1. Seizure Threshold and Psychoactive Drugs Sue Henderson

2. 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.

3. Seizure threshold & psychiatry Decreased threshold may result in medication induced seizures Increased or decreased: Implications ECT

4. Risk factors: Drug & Patient Drug related 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)

5. Patient Related Factors: Family history of seizures Personal history of seizures Brain injury Blood brain abnormality Cerebral arteriosclerosis Increased age Impaired kidney& liver Psychiatric illness 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)

6. 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

7. 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).

8. 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

9. Alcohol & Seizures Seizures can occur during: Binge – toxic effects and during withdrawal Withdrawal seizures Onset 7-48 hrs after last drink (95% in 1 st 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).

10. 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

11. 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)

12. Management: Address risk factors 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) Avoid abrupt withdrawal/dose changes

13. Patients with epilepsy Medications which alter seizure threshold should only be used if necessary and no safer alternative exists (Buchanan, 2001, p. 8)

14. 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)

15. Review Question The risk of clozapine induced seizures is dose related a.True b.False

16. 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

17. Review Question Which of the following agents is contraindicated in a patient with epilepsy? a. Bupropion b. Fluoxetine c. Mirtazapine d. Venlafaxine

18. 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.