Antidepressant-induced jitteriness/anxiety syndrome: systematic review

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Abstract

Background

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.

Aims

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.

Method

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

Results

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.

Conclusions

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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Most cited references 32

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Pharmacogenetics of antidepressant medication intolerance.

E. Rodrigues, Declan Murphy, Alan F. Schatzberg … (2003)

The authors sought to identify genetic markers for antidepressant medication intolerance. Genetic variation in drug metabolizing enzymes such as cytochrome P450 2D6 (CYP2D6) has been postulated to underlie antidepressant intolerance (pharmacokinetic effect). However, variation in genes encoding serotonin receptors could also explain antidepressant side effects (pharmacodynamic effect). An 8-week, double-blind, randomized pharmacogenetic study compared the widely prescribed antidepressants paroxetine (a selective serotonin reuptake inhibitor [SSRI]) and mirtazapine (not an SSRI) in 246 elderly patients with major depression. Genotypes were determined for the 102 T/C single nucleotide polymorphism (SNP) in the serotonin 2A (5-HT(2A)) locus (HTR2A), previously associated with psychotropic medication treatment outcome. Oligonucleotide microarrays were used to extensively characterize variation in the CYP2D6 gene. Clinical outcomes included treatment discontinuations, adverse events, medication compliance, and change in mood. Survival analysis showed discontinuations due to paroxetine-induced side effects were strongly associated with the HTR2A C/C genotype. There was a significant linear relationship between the number of C alleles and the probability of discontinuation. Side effect severity in paroxetine-treated patients with the C/C genotype was also greater. In contrast, HTR2A 102 T/C genotype had no effect on mirtazapine side effects. CYP2D6 genotype did not predict treatment outcome for either medication. Pharmacodynamic differences among patients due to variant 5-HT(2A) receptors appear to be more important than pharmacokinetic variation in determining paroxetine intolerance. Pharmacogenetic markers may be useful in predicting antidepressant treatment outcome.

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Systematic review and guide to selection of selective serotonin reuptake inhibitors.

Keith J. Edwards, Kurt I Anderson (1999)

A meta-analysis of 20 short term comparative studies of 5 selective serotonin reuptake inhibitors (SSRIs; citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) has shown no difference in efficacy between individual compounds but a slower onset of action of fluoxetine. There were suggestions that fluoxetine caused more agitation, weight loss and dermatological reactions than the other SSRIs. More patients discontinued fluvoxamine and fewer patients stopped sertraline because of adverse effects than their comparator SSRIs. The most common adverse reactions to the SSRIs were gastrointestinal (especially nausea) and neuropsychiatric (particularly headache and tremor). Data from the Committee on Safety of Medicines showed more reports of suspected reactions (including discontinuation reactions) to paroxetine, and of gastrointestinal reactions to fluvoxamine and paroxetine, than the other SSRIs during their first 2 years of marketing. Prescription-event monitoring revealed a higher incidence of adverse events related to fluvoxamine than its comparators. There were higher incidences of gastrointestinal symptoms, malaise, sedation and tremor during treatment with fluvoxamine and of sedation, tremor, sweating, sexual dysfunction and discontinuation reactions with paroxetine. Fluoxetine was not associated with a higher incidence of suicidal, aggressive and related events than the other SSRIs. Patients have survived large overdoses of each of the compounds, but concern has been expressed over 6 fatalities following overdoses of citalopram. Drug interactions mediated by cytochrome P450 enzymes are theoretically less likely to occur during treatment with citalopram and sertraline, but there is a sparsity of clinical data to support this. Methodological difficulties and price changes do not allow choice for recommendations on the choice of SSRI based on pharmacoeconomic data. Taking into account the strengths and weaknesses of the methods used to compare drugs, guidelines to the selection of individual SSRIs in clinical practice are proposed. Citalopram should be avoided in patients likely to take overdoses. Fluoxetine may not be the drug of first choice for patients in whom a rapid antidepressant effect is important or for those who are agitated, but it may have advantages over other SSRIs in patients who are poorly compliant with treatment and those who have previously had troublesome discontinuation symptoms. Fluvoxamine, and possibly paroxetine, should not be used as first choice in patients especially prone to SSRI-related adverse reactions, while paroxetine should be avoided if previous discontinuation of treatment was troublesome. When in doubt about the risks of drug interactions, citalopram or sertraline should be considered given the lower theoretical risk of interactions.

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Serotonin transporter polymorphisms and adverse effects with fluoxetine treatment.

Stefania Lamon-Fava, Che-Ming Lin, David Mischoulon … (2003)

The short (S) allele of the serotonin transporter gene-linked polymorphic region (5HTTLPR) has been associated with poorer antidepressant response in major depressive disorder (MDD) and with antidepressant-induced mania. This study investigated a possible association with treatment-emergent insomnia or agitation. Thirty-six outpatients with MDD were genotyped at 5HTTLPR and treated with open-label fluoxetine up to 60 mg/day. Treatment-emergent adverse effects were assessed at each study visit. Of nine subjects homozygous for the "S" allele, seven (78%) developed new or worsening insomnia, versus 6 of 27 (22%) non-"S"-homozygous subjects (Fisher's exact p =.005). Similarly, six of nine subjects homozygous for the "S" allele (67%) developed agitation, versus 2 of 27 (7%) of non-"S"-homozygous subjects (Fisher's exact p =.001). The "S" allele of the 5HTTLPR may identify patients at risk for developing insomnia or agitation with fluoxetine treatment. This preliminary result requires confirmation in larger samples.