Tardive Dystonia Induced by Switch of Atypical Antipsychotics

Tardive dystonia is a troublesome side effect of neuroleptics [12]. The elderly and female patients are at high risk [12]. Atypical anti-psychotics are known to produce fewer extrapyramidal symptoms, nonetheless, several reports show that olanzapine still possesses such a potential [18]. Prior reports of olanzapine-induced tardive dystonia are mostly observed in patients who are either neuroleptic-naïve or have been previously exposed to traditional antipsychotics [2] [3] [4] [6] [7] [8] [15] [16]. We report here a schizophrenic patient who developed tardive dystonia after switching her atypical antipsychotic from amisulpride to olanzapine. The dystonia was successfully resolved by using clozapine instead.

A 51-year-old female with a 20-year history of schizophrenia was regularly taking flupenthixol 9 mg daily for more than 10 years. Her height was 155 cm and her weight was around 54 kg. Her body mass index was 22.47. Due to the development of tardive dyskinesia, flupenthixol was discontinued when she was 49 years old and replaced with amisulpride 600 mg/day. She did not suffer from extrapyramidal side effects while taking amisulpride for one year.

However, at the age of 51 years, amisulpride 600 mg/day was completely switched to olanzapine due to an exacerbation of delusions. After taking olanzapine 20 mg/day for three months, her trunk inclined towards the right. Her score of the extrapyramidal symptom rating scale (ESRS) increased to 7 from 3. Her routine biochemical tests, including thyroid function, were unremarkable. There was no family history of movement disorder. The impression was tardive dystonia and olanzapine was gradually withdrawn and replaced with clozapine, which was increased from 25 mg/day to 150 mg/day over a 6-week period. The dystonia disappeared completely within six months.

One distinctive characteristic observed in this case is that flupenthixol-related tardive dyskinesia is successfully ameliorated by amisulpride. However, truncal dystonia emerged after replacing amisulpride with olanzapine for three months. Various dissociation speeds from dopamine D2 receptors of different anti-psychotics may play an important role in the pathogenesis. Amisulpride is known to possess a faster dissociation speed (K_off<1 min) than flupenthixol, which, apart from its high D2 occupancy (76%), may contribute to a lower D2 blockade to exert an anti-dystonic effect as observed in this patient [9]. Although olanzapine and amisulpride have similar D2 occupancies (74%), human-cloned dopamine D2 receptors release olanzapine at least ten times slower than they release amisulpride [19]. Thus, olanzapine will exert its relatively higher D2 blockade and increase the risk of tardive dystonia [14]. Furthermore, clozapine may exert its superior anti-dystonic effect through several mechanisms: rapid dissociation from D2 receptors (K_off<1 min), lower D2 occupancy (30–60%), marked anticholinergic effect, and high affinity for D1 receptor compared to olanzapine [5] [17] [19].

We might consider another possibility that rapid discontinuation of an antipsychotic with a high D2 affinity may result in the emergence of extrapyramidal symptoms [1]. Both flupenthixol and amisulpride have high D2 affinity, and D2 receptors tend to be up-regulated after lengthy exposure. When olanzapine was introduced, a relatively weak D2 blockade might have down-regulated the D2 receptors, thereby inducing tardive dystonia. However, the dose of olanzapine applied in our case should achieve a high affinity of D2 receptors, which made this assumption implausible [19]. Furthermore, amisulpride has the preferential blockade of effects involving presynaptic D2 mechanisms and limbic structures, which is distinct from that of classical neuroleptics [9] [14] and may contribute to its anti-dystonic effect.

Nonetheless, some studies show that olanzapine can treat tardive dystonia [10] [13]. A higher serotonergic blockade is one contributor that increases the basal activity of dopaminergic neurons, which serves to alleviate dystonia originally induced by D2 receptor antagonism [11]. The built-in anticholinergic activity of olanzapine is another contributor to its antidystonic effects. In this patient, the summation of the effects of slower dissociation of olanzapine from D2 receptors and the lack of pre-synaptic D2 blockade over the limbic area may outweigh its protective effects of serotonergic blockade and anti-cholinergic properties, thereby leading to tardive dystonia.

Since atypical anti-psychotics are increasingly used in schizophrenic patients, we should be aware of their potential extrapyramidal effects, especially when switching from an anti-psychotic with a relatively faster D2 dissociation, such as amisulpride, to an agent with a relatively slower D2 dissociation, such as olanzapine. Lastly, clozapine demonstrates superior efficacy in reducing atypical anti-psychotic-induced tardive dystonia.

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