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Parkinsonism associated with a serotonin and noradrenaline reuptake inhibitor, milnacipran
  1. M Arai
  1. Department of Neurology, Seirei Mikatahara General Hospital, Mikatahara-cho 3453, Hamamatsu, Shizuoka 433-8558, Japan
  1. Correspondence to:
 Dr M Arai;

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Milnacipran is a new class of antidepressant, a dual serotonin (5-HT) and noradrenaline (norepinephrine) reuptake inhibitor (SNRI).1 It shows no affinity for neurotransmitter receptors.1 The use of selective serotonin reuptake inhibitor (SSRI) has been associated with the occurrence and worsening of parkinsonism.2,3 However, SNRI induced parkinsonism has not been reported. A case is reported here in which severe parkinsonism occurred in association with the use of milnacipran.

A 83 year old woman was prescribed 200 mg of etidronate disodium once daily, and 0.25 μg of calcitriol for osteoporosis. In July 2001, she was prescribed 15 mg of milnacipran twice daily to alleviate her depressive state. Four months after starting milnacipran, she developed gait disturbance and tremors of the fingers and hands. Her family noticed tilting of her trunk to the left. The gait gradually deteriorated. In December 2001, she became unable to walk unaided. No other medications had been previously prescribed. She was referred to our clinic.

On examination, she was alert. Her face was expressionless, and she spoke in a low voice. Her cranial nerve functions were intact. Barré arm sign was negative. Bradykinesia and plastic rigidity were evident in her four limbs, which showed no obvious laterality. The rigidity was more marked in the proximal musculature. She had resting and postural tremors in the fingers and hands on both sides. Tendon reflexes were normal. Pathological reflexes were negative. The complete blood count, electrolytes, blood urea nitrogen, creatinine, liver function tests, and glucose were normal. Cranial magnetic resonance images demonstrated multiple small infarcts in the thalamus, basal ganglia, and cerebral white matter on both sides.

Because drug induced parkinsonism was suspected, milnacipran was withdrawn. In a few days, she could walk without assistance. Four weeks after withdrawal of the drug, she had slight rigidity and mild bradykinesia. Treatment with 300 mg of L-dopa and 30 mg of carbidopa failed to further improve her motor function. Thus, it was unlikely that she had Parkinson’s disease. A rechallenge procedure with milnacipran was not done, for she was no longer depressive. Because the temporal relation between the ingestion of milnacipran and the occurrence of parkinsonism was so noticeable, it is highly probable that milnacipran caused the severe parkinsonism. Because milnacipran is not metabolised by the hepatic cytochrome P450 system,1 it is unlikely that concurrent use of etidronate disodium and calcitriol affected plasma concentration of milnacipran.

Although several lines of evidence suggest that dopamine release in the striatum is regulated by serotonin, the effects of serotonin and SSRI on dopamine release in the striatum of normal animals are disputed. Some studies have demonstrated that stimulation of the 5-HT(1A) receptors inhibits dopamine release and tyrosine hydroxylation in the striatum. In the striatum of the animals with nigrostriatal dopaminergic denervation, 5-HT(1A) receptor density was upregulated.4 The density of dopamine D2 receptors in the striatum was increased after repeated administration of milnacipran.5 Infarcts in the basal ganglia might have impaired such adaptive changes in the dopaminergic system, rendering the patient susceptible to milnacipran induced parkinsonism. To my knowledge, this is the first reported case of parkinsonism associated with the use of SNRI. Clinicians should be aware that not only SSRI but SNRI can cause severe parkinsonism.


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  • Competing interests: none declared.

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