Adverse cognitive effects of antiepileptics

Here are excerpts from several articles that investigate the effects of antiepileptics, like gabapentin (Neurontin) and pregabalin (Lyrica), which are increasingly prescribed for pain simply because they are not opioids.

This is a followup from a previous post: Some antiepileptic drugs increase risk of dementia.

Adverse cognitive effect of gabapentin [Neurontin] in individuals with spinal cord injury: preliminary findings. – PubMed – NCBI – Spinal Cord Ser Cases. 2018 Jan  

Study design: Prospective observational cohort study.

Ten patients (three females, seven males) with traumatic spinal cord injury underwent testing, with a mean age of 35.6 years (range 19-59, SD ±15.74).

There were five patients with tetraplegia and five with paraplegia.

Nine tests to assess neuropsychological function and two tests to assess pain were performed at 1 week post initiation of therapy, and at 4 weeks post initiation of therapy. The neuropsychological tests assessed aspects of memory, attention, and executive function.

Results:

The average score for six out of the nine neuropsychological items administered at 1 week post initiation of gabapentin displayed a decrease in cognitive function when compared to baseline.

The average score for five out of nine neuropsychological items improved from 1 week post initiation of treatment to 4 weeks post initiation of treatment

Conclusions

Gabapentin therapy is associated with a tangible decline in memory, executive function, and attention in individuals with spinal cord injury.

However, owing to small sample size, loss of patient follow-up at the 4 week post-treatment assessment, and lack of a control group, we cannot definitively state that any decreases in cognition are solely attributable to treatment with gabapentin.

Cognitive effects of GABAergic antiepileptic drugs – 2010

Many patients undergoing long-term treatment of epilepsy complain of memory disorders, which entail worse quality of life.

The risk factors generating memory disorders include:

• morphological brain damage,
• the duration and course of epileptic seizures (conscience disorders),
• the time of diagnosis (the risk is greater if epileptic seizures start early in life),
• drug resistance,
• the presence of interseizure changes in the EEG in the form of sharp-wave discharges or sharp spike-wave/slow spike-wave complexes and
• improper pharmacotherapy (exceeding the admissible concentration of drugs in blood serum, polytherapy).

GABAergic neurotransmission of older antiepileptic drugs (barbiturates, benzodiazepines) makes them particularly prone to produce modest, but statistically significant disruption of cognitive processes.

This explains the search for new antiepileptic drugs that will improve, or at least not impair, cognitive functions.

The improvement of cognitive functions by new generation antiepileptic drugs results, among others, from their non-GA-BAergic mechanisms:

they influence the ion channels and glutaminergic transmission.

How can we overcome neuropsychological adverse effects of antiepileptic drugs?: Expert Opinion on Pharmacotherapy: Vol 18, No 6 – Mar 2017

Antiepileptic pharmacotherapy can very well have positive effects on cognition and behavior via control of seizures and interictal epileptic discharges, and/or via improvements of mood and psychiatric comorbidity.

However, more frequent and less appreciated are adverse effects of antiepileptic drugs (AEDs), causing new cognitive or behavioral problems or aggravating preexistent neuropsychological impairments

we would recommend a routine cognitive monitoring along with relevant changes of an individual antiepileptic treatment.

No pain patient is ever evaluated for cognitive abilities before and after starting antiepileptic drugs.

Peripheral nerve injury and gabapentin, but not their combinations impair attentional behavior via direct effects on noradrenergic signaling in the brain–  Free full-text article – /PMC4197111/ – Pain. 2014 Oct;

The antiepileptic agent, gabapentin, effectively treats acute postoperative and chronic pain but can also cause cognitive side effects.

Although analgesic mechanisms of gabapentin have been extensively studied in the spinal cord, little is known about its supraspinal mechanisms in pain and cognition.

systemically administered gabapentin activates noradrenergic neurons in the LC and induces noradrenaline release in the spinal dorsal horn in both normal and SNL rats

The cognitive impact of antiepileptic drugs – Free full-text article /PMC3229254/ – Ther Adv Neurol Disord. 2011 Nov

Abstract

Effective treatment of epilepsy depends on medication compliance across a lifetime, and studies indicate that drug tolerability is a significant limiting factor in medication maintenance

Available antiepileptic drugs (AEDs) have the potential to exert detrimental effects on cognitive function and therefore compromise patient wellbeing

On the other hand, some agents may serve to enhance cognitive function.

All these studies were conducted in patients with epilepsy, so any improvements found may be the result of seizure control,

In this review paper, we highlight the range of effects on cognition linked to a variety of newer and older AEDs, encompassing key alterations in both specific executive abilities and broader neuropsychological functions

Importantly, the data reviewed suggest that the effects exerted by an AED could vary depending on both patient characteristics and drug-related variables.

However, there are considerable difficulties in evaluating the available evidence.

Many studies have failed to investigate the influence of patient and treatment variables on cognitive functioning.

Again, because these drugs are a non-opioid treatment for pain, studies examining the negative effects will not be funded in this anti-opioid era.

Other difficulties include variation across studies in relation to design, treatment group and assessment tools, poor reporting of methodology and poor specification of the cognitive abilities assessed.

Introduction

The incidence of adverse effects is an important issue when prescribing antiepileptic drugs (AEDs), as some of the most effective medications for seizures are associated with a considerable degree of toxicity.

Older AEDs may still be prescribed, owing to advantages such as lower cost, wide availability and long-term experience, but often exhibit greater toxicity than newer drugs

Recently developed agents tend to differ in terms of mechanism of action and pharmacokinetic properties, and are often better tolerated than older drugs.

However, all AEDs have the potential to exert detrimental effects on cognitive function

There are currently more than 20 different agents which are licensed for use in treating seizures in the UK. These include phenobarbital and phenytoin, which were popular until the 1950s.

Over the next couple of decades, sodium valproate and carbamazepine were developed. These drugs, in addition to primidone and ethosuximide, were the six agents of choice until the 1990s, when a newer generation of drugs became available.

These include

• tiagabine,
• pregabalin,
• gabapentin,
• topiramate,
• clobazam,
• oxcarbazepine,
• lamotrigine and
• levetiracetam.

I don’t know which of these might be used off-label for pain management.

In terms of adverse cognitive effects the vulnerabilities of the individuals treated need to be carefully considered

Differing metabolic profiles in children, the elderly or the acutely unwell may lead to an increased chance of toxicity, and a further consideration is interactions with other medications the patient may be taking.

As well as adverse cognitive effects, some AEDs may have the advantage of improving cognitive performance.

Such beneficial influences may simply occur as a result of seizure control, or in association with positive effects on mood or psychiatric profile.

However, a number of agents may demonstrate efficacy in enhancing cognitive function in a more direct way, by improving alertness or cognitive capacity.

In this review of current literature, we highlight the range of effects on cognition linked to a variety of newer and older agents used to control seizures.

These include key alterations in both executive and broader neuropsychological functions, which can exert a critical influence on patients’ quality of life and wellbeing.

Antiepileptic drugs and cognition

Phenobarbital and primidone

Phenobarbital is considered to have worse cognitive effects than valproate or carbamazepine.

These drugs are not used for pain (that I know of).

When compared with carbamazepine, primidone has been found to cause more adverse effects on motor performance and attention/concentration tests

Phenytoin

Phenytoin has been implicated in declines in concentration, memory, visuomotor functions and mental speed

Another study reported slowed performance on information processing tasks with phenytoin in comparison with carbamazepine

A double-blind placebo-controlled study indicated attention and motor performance may improve after withdrawal

Carbamazepine

I was prescribed this drug over a decade ago, but could not ascertain any difference in my mood or my pain, so I stopped it.

A number of cognitive and psychomotor effects have been linked to carbamazepine.

A double-blind trial reported deterioration in measures of information processing speed and attention

A randomized, double-blind, placebo-controlled study [Hessen et al. 2006] involving 150 epilepsy patients on AED monotherapy (mainly carbamazepine or valproate) found that drug discontinuation significantly improved performance in tests that required complex cognitive processing under time pressure, but not in more simple tasks of attention and reaction time.

Forsythe and colleagues reported that carbamazepine-treated children performed worse than valproate-treated children on memory tasks

Detrimental effects on cognition are unlikely to be widespread. One study reported significantly worse performance on the Digit Symbol Substitution Test (DSST), but no difference for tracking tasks and visual analogue scales

Some positive effects on cognition have been reported, consisting mainly of improvements in memory.

Despite these encouraging findings, some studies suggest carbamazepine is more likely to lead to cognitive deterioration than improvement

Sodium valproate and ethosuximide

Studies are listed in Table 1.

A number of studies have indicated that valproate exerts little detrimental impact on cognitive function

However, a small minority of patients (5 of 364 adults in one study) can develop parkinsonism with associated memory problems and psychomotor slowing

Fortunately, the CAEs associated with valproate are likely to be reversible.

I wonder what it means when they say “likely to be reversible“…

Gabapentin [Neurontin]

Most studies tend to report little or no cognitive impairment in association with gabapentin, including double-blind studies

Pregabalin [Lyrica]

In one study, only 4% of patients taking pregabalin reported cognitive problems

When present, possible CAEs include deterioration in verbal and visual episodic memory

Other reports indicate that abnormal thinking may be rare.

although one report indicated this CAE could be 9–12 times more likely with pregabalin than with placebo

Topiramate [Topamax]

Studies are listed in Table 2

Reports indicate that CAEs are not uncommon with topiramate.

One study found 44% of patients reported experiencing CAEs after 1 year of treatment

Whatever the frequency of CAEs, they are the most likely reason for treatment withdrawal

• Cognitive side effects can include
• impaired concentration
• psychomotor slowing
• cognitive dulling
• detrimental effects on short-term memory
• language and comprehension problems
• and working memory
• poor verbal fluency and
• word-finding deficits 
• reduced IQ score and
• cognitive speed

Topiramate has been shown to exert more negative effects on cognition than a range of other AEDs. Poorer verbal fluency, attention and inhibitory performance have been reported than with lamotrigine.

Memory and attention effects may be worse than with valproate

and verbal fluency, cognitive speed and short-term memory were worse than with levetiracetam in one stud

Reassuringly, CAEs tend to reverse with discontinuation

Lamotrigine

I found this helpful for my mood swings at the starting dose of 25mg, which is generally tapered upwards to at least 100 or 200mg. I never felt additional benefit at anything higher than 25mg, even though it’s considered a sub-clinical dose that shouldn’t have an effect.

This is just another example of an “individual variation” which is increasingly ignored as financial interests are trying to standardize and “guide” our health care.

Studies are listed in Table 3.

It has been suggested that positive effects on cognition are related to EEG changes

Lamotrigine has also been shown to have a favourable cognitive profile in comparison with other AEDs.

Verbal fluency and attentional/inhibitory performance is better than with carbamazepine

a double-blind, randomized study of adults with partial seizures showed performance was better with lamotrigine than topiramate for verbal fluency, the Stroop test and the DSST

Oxcarbazepine

Studies have indicated no deterioration in learning, memory or attention in patients treated with oxcarbazepine

and little evidence of cognitive problems after 4–12 months of treatment

Levetiracetam

Studies are listed in Table 4.

The older agents likely to have the greatest cognitive toxic potential are phenobarbital and perhaps primidone.

These are never prescribed for pain.

Carbamazepine has the potential to lead to mild but sometimes significant difficulties relating to motor speed and performance on more attention-demanding tasks.

Minimal difficulties are also likely with sodium valproate taken at low doses.

With regards to newer drugs, topiramate is associated with more consistent evidence of detrimental influences on cognition.

Study findings for tiagabine are relatively promising, with the potential for positive effects on verbal fluency and visuomotor performance, although it is unclear whether these may be the result of seizure control

There is currently limited evidence of CAEs with the use of clobazam, and reported ‘abnormal thinking’ in association with pregabalin [Lyrica] requires further specification.

More favourable options may include gabapentin and oxcarbazepine, which have been associated with only minor cognitive difficulties

Based on the evidence reviewed, the agents least likely to interfere with cognitive processes are levetiracetam and lamotrigine.

Implications for clinical practice

Importantly, the data reviewed suggest that the effects exerted by an AED could vary depending on factors linked to patient characteristics and individual susceptibility.

Current or previous cognitive or psychiatric problems may also be linked to the cognitive effects of an AED.

The effects of antiepileptic drugs on cognitive functional magnetic resonance imaging – Free full-text /PMC4379315/ – Quant Imaging Med Surg. 2015 Apr;

This article gives a long and detailed explanation of how fMRIs work.

Abstract

The cognitive dysfunction caused by antiepileptic drugs (AEDs) has been extensively described, although the mechanisms underlying such collateral effects are still poorly understood.

The combination of functional magnetic resonance imaging (fMRI) studies with pharmacological intervention (pharmaco-MRI or ph-MRI) offers the opportunity to investigate the effect of drugs such as AEDs on brain activity, including cognitive tasks.

Here we review the studies that investigated the effects of AEDs [topiramate (TPM), lamotrigine (LMT), carbamazepine (CBZ), pregabalin (PGB), valproate (VPA) and levetiracetam (LEV)] on cognitive fMRI tasks.

Introduction

The adverse cognitive effects of antiepileptic drugs (AEDs) are well known and may affect many cognitive and behavioral domains.

Usually, these collateral effects have been associated with high dosages and polytherapy.

To investigate the effects of AEDs on brain function (and dysfunction) functional magnetic resonance imaging (fMRI) can be used as a research method given the possibilities to explore the ability of drugs to modify brain networks and circuits

fMRI relies on the blood oxygenation level-dependent (BOLD) signal changes to indirectly find neuronal activity in brain regions related to tasks or stimuli.

The brain corresponds to approximately 2% of the body weight, but uses about 20% of the glucose and oxygen, which are not stored in the brain. Therefore, a constant supply must exist.

Since in normal conditions the energy production depends mainly on the oxidative metabolism of oxygen, with increased synaptic activity there is a greater demand for glucose and oxygen.

This generates a local increase in the local cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen consumption (CMRO2).

A complex interplay between the variations of CBF, CBV and CMRO2 gives rise to a transient increase in the local concentration of oxyhemoglobin relative to deoxyhemoglobin.

This decreases the inhomogeneities in the magnetic field inside the voxel, because oxyhemoglobin (oxygenated hemoglobin) is diamagnetic and deoxyhemoglobin (deoxygenated hemoglobin) is paramagnetic.

Thus, when the MRI image is T2*-weighted, the signal intensity is increased.

With the aid of statistical tools these voxels can be detected.

After an event, the BOLD signal peaks at about 3-6 s and returns to baseline after approximately 20-30 s. These changes are usually modeled with the hemodynamic response function with one or two gamma-variate functions.

In task-related fMRI the subject performs a task (e.g., cognitive, finger tapping, button press) or is presented stimuli (e.g., checkerboard flicker) alternately with another condition, typically a rest period.

Although there is no formal definition of rest, usually the subject performs a control task (e.g., just lying still inside the scanner) or is presented a control stimulus

During the so-called resting-state fMRI (rs-fMRI) the subject lies in the scanner either with eyes open or closed and performs no specific task

Analysis of task-related fMRI is normally performed with general linear model (GLM).

FMRI has no proven risk of biological harm and uses no ionizing radiation.

It has been widely used to find the neurophysiological correlates of specific behavior and stimuli in different situations

The interpretation of the results in pathological conditions must be considered with care because the neurovascular coupling may be impaired due to the illness.

The ph-MRI studies assess the effect of pharmacological agents and the sources of data include drug-related brain changes or behavioral effects.

The knowledge about the effect of drugs in fMRI is of great importance in the clinical application of fMRI.

Cognitive ph-MRI studies usually compare the brain signal during task in placebo and drug conditions.

As in conventional fMRI a univariate approach and graph theory can be used. When the drug effect in the functional network is studied, more distributed influences of the AEDs in the functional connectome can be identified

Pharmacological fMRI studies with AEDs are difficult to perform, because usually patients are already under medication.

Therefore, participants are not recruited prior to the administration of the AED, making it more complex to control for effects such as genetic polymorphisms, family history of psychiatric or neurological illness, and concomitant use of other AEDs.