Olanzapine is a type of atypical antipsychotic that antagonizes dopamine D1, D2, and D4 receptors for which preclinical trials have already reported a 3 % chance of peripheral edema [1-2]. It also has an antagonistic effect on muscarinic M4, 5HT2c, 5HT6, and 5HT7, histamine H1, serotonin, and α1?noradrenergic receptors it is used for the management of the bipolar affective disorder and schizophrenia [3-5]. The common side effects seen with olanzapine use are sedation, weight gain, and postural hypotension [2]. However, recent research has pronounced some rare cases of peripheral edema with the use of olanzapine [6?8]. Among other atypical antipsychotics, which are found to be associated with peripheral edema in individual cases are risperidone, [9] quetiapine, [10] ziprasidone, [11] amisulpride, [12] paliperidone, [13] and clozapine [14]. Here we've presented a case of a schizophrenia-affected person who showed bilateral pedal edema on therapy with olanzapine.

A 58-year-old female patient reported to the outpatient department with an illness of a total duration of twenty years, which was insidious in onset, with a continuous and progressive course characterized by symptoms of suspiciousness towards others, being fearful, withdrawn behavior, actively avoiding social interaction, poor personal care, and hygiene, and having persistent second person auditory hallucinations. She was evaluated in detail and diagnosed as a patient with schizophrenia. All her baseline investigations were sent and came out to be normal. The patient was drug-naive and was never been a complaint about a single medication in past and was not taking any medications for the last 2 years for the above-mentioned complaints. The patient was started on olanzapine 10 mg per day, which was gradually hiked up to 15mg over the next week. After 4 days of therapy, she started complaining about swelling in bilateral feet and hands, which was equal on both sides and much more prominent in the lower limb. The pedal edema increased with the dose hike. History of hypertension, diabetes mellitus, and substance use had been ruled out. The patient as well as the family members accounted for no change in fluid intake or in dietary habits. She was not on any medication recognized to cause peripheral edema as steroids, nonsteroidal anti?inflammatory drugs, immunosuppressors, or any antihypertensive drugs. On general physical examination, she had severe pitting pedal edema (as shown in figure 1) and mild pitting edema in her hands, primarily based on the classification of severity of edema. Her blood pressure reading was 120/80 mm of Hg. On systemic examination i.e. (abdominal, cardiovascular, respiratory, and CNS examination) no abnormality was detected. A consultation-liaison was taken from the department of General medicine and the department of Cardiology. In assessment, her kidney function test with serum urea and creatinine, serum electrolytes, thyroid function test, liver function test, urine routine, chest X?ray, and electrocardiogram all came out to be normal. For further management, the Olanzapine dose was reduced and furosemide 5 mg was introduced. Within one-week swelling significantly decreased however reappeared after stopping the furosemide. Eventually, olanzapine was stopped in concern of the persistence of edema. Within 6-8 days her swelling decreased significantly and within the next few days it resolved completely but her psychotic symptoms became prominent for which she was then placed on risperidone 2 mg daily and hiked up to 4 mg on which she responded well as her PANSS score decreased from 74 (P=26, N=13, G=35) to 38 (P=13, N=7, G=18). In subsequent follow-up, no episode of edema was accounted. The patient scored 9 on the “Naranjo Adverse Drug Reaction Probability Scale, “suggesting a definite chance of adverse drug reaction. Informed consent from the patient to report this case as well for the image was obtained.

In the above-mentioned case, the edema can be attributed to olanzapine therapy, for the reason that edema resolved on tapering and stopping olanzapine. In our case, Furosemide was added to treat the edema, but it has to be noted that in most of the cases the edema because of Olanzapine was reported to be a self-limiting side effect, and does not require any specific intervention. In literature very few case reports were described accounting for bilateral eyelid edema associated with olanzapine [15]. There are numerous hypotheses were proposed to explain the edema due to olanzapine therapy. The first of them proposed that; the super-sensitivity of α1 receptors occurs when the patient remained non-compliant with the medications or within the drug-free period. When Olanzapine is started in these patients, it blocks α1 receptors which cause vasodilation and lowers vascular resistance which leads increase in permeability causing the edema. However alternative hypothesis accounted for Olanzapine having 5HT-2 receptors blocking property, which in turn leads to a decrease of inositol triphosphate, further resulting in down-regulation of ATP-dependent calcium channel pump, which ultimately causes a decrease in smooth muscle contraction, precipitating vasodilation and edema [16]. Another mechanism was proposed to have a dopaminergic blockade by olanzapine, which alters the renal regulation of fluid and electrolytes, leading to the production of edema [17]. It was observed that there are higher chances of edema with the higher doses of the Olanzapine or Atypical-antipsychotics while decreasing the dose or shifting the patient over long-acting injectables decreased the chances of edema due to smaller peak to trough fluctuations in plasma concentration [18]. It was reported to occur more frequently in females [18]. One study has reported an association of antithyroid antibodies to the Olanzapine-induced edema but it was not replicated in further studies [1]. Other antipsychotics which can cause similar side effect also share a common mechanism and so there is a need for rigorously monitoring the adverse events of this group as a whole.

As in keeping with preceding reviews and our case report, we would really like to conclude that when encountering such patients, one should keep in mind and actively look for any sign of edema when a patient is to be started on Olanzapine. The available literature suggests that this reaction is more frequent at higher doses but can occur at any dose of olanzapine, as noted in our case that despite decreasing the dose edema reappeared and persisted. Because of this nature, a gradual dose increase is advised in patients. However, individual predisposition to adverse effects cannot be negated. Mostly it is a self-limiting side effect, of which time of onset and time of resolution appears to be variable, which can range from 2 days to 2 months. If it is persisted despite stopping the offending agent diuretics can be used but the use of co-medications should be done with caution.

The authors don't have any conflict of interest.

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