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Annotation

Tischbirek CH, Wenzel EM, Zheng F, Huth T, Amato D, Trapp S, Denker A, Welzel O, Lueke K, Svetlitchny A, Rauh M, Deusser J, Schwab A, Rizzoli SO, Henkel AW, Müller CP, Alzheimer C, Kornhuber J, Groemer TW. Use-dependent inhibition of synaptic transmission by the secretion of intravesicularly accumulated antipsychotic drugs. Neuron . 2012 Jun 7 ; 74(5):830-44. PubMed Abstract

Comments on Paper and Primary News
Comment by:  Philip Seeman (Disclosure)
Submitted 15 June 2012 Posted 15 June 2012

Regrettably, despite the elegant methods, the antipsychotic concentrations applied were not clinically relevant and would all be toxic or lethal to humans if found at those concentrations in the human plasma water or in the spinal fluid.

For example, haloperidol was used at 500 to 5,000 nanomolar. However, the therapeutic concentration of haloperidol in the spinal fluid is between 1 and 5 nanomolar. The toxic concentration is about 10 times higher, and the comatose-lethal concentration is approximately 20 times higher (see Regenthal et al., 1999), all these concentrations being far lower than those used by Tischbirek et al.

In addition, chlorpromazine was used at 500 to 5,000 nanomolar. But the therapeutic concentration of chlorpromazine is between 3 and 10 nanomolar, the toxic concentration is about 10 times higher, and the comatose-lethal concentration is about 100 times higher (Regenthal et al., 1999), all these concentrations being far lower than those used by Tischbirek...  Read more


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Comment by:  Herbert Meltzer (Disclosure)
Submitted 15 June 2012 Posted 15 June 2012

Round and Round They Go
Tischbirek and colleagues are to be congratulated on completing a complicated, elegant in-vitro as well as in-vivo microdialysis study of the accumulation of a variety of antipsychotic drugs in synaptic vesicles in hippocampal tissue, their release upon neuronal depolarization, and their re-accumulation in neuronal terminals, where they appear to inhibit the further release of vesicles, leading to what they call use-dependent auto-inhibitory effects on synaptic transmission. The latter is the least convincing part of the study because they did not compare the concentrations of drugs in vesicles or in dialysates over periods that might parallel clinical treatment periods in patients, for example, weeks and months. Follow-up longitudinal studies of treatment effects on the levels of drugs within and releasable from vesicles will be of interest.

Tischbirek et al. claim their results are consistent with the delayed onset of clinical response to antipsychotic drugs, while others, for example, Kane and Kapur, are pressing the view that clinical...  Read more


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