Assessment 5 – Prescription Drugs
Introduction
There is an extensive list of prescription drugs that induce seizures (Zacarra et al., 1990; Grosset and Grosset, 2004). Most, but not all drugs on this list, act to influence the brain in one way or another. For example, these drugs may reduce anxiety, depression, or psychotic behavior or alternatively, may stimulate activity of the brain. However, some drugs such as antibiotics, surprisingly, do not fit in this category, yet are capable of inducing seizures (Sutter et al., 2015 Wanleenuwat et al., 2020). Previous blogs discussed potential seizure induction with caffeine and nicotine use (http://assessment 3 and http://assessment 4).
Basically, drugs with a history of seizure induction have the potential to remove normal inhibitory influences on the brain or enhance excitatory influences, both of which produce outcomes of inappropriate nerve activity termed seizures.
Ways drugs induce seizures
In general, drug-dependent seizures occur following use of a) higher than therapeutic drug doses (overdose) (Chen et al., 2015), b) use of drugs for prolonged periods (years) (Hill et al., 2015) or c) an abrupt withdrawal of a drug (Robertson and Sellers, 1982). Furthermore, according to Thundiyil et al, (2010) in a prospective observational study, there are many factors which can exacerbate drug-induced seizures such as “stimulant exposure, suicide attempt, initial hypotension, and admission acidosis or hyperglycemia”. These conditions not only complicate drug-induced seizures but may also lead to death.
This blog will focus on the seizure-inducing potential of drugs categorized as psychotropic medications. They include a) antidepressants, b) antipsychotics and c) anti-anxiety drugs. These are drugs with ” high epileptogenic potential”, that is ability to stimulate seizures (Lee et al., 2003).
Specific drugs: Antidepressant drugs
Hill et al., (2015) completed one of the most extensive evaluations of the effects of antidepressants on seizure induction. In the UK, this group evaluated records from 200,000 depressed patients (20-65 years of age) over a 5 year period to determine the time of first diagnosis of epilepsy/seizures while taking anti-depressant medication. Only individuals without a prior epilepsy/seizure diagnosis were included in this study.
Hill et al.,(2015) reported a significant increase in seizure induction with” all antidepressant drug classes”. Hill and his associates determined that 8 of the 11 most commonly prescribed antidepressants (see Table 1 for a list of these drugs) are associated with a first diagnosis of epilepsy/seizures. The top three antidepressants are trazodone (Desyrel), lofepramine (Gamanil, Lomont, Tymelyt) and venlafaxin (Effexor). The exceptions, that is antidepressants with no relation to induction of seizures, are sertraline (Zoloft), escitalopram (Lexapro) and mirtazapine (Remeron). Interestingly, the risk of seizure induction with antidepressant use is low if drugs are used for one year or less, the duration recommended by the FDA. Long term use, as in this study, up to 5 years is associated with a significant risk of a first diagnosis of epilepsy or seizures.
Antidepressants and mortality
Josephson et al., 2017 (electronic health records of >2 million individuals; 0.6% with epilepsy and followed for 6 years) found that use of antidepressants termed serotonin receptor uptake inhibitors (SRI) which include drugs like Effexor and Prozac, in patients with epilepsy (PWE) is associated with increased mortality, not decreased mortality as expected. Furthermore, use of 2 or more antidepressant prescriptions whether in PWE or otherwise, is statically associated with an ” elevated risk of all-cause mortality”. The authors indicate that their data does not prove a cause and effect relationship. Because of the limited number of PWE, the authors were unable to determine whether increased mortality was due to seizure-related deaths. Clinical trials are needed to determine the adverse effects of long term use of antidepressants.
Antipsychotic drugs
Antipsychotic drugs are prescribed for the treatment of psychosis (mania, paranoid states, acute schizophrenia, bipolar disorder and dementia). Hedges et al, (2003) concluded that antipsychotic drugs have the potential to lower seizure threshold and hence induce seizures. This applies to the older original antipsychotic drugs such as chloropromazine as well as the later second generation drugs such as Clozapine (Clozaril). Specific reports (Alper et al., 2007; Uvais and Sreeraj, 2018) indicate that Clozapine and Olanzpine (Zyprexa) induce seizures in a dose-related manner. It is speculated that antipsychotics induce seizures by inhibition the neurotransmitter, gamma-amino-butyric-acid (GABA).
Case study reports provide much of the data on antipsychotics and seizures. Whereas this is important information, it lacks the rigorousness of results obtained from randomized clinical trials. To date, no clinical trial has examined the effect of antipsychotic drugs on seizure induction, other than that which is reported in phase 4 clinical trial for FDA drug approval (accordingly, less than 1% experience seizures). Nevertheless, caution is advised since other factors such as ” history of seizure activity, concurrent use of other drugs that lower seizure threshold, rapid dose titration, slow drug metabolism, metabolic factors and drug-drug interactions” (Hedges et al., 2003), may play a role in facilitating seizure induction with antipsychotics.
Anti-anxiety drugs
Anti-anxiety drugs belong to a class of drugs termed benzodiazepines. This class includes one of the most commonly prescribe drugs, alprazolam (Xanax) (Ait-Daoud et al., 2018) (see Table 1 for similar drugs). As a class, these drugs are widely prescribed and are used for the treatment of panic disorders, obsessive-compulsive disorders, sleep disorders, muscle spasms, pre-anesthetics preparation and are also used as a standard drug choice for the treatment of convulsive disorders such as epilepsy and seizures (Goodman and Gilman, 2005). Benzodiazepines act by binding to and stimulating a select subset of GABA receptors to facilitate the anti-anxiety and anti-convulsive effects.
Evidence of adverse effects appeared early on, since their advent some 60 years ago of the original anti-anxiety drugs, Librium and Valium. In particular, it was clear that potentially serious withdrawal symptoms occurred with drug stoppage. Importantly, abrupt withdrawal of a drug from the benzodiazepine class leads to seizures (Robertson and Sellers, 1982). Withdrawal symptoms may be mild (headache) to severe. Specifically, “seizures, mania and death from convulsions” (Calcaterra and Barrow, 2014; Brett and Murmion, 2015) may occur. Generally, severe withdrawal symptoms are evident after prolonged use. Therefore, short term use of benzodiazepines not exceeding 6 months, is recommended (Brett and Murmion, 2015).
Conclusions
Antidepressants, antipsychotics and anti-anxiety drugs have the potential to induce seizures. This comes from several comprehensive medical record assessments and a wealth of case reports. The available data suggests that seizures occur primarily during long term use of antidepressants and antipsychotic drugs and on abrupt withdrawal of anti-anxiety drugs.
There remain many unanswered questions:
1. There is suggestive evidence that abrupt drug withdrawal even after short term use of an anti-anxiety drug may precipitate seizures. Unanswered: What is the minimum duration of anti-anxiety drug use for which seizure induction will not occur following discontinuation?
2. The literature suggests that drug-induced seizures are different from epilepsy. However, Hill et al., (2015) reported that a number of patients, with no prior history of epilepsy, received a first diagnosis of epilepsy while on antidepressants. Unanswered question: Is this observation important enough to warrant confirmation by additional studies?
3. The literature suggests that long term use of psychotropic drugs is highly associated with seizure induction. Unanswered: If psychotropic drugs are generally prescribed for extended periods of time, would a clinical trial be appropriate to determine the adverse effects of long term use of psychotropic drugs?
4. Unanswered questions: Should individuals with a prior history of epilepsy and seizure free without medication for years be prescribed psychotropic medications in the future? Can psychotropic drugs reactivate epilepsy?
Advice
Much of the seizure-inducing potential of psychotropic drugs can be reduced with short term (12 months or less) use and a prolonged (months) withdrawal when no longer needed. Lack of knowledge or contrary actions clearly elevate the chance for seizures or epilepsy.