PSYCHOTIC MAJOR DEPRESSION

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2 PSYCHOTIC MAJOR DEPRESSION Alan F. Schatzberg, MD Kenneth T. Norris, Jr. Professor Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford, CA

3 PSYCHOTIC MAJOR DEPRESSION Martin B. Keller, MD Professor Department of Psychiatry & Human Behavior Alpert Medical School Brown University Providence, RI

4 ALAN F. SCHATZBERG, MD Disclosures Research/Grants: None Speakers Bureau: None Consultant: BrainCells Inc.; CeNeRx BioPharma; Jazz Pharmaceuticals, Inc.; Neuronetics Inc.; NovaDel Pharma; PharmaNeuroBoost; Sanofi-aventis; Sunovion Pharmaceuticals Inc.; Takeda Pharmaceuticals North America, Inc. Stockholder: Amnestix, Inc.; BrainCells Inc.; CeNeRx BioPharma; Corcept Therapeutics; Forest Laboratories, Inc.; Merck & Co., Inc.; Neurocrine Biosciences, Inc.; NovaDel Pharma; Pfizer Inc.; PharmaNeuroBoost; Somaxon; Synosis Other Financial Interest: Named inventor on pharmacogenetic and antiglucocorticoid use patents on prediction of antidepressant response; Associate Editor, American Journal of Geriatric Psychiatry Advisory Board: None

5 MARTIN B. KELLER, MD Disclosures Research/Grants: None Speakers Bureau: None Consultant: CeNeRx BioPharma; Medtronic, Inc. Stockholder: None Other Financial Interest: None Advisory Board: CeNeRx BioPharma

6 LEARNING OBJECTIVE Devise a strategy to improve the management and outcomes in patients with psychotic depression.

7 MM Menu Calendar Tests Chart Review: James F. BACKGROUND Personal: 57-year-old Caucasian male, worked for the Federal Government in the Washington, DC area Neuropsychiatric History: Unremarkable. No psychiatric history. Intelligent, organized, and described as a hard-working, dedicated man. Medical History: Unremarkable. Family History: Born in Beacon, New York, son of Irish immigrants Married, wife had a history of problems with alcohol and a psychiatric history Work History: Worked as a news reporter as a teen Went to Princeton University for 3 years, did not graduate Worked at a bond company working his way to become president of the company Began working for the Federal Government at age 48 to work for the Treasury Department and then the Defense Department TODAY S VISIT Chief Complaint and Psychiatric Interview Findings: developed a number of symptoms suggestive of depression feeling exhausted having difficulty concentrating indecisiveness weight loss with a haggard appearance and sunken eyes precipitants included significant political stress at work made a suicide attempt that did not result in hospitalization Physical Findings: Weight loss, appears quite run down Questionnaire and Lab Findings: No abnormal findings

8 MM Menu Calendar Tests Chart Review: James F. Assessment and Plan: What are your initial diagnostic impressions? What further symptoms would you inquire about? How would you assess suicide risk? Treatment: Patient was started on an SNRI and took off from work. He went to his vacation home on the beach. He was visited by one of his aides at the beach house two weeks later. He said to his aide Bob, they are after me. As they walked on the beach, he thought the metal sockets in the sand for beach umbrellas had been wired to monitor his conversations. He thought the Kremlin had him marked for liquidation. What is your diagnosis? What are your concerns for safety of the patient? What treatment recommendations do you make or institute? Patient was hospitalized at Bethesda Naval Hospital. There he told a Navy psychiatrist he had failed at his job. At that time he was diagnosed as suffering from a severe reactive depression caused by intense pressure. He committed suicide in the hospital by a combination of hanging and falling from the 16th floor. This is the case of James Forrestall, Secretary of Defense, who died in 1949 and as described in Steve Vogel: The Pentagon, New York, Random House, 2007.

9 MM Menu Calendar Tests Chart Review: John R. BACKGROUND Personal: 50-year-old Caucasian male, accountant, married, father of 3 Neuropsychiatric History: Negative psychiatric history (confirmed by spouse) Medical History: History of mild hypertension Family History: Parents deceased Married with 3 children Wife works part-time Social History: Has friends, enjoys sports TODAY S VISIT Chief Complaint and Psychiatric Interview Findings: 50-year-old married father of 3 became depressed for the first time after he started working for a new boss, the boss was seen as critical of his work became increasingly agitated at home difficulty sleeping developed poor concentration anhedonic denied suicidal ideation denies any past history of depression or hypomania or mania Physical Findings: Unremarkable Questionnaire and Lab Findings: Unremarkable

10 MM Menu Calendar Tests Chart Review: John R. ASSESSMENT AND PLAN What is your diagnostic impression? What treatments would you consider? You start him on escitalopram and after 3 weeks at 20 mg per day there is little change. He is still depressed and is finding it more difficult to work. His wife joins him in the session and notes he stands by the window a great deal and peeks out fearing there are men parked in cars who are watching him. What is your response? What do you ask about? What treatment recommendations do you make? The patient his started on olanzapine 5 mg per day and it is increased to 15 mg per day. A month later he is no better and at this point he has taken a leave of absence from his job. He remains delusional and now fears being poisoned and is refusing to eat. What do you do next? What treatment changes do you consider? Patient is hospitalized and ECT is begun. Patient responds nicely to 6 bilateral treatments. What do you do next in terms of maintenance?

11 MAJOR DEPRESSION Severe with Psychotic Features Mood-congruent psychotic features Delusions of guilt Delusions of deserved punishment Nihilistic delusions Somatic delusions Delusions of poverty Hallucinations, typically auditory and transient Represents 15% of major depressive episodes American Psychiatric Association [DSM-IV-TR], 2000.

12 PSYCHOTIC DEPRESSION IN GENERAL POPULATION 18,980 subjects in five European countries Patients evaluated using Sleep-EVAL system Current prevalence of non-psychotic major depression: 2.0% Current prevalence of psychotic major depression: 0.4% 18.5% of major depression subjects had psychotic features Ohayon MM, et al. Am J Psychiatry. 2002;159(11):

13 INTRACELLULAR GLUCOCORTICOID SIGNALING ACTH (+) Hypothalamus CRF (+) Brain Pituitary Adrenal (-) (-) Glucocorticoid Glucocorticoids influence about 20% of the expressed human genome and their effects spare almost no organs or tissues. Chrousos & Kino. Science STKE 2005(304): pe48. Receptor Activated Receptor Complex Translation and Protein Synthesis Regulation of Gene Transcription mrna Nucleus Cell Membrane Chrousos GP, et al. Sci. STKE, 4 October 2005 Vol. 2005, Issue 304, p. pe48

14 DST NONSUPPRESSION IN 14 COMPARISON STUDIES % Nonsuppression 70% 60% 50% 40% 30% 20% 10% 0% 64% 41% PMD (N = 276) NPMD (N = 708) Mantel-Haenszel x 2 = 47.43, p <.001 Homogeneity of Effect Size x 2 = 11.39, p = NS Nelson JC, et al. Am J Psychiatry. 1997;154:

15 MAJOR NEUROPSYCHOLOGICAL DEFICITS IN PMD Attention (Kim et al. Prog Neuropsychopharmacol. 1999; Gomez et al. Biol Psych. 2006) Executive function (Schatzberg et al. Am J Psychiatry. 2000; Jeste et al. Am J Psychiatry. 1996; Nelson et al. Am J Psychiatry. 1998; Hill et al. Am J Psychiatry. 2004; Mifepristone et al. 2001; Gomez et al. Biol Psych. 2006) Response inhibition (Schatzberg et al. Am J Psychiatry. 2000) See supplemental bibliography for full references.

16 MAJOR NEUROPSYCHOLOGICAL DEFICITS IN PMD Story learning (Jeste et al. Am J Psychiatry. 1996) Verbal declarative memory (Schatzberg et al. Am J Psychiatry. 2000; Belanoff et al. 2001; Gomez et al. Biol Psych. 2006) Visual memory & visual-spatial perception (Hill et al. 2004) See supplemental bibliography for full references.

17 PMD: TREATMENT RESPONSE Low placebo response Poor response to tricyclics alone Responds well to amoxapine, antidepressants + antipsychotics, or ECT Possible response to atypical antipsychotics or SSRIs alone DeBattista C, et al. Treatment of Psychotic Depression. In Halbreich U, Montgomery SA, Eds. Pharmacotherapy for mood, anxiety, and cognitive disorders. American Psychiatric Press, Washington, DC pp

18 ECT IN PMD Psychosis was a predictor of relapse, as was comorbid Axis I and II disorders, site, and number of ECT treatments in the acute phase* Relapsed patients had a higher rate of psychotic depression (31.1% vs. 22.2%) * When controlling for site, # ECT treatments no longer significant Prudic J, et al. Biol Psychiatry. 2004;55(3):

19 ATYPICAL AP PLUS SSRI IN PMD OLZ + FLU (OFC) Study Period I Screening Study Period II Double-Blind Therapy Olanzapine 5-20 mg/day Fluoxetine mg/day Study Period III Open-Label Therapy Olanzapine mg/day 3-9 days Olanzapine 5-20 mg/day* Fluoxetine 0-60 mg/day Placebo Weekly Bi-Weekly visits 1 Week Weekly visits Monthly visits Bi-monthly visits Visit 1 Visit 2 Visit 6 Visit 8 Visit 301 Visit 304 Visit 307 Visit 311 Randomization or final visit * Olanzapine therapy initiated at 10 mg/day; 249 patients enrolled in this protocol, 2:2:1 ratio of randomization Rothschild AJ, et al. J Clin Psychopharmacol. 2004;24(4):

20 MEAN MODAL DOSE SUMMARY Study OFC (OLZ mg/flu mg) OLZ (mg) / / Combined 12.9/ Rothschild AJ, et al. J Clin Psychopharmacol. 2004;24(4):

21 RESPONSE RATE % Responders (HAM-D) 70% 60% 50% 40% 30% 20% 10% 0% p = % p = % 28.0% (n = 22) (n = 43) (n = 50) OFC OLZ PBO Rothschild AJ, et al. J Clin Psychopharmacol. 2004;24(4):

22 WEIGHT (KG) MEAN CHANGES COMBINED Subgroup OFC Change (N) OLZ Change (N) PBO Change (N) Overall 2.74 (45) 3.79 (89) 0.39 (90)* Male 2.24 (16) 4.69 (45)* 1.11 (47) Female 3.02 (29) 2.88 (44) (43)* * p <.05 vs. OFC Rothschild AJ, et al. J Clin Psychopharmacol. 2004;24(4):

23 HAM-D SCORES OLANZAPINE + PLACEBO VS. OLANZAPINE + SERTRALINE Hamilton Depression Scale (HAM-D) scores in subjects randomized to receive olanzapine plus placebo vs. olanzapine plus sertraline Meyers BS, et al. Arch Gen Psychiatry. 2009;66(8):

24 INTRACELLULAR CORTICOSTEROID RECEPTOR TYPES IN THE BRAIN Mineralocorticoid (MR) High affinity for cs (kd = 0.5 nm) In limbic structures Agonist: aldosterone Antagonist: RU 26752, spironolactone Glucocorticoid (GC) Lower affinity for cs (kd = 5.0 nm) Ubiquitous Agonist: dexamethasone Antagonist: RU DeKloet ER, et al. Endocr Rev. 1998;19(3):

25 MIFEPRISTONE (AKA, C-1073, RU-486) Formulated 1981 by Roussell-Uclaf Approved in Europe and Asia 1988 Approved in United States September 28, 2000 Progesterone receptor antagonist GRII antagonist (no GRI antagonist) Virtually no affinity for any other receptor

26 MIFEPRISTONE Multiple Fixed-Dose Study 440 patients 300, 600, and 1200 mg mifepristone for 7 days vs. placebo Multicenter BPRS PSS response at both day 7 and 56 Blasey C, et al. J Clin Psychopharmacol, in press.

27 MIFEPRISTONE Multiple Fixed-Dose Study BPRS PSS at Days 7 and 56 Response Rate (%) 50% 40% 30% 20% 10% 0% 44% Mifepristone 34% Placebo p =.144 Blasey C, et al. J Clin Psychopharmacol, in press.

28 MIFEPRISTONE Multiple Fixed-Dose Study Response Rate (%) 60% 50% 40% 30% 20% 10% BPRS PSS Days 7 and 56 52% 34% 0% Mifepristone Placebo p =.023 Blasey C, et al. J Clin Psychopharmacol, in press.

29 MIFEPRISTONE Multiple Fixed-Dose Study 300 mg 600 mg 1200 mg > % 48% 56% > % 63% 81% Blasey C, et al. J Clin Psychopharmacol, in press.

30 SUMMARY & CLINICAL CONNECTIONS PMD is a severe and relatively common subtype PMD associated with elevated HPA axis activity and neurocognitive impairment Currently effective therapies are primarily AP/AD combination and ECT Mifepristone appears to reduce psychotic symptoms in PMD

31 SUMMARY & CLINICAL CONNECTIONS Mifepristone accentuates cortisol and ACTh rhythm Changes in HPA measures appear to be associated with durability of response

32 QUESTIONS AND ANSWERS

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