The British Journal of Psychiatry (2009) 194, 483–490. doi: 10.1192/bjp.bp.107.048371 Review article Antidepressant-induced jitteriness/anxiety syndrome: systematic review Lindsey I. Sinclair, David M. Christmas, Sean D. Hood, John P. Potokar, Andrea Robertson, Andrew Isaac, Shrikant Srivastava, David J. Nutt and Simon J. C. Davies Background Early worsening of anxiety, agitation and irritability are these strategies is lacking. There was conflicting and thought to be common among people commencing inconclusive evidence as to whether the emergence of this antidepressants, especially for anxiety disorders. This syndrome had a predictive value on the response to phenomenon, which may be termed jitteriness/anxiety treatment. It appears to be a separate syndrome from syndrome, is cited as an explanation for early treatment akathisia, but evidence for this assertion was limited. failure and caution in using selective serotonin reuptake The effect of jitteriness/anxiety syndrome on suicide rates inhibitors (SSRIs). However, we believe that it is inconsistently has not been evaluated. Three studies examined genetic defined and that robust evidence to support the variations and side-effects from treatment, but none was phenomenon is lacking. specifically designed to assess jitteriness/anxiety syndrome. Aims Conclusions To review systematically all evidence relating to jitteriness/ Jitteriness/anxiety syndrome remains poorly characterised. anxiety syndrome to identify: constituent symptoms; Despite this, clinicians’ perception of this syndrome medications implicated; disorders in which it was reported; influences prescribing and it is cited to support postulated incidence; time course; management strategies; relationship mechanisms of drug action. We recommend systematised of this syndrome to therapeutic response; distinction evaluation of side-effects at earlier time points in between syndrome and akathisia; relationship between antidepressant trials to further elucidate this clinically syndrome and suicide; and genetic predispositions. important syndrome. Method A systematic search identified articles and these were Declaration of interest included in the review if they addressed one of the above There are no direct conflicts of interest relating to any of the aspects of jitteriness/anxiety syndrome. authors and the contents of this work. This study was not commissioned, funded or sponsored by any pharmaceutical Results company or other financial enterprise. Over the past 20 years Of 245 articles identified, 107 articles were included for D.J.N. and his research group (which during the period in review. No validated rating scales for jitteriness/anxiety which the review was designed and conducted has included syndrome were identified. There was no robust evidence S.J.C.D., S.D.H, D.M.C, S.S. A.R. and L.I.S) have received funds that the incidence differed between SSRIs and tricyclic (research grants, speakers fees or consultancy payments) antidepressants, or that there was a higher incidence in from every major pharmaceutical company with an interest anxiety disorders. Published incidence rates varied widely in the psychiatric field. D.J.N. has also received legal fees from 4 to 65% of people commencing antidepressant from companies, medical defence organisations and the treatment. Common treatment strategies for this syndrome British Legal Aid board in relation to court cases regarding included a slower titration of antidepressant and the addition the effects of psychotropic drugs. He holds approximately of benzodiazepines. Conclusive evidence for the efficacy of 300 GlaxoSmithKline shares. Many people starting antidepressants experience transient worsening Method in anxiety, agitation and irritability. Medical literature1–3 and 4,5 guidelines cite this phenomenon, advising caution when Search strategy prescribing selective serotonin reuptake inhibitors (SSRIs), We systematically searched online databases (Medline, PubMed, especially for anxiety disorders. This phenomena is also used to ProQuest and Cochrane) from January 1966 to May 2006 for all support theoretical hypotheses of antidepressant action.6 relevant English language articles. We used the following search However, we believe it remains inconsistently and poorly defined. terms: jitteriness; jitteriness syndrome; activation (syndrome); For consistency in this systematic review we use the term initiation (syndrome) alone as well as in combination with either jitteriness/anxiety syndrome to encompass the range of symptoms SSRI OR serotonin reuptake inhibitor OR tricyclic antidepressant; reported as part of the early antidepressant activation phenomena. drug-induced akathisia; SSRI AND early onset OR psychomotor To clarify the evidence base for jitteriness/anxiety syndrome agitation OR aggression OR hostility OR impulsivity; and TCA/ we systematically reviewed all existing evidence relating to it, tricyclic OR SSRI AND initial AND anxiety. We scrutinised addressing the following questions: what symptoms constitute reference lists for other relevant articles. jitteriness/anxiety syndrome; which medications are implicated; in which disorders has it been reported; what is the incidence; what is the time course; what management strategies are effective; what is the relationship to therapeutic response; what is the Study selection and ranking relationship between this syndrome and akathisia; what is the A total of 245 articles were identified. Abstracts were assessed for relationship between this syndrome and suicide; is there a genetic inclusion by two independent investigators. We expected to find predisposition? limited information; therefore, articles were included from all 483 Downloaded from https://www.cambridge.org/core. 03 Oct 2021 at 21:24:35, subject to the Cambridge Core terms of use. Sinclair et al levels of evidence provided they were judged to address one of the question addressed. Online Table DS2 contains the remaining 41 predefined questions. Examination of the abstracts revealed 138 articles found not to be relevant to any of these questions. were uninformative, often pertaining to different syndromes (usually neonatal jitteriness). Thus 107 articles were assessed for What symptoms constitute jitteriness/anxiety inclusion. Included papers were independently reviewed by two syndrome? investigators (D.M.C. and S.J.C.D.) for relevance to each question in turn. The overall evidence for each question was evaluated with Despite being described almost 30 years ago, no studies were the following scheme using the Oxford Centre of Evidence-based designed to validate a cluster of symptoms that may constitute Medicine Levels of Evidence7: evidence level A consistent grade 1 jitteriness/anxiety syndrome. Therefore, descriptions of the studies; level B consistent grade 2 or 3 studies (or extrapolations syndrome vary and are of evidence level D. Thirteen papers from grade 1 studies); level C grade 4 studies (or extrapolations described jitteriness/anxiety syndrome or activating symptoms. from grade 2 or 3 studies); level D grade 5 evidence or troubling Although symptoms such as insomnia, anxiety, irritability, inconsistencies in evidence. increased energy and restlessness appear in most descriptions Our ranking deviated slightly from the Oxford Centre of (Table 1) consistency is lacking and no symptom is ubiquitous. 8 Evidence-based Medicine Levels of Evidence in the following man- The Food and Drug Administration (FDA) advisory and et al9 ner. Anticipating most articles to be ranked at the lower grades, we subsequent commentary by Culpepper suggest hypomania distinguished case studies and small case series from papers and mania are symptoms of the ‘activation syndrome’. However, consisting entirely of authors’ opinions by ranking single case this approach, based on expert opinion not experimental descriptions and small case series as level 4. Therefore only papers evidence, constitutes a departure from previous literature. et al 10 et al11 et al12 addressing one of our predetermined questions but containing Amsterdam , Ramos and Yeragani devised neither objective evidence nor case descriptions were ranked as scales based on subjective reports to quantify symptom severity. level 5. If papers were relevant for more than one question they None of these scales have been validated or used in subsequent received specific rankings for their utility in answering each research, nor were objective measures incorporated. Therefore, question. Differences between investigators on article ranking we are currently unable to determine a reliable framework for were resolved by direct discussion. Papers addressing jitteriness/ description or quantification of symptoms. anxiety syndrome, but not pertaining to one of the predetermined questions were looked at separately. Which medications are implicated? Evidence from randomised placebo-controlled double-blind trials Results suggests both imipramine and fluoxetine cause jitteriness/anxiety syndrome. Yeragani et al12 performed a randomised controlled Online Table DS1 contains all 66 articles providing evidence trial (RCT) of early side-effects in treating panic disorder and relevant to the questions, with independent rankings for each related this to serum iron levels. Imipramine was significantly Table 1 Contrasting descriptions of constituent symptoms of jitteriness/anxiety syndrome FDA public health Zitrin et al23 Gorman et al17 Pohl et al22 Yeragani et al12 Amsterdam et al10 advisory8 Insomnia Insomnia Insomnia Sleeplessness Insomnia