Using TMS and EEG to study a novel class of drug

'The drug we studied has been approved by the FDA for the treatment of postpartum depression,' says Clinical Scientist and Research Physician Kaye de Cuba. 'It is the neurosteroid allopregnanolone which also occurs naturally in the human body and is made out of progesterone. With our study, we wanted to find out more about its mechanism of action and whether TMS and EEG would be sensitive biomarkers.’

'Allopregnanolone acts on the GABA receptor,' says Dr Gabriel Jacobs, Research Director Psychiatry. 'We have done a lot of research with GABAergic substances in recent years, so it is familiar territory for us. But this substance works differently: it is not an agonist, like benzodiazepines for example, but a positive allosteric modulator: it changes the shape of the GABA-A receptor, thereby enhancing the action of the naturally present GABA. During pregnancy, when progesterone levels are high, allopregnanolone helps stabilise a woman’s mood. After childbirth, progesterone levels drop sharply, so there will be less allopregnanolone. This can be a trigger for postpartum depression in some women.'

Now that allopregnanolone has proved useful in the treatment of postpartum depression, the question arose whether it could also be applied in other indications. ‘We found it really interesting to participate in the exploration of other possible uses of this neurosteroid,’ says Jacobs.

The study conducted in 2023 used a crossover design to compare the effects of allopregnanolone with a placebo and with the benzodiazepine lorazepam, a classic GABA receptor agonist. De Cuba: 'We wanted to gain more insight into the effect of allopregnanolone, which is why we also wanted to compare it with lorazepam, because the mechanism of action of benzodiazepines is better understood.'

The effects of the drugs were investigated using EEG analysis and TMS. TMS, which is performed at CHDR by the Experimental Medicine group, measures the effect of magnetic pulses on the cerebral cortex, aimed at the part of the motor cortex that controls the hand. The responses are measured using electromyography of the hand and evoked potentials using the EEG. Inhibitory neurotransmitters such as GABA and compounds acting on the GABA receptor may influence both the amplitude and the timing of responses to the magnetic pulse.

De Cuba is currently analysing the results. 'We are now in the early stages of our data analysis, so I’m really curious about the similarities and differences between lorazepam and allopregnanolone in the effects we measured and the added value of our TMS approach. It’s fascinating to be involved in the research on this drug, especially knowing that other neurosteroids are being developed, including cholesterol metabolites. This is a really interesting new development.'