Published: September 2002

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Agitation, Restlessness and Suicidal Behaviour with Fluoxetine, Paroxetine and Sertraline

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Prescriber Update 23(3): 37-38
September 2002

Professor Pete Ellis, Psychiatrist, Department of Psychological Medicine, Wellington School of Medicine.

There have been rare reports of fluoxetine and, more recently, paroxetine and sertraline being associated with aggressive or suicidal thoughts and behaviour.  Due to similar pharmacological profiles, the same reactions may occur with other selective serotonin re-uptake inhibitors (SSRIs).  It is possible that these reactions can be attributed to akathisia (involuntary severe motor restlessness).  However, the most common reason for self-harm behaviour during treatment with any antidepressant is worsening depression.  The development of severe agitation or self-harm behaviour is an indication that the patient and their antidepressant therapy require prompt review.  Patients should be advised to seek medical attention as soon as possible if they develop agitation or restlessness, or if their depression worsens.

Reports of aggressive and suicidal behaviour with SSRIs investigated

Soon after the introduction of fluoxetine internationally, it was claimed to cause suicidal thinking and behaviour.¹  This allegation was investigated by a number of regulatory agencies, including the Food and Drug Administration in the United States in 1991, and was not substantiated.  More recently, there have been several further case reports, some given media prominence, and some leading to legal proceedings, not only in relation to fluoxetine^2,3 but also to paroxetine and sertraline.^4-6  Systematic reviews continue to support the view that selective serotonin re-uptake inhibitors (SSRIs) are effective and are not associated with increased suicidality or increased violence.⁷  However, these reports^1-6 raise questions about whether the small group of patients experiencing the rare side effect of akathisia are at increased risk of suicide.

Behaviour change may be due to SSRI-induced akathisia

Detailed case reports^1,4 describe the emergence of marked restlessness and agitation, followed by suicidal thinking or behaviour, in patients soon after commencing fluoxetine or other serotonergic agents.  This restlessness and agitation may reflect akathisia (involuntary severe motor restlessness).  Although more commonly associated with antipsychotics, reflecting dopamine receptor blockade, interactions between the serotonergic and dopaminergic systems may account for akathisia also occurring with SSRIs.^8-10  A putative link between akathisia and suicidal behaviour is less clear, and not all of the more recent case reports describe preceding restlessness.^1,4  Older groups of antidepressants have also been associated with increased suicidal thinking and behaviour, although not related to increased restlessness.¹¹

Agitation or harmful behaviour signals need to review both patient and treatment immediately

The key issues in treating depression are the selection of an appropriate treatment in conjunction with the depressed person, and the use of an adequate dose for an adequate length of time, along with attention to current stressors.  The most common reason for suicidal ideation or behaviour during treatment with any antidepressant remains worsening depression.  The development of agitation or self-harm behaviour (from any cause) indicates the need to increase support to ensure the patient's safety, as well as a review of treatment to check that it is optimised for that person.

Informing patients to seek help may help reduce adverse outcomes

As with many medicines, rare serious side effects may emerge during treatment and patients should be aware of these and what action to take.  It is recommended that all patients taking SSRIs should be advised that if they become particularly agitated or restless, they should seek medical advice and stop their antidepressant in the interim.  In addition, any serious worsening of their symptoms, particularly in relation to suicidal thoughts, should be reported urgently to their treating doctor (or on-call colleague).  Severe agitation, severe restlessness/akathisia, and/or increased suicidality with SSRIs have been added as adverse reactions of current concern.

Competing interests (author): the author is supervising a PhD student whose research has been funded by Eli Lilly.  He has accepted invitations from pharmaceutical companies to speak at several meetings relating to prescribing in general, as well as other topics.  He has a beneficial interest in shares of certain pharmaceutical companies, including some who manufacture antidepressants, including SSRIs.

Correspondence to Professor Pete Ellis, Department of Psychological Medicine, Wellington School of Medicine, PO Box 7343, Wellington South. E-mail: ellis@wnmeds.ac.nz

References

1. Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-210.
2. Leon AC, Keller MB, Warshaw MG, et al. Prospective study of fluoxetine treatment and suicidal behavior in affectively ill subjects. Am J Psychiatry 1999;156:195-201.
3. Healy D, Langmaak C, Savage M. Suicide in the course of treatment of depression. J Psychopharmacology 1999;13:94-99.
4. Healy D. Emergence of antidepressant induced suicidality. Primary Care Psychiatry 2000;6:23-28.
5. Jackson A. Two years' jail for anti-depressant killer. Sydney Morning Herald 24 May 2001 www.smh.com.au/news/0105/24/update/news108.html
6. Bosely S. Murder, suicide. A bitter aftertaste for the 'wonder' depression drug. Guardian 11 June 2001 www.guardian.co.uk/Archive?article?0,4273,4201752,00.html
7. Walsh M-T, Dinan TG. Selective serotonin reuptake inhibitors and violence: a review of the available evidence. Acta Psychiatr Scand 2001;104:84-91.
8. Teicher MH, Glod C, Cole JO. Antidepressant drugs and the emergence of suicidal tendencies. Drug Safety 1993;8:186-212.
9. Power AC, Cowen PJ. Fluoxetine and suicidal behaviour. Some clinical and theoretical aspects of a controversy. Br J Psychiatry 1992;161:735-741.
10. Tueth MJ. Revisiting fluoxetine (Prozac) and suicidal preoccupations. J Emergency Med 1994;12:685-687.
11. Macleod AD. Paradoxical responses to antidepressant medications. Ann Clin Psychiatry 1991;3:239-242.