Cognitive Safety is Largely Ignored in Clinical Drug Trials: A Study of Registered Study Protocols.

BACKGROUND AND OBJECTIVE: The number of reports on suspected drug-induced memory impairment submitted to the US Food and Drug Administration increased 30-fold from 2000 to 2022. Drugs are the most common cause of reversible dementia. However, there is very little research on drug-induced cognitive impairment. The aim of this study was to investigate if and how an assessment of cognitive safety was included in recent, registered, controlled, clinical drug trials. METHODS: The clinical trials registry ( www. CLINICALTRIALS: gov ) was searched for randomized controlled clinical trials with available study protocols. After excluding irrelevant trials such as surgical procedures, local or short-term treatment, and dietary supplements, 803 trials were included in this study. The protocols were manually reviewed for information on if, and how, cognitive safety had been assessed. Trial drugs were categorized into those targeting the central nervous system or not, as well as older and newer drugs. Methods used for the assessment of cognitive function were categorized into questionnaires, screening instruments, and neuropsychological tests. If the trial results were published, we examined whether the publication contained any data on cognitive safety that had emerged from the trial. RESULTS: The start dates of the screened trials ranged from 31 July, 2009, to 4 April, 2021. Out of the 803 trials, 52 (6.5%) actively assessed cognitive safety. The remaining trials relied solely on spontaneous reporting. Of 429 trials studying a new drug, 32 (7.5%) actively assessed cognitive safety. One hundred and fifty-eight trials examined drugs intended to, or known to have, pharmacological effects on the central nervous system. Of these, 21 (13.5%) assessed cognitive safety. Most of the trials that assessed cognitive safety used either crude screening tools or questionnaires. CONCLUSIONS: Cognitive safety is largely ignored by recent controlled clinical trials. This applies even to trials assessing new drugs and trials assessing central nervous system drugs. There is an urgent need for drug manufacturers, regulatory authorities, and the medical profession to address the cognitive safety of drugs.

Rash during lamotrigine treatment is not always drug hypersensitivity: A retrospective cohort study among children and adults.

Purpose Cutaneous adverse drug reactions (cADRs) are a major cause of lamotrigine (LTG) discontinuation. Remarkable variation in their reported incidence suggests confounders and diverse terms and definitions. The aim of this study was to identify immunological cADRs and to throw light on classification and differential diagnoses in children and adults. Methods Hospital records of 2683 patients with epilepsy (1897 adults, 786 children) were retrospectively screened. Of these, 403 patients (236 adults, 167 children) with first time exposure to LTG were reviewed. Skin reactions were categorized into possible or probable cADRs due to LTG hypersensitivity, and other skin reactions (OSRs) unlikely to be caused by this mechanism. Results 29 of 403 patients (7.2%) reported emergent skin symptoms within 3 months of treatment with LTG of which 20 (5%: 5.9% adults, 3.6% children) were categorized as possible or probable cADRs. Concomitant infection appeared to be present in several cases, particularly in children. OSRs were found in 4.2% of the children using LTG, compared to 0.8% of the adults (p = 0.04). Conclusions Rash during the early phase of LTG treatment is not always drug hypersensitivity. Whenever skin symptoms occur, other potential causes should receive attention to avoid needless discontinuation, particularly in children. However, when early symptoms and signs of severe cADRs are suspected, LTG should promptly be discontinued.

Widespread skeptic attitudes among people with epilepsy toward generic antiseizure drugs - A Swedish survey study.

PURPOSE: To explore associations between the characteristics of people with epilepsy (PWE) and their attitudes toward generic substitution of antiseizure drugs (ASDs) in epilepsy. METHODS: This was a cross-sectional survey study directed at adults with epilepsy using selected brand drugs: Keppra®, Lamictal®, Lyrica® or Topimax®. Symptoms of anxiety and depression, sense of self-efficacy, and beliefs about medicines were assessed. Caregivers were asked to answer for persons with intellectual or communicative difficulties. RESULTS: The total response rate was 41% (n = 178). Almost half (46%) of subjects stated that they would oppose generic substitution (Gen-NEG) if suggested by their neurologist, while 71% would worry about adverse effects and/or increased seizure frequency after a putative switch. Age ≥50 increased the odds of being Gen-NEG (adjusted OR: 2.20, 95% CI: 1.18-4.11). Negative associations with both Gen-NEG and worriers were found for education level of high-school diploma or above, employment/studies, and prior experience of generic ASD switch. The proportion of worriers was much higher among caregivers (21/22) compared to subjects with epilepsy (106/156). CONCLUSION: High proportions of PWE express concerns regarding generic substitution of ASDs. The elderly and caregivers seem to express particular concerns. Identifying ways to diminish negative outcomes and worries in connection with a switch is an important future field of research in order to ensure high quality, cost-effective health care for the most vulnerable people in our societies.

[Pharmacokinetics of antidepressants during pregnancy]. / Allt fler kvinnor i fertil ålder tar antidepressiva läkemedel.

Depression is common during pregnancy, and a considerable proportion of pregnant women take antidepressants. Modern antidepressants (e.g. SSRIs) are fairly safe to use during pregnancy. Several physiological changes occur in the pregnant state, possibly affecting the pharmacokinetics of many drugs. Metabolism via CYP enzymes are important for the elimination of antidepressants. This metabolism may increase, decrease or remain constant throughout pregnancy. The activity of CYP2D6 increases drastically with pregnancy progression, causing decreasing serum concentrations of drugs metabolised via this enzyme. Examples of such drugs are paroxetine and fluoxetine. The field of pregnancy-related pharmacokinetics of antidepressants is still in its early stages. More research will be necessary in the future, to enable evidence-based clinical decisions and optimise antidepressant treatment for pregnant women.

The emerging role of omega-3 fatty acids as a therapeutic option in neuropsychiatric disorders.

The prevalence of neurologic and psychiatric diseases has been increasing for decades and, given the moderate therapeutic efficacy and safety profile of existing pharmacological treatments, there is an urgent need for new therapeutic approaches. Nutrition has recently been recognized as an important factor for the prevention and treatment of neuropsychiatric disorders. The omega-3 polyunsaturated fatty acids (n-3 PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) play critical roles in neuronal cell function and neurotransmission as well as inflammatory and immune reactions that are involved in neuropsychiatric disease states. A large number of experimental and epidemiological studies provide a strong basis for interventional clinical trials that assessed the clinical efficacy of n-3 PUFAs in various neurological and psychiatric disorders. Most of these trials found beneficial effects of dietary supplementation with EPA and DHA, and no serious safety concerns have emerged. This review gives an introduction to recent findings on the clinical efficacy of n-3 PUFAs in various neuropsychiatric disorders and the underlying biochemical mechanisms. In addition, the reader will be enabled to identify common methodological weaknesses of clinical studies on n-3 PUFAs, and suggestions for the design of future studies are given.

Quality of life after switching to generic levetiracetam - A prospective comparative study.

BACKGROUND: Improved quality of life (QoL) is one of the most important objectives in the treatment of epilepsy. Recent prospective, clinical studies proved no significant differences between brand antiepileptic drugs (AEDs) and their generic equivalents in terms of seizure control, pharmacokinetics, or safety. In this study, we focused on possible changes in QoL and adverse events in connection with generic substitution of levetiracetam (LEV). METHODS: This was a prospective, naturalistic, two-cohort, twin-center study. After a baseline period of 10 weeks, outpatients with epilepsy on stable treatment with Keppra® either continued on this brand (reference group, n = 16) or switched to generic LEV (1A Pharma®) (study group, n = 16) for an eight-week study period. The Quality of Life in Epilepsy Inventory-31 (QOLIE-31) and an adverse events' questionnaire were administered at inclusion, after baseline, and at the end of the study period. The study protocol included a close clinical follow-up with repeated LEV serum concentration measurements and nurse-led outpatient visits. RESULTS: Clinically relevant improvements in overall QOLIE-31 scores according to minimally important change (MIC) estimates were seen in both groups. QOLIE-31 subscales in both groups showed significantly less worry about seizures at the end of the study compared to scores at inclusion (study group: p = 0.01; reference group: p = 0.02). No significant deterioration in QoL or adverse events were observed following generic substitution. No switchbacks occurred. CONCLUSIONS: We found reduced seizure worries over time among people with epilepsy allocated to either generic switch or continued treatment with brand LEV. We hypothesize that the nurse-led structured follow-up had an impact on seizure worries and switchback rates because of reduced nocebo effects. Further studies on generic AED substitution, focusing on psychological outcome measures, are warranted to test this supposition.

An evaluation of zonisamide, including its long-term efficacy, for the treatment of focal epilepsy.

INTRODUCTION: About 70 million people worldwide are estimated to suffer from epilepsy. Despite a large variety of old and new antiepileptic drugs on the market, about 30% of people with epilepsy do not become seizure-free with medical treatment. This is a major individual and public health burden. Most of these difficult-to-treat patients are having focal seizures. Zonisamide is effective against focal seizures in adults and children and, thus, a therapeutic option for such patients. Its safety profile needs special attention. Areas covered: Herein, the authors discuss the pharmacology, clinical efficacy and the adverse effects of zonisamide. The article is derived from clinical trial data, long-term studies, meta-analyses, review articles, text books, webpages, and official license information. Expert opinion: Zonisamide has proven to be efficacious in focal epilepsy in children and adults, although it is not more effective than carbamazepine or other antiepileptic drugs. It is also effective in generalized epilepsy and in several other conditions of the CNS. Its safety profile may prevent it from becoming a first-line drug for focal epilepsy or any other indication.

Mechanisms Underlying Aggressive Behavior Induced by Antiepileptic Drugs: Focus on Topiramate, Levetiracetam, and Perampanel.

Antiepileptic drugs (AEDs) are effective against seizures, but their use is often limited by adverse effects, among them psychiatric and behavioral ones including aggressive behavior (AB). Knowledge of the incidence, risk factors, and the underlying mechanisms of AB induced by AEDs may help to facilitate management and reduce the risk of such side effects. The exact incidence of AB as an adverse effect of AEDs is difficult to estimate, but frequencies up to 16% have been reported. Primarily, levetiracetam (LEV), perampanel (PER), and topiramate (TPM), which have diverse mechanisms of action, have been associated with AB. Currently, there is no evidence for a specific pharmacological mechanism solely explaining the increased incidence of AB with LEV, PER, and TPM. Serotonin (5-HT) and GABA, and particularly glutamate (via the AMPA receptor), seem to play key roles. Other mechanisms involve hormones, epigenetics, and "alternative psychosis" and related phenomena. Increased individual susceptibility due to an underlying neurological and/or a mental health disorder may further explain why people with epilepsy are at an increased risk of AB when using AEDs. Remarkably, AB may occur with a delay of weeks or months after start of treatment. Information to patients, relatives, and caregivers, as well as sufficient clinical follow-up, is crucial, and there is a need for further research to understand the complex relationship between AED mechanisms of action and the induction/worsening of AB.

Should pregnant women receive lower or higher medication doses? / Skal gravide ha lavere eller høyere legemiddeldoser?

Choosing appropriate medication doses for pregnant women is a difficult balancing act, as the mother's need for treatment must be weighed against the risk of fetal harm. The latter is frequently considered to be the most pressing concern, with the result that drugs are discontinued or doses reduced. It is perhaps less well known that pregnant women often need higher medication doses than those who are not pregnant.

Zonisamide serum concentrations during pregnancy.

PURPOSE: To investigate the change in zonisamide (ZNS) serum concentration and its consequences in pregnant women with epilepsy. METHODS: Six hospitals in Norway and Denmark screened their records for women who had been using ZNS during pregnancy. Absolute serum concentrations as well as concentration/dose (CD)-ratios were compared to non-pregnant values. Descriptive data on seizure control and obstetrical data were also collected. RESULTS: 144 serum concentrations from 23 pregnancies in 15 individual women with epilepsy were included (six on monotherapy). The mean ZNS serum concentration fell to a minimum of 58.6 ±â€¯15.1%, while the C/D-ratio fell to as low as 55.1 ±â€¯15.3% of the non-pregnant-value. The lowest values were seen in gestational months six to nine, and the individual nadir varied considerably (range: 24-81% of the non-pregnant value). Four out of ten previously seizure-free patients experienced breakthrough seizures. Gestational age, weight at birth and head circumference of the newborns were within the reference ranges. CONCLUSIONS: ZNS serum concentrations may fall by over 40% during pregnancy, with large interindividual variability. In some patients, this may lead to worsened seizure control. These findings are in line with reports on other AEDs and suggest that regular therapeutic drug monitoring and dose adjustments may be useful.

Reference ranges for antiepileptic drugs revisited: a practical approach to establish national guidelines.

BACKGROUND AND OBJECTIVE: Laboratories sometimes use different reference ranges for the same antiepileptic drug (AED), particularly for new and poorly investigated drugs. This may contribute to misunderstandings, concerns or inappropriate dose changes, which in turn may affect therapeutic effect, drug safety or treatment adherence. Therefore, the Norwegian Association of Clinical Pharmacology wished to update and harmonize the reference ranges for AEDs and establish national guidelines for Norway. METHODS: A working group collected information on the reference ranges used by Norwegian laboratories for all commonly used AEDs. These reference ranges were compared to recent recommendations by the International League Against Epilepsy, current literature, applicable clinical studies, reference ranges used by leading Northern European epilepsy centers outside of Norway, and routine data derived from Norwegian laboratory databases. RESULTS: Reference ranges varied between laboratories for four of 23 available AEDs (lamotrigine, valproate, eslicarbazepine and oxcarbazepine). For four AEDs (brivaracetam, perampanel, stiripentol and sulthiame), reference ranges had not previously been established. In total, 13 reference ranges were either harmonized, updated or newly established. No changes were applied to the remaining 10 AEDs. CONCLUSION: Updated and harmonized reference ranges are now available for 22 of the 23 AEDs available in Norway. The exception is vigabatrin (reference range not applicable). Revision of reference ranges is an important part of pharmacovigilance of AEDs and must be a continuous process based on current literature and clinical experience.

Impact of generic substitution on levetiracetam serum concentration-A prospective study in an outpatient setting.

BACKGROUND: Switching patients from a branded antiepileptic drug (AED) to a generic is often challenging. Several studies have shown that considerable proportions of patients report deteriorated seizure control or increased adverse effects, enforcing a switchback to the original drug. Since tolerability and seizure control usually correlate with AED serum concentrations, we examined the fluctuation of levetiracetam (LEV) serum concentrations in patients with epilepsy before and after generic substitution. METHODS: This was an 18-week, naturalistic, open, prospective, two-center study. After a baseline period of 10 weeks, 33 outpatients on stable treatment with branded LEV (Keppra®) either continued with this product or were switched overnight to a generic LEV preparation (1A Pharma) for an eight-week study period. Throughout the study, patients were monitored with bi-weekly LEV serum concentration measurements and seizure diaries. RESULTS: 16 out of 33 patients were switched to a generic LEV product. No switchbacks were seen. LEV dose, LEV serum concentrations, fluctuation index and concentration/dose-ratio (C/D-ratio) were not significantly different within-group (baseline vs. study period) or between-group. Large within-subject variability in serum concentrations was seen in both groups. None of the patients that were seizure-free before inclusion experienced seizures while on the generic LEV product. CONCLUSIONS: Our results show equal fluctuation of LEV serum concentrations with branded LEV and the generic LEV. Most importantly, within-subject variability was much larger than the small, non-significant differences between brands.

Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome.

BACKGROUND: Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy. METHODS: This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible. RESULTS: TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53µmol/L (range 13-132µmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three. CONCLUSION: Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful.

No association between non-bullous skin reactions from lamotrigine and heterozygosity of UGT1A4 genetic variants *2(P24T) or *3(L48V) in Norwegian patients.

PURPOSE: High initial serum concentrations increase the risk of cutaneous adverse reactions. Genetic variants of the main metabolizing isoenzyme, uridine diphosphate glucuronosyltransferase (UGT) 1A4 influence the elimination of lamotrigine (LTG). Our aim was to investigate the potential association between the two best studied variants, *2 (P24T) and *3 (L48V), and the occurrence non-bullous skin reactions from LTG. METHOD: The study included 29 patients of Caucasian ethnicity with a history of non-bullous skin reactions from LTG. 184 subjects tolerant to LTG for at least three months were used as controls. UGT1A4 genotyping was performed in all patients and controls by sequencing of the first part of exon 1. Six controls were excluded due to rare genetic variants. RESULTS: Two of 29 subjects (7%) with rash from LTG were heterozygous for UGT1A4 *2, compared to 23 of 178 (13%) tolerant controls (p=0.54). Four of 29 subjects (14%) with rash from LTG were heterozygous for UGT1A4 *3 compared to 25 of 178 (14%) tolerant controls (p=0.97). CONCLUSION: It is unlikely that heterozygosity of the UGT1A4 genetic variants *2(P24T) or *3(L48V) influences the risk of non-bullous skin reactions in patients treated with LTG.

Hormone replacement therapy with estrogens may reduce lamotrigine serum concentrations: A matched case-control study.

Lamotrigine (LTG) is an antiepileptic drug that is metabolized via glucuronidation. Since the glucuronidizing enzyme is inducible by estrogens, LTG serum concentrations may fall by 50-60% when combined with hormonal contraceptives that contain ethinyl estradiol (EE). Little is known about a possible interaction between estrogens used for hormone replacement therapy (HRT) and LTG, and the few available data are conflicting. Data from serum samples analyzed for LTG were therefore retrieved from a routine therapeutic drug monitoring database. Users of HRT and EE were identified and matched with controls for age and dose. No enzyme-inducing or enzyme-inhibiting comedication was allowed. LTG serum concentration-to-dose ratios (CDRs) were calculated. Case groups and their respective control groups were compared by the Mann-Whitney U test. Seventy-nine HRT users (dose range 1-4 mg/day) and 200 EE users (dose range 20-40 µg/day), as well as 158 and 400 matching controls, respectively, could be included. Both EE users and HRT users had significantly lower mean LTG CDRs than their respective matched controls. These results suggest that HRT with estrogens may reduce serum LTG concentrations.

The Impact of Pharmacokinetic Interactions With Eslicarbazepine Acetate Versus Oxcarbazepine and Carbamazepine in Clinical Practice.

BACKGROUND: Eslicarbazepine acetate (ESL) is a new anti-epileptic drug (AED) chemically related to oxcarbazepine (OXC) and carbamazepine (CBZ) and is increasingly used in clinical practice. The purpose of the study was to investigate 2-way pharmacokinetic interactions between ESL and other AEDs as compared to OXC and CBZ. METHODS: Anonymous data regarding age, gender, use of AEDs, daily doses and serum concentration measurements of ESL, OXC, CBZ and lamotrigine (LTG) and other AEDs were retrieved from 2 therapeutic drug monitoring (TDM) databases in Norway. Drugs were categorized according to their known potential for interactions. Concentration/dose (C/D) ratios were calculated. RESULTS: Data from 1100 patients were available. The C/D ratios of ESL and OXC were unchanged in combination with enzyme-inducing AEDs or valproate (VPA). The C/D ratio of CBZ decreased by 40% and 22% in combination with other enzyme-inducing AEDs or VPA, respectively, pointing to an increased clearance. ESL demonstrated no significant enzyme-inducing effect on LTG metabolism although there was a 20% and 34% decrease in the C/D ratio of LTG in combination with OXC and CBZ, respectively. CONCLUSIONS: Possible pharmacokinetic interactions have been studied for ESL as compared to OXC and CBZ. The pharmacokinetics of ESL is not affected by enzyme-inducing AEDs or VPA and does not affect the metabolism of LTG in contrast to OXC and CBZ. The study demonstrates the value of using TDM databases to explore the potential for pharmacokinetic interactions of new AEDs.