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42-Year-Old Male with Long History of Bipolar Disorder

Don is a 42-year old with an almost 20-year history of bipolar disorder. When diagnosed, he received carbamazepine (600 mg daily) and haloperidol (40 mg daily) to treat a manic episode. He experienced tardive dyskinesia, causing muscle spasms in his neck. His TD symptoms disappeared after discontinuing haloperidol.
The patient experienced another manic episode, successfully treated with haloperidol (6 mg daily) and lithium carbonate.

When Don experienced his third manic episode, he was treated with olanzapine (30 mg daily) combined with lithium carbonate. He developed worsening tardive dyskinesia symptoms.

During the next 7 years, his medical team tried several antipsychotics combined with lithium carbonate to relieve his TD symptoms. No combination helped Don. His tardive dyskinesia assessment score rose to 70.

His clinic introduced clozapine, combined with aripiprazole and lithium carbonate, and gradually increased the clozapine to 250 mg daily. Blood counts were regularly monitored. By the fifth week of treatment, Don’s TD symptoms decreased in severity from 70 to 22.

What mechanisms are in play to produce this patient’s dramatic improvement?
Do the risks of clozapine outweigh the benefits?