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Antidepressant-induced jitteriness/anxiety syndrome: systematic review

  • Lindsey I. Sinclair (a1), David M. Christmas (a1), Sean D. Hood (a2), John P. Potokar (a1), Andrea Robertson (a3), Andrew Isaac (a4), Shrikant Srivastava (a1), David J. Nutt (a1) and Simon J. C. Davies (a1)...



Early worsening of anxiety, agitation and irritability are thought to be common among people commencing antidepressants, especially for anxiety disorders. This phenomenon, which may be termed jitteriness/anxiety syndrome, is cited as an explanation for early treatment failure and caution in using selective serotonin reuptake inhibitors (SSRIs). However, we believe that it is inconsistently defined and that robust evidence to support the phenomenon is lacking.


To review systematically all evidence relating to jitteriness/ anxiety syndrome to identify: constituent symptoms; medications implicated; disorders in which it was reported; incidence; time course; management strategies; relationship of this syndrome to therapeutic response; distinction between syndrome and akathisia; relationship between syndrome and suicide; and genetic predispositions.


A systematic search identified articles and these were included in the review if they addressed one of the above aspects of jitteriness/anxiety syndrome.


Of 245 articles identified, 107 articles were included for review. No validated rating scales for jitteriness/anxiety syndrome were identified. There was no robust evidence that the incidence differed between SSRIs and tricyclic antidepressants, or that there was a higher incidence in anxiety disorders. Published incidence rates varied widely from 4 to 65% of people commencing antidepressant treatment. Common treatment strategies for this syndrome included a slower titration of antidepressant and the addition of benzodiazepines. Conclusive evidence for the efficacy of these strategies is lacking. There was conflicting and inconclusive evidence as to whether the emergence of this syndrome had a predictive value on the response to treatment. It appears to be a separate syndrome from akathisia, but evidence for this assertion was limited. The effect of jitteriness/anxiety syndrome on suicide rates has not been evaluated. Three studies examined genetic variations and side-effects from treatment, but none was specifically designed to assess jitteriness/anxiety syndrome.


Jitteriness/anxiety syndrome remains poorly characterised. Despite this, clinicians' perception of this syndrome influences prescribing and it is cited to support postulated mechanisms of drug action. We recommend systematised evaluation of side-effects at earlier time points in antidepressant trials to further elucidate this clinically important syndrome.

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Corresponding author

Simon Davies, Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. Email:


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Declaration of interest

There are no direct conflicts of interest relating to any of the authors and the contents of this work. This study was not commissioned, funded or sponsored by any pharmaceutical company or other financial enterprise. Over the past 20 years D.J.N. and his research group (which during the period in which the review was designed and conducted has included S.J.C.D., S.D.H, D.M.C, S.S. A.R. and L.I.S) have received funds (research grants, speakers fees or consultancy payments) from every major pharmaceutical company with an interest in the psychiatric field. D.J.N. has also received legal fees from companies, medical defence organisations and the British Legal Aid board in relation to court cases regarding the effects of psychotropic drugs. He holds approximately 300 GlaxoSmithKline shares.



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Antidepressant-induced jitteriness/anxiety syndrome: systematic review

  • Lindsey I. Sinclair (a1), David M. Christmas (a1), Sean D. Hood (a2), John P. Potokar (a1), Andrea Robertson (a3), Andrew Isaac (a4), Shrikant Srivastava (a1), David J. Nutt (a1) and Simon J. C. Davies (a1)...


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Antidepressant-induced jitteriness/anxiety syndrome: systematic review

  • Lindsey I. Sinclair (a1), David M. Christmas (a1), Sean D. Hood (a2), John P. Potokar (a1), Andrea Robertson (a3), Andrew Isaac (a4), Shrikant Srivastava (a1), David J. Nutt (a1) and Simon J. C. Davies (a1)...
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Systematic Review Vs Narrative Review.

Vivek Agarwal, Specialty Registrar
01 July 2009

We would like to first thank Sinclair and colleagues(1), for bringingthe information on this important topic together in a coherent narrative. At the risk of contradicting our first statement, we felt that there was an attempt in this review to answer too many questions, so then, "Is it really a systematic review?"

According to Trisha Greenhalgh(2), the first two essential elements of a systematic review are - a precisely defined question and a thorough search that includes foreign language literature.

The paper begins with a clear statement of its aim, but this is followed by a list of questions, which makes the scope of this venture toobroad to be described as a systematic review. It may be more appropriate, then, to call it a narrative review.

Cook et al(3) have clearly distinguished between these two types of integrative research approaches.

A systematic review is produced to answer a specific and narrow clinical question, explores comprehensive sources with an explicit search strategy, employs a uniformly applied selection process and there is rigorous critical appraisal of all selected studies. There is usually a quantitative summary in the end.

A narrative review, on the other hand, often, is very broad in scope,the search and selection process may not be explicit leaving room for potential bias, critical appraisal may be variable and the result is a qualitative summary.

On reading the paper in detail, we felt that it has features of both types of reviews. We would like to leave it up to the readers to decide whether they feel it is a systematic review, which is not quite systematicor to call it a narrative review, which has been done robustly.

1. Sinclair L, Christmas DM, Hood SD, Potokar JP, Robertson A, Isaac A, Srivastava S, Nutt DJ, and Davies SJC. Antidepressant-induced jitteriness/anxiety syndrome: systematic review. The British Journal of Psychiatry 2009; 194: 483-490

2. Greenhalgh T. How to read a paper: Papers that summarise other papers (systematic reviews and meta-analyses). British Medical Journal 1997; 315: 672-675

3. Cook DJ, Mulrow CD and Haynes RB. Systematic Reviews: Synthesis ofBest Evidence for Clinical Decisions. Annals of Internal Medicine 1997; 126: 376-380
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