Download Antidepressant-induced jitteriness/anxiety syndrome

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
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.
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.
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.
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.
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
Many people starting antidepressants experience transient worsening
in anxiety, agitation and irritability. Medical literature1–3 and
guidelines4,5 cite this phenomenon, advising caution when
prescribing selective serotonin reuptake inhibitors (SSRIs),
especially for anxiety disorders. This phenomena is also used to
support theoretical hypotheses of antidepressant action.6
However, we believe it remains inconsistently and poorly defined.
For consistency in this systematic review we use the term
jitteriness/anxiety syndrome to encompass the range of symptoms
reported as part of the early antidepressant activation phenomena.
To clarify the evidence base for jitteriness/anxiety syndrome
we systematically reviewed all existing evidence relating to it,
addressing the following questions: what symptoms constitute
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
relationship between this syndrome and akathisia; what is the
relationship between this syndrome and suicide; is there a genetic
predisposition?
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.
Method
Search strategy
We systematically searched online databases (Medline, PubMed,
ProQuest and Cochrane) from January 1966 to May 2006 for all
relevant English language articles. We used the following search
terms: jitteriness; jitteriness syndrome; activation (syndrome);
initiation (syndrome) alone as well as in combination with either
SSRI OR serotonin reuptake inhibitor OR tricyclic antidepressant;
drug-induced akathisia; SSRI AND early onset OR psychomotor
agitation OR aggression OR hostility OR impulsivity; and TCA/
tricyclic OR SSRI AND initial AND anxiety. We scrutinised
reference lists for other relevant articles.
Study selection and ranking
A total of 245 articles were identified. Abstracts were assessed for
inclusion by two independent investigators. We expected to find
limited information; therefore, articles were included from all
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Sinclair et al
levels of evidence provided they were judged to address one of the
predefined questions. Examination of the abstracts revealed 138
were uninformative, often pertaining to different syndromes
(usually neonatal jitteriness). Thus 107 articles were assessed for
inclusion. Included papers were independently reviewed by two
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
the following scheme using the Oxford Centre of Evidence-based
Medicine Levels of Evidence7: evidence level A consistent grade 1
studies; level B consistent grade 2 or 3 studies (or extrapolations
from grade 1 studies); level C grade 4 studies (or extrapolations
from grade 2 or 3 studies); level D grade 5 evidence or troubling
inconsistencies in evidence.
Our ranking deviated slightly from the Oxford Centre of
Evidence-based Medicine Levels of Evidence in the following manner. Anticipating most articles to be ranked at the lower grades, we
distinguished case studies and small case series from papers
consisting entirely of authors’ opinions by ranking single case
descriptions and small case series as level 4. Therefore only papers
addressing one of our predetermined questions but containing
neither objective evidence nor case descriptions were ranked as
level 5. If papers were relevant for more than one question they
received specific rankings for their utility in answering each
question. Differences between investigators on article ranking
were resolved by direct discussion. Papers addressing jitteriness/
anxiety syndrome, but not pertaining to one of the predetermined
questions were looked at separately.
Results
Online Table DS1 contains all 66 articles providing evidence
relevant to the questions, with independent rankings for each
Table 1
question addressed. Online Table DS2 contains the remaining 41
articles found not to be relevant to any of these questions.
What symptoms constitute jitteriness/anxiety
syndrome?
Despite being described almost 30 years ago, no studies were
designed to validate a cluster of symptoms that may constitute
jitteriness/anxiety syndrome. Therefore, descriptions of the
syndrome vary and are of evidence level D. Thirteen papers
described jitteriness/anxiety syndrome or activating symptoms.
Although symptoms such as insomnia, anxiety, irritability,
increased energy and restlessness appear in most descriptions
(Table 1) consistency is lacking and no symptom is ubiquitous.
The Food and Drug Administration (FDA) advisory8 and
subsequent commentary by Culpepper et al 9 suggest hypomania
and mania are symptoms of the ‘activation syndrome’. However,
this approach, based on expert opinion not experimental
evidence, constitutes a departure from previous literature.
Amsterdam et al,10 Ramos et al11 and Yeragani et al12 devised
scales based on subjective reports to quantify symptom severity.
None of these scales have been validated or used in subsequent
research, nor were objective measures incorporated. Therefore,
we are currently unable to determine a reliable framework for
description or quantification of symptoms.
Which medications are implicated?
Evidence from randomised placebo-controlled double-blind trials
suggests both imipramine and fluoxetine cause jitteriness/anxiety
syndrome. Yeragani et al12 performed a randomised controlled
trial (RCT) of early side-effects in treating panic disorder and
related this to serum iron levels. Imipramine was significantly
Contrasting descriptions of constituent symptoms of jitteriness/anxiety syndrome
Zitrin et al23
Gorman et al17
Pohl et al22
Yeragani et al12
Insomnia
Insomnia
Insomnia
Sleeplessness
Jitteriness
Jitteriness
Jitteriness
Jitteriness
Irritability
Irritability
Unusual energy
Increased energy
Amsterdam et al10
Insomnia
Irritability
Irritability, hostility
Overanxious,
Nervousness
Anxiety
Feeling euphoric,
increased energy
Increased anxiety
More severe panic attacks
Restlessness
Motor restlessness
FDA public health
advisory8
Panic attacks
Restlessness plus inability
to remain still over five
domains (at all, legs, lying,
standing, sitting)
Restlessness/
fidgetiness
Akathisia
‘Amphetamine speedlike response’
Trembling
Feeling on edge
Agitation
Shakiness
Inner shakiness
Agitation
Anticipating the worst
Unable to relax
Easily startled
Impulsivity
Diarrhoea
Palpitations
Limb sensations
Hypomania, mania
FDA, Food and Drug Administration.
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Antidepressant-induced jitteriness/anxiety syndrome
more likely to cause symptoms of jitteriness/anxiety syndrome
(Table 1) than placebo or diazepam. Limitations are small
numbers (n = 52) and unknown randomisation or concealment
measures.
Beasley et al13 analysed data from a double-blind RCT
(n = 706) of fluoxetine (up to 80 mg/day) v. imipramine (up to
300 mg/day) and placebo. The primary aim was to examine
efficacy of fluoxetine in treating depression and not to detect
jitteriness/anxiety syndrome. However, participants were
reviewed weekly to assess for symptoms of the syndrome
(agitation, anxiety, nervousness, insomnia), which were recorded
only if new or they had worsened from baseline. They reported
significantly greater symptoms of the syndrome with fluoxetine
(28%) compared with placebo (17%). There was a non-significant
trend linking imipramine to more symptoms of jitteriness/anxiety
syndrome than placebo. Treatment discontinuations because of the
syndrome symptoms were: fluoxetine (5%), imipramine (5%)
and placebo (0%), a statistically significant difference for both
medications compared with placebo.
Beasley et al14 subsequently examined pooled data (total
n = 746) from three RCTs involving fluoxetine in depression.
The primary focus of these trials was to examine efficacy of
differing fluoxetine doses. Symptoms of jitteriness/anxiety
syndrome (agitation, anxiety, nervousness, insomnia) were
recorded weekly only if they were new or worsened during
treatment. The trial employing lower daily doses (5, 20, 40 mg)
reported statistically significant increases in jitteriness/anxiety
syndrome symptoms for 5 and 20 mg, but not 40 mg compared
with placebo. The two trials employing higher doses found a
statistically significant increase of jitteriness/anxiety syndrome
symptoms in the 40 and 60 mg groups but not the 20 mg group.
The authors’ opinion of a dose–response relationship between
fluoxetine and activation, through increased activation at the
highest doses, is open to debate – the trial incorporating 60 mg/
day dosing had the highest placebo response and is contradicted
by the inverse dose–response of the low-dose trial.
Toni et al’s naturalistic open study of 326 people with panic
disorder over 3 years examined jitteriness/anxiety syndrome
incidences with tricyclics (imipramine or clomipramine) and
paroxetine.2 Symptoms occurred in 16% of those on tricyclics
and 7% of those on paroxetine. Limitations included high dropout rates, selection bias (participants previously developing
jitteriness on tricyclics received paroxetine), a lack of masking,
operationalised definition of jitteriness/anxiety syndrome and
placebo comparison.
Harada et al completed a retrospective case-note survey of
people prescribed antidepressants looking specifically for
jitteriness/anxiety syndrome symptoms in the FDA Public Health
Advisory report8 (Table 1), in the first 3 months of treatment.15
Paroxetine, fluvoxamine, milnacipran, amoxapine, clomipramine
and mianserin were implicated in producing jitteriness/anxiety
syndrome symptoms. However, activation required only one
symptom following treatment, with no baseline reference point.
Information was obtained from case notes, introducing various
biases. Therefore, it is unclear if symptoms were accurately
ascertained and whether antidepressant medication was associated.
Further evidence has chiefly implicated fluoxetine10,16–20 and
imipramine.21–26 There is also evidence for jitteriness/anxiety
syndrome with other tricyclics (clomipramine,11,27,28 dothiepin
(dosulepin)26 and desipramine,22 other SSRIs (sertraline (on dose
titration rather than initiation)29 and paroxetine)30,31and the
5-HT1A agonist buspirone,32 although less frequently than with
imipramine.33
Tollefson et al examined data from the US investigational new
drug database.34 New emergence or worsening of item 9 of the
Hamilton Rating Scale for Depression (HRSD) on psychomotor
agitation, as a surrogate marker for jitteriness/anxiety syndrome,
was compared across 31 placebo or comparator (tricyclic)
controlled trials of fluoxetine treating depression. They found
no significant difference between incidences of worsening
psychomotor agitation between fluoxetine, tricyclics or placebo.
However, most participants reported psychomotor agitation at
entry and the HRSD item 9 may have been unable to detect
changes. Other papers have reported no excess in jitteriness/
anxiety syndrome symptoms on reboxetine35 or sertraline36
compared with placebo.
Few studies have compared jitteriness/anxiety syndrome
incidence between antidepressants. Harada et al15 found no
relation between antidepressant class and jitteriness/anxiety
syndrome incidence. Beasley et al13 found no difference between
fluoxetine and imipramine, and Tollefson & Sayler34 found none
between fluoxetine and tricyclics. Pohl et al22 suggested that there
may be a greater risk with desipramine than imipramine, but
small numbers were studied.
There is most evidence that imipramine and fluoxetine can
cause jitteriness/anxiety syndrome. However, for both drugs
evidence is contradicted by a minority of studies (level D).
Evidence implicating other antidepressants is less abundant (level
D). There is little robust evidence comparing rates of jitteriness/
anxiety syndrome between different antidepressants (level D).
In which disorders has jitteriness/anxiety syndrome
been reported?
Considering panic disorder with and without agoraphobia,
Yeragani et al12 found significantly increased rates of jitteriness/
anxiety syndrome with imipramine compared with diazepam or
placebo in an RCT in panic disorder. Lower rated evidence
derives from naturalistic studies,2 retrospective side-effect
studies,25 case series,21 single-blind trials11,27 and a double-blind
trial with limited evaluation or comparison of jitteriness/anxiety
syndrome symptoms.23
Regarding jitteriness/anxiety syndrome in major depression,
Beasley et al13 found significantly more symptoms in fluoxetinetreated participants with depression compared with placebo in
an RCT (described above). Further evidence in SSRI-treated
individuals with depression is provided by Beasley et al14 and
Hu et al.37 Stahl et al35 found no significant difference between
reboxetine and placebo in a summary of nine RCTs in treating
people with depression but reboxetine has not been associated
with jitteriness/anxiety syndrome in other disorders. Tollefson et
al34 also found no difference in agitation scores (taken from item
9 of the HRSD) between fluoxetine (20 mg) and placebo-treated
groups of people with depression in their analysis of RCT data.
These varying conclusions could be explained by a number of
factors including differing methodologies (e.g. definitions of
jitteriness/anxiety syndrome), differing medications and using
data for purposes which it was not originally intended.
Less evidence exists for jitteriness/anxiety syndrome in other
disorders. There is one retrospective analysis of RCT data in
obsessive–compulsive disorder,28 one case report in generalised
anxiety disorder,32 a report of two cases in social phobia24 and
in a double-blind trial with limited evaluation of jitteriness/
anxiety syndrome in agoraphobia, simple and mixed phobias.23
Harada et al15 found no correlation with diagnosis of an
anxiety disorder or major depressive disorder and jitteriness/
anxiety syndrome incidence. They did find some positive
correlation between ‘tendency of Axis II diagnosis’ (with
abnormalities in any one of cognition, affectivity, interpersonal
functioning and impulse control) and the syndrome.
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Sinclair et al
In summary, there is most evidence that jitteriness/anxiety
syndrome occurs in people with panic disorder (evidence level
C). The evidence in major depression is contradictory (level D)
and there is very little evidence beyond case reports that
jitteriness/anxiety syndrome exists in obsessive–compulsive disorder, generalised anxiety disorder, social phobia and mixed or
simple phobias (level D). No papers directly compared the rates
of the syndrome between disorders.
What is the incidence of jitteriness/anxiety
syndrome?
Published incidences of jitteriness/anxiety syndrome vary
considerably (4–65%), through differing criteria for jitteriness/
anxiety syndrome ‘caseness’, differing methods and times of
collecting data and variations between cultures, disorders and
medications implicated. Table 2 illustrates rates for each study
where this could be calculated. Thus, predictions of incidence
are at evidence level D.
Is there a known time course of jitteriness/anxiety
syndrome?
Available evidence suggests jitteriness/anxiety syndrome has an
early onset, but whether symptoms persist is unclear. From
prescription event monitoring Edwards & Anderson39 determined
rates of symptoms for the first 2 months treatment with the SSRIs
paroxetine, fluoxetine and fluvoxamine (Table 3). Although this
methodology may be associated with underreporting, adverse
events reported in the first month were greater for agitation,
anxiety, hyperactivity and irritability for all three drugs, suggesting
either remission of jitteriness/anxiety syndrome symptoms or
excess treatment cessation among those affected. Only hypomania
was increased in the second month, suggesting its aetiology may
derive from a different mechanism to the main jitteriness/anxiety
syndrome symptoms. Thus the contention of the FDA8 that hypomania and mania are components of jitteriness/anxiety syndrome
requires further consideration. Ramos et al11 found a short-lived
5–6 day syndrome with first day onset in an uncontrolled trial
of imipramine in panic disorder. Yeragani et al12 reported
jitteriness symptoms peaking in week one and diminishing
following week two. Aronson21 found a short-lived 3–13 day
syndrome in panic disorder. Five of seven participants developing
jitteriness/anxiety syndrome had no symptoms by week eight.
Beasley et al14 calculated rates of symptoms by week from RCT
data. Onset was in the first week, but persisted beyond the endpoint (week six). Hu et al37 conducted a retrospective telephone
survey of patients taking SSRIs for over 3 months, assessing if
side-effects began within 2 weeks and whether these persisted
beyond 3 months. High rates of insomnia (64%) and anxiety
(71%) were found in the first 2 weeks. Both symptoms persisted
with high prevalence at 3 months (56% and 49% respectively).
Table 2
Incidences of jitteriness/anxiety syndrome by paper
Level of
Incidence of jitteriness/anxiety syndrome evidence
Paper
Ackerman et al28 Clomipramine, 3%
Fluoxetine, 4%
4
Amsterdam et al10 33%
4
Aronson21
32%
4
Beasley et al13
Fluoxetine: any, 28% (discontinuation, 5%) 4
Imipramine: any, 21% (discontinuation, 5%)
Placebo: any, 17% (discontinuation, 1%)
Gorman et al17
35%
4
Harada15
4%
4
Hu et al37
Any, 19% (bothersome, 11%)
4
Lotufo-Neto et al27 5%
4
Louie et al18
26%
4
Noyes et al25
20%
4
Perlis et al19
Activation, 21%
Anxiety, 15%
4
Pohl et al22
27%
4
Pohl et al36
0%
4
Pohl et al33
Imipramine, 45%
Buspirone, 17%
4
Ramos et al11
27%
3B
Stahl et al35
Reboxetine: agitation, 4% (anxiety, 2%)
Placebo: agitation, 4% (anxiety, 4%)
No significant difference between groups
3B
Tollefson
& Sayler34
Fluoxetine: any worse, 29% (substantially
worse, 3%) v. placebo: any worse, 31%
(substantially worse, 4%)
Fluoxetine: any worse, 33% (substantially
worse, 7%) v. tricyclic antidepressants:
any worse, 29% (substantially worse, 6%)
No significant group difference
2B
Toni et al2
Tricyclic antidepressants, 16%
Paroxetine, 7%
2C
Yeragani et al12
44%
3B
Zajecka et al38
11%
3B
Zitrin et al23
18%
4
There is some evidence that jitteriness/anxiety syndrome has
an early onset in the first 2 weeks (evidence level C). There is
limited and contradictory evidence regarding persistence of the
syndrome (level D).
What is the relationship between jitteriness/anxiety
syndrome and therapeutic response?
Reports conflict on whether jitteriness/anxiety syndrome predicts
therapeutic response. Ackerman et al28 performed a retrospective
data analysis of two RCTs (fluoxetine and clomipramine in
obsessive–compulsive disorder) calculating risk ratios to
determine whether early side-effects and demographic variables
Table 3 Prescription event monitoring data: incidence (per 1000 individuals) for selected adverse events in the first month of
treatment compared with month 2 39
Fluoxetine
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Fluvoxamine
Paroxetine
Month 1
Month 2
Month 1
Month 2
Month 1
Month 2
Agitation
5.9
1.6
9.3
2.0
5.0
1.9
Anxiety
8.3
3.6
9.1
2.9
4.3
1.5
Hyperactivity
1.1
0.0
0.1
0.0
0.5
0.1
Irritability
0.6
0.4
0.1
0.8
0.5
0.1
Mania/hypomania
0.2
0.9
0.1
0.6
0.5
0.4
Antidepressant-induced jitteriness/anxiety syndrome
predicted outcome. Early nervousness predicted small increases in
response to both clomipramine and fluoxetine. However, this was
relatively rare and most responders did not experience it.
However, other reports suggest jitteriness/anxiety syndrome
predicts a poor outcome. Gorman et al17 noted that no people
developing jitteriness/anxiety syndrome responded to fluoxetine
for panic disorder in a small uncontrolled study. Pohl et al22
reported individuals with panic disorder who developed the
syndrome tolerated significantly less medication and a nonsignificant trend towards poorer response, but no significant
interaction regarding dose of medication.
Jitteriness/anxiety syndrome has been linked to early treatment
discontinuation. Noyes et al25 cite ‘overstimulation’ as the main early
side-effect causing treatment cessation (7 of 19 in the first 6 weeks)
in their retrospective follow-up of panic disorder. Aronson21 found
13 participants dropped out because of intolerable symptoms in a
naturalistic trial of 60 people. Neither of these trials had placebo
or comparator drugs. Zitrin et al23 alluded to a subgroup developing
the syndrome who could not tolerate therapeutic doses of imipramine, but nevertheless improved on lower doses. No data were
presented to verify this assertion.
There is conflicting evidence that jitteriness/anxiety syndrome
predicts either an improved or poorer prognosis (level D). Limited
evidence suggests people with panic disorder with the syndrome
may tolerate only lower doses of tricyclic antidepressants without
affecting outcome (level D). There is little evidence that it causes
treatment cessation (level D).
Which management strategies are effective for
jitteriness/anxiety syndrome?
Four management strategies were found for jitteriness/anxiety
syndrome: initial slow titration from low doses of antidepressant,
augmentation with benzodiazepines and symptomatic treatment
with antipsychotics or beta-blockers.
In an open trial using alprazolam to treat those individuals
developing the syndrome on fluoxetine, Amsterdam et al10
reported that it significantly reduced symptoms. However, biases
are inherent in the open design and the possibility of spontaneous
remission of the syndrome. Use of low initial doses and slow
titration of antidepressants to prevent side-effects has not been
evaluated specifically for jitteriness/anxiety syndrome. In an
RCT, Pohl et al36 investigated efficacy of sertraline in panic
disorder. The syndrome was no more frequent with sertraline than
with placebo. The authors believed this was through the low initial
starting dose (25 mg/day), but the trial was not designed to assess
this. Giesecke16 reported an individual with panic disorder
developing jitteriness/anxiety syndrome on fluoxetine, managed
successfully by reducing the dose to 1 mg/day and titrating up
slowly over several months.
Pohl et al,26 described two individuals with jitteriness/anxiety
syndrome treated successfully with low doses of perphenazine.
Lipinski et al40 described five individuals with fluoxetine-induced
akathisia, reported to be indistinguishable from jitteriness/anxiety
syndrome. All improved with the addition of the beta-blocker
propanolol. Evidence levels for either starting at a low dose of
antidepressant, early augmentation with a benzodiazepine,
symptomatic treatment with antipsychotics or beta-blockers are
all low (level D).
What is the relationship of jitteriness/anxiety
syndrome to akathisia?
No studies were designed to address the relationship between
jitteriness/anxiety syndrome and akathisia. Harada et al’s15
retrospective study (described earlier) specifically looked for
akathisia as part of their definition of jitteriness/anxiety syndrome.
Of 31 individuals developing the syndrome, none had akathisia.
Pohl et al26 described two individuals with the syndrome
responding to phenothiazines, which exacerbate akathisia.
Lipinski et al40 reported five people with fluoxetine-induced
akathisia, which the authors believed indistinguishable from
jitteriness/anxiety syndrome. Further case reports made no
attempt to determine whether jitteriness/anxiety syndrome was
distinct from akathisia.41 Overall, the little evidence that exists
suggests jitteriness/anxiety syndrome is a separate entity from
akathisia (level D).
What is the relationship between jitteriness/anxiety
syndrome and suicide?
Tollefson et al42 performed a retrospective data analysis of 17
RCTs, comparing rates of suicidality (a suicidal act or ideation)
and examining the temporal relation with defined side-effects,
including activation. They found no significant relationship
between activating side-effects and suicidality, nor any significant
differences in rates of suicidality between the groups (fluoxetine,
tricyclic and placebo). All data were gathered retrospectively from
studies not designed to test this hypothesis, using measures such
as item 3 of the HRSD to obtain information on suicidal ideation
and adverse event data for suicidal acts. This may not give a
complete or generalisable picture of events. During these trials it
is not known whether a disproportionately high number of people
developing the syndrome dropped out early, obscuring any
relationship between suicidality and the syndrome.
Hammad pooled results from RCTs using SSRIs and atypical
antidepressants (venlafaxine, nefazodone, mirtazapine and
buproprion) in the treatment of children and adolescents. He
calculated the relative risk of suicidality (suicidal ideation, acts
or possible suicidal behaviour) between active arms and placebo.
He found significantly increased relative risks of suicidality if
symptoms of activation were present.43 Again, caution is needed
interpreting these results because of the post hoc analysis and
multiple outcomes from data analysis in which jitteriness/anxiety
syndrome and suicidality were not primary outcomes.
Subsequent to our initial search a further relevant study has
been published. Perlis et al19 found a significant association
between treatment-emergent agitation and emergent suicidal
ideation, defined by item 3 of the HRSD, using trial data. Again,
the study was not designed to assess rates of jitteriness/anxiety
syndrome or suicidal ideation. It was an open, uncontrolled trial
with no information on temporal relationships between
emergence of suicidal ideation and activation. Suicidal ideation
also related to worsening mood and it is unclear whether
activation represented a genuine side-effect or a worsening general
clinical picture. Remaining evidence on jitteriness/anxiety
syndrome and suicidality is limited to case reports.44 As yet there
is no direct evidence to support an association of the syndrome
and completed suicide, and currently only limited evidence to
support the hypothesis that its symptoms are associated with
greater suicidal acts or ideation (evidence level D).
Is there a genetic predisposition to jitteriness/anxiety
syndrome?
Three studies examined genetic bases of agitation and motor
activity as adverse events in antidepressant treatment, but there
is no published work specific to genetic predispositions for
jitteriness/anxiety syndrome.
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Sinclair et al
Putzhammer et al45 studied the 5-HTT (serotonin transporter)
polymorphism in major depression, reporting LL homozygous
carriers that were treated with SSRIs formed a distinct group
having significantly higher night-time motor activity (compared
with SS or SL) measured by actigraphy on day 5. These individuals
had a trend towards greater movements during the day on the
movement and activation scale, but no other symptoms pertaining
to jitteriness/anxiety syndrome were addressed. In contrast to
Putzhammer, Perlis et al46 found that SS homozygous carriers
had significantly more insomnia, agitation and a poorer response
to treatment. Murphy et al47 studied the 5-HT2A receptor gene
reporting that a single nucleotide polymorphism (T/C) had a
significant impact on paroxetine side-effect and discontinuation
rates (with no effect in a parallel mirtazapine treated group).
Patients with the CC genotype had more frequent and severe
adverse events and poorer adherence than other individuals. At
present there is little evidence to link jitteriness/anxiety syndrome
symptoms to known genetic polymorphisms (level D).
Discussion
In this systematic review we identified and examined all available
scientific evidence relating to our predetermined questions on
jitteriness/anxiety syndrome, finding a total of 107 relevant
papers. A different approach that could be adopted in future
would be to scrutinise systematically all RCTs of antidepressants
for symptoms and symptom clusters developing early in
treatment. The fact that there are no validated, or commonly used,
measures for jitteriness/anxiety syndrome highlights how little
objective evidence there is pertaining to it. Indeed, the terms
commonly used such as ‘jitteriness’ and ‘activation syndrome’
are ill-defined and require clarification. Nevertheless, jitteriness/
anxiety syndrome is frequently discussed in clinical guidelines4,5
and used to substantiate theories on neurotransmitter function.5,6
This presents a problem for the clinician, the psychopharmacologist
and for any systematic review. How can the evidence for a
syndrome that has not been clearly defined be reviewed with
accuracy? Many papers reviewed could have been measuring
phenomena irrelevant to jitteriness/anxiety syndrome. The lack
of objective measures of activation, such as actigraphy,
compounds this problem.
For consistency, we started from the contemporary viewpoint
that jitteriness/anxiety syndrome exists,5 typically causes an
anxiety-like overactivity state,8,23 starts early in antidepressant
treatment23 and has short duration.12 In deciding whether
individual symptoms also constituted jitteriness/anxiety syndrome,
we took the view that measuring a symptom cluster was preferable,
but would accept individual symptoms if they fitted into the classical
descriptions of the syndrome (such as worsened anxiety, restlessness,
etc.) and were described as commencing in the first weeks of
treatment. This approach risks comparing different entities when
comparing different papers, but allowed examination of the largest
breadth of evidence. From this working definition, many antidepressant trials are likely to overlook jitteriness/anxiety syndrome;
they usually start to measure symptoms and side-effects after a
few weeks’ treatment.
Although most reports of jitteriness/anxiety syndrome occur
with imipramine and fluoxetine, there is no good evidence that
it is more common in one drug than another. The fact that most
reports relate to these drugs may be as a result of genuine
pharmacological properties, that these drugs are or were
previously the recommended medication for certain diagnoses
or just the most commonly used medication in their classes.
It is often suggested that jitteriness/ anxiety syndrome is
488
predominantly a side-effect of SSRIs. However, after much
research interest in the 1980s, the association of the syndrome
with tricyclics is now rarely discussed. Similarly with the SSRIs,
after considerable interest in this syndrome following their
introduction, there has been a decline in reporting as clinicians
became more experienced with them. However, rather than being
forgotten, jitteriness/anxiety syndrome continues to influence
clinical guidelines on SSRIs despite the limited robust evidence.
Trends in reporting have undoubtedly affected the evidence
available.48 Publication and reporting bias are issues that could
not be examined here and their effect is unclear, whether overreporting of positive cases when interest is high or underreporting
by industry.
Jitteriness/anxiety syndrome was first described in individuals
with panic disorder taking tricyclic antidepressants and thought to
be confined to panic disorder or a clinical picture involving panic
attacks.22,49 It may be that the perceived emphasis on the
syndrome in panic disorder reflects reporting and research trends
rather than any susceptibility conferred by panic. There is as much
evidence that this syndrome occurs in major depression as other
non-panic anxiety disorders.
Estimations of the incidence of jitteriness/anxiety syndrome
vary widely. This may be as a result of factors addressed here, such
as disorder treated and medication prescribed. Methodological
differences will account for some of the variation. Examples would
be: differing criteria for ‘caseness’ (including individual symptoms
v. syndrome); variations in monitoring methods and times;
different populations; and cultural variations. However, much of
the variation may be as a result of the poor-quality data available.
Most of the studies that looked for a jitteriness/anxiety syndrome
were not generalisable to patient populations as a whole, or were
retrospective using methods open to bias such as case-note
reviews or telephone interviews. Studies that could yield robust
rates for the syndrome, large RCTs, often do not assess individuals
until 2 weeks have elapsed. Adverse effects are then usually
obtained by ‘non-probing’ questions, which although having
merits, may not identify a syndrome beginning and subsiding
within the first week. It would therefore be advantageous for the
identification of all early side-effects to assess people earlier in
trials.
Available evidence supports the theory that this syndrome
appears early in treatment, perhaps in the first week. This evidence
is however weak. It is unclear how long jitteriness/anxiety
syndrome persists. Some studies, especially those examining panic
disorder, have found a short-acting syndrome.11,12,21 Others
examining persistent side-effects in depression report jitteriness/
anxiety syndrome symptoms persisting for several months.37
There is no clear evidence of a syndromic difference with respect
to differing disorders. It is more likely that methodological
differences between studies account for this. Our own search
strategy, acknowledging the current opinion that jitteriness/
anxiety syndrome is an early side-effect and therefore including
papers that look for early side-effects may have introduced biases.
However, to review all side-effects occurring throughout
treatment would have broadened the scope of this review to the
point that our results would not reflect the issue in hand, the
delineation of jitteriness/anxiety syndrome.
Despite being regularly discussed in reviews on anxiety
disorders5,50–52 and being common practice, evidence for a slow
titration of antidepressant or benzodiazepine augmentation is
poor. Without valid instruments to quantify symptom severity,
prospective studies have to rely upon a reduction in the incidence
of this syndrome per se as an end-point. A further problem in
studying the management of symptoms is the presumed short
natural time course, such that any decrease in symptoms may
Antidepressant-induced jitteriness/anxiety syndrome
be as a result of the natural resolution of the syndrome. Studies
researching this question in future will require a placebo control.
Surprisingly, no study has determined whether patient education
affects perceived severity of jitteriness/anxiety syndrome or
associated discontinuation rates. This may impact upon
persistence with medication if people are aware of the syndrome,
its benign nature and short time course.
The question of whether jitteriness/anxiety syndrome is a
prognostic factor for the response to medication remains
unanswered. It is possible jitteriness/anxiety syndrome has
different consequences in different disorders, but this has not been
studied. The current consensus that the syndrome affects
treatment outcomes by increasing discontinuation has little
evidence to support it despite face validity. The possibility that
people who continue treatment despite developing jitteriness/
anxiety syndrome may achieve better treatment efficacy than those
not developing the syndrome has still to be elucidated.
Despite the paucity of evidence addressing the issue of
whether jitteriness/anxiety syndrome and antidepressant-induced
akathisia are similar entities, this subject has generated some
interest. Indeed, we found four reviews53–56 addressing
antidepressant-induced akathisia (to varying degrees) which
outnumbers the number of papers providing evidence,15,26,40
totalling seven cases and one retrospective case-note survey. This
is important as both antidepressant-induced akathisia and
jitteriness/anxiety syndrome are postulated to be drivers for
the disputed theory that suicide rates increase early on in
antidepressant treatment.8,9,44
No studies have addressed whether jitteriness/anxiety syndrome
is related to completed suicide. This is not surprising given the rarity
of completed suicide and difficulty defining jitteriness/anxiety
syndrome. For suicidality, two of three studies identified suggested
an association but had clear methodological limitations. Despite
this, the FDA Public Health Advisory issued a warning in 2004
stating jitteriness/anxiety syndrome-like symptoms may be related
to suicidality early in treatment. The medications listed were
SSRIs, buproprion, venlafaxine and mirtazapine. There was no
mention of tricyclic antidepressants despite the evidence of their
association with the syndrome being comparable with that for
SSRIs. Debate whether SSRIs induce an early increase in suicide
rates is ongoing and not one covered by this review. However,
there is a need to evaluate evidence objectively before comment,
given the high media profile of this issue. There is also some
perception among people that such an association could exist.
For example, the 2004 UK Committee on Safety of Medicines
Working Group on safety of SSRIs included a summary of
questionnaire responses from people on paroxetine following a
BBC documentary.57 Suicidal ideas ‘in the first few days’ were
reported by 8 of 38 respondents who provided information on
the time course of events, although this data is prone to
considerable selection and recall bias. Currently the presence of
jitteriness/anxiety syndrome cannot be said to affect suicide rates
or suicidality by itself, although more robust evidence may emerge
if the syndrome is measured prospectively in large cohorts
prescribed antidepressants.
If the hypothesis that variations in brain receptors and
enzymes confer differing susceptibility to diseases is correct, then
it follows that the same variations may well affect response to
medications, including side-effects. However, it is likely that these
effects will be spread across interactions of several genes and may
vary with other environmental factors and epigenetic phenomena.
These factors possibly contributed to the contradictory findings of
Putzhammer et al45 and Perlis et al46 about which alleles of the
5-HT transporter gene conferred greatest risk for increased
movement and agitation when treated with SSRIs.
Mechanisms
What are the mechanisms underlying jitteriness/anxiety
syndrome? Many hypotheses exist but the most likely explanation
is that the syndrome is caused by the increase in 5-HT function
that SSRIs and other antidepressant drugs produce, which may
impact on key postsynaptic receptors. Elevation in anxiety acutely
after SSRIs and other serotonin-promoting agents can be seen in
preclinical models and this can be blocked by antagonists of
5-HT-2 receptors.58 It would be interesting to examine in future
research whether drugs acting as antagonists at this receptor, such
as the antidepressant mirtazapine or the atypical antipsychotic
olanzapine, would attenuate the jitteriness/anxiety syndrome in
humans.
Implications
Robust evidence regarding the aspects of jitteriness/anxiety
syndrome we examined does not exist, in contrast with the
prominence and influence the syndrome has in prescribing
guidelines and clinical practice. This provides a mandate for
further research into jitteriness/anxiety syndrome. In particular
it is unclear which factors (e.g. diagnosis, medication class or
genetics) are associated with increased risk. Neither are the
ramifications of the syndrome clear, but poor adherence, nonresponse or indeed improved response are possible outcomes.
We advocate further specific research into this clinically important
area, leading both to a better understanding of the neurochemistry
of antidepressants and to improved patient care.
Lindsey I. Sinclair, MBBS, David M. Christmas, MB, ChB, Psychopharmacology
Unit, University of Bristol, UK; Sean D. Hood, MBBS, School of Psychiatry & Clinical
Neurosciences (M521), The University of Western Australia, Perth, Australia;
John P. Potokar, MD, Psychopharmacology Unit, University of Bristol, UK;
Andrea Robertson, MB, ChB, Edinburgh (NHS) Community Health Partnership,
Edinburgh, UK; Andrew Isaac, MBBS, Warwickshire (NHS) Primary Care Trust,
Warwick, UK; Shrikant Srivastava, MD, David J. Nutt, DM, Simon J. C. Davies,
DM, Psychopharmacology Unit, University of Bristol, UK.
Correspondence: Simon Davies, Psychopharmacology Unit, University of
Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK.
Email: [email protected]
First received 19 Dec 2007, final revision 12 Sep 2008, accepted 5 Dec 2008
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4: 399–408.
Type of paper
RCT
RCT
RCT
RCT
RCT
RCT
RCT
RCT data analysis
RCT data analysis
RCT data analysis
RCT data analysis
RCT data analysis
RCT data analysis
RCT data analysis
Cohort
Cohort
Cohort
Cohort
Retrospective cohort
Retrospective cohort
Case–control
Murphy et al47
Oehrberg et al30
Pohl et al33
Pohl et al36
Yeragani et al12
Zajecka et al38
Zitrin et al23
Ackerman et al28
Beasley et al14
Beasley et al13
Hammad43
Stahl et al35
Tollefson & Sayler34
Tollefson et al42
Akiskal et al59
Perlis et al46
Putzhammer et al45
Noyes et al25
Harada15
Schneier et al20
Juurlink et al60
5
5
4
4
4
4
4
4
4
4
4
4
4
4
4
2B
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
2B
3B
4
4
4
4
3B
3B
4
4
Symptoms Medications Disorders Incidence
Papers with relevance to defined questions
Paper
Table DS1
4
4
4
4
4
3B
5
4
4
5
4
5
Timing Management Response
Level of evidence
4
Akathisia
5
5
4
4
4
4
5
Suicide Genetics
Comments
Comment in discussion regarding JAS and suicide
Case-note review of uncontrolled cohort of
individuals. JAS not primary outcome
Case-note review of uncontrolled cohort. Subject to
reporting and recording biases
Case-note and telephone follow-up. Not masked, no
control, subject to reporting and recall bias
Confounded by use of benzodiazepines on those
with early side-effects. Unclear if actigraphy is true
measure of JAS
Unclear if side-effects elicited relate to JAS
Opinion in discussion, conceptualising JAS as mixed
affective state affecting suicide rate
Analysis of 17 RCTs data. Primary outcome of trials
not JAS
31 RCTs. Used item 9 of HRDS as proxy measure
of agitation
Data analysis of 9 RCTs. Finding JAS not primary
outcome
Analysis of RCT data. Primary outcome of original
trials not JAS
Post hoc analysis of side-effect data from RCT.
JAS not primary outcome of original trials
Post hoc analysis of side-effect data from 3 RCTs.
JAS not primary outcome of original trials.
Retrospective data analysis from 2 RCTs, JAS not
primary outcome of original trials. Drop-out data not
included
No systematic rating of side-effects. No betweengroup comparisons of JAS
JAS not primary outcome for original trials. Unable to
compare early and late side-effects as groups differ
JAS primary outcome. Small numbers per group
JAS not primary outcome
JAS not primary outcome of trial. No systematic
evaluation of JAS
JAS not primary outcome of trial. No systematic
assessment of JAS
Describes mechanisms of drug intolerance but does
not directly address JAS
n
1138
25
729
107
62
36
254
3065
4737
–
4555
706
746
520
111
299
52
168
60
120
246
The British Journal of Psychiatry (2009)
194, 483–489. doi: 10.1192/bjp.bp.107.048371
Data supplement
1
2
Uncontrolled trial
Uncontrolled trial
Uncontrolled trial
(data analysis)
Uncontrolled trial
(data analysis)
Naturalistic open
study
Prescribing database
study
Survey
Case series
Case series
Case series
Case series
Ramos et al11
Gorman et al17
Louie et al18
Perlis et al19
Toni et al2
Mark et al61
Hu et al37
Pohl et al22
Jackson & Lydiard24
Aronson21
Pohl et al26
Case series
Case series
Case series
Case study
Case
Case
Case
Case
Case
Case
Clinical guideline
Clinical guidelines
Regulatory body
advice
Liegghio et al32
Lipinski et al40
Zubenko et al63
Giesecke16
Eberstein et al64
Guile29
Hansen65
Olivera66
Vorstman et al44
Yeragani et al67
NICE4
Baldwin et al5
FDA8
Girischandra et al
Case series
Uncontrolled trial
62
Uncontrolled trial
Amsterdam et al
Lotufo-Neto et al27
Type of paper
(continued)
10
Paper
Table DS1
5
4
4
4
5
5
4
5
4
5
5
5
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
5
5
5
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
2C
4
4
4
3B
4
4
Symptoms Medications Disorders Incidence
4
4
4
3B
4
4
4
4
5
5
4
5
4
4
Timing Management Response
Level of evidence
5
5
5
5
4
5
4
Akathisia
5
4
4
Suicide Genetics
Expert opinion
JAS not based upon systematic review
Clinical guideline
Case not described, therefore opinion only
Case of JAS-like symptoms with suicidal ideation
Descibes akathisia. No attempt to compare with JAS
SSRI-induced akathisia. No attempt to compare with
JAS
1 case, JAS symptoms on dose increase
No attempt to distinguish JAS and akathisia
Case describing JAS and its management
Cases of akathisia. No discussion regarding JAS
SSRI-induced akathisia compared with JAS
Case reports of buspirone-induced JAS
Antidepressant-induced akathisia, no attempt to
compare with JAS
Description of cases
No structured assessment for JAS. JAS not primary
outcome of trial. Non-masked, protocol altered as
trial progressed
Describes 2 cases of JAS
No masking of assessors. Participants to recording
bias. Non-consecutive cases
Telephone survey. Participants to recall bias
Numerous assumptions regarding prescriptions
No systematic evaluation for JAS. Differential treatment of participants
Based on open uncontrolled trial, JAS not primary
outcome. Proxy measures of outcomes
Unmasked, uncontrolled study. Late assessment of
side-effects (recall bias)
Non-controlled trial. Non-consecutive recruitment.
Protocol changed during trial
Non-consecutive sample. Single blind. No comparator
treatment
Single blind. JAS not primary outcome. No control
group
No control group. Good monitoring of symptoms
Comments
–
–
–
–
1
1
1
1
1
1
5
5
4
2
2
60
2
180
401
326
830
133
20
70
82
54
n
3
5
Review
Review
Review
Review
Nutt71
Rey & Martin72
Sachdev & Kruk56
Scott et al52
5
Review
Westenberg3
5
5
5
5
5
5
5
5
5
4
5
5
4
5
5
5
5
5
5
5
5
5
5
Timing Management Response
Level of evidence
5
5
5
5
5
5
Akathisia
RCT, randomised controlled trial; JAS, jitteriness/anxiety syndrome; NICE, National Institute for Health and Clinical Excellence; FDA, Food and Drug Administration.
5
5
Review
Westenberg et al49
5
5
5
Walkup & Labellarte73 Review
5
Review
Lydiard et al70
5
Review
Liebowitz & Klein50
5
Review
5
Review
Edwards & Anderson39 Review
5
Lane53
Review
Culpepper et al9
5
Goodman et al69
Review
Balon48
Review
4
Review
Argyropoulos et al51
5
Ener et al55
5
Review
Alexander68
5
Symptoms Medications Disorders Incidence
Type of paper
Opinion
Yeragani et al54
(continued)
Paper
Table DS1
5
5
5
5
Suicide Genetics
Comments
Expert opinion
Expert opinion
Expert opinion
Expert opinion
No objective data, descriptive review
Discussion on JAS and suicidal behaviour in
adolescents
Expert opinion
Review
Expert opinion
Review paper regarding pathophysiology of JAS
Theroretical discussion regarding JAS driving suicide
Expert opinion focused on biological causes of
akathisia and JAS
Uses Committee on Safety of Medicine data of
medication side-effects
Expert opinion
Expert opinion
Expert opinion
Expert opinion
Expert opinion. No empirical data
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
n
Table DS2
Papers reviewed but not found to contribute to evidence base for the above questions
Paper
Type of paper/study
Aguglia et al74
RCT. JAS not assessed. Differential use of benzodiazepines
Akagi & Kumar41
Case series
Bagdy et al58
Preclinical data
Bakker et al75
Meta-analysis
Baldwin & Birtwistle76
Review
Beasley et al77
Meta-analysis regarding suicide
Beasley et al78
Duplicate data
Beasley et al79
Duplicate data
Bennett et al80
Review
Blomhoff et al81
RCT
Bordet et al82
RCT
Burghardt et al83
Experiment using rat subjects
Charney & Heninger84
Open trial of intravenous tryptophan
Cheung et al 85
Review
Cowley et al 86
Case–control study
Damluji & Ferguson87
4 cases
De Wilde et al 88
RCT nil regarding JAS
Den Boer & Westenberg89
RCT
Gibbons et al 90
Cohort study
Gregor et al91
Database analysis
Griest et al92
Meta-analysis
Gunnell et al 93
Meta-analysis
Hall & Lucke94
Review
Healy & Whitaker95
Review
Healy96
Review
Khan et al 97
Review
King et al 98
Case series
Liebowitz et al 99
RCT
Musa & Staneluis100
Retrospective data analysis of 2 RCTs
Patris et al 101
RCT, nil regarding JAS
Roy-Byrne et al 102
Cohort trial follow-up of medications taken by panic disorder participants
Sheehan & Harnett-Sheehan1
Review
Simon et al 103
Cohort
Slaap et al 104
Open trial
Slaap et al 105
Pooled data of 2 RCTs
Smith et al 106
Nil regarding JAS
Stein et al 107
Review
Tiihonen et al 108
Cohort study
Toni et al 109
Duplicate data
Volkers et al 110
Open trial
Wade et al 111
RCT
RCT, randomised controlled trial; JAS, jitteriness/anxiety syndrome.
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5
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
BJP 2009, 194:483-490.
Access the most recent version at DOI: 10.1192/bjp.bp.107.048371
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