Medicines Q&As

UKMi Q&A No. 150.5

How do you switch between , SSRI and related ?

Prepared by UK Medicines Information ( UKMi ) pharmacists for NHS healthcare professionals Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp Date prepared: November 2015

Summary ♦ Care is required when switching between antidepressants. ♦ When switching between selective inhibitors, tricyclic and related antidepressants, it is considered safer, in order to avoid inducing a drug discontinuation syndrome or precipitating drug interactions, to incrementally reduce the dose of the first and discontinue it before starting the second antidepressant. This is not always possible. In severely depressed patients who have failed to respond to one antidepressant, or in cases of severe adverse reaction, it may be necessary to shorten the process of substitution. ♦ Cross-tapering is an option for some switches but should always be done cautiously. ♦ Patients should be assessed on an individual basis to determine how quickly the switch can be done. ♦ The potential for errors with complicated switching regimens should be considered.

Background The main reasons for switching antidepressants are an inadequate response to initial therapy despite being used at the right dose for an appropriate duration of time, or the presence of intolerable side effects. When switching between antidepressants there is the potential for interaction between the two agents and/or for the patient to experience drug discontinuation symptoms from withdrawal of the first drug.

Most commonly used antidepressants affect serotonin transmission. Concomitant or sequential use can increase the risk of . The characteristic symptoms of this syndrome include altered mental state (agitation, confusion), autonomic dysfunction (fever, sweating) and neuromuscular abnormalities (tremor, in-coordination); convulsions and fatalities have been reported [1,2]. Although serotonin syndrome can occur exceptionally after taking only one drug, it is more likely to develop when two or more drugs with activity are taken together [1].

Symptoms of antidepressant discontinuation syndrome are likely when a drug is stopped abruptly after regular administration for six weeks or more [2]. Most antidepressants should be withdrawn by reducing the dose gradually over a minimum of four weeks, using patients’ symptoms as a guide to the speed of withdrawal. and vortioxetine are the exceptions. Because of their long half-lives, vortioxetine can be stopped abruptly as can fluoxetine at a dose of 20mg daily; at higher doses, incremental withdrawal is required with fluoxetine [2].

When switching antidepressants, individual patient circumstances should be assessed, taking into account the following factors: ♦ the urgency of the switch. In severely depressed patients who have failed to respond to one antidepressant, or in cases of severe adverse reaction, it may be necessary to shorten the process of substitution. With less urgency a more cautious approach can be used. ♦ the patient’s physical condition. Caution is required in older patients and those with co-morbidities. ♦ the current dose of the first antidepressant and how easily this can be withdrawn. ♦ the duration of antidepressant treatment. If this has been less than 6 weeks then it may be possible to shorten the withdrawal period or stop the drug abruptly. ♦ the risk of serotonin syndrome. Serotonin syndrome is more likely to occur if the patient is on other drug therapy with serotonergic activity, for example , , , , and [1,3]. ♦ any history of discontinuation reactions. ♦ the risk that the switching regimen will confuse the patient and result in medication error.

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk

Few studies have specifically examined the best strategy for switching between antidepressants. The following advice is based on available information, theoretical concerns and clinical experience. It is intended for general guidance only. For patients with complex medical or drug histories, specialist advice should be sought. Whichever strategy is used, patients should be closely monitored for adverse effects.

Answer In practice, switches between selective serotonin reuptake inhibitors (SSRIs), tricyclic (TCA) and related antidepressants can be carried out in one of three ways:

1. Gradual withdrawal and then switch Gradually withdrawing the first antidepressant over several weeks and starting the second antidepressant, at a low dose, either ♦ immediately after discontinuation, or ♦ after a washout period. The washout period (time between stopping one drug and starting another) is dependent on the half-life of the first drug. As a general rule the majority of a drug is eliminated from the body within five half-lives.

2. Cross-tapering Gradually reducing the dose of the first antidepressant while starting the second antidepressant at a low dose and then increasing this dose as the first drug is withdrawn.

Cross-tapering is an option when switching between some antidepressants. It is unnecessary if switching from fluoxetine because of the long half-life of the drug (see immediate switch). is a potent inhibitor of serotonin reuptake and serotonin syndrome is more likely to occur if it is co-administered with SSRIs, or , therefore cross-tapering is not recommended, except under specialist use [2,3]. Clomipramine should be withdrawn before starting an SSRI, venlafaxine or duloxetine, and vice versa if switching to clomipramine [2].

Due to the potential for serious drug interactions, cross-tapering with TCAs is inadvisable with and , although it can be done very cautiously if necessary. As fluvoxamine is a potent inhibitor of the cytochrome P450 1A2 isoenzyme which is largely responsible for metabolism of , clomipramine and [3,4], concomitant use can result in increased TCA levels [3]. Paroxetine and fluoxetine are inhibitors of cytochrome P450 2D6 isoenzyme and concomitant use with clomipramine or may result in increased plasma levels of these TCAs [3,5,6].

When cross-tapering from a TCA to an SSRI, gradually reduce the dose of TCA to 25-50mg daily and start the SSRI at the normal starting dose. Gradually discontinue the TCA over the next 5 to 7 days [3]. If cross- tapering from venlafaxine to an SSRI, reduce the dose of venlafaxine then start the SSRI at half the normal starting dose e.g. 10mg daily or fluoxetine 10mg daily [2].

Cross-tapering should always be carried out cautiously. An example of cross-tapering between citalopram and is given below. The example uses a weekly schedule; however, some patients may not tolerate this, and for these patients a two week schedule or longer may be more appropriate [7]. The speed of cross-tapering is best judged by monitoring patient tolerability [2].

Switch Week 1 Week 2 Week 3 Week 4 From citalopram 20mg daily 10mg daily 5mg daily Nil 40mg daily To mirtazapine 15mg daily 30mg daily 30mg daily 45mg daily (if required)

3. Immediate switch Stopping the first antidepressant abruptly, and starting the second antidepressant at a low dose, either ♦ immediately after stopping, or ♦ following a washout period.

In theory, because the half-lives of SSRIs are similar, it should be possible to immediately switch from one to another, with administration of the second SSRI ameliorating the withdrawal effects of the first [2]. The

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk exception is fluoxetine which has a long half-life and a washout period is required. This regimen may be an option if the first antidepressant has been taken for less than six weeks or if severe side effects with the first antidepressant have occurred. If this regimen is chosen, a low starting dose of the second SSRI should be used and titrated up. This method has also been suggested for switching from SSRIs to venlafaxine [8,9] and from SSRIs to duloxetine [10]. Discontinuation syndromes can occur with all classes of antidepressants therefore an immediate switch may put the patient at risk of discontinuation symptoms (especially with paroxetine and venlafaxine [2,11], particularly if the switch is to an agent of a different class [12].

Agomelatine switching is an antidepressant agent with selective action at melatonin receptors and selective antagonist action at serotonin 5HT- receptors. It does not affect uptake of serotonin, noradrenaline or [13]. Abrupt withdrawal of agomelatine has not been associated with discontinuation symptoms. This means that no dose tapering is necessary when stopping treatment [14,15]. No significant problems have been reported when agomelatine is taken with most other antidepressants so patients can be switched to and from this with negligible risk [3]. When switching from another antidepressant to agomelatine, agomelatine can be started whilst gradually withdrawing the first antidepressant. The exception is fluvoxamine which affects the metabolism of agomelatine by inhibiting cytochrome P450 1A2 (CYP1A2) thus increasing agomelatine levels [3,14]. It is recommended that when switching from fluvoxamine to agomelatine, fluvoxamine is withdrawn gradually and a three to seven day washout period is allowed before starting agomelatine [2,15].

Vortioxetine switching Vortioxetine is a new antidepressant and there is limited experience when switching, therefore extra caution is required, particularly when switching to or from inhibitors of CYP2D6, such as fluoxetine and paroxetine [2]. The manufacturer advises that vortioxetine can be stopped without gradual dose reduction [16]. However when switching to another antidepressant, doses above 10mg should be reduced to 10mg over a period of 7 days before stopping and starting the new antidepressant [2]. In studies in which patients were abruptly switched from an SSRI or a serotonin and noradrenaline (SNRI) to vortioxetine, about 25% experienced [17,18]. However, in a study in which patients were gradually switched from an SSRI or SNRI by cross tapering doses, rate of nausea was 16% with vortioxetine [19].

Suggested guidelines for switching between individual antidepressants are included in Table 1 , at the end of the document.

Limitations Few studies have investigated the best strategy for, and outcomes of, switching antidepressants. The literature search was limited to adults only, therefore guidance may differ for children and young adults.

References 1. Baxter K, editor. Stockley’s Drug Interactions. London: Pharmaceutical Press. Accessed via www.medicinescomplete.com on 11/11/15. 2. The Maudsley Prescribing Guidelines. 12th edition. Oxford: Wiley-Blackwell; 2015. 3. Bazire S, editor. Psychotropic Drug Directory. The professionals’ pocket handbook and aide memoire. Warwick: Lloyd-Reinhold Communications LLP; 2014. 4. Summary of Product Characteristics - Faverin . Abbott Healthcare Products Ltd. Date of last revision of text 12/08/15. Accessed via www.medicines.org.uk on 11/11/15. 5. Summary of Product Characteristics – Seroxat. GlaxoSmithKline UK. Date of last revision of text 23/10/15. Accessed via www.medicines.org.uk on 11/11/15. 6. Summary of Product Characteristics - Prozac . Eli Lilly and Company Ltd. Date of last revision of text 09/10/14. Accessed via www.medicines.org.uk on 11/11/15. 7. Personal Communication. Agatha Munyika. Medicines Information Pharmacist. Mossley Hill Hospital, Liverpool. September 2006 and August 2009. 8. Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin Psychiatry 2001; 62: 12-7. 9. Haddad PM, Anderson IM. Recognising and managing antidepressant discontinuation symptoms. Adv Psychiatr Treat 2007: 13; 447-57. 10. Perahia DGS, Quail D, Desaiah D, Emmanuelle C, Fava M. Switching to duloxetine from selective serotonin reuptake inhibitor antidepressants: A multicentre trial comparing 2 switching techniques. J Clin Psychiatry 2008; 69: 95-105.

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk

11. Personal communication. Anne Connolly. Medicines Information Pharmacist. Maudsley Hospital, London. July 2007 and July 2009. 12. Wohlreich MM, Mallinckrodt CH, Watkin JG et al. Immediate switching of antidepressant therapy: Results from a of duloxetine. Ann Clin Psychiatry 2005; 17: 259-68. 13. London New Drugs Group. APC/DTC briefing document. Agomelatine. June 2009. 14. Summary of Product Characteristics. Valdoxan. Servier Laboratories Limited. Date of last revision of text 11/2014. Accessed via www.medicines.org.uk on 11/11/15. 15. McAllister-Williams RH, Baldwin DS, Haddad PM, Bazire S. The use of antidepressants in clinical practice: focus on agomelatine. Hum Psychopharmacol Clin Exp 2010; 24: 95-102. 16. Summary of Product Characteristics - Brintellix tablets. Limited. Date of last revision of text 17/06/15. Accessed via www.medicines.org.uk on 05/11/15. 17. Jacobsen PL, Mahableshwarkar AR, Chen Y, Chrones L, Clayton AH. Effect of Vortioxetine vs. on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced . J Sex Med 2015; 12: 2036-48. 18. Jacobsen PL, Harper L, Chrones L, Chan S and Mahableshwarkar AR. Safety and tolerability of vortioxetine (15 and 20 mg) in patients with major depressive disorder: results of an open-label, flexible dose, 52-week extension study. Int Clin Psychopharmacol 2015; 30: 255-64. 19. Montgomery SA, Nielson RZ, Poulsen LH, Haggstrom L. A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine. Hum Psychopharmacol 2014; 29: 470-82.

Quality Assurance Prepared by Simone Henderson North West Medicines Information Centre, Pharmacy Practice Unit, 70 Pembroke Place, Liverpool, L69 3GF.

Contact [email protected]

Date this version written November 2015

Checked by Joanne McEntee, Christine Proudlove, Nicola Bradley. North West Medicines Information Centre, Pharmacy Practice Unit, 70 Pembroke Place, Liverpool, L69 3GF.

Date of check November 2015

Search strategy • In-house databases/resources. • Medline: 1. Antidepressive-agents AND Substance-withdrawal-syndrome 2. Antidepressive-agents OR Antidepressive-Agents-Second –Generation OR Antidepressive- Agents-Tricyclic OR Serotonin-Uptake-Inhibitors OR Monoamine-Oxidase-Inhibitors AND Switch$. 3. Vortioxetine and Switch$. Search limited to ‘human’, ‘english’ and ‘adults’. • Embase: 1. Antidepressant-agent AND Drug-withdrawal 2. Antidepressant-agent OR Tricyclic-Antidepressant-Agent OR Serotonin-Uptake-Inhibitor OR Monoamine-Oxidase-Inhibitor AND Switch$. 3. Vortioxetine and Switch$. Search limited to ‘human’, ‘english’ and ‘adults’. • electronic Medicines Compendium (eMC) www.medicines.org.uk • Expert comments: Agatha Munyika. Medicines Information Pharmacist. Mossley Hill Hospital Liverpool. July 2009. Anne Connolly. Medicines Information Pharmacist. Maudsley Hospital, London. July 2009.

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk

Medicines Q&As

Table 1: Switching antidepressants: Use this table in conjunction with the previous notes

1st agent  # Citalopram, Fluvoxamine Fluoxetine TCA Clomipramine * Venlafaxine Duloxetine Mirtazapine ** Agomelatine Vortioxetine escitalopram, (except 2nd agent  paroxetine, or clomipramine)

Citalopram, Discontinue first Discontinue Discontinue Cross-taper Discontinue Cross-taper Immediate Cross-taper Cross-taper Cross-taper Cross-taper escitalopram, SSRI gradually SSRI SSRI gradually cautiously with SSRI gradually cautiously, switch starting cautiously [2] cautiously [2] cautiously [2] cautiously paroxetine or and stop - start gradually and and stop - start low dose of and stop - start starting with with duloxetine starting with sertraline second SSRI at stop - start fluoxetine 10mg TCA [2] clomipramine at low dose 60mg daily has low-dose low dose the fluvoxamine the following low dose the venlafaxine been well vortioxetine [2] following day [2] at low dose day [2] following day [2] e.g. 37.5mg tolerated or the following daily and [2,3,10] day [2] increase very Immediate slowly [2] switch [8,9,15] or Immediate switch (caution if fluoxetine or paroxetine used) [8,9]

Fluvoxamine Discontinue Discontinue Cross-taper Discontinue Discontinue Discontinue Cross-taper Cross-taper Discontinue Discontinue fluvoxamine fluvoxamine cautiously with fluvoxamine fluvoxamine fluvoxamine cautiously. Start cautiously [2] fluvoxamine fluvoxamine gradually and gradually and low dose of gradually and gradually and gradually and mirtazapine at gradually and gradually and stop - start SSRI stop - start TCA [2] stop - start stop - start stop - start 15mg daily [2] stop – start stop. Start at low dose the fluoxetine 10mg clomipramine at venlafaxine at duloxetine at agomelatine 7 vortioxetine at following day [2] the following low dose the low dose the low dose the days later [2] low dose the day [2] following day [2] following day following day following day [2] [2] [2] or Immediate switch starting with duloxetine 60mg daily has been well tolerated [2]

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk

1st agent  # Citalopram, Fluvoxamine Fluoxetine TCA Clomipramine * Venlafaxine Duloxetine Mirtazapine Reboxetine ** Agomelatine Vortioxetine escitalopram, (except 2nd agent  paroxetine, or sertraline clomipramine)

Stop fluoxetine § Stop Stop fluoxetine § Stop fluoxetine § Stop Immediate Cross-taper Cross-taper Cross-taper Stop fluoxetine§ Fluoxetine § § abruptly – start fluoxetine abruptly – start abruptly – start fluoxetine switch starting cautiously cautiously [2] cautiously [2] abruptly – start § 20mg daily second SSRI at abruptly – TCA at low low dose abruptly – start with duloxetine starting with vortioxetine at half the normal start low dose dose 4 to 7 clomipramine 2 venlafaxine at 60mg daily has mirtazapine low dose 4 to 7 starting dose 4 fluvoxamine 2 days later and weeks later [2] low dose e.g. been well 15mg daily [2] days later [2] to 7 days later weeks later increase dose 37.5mg daily tolerated [2,3] [2] [2] very slowly and increase [2,3,9] dose very slowly [2]

TCA Gradually Cross-taper Halve dose of Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Reduce the reduce the dose cautiously [2] TCA, add cautiously [2] cautiously [2] cautiously, cautiously cautiously [2] cautiously [2] cautiously [2] dose of TCA to (except of TCA to 25- fluoxetine and starting with starting with half, start clomipramine) 50mg daily - then slowly venlafaxine duloxetine* vortioxetine, start SSRI then withdraw TCA 37.5mg daily 30mg daily and then slowly slowly withdraw [2] [2] increase dose withdraw TCA TCA* over next very slowly [2] [2] 5 to 7 days [3] Discontinue Discontinue Discontinue Cross-taper Discontinue Discontinue Cross-taper Cross-taper Cross-taper Discontinue Clomipramine * clomipramine clomipramine clomipramine cautiously [2] clomipramine clomipramine cautiously [2] cautiously [2] cautiously [2] clomipramine gradually then gradually then gradually then gradually and gradually and gradually and stop – start stop – start stop – start stop - start stop - start stop – start SSRI at low fluvoxamine fluoxetine 10mg venlafaxine at duloxetine at vortioxetine at dose the at low dose daily the low dose the low dose the low dose the following day [2] the following following day following day following day following day day [2] [2] [2] [2] [2]

Venlafaxine Cross-taper Discontinue Discontinue Cross-taper* Discontinue Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper cautiously with gradually then gradually then using a very gradually then cautiously with cautiously [2] cautiously [2] cautiously [2] cautiously low dose SSRI stop – start stop – start low starting stop – start low dose starting with [2] fluvoxamine fluoxetine 10mg dose of TCA clomipramine at duloxetine e.g. low-dose or at low dose daily the e.g. low dose the 30mg daily vortioxetine [2] [2] following day amitriptyline following day [2] or Immediate [2] 25mg daily [2] switch (caution if immediate fluoxetine or switch starting paroxetine used) with duloxetine [8] 60mg daily has been well tolerated [2]

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk

1st agent  # Citalopram, Fluvoxamine Fluoxetine TCA Clomipramine * Venlafaxine Duloxetine Mirtazapine Reboxetine ** Agomelatine Vortioxetine escitalopram, (except 2nd agent  paroxetine, or sertraline clomipramine)

Duloxetine Cross-taper Discontinue Discontinue Cross-taper Discontinue Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper cautiously with gradually then gradually then cautiously using gradually then cautiously with cautiously [2] cautiously [2] cautiously [2] starting with low dose SSRI stop – start stop – start a very low stop – start low dose low-dose [2] fluvoxamine fluoxetine 10mg starting dose of clomipramine at venlafaxine vortioxetine [2] at low dose daily the TCA e.g. low dose the e.g. 37.5mg the following following day amitriptyline following day [2] [2] day [2] [2] 25mg daily [2]

Mirtazapine Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2]

Reboxetine Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2] cautiously [2]

Agomelatine Stop Stop Stop Stop Stop Stop Stop Stop Stop Stop agomelatine agomelatine agomelatine agomelatine agomelatine agomelatine agomelatine agomelatine agomelatine agomelatine abruptly – start abruptly – abruptly – start abruptly – start abruptly – start abruptly – start abruptly – start abruptly – start abruptly – start abruptly – start SSRI the start fluoxetine the TCA the clomipramine the venlafaxine duloxetine the mirtazepine the reboxetine the vortioxetine the following day fluvoxamine following day following day following day [2] the following following day following day following day following day [2,14,15] the following [2] [2] day [2] [2] [2] [2] [2] day [2]

# Cross-taper Stop Stop Cross-taper Stop Cross-taper Cross-taper Cross-taper Cross-taper Cross-taper Vortioxetine # # # cautiously vortioxetine vortioxetine cautiously with vortioxetine cautiously with cautiously with cautiously [2] cautiously [2] cautiously [2] starting with low- abruptly – abruptly – start low-dose TCA abruptly – start low-dose low-dose dose SSRI [2] start fluoxetine 10mg [2] clomipramine at venlafaxine duloxetine [2] fluvoxamine the following low dose the e.g. 37.5mg at low dose day [2] following day [2] [2] the following day [2]

* See notes regarding cross-tapering. Cross-tapering clomipramine with venlafaxine, duloxetine or a SSRI is not recommended. ** Switching to reboxetine as antidepressant monotherapy is no longer recommended [2]. § Fluoxetine at doses greater than 20mg may need to be withdrawn gradually, over 2 weeks, rather than stopping abruptly [2]. # See notes on vortioxetine. Vortioxetine at doses greater than 10mg should be reduced to 10mg over 1 week before stopping [2].

Medicines Q&A 150.5 How do you switch between tricyclic, SSRI and related antidepressants? November 2015 Available through NICE Evidence Search at www.evidence.nhs.uk