1. Schizophrenia Consult
Antipsychotics
What’s the right dose?
How low can it go?
How much is too much?
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Option 1
Schizophrenia Consult
Sara Dugan, Pharm.D., BCPP, BCPS
April 17, 2018

2. Objectives
Identify biological, social, and psychological factors that affect psychotic illness
Define the mechanisms or rationale for treatments appropriate for psychotic illness
Integrate biological, social and psychological considerations when designing and implementing treatment of individuals affected by psychotic illness.

3. PORT Guidelines
Treatment of acute positive symptoms in treatment-responsive people with schizophrenia: Acute antipsychotic medication dose
Doses of first generation antipsychotics (FGA) 300 – 1000 chlorpromazine equivalents (CPZ)
Recommend lower doses in first-episode schizophrenia patients
Maintenance dose 300 – 600 CPZ
Aripiprazole 10 – 30 mg
Olanzapine 10 – 20 mg
Paliperidone 3 – 15 mg
Quetiapine 300 – 750 mg
Risperidone 2 – 8 mg
Ziprasidone 80 – 160 mg
Maintenance dose for aripiprazole, olanzapine, paliperidone, quetiapine, risperidone and ziprasidone should be dose found to be effective for reducing positive psychotic symptoms in the acute phase of treatment
Fluphenazine Decanoate 6.25 – 25 mg q 2 weeks
Haloperidol Decanoate 50 – 200 mg q 4 weeks
Risperidone Long Acting Injection 25 – 75 mg q 2 weeks
Kreyenbuhl J, et al. Schizophrenia Bulletin 2009.

4. A look at First Episode Prescribing
Review of prescription data from Recovery After an Initial Schizophrenia Episode Project’s Early Treatment Program (RAISE-ETP) n=404
Drug
# Prescriptions
Median dose mg/day
Mean dose mg/day
Dose range mg/day
Risperidone
108 3
2.9
0.25 – 7.0
Risperidone Long Acting 1 75
Olanzapine 51 15
16.5
2.5 – 40
Aripiprazole 35 10
2 – 20
Paliperidone 17 6
5.8
3 – 9
Paliperidone Long Acting 13
136.5
149.5
117 – 234
Quetiapine 28
300
309.7
20 – 800
Haloperidol 12
11.3
3 – 30
Haloperidol Long Acting 4
81.2
50 – 125
Ziprasidone 80
102.2
40 – 200
Lurasidone 40
66.7
40 – 120
Asenapine 2
Clozapine
250
200 – 300
Thiothixene 5
Fluphenazine
Loxapine
Perphenazine
Robinson D, et al. Am J Psychiatry 2014.

5. Neuroprotective or Neurotoxic?
Use of antipsychotics associated with decreased risk of relapse
Relapses associated with reduced brain volume
Longitudinal imaging suggest that greater intensity of antipsychotic treatment associated with smaller gray matter volumes
Suzuki T, et al. Hum Psychopharm Clin Exp
Andreasen NC, et al. Am J Psychiatry 2013.
Ho BC, et al. Arch Gen Psychiatry 2011.

6. Do low dose antipsychotics work?
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7. Evaluating a range of risperidone doses
Double-blind trial in patients with schizophrenia
Treatment for 8 weeks
6 groups
Risperidone 2 mg, 6 mg, 10 mg and 16 mg daily
Haloperidol 20 mg daily
Placebo
Clinical Global Impression – Severity of Illness
All medications superior to placebo
Clinical Global Impression – Improvement
All but Ris 2 mg superior to placebo
Positive and Negative Syndrome Scale (PANSS)
Total score
Ris 6, 10, 16 mg and hal 20 mg superior to placebo
Positive symptoms
All Ris doses superior to placebo
Dyskinesia with Ris 6, 10 and 16 mg
Treatment for 8 weeks after single placebo wash out doses increased to maintenance doses in 1 week
N=135 all inpatients- Canadian trial
No difference seen in parkinsonism with ris although appeared to increase with dose but no different than placebo hal was greater than ris 2, 6 and 16 mg for parkinsonism
Chouinard G, Jones B, Remington G, Bloom D, Addington D, et al. A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993;13(1):25-40.
Chouinard G, et al. J Clin Psychopharmacol 1993

8. A look at Quetiapine doses
Double-blind 6 week treatment of patients with schizophrenia
Groups (n = 361)
Quetiapine 75, 150, 300, 600 or 750 mg
Haloperidol 12 mg
Placebo
Efficacy
Brief Psychiatric Rating Scale (BPRS)
MC R DB PC Initially had 1 week single blind placebo wash out then doses titrated up over the first week
Patients were hospitalized with schizophrenia
* P < 0.05
Arvanitis LA, et al. Biol Psychiatry 1997.

9. Can low doses also work for maintenance treatment of schizophrenia?
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10. A look at long-acting injections
Randomized, double-blind trial for 48 weeks
Patients with schizophrenia n=41
Groups
Haloperidol decanoate 60 mg IM every 4 weeks
Placebo
Significantly more relapses with placebo
DB period preceeded by 15 week single blind run in phase treated with 60 mg hal dec (3.6 mg daily oral). Steady state hal levels reached at 11 weeks; mean ss level 6.3 nmol/L in placebo group 50% decrease in mean hal plasma concentration seen 8 weeks after withdrawal of hal- hal concentration seen as a predictor of relapse
No difference in EPS- more hal pts on biperiden and more placebo pts on sedatives
Eklund K, Forsman A. Minimal effective dose and relapse double blind trial: haloperidol decanoate vs. placebo. Clin Neuropharmacol 1991;14 Suppl 2:S7-12.
Eklund K, Forsman A. Clin Neuropharmacol 1991

11. Suggested change in cognition
Open label 28 week trial
Patients (n=61) with schizophrenia with remission of positive symptoms and stable dose at least 3 months
25% dose reduction at baseline then again at week 4
Cognitive function evaluated by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)
Multicenter OL parallel group 28 wk randomized controlled trial at 6 psychiatric hospitals and clinics in Tokyo
On at least 2 mg ris and 5 mg olz
Maintained 50% of original dose for remaining 24 weeks
Significant reductions in Total score RBANS, immediate memory, language
No difference in PANSS total score or positive score but significantly greater decrease in PANSS negative score
Takeuchi H, et al. Schizophrenia Bulletin 2013.

12. Standard dose vs. low dose antipsychotics
Meta-analysis
13 studies, n=1395
Standard dose n=739
Low dose n=457
Very low dose n=199
Primary outcome
Treatment failure
Drug
Defined Daily Dose
PORT Dose
Quetiapine
400 mg
300 – 750 mg
Ziprasidone
80 mg
120 – 160 mg
Olanzapine
10 mg
10 – 20 mg
Risperidone long acting
25 mg q 2 weeks
25 – 75 mg q 2 weeks
Fluphenazine Decanoate
14 mg q 2 weeks
6.25 – 25 mg q 2 weeks
Haloperidol decanoate
92 mg q 4 weeks
50 – 200 mg q 4 weeks
Treatment failure including d/c of treatment for any reason
Study duration varied from 24 weeks to 104 weeks
Uchida H, Suzuki T, Takeuchi H, Arenovich T, Mamo DC. Low dose vs. standard dose of antipsychotics for relapse prevention in schizophrenia: meta-analysis. Schizophrenia Bulletin 2011;37(4):
Low dose ≥ 0.5 but <1 DDD
Very low dose < 0.5 DDD
Uchida H, et al. Schizophrenia Bull 2011.

13. Standard vs. Low dose antipsychotics*
Uchida H, et al. Schizophrenia Bulletin 2011.

14. Revisit dosing to balance efficacy and safety
Continuous treatment to prevent relapses
Optimal antipsychotic dosing regimen may change over time
Increased adverse effects or neurotoxicity
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