Lithium and neuroleptics in combination: the spectrum of neurotoxicity [corrected]

Classifying neurotoxicity in relation to neuroleptic use has been a longstanding concern with clinical, research, and epidemiologic import. This study examines the clinical manifestations of neurotoxicity and current concepts regarding its classification. The Food and Drug Administration (FDA) Spontaneous Reporting System data base and extant literature were reviewed for lithium/neuroleptic neurotoxicity spectrum cases. Lithium-alone (LI), lithium/haloperidol (LiHal), and lithium/non-haloperidol neuroleptics (Li-NonHal) groups, each paired for recovery and sequelae, were established for 237 cases. Data on demographic factors, psychiatric diagnosis, and symptoms/signs/findings were tabulated. Neuroleptic malignant syndrome (NMS) was used as a paradigm for severe neurotoxicity; the cases were evaluated by two strict, published sets of NMS diagnostic criteria and two "probable" classifications (one published and one established for study) based on these criteria. Altered consciousness was prominent in all groups. Hypertonia/rigidity was most pronounced in both LiHal groups, possibly reflecting higher relative neuroleptic dosing; Li and LINonHal recovery and sequelae pairs showed lower, similar percentages. Among other physical findings, tremor was either most common or prominent. Neither set of strict criteria diagnosed NMS in more than 30 percent of cases in any group. Expansion of classifications to include "probable" diagnoses resulted in appreciable global group percentage increases for only one set of criteria. The high percentage of study cases not meeting even "probable" NMS criteria, despite marked clinical morbidity that at times resulted in permanent sequelae, provides a cautionary note regarding the limitations of formulated diagnostic criteria. Data base caveats notwithstanding, study findings support the consideration of a spectrum approach to classifying and diagnosing psychotropic-related neurotoxicity.