Venlafaxine–lithium toxicity: suitability for use in the elderly

To the Editor: Adan-Manes et al. (1) have described a useful and instructive case report and analysis of venlafaxine induced serotonin toxicity (ST) with lithium. I suggest some points will benefit from further elaboration and emphasis. Venlafaxine is revealing itself to be the most toxic of all the new antidepressants. Data revealing this come from its’ greater fatal toxicity index of 13Æ2 deaths per million scripts (CI 9Æ2–18Æ5) vs. selective serotonin reuptake inhibitors (SSRIs), and even some tricyclic antidepressant (TCAs), e.g. nortriptyline, at 5Æ5 deaths per million scripts (CI 2Æ2–11Æ4) (2, 3). The unique HATS database kept by Professor Whyte’s group is the definitive data set on the frequency and features of ST following over-dose. It shows that both seizures and ST occur approximately twice as frequently with venlafaxine compared to other SSRIs. The series of papers published by Whyte’s HATS group are required reading for anyone wishing to understand ST (3–6). The ST criteria referred to by Adan-Manes et al. (1), as being expounded by Boyer (and implicitly attributed to him), in his excellent paper, are not Boyer’s work at all: ‘Boyer and Shannon have recently suggested the presence of.and clonus (either spontaneous or inducible) as the main clinical feature’, but were derived by Professor Whyte by applying classification and regression tree (CART) rules to the HATS data, as acknowledged in Boyer’s appropriately referenced paper (6). My database of serotonin toxicity case reports (7) also suggests that interactions involving venlafaxine may be more severe than those involving other SSRIs. This includes interactions with monoamine oxidase inhibitor (MAOIs) that can be severe and even fatal after only one small therapeutic dose (8–11). In contrast, a paper systematically reviewing evidence of toxicity with therapeutic combinations of SSRIs and lithium has failed to find any increase (12). Another especially intriguing aspect of this detailed account by Adan-Manes et al. (1) is the high dose of risperidone shortly before the episode described. Risperidone, being a cytochrome P450 2D6 (CYP2D6) inhibitor, would be expected to elevate levels of venlafaxine, a drug metabolised by CYP2D6. Yet there was no sign of ST during co-administration of venlafaxine and risperidone. This strengthens the authors’ supposition that the effect of lithium was crucial. However, lithium is a weakly serotonergic drug and it is therefore unlikely that the appearance of pronounced ST symptoms (if that is what they were) was due only to lithium. [If lithium was strongly serotonergic a definite increase in serotonergic side effects, and toxicity, would be expected with SSRIs. Hawley’s paper (12), as well as various other evidence, indicates that this is not the case]. Two other mechanisms might throw further light on to this case. First, it might have been simply lithium toxicity: the apparent absence of inducible clonus or pyrexia, and the early appearance of ‘confusion’, which is not characteristic of mild/ early stage ST, probably support this interpretation. Secondly, 5-HT2A receptor supersensitivity may have developed in response to potent 2A antagonism of risperidone (the most potent 2A antagonists of all the new neuroleptics). This case has some interesting similarities to that reported by Zerjav-Lacombe et al. (13) who first postulated supersensitivity in a case involving clomipramine and lithium after cessation of clozapine. It is also notable that older patients, and those with organic brain disease, are particularly susceptible to severe and atypical reactions to CNS drugs, e.g. Lewy body dementia and neuroleptics (14, 15). Lithium toxicity can have variable neurological manifestations, including myoclonic jerks, and may occur with ‘therapeutic’ plasma levels (16). However, irregular myoclonus does not have the specific diagnostic significance for ST that inducible clonus has. It should also be noted that cases of venlafaxine toxicity have been erroneously reported as neuroleptic malignant syndrome, e.g. (17–20). Such reports, and the differential diagnosis of NMS and ST, have been discussed and analysed elsewhere (21–25). Journal of Clinical Pharmacy and Therapeutics (2007) 32, 529–531