Download Dr. Anbarasan`s PowerPoint slides

Psychoactive Medications and
Seizures—Challenges and Pitfalls
Deepti Anbarasan, MD
The Neurological Institute of New York, Columbia University Medical Center,
New York, New York
A REPORT FROM THE 69th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY
© 2016 Direct One Communications, Inc. All rights reserved.
1
Epilepsy and Depression

People with depression are 3–7 times more likely to
develop epilepsy than those without depression.

People with a history of depression are also more
likely to experience intractable epilepsy.

People with epilepsy are more likely to report higher
rates of depression than those without epilepsy.

People with epilepsy also have significantly higher
rates of mood and anxiety disorders and of suicidal
ideation.
Blum D et al. Neurology. 2002;Suppl 3:A175; Ettinger A et al. Neurology. 2004;63:1008; Tellez-Zenteno JF et al.
Epilepsia. 2007;48:2336
© 2016 Direct One Communications, Inc. All rights reserved.
2
Epilepsy and Depression continued
Prevalence of depression and other psychiatric
conditions in patients with and without epilepsy:
Tellez-Zenteno JF et al. Epilepsia. 2007;48:2336
© 2016 Direct One Communications, Inc. All rights reserved.
3
Epilepsy and Bipolar Affective Disorder

A 2005 population-based study compared the
prevalence of bipolar symptoms between patients
with epilepsy and those with other conditions such
as migraine, diabetes, or asthma.

Bipolar symptoms were 1.6–2.2 times more common
among patients with epilepsy than among patients
with other chronic illnesses.
Ettinger A et al. Neurology. 2005;65:535
© 2016 Direct One Communications, Inc. All rights reserved.
4
Evaluation for Psychiatric Comorbidities

The severity and probably the duration of epilepsy
may be risk factors for psychiatric comorbidities,
such as depression and anxiety.

When compared with extratemporal-lobe epilepsy,
temporal-lobe epilepsy traditionally has been
associated with higher rates of psychiatric disorders;
however, this finding has not been noted
consistently.

Patients with mesial temporal sclerosis may have a
higher prevalence of major depressive disorder.
Kobau R et al. Epilepsia. 2006;47:1915; Quiske A et al. Epilepsy Res. 2000;39:121; Sanchez-Gistau V et al.
Epilepsia. 2012;53:386
© 2016 Direct One Communications, Inc. All rights reserved.
5
Psychiatric Effects of AEDs
Putative psychiatric effects associated with the use of
antiepileptic drugs (AEDs):
© 2016 Direct One Communications, Inc. All rights reserved.
6
Psychiatric Effects of AEDs continued

Depressive side effects is associated with the use of
AEDs that have prominent properties associated
with g-aminobutyric acid (GABA), such as
barbiturates, topiramate, tiagabine, and vigabatrin.

In contrast, glutaminergic AEDs, such as felbamate,
perampanel, and lamotrigine, have activating,
anxiogenic, and antidepressant effects.

Both sodium- and calcium-channel blockers may
have mood-stabilizing effects.
Ketter T et al. Neurology. 1999;53(5 Suppl 2):S53
© 2016 Direct One Communications, Inc. All rights reserved.
7
AEDs and Suicidality

A meta-analysis of 199 randomized, placebo-controlled
trials evaluating 11 AEDs led the FDA to issue an alert
in 2008 that the use of these drugs was associated with
a statistically significant 1.8-fold increased risk of
suicidality.

The methodology of this study drew criticism, and
several studies subsequently investigating whether
AEDs may increase the risk of suicidality have yielded
inconsistent results.

The current consensus is that the benefits of AED
therapy in patients with epilepsy outweigh the risks of
uncontrolled seizures.
Hesdorffer DC, Kanner AM. Epilepsia. 2009;50:978; Arana A et al. N Engl J Med. 2010;363:542; Olesen JB et al.
Pharmacoepidemiol Drug Saf. 2010;19:518
© 2016 Direct One Communications, Inc. All rights reserved.
8
Antidepressants and Epilepsy

In the general population, use of antidepressants
confers a 7-fold risk of unprovoked seizures, whereas
the incidence of seizures associated with the use of
antipsychotics has been reported to be 1.2%–1.3%.

However, seizures are a relatively rare side effect of
psychotropics; when used properly, the risk of
seizures associated with the administration of these
drugs approaches that in the general population.

Therapy with selective serotonin reuptake inhibitors
(SSRIs) generally is believed to be safe with regard to
seizures; however, hyponatremia, an idiosyncratic
side effect of SSRIs, may lower the seizure threshold.
Pisani F et al. Drug Saf. 2002;25:91; Alldredge BK. Neurology. 1999;53(Suppl 2):S68
© 2016 Direct One Communications, Inc. All rights reserved.
9
Antidepressants and Epilepsy continued

Bupropion is associated with an approximate 0.4%
incidence of seizures in patients receiving less than
450 mg/d; however, the risk of seizures increases
with higher daily doses.

Phenylpiperazines, such as trazodone and
nefazodone, are probably safe in patients with
epilepsy, although these drugs should be used
cautiously with AED inducers.

Tricyclic antidepressants (TCAs) can lower the
seizure threshold, and use of certain TCAs have a
known dose-dependent effect on seizure incidence.
Peck AW et al. J Clin Psychiatry. 1983;44(5 pt 2):197
© 2016 Direct One Communications, Inc. All rights reserved.
10
Other Psychotropic Medications

Both typical and atypical antipsychotics may cause
seizures, although the risk varies:
» Clozapine and chlorpromazine are associated with a
relatively high risk of seizures.
» Olanzapine and quetiapine are associated with a relatively
moderate risk of seizures.
» Fluphenazine, haloperidol, risperidone, and ziprasidone are
associated with a relatively low risk of seizures.

Administration of anxiolytics and sedative-hypnotic
medications in general is associated with a low risk
of seizures; however, abrupt withdrawal of these
psychoactive medications is not recommended.
Pisani F et al. Drug Saf. 2002;25:91; Lee F et al. Expert Opin Drug Saf. 2003;3:233
© 2016 Direct One Communications, Inc. All rights reserved.
11
Other Psychotropic Medications continued

Lithium therapy should not be withheld if other
mood stabilizers are ineffective or poorly tolerated,
as the evidence for lithium’s putative proconvulsant
effects is conflicting.

Preferred agents to manage depression in patients
with epilepsy are SSRIs, trazodone, mirtazapine, and
(possibly) venlafaxine.

Risperidone therapy is preferred for long-term
treatment of psychosis, whereas use of haloperidol is
acceptable for short-term treatment of psychosis in
patients with epilepsy.
Lee F et al. Expert Opin Drug Saf. 2003;3:233
© 2016 Direct One Communications, Inc. All rights reserved.
12
Other Psychotropic Medications continued
Nine critical guiding principles to consider before using
psychotropic medications in patients with epilepsy:
1. Check carefully for predisposing factors
2. Use the minimal effective dose
3. Minimize polytherapy
4. Start low and go slow
5. Avoid abrupt discontinuation or dose changes
6. Consider using antiepileptic drugs with psychotropic
properties
7. Monitor plasma drug concentrations
8. Pay attention to sudden electroencephalographic changes
9. Consider changing the psychotropic drug or optimizing the
antiepileptic drug regimen if seizures worsen
© 2016 Direct One Communications, Inc. All rights reserved.
13
Antipsychotic Medications
and the Metabolic Syndrome

The metabolic syndrome is associated with a variety
of health issues, including hypertension, renal
disease, atherosclerotic cardiovascular disease,
stroke, and type 2 diabetes.

Patients with mental illness, many of whom are on
psychotropic medications, may be especially
susceptible to the metabolic syndrome, which is:
» 1–2 times more prevalent in patients with depression;
» 1.5–2 times more prevalent in patients with bipolar
disorder; and
» 2–3 times more prevalent in patients with schizophrenia
than in control groups.
Grundy S et al. Circulation. 2005;112:285; De Hert M et al. World Psychiatry. 2011;10:138; Simon G et al.
Gen Hosp Psychiatry. 2008;30:32
© 2016 Direct One Communications, Inc. All rights reserved.
14
Antipsychotic Medications
and the Metabolic Syndrome continued

Antipsychotic medications, especially when used
with other psychotropic agents, can significantly
increase the prevalence of metabolic syndrome.

Clozapine and olanzapine confer the highest risk of
inducing the metabolic syndrome.

Starting in July 2016, all patients who are prescribed
antipsychotics will need to undergo a structured
metabolic screening test that includes an annual:
» Lipid panel;
» Fasting glucose or hemoglobin A1c measurement;
» Blood pressure readings; and
» Determination of the patient’s body mass index.
De Hert M et al. World Psychiatry. 2011;10:138; Steylen P et al. Clin Neuropsychiatry. 2012;9:75
© 2016 Direct One Communications, Inc. All rights reserved.
15
Changes in Heart Rhythm

Antipsychotics also may cause QTc prolongation, a
predisposing factor for torsades de pointes (TdP).

Other factors that can increase the risk of TdP
include hypokalemia, female gender, drug-drug
interactions, advancing age, genetic predisposition,
hypomagnesemia, heart failure, and bradycardia.

Chlorpromazine, haloperidol, and thioridazine is
associated with a definite risk of TdP

Aripiprazole, clozapine, iloperidone, olanzapine,
risperidone, and paliperidone are associated with a
possible risk of TdP.
European Medicines Agency (EMEA). ICH Topic E14 (November 2005)
© 2016 Direct One Communications, Inc. All rights reserved.
16
Adverse Drug Interactions

The recent increase in adverse events related to
drug-drug interactions has been attributed to several
factors, including:
» An aging population with more complex medical needs;
» Increased availability of more medications; and
» Increased use of more than one pharmacy by patients to fill
their prescriptions.

Both pharmacokinetic and pharmacodynamic factors
need to be monitored in patients using psychotropic
drugs and/or AEDs.
© 2016 Direct One Communications, Inc. All rights reserved.
17