The IDIC-15 subject that we report had a dramatic worsening of her seizures when Pregabalin was added as third drug to ongoing treatment with lamotrigine and oxacarbazepine and almost complete seizure control when Pregabalin was stopped and lacosamide added.
Pregabalin is a gamma-aminobutyric acid (GABA) analog, structurally derived from GABA by the addition of an aliphatic side chain at the 3-position (S-(+)-3-isobutyl-GABA). Its anti-epileptic effect is mediated by the high-affinity binding to the α2δ subunit of the voltage-dependent calcium channel . Although it is structurally related to GABA, pregabalin at therapeutic doses does not bind to GABA-A or GABA-B receptors, nor affects GABA uptake or degradation [15, 16]. There is however evidence that in human motor cortex pregabalin produces a physiological effect similar to that of GABAergic drugs  and the drug affects the GABA transporter GAT-1, increasing neuronal GABA uptake .
There is no obvious explanation for the seizure worsening induced by pregabalin. In IDIC-15 both the intellectual disability and the seizure disorder are likely related to the abnormal GABA receptor morphology and function. The IDIC 15 chromosome in the subject we report, includes 8 Mb spanning 15q11-13.1 and results in 4 copies of the 21 genes found in this genomic interval, including genes encoding GABRB3, GABRA5, and GABRG3, and it is likely that the abnormal receptor configuration and distribution may modify the affinity of pregabalin for GABA receptors and its pharmacological effect. Interestingly, microdeletions in the 15q11.2 in the proximal BP1 – BP3 and BP2 – BP3 regions, have also been associated with a varied phenotype that include developmental and language delay, intellectual deficit, behavioral problems, autism, and seizures . The mechanism leading to the neurological dysfunction is unknown, but it may be related to the deletion of the NIPA1 and CYFIP1genes that are important in neurological development . Other microdeletions in the 15q13.3 have been associated with idiopathic generalized epilepsy and other neuropsychiatric disorders including autism, schizophrenia, and autism . Among the most common microdeletions are those affecting CHRNA7 in the BP4-BP5 region, the gene encoding the alpha 7 subunit of the nicotinic receptor , which can modulate GABA receptors’ function . While it is possible that seizure activity can be related to abnormal cholinergic modulatory activity, in our case the duplication does not encompass the more distal BP4 – BP5 regions of the CHRNA 7 gene.
Increased of seizure activity and modification of seizures patterns have been reported with other drugs, including the GABAergic drugs vigabatrin  and tiagabine  and as well as drugs that are not GABAergic such as levetiracetam . Gabapentin, a drug pharmacologically related to pregabalin, has been reported to induce life-threatening myoclonic status in a patient with benign adult familial myoclonic epilepsy . While there may be other reasons that could explain the severe exacerbation of the seizure disorder after the introduction of pregabalin, the temporal coincidence and the worsening of the seizure disorder with increased dose of the drug suggest a direct effect of the drug. It is unlikely that the dramatic increase in seizure frequency and the appearance of different seizure patterns can be explained by a late effect of the trauma. While the subject’s stereotypical seizures had increased in frequency, the dramatic worsening occurred a year after the trauma, when pregabalin was introduced. Further, the progressive worsening of her seizures with increasing dose of pregabalin, the appearance of unusual seizure patterns, and the rapid improvement after pregabalin was removed and lacosamide introduced point to a pharmacological cause. It is however impossible to determine whether the dramatic improvement that she then experienced was due to the removal of pregabalin, the addition of lacosamide, or a combined effect.