Seizure Threshold

Most conventional antipsychotics are associated with a dose-depen-dent risk of a lowered seizure threshold, although the incidence of seizures with most of these drugs is quite small (Devinsky et al. 1991). Of all the conventional antipsychotics, molindone and fluphenazine have been shown most consistently to have the lowest potential for this side effect (ltd and Soldatos 1980 Ohver et al. 1982). The atypical antipsychotic clozapine is associated with a dose-dependent risk of seizure. 

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Other sedative-hypnotic medications, such as barbiturates, may play a useful role in severe withdrawal from this group of drugs. For example, in a case series of GBL withdrawal, use of intravenous pentobarbital in the range of 1-2 mg/kg/hour lowered the total requirement for intravenous lorazepam (Sivilotti et al. 2001). Antipsychotic medications are often used to reduce psychotic agitation. However, because antipsychotic medications lower the seizure threshold and may contribute to loss of central control of temperature leading to hyperthermia or neuroleptic malignant syndrome (NMS), they are not indicated as first-line medications for GHB withdrawal delirium (Dyer and Roth 2001 McDaniel and Miotto 2001 Sharma et al. 2001). If anti-... 

Gilbert ME, Mack CM. 1995. Seizure thresholds in kindled animals are reduced by the pesticides lindane and endosulfan. Neurotoxicol Teratol 17(2) 143-150. 

The anticonvulsant activity of a drug may also be evaluated by measuring its ability to raise the convulsive threshold, i.e. the amount of applied current or infused PTZ required to just evoke a seizure. Comparison of the efficacy of drugs in the threshold and maximal seizure tests may distinguish between their abilities to raise seizure threshold or reduce seizure spread and development. 

Using this model, the ability of PCP, ketamine, and several anticonvulsants to antagonize hippocampal seizures and elevate seizure thresholds was tested both before and after kindling. 

The rats were next administered twice daily hippocampal stimulation (2xthreshold) until three consecutive stage V convulsive responses (Racine 1972) were obtained, indicating that the rats were fully kindled. The average number of stimulations to achieve the kindled state was 41.4 2.3 stimulations. Drug effects on seizure threshold and the kindled seizure were assessed as described above for the prekindled seizure. 

TABLE 2. Increased sensitivity of hippocampal seizure threshold to drug effects following kindling... 

Freeman, F.G. Jarvis, M.F. and Duncan, P.M. Phencyclidine raises kindled seizure thresholds. Pharmacol Biochem Behav 16 1009-1011, 1982. 

Avoid phenothiazines and haloperidol, as both may lower the seizure threshold... 

Traditional CNS stimulants have the potential to increase blood pressure and heart rate when used long term. In addition, excessive CNS stimulation can cause tremors and tics and can carry over into evening hours, where initiation of normal nighttime sleep can be disrupted. Caution should be used in patients with underlying cardiovascular or cerebrovascular disease and in patients with a history of seizures because stimulants may lower the seizure threshold. 

The tricyclic antidepressants (TCAs), such as imipramine, can alleviate symptoms of ADHD. Like bupropion, TCAs likely will improve symptoms associated with comorbid anxiety and depression. The mechanism of action of TCAs is in blocking norepinephrine transporters, thus increasing norepinephrine concentrations in the synapse the increase in norepinephrine is believed to alleviate the symptoms of ADHD. TCAs have been demonstrated to be an effective non-stimulant option for ADHD but less effective than stimulants. However, their use in ADHD has declined owing to case reports of sudden death and anticholinergic side effects6,13 (Table 39-3). Further, TCAs may lower seizure threshold and increase the risk of car-diotoxicity, (e.g., arrythmias). Patients starting on TCAs should have a baseline and routine electrocardiograms. 

Use of diethylpropion for a period longer than 3 months is associated with an increased risk for development of pulmonary hypertension. When used as directed, reported common central nervous system adverse effects included overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, jitteriness, anxiety, nervousness, depression, drowsiness, malaise, mydriasis, and blurred vision. In addition, diethylpropion can decrease seizure threshold, subsequently increasing a patient s risk for an epileptic event. Other organ systems also can adversely be affected, resulting in tachycardia, elevated blood pressure, palpitations, dry mouth, abdominal discomfort, constipation,... 

The answer is c. (Hardman7 p 408.) Clozapine differs from other neuroleptic agents in that it can induce seizures in nonepileptic patients In patients with a history of epileptic seizures for which they are not receiving treatment, stimulation of seizures can occur following the administration of neuroleptic agents because they lower seizure threshold and cause brain discharge patterns reminiscent of epileptic seizure disorders. 

Drugs that act on the H3 receptor are being developed for the treatment of obesity, sleep disturbances, epilepsy and cognitive disorders. The ability of histamine to promote arousal, suppress appetite, elevate seizure threshold and stimulate cognitive processes implies that compounds able to enhance the release of neuronal histamine should mimic these effects. Several H3 antagonists currently in development demonstrate such activity and show promise as effective and novel therapeutic agents [40, 84-86]. Because H3 agonists suppress the release of... 

Increased or decreased antidepressant response increased toxicity Decreased antihypertensive efficacy Decreased antihypertensive efficacy Increased hypoglycemic effects Possible additive lowering of seizure threshold Decreased antihypertensive efficacy tachycardia CNS stimulation Increased therapeutic and possibly toxic effects of both drugs hypertensive crisis delirium seizures hyperpyrexia serotonin syndrome Increased hypoglycemic effects... 

Possible lowering of seizure threshold and reduced antidepressant response Increased CNS depressant effects... 

Medications that lower seizure threshold Increased incidence of seizures... 

Tricyclic antidepressants (TCAs) Epilepsy Lower seizure threshold (more so if toxic levels of TC A)... 

Miller PE, Fink GB. 1973. Brain serotonin level and pentylenetetrazol seizure threshold in dieldrin and endrin treated mice. Proc West Pharmacol Soc 16 195-197. 

The CASR functions as an extracellular calcium sensor for the parathyroid gland and the kidney. CASR serves to maintain a stable calcium concentration, without which many aspects of homeostasis are adversely affected. For example, the effect of CASR variants on seizure threshold in the brain is reviewed in Subheading... 

Lastly, nomifensine was an interesting antidepressant that also had noradrenaline, dopamine and, due to its 4-hydroxy metabolite, serotonin reuptake properties. It was withdrawn some years ago because of the occurrence of haemolytic anaemia in a small number of patients. It was a particularly effective drug in the treatment of depression in patients with epilepsy as, unlike many antidepressants available at that time, it did not affect the seizure threshold. 

Due to their cationic amphiphilic nature, the TCA exert membrane-stabilizing effects that can lead to disturbances of cardiac impulse conduction with arrhythmias as well as decreases in myocardial contractility. All TCA lower the seizure threshold. Weight gain may result from a stimulant effect on appetite. 

Seizure threshold Promethazine may lower the seizure threshold consider this when giving to people with known seizure disorders or when giving in combination with narcotics or local anesthetics that also may affect seizure threshold. 

Seizure disorders Because TCAs lower the seizure threshold, use with caution in patients with a history of seizures or other predisposing factors (eg, brain damage of varying etiology, alcoholism, concomitant drugs known to lower the seizure threshold). However, seizures have occurred both in patients with and without a history of seizure disorders. Seizure was identified as the most significant risk of clomipramine use. 

Seizures Bupropion is associated with a dose-related risk of seizures. Discontinue bupropion and do not restart in patients who experience a seizure while on treatment. Use extreme caution when bupropion is administered to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or prescribed with other agents (eg, antipsychotics, other antidepressants, theophylline, systemic steroids) that lower seizure threshold. 

Seizure disorders Methylphenidate may lower the seizure threshold in patients with a history of seizures, with prior EEG abnormalities in absence of seizures, and, very rarely, in the absence of history of seizures and no prior EEG evidence of seizures. 

Concomitant medications - Many medications (eg, antipsychotics, antidepressants, theophylline, systemic steroids) and treatment regimens (eg, abrupt discontinuation of benzodiazepines) are known to lower seizure threshold. 

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