The first patient to receive olanzapine: A recollection

Olanzapine was approved for general use in patients with schizophrenia 25 years ago, in September 1996: however, the first patient to receive it did so in December 1988, by participating in a safety and dose‐finding study of an experimental compound, then designated LY170053, developed by the Eli Lilly pharmaceutical company at its neuroscience research centre in Erl Wood, Surrey. Awareness of the superior efficacy of clozapine when compared to other antipsychotic drugs had encouraged the search for related compounds which might preserve its efficacy and the reduced burden of extrapyramidal adverse effects, whilst avoiding tolerability problems such as weight gain and the risks of neutropenia and agranulocytosis. LY170053 had a marked molecular resemblance to clozapine, possessed somewhat similar pharmacological properties (Bymaster et al., 1996), and its administration produced effects in experimental animals like those seen with antipsychotic drugs (Moore et al., 1992), indicating that an initial investigation in patients was warranted. But pre‐clinical studies had suggested potential hepatoxicity, and the dosage for exerting possible antipsychotic effects in patients remained uncertain: such an investigation would necessarily involve exclusion of patients with any evidence of hepatic disease or dysfunction, and careful monitoring of liver function tests at baseline and during dosage escalation, whilst assessing any treatment effects on positive and negative features of schizophrenia. Dominic was in his early twenties when he arrived in London to labour on a building site. He soon missed his distant family, found it hard to banter with his robust workmates, became troubled by persecutory delusions and auditory hallucinations, and neglected his basic needs. He may have experienced something similar a few years before coming to England but was not able to recall having ever undergone psychotropic drug treatment. He knew he was unwell and readily consented to participate in the study. As baseline blood tests proved unremarkable, he started medication at the initial dosage of 10 mg/day, expecting twice‐weekly increases according to a pre‐ determined protocol, to a maximum of 120 mg/day over four weeks, with a potential two‐week extension. All went well, at first, although the ward pharmacist and nursing staff found it hard to dispense and offer a tablet called ‘LY170053’, referring to it informally as ‘lillazapine’. Delusions lessened in intensity in the second week of treatment, hallucinations become less frequent, and his appetite increased: but on Day 19, when the study medication dosage was 30 mg/day, he said he felt weak and sluggish: “I just don't feel right, doc”. Levels of ALT and AST enzymes were both greater than 2.5 times the upper limit of normal, and an ESR was raised. Treatment was stopped and hepatic enzymes returned to within normal limits within a week. He was switched to what was then conventional antipsychotic treatment (chlorpromazine) and improved further, leaving hospital to return to his family home. Based on the experience of this first patient, the study protocol was amended, with a lower starting dose and reduced pace and extent of dose escalation, and the maximal dose in remaining participants was 20 mg/day. No further patients were withdrawn because of tolerability concerns. LY170053 administration was associated with antipsychotic effects (median scores on the Comprehensive Psychopathological Rating Scale diminished from 44 at Baseline to 10 at Week 4) and the severity of extrapyramidal features also reduced: but three further patients had emergent abnormal liver function test results, and prolactin levels were found to be elevated in two patients at Week 4. These adverse effects caused worries about the potential balance of risk and benefit, but there was sufficient evidence to support further studies using a randomised placebo‐controlled design (Baldwin & Montgomery, 1995). These studies demonstrated that the medication then named olanzapine was efficacious in treating patients experiencing acute episodes of schizophrenia and in preventing relapse. Eli Lilly received regulatory approval in the United States and Europe and the drug swiftly became a ‘blockbuster’ medicine. Although liver function tests were found to be elevated in between 8% and 27% of patients undergoing olanzapine treatment (Tollefson et al., 1997), sporadic case reports of liver dysfunction (Jadallah et al., 2003; Ozcanli et al., 2006; Raz et al., 2001; Tchernikovsky & Sirota, 2004) were not followed by more reliable evidence of substantial hepatotoxicity. Additional indications for treating patients with acute manic episodes and in the prevention of relapse in bipolar disorder were secured through ‘product life‐cycle management’ and olanzapine is included within and BAP and NICE guidelines for schizophrenia and bipolar disorder. Undoubtedly, many thousands have benefited greatly from olanzapine treatment: but patients and clinicians gradually became aware of troublesome adverse effects during olanzapine and other antipsychotic treatment such as weight gain and metabolic syndrome with its attendant risk of type II diabetes mellitus (De Hert et al., 2012), and some of the initial promise of olanzapine and other ‘second generation antipsychotic drugs’ has sadly not been fulfilled (Citrome, 2019).