A study on the epidemiology of incident seizures in patients with neuropsychiatric disorders

Pharmacoepidemiology studies use and effects of drugs in large numbers of people. It thus allows the investigation and quantification of rare beneficial or adverse events of drugs used by the general population under “real-world” conditions. Pharmacoepidemiologic research strongly depends on and has been facilitated by the development of large scale health care databases. Among these the U.K. Clinical Practice Research Datalink (CPRD) stands as one of the largest and best validated medical records databases worldwide. CPRD was initiated more than 25 years ago and contains records on diagnoses, drug prescriptions, demographics, lifestyle variables and medical procedures performed from over 12 million patients contributing 64 million person-years of prospectively recorded primary healthcare data.
CPRD data was employed in all studies carried out in this thesis. The goal was set to identify and analyze risk factors of new-onset seizures in patients with neuropsychiatric disorders. While it has long been suspected that patients suffering from neuropsychiatric disorders exhibit an increased risk of new-onset seizures no significant real-world evidence exists on risk factors causing these seizures.
We first investigated risk factors of new-onset seizures in adult patients with depression. Our results suggest that patients suffering from depression were at an increased risk of seizures if they abused drugs, suffered from alcoholism, had a history of cerebrovascular disease or recent brain injury, comorbid dementia, or comorbid psychiatric disorders. Additionally we found current users of cephalosporins or antiarrhythmics to be at an increased risk of seizures compared with non-users of these drug classes.
In a follow-up study we assessed the association between antidepressant drug use and new-onset seizures in adult patients with depression. Our data suggest that the absolute risk of seizures in this population was rare, irrespective of whether patients used antidepressants or not. Additionally we found that the use of selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) was associated with a twofold increased risk of seizures compared to non-use. However, tricyclic antidepressants (TCAs) at low doses, as prescribed in this primary care setting, were not associated with seizures. Among users of SSRIs and SNRIs, treatment initiation was associated with a higher risk of seizures compared to longer-term treatment. Finally, we could demonstrate that higher doses of antidepressants prescribed showed a clear tendency to be associated with an increased risk of seizures than lower doses, although small sample sizes limited conclusiveness.
In the final study of this thesis, the potential association between antipsychotic drug use and new-onset seizures among patients with different underlying neuropsychiatric disorders was investigated. The results obtained in this study demonstrate that the association between antipsychotic drug use and seizures is strongly modified by the underlying neuropsychiatric indication. Our data shows that patients with dementia exhibited a significantly higher risk of seizures than patients with affective disorders, irrespective of the use of antipsychotics. Additionally, in patients with affective disorders, current use of medium to high potency first-generation antipsychotics (haloperidol, prochlorperazine, or trifluoperazine) was associated with a more than twofold increased risk of seizures compared to non-use of antipsychotics. Lastly, in all of these patients, use of all other antipsychotics was not associated with new-onset seizures. In patients with dementia, current use of the second-generation antipsychotics amisulpride, aripiprazole, risperidone, or sulpiride, was not associated with seizures, while current use of all other antipsychotics was associated with an increased risk of seizures.
We found that the inability to adjust for confounding by disease severity, the unproven validity of the diagnoses of affective disorders and seizures, and the limited sample sizes in sub-analyses posed a certain limit to our studies.
Nevertheless, all studies carried out in this thesis provide new insight into the poorly understood relationship between neuropsychiatric disorders and new-onset seizures. Formally quantifying the occurrence of seizures and assessing risk factors for seizures among this restricted study population was only feasible through access to the large existing data set comprising detailed patient information available from the CPRD.