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  1. 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

  2. Prevalence ofPsychiatric Disorders in Epilepsy 1Kanner 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.

  3. Pharmacoresistant Epilepsy Controlled Epilepsy Gen. Population (Annual) Gen. Population (Lifetime) Prevalence of Depression in Epilepsy 60 50 40 % Depressed Patients 30 20 10 0 Population • 1Kanner 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.

  4. QOLIE-89 Total Score r = -0.73 P<0.001 0 5 10 15 20 25 30 35 40 Beck Depression Inventory Score Depression Correlates With Quality of Life in Pharmacoresistant Epilepsy • HRQOL scores correlated with: • Depression • AED toxicity • Independent of seizure frequency Gilliam F, et al. Neurology. 2002;58(suppl 5):S9-S19.

  5. Risk of Suicidal Ideation and Attempt in People With Epilepsy People With Epilepsy General Population 25 20 15 10 5 0 19% 14% % of Population 5% 1% Ideation1,2 Behavior/Attempts 1Boylan LS, et al. Neurology. 2004;62:258-261. 2Jones JE, et al. Epilepsy Behav. 2003;4:S31-S38. Publishers; 1997:2141-2151.

  6. 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%

  7. 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

  8. 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 1Thase ME, Rush AJ. In: Bloom FE, Kupfer DF, eds. Psychopharmacology: The Fourth Generation of Progress. New York, NY: Raven Press, Ltd.; 1995:1082-1097.

  9. 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.

  10. Diagnostic Algorithm for Major Depression (Cont’d) Follow-Up Clinical Interview • Five or More Symptoms for Major Depression • Depressed mood • Anhedonia • Weight change • Suicidal ideation • Sleep disturbance • Poor concentration • Psychomotor problems • Excessive guilt • Lack of energy • 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.

  11. 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)

  12. Screening Instruments for Evaluating Depression *Internal Consistency, †Interrater Reliability1Arnau, 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.

  13. Psychometric Properties of the QIDS • 16-item abbreviated version of the IDS • Includes only items assessing DSM-IV criterion • Scores 9 symptom domains • Psychometric Overview • 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.

  14. 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.

  15. 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 NeurosurgPsychiatry. 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.

  16. Neuroanatomic Mechanisms of Depression in Epilepsy • Brain regions commonly affected in epilepsy may lead to clinical expressions of depression • Amygdala • Hippocampus • Prefrontal cortex • Research suggests a bi-directional relationship between epilepsy and depression Hecimovic H, et al. Epilepsy Behav. 2003;4;S25-S30.

  17. 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

  18. Neurotransmitter Abnormalities (Animal Models and Pharmacology) Gliosis and Neuronal Cell Loss (Neuropathologic Studies) Decreased 5HT-1A Receptor Binding in Temporal Lobe and Raphe Hippocampal and Frontal Lobe Atrophy (MRI) Potential Common Pathogenic Mechanisms of Depression and Epilepsy Depression

  19. Considerations in the Treatment of Epileptic Patients With Depressed Mood Did the depressive episode follow the discontinuation of an AED possessing mood-stabilizing 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 • 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? Kanner AM, et al. Epilepsy Behav. 2003;4:S11-S19. Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

  20. 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? • Postictal depression usually responds poorly to antidepressant therapy; consider an optimal prophylactic AED • Consider impact of forced normalization • Treatment with antidepressant can be considered • Do depressive symptoms have a temporal relationship with the occurrence of seizure frequency? Kanner AM, et al. Epilepsy Behav. 2003;4:S11-S19. Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

  21. SSRIs citalopram (Celexa®), escitalopram(Lexapro®)fluoxetine (Prozac®), paroxetine (Paxil®), sertraline (Zoloft®) Norepinephrine/serotonin reuptake inhibitors venlafaxine (Effexor®) Tricyclics imipramine (Tofranil®), nortriptyline (Pamelor®) 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 Treatment Options for Depression in Epilepsy Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

  22. Antidepressants With Low Proconvulsant Activity *TCA , †SSRI, ‡NE/5HT modulator, § MAOI, ║Serotonin modulator. Harden CL, Goldstein MA. CNS Drugs. 2002;16:291-302.

  23. Antidepressants With Relatively Moderate and High Proconvulsant Activity1,2 *TCA , †SSRI, ‡SNRI, § tetracyclic, ║DNRI. 1Adapted from Harden CL, Goldstein MA. CNS Drugs. 2002;16:291-302. 2American Psychiatric Association. pract/treatg/pg/ Practice%20Guidelines8904/MajorDepressiveDisorder_2e.pdf.

  24. Psychiatric Drugs and AEDsDrug-Drug Interactions Kanner AM, et al. Epilepsy Behav. 2000;1:37-51.

  25. 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 G, et al. Epilepsy Res. 2000;42:203-210.2Harden CL, et al. Epilepsy Behav. 2000;1:93-99 3Data on file. Cyberonics, Inc.

  26. 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 Physician’s Manual. Houston, Tex; 2005; Henry TR. Neurology. 2002;59(suppl 4):S3-S14; Krishnamoorthy ES. Epilepsy Behav. 2003;4:S46-S54.

  27. 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!

  28. Case 1 • Woman in her early 40’s 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

  29. Case 1, cont’d • 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)

  30. 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?

  31. 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

  32. 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