Non-A, non-b=hcv; IFN/RBV; DSM-5/Ham-D, OLT; SSRI, P450

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1 James A. Bourgeois, O.D., M.D. Vice Chair Clinical Affairs and Director, CL Service University of California San Francisco Non-A, non-b=hcv; IFN/RBV; DSM-5/Ham-D, OLT; SSRI, P450 Localize! Sequence! 1

After seminar, attendees will be able to: Describe psychiatric L co-morbidity in HCV Discuss risk of i psychiatric side effects from IFN v Plan psychopharmacological treatment for e patients with

Recurrence of Hepatitis C in Patients after Liver Transplantation with Interferon and Ribavirin Co-Investigator Principal Investigator - Lorenzo Rossaro, M.D.

2 After seminar, attendees will be able to: Describe psychiatric L co-morbidity in HCV Discuss risk of i psychiatric side effects from IFN v Plan psychopharmacological treatment for e patients with rhcv disease and IFN o f a s h e : ( Editorial Board AAP/APP No pharmaceutical financial support in last 12 months for the content of the course Past Grant Support for this topic Treatment of Recurrence of Hepatitis C in Patients after Liver Transplantation with Interferon and Ribavirin Co-Investigator Principal Investigator - Lorenzo Rossaro, M.D. Schering Corporation Grant Amount: $30,000 July December 2004 Psychiatric Co-morbidity in HCV Psychiatric Side Effects of IFN for HCV Clinical Assessment and Management Psychopharmacological Approaches Surveillance, Low RL treatment vs. Prophylaxis 2

Psychiatric Illness is Common with HCV Psychiatric Illness likely increases risk of HCV Psychiatric side effects from IFN are a major limiting factor; intervention is needed to facilitate treatment

3 Psychiatric Illness is Common with HCV Psychiatric Illness likely increases risk of HCV Psychiatric side effects from IFN are a major limiting factor; intervention is needed to facilitate treatment completion Extensor Major review of HCV/IFN/Psychiatric aspects HCV untreated 2-57% rate of depression HCV and IFN: Cognitive, affective, behavioral components, fatigue, insomnia Cognitive Sx 2-14% Depressive Sx 3-57% (most studies 10-40%) Irritability Sx 35% Fatigue Sx 90% million HCV in US 10-20% severe mental illness have HCV Cognitive Sx of IFN: decreased motivation, apathy, impaired executive function, amnesia Depression with IFN in 10-50% Maintain antidepressant through IFN Prophylaxis with antidepressants can be considered 3

306 HCV patients Mood disorders in 38% Personality disorders

Aphasia 110 HCV and IFN pts ΑPOE ε 4 allele predicted mood

35% Anxiety 30% Anger/irritability 29% Schizophrenia 42

4 306 HCV patients Mood disorders in 38% Personality disorders in 30% PTSD in 19% Alcohol use disorders in 86% IVDU in 28% Aphasia 110 HCV and IFN pts ΑPOE ε 4 allele predicted mood symptoms Lethargy, fatigue, loss of energy 70% Depressed mood 35% Anxiety 30% Anger/irritability 29% Schizophrenia 42 HCV/IFN patients followed for 24 weeks 18 (43%) had SI during treatment ECT 4

5 42 HCV/IFN/RBV patients, 11 in psychiatric care at baseline Among 31 others, 15 required psychiatric treatment during study; 7 met criteria for MDD Analysis 135 patients HCV 32.6% lifetime risk MDD (vs. 12.8%) IFN treated and drug abusers excluded 84 cases on HCV/IFN 58% cumulative frequency of depression, anxiety, anger/hostility 8% stopped IFN due to psych factors Frontal lobe 5

4 on antidepressant at baseline 2 others started antidepressants during Rx Mean CES-D increased to max at 12 weeks,

6 162 HCV/IFN/RBV patients Zung scores significantly increased by week 4 39% severe depression on Zung Stain 10 Pts with recurrent HCV post OLT and IFN/RBV 9 completed Rx CES-D for depression 2 moderate-severe depression at baseline 4 on antidepressant at baseline 2 others started antidepressants during Rx Mean CES-D increased to max at 12 weeks, then declined slightly Citalopram in 15 MDD and HCV Mean dose 27 mg/day Well tolerated 7 with GI sx 7 with sexual sx Glia 6

39 HCV/IFN cases 33% developed IFN-associated MDD Onset 12 weeks of IFN 85% of MDD cases responded to SSRI, mean citalopram 36 mg/day 5 cases with psychotic sx during IFN, all Rx olanzapine 2.

7 39 HCV/IFN cases 33% developed IFN-associated MDD Onset 12 weeks of IFN 85% of MDD cases responded to SSRI, mean citalopram 36 mg/day 5 cases with psychotic sx during IFN, all Rx olanzapine 2.5 mg qhs One also received bupropion 150 mg bid One also received citalopram 40 mg qd and gabapentin 300 mg qhs Anatomy Contraindications to IFN/RBV for HCV ICD-9 code based screening , initally 15,561,021 screened, 45,690 were HCV + MDD with suicide attempt (only 1 case) Bipolar disorder (2958 cases, 6.5%) was most frequent contraindication (no severity assessment) 7

8 Subthreshold hypomania/mania hx found to predict IFN-associated depression Thoughtful use of typical psychopharmacological agents is needed in HCV-associated psychiatric illness Chicken/egg/omelette issues Pre-morbid psychiatric illness may be made worse by HCV/IFN and needs to be managed HCV/IFN may result in new psychiatric illness which needs to be managed Not all SSRI are created equal! Hepatic enzyme inhibition may be problematic (P450 system) Problem: Paroxetine, Fluoxetine, Fluvoxamine, high doses of Sertraline Safer: Citalopram, Escitalopram, low doses of Sertraline Direct effects of SSRI are similar 8

CYP2D6 inhibitors paroxetine, fluoxetine, sertraline can increase levels of TCAs Lower protein binding of venlafaxine Caution re retinopathy, GI bleed, platelet dysfunction with SSRI Venlafaxine -

9 CYP2D6 inhibitors paroxetine, fluoxetine, sertraline can increase levels of TCAs Lower protein binding of venlafaxine Caution re retinopathy, GI bleed, platelet dysfunction with SSRI Venlafaxine - relatively less protein bound; cases of hepatotoxicity Duloxetine cases of hepatotoxicity Mirtazapine - rare decreased white count, but it is sedating and does not cause nausea, increases appetite thus good in wasting Bupropion - seizure risk but may be stimulating and increase attention and concentration. Not associated with weight gain, may induce insomnia 9

10 Atypical antipsychotics are now typical but Risperidone, Ziprasidone, Quetiapine may be associated with increased QTc Olanzapine >Risperidone and Quetiapine associated with increased glucose and lipids Aripiprazole may be stimulating; Aripiprazole and Ziprasidone less likely to increase weight Clozapine may increase delirium and seizure risk Not to be neglected in depressed and apathetic patients, subject to usual caution re: substance abusers Methylphenidate, Modafinil Caution with BZPs in substance abusers Consider long t1/2 agents (e.g. clonazepam) rather than short t1/2 agents (e.g. alprazolam) Clonazepam Buspirone no abuse potential 10

11 Recognition of psychiatric aspects of HCV Screening for psychiatric co-morbidity Non-pharmacological treatments (recovery programs, psychotherapy, social interventions) Monitor cases on several dimensions (mood, cognitive, anxiety, psychotic) At onset of IFN/RBV case, full psychiatric history and examination, including cognitive status and mood rating scale Fully treat any pre-existing psychiatric disorder before starting IFN/RBV Maintain treatment throughout IFN/RBV period before considering tapering later IFN-associated psychiatric illness risk appears to peak at 2-3 months of IFN exposure surveillance and intervention For IFN-induced psychiatric illness, maintain treatment throughout IFN exposure Re HCV/IFN associated mood disorders Schaefer et al. J Hepatology 2012; 57: Low threshold treatment for mood sx Prophylaxis? Hx MDD/MDD at start of IFN/Hx IFN-associated mood disorder (Galvao-de Ameida Gen Hosp Psych 2010; 32: ) Routinely (Sarker and Schaefel Psychosomatics 2014; 55: ) Weiss and Morgello (GHP 2009; 31: ): 33% recommend/offer prophylaxis s psych hx, 75% if hx depression 11

12 Review of antidepressant pretreatment for IFN-associated depression 8 trials (7 HCV) Pretreatment reduced IFN depression incidence Lower mean depression scores at 24 weeks Effect not dependent on pre-existing psychiatric illness Current review and recommendations Genotype 1 (75%): Sofosbuvir and pifn/rbv x 12 weeks or simeprivin (12 weeks) and pifn/rbv (24 weeks)* Genotype 2/3 (25%): Simeprevir and RBV (2= 12 weeks, 3= 24 weeks) HIV/HCV co-infection and compensated cirrhosis same as HCV monoinfection Psychiatric illness precedes and follows both HCV and IFN treatment Surveillance for psychiatric illness (particularly mood disorders) throughout course of treatment for HCV is essential Psychiatric illness associated with IFN-based treatments is a common treatment limiting complication but is treatable Surveillance with prompt response, maintenance treatment, targeted prophylaxis and broad prophylaxis may all be considered 12

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