other MAOIs, but patients should still be advised to avoid consumption of large amounts of tyramine rich foods and to avoid taking sympathomimetics [11].
Reboxetine has been shown to be metabolised predominately by the CYP450 pathway in in vitro studies, to inactive metabolites, which are renally excreted [18,30]. Reboxetine is not thought to have any clinically significant effects on CYP450 enzymes [18,30]. Systemic exposure and half life are approximately doubled in patients with renal insufficiency and therefore the manufacturer recommends a 50% reduction in starting dose for patients with RI [30]. The manufacturers of reboxetine do not recommend its use in the elderly due to limited evidence of its use in this patient group [30].
Venlafaxine is extensively metabolised via the CYP450 pathway to active metabolites which are mainly excreted in the urine [18, 31]. The half lives of venlafaxine and its metabolites have been shown to increase in RI [7, 18]. The manufacturer recommends reducing the dose by 50% in severe RI [31]. Venlafaxine has been shown to cause hypertension and monitoring of blood pressure is indicated for all patients taking venlafaxine but is especially important for those with pre-existing hypertension [10-11, 31]. Venlafaxine also has an increased bleeding risk and it should be used cautiously in patients with cardiovascular disease [11, 31]. Avoid using the XL preparations if the GFR is <30ml/min [5]
Agomelatine is one of the newer antidepressants and there is very little information available regarding its use in RI. Agomelatine is metabolised via the CYP450 pathway to inactive metabolites which are renally excreted [32]. No dosage modification in severe RI is recommended by the manufacturers but caution should be used due to the lack of clinical experience in this patient group [32].
Trazodone is a tricyclic related drug and therefore has cautions similar to the TCAs [11]. Trazodone is extensively metabolised by the CYP450 pathway to active metabolites which are renally excreted [18, 33]. In general doses do not need to be reduced in RI but it is advisable to start with a low dose and increase the dose cautiously [4-5, 33].
Due to the complexity of using lithium in RI, seek specialist advice before lithium is prescribed.
Summary
· Data on the use of antidepressants in renal impairment are limited.
· The majority of antidepressants can be used in renal impairment with caution.
· The choice of the initial antidepressant is based on the same general principles as in normal renal function.
· Specific increased risks due to renal disease need to be considered.
· Start with a low dose, titrate slowly and monitor patients closely.
· Side effects may be enhanced in renal impairment.
· Extra caution may be needed when switching between antidepressants as half lives may be extended.
· Lofepramine and duloxetine are contraindicated by their manufacturers in severe renal impairment.
Limitations
This Medicines Q&A is not designed to be a standalone resource on choice or dosing of antidepressants in renal impairment. Readers are advised to use standard drug dosing in renal disease resources to support decision making. This Q&A is intended for use in adult patients only. The use of antidepressants for indications other than depression is outside the scope of this Q&A. The use of antidepressants in renal replacement therapies is not discussed here.
6
Available through NICE Evidence. Search at www.evidence.nhs.uk
Table 1: Summary of information on the use of antidepressants in renal impairment from the manufacturer’s product information, Renal Drug Handbook and the Maudsley Prescribing Guidelines. (Details based on current editions and correct at the time of writing).
Manufacturers' Information / Renal Drug Handbook [4] / The Maudsley Prescribing Guidelines [5]TCAs / · Monitor all patients given TCAs for urinary retention, confusion, sedation and postural hypotension.
Amitriptyline / · No information on dose adjustment available from the manufacturer [20] / · <10-50 mL/min dose as in normal renal function
· Introduce gradually due to dizziness and postural hypotension
· Withdraw treatment gradually / · Dose as in normal renal function, but start with a low dose and increase slowly
· Plasma monitoring may be useful
· Has been used to treat pain in renal disease
Clomipramine / · The effects of RI on the pharmacokinetics of clomipramine have not been determined. [21] / · 20-50 mL/min dose as in normal renal function