AboutDr Alan Galbraith Expertise I can answer most questions on drugs, both medical and "recreational". Answers can be given in either technical or layperson terminology. My main areas of interest are psychiatric, gastrointestinal and cardiovascular drugs.
Experience I have been a university lecturer/head of department for almost thirty years, but am now retired. My research interests were alcohol, smoking and cardiovascular disease. I am already a well established and highly rated expert in the pharmacy section of this site.
Publications Principal author of "Fundamentals of Pharmacology" Editions 1-4 published between 1994 and 2004 by Pearson Education, Australia. Author of the 5th edition published 2007.
Author of many scientific papers.
Education/Credentials BSc(Hons);MSc;PhD;HECert
Awards and Honors The 4th edition of my textbook was awarded the the Educational Book of the Year Award in Australia.
Past/Present Clients See my profile in the pharmacy section.
Expert: Dr Alan Galbraith Date: 4/1/2008 Subject: switching antidepressants
Question Dr. Galbraith -
My mother is 76, she has suffered chronic depression for many years, and has been on Lorazepam for anxiety since 1976. She was put on Mirtazapine (Remeron) 15mg in 2001. It appeared to help her very quickly. The dose was increased over time, and she has now been on 45mg. for about two years. She has done well on the drug, but has put on 42 lbs., despite not eating more (I live with her, I can vouch for this). She also now has a high cholesterol count for the first time in her life, and after always having a low blood pressure, this has also increased. She also suffers from severe scoliosis of the spine, and the Mirtazapine seems to have exacerbated her general pain levels. She has always been a lively, active person - she was an actress, dancer and producer in musical theatre, and is not the typical geriatric patient!
When and if she tries to cut down the Mirtazapine, however small the increment, after about 48 hours bad anxiety starts and she has to return to the usual dose. She then stabilizes within a few days. We have tried this several times.
I am a qualified clinical hypnotherapist and psychotherapist used to dealing with anxious clients, and I do feel her anxiety when she cuts down the dose is related to the drug, rather than any psychological dependence.
We would like to try switching to Fluoxetine (Prozac) to see if we can control the weight gain and pain level, but in view of her extreme difficulty in cutting down the Mirtazapine, it would have to be done by cross-tapering. I would very much welcome your opinion about trying this, and any advice that you might give us.
Thanks you,
Russell
Answer Dear Russell
I am appending a fact sheet on switching antidepressants seeing you are clinically minded and should understand this easily. There should be no problems in your proposed switch but I would recommend one of the newer antidepressants but there is often a problem of weight gain with many of them. Trial and error is needed if weight gain becomes burdensome.
Get back to me if there are ant points you wish clarified. A change to tricyclics could also be considered.
Regards
Alan Galbraith
Switching between tricyclic, SSRI and related antidepressants
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Expires 31 July 2009
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.
All commonly used antidepressants affect serotonin transmission. Concomitant or sequential use can increase the risk of serotonin syndrome. 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 serotonergic activity are taken together [1].
Symptoms of antidepressant discontinuation syndrome are likely when a drug is stopped abruptly after regular administration for eight 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. Fluoxetine is the exception. Because of its long half-life, fluoxetine at a dose of 20mg daily can be stopped abruptly; at higher doses, incremental withdrawal is required. For more detailed guidance on discontinuation of antidepressants, see Medicines Q&A no. 10.2.
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 8 weeks then it may be possible to shorten the withdrawal period or stop the drug abruptly (see Medicines Q&A no. 10.2).
• 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 triptans, opioids, tramadol, selegiline, lithium, linezolid and dextromethorphan [2,3].
• any history of discontinuation reactions.
• the risk that the switching regimen will confuse the patient and result in medication error.
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). Clomipramine should not be co-administered with SSRIs or venlafaxine, except under specialist use, and therefore cross-tapering is not recommended [2,3]. A washout period before switching to or from clomipramine is advised to reduce the risk of serotonin syndrome [1,3].
Due to the potential for serious drug interactions, cross-tapering with TCAs is inadvisable with paroxetine and fluvoxamine, 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 the metabolism of amitriptyline, clomipramine and imipramine [3,4], concomitant use can result in increased TCA levels [3]. Paroxetine is an inhibitor of the cytochrome P450 2D6 isoenzyme and concomitant use with clomipramine or nortriptyline may result in increased plasma levels of these TCAs [5].
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. citalopram 10mg daily or fluoxetine 20mg on alternate days [2,6].
Cross-tapering should always be carried out cautiously. An example of cross-tapering between citalopram and mirtazapine 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 [6]. The speed of cross-tapering is best judged by monitoring patient tolerability [2].
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 the SSRIs (with the exception of fluoxetine) are similar, it should be possible to immediately switch from one to another, with the administration of the second SSRI ameliorating the withdrawal effects of the first [2]. This regimen may be an option if the first antidepressant has been taken for less than eight 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 [7]. 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 [8]), particularly if the switch is to an agent of a different class [9].
Suggested guidelines for switching between individual antidepressants are included in Table 1.
Table 1: Switching antidepressants: Use this table in conjunction with the previous notes
1st agent SSRI TCA * Venlafaxine Duloxetine Mirtazapine
2nd agent
SSRI
with the exception of fluoxetine Discontinue first SSRI gradually and stop - start second SSRI at low dose the following day [2]
or
Immediate switch [7] Discontinue SSRI gradually and stop - start TCA the following day. If the SSRI being stopped is paroxetine or fluvoxamine, ideally leave a gap of a few days [3] or
Cross-taper cautiously * [2] Cross-taper cautiously, starting with venlafaxine 37.5mg daily and increase very slowly [2]
or
Immediate switch [7]
Discontinue SSRI gradually and stop - start duloxetine 60mg on alternate days the following day and increase dose slowly [2] Cross-taper cautiously [2]
Fluoxetine
20mg daily Stop fluoxetine abruptly – start second SSRI at half the normal starting dose 4 to 7 days later [2] Stop fluoxetine abruptly – start TCA at low dose 4 to 7 days later and increase dose very slowly [1,2,3] Stop fluoxetine abruptly – start venlafaxine 37.5mg daily 4 to 7 days later and increase dose slowly [2] Stop fluoxetine abruptly – start duloxetine 60mg on alternate days 4 to 7 days later and increase dose slowly [2] Stop fluoxetine abruptly – start mirtazapine 4 to 7 days later [8]
TCA *
Gradually reduce the dose of TCA to 25-50mg daily - start SSRI then slowly withdraw TCA * [3] Cross-taper cautiously [2] Cross-taper * cautiously, starting with venlafaxine 37.5mg daily [2] Cross-taper using a starting dose of duloxetine 60mg on alternate days and increase dose slowly [2] Cross-taper cautiously [2]
Venlafaxine Reduce venlafaxine dose then cross-taper using half the normal starting dose of SSRI e.g. fluoxetine 20mg on alternate days [2,6] or
Immediate switch [7] Cross-taper * using a low starting dose of TCA e.g. amitriptyline 25mg daily [2] Discontinue venlafaxine gradually and stop – start duloxetine 60mg on alternate days the following day and increase dose slowly [2] Cross-taper cautiously [2]
Duloxetine Discontinue duloxetine gradually and stop – start SSRI the following day [2] Cross-taper using a low starting dose of TCA e.g. amitriptyline 25mg daily [2]
Discontinue duloxetine gradually and stop – start venlafaxine the following day [2] Discontinue duloxetine gradually and stop – start mirtazapine the following day [2]
Mirtazapine Cross-taper cautiously [2] Discontinue mirtazapine gradually and stop – start TCA the following day [2] Cross-taper cautiously [2] Discontinue mirtazapine gradually and stop – start duloxetine 60mg on alternate days the following day and increase slowly [2]
* See notes on previous page regarding cross tapering. Cross tapering clomipramine with venlafaxine or a SSRI is not recommended.
Summary
• Care is required when switching between antidepressants.
• When switching between SSRI, TCA 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 antidepressant 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 medication errors with complicated switching regimens should be considered.
Limitations
Few studies have investigated the best strategy for, and outcomes of, switching antidepressants.
Disclaimer
• Medicines Q&As are intended for healthcare professionals and reflect UK practice.
• Each Q&A relates only to the clinical scenario described.
• Q&As are believed to accurately reflect the medical literature at the time of writing.
• See NeLM for full disclaimer.
References
1. Baxter K, editor. Stockley’s Drug Interactions. London: Pharmaceutical Press. Accessed via www.medicinescomplete.com on 23/07/07.
2. The Maudsley Prescribing Guidelines. 9th edition. London: Martin Dunitz Ltd; 2007. p235-43, 248.
3. Bazire S, editor. Psychotropic Drug Directory. The professionals’ pocket handbook and aide memoire. Aberdeen: HealthComm UK Ltd; 2007. p199-205, 399.
4. Summary of Product Characteristics - Faverin. Solvay Healthcare. Accessed via www.emc.medicines.org.uk on 23/07/07.
5. Summary of Product Characteristics – Seroxat. GlaxoSmithKline UK. Accessed via www.emc.medicines.org.uk on 23/07/07.
6. Personal Communication. Agatha Munyika. Medicines Information Pharmacist. Mossley Hill Hospital, Liverpool. September 2006.
7. Marangell LB. Switching antidepressants for treatment-resistant major depression. J Clin Psychiatry 2001; 62: 12-7.
8. Personal communication. Anne Connolly. Medicines Information Pharmacist. Maudsley Hospital, London. July 2007.
9. Wohlreich M, Mallinckrodt C, Watkin J et al. Immediate switching of antidepressant therapy: Results from a clinical trial of duloxetine. Ann Clin Psychiatry 2005; 17: 259-68.
Quality Assurance
Prepared by
Simone Henderson
North West Medicines Information Centre, Pharmacy Practice Unit, 70 Pembroke Place, Liverpool, L69 3GF.
Contact
druginfo@liv.ac.uk
Date Prepared
July 2007.
Checked by
Joanne McEntee
Christine Proudlove
North West Medicines Information Centre, Pharmacy Practice Unit, 70 Pembroke Place, Liverpool, L69 3GF.
