Gastrointestinal hypomotility: an under-recognised life-threatening adverse effect of clozapine.
OBJECTIVE
To highlight some problems that may occur when investigating clozapine-associated deaths including (i) that death may be related to gastrointestinal hypomotility and (ii) that post-mortem blood clozapine and norclozapine concentrations may not reflect ante-mortem concentrations.


METHODS
A 41-year-old male died 40 min after admission to hospital as a result of aspiration complicating severe, clozapine-induced constipation. At post-mortem the small bowel was dilated and contained bloodstained mucus, particularly within the jejunum. The large bowel was considerably dilated and contained large quantities of foul-smelling, bloodstained fluid and a small amount of stool. Its lining was focally congested, but there was no other obvious abnormality. Analysis of serum obtained on admission revealed clozapine and norclozapine concentrations of 0.56 and 0.43 mg/L, respectively, whereas post-mortem femoral whole blood obtained <34 h after death showed clozapine and norclozapine concentrations of 3.73 and 1.75 mg/L, respectively. In 6 out of a further 12 clozapine-associated deaths investigated 2002-9 there were reports of gastrointestinal tract problems of varying severity.


CONCLUSIONS
Severe constipation or paralytic ileus in clozapine-treated patients may lead to intestinal necrosis and/or perforation, or pulmonary aspiration. In some such cases the immediate cause of death may be obvious, but in others only careful assessment of the clinical course of the terminal illness may reveal gastrointestinal hypomotility as a likely underlying cause of death.
Flanagan
R J
RJ
Toxicology Unit, Department of Clinical Biochemistry, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK. robert.flanagan@nhs.net
Ball
R Y
RY
D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000097:blood; D001929:Brain Edema / Q000473:pathology; D003024:Clozapine / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000097:blood; D003248:Constipation / Q000139:chemically induced* / Q000150:complications; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D007418:Intestinal Pseudo-Obstruction / Q000139:chemically induced*; D007422:Intestines / Q000473:pathology; D008168:Lung / Q000473:pathology; D008297:Male; D011654:Pulmonary Edema / Q000473:pathology; D053120:Respiratory Aspiration / Q000209:etiology; D013154:Spleen / Q000473:pathology
D014150:Antipsychotic Agents; C058272:norclozapine; D003024:Clozapine