Seizure Threshold and
Psychoactive Drugs
Sue Henderson
Definition: Seizure threshold
• Everyone has a genetically determined
balance between excitatory and inhibitory
forces in brain.
• Low threshold for seizures (higher
excitatory)
• High threshold (greater inhibition).
• A low seizure threshold makes it easier for a
patient to experience seizures.
Seizure threshold & psychiatry
• Decreased threshold may result in
medication induced seizures
• Increased or decreased: Implications ECT
Risk factors: Drug & Patient
• Drug related
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Poly-pharmacy
High dose (including overdose)
Rapid titration
Abrupt withdrawal
Abrupt dose change
Intrinsic epileptogenicity
Prolonged treatment
High serum levels (Lee, Finlay & Alldredge, 2003, p236)
Patient Related Factors:
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Family history of seizures
Personal history of seizures
Brain injury
Blood brain abnormality
Cerebral arteriosclerosis
Increased age
Impaired kidney& liver
Psychiatric illness
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Substance abuse
AIDS/HIV
CNS infections
Alcohol abuse (Lee, Finlay &
Alldredge, 2003, p236)
• Abnormal glucose
levels (too high or too
low) (Kirchner, Veliskova, &
Velisek, 2006)
Drugs: Lower Seizure Threshold
Antispsychotics
• Clozapine only drug with black box warning (US)
• Olanzepine
• Quetiapine
Other
• Bupropion Immediate Release (Alper et al, 2007, p. 347)
• Clomipramine
• Pethidine
Clozapine
• Lowers seizure threshold in a dose dependent
manner.
• Caution administering clozapine to patients having
a history of seizures or other predisposing factors.
• Sedation + lower the seizure threshold caution re:
driving, operating machinery, other activities
where sudden loss of consciousness could cause
serious risk patient/others (especially during the
initial weeks of treatment).
Drugs: Raise Seizure Threshold
• Benzodiazepines
• Anticonvulsants
• Sudden cessation of these drugs can result
in withdrawal seizures
Other drugs
• By means of water intoxication with
subsequent metabolic changes in the body
Alcohol & Seizures
Seizures can occur during:
• Binge – toxic effects and during withdrawal
Withdrawal seizures
• Onset 7-48 hrs after last drink (95% in 1st 12 hrs)
• Generalised tonic-clonic (3-20% have some
focality), no aura.
• 40% single seizure, 90% have < 5 in 6 hr period
• Only 3% develop status epilepticus (should
prompt search for other causes) (Shockley, 2007).
Electroconvulsive therapy
• Therapeutic effectiveness of ECT
influenced by brain’s anticonvulsant action.
• Threshold rises variably over a course ECT
• Patients on drugs that raise the seizure
threshold require higher stimulus
• Patients on drugs that lower the seizure
threshold require lower stimulus
Substance Lower Threshold
• Stimulants - cocaine is the most likely to
induce seizures when abused to intoxication
• Smoking and IV cocaine more likely to
induce seizures than intranasal use
• PCP can lower the seizure threshold but less
frequently than cocaine
(Bradley, Daroff, Fenichel, & Jankovic, 2004)
Management: Address risk factors
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Assess patient for seizure risk factors
Avoid poly-pharmacy
Low starting doses
Slow dose escalation
Maintenance of minimal effective dose
(Pisani, Oteri, Costa, Di Raimondo, & Di Perri, 2002)
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Avoid abrupt withdrawal/dose changes
Patients with epilepsy
• Medications which alter seizure threshold
should only be used if necessary and no
safer alternative exists (Buchanan, 2001, p. 8)
Summary
• Reduced seizure threshold associated with a
limited subgroup of agents (Alper et al, 2007)
• Depression, psychotic disorders, OCD (Alper et al,
2007), Substance abuse (Alper et al, 2007, Brust, 2006)
associated with reduced seizure threshold
• 2nd generation antidepressants (other than
Bupropion), have an apparent anticonvulsant
effect (Alper et al, 2007)
Review Question
The risk of clozapine induced seizures is dose
related
a. True
b. False
Review Question
Which one of the following substances of
abuse is the most likely to lower the seizure
threshold during intoxication?
a. Morphine
b. PCP
c. Cocaine
d. Cannabis
e. Alcohol
Review Question
Which of the following agents is
contraindicated in a patient with epilepsy?
• a. Bupropion
• b. Fluoxetine
• c. Mirtazapine
• d. Venlafaxine
References
Alper, K., Schwartz, R., Kolts, R., Khan, A. (2007). Seizure incidence in
psychopharmacological clinical trials: An analysis of Food and Drug Administration
(FDA) summary basis of approval reports. Biological Psychiatry, 62, 345-354
Bradley, W. G., Daroff, R. B., Fenichel, G., & Jankovic, J. (Eds.). (2004). Neurology in
clinical practice (4th ed.). Philadelphia: Butterworth-Heinemann.
Bruist, J. C. M. (2006). Seizures and substance abuse: Treatment and considerations.
Neurology, Suppl 4), S45-S48
Buchanan, N. (2001). Medications which may lower seizure threshold. Australian
Prescriber, 24(1), 8-9
Kirchner, A., Veliskova, J., & Velisek, L. (2006). Differential effects of low glucose
concentrations on seizures and epileptiform activity in vivo and in vitro. European
Journal of Neuroscience, 23(6), 1512-1522.
Lee, K. C., Finley, P. R., & Alldredge, B. K. (2003). Risk of seizures associated with
psychotropic medications: Emphasis on new drugs and new findings. Expert Opinion on
Drug Safety, 2(3), 233-247.
Pisani, F., Oteri, G., Costa, C., Di Raimondo, G., & Di Perri, R. (2002). Effects of
psychotropic drugs on seizure threshold. Drug Safety, 25(2), 91-110.
Shockley, L. (2007). Withdrawal alcohol. In J. Schaider, S. R. Hayden, R. E. Wolfe, R. M.
Barkin & P. Rosen (Eds.), Rosen & Barkin's 5-minute emergency medicine consult (3rd
ed., pp. 1234-1235). Philadelphia: Lippincott Williams & Wilkins.