Raoul Di Perri

Effects of Psychotropic Drugs on Seizure Threshold

Psychotropic drugs, especially antidepressants and antipsychotics, may give rise to some concern in clinical practice because of their known ability to reduce seizure threshold and to provoke epileptic seizures. Although the phenomenon has been described with almost all the available compounds, neither its real magnitude nor the seizurogenic potential of individual drugs have been clearly established so far. In large investigations, seizure incidence rates have been reported to range from ∼0.1 to ∼1.5% in patients treated with therapeutic doses of most commonly used antidepressants and antipsychotics (incidence of the first unprovoked seizure in the general population is 0.07 to 0.09%). In patients who have taken an overdose, the seizure risk rises markedly, achieving values of ∼4 to ∼30%. This large variability, probably due to methodological differences among studies, makes data confusing and difficult to interpret. Agreement, however, converges on the following: seizures triggered by psychotropic drugs are a dose-dependent adverse effect; maprotiline and clomipramine among antidepressants and chlorpromazine and clozapine among antipsychotics that have a relatively high seizurogenic potential; phenelzine, tranylcypromine, fluoxetine, paroxetine, sertraline, venlafaxine and trazodone among antidepressants and fluphenazine, haloperidol, pimozide and risperidone among antipsychotics that exhibit a relatively low risk. Apart from drug-related factors, seizure precipitation during psychotropic drug medication is greatly influenced by the individual’s inherited seizure threshold and, particularly, by the presence of seizurogenic conditions (such as history of epilepsy, brain damage, etc.). Pending identification of compounds with less or no effect on seizure threshold and formulation of definite therapeutic guidelines especially for patients at risk for seizures, the problem may be minimised through careful evaluation of the possible presence of seizurogenic conditions and simplification of the therapeutic scheme (low starting doses/slow dose escalation, maintenance of the minimal effective dose, avoidance of complex drug combinations, etc.). Although there is sufficient evidence that psychotropic drugs may lower seizure threshold, published literature data have also suggested that an appropriate psychotropic therapy may not only improve the mental state in patients with epilepsy, but also exert antiepileptic effects through a specific action. Further scientific research is warranted to clarify all aspects characterising the complex link between seizure threshold and psychotropic drugs.

Validating screening instruments for neuroepidemiologic surveys: Experience in Sicily☆

In a hospital setting in Sicily, we assessed a screening instrument developed for a prevalence survey of parkinsonism, peripheral neuropathies, stroke, and epilepsy. The subjects consisted of (1) hospital patients with any of the above-mentioned diseases, to investigate sensitivity; and (2) hospital visitors free of all these diseases, to investigate specificity. The standard for comparison was a clinical evaluation based on specified criteria. Trained interviewers administered the screening instrument, asking subjects to answer symptom questions and to perform simple physical tasks. For the questions and tasks together, the sensitivity estimates were 100% for parkinsonism (n = 21), 96% for peripheral neuropathies (n = 22), 96% for stroke (n = 22), and 96% for epilepsy (n = 22), while the specificity estimate was 86% (n = 21). Analogous estimates were computed for the set of questions, for the set of tasks, and for each question and task individually. Despite limitations in our approach, we concluded that the screening instrument would be adequate for its intended use.

Ischaemic Stroke in Young People: A Prospective and Long-Term Follow-Up Study

Background: A few studies have comprehensively assessed the epidemiology, aetiology, prognosis, and secondary prevention of ischaemic stroke in young adults. To gain further information on this field, we have prospectively studied a hospital-based series of young adults with a first-ever episode of cerebral ischaemia (CI). Methods: Sixty consecutive patients aged 17–45 with ischaemic stroke (55 patients) or transient ischaemic attack within 24 h before hospital admission were recruited and investigated by a standardized rigorous protocol. The patients were followed up for ≧1 year after hospital discharge. Arbitrary doses of aspirin 100 mg/d or ticlopidine 250 mg b.i.d. in case of intolerance to aspirin were given for the secondary prevention. Adjusted-dose oral anticoagulation (INR target 2.5) was used in the presence of cardioembolism or hypercoagulable states. Endpoints included the residual disability, rated by modified Rankin Scale (RS) and Barthel Index (BI), and poststroke recurrence. Results: CI was associated with two or more risk factors in 61.6% of patients. Cigarette smoking was more frequently associated with male gender (p < 0.05) and migraine history with female sex (p < 0.05). The atherothrombotic diagnostic subtype and the subtype from ‘other cause’ predominated significantly among patients ≧35 years old (p < 0.05) and <35 years (p < 0.025), respectively. The ‘other cause’ subset was more frequent in female gender (p < 0.05). Transoesophageal echocardiography (TEE) detected potential cardiac sources of emboli (PCSE) at an extent 3 times higher (p < 0.0001) than transthoracic echocardiography. Congenital heart defects were nearly threefold more frequent than acquired ones, with a prevalence of patent foramen ovale. At a mean of 6.1 ± 2.6 years (confidence interval 5.4 to 6.8), follow-up data were available for only 54 patients, since five patients were lost and one died in the acute phase. Poststroke recurrence rate was low (7.4%) and no event was fatal. General handicap was severe to moderately severe (RS>3) in 11% of the patients, slight to moderate (1≧RS≤3) in 59% and absent in 30% (RS = 0). Functional disability was relatively low with 50% of the patients independent (BI ≧95), 38.9% partially dependent (BI 60 to 86), and 11.1% fully dependent (BI <60). Thirty-seven (68.5%) patients returned to work, although adjustments (other job or part-time employment) were necessary for 10 out of them (27%). Conclusions: The present study, though limited by the relatively small number of subjects, suggests that the overall prognosis of ischaemic stroke in young adults is good. We strongly recommend TEE in all patients with ischaemic stroke as an essential tool to increase the detection of PCSE and make the therapeutic approach more efficient.

Door-to-Door Prevalence Survey of Neurological Diseases in a Sicilian Population

In three municipalities of Sicily, a prevalence survey of major neurological diseases was conducted door-to-door using screening and examination to find cases. This was the first large-scale neuroepidemiologic survey of that type undertaken in Italy: 24,496 persons were screened yielding 1,538 positives, of whom 1,408 were examined directly by neurologists and 110 were evaluated on the basis of existing medical documentation. In the article, we provide (1) a description of the population investigated and the survey methods employed; (2) details of the cooperation and the attrition experienced in the survey; and (3) age and sex tallies for the study population, including some on education level and occupation.

Prevalence and Characteristics of Epilepsy in the Aeolian Islands

Summary:  Purpose: To estimate the prevalence and define the clinical characteristics of epileptic disorders in the 13,431 residents of the Sicilian Aeolian archipelago, on June 1, 1999.

Valproic acid-ethosuximide interaction: a pharmacokinetic study.

Summary: The present pharmacokinetic study was designed to investigate the possible interaction between valproic acid (VPA) and ethosuximide (ESM) in humans. Six drug‐free healthy volunteers, four men and two women, 18–42 years of age, received a single oral dose of 500 mg ESM before and during a treatment with VPA at 800‐ to 1,600‐mg daily doses. The second ESM dose was given 9 days after VPA administration was started. In this latter condition, a significant (p < 0.05) increase in ESM serum half‐life, from 44 to 54 h on average, and a significant (p < 0.05) decrease in total body clearance, from 11.2 to 9.5 ml/min on average, were observed. Other pharmacokinetic parameters were unchanged and showed values similar to those reported in the literature. Serum VPA levels ranged between 66.8 and 95 μg/ml. Two subjects showed no evidence of interaction. Although a great interindividual variability in the occurrence of VPA‐ESM interaction can be observed, the present study indicates that VPA is able to inhibit the metabolism of ESM. Possible factors affecting this interaction are hypothesized and discussed.

Effect of Viloxazine on Serum Carbamazepine Levels in Epileptic Patients

Summary: The present study describes the interaction between carbamazepine (CBZ) and viloxazine, a recently synthesized antidepressant agent. Seven epileptic patients on chronic anticonvulsant therapy showed a significant (p <0.005) increase in steady‐state serum CBZ levels (from 8.1 ± 2.5 SD to 12.1 ± 2.5 SD μg/ml) when viloxazine (300 mg/day) was added to the therapy. The effect was associated with the appearance of mild CBZ intoxication. The symptoms of this intoxication (i.e., dizziness, ataxia, fatigue, drowsiness) disappeared rapidly, and serum CBZ levels decreased to the basal values, when viloxazine administration was stopped.

Prevalence of Stroke: A Door-to-Door Survey in Three Sicilian Municipalities

As part of a door-to-door survey, we screened for stroke among the inhabitants of three Sicilian municipalities (n = 24,496 as of November 1, 1987). Neurologists then investigated those subjects suspected to have had a stroke. Diagnoses of first-ever strokes were based on specified criteria and were reviewed by an adjudication panel. We found 189 subjects who had experienced at least one completed stroke (180 definite, 9 possible); 15 strokes were hemorrhagic, 71 ischemic, and 103 uncertain. The prevalence (cases/100,000) was 771.6 in the total population and 1,893.6 in those aged 40 years or over. The prevalence increased steeply with age, was higher in men between 60 and 79 years, but was higher in women thereafter. Age-specific figures were similar in the three study municipalities. Although all first-ever strokes had been previously diagnosed, 40% of the subjects had not been hospitalized for this condition.

Increased Dipropylacetic Acid Bioavailability from Dipropylacetamide by Food

Summary: The present study was designed to investigate the influence of food on dipropylacetic acid (DPA) absorption from dipropylacetamide (DPM). Six healthy male volunteers received at weekly intervals, in a crossover randomized fashion, a single oral dose of 600 mg DPM, as 2 × 300‐mg capsules, in a fasting state and after a standard meal. In the latter state, the lag time of DPA appearance in the serum increased significantly (p < 0.02) from 0.6 ± 0.2 to 2.3 ± 1.2 h (mean values ± SD). Maximal DPA serum levels and bioavailability increased significantly (p < 0.05), with mean values of 27.7 ± 19.8 and 19.0 ± 14.7%, respectively, following food. The slower gastric emptying with a consequent improved DPM exposure to metabolizing enzymes and changes in gastric pH probably accounted for these findings. These results suggest that it is more advantageous to take DPM after meals. This helps to reduce gastrointestinal disturbances and to promote DPA absorption.

The effects of amineptine on the mood and nocturnal sleep of depressed patients

The effect of amineptine, a new tricyclic antidepressant, was studied on the sleep of 12 depressed patients. A single blind comparative trial vs placebo was carried out and changes in depression symptoms were recorded using Hamilton Rating Scale for Depression (HRSD). The sleep was evaluated according to the Rechtschaffen and Kales criteria to determine various parameters. Amineptine treatment induced statistically significant reduction of HRSD total score after 14 days of treatment. Polysomnographic analysis revealed significant differences between depressed patients and healthy volunteers.