Mood Disorders in Women with Epilepsy

Cynthia Harden, MD

Laura Ponticello, RN
Comprehensive Epilepsy Center Department of Neurology and Neuroscience

Weill Medical College of Cornell University

New York, NY

Prevalence of Psychiatric Disorders in Epilepsy

Prevalence, % Epilepsy Patients General Population 2-4 2.5-6.5 1-2 0.5-0.7

Depression1-3 Anxiety/Panic Disorder4 Bipolar Disorder5 Psychosis6

20-55 19-45 8-12 2-8

AM. Biol Psychiatry. 2003;54:388-398. 2Ettinger A, et al. Neurology. 2004;63:1008-1014. 3Wrench J, et al. Epilepsia. 2004;45:534-543.4Weissman MM, et al. J Clin Psychiatry. 1986;47(suppl 6)11-17. 5 Blum D, et al. In: Program and abstracts of the 54th Annual Meeting of the AAN; April 13-20, 2002. 6Kessler RC, et al. Arch Gen Psychiatry. 1994;51:8-19, 7Ettinger AB, et al Neurology. 2005;65:535-40.

1Kanner

Prevalence of Depression in Epilepsy

60 50 % Depressed Patients

Pharmacoresistant Epilepsy Controlled Epilepsy Gen. Population (Annual) Gen. Population (Lifetime)

40

30

20

10

0
Population
AM. Biol Psychiatry. 2003;54:388-398. 2Ettinger A, et al. Neurology. 2004;63:1008-1014. 3Wrench J, et al. Epilepsia. 2004;45:534-543. 4Waraich P, et al. Can J Psychiatry. 2004;49:124-138. 5Boylan LS, et al. Neurology. 2004;62:258-261.
1Kanner

Depression Correlates With Quality of Life in Pharmacoresistant Epilepsy

100
QOLIE-89 Total Score

80 60 40 20 0
r = -0.73 P<0.001

HRQOL scores correlated with: Depression AED toxicity

Independent of seizure frequency

10

15

20

25

30

35

40

Beck Depression Inventory Score

Gilliam F, et al. Neurology. 2002;58(suppl 5):S9-S19.

Risk of Suicidal Ideation and Attempt in People With Epilepsy

People With Epilepsy
25

General Population

% of Population

20 15 10

19% 14%

5%

5
1%

Ideation1,2

Behavior/Attempts
1Boylan 2Jones

LS, et al. Neurology. 2004;62:258-261. JE, et al. Epilepsy Behav. 2003;4:S31-S38. Publishers; 1997:2141-2151.

Depression in women with epilepsy

Being female is a risk factor for depression in epilepsy (Ettinger et al, 2004) 642 consecutive women of childbearing age with epilepsy were evaluated with the Hamilton Depression Scale and HRQOL (Beghi et al., 2004) Depression of any severity was present in 38%
Mild 19% Moderate 9% Major 10% Severe <1%

Risk Factors for Depression in Women with Epilepsy (Beghi et al., 2004)
Any depression, or moderate to severe depression*
Concurrent disability Treatment for associated conditions (neurologic, endocrine, cardiovascular, orthopedic)* Seizures in past 6 months* Being a housewife or unemployed*

Depression was associated lower HRQOL scores

Defining Treatment Resistant Depression

Similar criteria to pharmacoresistant epilepsy

Lack of adequate clinical response after 2 well-delivered treatments at adequate dose and duration from 2 different classes of treatment1

ME, Rush AJ. In: Bloom FE, Kupfer DF, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press, Ltd.; 1995:1082-1097.

1Thase

Diagnostic Algorithm for Major Depression

Two-Question Screening Procedure
During the past month, have you often been bothered by feeling down, depressed, or hopeless? During the past month, have you often been bothered by having little interest or pleasure in doing things?

If no to both, major depression is unlikely May inquire about intermittent symptoms proximal to seizures in PWE to assess atypical manifestation of depression. If yes to either, proceed with the follow-up clinical interview or administer screening instrument

Adapted in part from: Whooley MA, Simon GE. N Engl J Med. 2000;343:1942-1950.

Diagnostic Algorithm for Major Depression (Contd)

Follow-Up Clinical Interview
Five or More Symptoms for Major Depression

Depressed mood Weight change

Anhedonia Suicidal ideation

Sleep disturbance
Psychomotor problems Lack of energy

Poor concentration
Excessive guilt

Consider referral to Psychiatry for further evaluation of depression

Adapted in part from: Whooley MA, Simon GE. N Engl J Med. 2000;343:1942-1950. American Psychiatric Association. DSM-IV-TR. R.R American Psychiatric Association: Washington, DC; 2000.

Depression Assessment Tools

Patient Administered Beck Depression Inventory-II (BDI-II) Inventory of Depressive Symptomatology (IDS) Quick Inventory of Depressive Symptomatology (QIDS) Zung Self-Rating Depression Scale (SDS) Physician Administered Hamilton Rating Scale for Depression (HAMD) Montgomery-Asberg Depression Rating Scale (MADRS) Cornell Dysthymia Rating Scale (CDRS) Center for Epidemiologic Studies Depression Scale (CES-D)

Screening Instruments for Evaluating Depression

Instrument
BDI-II1 IDS2 QIDS2 SDS HAMD MADRS CDRS6

Items Time, min

21 30 16 20 17 10 20 5-10 5-10 <5 <5 10 2-20 5-10

Reliability*
.94 .92 .86 .843 .46-.974 .825 .90

CES-D7

20

5-7

.85-.90*

*Internal Consistency, Interrater Reliability 1Arnau, et al. Health Psychology. 2001;20:112-119. 2Rush, et al. Soc Bio Psych. 2003;54:573-583. 3Dugan W, et al. Psychooncology. 1998;7:483-493. 4Bagby RM, et al. Am J Psychiatry. 2004;161:2163-2177. 5Maier W, et al. J Psychiatr Res. 1988;22:3-12. 6Hellerstein DJ, et al. J Affective Disorders. 2002;71:85-96. 7Vahle VJ, et al. Arch Phys Med Rehabil. 2000;84:S53-S62.

Psychometric Properties of the QIDS

16-item abbreviated version of the IDS

Includes only items assessing DSM-IV criterion Scores 9 symptom domains High internal consistency though less than that of the IDS Excellent interrater reliability Acceptable discriminant validity
QIDS-SR less sensitive to residual symptoms than the IDS-SR
Rush AJ, et al. Biol Psychiatry. 2003;54:573-583.

Psychometric Overview

Psychometric Properties of the Cornell Dysthymia Rating Scale

20-item clinician-administered instrument

Collateral and patient-based ratings

High interrater reliability Excellent internal consistency and sensitivity Total scores correlate well with depressive subtypes of various intensity-mild depressive symptoms rather than major depression

Hellerstein DJ, et al. J Affective Disord. 2002;71:85-96.

Seizure Focus and Risk of Depression

Frontal and temporal lobe dysfunction1-6
Appears to be associated with bilateral reduction in inferofrontal metabolism7 and mesial temporal sclerosis8 Risk of depression is elevated with involvement of limbic structures7 Patients with psychic auras are more likely to experience depression than those without auras or with somatosensory auras7

1Victoroff

JI, et al. Arch Neurol. 1994;51:155-163. 2Perini GI, et al. J Neurol Neurosurg Psychiatry. 1996;61:601-605. 3Gilliam F, et al. Epilepsia. 2000;41(suppl 7):54. Abstract 1.193. 4Bromfield EB, et al. Arch Neurol. 1992;49:617-623. 5Mayberg HS, et al. Ann Neurol. 1990;28:57-64. 6Eison MS. J Clin Psychopharmacol. 1990;10(suppl 3):26S-30S. 7Kanner A. Epilepsy Behav. 2003;4:S11-S19. 8Quiske A, et al. Epilepsy Res. 2000;39:121-125.

Neuroanatomic Mechanisms of Depression in Epilepsy

Brain regions commonly affected in epilepsy may lead to clinical expressions of depression
Hippocampus

Amygdala

Prefrontal cortex

Research suggests a bi-directional relationship between epilepsy and depression

Hecimovic H, et al. Epilepsy Behav. 2003;4;S25-S30.

Neurobiological Aspects of Depression

Monoaminergic theory
Depression is associated with abnormal monoaminergic transmission Alleviation of symptoms via reconstitution of normal 5-HT and NE transmission Other neurotransmitters such as DA and GABA, have been implicated as well

Potential mechanisms of structural changes in primary depression

Deficiencies in neurotrophic support have been postulated as a potential pathogenic mechanism mediating hippocampal atrophy and frontal lobe changes Deficiencies may be reversed by antidepressant treatment High cortisol secretion has also been suspected to mediate hippocampal atrophy
Hecimovic H, et al. Epilepsy Behav. 2003;4;S25-S30.

Potential Common Pathogenic Mechanisms of Depression and Epilepsy

Gliosis and Neuronal Cell Loss (Neuropathologic Studies)

Neurotransmitter Abnormalities (Animal Models and Pharmacology)

Depression

Decreased 5HT-1A

Receptor Binding in Temporal Lobe and Raphe

Hippocampal and Frontal Lobe Atrophy (MRI)

Considerations in the Treatment of Epileptic Patients With Depressed Mood

Did the depressive episode follow the discontinuation of an AED possessing mood-stabilizing properties?

CBZ, VPA, or LTG: reintroduction of that AED or another mood-stabilizing agent may be sufficient

Did the depressive episode follow the introduction or dose increment of an AED with negative psychotropic properties?

LEV, PB, PRM, TGB, TPM, or VGB: lower dose or discontinue that AED
If culprit agent provides best seizure control, counteract negative psychotropic effects with an antidepressant
Kanner AM, et al. Epilepsy Behav. 2003;4:S11-S19. Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

Considerations in the Treatment of Epileptic Patients With Depressed Mood (Cont'd)

Did the depression/depressive symptoms follow sudden cessation of seizures in a previously intractable epilepsy?
Consider impact of forced normalization Treatment with antidepressant can be considered

Do depressive symptoms have a temporal relationship with the occurrence of seizure frequency?
Postictal depression usually responds poorly to antidepressant therapy; consider an optimal prophylactic AED

Kanner AM, et al. Epilepsy Behav. 2003;4:S11-S19. Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

Treatment Options for Depression in Epilepsy

SSRIs citalopram (Celexa), escitalopram(Lexapro)f luoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft) Norepinephrine/serotonin reuptake inhibitors venlafaxine (Effexor) Tricyclics imipramine nortriptyline (Pamelor) (Tofranil), MAO inhibitors Only to be used by psychiatrists AEDs (prophylactic agents)

VPA, CBZ, LTG

Lithium Can worsen seizures VNS

Electroconvulsive Therapy
Not contraindicated in seizure disorders
Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

Antidepressants With Low Proconvulsant Activity

Percentage of Patients Experiencing Seizures: (0.1%) Drug imipramine* (Tofranil) doxepin* (Sinequan) Percentage 0.1 at 200 mg/day 0.1

paroxetine (Paxil)
amitriptyline* (Elavil) desipramine* (Norpramin)/nortriptyline*(Pamelor) mirtazapine (Remeron) phenelzine (Nardil)/ tranylcypromine (Parnate) trazodone (Desyrel)/nefazodone (Serzone)
* TCA , SSRI, NE/5HT modulator, MAOI, Serotonin modulator.

0.1
0.06 0.05-0.1 (unknown) 0.04 Rare (unknown) Rare (unknown)

Harden CL, Goldstein MA. CNS Drugs. 2002;16:291-302.

Antidepressants With Relatively Moderate and High Proconvulsant Activity1,2

Percentage of Patients Experiencing Seizures (>0.1%) Drug Percentage maprotiline (Ludiomil) 3.3 and 15.6 amoxapine (Asendin) >1.0 bupropion (Wellbutrin/XL) 0.44 at 450 mg/day 2.2 at >450 mg/day clomipramine* (Anafranil) imipramine* (Tofranil) citalopram (Celexa) venlafaxine (Effexor/XR) fluvoxamine (Luvox)/fluoxetine (Prozac)
* TCA , SSRI, SNRI, tetracyclic, DNRI.
1Adapted

0.5 at 250 mg/day 1.66 at >250 mg/day 0.6 at >200 mg/day 0.3 0.26 0.2

from Harden CL, Goldstein MA. CNS Drugs. 2002;16:291-302. 2American Psychiatric Association. http://www.psych.org/psych_ pract/treatg/pg/ Practice%20Guidelines8904/MajorDepressiveDisorder_2e.pdf.

Psychiatric Drugs and AEDs Drug-Drug Interactions

Some SSRIs May Inhibit Cytochrome P450 Enzymes Fluoxetine Fluvoxamine Nefazodone Sertraline Paroxetine Venlafazine AEDs that may have levels increased by SSRI use AEDs Phenytoin Barbiturates Carbamazepine Tiagabine Zonisamide

Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

Mood Effects in VNS Therapy Patients With Pharmacoresistant Epilepsy

VNS patients experienced significant positive mood changes at 3-month follow-up Improvement in mood was sustained at 6-month visit and was independent of effects on seizure activity1 VNS-treated patients demonstrated improvements in mood as assessed by CDRS, HAMD, and BDI2

Mood reported as better or much better by 44% of Registry patients after 1 year of VNS Therapy3
1Elger 2Harden

G, et al. Epilepsy Res. 2000;42:203-210. CL, et al. Epilepsy Behav. 2000;1:93-99 3Data on file. Cyberonics, Inc.

Nonpharmacologic Options for Treatment of Depression in Patients With Epilepsy

Psychotherapy
Cognitive behavioral therapy (CBT) Interpersonal psychotherapy (IPT)

ECT
Patients with severe functional impairment and/or treatment resistant depression Psychiatrists are reluctant to use in patients with pharmacoresistant epilepsy

Vagus nerve stimulation (VNS)

Indicated for treating pharmacoresistant epilepsy Does not exacerbate depression, anxiety, or psychosis
Nemeroff CB, et al. Proc Natl Acad Sci U S A. 2003;100:14293-14296; Swartz HA, et al. Psychiatr Serv. 2004;55:448-450; Lisanby SH, et al. CNS Spectr. 2003;8:529-536; Morris GL III, et al. Neurology. 1999;53:1731-1735; Cyberonics, Inc. Depression Physicians Manual. Houston, Tex; 2005; Henry TR. Neurology. 2002;59(suppl 4):S3-S14; Krishnamoorthy ES. Epilepsy Behav. 2003;4:S46-S54.

Summary
Depression is a common comorbidity with epilepsy, especially for women, and compromises quality of life!

Clinicians should screen patients for depression at the least with two simple questions and initiate a plan for further evaluation and treatment if depression is suspected!

Case 1
Woman in her early 40s with intractable partial epilepsy since age 14
Nocturnal and diurnal convulsive seizures Multiple medication failures of all available AEDs mostly due to non-serious side effects; now back to old standbys phenytoin and phenobarbital No risk factors for epilepsy Video-EEG shows interictal independent temporal spikes, left more frequent than right; no seizures recorded MRI shows cerebellar atrophy

Case 1, contd
Assessment of seizure frequency and severity compromised during office visits by tearfulness, excessive sensitivity during discussions and tangential ideation Social status: recent divorce and subsequent financial and insurance issues, two small children at home, low educational level, not employed Coping with all issues is marginal as per patient report Is it likely that she is depressed? (yes or no by response buttons)

What would you do?

A. Refer for psychiatric evaluation (in light of social and financial issues)? B. Start antipressant? C. Refer for psychotherapy? D. All of the above?

What we did
Added Celexa 10 mg per day

Referred for home care for help with children

Referred for psychotherapy with our social worker-patient kept appointments sporadically Implanted VNS for seizure control

How patient did

Depression much improved with interventions as above Coping skills have become much more stabilized Seizures not improved with VNS according to patient, although she seems better, and she has some somatic complaints related to VNS Will refer for investigational drug study or epilepsy surgery