Sudden discontinuation of serotonin reuptake inhibitors (SRI) can lead to a number of psychological (e.g., nervousness, anxiety, crying spells, psychomotor agitation, irritability, depersonalization, decreased mood, memory disturbances, confusion, decreased concentration, and/or slowed thinking) and somatic (e.g., nausea, dizziness, headache) symptoms.
Recent studies have shown that withdrawal symptoms are common with paroxetine, venlafaxine and fluvoxamine, but relatively rare and mild with fluoxetine cessation, likely as a result of its longer half-life. We report an unusual case of a patient who developed delirium after abrupt discontinuation of fluoxetine.
1. Introduction
Sudden discontinuation of serotonin reuptake inhibitors (SRI) can lead to a number of psychological (e.g., nervousness, anxiety, crying spells, psychomotor agitation, irritability, depersonalization, decreased mood, memory disturbances, confusion, decreased concentration, and/or slowed thinking) and somatic (e.g., nausea, dizziness, headache) symptoms. The somatic symptoms can be grouped into five clusters: disequilibrium (e.g., dizziness, vertigo, ataxia), gastrointestinal (e.g., nausea and vomiting), sleep disturbances (e.g., insomnia, disturbing dreams, hypnagogic hallucinations), sensory disturbances (e.g., paresthesias, including feeling “electric shocks”), and flu-like symptoms (e.g., rhinorrhea, extreme fatigue, lethargy, myalgia, chills) [1]. This constellation of symptoms has been referred to as the SRI discontinuation syndrome (SRI-DS) when the following diagnostic criteria are met: (1) cessation of the selective serotonin reuptake inhibitor (SSRI) after at least a 1 month period of use, (2) development of symptoms within 1–7 days after the cessation of the SSRI, and (3) presence of clinically significant impairment that cannot be attributed to a general medical condition or recurrence of the underlying mental disorder for which the SRI was originally prescribed [2]. Recent studies have shown that discontinuation symptoms are common with paroxetine, venlafaxine and fluvoxamine, but relatively rare and mild with fluoxetine cessation, likely as a result of its longer half-life [1]. We report an unusual case of SRI-DS in a patient who developed severely debilitating psychiatric symptoms after abrupt discontinuation of fluoxetine.
2. Case report
A 53-year-old cognitively high functioning retired intensive care nurse with a history of secondary progressive multiple sclerosis (MS) self-discontinued her medications except for baclofen because she developed a flu-like illness with fever, headache and diarrhea. For chronic fatigue the patient had been on a daily regimen of fluoxetine 40 mg (for 14 years), modafinil 200 mg and amantadine 200 mg. In addition she took oxybutynin 10 mg three times a day for a spastic bladder, interferon beta injections every other day for multiple sclerosis, and levothyroxine 88 ?g daily for hypothyroidism. She had no history of psychiatric disease or cognitive impairment. Within a few days of stopping her medications, her family noted that she was not herself. She presented to the emergency room 1 week after drug discontinuation with confusion (could not give an accurate history), auditory (hearing her son’s voice who was not there) and visual (seeing her sister who was not there) hallucinations, grandiose delusions (stating: “I am Jesus”) and emotional lability (having uncontrollable crying spells). A psychiatric consultation was obtained and she was given the diagnosis of delirium.
Upon admission, she was continued on her baclofen and restarted on her synthroid. No other medications were restarted on admission. An extensive work-up including laboratory testing of blood, cerebral spinal fluid and a brain MRI, did not support an infectious, metabolic, inflammatory, or autoimmune etiology to her symptoms. During the first 2 days of her hospital stay she had persistent disorientation, depersonalization, and a complaint of extremely vivid dreams. On hospital day 3 we became aware that the patient, until recently, had taken fluoxetine and suspected that she may suffer from SRI-DS. Fluoxetine was reinstated and by the following morning the patient had returned to her baseline mental status and was discharged home. She was seen 3 months later by her primary care physician who noted that the patient was “alert and oriented with linear and goal directed thought processes.” The patient herself reported doing well and she continues to take fluoxetine 40 mg daily.
3. Discussion
This case highlights an unusual presentation of SRI-DS with severely disabling psychiatric symptoms following fluoxetine discontinuation that resolved on reinstitution of the medication. Although symptoms associated with discontinuation of fluoxetine have been described in previous case reports [6] and [7] discontinuation of fluoxetine is believed to be relatively safe causing fewer and less severe symptoms than cessation of SSRIs with shorter half-lives [1]. In fact, two independent double-blind placebo controlled studies examining abrupt discontinuation of fluoxetine found no significant clinical risk associated with its discontinuation [4] and [5].
SRI-DS has been described with all available antidepressant agents, including tricyclic antidepressants (TCAs), monoaminooxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors, and atypical agents (e.g., venlafaxine, duloxetine and mirzatapine) [1]. The rate of SRI-DS varies according to the agent class from 29.4% with TCAs to 32.2% with MAOIs [1]. Within the SSRI class relatively high SRI-DS rates ranging from 42 to 86% have been reported with short acting agents such as paroxetine (T1/2 = 18 h), fluvoxamine (T1/2 = 15 h), and venlafaxine (T1/2 = 5 h), whereas longer-acting agents such as fluoxetine (T1/2 = 84 h, T1/2 active metabolite = 4–16days) and sertralines (T1/2 = 26 h, T1/2 active metabolite = 62–104 h) have lower rates of SRI-DS (0–15%) [1] and [3].
It is possible that certain characteristics made our patient more susceptible to SRI-DS. Multiple sclerosis has been associated with serotonergic neuronal atrophy and thus a relative lack of serotonin at baseline may have made her more vulnerable to the sudden decline of circulating serotonin [8]. Moreover, the simultaneous discontinuation of modafinil, which has been thought to potentiate the effects of SSRIs, may have exacerbated the SRI-DS symptoms [9].
Although the patient’s symptoms are most likely attributable to SRI-DS, alternative etiologies need to be considered. Delirium caused by an MS attack has been described but is unlikely in this case because the MRI of the brain demonstrated no new lesion suggestive of an MS attack. Delirium due to the flu-like illness is unlikely because the patient’s fever and other flu-like symptoms had resolved when she became delirious. Meningitis or encephalitis as a cause of her delirium was excluded based on her normal CSF profile and delirium caused by thyroid dysfunction was ruled out based on normal thyroid function tests. The patient discontinued multiple medications simultaneously, raising the possibility that her condition was caused by withdrawal from a drug other than fluoxetine. This, however, is unlikely as her symptoms resolved with reinstitution of fluoxetine, while none of her other medications were reinstituted.
As with other SSRIs, fluoxetine should be tapered slowly and patients should be counseled on the potential side effects of abrupt discontinuation. Physicians should be aware that fluoxetine discontinuation can lead to a severe SRI-DS with delirium. The early recognition of this syndrome will obviate extensive testing for alternative causes and will lead to effective therapy with reinstitution of the drug.
Keywords: Serotonin reuptake inhibitor; Fluoxetine; Discontinuation syndrome; Psychiatric symptoms; Multiple sclerosis; Delirium; Withdrawal symptoms
Diana Blum, Jose’ Maldonadob, Everett Meyer and Maarten Lansberg
Stanford University, Department of Neurology, 300 Pasteur Drive Stanford, Rm. A343, CA 94305, United States
Stanford University, Department of Psychiatry, 300 Pasteur Drive Stanford, CA 94305, United States
Stanford University Medical School, 300 Pasteur Drive Stanford, CA 94305, United States
Received 3 May 2007; revised 9 August 2007; accepted 18 August 2007. Available online 29 October 2007.
References
[1] M. Fava, Prospective studies of adverse events related to antidepressant discontinuation, J Clin Psychiatry 67 (4) (2006), pp. 14–21.
[2] K. Black, C. Shea and S. Dursun et al., Selective serotonin reuptake inhibitor discontinuation syndrome: proposed diagnostic criteria, J Psychiatry Neurosci 25 (2000), pp. 255–261.
[3] J.F. Rosenbaum, M. Fava and S.L. Hoog et al., Selective serotonin reuptake inhibitor discontinuation syndrome: a randomized clinical trial, Biol Psychiatry 44 (1998), pp. 77–87.
[4] D. Michelson, M. Fava and J. Amsterdam et al., Interruption of selective serotonin reuptake inhibitor treatment. Double-blind, placebo-controlled trial, Br J Psychiatry 176 (2000), pp. 363–368.
[5] J. Zajecka, J. Fawcett and J. Amsterdam et al., Safety of abrupt discontinuation of fluoxetine: a randomized, placebo-controlled study, J Clin Psychopharmacol 18 (1998), pp. 193–197.
[6] E. Einbinder, Fluoxetine withdrawal?, Am J Psychiatry 152 (1995), p. 1235.
[7] J.A. Stoukides and C.A. Stoukides, Extrapyramidal symptoms upon discontinuation of fluoxetine, Am J Psychiatry 148 (1991), p. 1263.
[8] R. Sandyk, Serotonergic neuronal atrophy with synaptic inactivation, not axonal degeneration, are the main hallmarks of multiple sclerosis, Int J Neurosci 95 (1998), pp. 133–140.
[9] L. Ferraro, K. Fuxe and L. Agnati et al., Modafinil enhances the increase of extracellular serotonin levels induced by the antidepressant drugs fluoxetine and imipramine: a dual probe microdialysis study in awake rat, Synapse 55 (2005), pp. 230–241.
