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EDITORIALS: Andre Tylee and Paul Walters Onset of action of antidepressants BMJ 2007; 334: 911-912 [Full text]

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Rapid Responses published:

Antidepressants are effective in hours, not weeks

Bruce G Charlton   (4 May 2007)

A word of caution

Michael Reschen   (5 May 2007)

Clarification of Amount of Early Benefit from Antidepressants

Alex J Mitchell   (5 May 2007)

Onset of action of antidepressants - a pain physician's view.

Dr Peter Thomas, Dr Winston F de Mello,Consultant in Anaesthesia and Pain Medicine , Wythenshawe Hospital,University HospitalsTrust, Manchester   (11 May 2007)

Antidepressants are effective in hours, not weeks 4 May 2007
Bruce G Charlton, Reader in Evolutionary Psychiatry Newcastle University, UK, NE1 7RU Send response to journal: Re: Antidepressants are effective in hours, not weeks	The antidepressant effect on depressive symptoms (such as anxiety, fatigue, or demotivation) is rapid and direct, but the effect on depressed mood is slow, indirect and less predictable [1]. The pharmacological action of antidepressants is related to absorption and receptor-binding, which happens in hours (amplified by rising blood levels over several days). A patient should therefore feel the onset of symptomatic relief within hours (although each drug's symptomatic effect effect varies between the different pharmacological classes [1]). Depressed mood takes much longer to respond to depressive symptom relief - and indeed mood may not respond because it is is an long term outcome of many causes including personality and circumstances. So anxiety may by relieved two hours after taking an SSRI, but it may take weeks before this benefit is assimilated into the long-term mood. Future studies should focus on measuring relief of depressive symptoms, which is a much more rapid and certain antidepressant effect than the mood response. 1. Charlton B. Psychiatry and the human condition. Oxford: Radcliffe Medical Press, 2000. Competing interests: None declared
A word of caution 5 May 2007
Michael Reschen, SHO General Medicine John Radcliffe, Oxford Send response to journal: Re: A word of caution	I note that just 2 months ago a study in the BMJ showed that suicidality was highest during the first 30 days of antidepressant use. Competing interests: None declared
Clarification of Amount of Early Benefit from Antidepressants 5 May 2007
Alex J Mitchell, Consultant Liaison Psychiatrist and Hon SnR Lecturer University of Leicester LE1 5WW Send response to journal: Re: Clarification of Amount of Early Benefit from Antidepressants	I welcome Tylee and Walters call for further refinement of the onset of action concept. Much of the confusion in this area arises from our categorical measures of outcome (response, remission, recovery, relapse, recurrence) together with infrequent monitoring of patients in trials (2 weeks, 4 weeks, 6 weeks) which miss subtle and cumulative changes in mood. It is important to understand that although definitions of response and remission vary, response (usually defined as a 50% reduction in baseline score) occurs relatively early whereas remission and recovery occur relatively late, and very rarely within 2 weeks. I would however like to correct one area of uncertainty which neither this editorial nor my previous editorial1 makes particularly clear but is likely to cause confusion for readers. The notion that “most benefit is evidence in the first two weeks, not six” may be misleading. This is largely based on the observation in the Posternak and Zimmerman meta-analysis2 from 66 trials of at least 6 weeks duration that 60% of improvement that occurred across all trials within the six week period took place during week 1 and 2. However,  patients continued to improve after six weeks and in longer trials which reflect clinical practice more closely, a substantial amount of improvement occurs after week 2. Thus, although it is accurate to say that more improvement occurs in the first two weeks than in any subsequent two week period, in most clinical situations more improvement occurs from week 3 to the end of treatment than from baseline to week 2. This is perhaps best illustrated by the following table using data from several trials showing a logarithmic improvement of 20% per week, extending to 12 weeks. Note these are simplified mean responses and individual trials and individual patients will vary.  It can be seen that in a typical 12 week trial it takes about 4 additional weeks to bring about the same amount of benefit as seen in weeks 1 & 2 (36%) but most benefit (61%) is seen after week 2. What is clear is that the rate of improvement is highest in the first week, possibly on the first day (this has been poorly studied) and that the notion of a delay in the onset of action is hard to justify.   Table: Typical Antidepressant Responses Week HAM-D Score HAMD-D Change % Overall Change 0 25.00 0.00 0.00 1 20.00 5.00 0.20 2 16.00 4.00 0.16 3 12.80 3.20 0.13 4 10.24 2.56 0.10 5 8.19 2.05 0.08 6 6.55 1.64 0.07 7 5.24 1.31 0.05 8 4.19 1.05 0.04 9 3.36 0.84 0.03 10 2.68 0.67 0.03 11 2.15 0.54 0.02 12 1.72 0.43 0.02 References 1. Mitchell, AJ. Two week delay in onset of action of antidepressants: new evidence. British Journal of Psychiatry 2006; 188: 105-106 2. Posternak, M. A. and Zimmerman, M. (2005) Is there a delay in the antidepressant effect? A meta-analysis. Journal of Clinical Psychiatry, 66, 148-158. Competing interests: None declared
Onset of action of antidepressants - a pain physician's view. 11 May 2007
Dr Peter Thomas, Specialist Registrar in Anaesthetics Wythenshawe,M239LT, Dr Winston F de Mello,Consultant in Anaesthesia and Pain Medicine , Wythenshawe Hospital,University HospitalsTrust, Manchester Send response to journal: Re: Onset of action of antidepressants - a pain physician's view.	We read Professor Tylee’s editorial (1) on the onset of action of antidepressants with great interest. We would like to offer a pain physician’s view on this topic. Amitriptyline is our favourite choice of antidepressant in the pain clinic. We tend to start with 2.5mg to 5 mg orally at 1900 hrs and gently increase the dose to a target range of 10mg to 30 mg over time dependent on the patient’s physical status, co- morbidity, concurrent therapy and the drug side effect experienced. We warn the patients that the benefits are attained over a six to eight week period. In the first two weeks we expect better sleep hygiene, then in the next two weeks improvement in pain relief and in the fourth to sixth week an elevation of mood; all of which are important for a patient with chronic pain. In order to improve compliance we deliberately encourage a six to eight week trail of the highest dose possible without unacceptable side effects for a given patient. If the benefit of antidepressants in chronic pain is evident earlier than what is suggested by conventional wisdom; then instructions to our patient can be suitably modified if confirmed by further research. (1) Tylee A, Walters P. Onset of action of antidepressants.BMJ2007; 334:911-2 Competing interests: None declared