neurological effects following SSRI discontinuation (PANES).
- Dr Ben Green, MRCPsych,
Psychiatrist, Halton Hospital, UK and Hon. Senior Lecturer, University
of Liverpool, UK
- These prolonged
reactions were first described here in Spring 2000. No other reports are known
of, although this condition may well be more widespread than is presently
- Selective serotonin reuptake
inhibitor (SSRI) discontinuation syndrome has been described in the literature
as a cluster of symptoms and signs that occur after SSRIs such as paroxetine,
sertraline and fluoxetine have been discontinued Abrupt withdrawal of antidepressant
therapy for 5-8 days is associated with symptoms such as dizziness, ataxia,
paraesthesiae, gastrointestinal and flu-like symptoms, and other sensory and
sleep disturbances. Psychiatric symptoms include anxiety, agitation, lability
of mood, hypersexuality, crying spells, behaviour change and irritability.
- The SSRI discontinuation
syndrome appears to be most marked with paroxetine and to a lesser degree
sertraline, with few symptoms seen with fluoxetine (Rosenbaum et al, 1998).
The frequency and severity of these symptoms appear to vary according to the
half-life of the SSRI (Schatzberg et al, 1997). Schatzberg et al comment that
most discontinuation symptoms rare 'short-lived', but that some effects may
be longer lasting.
- Traditional explanations
the pharmacology of SSRIs discuss the effects on the postsynaptic serotonin
receptor, but the SSRIs work at a variety of locations and their effects reverberate
through the nervous and endocrine systems, so that in animal models there
may be altered neuroendocrine function for weeks after ceasing fluoxetine.
Even 60 days after discontinuation of fluoxetine, the oxytocin response in
animals was still significantly reduced by 26% compared with controls.
and dyskinesias of the jaw have presviously been described with SSRIs (Fitzgerald
& Healy, 1995). This report considers four patients on SSRIs who all
suffered prolonged neurological symptoms for months after discontinuing
A. a 29 year old married lady with a moderate depressive disorder was switched
to paroxetine by her general practitioner after an initial prescription of
dothiepin. She had found the tricyclic dothiepin too sedating and after a
week or so of this medication requested a change. After two weeks on paroxetine
20 mg daily she was reviewed by a consultant psychiatrist who increased the
dose to 40 mg daily. The patient suffered a dystonic reaction to the paroxetine
that required physician review and admission, but apparently responded well
to procyclidine. The paroxetine was discontinued. Unfortunately the dystonic
reaction persisted off all medication and required further medical admission
and the re-prescription of procyclidine. The depression continued unabated
and a tricyclic was started with some improvement in mood. Seven months after
the paroxetine had been stopped the tardive dystonia was noted to be present
and to vary with anxiety levels, body posture, alertness, and emotional state.
35-year-old man (Mr B) was prescribed paroxetine 30 mg daily for depression.
The depression resolved and the paroxetine was continued at the same dose
for two years. The medication was discontinued in a staged way, with reductions
to 20, then 10 mg, managed over six weeks or so. Symptoms of withdrawal occurred
throughout this period and comprised vivid nightmares, lability of mood, irritability,
hypersexuality, episodic lightheadedness, episodic electric-shock like sensations,
glove paraesthesiae, and ataxia. These symptoms ended two weeks after the
withdrawal regime was finished. Nevertheless the patient continued to describe
problems of an episodic nature well after the paroxetine had been discontinued.
These episodes lasting hours to days at a time and comprised paraesthesiae,
dizziness, mild ataxia, and slurred speech. These episodes have occurred intermittently
throughout twelve months of follow-up during which time the patient has been
drug-free. There are no focal neurological signs or any features suggestive
of progressive neurological disease, nor was there a family history of neurological
C., a 29-year-old mother of one, became ill with depression when her son was
aged eight months. She was suicidal and required hospital admission where
she was started on fluoxetine 20 mg daily. The antidepressant worked well
and her mood was restored within four weeks of admission. She was discharged
home, but commented that her sleep was occasionally disturbed by bad dreams
and she was aware of twitching in the bed. She was kept on the fluoxetine
for a further twelve months and at outpatient reviews mentioned that her sleep
was still occasionally disturbed by nocturnal twitching. She said that her
husband had started to sleep separately, because he was 'tired of being kicked'
in the middle of the night. The fluoxetine was discontinued eighteen months
after the admission. Mrs C described no worsening of her mood and was euthymic
and outpatient review. However, she was distressed to report that her nocturnal
twitching, which took the form of sudden myoclonic jerks of her limbs, had
actually worsened off fluoxetine. During the day these abnormal involuntary
movements were less marked and more easily disguised, but nonetheless problematic
for the patient. At follow-up eight months after discontinuation the untoward
myoclonic jerks were continuing. There are no focal neurological signs or
any features suggestive of progressive neurological disease, nor was there
a family history of neurological disease.
D., a 49 year old health professional was prescribed 20 mg paroxetine daily
in April 2000 for a depressive disorder. This relieved the depression, but
aftr three months the patient started to develop paresthesiae in the right
hand, and some weeks later experienced her fingers being 'fumbly'. She visited
her GP and complained that although her mood was satisfactory there were unpleasant
side effects. He asked her to reduce the dose to 10 mg daily. Mrs D began
to experience painful, restless legs at night and vivid dreams. The tingling
in her hand spread into her body and head. After a week of the 10 mg dose
the patient discontinued the paroxetine altogether in the belief that the
paroxetine would be out of her system in a few days and her symptoms would
subside. The symptoms however persisted. She took a week off work, but the
following symptoms persisted for the next three months:
in hands and feet spreading up arms and legs intermittently
- stiffness in
on her feet with wide gait
- clumsy fingers
- loose bowels
These symptoms appeared
worst at the end of the day, following heavy physical work,and with even small
amounts of alcohol. By December, four months after discontinuing the paroxetine
most of the symptoms had reduced in severity to near normal.
E., a 48 year old woman was prescribed citalopram by her GP for eleven months.
The indication for the prescription was chronic anxiety. For fifteen months
folowing the discontinuation of this therapy she suffered headaches and dizziness.
She also complained of a fluttering sensation across her scalp. To date there
has been little improvement.
- These five patients all
demonstrated neurological side effects or withdrawal effects that occurred
either during SSRI therapy or in the discontinuation phase associated with
an SSRI. However, these neurological effects persisted for months after
discontinuation and in most cases persist up until the time of writing. Whether
the association with treatment or discontinuation is causal could be debated,
but the chronological association seems good and three of the five patients
(Mr B, Mrs C and Mrs D) were psychotropic drug-na´ve at the start of the SSRI
therapy and wholly drug free following this.
- The three SSRIs prescribed
and mentioned above (fluoxetine, paroxetine and citalopram) differ in terms
of structural and pharmacokinetic properties, but share a relatively selective
ability to affect serotonin re-uptake. Paroxetine and citalopram have a relatively
short half-life and it may be that they are more prone to association withe
discontinuation effects and PANES.
- It may be that this common
ability of the SSRIs (to affect serotonin re-uptake), or an indirect consequence
of this ability is responsible for these persistent adverse neurological effects.
These effects appear to have been first described in this report.
- There is something of
a similarity to the effects seen after benzodiazepine discontinuation (Ashton,
1987). In benzodiazpine witrhdrawal the symptoms occur 1-2 weeks after withdrawal
and may persist to some degree. Th mechanism is thought to be related to GABA-ergic
- Further case reports
and surveillance data are needed to establish the significance or otherwise
of what we propose to be persistent adverse neurological effects of SSRIs
- Dr Ben Green, MRCPsych,
- Consultant Psychiatrist,
Halton Hospital, UK and Hon. Senior Lecturer, University of Liverpool, UK
Ashton, H (1987)Brain systems,
disorders and psychotropic drugs. Oxford, OUP.
Fitzgerald K, Healy, D.
(1995) Dystonias and dyskinesias of the jaw associated with the use of SSRIs.
Human Psychopharmacology, 10, 215-219.
Rosenbaum JF; Fava M; Hoog
SL; Ascroft RC; Krebs WB (1998) Selective serotonin reuptake inhibitor discontinuation
syndrome: a randomized clinical trial [see comments] Biol Psychiatry, 1998 Jul,
- Raap DK; Garcia F; Muma
Na et al. (1999) Sustained desensitization of hypothalamic 5-Hydroxytryptamine1A
receptors after discontinuation of fluoxetine: inhibited neuroendocrine responses
to 8-hydroxy-2-(Dipropylamino)Tetralin in the absence of changes in Gi/o/z
proteins. J Pharmacol Exp Ther, Feb, 288:2, 561-7.
Schatzberg AF; Haddad P;
Kaplan EM et al. (1997) Serotonin reuptake inhibitor discontinuation syndrome:
a hypothetical definition. Discontinuation Consensus panel. J Clin Psychiatry,
1997, 58 Suppl 7:, 5-10
See also Venlafaxine
- long-term adverse effects (2002)
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