Epilepsy is a clinically complicated syndrome and a commonly diagnosed neurological disorder. In addition to seizures, a high proportion of patients also develop comorbidities. It has been found that ~50% of adult patients with active epilepsy have comorbid conditions, including somatic as well mental comorbidities, with anxiety and depression being the most common psychiatric comorbidities. A number of previous studies have reported that about 16–23 and 18–22% of patients with epilepsy (PWE) suffered from comorbid depression and anxiety disorders, respectively, with the prevalence of the former in patients with recurrent seizures being as high as 55%. The presence of the psychiatric comorbidities can increase the recurrence, mortality, and severely affect the quality of life in PWE (1–4). Likewise, the various somatic comorbidities can complicate antiepileptic therapy and increase the medical and social burden.

Anti-seizure medications (ASMs) are currently being used as the main treatment for epilepsy. Epilepsy-associated comorbidities have a crucial impact on the treatment decisions, and some ASMs may also influence these comorbidities (5). Consequently, in clinical practice, it is necessary to screen and diagnose the different comorbidities in a timely and accurate manner. This can aid to comprehensively assess the necessity, safety, as well as feasibility of the treatment, which can facilitate the selection of appropriate treatment plan, individualize the therapy based on the etiology and significantly improve the symptoms in PWE (6, 7).

The new ASM lacosamide has been approved for the management of patients with partial-onset seizures because to its effectiveness, safety and tolerability (8–13). The seizures are primarily caused by abnormal excess or synchronization of the neuronal activity (14). The voltage-gated sodium channels (VGSCs) are activated during the membrane depolarization and play a crucial role in the generation and transmission of action potentials in the neurons by controlling the flow of sodium ions across the cell membrane (15). Abnormal activity of VGSCs has been found to closely linked with the pathophysiology of epilepsy (16). In contrast to the conventional sodium channel blocking ASMs (i.e., phenytoin and carbamazepine, etc.), it has been postulated that lacosamide can selectively increase the slow inactivation of VGSCs, thereby controlling the pathophysiological neuronal hyperexcitability by regulating the long-term availability of sodium channels (17–19). Electrophysiologic studies have shown that lacosamide can alter the slow inactivation voltage curve toward hyperpolarization and significantly accelerate the slow inactivation state of VGSCs (20–22). In addition, lacosamide can enhance the slow inactivation of VGSCs at potentials close to the resting membrane potential of the neurons, thus inhibiting action potential generation and neuronal firing (22). Moreover, another recent in vitro study has suggested that lacosamide can bind to fast-inactivated states of VGSCs similarly to other sodium channel blockers, but with slower binding and unbinding kinetics (23). Abnormal axon sprouting can lead to the rewiring of neuronal circuits, which can also contribute to epileptic seizures (24, 25). Collapsin response mediator protein-2 (CRMP2) is a cytoplasmic protein that is expressed mainly in neurons and oligodendrocytes, and can mediate the neuronal polarity, neurite outgrowth and axonal growth (26). Lacosamide may also regulate CRMP2 in an indirect functional interaction to prevent the formation of excitatory synaptic connections in epileptogenesis (5, 27, 28). In addition, to enhance the pharmacological effects, lacosamide can be combined with a variety of ASMs or non-ASMs due to the modest influence of drug-drug interactions during the metabolism (29). In recent years, lacosamide has also been found to have substantial positive effects on multiple epilepsy-associated comorbidities, and thus may lead to novel strategies for the clinical treatment options (3, 29).

Epilepsy-associated comorbidities can increase the risk of seizures by up to tenfold, thus suggesting that epilepsy and epilepsy-associated comorbidities share diverse pathophysiological mechanisms (30). Certain comorbidities can induce epilepsy by direct or indirect mechanisms (1), and epilepsy or antiepileptic treatment might also trigger or promote some comorbidities (31). In addition, some shared risk factors or genetics can contribute to the development of epilepsy-associated comorbidities (1, 32).

In recent years, researchers have explored the effects of lacosamide on anxiety and depression in PWE. A post hoc analysis of a large randomized controlled trial SP0993 revealed that the efficacy of lacosamide monotherapy was comparable to that of carbamazepine controlled-release (CBZ-CR) in a subgroup of epilepsy patients with comorbid psychiatric disorders, such as anxiety, depression, and insomnia (71). Moreover, in patients with partial-onset seizures, the treatment of epilepsy with lacosamide also may improv anxiety, depression as well as quality of life without worsening indicators of sleep quality and fatigue (3, 73, 74). In addition, lacosamide improved mania, anxiety, depression, and global functioning in the short term when used for the treatment of patients with bipolar disorder compared to other ASMs (72).

However, whether lacosamide can positively affect mood disorders in PWE remains controversial, with some studies suggesting that it has no significant effect on the mood or can exhibit only positively affects patients with major depressive symptoms at the baseline (75), but it is unlikely to have a negative impact and no serious safety concerns have been reported. Under standard clinical treatment conditions, the incidence of the cardiovascular and psychiatric adverse events associated with lacosamide is minimal, which was identical to the incidence of treatment discontinuation owing to adverse events (76). Therefore, it might still be a safe and effective treatment option for PWE with psychiatric comorbidities (the details of the included clinical trials are presented in Table 1).

The prevalence of the comorbid epilepsy in people with intellectual disability (PWID) ranges from 20 to 30% and increases with severity of intellectual disability (ID). It has been established that ~16% of people with epilepsy also have some degree of ID, which is significantly higher than the prevalence of <1% in the overall population (77–79). The patients with such comorbidities might exhibit more complicated neuropsychiatric characteristics that can impair the treatment outcomes, exacerbate clinical management challenges, and raise the risk of mortality (80, 81).

Brenner et al. (82) included 132 patients with refractory epilepsy in PWID in study whose primary endpoint variables were the retention rates of lacosamide which were estimated by the Kaplan-Meier method. The results showed that the retention rates were 64% at 1 year, 57% at 2 years, and 56% at 3 years, and that ID and seizure severity did not affect the continued use of the drug. However, except for a high incidence of behavior-related side effects, other adverse events were similar to those reported in the previous studies in the general population. Overall, the findings of this study concluded that lacosamide may be effective and safe for the management of epilepsy patients in PWID. In addition, another non-interventional, single-center study reported evaluating the efficacy of lacosamide in patients with ID and drug-resistant epilepsy. The results showed improved Clinical Global Impression scale in 61% of patients, with retention rates of 71 and 65% at 12 and 24 months, respectively, thus suggesting that adjunctive lacosamide may be a suitable antiepileptic treatment option for ID patients (83).

Stroke is a common cause of epilepsy in the elderly population, with seizure rates ranging from 3.3–3.8 to 7–14% following ischemic and hemorrhagic strokes, respectively (84–87). Seizures in the stroke patients may be caused by distinct mechanisms such as release of cytotoxic neurotransmitter leading to the neuronal hyperexcitability and deposition of gliosis and hemosiderin (88). Seizures are also prevalent in patients affected with brain tumors, with a risk of 60–100% for low-grade gliomas and 40–60% for glioblastomas (89).

According to the findings of a small observational study, 50% of elderly patients with post-stroke non-convulsive status epilepticus (NCSE) displayed controlled epileptic activity within 45–60 min of intravenous lacosamide treatment, with no recurrence and adverse effects reported over a 24-h period. This finding confirmed that lacosamide was safe and effective, thus suggesting that it has the potential to become the drug of choice for the prevention and treatment of post-stroke NCSE in the elderly (90). In a prospective study compared with the historical control group, it was concluded that the clinical efficacy of lacosamide as an add-on therapy might be superior to the historical group treated with levetiracetam in patients with brain tumor-related epilepsy, without affecting the mood and quality of life (91). Rosenow et al. (92) analyzed the efficacy of lacosamide in epilepsy patients of cerebrovascular etiology based on three large clinical studies and reported that the monotherapy efficacy of lacosamide was numerically superior to carbamazepine-CR, with a higher proportion of lacosamide patients being seizure-free after 6 and 12 months of therapy than carbamazepine-CR patients. These observations suggested that lacosamide may be useful for the treatment of epilepsy with cerebrovascular etiology.

In addition to the aforementioned disorders, several common somatic comorbidities of epilepsy include the cardiovascular, musculoskeletal, respiratory, and nutritional disorders (93, 94). Traditional ASMs (e.g., carbamazepine) have a high potential for drug-drug interactions, negatively affect the lipid metabolism and can elevate the levels of various cardiac markers (95). Therefore, epilepsy-associated comorbidities can also restrict the options for epilepsy treatment (44). Among the newer ASMs, lacosamide can display relatively less interactions with other drugs, and studies have shown that it also has fewer respiratory effects, with nasopharyngitis being a frequent adverse event (7.2–17.2% occurrence) (8, 96). It has been reported that the drug does not prolong the QTc interval or adversely affect the heart rate in adult patients with partial-onset seizures and the maximum recommended dose (400 mg/day) of adjunctive lacosamide is not significantly associated with cardiac effects, except for small changes in PR interval without any major symptomatic consequences (97). It has also been found that favorable changes in the hormones and lipid levels can be observed in PWE after the lacosamide treatment (98).

In all clinical studies, dizziness is the most common adverse effect of lacosamide (99, 100). In randomized, double-blind, placebo-controlled studies, the incidence of dizziness associated with lacosamide ranged from 23.1 to 25.9%, compared to 8–9.2% for placebo (101, 102). A 3-year follow-up of 473 PWE suggested a final dizziness rate of 26.4% (103). Another typical TEAE of lacosamide is headache. Ben-Menachem et al. (104) conducted a long-term trial of 116 patients on open-label treatment, with a median exposure duration of 854 days, and headache incidence was 9.4%. In another double-blind study with a median exposure time of 630 days, 15.1% of participants in the lacosamide group experienced headaches (96). Vision-related adverse effects such as diplopia are thought to be associated with sodium channel blockers (105). Rosenow et al. (106) recruited 376 patients and found a 13.8% incidence of diplopia over the course of 3 years. Nausea/vomiting and somnolence are also common side effect associated with lacosamide treatment (12, 107). A meta-analysis revealed that the incidence of nausea/vomiting was 9.3% (108). Long-term follow-up showed a range of 6.1% to 8.7% somnolence occurrence (96, 103). The above-mentioned frequent side events are more likely to occur during the first 3 months of treatment, and the majority are well-tolerated (100). It is noteworthy that between 0.4 and 1.7% of lacosamide-treated individuals experienced suicidal ideation or behavior (62, 101, 109). Although there is no evidence to suggest that lacosamide increases the risk of suicide-related events more than other ASMs, caution is still necessary (100).

The complex pathogenesis and clinical manifestations of epilepsy, as well as the propensity to acquire various comorbidities simultaneously can pose significant challenge to application of optimal therapy and increase the clinical burden. Different ASMs can also exacerbate or induce epilepsy-associated comorbidities along with their anti-epileptic effects. Consequently, numerous considerations are needed while selecting a suitable pharmacological treatment strategy. The current findings support that lacosamide may have substantial positive effects on multiple comorbidities without exhibiting serious safety concerns and may provide some reference for clinical treatment. Future studies with larger sample sizes or in specific subgroups of patients are also expected to further validate and demonstrate the influence of lacosamide on the clinical benefit in epilepsy patients with different comorbidities.

ZH drafted the manuscript. JL conceptualized and designed the study and revised the manuscript. Both authors contributed to the article and approved the submitted version.