Serotonin Syndrome after Discontinuation of Olanzapine in a Combined Treatment with Duloxetine – Case Report H. Himmighoffen, E. Seifritz, H. Boeker Hospital for Affective Disorders and General Psychiatry Zurich East, Center for Affective and Anxiety Disorders, University of Zurich, Zurich, Switzerland Combinations of serotonergic antidepressants and atypical antipsychotics and higher doses of antidepressants are common strategies in the management of treatment-resistant depression. This approach is associated with an increased risk of adverse drug interactions. We report on a patient who was treated with high-dose duloxetine in combination with olanzapine and developed a serotonin syndrome after withdrawal of olanzapine. Previous studies suggest that the activation of 5HT-2A receptors in the brain contribute to the pathophysiology of serotonin syndrome. Olanzapine, like many other atypical antipsychotics, shows a high affinity and occupancy of 5HT-2A receptors, blocking postsynaptic serotonergic action. Therefore, discontinuation of olanzapine in a patient on a high-dose SSRI or SNRI may precipitate a serotonin syndrome. We hypothesize that a serotonin syndrome may be prevented by olanzapine co-administration.
Introduction ▼ Combinations of serotonergic antidepressants and atypical antipsychotics [1, 2] and higher doses of antidepressants [2] are common strategies in the management of treatment-resistant depression. This approach increases the risk of adverse drug interactions. Here, we report on a patient who was treated with the selective serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine in a higher dose combined with the atypical antipsychotic olanzapine.
Case Report ▼ Mrs. M. is a 60-year-old woman with a recurrent depressive disorder. Her current episode was severe without psychotic symptoms (ICD-10 F33.2) and treatment-resistant, i. e., she had already received more than 2 different antidepressants in adequate doses including mianserin, sertraline, venlafaxine, and bupropion plus a trial of intravenous administration of tricyclic antidepressants (clomipramin/maprotiline) and also several other therapeutic attempts including sleep deprivation therapy, augmentation with lithium (showing no positive effects), additional use of antipsychotics (quetiapine and olanzapine) and most recently a series of electroconvulsive therapy (ECT), which showed a temporary improvement but no lasting positive effects and subsequently a deterioration. She then received a combination of duloxetine (120 mg/d), olanzapine (5 mg/d) and zolpidem (12.5 mg/d) over 4 months and was transferred to our specialized day clinic for affective disorders. Only partially remitted,
she repeatedly experienced deteriorations to her mental and physical condition throughout the course of treatment. She also suffered from a comorbid anxiety disorder, fibromyalgia and chronic neuropathic pain. In the further course of treatment, olanzapine was increased up to 10 mg/d without positive effects. As there were no positive effects and also a weight gain of 20 kg in the 4 months of taking olanzapine, it was decided to taper and stop olanzapine. On day 1 olanzapine was reduced to 5 mg/d while at the same time lorazepam up to 3 mg/d was added and pregabalin started with 25 mg/d. On day 25 olanzapine was further reduced to 2.5 mg/d while pregabalin had been increased up to 100 mg/d and lorazepam reduced to 2.5 mg/d. Mrs. M. showed distinct improvement concerning her pain and anxiety, followed by an improvement in her mood state. On day 34 olanzapine was stopped. On day 41 pregabalin was increased to 150 mg/d while lorazepam could subsequently be reduced stepwise to 1.5 mg/d on day 46. Duloxetine (120 mg/d) and zolpidem (12.5 mg/d) were maintained throughout. On day 49, exactly 15 days after olanzapine had been stopped, Mrs. M. began complaining of the following symptoms: sweating, nausea, diarrhoea and tachypnoea without fever, followed by uneasiness, disturbed sleep, muscle aches and cramps, anxiety and frightening thoughts that “she could go crazy”. She also reported possible delirious symptoms: She said she had seen “a bathtub in a bathroom with glass marbles on the floor”. Clinically, she was fully oriented and conscious. However, she suffered from agitation, akathisia, hypertension ( > 170/100 mmHg), a moderate tremor in her hands and arms as well as a generalized hyperreflexia. The clinical examination showed no spontaneous myoclonus but an inducible ankle clonus. Laboratory tests showed normal electrolytes, liver enzymes, renal parameters, CRP and CBC. The patient was diagnosed clinically with a serotonin syndrome. The diagnosis was made by a psychiatrist with significant clinical experience with serotonin syndrome and well-grounded clinical experience in neurology and internal medicine and according to Sternbach’s criteria [3] and the Hunter serotonin toxicity criteria [4]. The diagnosis was additionally supported by an elevated blood level of duloxetine of 426 nmol/L (67–270 nmol/l) [5]; the level of pregabalin was 9 μmol/L (13–75 μmol/L). The patient had never had a serotonin syndrome under other serotonergic drugs before. Immediate therapeutic actions included a reduction of duloxetine from 120 to 60 mg/d and a higher dose of lorazepam (3 mg/d). The patient showed a significant improvement of the symptoms the following day, and within 3 days they had disappeared completely.
Discussion ▼ The symptoms presented by this patient were consistent with the diagnosis of serotonin syndrome meeting Sternbach’s criteria [3] and the Hunter serotonin toxicity criteria [4]. One criterion demanded by Sternbach [3] for the diagnosis of a serotonin syndrome was not fulfilled: Duloxetine had not been recently introduced or increased as it was already being taken in a higher dose over a period of 4 months. Case reports of serotonin syndrome, induced by duloxetine alone or in combination with other drugs, have been reported in the literature [6–8]. However, to the best of our knowledge, this is the first case report of serotonin syndrome occurring upon withdrawal of olanzapine, a serotonin (5HT-2A) receptor antagonist, in co-medication with the SNRI duloxetine.
Himmighoffen H et al. Serotonin Syndrome after Discontinuation … Pharmacopsychiatry 2011; 44: 75–76
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Declaration of Interest ▼ Holger Himmighoffen and Erich Seifritz report no competing interests. Heinz Boeker has received financial support from Eli Lilly for carrying out a neuroimaging study in depression.
13 Haslett CD, Kumar S. Can olanzapine be implicated in causing serotonin syndrome? Psychiatry Clin Neurosci 2002; 56: 533–535 14 Isbister GF, Downes F, Whyte IM. Olanzapine and serotonin toxicity. Psych Clin Neurosci 2003; 57 15 Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999; 60 (suppl 10): 5–14 16 Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors: Focus on newer generation compounds. Life Sci 2000; 68: 29–39 17 Boddy R, Ali R, Dowsett R. Use of sublingual olanzapine in serotonin syndrome (abstract). Clin Toxicol 2004; 42: 725 received revised accepted
02.07.2010 06.09.2010 01.10.2010
Bibliography DOI http://dx.doi.org/ 10.1055/s-0030-1268420 Published online ahead of print: 15 December 2010 Pharmacopsychiatry 2011; 44: 75–76 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence H. Himmighoffen, MD Hospital for Affective Disorders and General Psychiatry Zurich East Center for Affective and Anxiety Disorders University of Zurich Lenggstraße 31 P.O. Box 1931 8032 Zurich Switzerland Tel.: + 41/44/384 2364 Fax: + 41/44/383 4456 holger.himmighoff
[email protected]
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Himmighoffen H et al. Serotonin Syndrome after Discontinuation … Pharmacopsychiatry 2011; 44: 75–76
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We believe that it is particularly important to be aware of the increased risk of occurrence of the serotonin syndrome in patients receiving multiple medications and higher-dose serotonergic medications. Accurate diagnostic decision rules have been developed to improve the making of a correct diagnosis [3–5]. However, serotonin syndromes remain underreported and are frequently misdiagnosed [9, 10]. Previous studies suggest that the activation of 5HT-2A receptors in the brain stem and spinal cord contributes to the pathophysiology of serotonin syndrome [3, 4, 11]. 2 reports in the literature implicate olanzapine therapy itself in causing a serotonin syndrome [12, 13]. However, both of these patients were taking multiple serotonergic medications that could have caused the serotonin syndrome [14]. Olanzapine shows a high affinity and occupancy of 5HT-2A receptors, blocking postsynaptic serotonergic action [15, 16]. Thus, it should be considered that serotonin syndrome can emerge upon discontinuation of an atypical antipsychotic without SNRI or SSRI dose change. We also hypothesize that serotonin syndrome may be prevented by olanzapine, which upon discontinuation becomes manifest. This hypothesis is supported by a case report in which sublingual olanzapine was used successfully to treat serotonin syndrome [17]. This could also explain why our patient only developed serotonin syndrome 4 months after receiving duloxetine when olanzapine was stopped and not after a recent introduction or increment of duloxetine, as she additionally received olanzapine when duloxetine was introduced and increased.
