Epidemiological Study of Acute Poisoning for Antiepileptic Drugs: A 2-Year Retrospective Study in Cracow, Poland Epidemiological Study of Acute Poisoning for Antiepileptic Drugs: A 2-Year Retrospective Study in Cracow, Poland

The aim of this study was designed to examine the rate of occurrence of antiepileptic drug overdose in 2002 and 2012 in Cracow, Poland, and analyze the demographics and clinical features of the patients Antiepileptic drugs (AEDs) intoxication. A retrospective study included all the patients admitted in to the Toxicology Units in Cracow for AED intoxications in 2002 and in 2012. Patients were identified of discharge diagnoses (ICD-10). AED intoxication were 5.40% of the total admissions. Mean age of the patients was 35.88 ± 12.54 years. The female-to-male ratio was 1:1.7. The most frequent AED was carbamazepine ( n = 140), followed by valproate ( n = 31). The most frequent motivation was intentional intoxication ( n = 166, 94.86%). Ethanol was coingested by 51 patients (29.14%). Most of the patients ingested other drugs (32%). Antiepileptic drugs intoxication accounted for only of 7.13% of all cases admitted to the abovementioned toxicology units in 2002 and 2012 in Cracow. Our studies show that most of the AED poisoning cases in those years were caused by drugs belonging to the old generation antiepileptic drugs, including carbamazepine and valproic acid. The majority of the intoxication cases was related to suicidal poisoning and commonest identified reason of self-intoxication were issues with self including attention-seeking behavior.


Introduction
Antiepileptic drugs (AEDs) are mainly used in the treatment of epilepsy and treatment of some mental disorders. Patients suffering from it are at increased risk of suicidal ideation, suicide attempts, and completed suicides. The widespread use of AEDs resulted also in the fact that this group of drugs is frequently encountered as the cause of acute toxicity among patients treated at the toxicology unit around the world. Few data are available regarding the rate of AED overdose in individual countries. For example, AEDs are approximately 3% of the intoxication cases in the USA [1]. Other studies shows a 25% increase in the rate of occurrence of antiepileptic drug overdose between 2000 and 2006 [2,3] in the USA. Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System states that AEDs comprise 3.2% of all causes of poisoning in adults (>19 years old) [4]. The Brazilian study by Bonilha et al. show that in Saõ Paulo and its outskirts in 2001, AED poisoning accounted for 16% of all the poisonings [5]. In Edinburgh (the UK, Scotland) for the period from 2000 to 2007, AED poisonings accounted for 3.4% of all poisonings [6]. In Marmara region (Uludag) in west Turkey for the period 1996-1999, 6.7% of medicinal intoxications was due to AEDs [7]. In France (Paris emergency departments), the prevalence of poisoning with AEDs for the period 1992-1993 was 2.9% and for 2001-2002 was 0.9% [8]. In Iran (studies conducted in the referral center for all cases of poisoning occurring in Tehran), AED poisoning accounted for 4.8% of all the pharmaceutical intoxications [9].

Aim
This study was designed to examine the rate of occurrence of antiepileptic drug overdose in 2002 and 2012 in Cracow, Poland, and to analyze the demographics and clinical features of the patients AED intoxication.

Statistical analysis
The data were collected in a Microsoft Excel database. Data are presented as mean and standard deviation (SD). Statistical analysis was performed using Statistical Programme for Social Sciences (SPSS). We used Pearson's χ 2 test to evaluate the association (and its strength) of the frequencies of data distribution among the different drug groups. A value of p<0.05 was considered to be statistically significant.

Results
Of all the poisoning cases (n = 2455 patients), 175 (7.13%) patients with AED intoxications were admitted to the Toxicology Unit in Cracow, Poland, in 2002 and 2012. Females accounted for 37.14% of the cases and males accounted for 62.86% with a female-to-male ratio of 1:1.7. The mean age of patients in the sample was 35.88 years (SD ± 12.54). Out of 175 patients with AED intoxications, 170 took one of the antiepileptic drugs, while 5 patients received more than one AED (carbamazepine [CBZ] + valproid acid [VPA]). The majority of patients receiving AED took carbamazepine only (n = 140). Valproate (n = 31) was the second most common (but 5 out of 31 have taken VPA in combination with CBZ). Smaller numbers were found for the remaining AEDs (<1% each): lamotrigine (n = 1), phenytoin (n = 1), and topiramate (n = 2)-see Table 2. Men were more likely to ingest carbamazepine than women (Person χ 2 = 11.7, p < 0.0001). The distribution of serum levels of AEDs was found as follows: 11 patients had therapeutic serum levels, 4 patients had subtherapeutic level of drugs, while in 141 cases, the drug concentrations were at the toxic level. AED concentrations in serum could not be measured in 23 patients (13.14%). Table 3 shows the serum-level distributions for individual antiepileptic drugs.

Topiramate level N (%)
Toxicological analysis confirmed presence of TPM in blood. 1

Lamotrigine level N (%)
Toxicological analysis confirmed presence of LTG in blood 1
The PSS was minor in 93 patients, moderate in 71 patients, severe in 10 patients, and fatal in 1 patient. Alcohol was involved in 29.14% of cases. An alcohol consumption did not differ significantly depending on the gender (Pearson's χ 2 = 0.1, p = 0.745).
One-third of the patients (33.71%) had at least one suicide attempt before hospitalization; however, no information was available regarding the severity of these suicide attempts. Two patients (1.14%) had attempted suicide during hospitalization.
Suicidal and accidental poisoning, respectively, represented 94.86% and 3.43% of acute intoxications cases. The cause of poisoning in three cases (1.71%) could not be found. The most frequent reason of intoxication was issues with self-including attention-seeking behavior (16%), followed by person to person conflicts (12.57%). The frequency of poisoning cases between different circumstances did not differ significantly depending on the gender (Pearson's χ 2 = 0.5, p = 0.920). There was no association between previous history of parasuicide, gender, and AED intoxication (p > 0.05).
Nearly half of the poisoned patients (44.57%) described in this report were treated with AEDs because of epilepsy or psychotic disorders prior to the poisoning.
More than half of the patients had a diagnostic history of psychiatric disorders, and 66 (37.71%) a diagnostic history of alcoholism.
Most patients (68%, n = 119) were discharged to homes in good condition, 33 (18.9%) were transferred to a psychiatric ward. As many as 22 patients (12.57%) did not complete hospitalization because they left the hospital at their own request.
The characteristics of the suicide attempts are shown in Table 4.

Discussion
Our results show a lower probability of AED intoxication in women than in men (37.1% vs. 62.9%). However, most studies observe that women were more likely than men to undergo drugs intoxications, including antiepileptic drugs [7,[11][12][13][14]. In Poland, women more often than men attempted suicide; however, men tend to be more successful than women in actual lethality. Other studies have confirmed this result [15][16][17]. In Poland, according to the data by the Police Headquarters the most common way to commit suicide is hanging (72%), other popular methods often include: jumping from a height (6.9%) and poisoning (4.6%) [18]. The Polish study by Bolechała et al. show that in Cracow, in 1991-2000, suicidal poisoning was in the male-to-female ratio of 1.8:1 [19].
In 2002, 5100 people died by suicide in Poland. According to the data, the vast majority of the suicides were committed by males (n = 4215). Whereas, in 2012, in Poland 4177 people committed suicide, including 3569 men [18]. In our study, twofold more men in 2002 committed suicide than in 2012.
In our study, the most commonly encountered drug was carbamazepine which generally corresponded with community prescribing patterns. It is also compatible with reports from Edinburgh [6], Iran (Tehran) [9], and São Paulo [5]. Another frequently used drug in our study was valproic acid. It is known from the literature that the number of overdose cases of sodium valproate is steadily increasing in civilized countries [20,21]. Carbamazepine and sodium valproate were the most frequently used AEDs. In the present study, men were more likely to use carbamazepine than women (p < 0.0001). However, in a study by Nixon et al. (data from Edinburgh, the UK), women were more likely to ingest lamotrigine than men (p < 0.0001) and less likely to ingest sodium valproate (p = 0.0234) [6].
In our study, a higher than expected proportion of patients had coingested other (taken for reasons other than epilepsy) drugs (32%), which was in concordance with a previous report from Turkey [22]. However, this proportion was higher in the study by Nixon et al. in Edinburgh (65.4%) [6]. In our study, the most frequently taken drug types were antipsychotics (12%) as in the study by Çelenk [18].
The suicide risk in patients with epilepsy is significantly higher than in the general population. Standardized mortality ratio for suicides among epileptic patients is estimated at 3.5-5.8 in comparison with the general population [23,24]. In a review of 21 studies, a mean of 11.5% (range: 0-67%) of the deaths of patients with epilepsy were attributed to suicide [25]. The proportion of deliberate self-poisoning was 94.86% in our study. Suicide attempt was the most frequent circumstance observed in Brazil (Saõ Paulo) [5] and Iran (Tehran, 98.9%) [9], too.
In a study by Harris et al., suicide attempt among patients with epilepsy increases future suicide risk to 38.4% compared with the general population [26]. Similar results were obtained in the Swedish study (data from Stockholm county area), where that percentage was 46.2% [17]. Our study show that every third patient had a history of previous parasuicide. Our findings are consistent with those of Hassanian-Moghaddam et al. [9]. Previous suicide attempt is a risk factor for suicide attempts in future.
The most important reasons for suicide attempts in epileptic patients are common to general population and other chronic disease. Some authors suggest that concomitant depression and other psychiatric disorders are the main risk factors of suicidal thoughts [27]. Danish study confirmed that 2.32% (n = 492) individuals who committed suicide had epilepsy compared with 0.74% (n = 3140) controls. In case of comorbid psychiatric disease, overall risk of suicide in epileptic patients appears to be nearly 14-fold higher, including 32-fold for affective disorders and 12-fold for anxiety disorders [28], and it is almost twice higher in the case of those with previous mental disorders and 12.5-fold for schizophrenia [29]. Similarly, Swedish study showed that epilepsy concomitant with psychiatric disorders is associated with ninefold higher risk of suicide [23]. Logistic regression analysis in a study by Hassanian-Moghaddam et al. revealed that the presence of medical disorders and history of psychiatric events is associated with AED intoxication [9]. In the present study, most patients had a history of psychiatric disorders (i.e., depression, personality disorders, bipolar disorder, and schizophrenia) or somatic disorders.
The mental illness (including depression, bipolar disorder, schizophrenia, and others) was the cause for the vast majority of suicides in Poland, in both 2002 and 2012 (respectively, n = 1017 and n = 808) [18].
On the other hand, Buljan et Santić demonstrated that among hospital-treated epilepsy patients, beside psychiatric comorbidity, difficult family situation is a significant factor of higher suicide risk. Study results showed that 14.6% of the epileptic patients treated at one hospital in Zagreb (Croatia) have attempted suicide [30]. This study revealed that person-toperson conflicts were reasons for attempting suicide for 12.57% of the patients. In our study, in 107 if the cases, the cause of suicide is unknown because some patients discharged from hospital at their own request refused to answer the question on the reason for attempting suicide.
Alcoholism is associated with a high risk for suicidality, suicide attempts, and completed suicides [31,32]. Up to 40% of the persons with alcoholism attempt suicide at some time or other, and 7% end their lives by committing suicide [33]. Alcohol dependence syndrome was diagnosed in 37.71% of our patients. Ethanol was coingested by 51 patients (29.14%) in this study and by 94 patients (15.3%) in a study by Nixon et al. [16]. Alcohol use is associated with risk behaviors [34,35]. People who are under the influence of alcohol are more likely to attempt suicide. Alcohol intoxication increases suicide risk up to 90 times in comparison with abstinence [34].
In Poland, in 2002 and in 2012 among the suicides, the vast majority was under the influence of alcohol (respectively, n = 1069 and n = 1438) [18].
In 2008, the FDA issued an alert contained a warning against an increased risk of suicidality (suicidal ideation or behavior) for antiepileptic drugs [36]. The FDA analyzed the reports of suicidality from placebo-controlled clinical studies of 11 antiepileptic drugs. In this analysis, patients receiving antiepileptic drugs had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.22%). In the present study, 44.57% of the patients described in this report were treated with AED because of the epilepsy or psychotic disorders prior to the poisoning. The number of cases of AED overdose is less in 2012 than in 2002, almost half. Some explanation for this may be that currently, there is a widespread use of drugs in the new generation. These newer drugs are more efficacious and have a better safety as compared with conventional (older) AED. In our study, most of the patients had toxic serum drug levels (n = 141, 80.57%). In the abovementioned study from north Turkey, 28 patients (43.8%) had toxic serum AED level [22]. The knowledge of concentration range is significantly useful in clinical practice.
After treatment in the Toxicology Unit, a higher proportion of overdose patients discharged to go home (68%), whereas 18.9% of the patients required transfer to a psychiatric facilities. One death occurred in this study. Like our observation, Nixon et al. reported in the UK study that 14% of antiepileptic drug-overdose patients required transfer to a psychiatric facility, and 78.3% were discharged home [6].

Conclusion
Antiepileptic drugs intoxication accounted for only of 7.13% of all the cases admitted to the abovementioned toxicology units in 2002 and 2012 in Cracow, Poland, and AED poisoning is more common among males. Our studies show that most of AED poisoning cases in those years were caused by drugs belonging to the old generation antiepileptic drugs, including carbamazepine and valproic acid. The majority of intoxication cases were related to suicidal poisoning (94.86%), and commonest identified reason of self-intoxication were issues with selfincluding attention-seeking behavior (16%). Second leading established cause of suicide attempts were person-to-person conflicts (12.57%). Drugs combinations (AED + other drugs) were recorded in 32% of the cases and in 29.14% there occurred combinations between AEDs and alcohol.
Our study was a university hospital-based study, so these results may not be representative of the general population. However, these data still provide important information on the characteristics of the poisoning in this part of Poland. Further work is required to determine the rate of occurrence of antiepileptic drug overdose.