The Mystery of the Neuroleptic Threshold Method

Psychiatrists are very much struggling to figure out the "perfect" dose for antipsychotic drugs. Today, we’re going back to the early days to look at a fascinating, forgotten method called the "Neuroleptic Threshold."

The Discovery

It started right after the development of Chlorpromazine in 1953. Doctors soon realised that the drug caused movement disorders like muscle rigidity or tremor.

A German psychiatrist named Hans-Joachim Haase had a hunch. In 1954, he proposed that the drug’s ability to fight psychosis was linked to these side effects. He believed that to truly work against delusions or hallucinations,the dose had to be high enough to slightly inhibit the patient's movement.

The "Handwriting Test"

To find this "sweet spot," Haase coined the term "Neuroleptic Threshold (NT)." But how do you measure something so subtle as a threshold? Believe it or not, he used poetry.

Before starting treatment, he had patients write out a a German poem:

Der Mai ist gekommen

Die Blüten schlagen aus

Da bleibe, wer Lust hat

Mit Sorgen zu haus

The dose was increased in very small steps, e.g. 1mg haloperidol per day, and the surface are of the handwriting regularly measured. The moment the handwriting started to shrink—micrographia, a very subtle form of motor side-effects—patients had reached their threshold.

Why not just use the standard dose written on the medicationbox?"

Haase argued that standard doses are frequenly wrong. Hefound that there is an up to 15-fold difference in when individuals reach the NT dose.

Haase determined the neuroleptic threshold for approximately 30 antipsychotics through various doctoral theses (Abraham et al. 1996).

In his clinic, roughly 170 patients performed the writing test daily, totaling about 50,000 handwriting samples per year.

He automised the measurements in the 1980s with an electronic writing tablet.

A breakthrough was the double-blind study by Joseph McEvoy published in 1991. To determine the NT in patients with schizophrenia the even simpler method of cogwheelrigidity was used. The NT dose in the intervention group was around 3mg haloperidol/day. Patients on these lower "threshold" doses got the same clinical benefits but with far fewer side effects than those on standard doses.

What is the significance of this method for today?

Understandably, the NT fell into obscurity when second-generation antipsychotics were introduced, some of which—especially clozapine—do not cause movement disorders.But Haase early created a link between clinical efficacy of antipsychotics with a brain mechanism. He assumed that the neuroleptic threshold is directly linked to the extrapyramidal motor system, long before the availability of PET.

Today, we have high-tech PET scans to look at the brain, and they actually back Haase up!

Modern PET studies showed that you need to occupy at least 65% of dopamine receptors for an antipsychoit effect and that for most first-episode pateints 2.5mg/d haloperidol are sufficient, very similar to the McEvoy study.

However, there is a lot of interindividual variability in the doses needed to reach the threshold. Thus, the "Haase Threshold" may be a possibility to titrate patients into the therapeutic window.

It could work not only in first-generation antipsychotics but also drugs like risperidone which cause movement disorders

Maybe someone picks this idea up and does a PET study!

It’s a powerful reminder from 1953: if patients are experiencing movement disorders, they are likely being overdosed.

Sometimes, the most high-tech start with something as simple as a pen and a piece of paper.

References

Abraham D et al. The "neuroleptic threshold". Psychiatr Prax 1996;3:109-16.

Haase, HJ: Über Vorkommen und Deutung des psychomotorischen Parkinsonsyndroms bei Megaphen- bzw. Largactil-Dauerbehandlung, Nervenarzt 25 (1954), S. 486

McEvoy JP et al. Optimal Dose of Neuroleptic in Acute Schizophrenia. Arch Gen Psych 1991;48:739-745