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1 John Kasckow, MD, PhD VA Pittsburgh Health Care System Western Psychiatric Institute and Clinic, UPMC VA Pittsburgh Health Care System I received help from Bosch Health Care 1

2 Diagnoses of Interest Early Onset Schizophrenia Late Onset Schizophrenia Very Late Onset Schizophrenia Like Psychoses Recommendations for Drug Dosing in Late Life Schizophrenia 1. Simple Regimen 2. Be aware of patients who are very sensitive to medications 3. Gradual Dose Titration 4. Timely and thorough assessments of therapeutic and side effects Tsuboi et al Curr Psychiatry Rep 13: ,

3 Antipsychotic Treatment of Older Patients with Schizophrenia An expert review panel recommended risperidone ( mg/day) as the first line of treatment. Quetiapine ( mg/day), olanzapine ( mg/day), and aripiprazole (15 30 mg/day) were viewed as good second line treatments. Starting dosages for late onset persons at 25% of the recommended adult dose and maintenance doses at 25 50% of the adult dose. Often, effective doses for early onset can be 50 75% of younger patients. Alexopoulos et al. J Clin Psychiatry 65 Suppl 2: Antipsychotic Treatment of Older Patients with Schizophrenia Lack of controlled studies, e.g., CATIE trial ranges from ages 18 to 65. Federal warnings about increased mortality risk in elderly dementia patients adds to the concern regarding use of antipsychotic medications. Manschreck & Boshes Harvard Rev Psychiatry 15:245 58,

4 Clozapine 43% of individuals aged had at least a 20% improvement on the total BPRS score compared with 5 patients (17%) aged 65 and older (p = 0.02). Based on this, perhaps there is a more limited response in the elderly Sajatovic et al. Psychiatric Services 49: 340, 1998 Newer Medications Paliperidone Iloperidone Asenapine Lurasidone There is limited data to support their safety, tolerability and efficacy in older patients with schizophrenia Howland, J Psychosoc Nurs Mental Health Serv, 49:13 5, 2011; Rado and Janicak; Drugs Aging; 29: ,

5 Antipsychotics in Older Patients with Schizophrenia 2 large studies of risperdal at mean doses of 2.4 mg/day (n = 103) and 3.7 mg/day (n = 180) 1 Subanalysis (n = 57 from the original sample of 615 patients) showed the effectiveness of long acting risperidone in a stable elderly population with a mean baseline PANSS score of 73 Fleischhacker et al J Clin Psychiatry 64: 1250, 2003; Davidson et al Int J Geriatric Psychiatry 15:506, 2000; Madhusoodanan et al Am J Ger Psychiatry 7:132, PET study reported a decrease in frontal and temporal activity in association with improvement of psychotic symptoms in 6 patients with schizophrenia (age yrs) treated with risperidone 4 6 mg Berman et al Psychopharmacol Bulletin 32:95, 1996 International Multisite Double Blind Trial of the Atypical Antipsychotics Risperidone and Olanzapine in 175 Elderly Patients with Chronic Schizophrenia Only one large scale randomized, double blind controlled trial comparing 2nd generation antipsychotics risperidone (1 3 mg/day) and olanzapine (5 mg to 20 mg/day) in adults older than 60. Improvements seen in both groups with (+) symptoms, ( ) symptoms, disorganized thoughts, and symptoms of anxiety/depression. No significant differences in side effects except for more weight gain in the olanzapine group. Jeste et al (2003) Am J Ger Psychiatry 11:

6 Antipsychotics in Older Patients with Schizophrenia A subanalysis of the EFESO trial (Estudio Farmaco epidemiologico en la Esquizo frenia con Olanzapina) study in those 60 and older in a 6 month naturalistic setting Benefit noted with olanzapine (mean dose 11.7 mg/day) vs others (risperidone or other 1st generation antipsychotics) using measures of functioning, subjective status and EPS rates Magnitude of effect less in the older subpopulation (nonsignificant differences; due to lower number of patients 135/2967) Use of anticholinergics less frequent in patients taking olanzapine Ciudad et al Eur Psychiatry 19:358; 2004; Gomez et al J Clinical Psychiatry 61: 335; 2000 Late Onset Schizophrenia Lack of published data specifically examining antipsychotics in late onset schizophrenia (LOS); investigations have often mixed early and late onset patients. Only one randomized trial using risperidone and olanzapine, and both were well tolerated, but study had no other usable data. Open studies of typical antipsychotics in LOS indicated that 48% 61% of patients demonstrated full remission of psychotic symptoms. Cognitive behavioral therapy and social skills training also have shown promise. Cochrane Database Syst Review 2012 Feb 15;2:CD doi: / cd pub2 6

7 Case series: Very Late Onset Schizophrenia like Psychoses 8 outpatients/13 inpatients for very late onset schizophrenia like psychoses who had been treated naturalistically with a 2nd generation antipsychotic during hospitalization or during 9 months of outpatient care. Most common symptom: persecutory delusions +/ hallucinations Mean age: 76 Mean age of onset = 70 yrs for outpatients and 74 for inpatients E record standardized symptom severity response ratings were converted into positive treatment response thresholds. Scott et al International Psychogeriatrics 23: 742, 2011 Case series: Very Late Onset Schizophrenia like Psychoses 38% of outpatients/77% of inpatients met criteria for a positive treatment response with sign/symptom amelioration; patients with less chronic more severe symptoms responded at a higher rate. Daily doses used: Risperidone 1 3 mg Risperidone LA 12.5 mg q 2 weeks Quetiapine mg Olanzapine Aripiprazole mg Limitations retrospective, small sample, naturalistic treatment, dependence on basic outcome ratings, e.g., mild, moderate, severe Scott et al International Psychogeriatrics 23: 742,

8 Adjunctive Treatments for Older Persons with Schizophrenia Individuals with subsyndromal depression (n = 198) treated with citalopram 20 mg/day or more vs placebo. Improvement seen with depressive symptoms, mental functioning, quality of life, social functioning. Those with baseline suicidal ideation had improvements Zisook et al J Clinical Psychiatry, 70: ; 71: 915, 2010; Kasckow et al Intl J of Geriatric Psychiatry, 16: 1163, Adjunctive Treatments for Older Persons with Schizophrenia Trazodone effective against tardive dyskinesia in a 5 week study at weeks 2 and 3. Hayashi et al. Int Clinical Psychopharmacology 12: Donepezil no effect on cognitive symptoms when augmenting antipsychotic therapy in elderly patients with schizophrenia Mazeh et al. Int Psychogeriatrics 18:429, 2006 Helped improve tardive tremor and MMSE score in another small study Bergman et al. J Clinical Psychiatry 66:107,

9 Adjunctive Treatments for Older Persons with Schizophrenia Galantamine no difference from placebo in ameleriorating tardive dyskinesia Discontinuation associated with rebound in tardive dyskinesia Caroff et al. J Clin Psychiatry. 68: Adjunctive Treatments for Older Persons with Schizophrenia Prospective 12 week open label study examining adjunct extended release divalproex in older adults with schizophrenia (n = 20); add on to antipsychotic treatment Mean age 61; range 49 79; mean dose of divalproex: 587 +/ 247 mg Reductions in PANSS scores, Global Assessment Scale Scores and Geriatric Depression Scale Scores Primary side effect sedation which was dose and titration speed dependent No changes in weight Sajatovic et al. International J Geriatric Psychiatry 23:

10 Antipsychotics Adverse Effects Aging associated with increased sensitivity through central pharmacodynamic mechanisms. These findings support the use of lower antipsychotic doses Uchida et al 70: 397 J Clinical Psychiatry, 2009 Threshold for EPS lower in older patients > 75% D2 receptor occupancy (risperidone dose of 3 mg/day) associated with lower attention subscale scores on the Dementia rating Scale 2 Uchida et al J Clin Psychopharmacology 29: 571; 2009; Uchida et al 17: 255, Am J Geriatric Psychiatry

11 Antipsychotics Adverse Effects Psychiatric patients in general are highly vulnerable to metabolic problems (in part because of smoking and lifestyle issues) Correll et al Psychiatric Services 61: 892, 2010; Bobes et al 119: 101, Schizophrenia Res 2010 Tardive Dyskinesia Risk of developing tardive dyskinesia with conventional antipsychotic medications: 29% (after 1 year nearly 6x that of younger persons), 50% (2 years) 63% (3 years) Rates substantially lower with 2 nd generation antipsychotic medications (5% after one year) Other side effects: EPS and anticholinergic effects are higher in elderly persons. 11

12 Tardive Dyskinesia Risperidone cumulative TD rate was 5.3% after 1 year; and 7.2% after 2 years Olanzapine cumulative TD rate was 6.7% after 1 year and 11.1% after 2 years. Jeste et al. Am J Geriatric Psychiatry 7:70 76, 1999; Jeste et al. J Clin Psychiatry 61 Suppl 4:27 32; Woerner et al. Neuropsychopharmacology. 36: , 2011 Psychosocial Interventions in Middle Aged and Older Patients with Schizophrenia Integrated Psychological Therapy Mueller et al. Am J Geriatr Psychiatry. 21: , 2013 Functional Adaptation Skills Training (FAST) Patterson et al. American Journal of Geriatric Psychiatry, 11, 17 23, 2003 Helping Older People Experience Success (HOPES) Pratt et al, 2008 American Journal of Psychiatric Rehabilitation. 11: 41 60,

13 Psychosocial Interventions in Middle Aged and Older Patients with Schizophrenia Cognitive Behavioral Social Skills Training (CBSST) Granholm et al, 2005 Am J Psychiatry. 162(3):520 9, 2005 Cognitive Remediation Therapy McGirk & Mueser, Am J Psychiatry. 164: , 2007 Greenwood et al, 2005 Schizophr Bull. 31: ,