Here are the key points about risperidone dosing:
- Start low at 0.5-1 mg per day divided into 1-2 doses
- Gradually increase the dose over 1-2 weeks until reaching the target dose of 2-4 mg per day divided into 1-2 doses
- Maintain the target dose for 2-4 weeks before beginning to taper down the dose gradually
- Decrease the dose over 1-2 weeks by 0.5-1 mg increments until discontinuing the medication
This sequential approach aims to minimize adverse effects by starting low and increasing slowly while still achieving the therapeutic dose range.
Practical Experience in Bipolar Disorder Treatment
1. Practical Experience
•Approach to treatment
•Evidence of Efficacy and Effectiveness
•Pharmacology
•Adverse Effects
•Activation, Agitation, Akathisia
Gary Sachs, MD
Associate Professor of Psychiatry, Harvard Medical School
Director, Bipolar Clinic and Research Program
Massachusetts General Hospital
2. Depression is the most common overt
expression of Bipolar Disorders
52%
31% 37:1
BP II
BPI 10%
BPI 1.4%
BPII
Judd et al % weeks % weeks
NIMH CDS, 2001 Depression Manic Spectrum
4. Critical Iterative approach
decision point
Evidence Individual factors
A-F
Menu of reasonable choices
+++ Option A €€€€
++ Option B $$$$
+++ Option C ££££
Measurement
Educate
Negotiate
Intervention
5. Selection of Initial Intervention
Sequential Care: Urgent Care:
Most Benign Most Effective
Usually
Monotherapy Combination Therapy
Usually
driven by Aggressive titration
Start Low
Patient driven by
to
Go Slow
Preference effective dose range
Clinician’s responsibility
9. Quality of evidence made simple
A. Double blind placebo controlled
trial with adequate sample*
B. Double blind comparison studies with adequate sample*
C. Open comparison trials with adequate sample*
D. Uncontrolled observation or controlled study with ambiguous result
E. No published evidence (+/- class effect)
F. Available evidence negative
* statistical power > 0.8 to detect meaningful differences at p< 0.05
10. Quality of Evidence for Widely Used Psychotropics
Prophylaxis Acute Mania /Mixed Acute Bipolar Depression Rapid Cycling
Lithium A+ A+ B C-
Divalproex A- A+ D D
Carbamazepine D A+ D D
Lamotrigine A+ F A A
Gabapentin E- F D D
Topiramate E- D D D
Oxcarbazepine E- D E- D
Aripiprazole A A+ D D
Clozapine D D E D
Haloperidol D A E- E-
Olanzapine A A+ A D
Risperidone E+ A+ D D
Quetiapine E+ A+ A D
Ziprasidone E+ A+ E- E-
Omega 3 D E- F F
17. A Simple Metric for Effect Size
Number Needed to Treat (NNT)= 1/(Active Response Rate - Placebo Response Rate )
Study Response Rate
Tohen 19991 Olanzapine (OLZ)=49% NNT Acute Mania 6.7
Placebo=24%
Tohen 20002 OLZ=65% 5.9
Placebo=43% 5.3
Khanna 20053 Risperidone (RIS)=73% 4.8 4.8
4.5
Placebo=36%
4.0
Hirschfeld 20044 RIS=43%
Placebo=24%
Vieta 20055 Quetiapine (QTP)=48%
2.7
Placebo=31%
Keck 20036 Ziprasidone (ZIP)=50%
Placebo=35%
Keck 20037 Aripiprazole (ARI)=40%
Placebo=19%
Sachs 20068 ARI=53%
Placebo=32% RIS3 OLZ1 OLZ2 ARI7 ARI8 RIS4 QTP5 ZIP6
1. Tohen M et al. Am J Psychiatry. 1999;156:702-709; 2. Tohen M et al. Arch Gen Psychiatry. 2000;57:841-849; 3. Khanna S et
al. Br J Psychiatry. 2005;187:229-234; 4. Hirschfeld RM et al. Am J Psychiatry. 2004;161:1057-1065; 5. Vieta E et al. Curr Med
Res Opin. 2005;21:923-934; 6. Keck PE Jr et al. Am J Psychiatry. 2003;160:741-748; 7. Keck PE Jr et al. Am J Psychiatry.
2003;160:1651-1658; 8. Sachs G et al. J Psychopharmacol. 2006;epub Feb 14.
18. Risperidone Monotherapy for Acute Mania
Same protocol different result
Dosing Matters
RIS-USA-239 RIS-IND-2
nt
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2
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Change in total YMRS score
-5 -5
-10 * -10
* * *
-15 * -15 *
-20 -20
** **
-25 -25
**
LOCF analysis. *P<.001 risperidone vs placebo. LOCF analysis. *P<.01; †P<.001 risperidone
vs placebo.
Hirschfeld RM et al. 2004;161:1057-1065. Am J Psychiatry. Khanna S et al. 2005:187:229-34 Br J Psychiatry.
19. Real-World Pharmaco-Epidemiology
New Treatment Starts at MGH Bipolar Clinic
N=466 with at least 4 visits/year
Median treatment duration (d)
Recovered/recovering (%)
197
162 166
127
97 99
67%
59% 53% 54% 57%
47%
Lithium Valproate Lamotrigine Atypical Antidepressants Anxiolytics
(n=49) (n=38) (n=89) Antipsychotics (n=264) (n=93)
(n=216)
MGH=Massachusetts General Hospital.
Sachs G et al. APA, 2006; Toronto Canada
25
20. MGH Bipolar Clinic
Atypical Antipsychotics with least 20 new starts
% Recovered ≤ 12 months
111
Median Duration (days)
112
% Recovering ≤ 3 months
No significant differences
111 112
84.5
75
64% 65% 65%
59%
51%
43% 43%
33%
Olanzapine Risperidone Quetiapine Aripiprazole
n=36 n=49 n=77 n=46
MGH=Massachusetts General Hospital.
Sachs G et al. Presented at: APA 2006 Toronto, Canada
26
21. MGH Bipolar Clinic
Antidepressants with least 20 new starts
111
% Recovered ≤ 12 months
111
Median Duration (days)
112
% Recovering ≤ 3 months
No significant differences 145
119
109
103 100100
75% 72% 75%
63% 62%
54% 56% 55%
48%
43%
Bupropion Paroxetine Venlafaxine Citalopram Trazodone
n=52 n=43 n=21 n=20 n=20
MGH=Massachusetts General Hospital.
Sachs G et al. Presented at: APA 2006 Toronto, Canada
27
22. Pharmacology
2007
Many drugs act as fixed ratio combination agents
Unintended Polypharmacy of Monotherapy
23. Pharmacologic Determinants of Clinical Response
Drug Individual
Site of Action Concentration Biology
at Site of Action
Affinity for Absorption Genetics
receptor Distribution Age
Metabolism Disease
Intrinsic Elimination Environment
activity at
site (ADME) (GADE)
Preskorn SH. Clinical Pharmacology of Selective Serotonin Reuptake Inhibitors.
24. Relative Binding Affinity (RBA):
The affinity of a drug for a secondary
site(s) target in relationship to most
potent binding site
Kd for secondary receptors
RBA =
Kd for primary receptor
Preskorn S J Psychiat Practice 9:376-384, 2005
Preskorn SH. J Psych Pract. 2004
25. Drug Concentration, Receptor Occupancy,
and Selectivity
=1 3 fold 10 fold 100 fold
Target
Range of
100% Therapeutic
Action
75%
Nonselective
% Bound
50%
Selective
25%
Highly Selective
0.01 0.1 1 10 100 1,000
Concentration (nM)
26. In vitro Affinity Profiles:
Known receptor affinities relative to most potent binding activity
Haloperidol profile relative to its most potent binding
Alpha1 5HT2A M-1
H1 5HT1A 5HT2C
D2
1 10 100 1,000 10,000
Aripiprazole profile relative to its most potent binding
D2 5HT1A 5HT2A 5HT2C Alpha1
H1 M-1
1 10 100 1,000 10,000
Clozapine profile relative to its most potent binding
Alpha1 5HT2A
M-1 D2 5HT1A
H1 5HT2C
1 10 100 1,000 10,000
Arnt and Sharfeldt 1998; Daniel 1999; Bymaster et al 1996; Seegers et al 1995. Adapted from Preskorn 2006
27. In vitro Affinity Profiles:
Known receptor affinities relative to most potent binding activity
Olanzapine profile relative to its most potent binding
Alpha1
M-1 5HT2A H1 D2 5HT2C 5HT1A
1 10 100 1,000 10,000
Quetiapine profile relative to its most potent binding
Alpha1 H1 M-1 D2 5HT2A 5HT2C 5HT1A
1 10 100 1,000 10,000
Risperidone profile relative to its most potent binding
Alpha1
D2 H1 M-1
5HT2A 5HT2C 5HT1A
1 10 100 1,000 10,000
Ziprasidone profile relative to its most potent binding
5HT2A 5HT2C 5HT1A D2 Alpha1 H1 M-1
1 10 100 1,000 10,000
Arnt and Sharfeldt 1998; Daniel 1999; Bymaster et al 1996; Seegers et al 1995. Adapted from Preskorn 2006
29. Risperidone: Dosing
Usual
1- 4 mg Effective 0.5 - 3 mg
Range
2-4 1-2
mg/q mg/q
1-2 wks 2-4wks
3-4 mg
qd Day 22-28
2-4 mg Day 3-28
qd-bid
2-3 mg
qd Day 15-21
1-2 mg
1-2 qd Day 8-14
Day 1-7
mg
qd- 0.5-2mg
qd-bid Day 1-7
bid
Urgent Sequential
Care Care
30. Aripiprazole: Dosing
15-30 mg Usual 15 - 30 mg
Effective
Range
15 15
mg/q 2-4wks
1-2 wks
15-30 mg
qd Day 3-28
15-30 mg Day 8-28
qd
15-30 mg
Day 1-7
qd
5-10 mg Day 1-7
qd
Urgent Sequential
Care Care
31. Olanzapine: Dosing
Usual
10-30 mg Effective 5 - 20 mg
Range
5-10 2 .5 -10
mg/q mg/q
1-2 wks 2-4wks
20-30 mg Day 22-28
15-30 Day 3-28 qd
mg
qd
10-20 mg Day 8-21
qd
10-20 Day 1-7
mg
qd 5-10mg
qd Day 1-7
Urgent Sequential
Care Care
32. Somnolence as an Adverse Event
Number needed to observe=1/(active drug rate - placebo rate)
50
Number of Cases Needed
to cause an extra case of
Significant Somnolence
33
14 14
6
Olanzapine Quetiapine Ziprasidone Aripiprazole Risperidone
Physicians’ Desk Reference ® 57th ed., Montvale, NJ: Medical Economics; 2003.
33. Clinically Significant Weight Gain (≥7%)
Atypical Antipsychotics vs Placebo
NNT 25 20 12 6 4
35 35 35 35 35
30 30 30 30 30
Incidence (%)
25 25 25 25 25
20 20 20 20 20
15 15 15 15 15
10 10 10 10 10
5 5 5 5 5
0 0 0 0 0
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ac
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Abilify® [package insert]. Princeton NJ: Bristol-Myers Squibb and Rockville, Md: Otsuka America Pharmaceutical;
2005; Geodon® [package insert]. New York, NY: Pfizer; 2004; Risperdal ® [package insert]. Titiusville, NJ:
Janssen Pharmaceutica Products, LP; 2003; Seroquel ® [package insert]. Wilmington DE: AstraZenaca; 2004;
Zyrexa® [package insert]. Indianapolis, Ind: Eli Lilly and Company; 2004.
39. YMRS Total: Mean Change Baseline to Endpoint
High or Low Agitation
* * * *
* *
*P ≤ 0.0005, unadjusted means.
• Including baseline YMRS score as a covariate and least-square
means, aripiprazole-treated patients showed significant
improvements at endpoint compared with placebo-treated patients
in both high and low agitation groups
40. Mean CGI-BP Scores:
Acutely Manic Patients With High or Low Agitation
* * * * *
*P ≤ 0.05, unadjusted means.
• Including baseline CGI-BP Severity score as a covariate and least-
square means, aripiprazole-treated patients showed significant
improvements at endpoint compared with placebo-treated patients
in both high and low agitation groups
41. PEC Scores: Mean Change Baseline to Endpoint
• Including baseline PEC score as a covariate and least-square
means, aripiprazole-treated patients showed significant
improvements at endpoint compared with placebo-treated patients
in both high and low agitation groups
42. Make the Guidelines your own!
Customized Self guidance, not imperative directive
• Every clinical user can
• Define decision points
• Weigh options
• Discipline assessment and intervention
• Utility requires
– Concision
– Critical Awareness of the evidence
• Subject to revision
• New data becomes available
• New Interventions become available
– Integration of Measurement into management
www.manicdepressive.org
Editor's Notes
BPI n=135 BPII n=71
Collaborative care uses the idea of encouraging patients to participate in choosing their medications whenever practical. This is done by sharing the profiles of drugs which are on a menu of resonable choices. STEP will provide practical tables which summarize the profiles of the most commonly used medications. Treating psychiatrists will determine what is reasonable for a given patient and help the patient select the most advantageous treatment. By enlisting the patient and their supports as collaborators in managing their treatment we expect to improve concordance between the treatment plan and patient practice.
A good understanding of each individual patient enables clinical decision makers to weigh a wide array of individual factors in selecting medications and other elements of the therapeutic plan. While most of these are widely appreciated some deserve emphasis or explanation.
This adaptation of the
Pivotal trials show us that treatments for Bipolar mania are more efficacious than placebo and at the same time gives us an estimate of unmet clinical need. We can compute an index of clinical effectiveness by taking the product of the response rate and the completion rate. Then by calculating the number needed to treat to see one additional patient get the benefit of clinical effectiveness we’d find our best treatments require 5-10 patients be treated before treatment contributes an extra patient getting an increment of clinical effectiveness.
Risperidone (Risperdal ® , Janssen Pharmaceutica Products, L.P.), an oral dopamine (D 2 ) and serotonin (5HT 2 ) antagonist, represents a milestone in the management of bipolar disorder. Approved by the FDA in December 2003, risperidone is the second atypical antipsychotic indicated as monotherapy or in combination with lithium or valproate for the short-term treatment of acute manic or mixed episodes associated with bipolar I disorder. The efficacy and safety of risperidone in treating acute manic or mixed episodes of bipolar disorder were established in 2 monotherapy trials and in 1 trial in which risperidone was used in combination with either lithium or valproate. The first study, reported by Hirschfeld et al, was a 3-week, placebo-controlled trial in which 262 manic patients with or without psychotic symptoms were randomly assigned to receive either placebo or risperidone (flexible dose of 1 to 6 mg/d). 1 On average, patients taking risperidone (mean 4.1 mg/d) experienced an 11-point reduction in YMRS total score compared with a 5-point reduction among placebo-treated patients ( P <.001). Clinical response, as determined by a ≥50% reduction in total manic symptom scores, was 43% for patients treated with risperidone and 24% in those receiving placebo. Patients with and without psychotic features who received risperidone showed significantly greater improvements in YMRS total score than patients receiving placebo, suggesting that the antimanic effect of risperidone is independent of its antipsychotic effects. The second, similarly designed, monotherapy trial included 290 bipolar I patients with manic or mixed episodes. 2 On average, patients receiving risperidone (median dose 6 mg/day) had a total reduction of 22.7 points in YMRS total score compared with a 10.5-point reduction in patients treated with placebo ( P <.001). Compared with the placebo group, significantly greater improvements in YMRS total scores at weeks 1 and 2 were observed in the risperidone group. At the end of the 3-week study, 73% of patients receiving risperidone achieved a clinical response, compared with 36% taking placebo. The most common side effects experienced in both risperidone monotherapy studies included extrapyramidal symptoms, tremor, insomnia, somnolence, and headache. The investigators concluded that risperidone effectively and safely treats acute bipolar mania, with onset of action as early as week 1. The adjunctive therapy trial will be discussed shortly [refer to Slide 14]. References: 1. Hirschfeld RMA, Keck PE, Karcher K, Kramer ML, Grossman F. Rapid antimanic effect of risperidone monotherapy: a 3-week multicenter, randomized, double-blind, placebo-controlled trial. Am J Psychiatry 2004; 2. Khanna S, Vieta E, Lyons B, Grossman F, Kramer ML. Risperidone in the treatment of acute mania: double-blind, placebo-controlled study. Br J Psychiatry 187:229-34: 2005
Pivotal trials show us that treatments for Bipolar mania are more efficacious than placebo and at the same time gives us an estimate of unmet clinical need. We can compute an index of clinical effectiveness by taking the product of the response rate and the completion rate. Then by calculating the number needed to treat to see one additional patient get the benefit of clinical effectiveness we’d find our best treatments require 5-10 patients be treated before treatment contributes an extra patient getting an increment of clinical effectiveness.
Our clinic stresses long-term treatment, and our results for lithium suggest interventions in a specialty clinic setting may more than double the median duration of treatment observed by Johnson. HOWEVER, even in with specialized care the majority of New treatments are used less that 6 months. This is all the more remarkable in light of the positive results recorded in more that half the treatments trials.
Our clinic stresses long-term treatment, and our results for lithium suggest interventions in a specialty clinic setting may more than double the median duration of treatment observed by Johnson. HOWEVER, even in with specialized care the majority of New treatments are used less that 6 months. This is all the more remarkable in light of the positive results recorded in more that half the treatments trials.
Our clinic stresses long-term treatment, and our results for lithium suggest interventions in a specialty clinic setting may more than double the median duration of treatment observed by Johnson. HOWEVER, even in with specialized care the majority of New treatments are used less that 6 months. This is all the more remarkable in light of the positive results recorded in more that half the treatments trials.
First ever study addressing treatment for depressed Bipolar patients, not responsive to standard antidepressants
The top graph in Figure 3 illustrates a drug with a 3-fold difference in binding affinity for target X versus Y. This drug will always have a greater effect on X than Y. Nevertheless, substantial occupancy of X (i.e., 50% or more) cannot be achieved with such a drug without also producing some occupancy of Y. The middle graph in Figure 3 shows a drug with a 10-fold (i.e., one order of magnitude) difference in binding affinity for X versus Y. With this drug, virtually complete occupancy of X can be achieved at a concentration that produces only minimal occupancy of Y. The bottom graph shows a drug with a 100fold (i.e., two orders of magnitude) difference in affinity for X versus Y. In this case, no detectable occupancy of Y is achieved at a concentration that produces full occupancy of X. Once that degree of separation has been achieved, further increases in selectivity (i.e., three or four orders of magnitude) may be of interest to the researcher but are of doubtful clinical consequence -- a comment that may help to put into proper perspective marketing claims about how "selective" a drug is. As a general rule, approximately 70%-80% occupancy of a site of action appears to be needed for most psychiatric drugs to achieve a clinically meaningful effect.2,4,7 Increases in occupancy above 80% are often associated with more of an increase in adverse effects than in efficacy. This general rule is consistent with the fact that all the fixed dose studies with single mechanism of action drugs (e.g., SSRIs) show a flat dose-response curve with regard to efficacy but an ascending dose-response curve with regard to adverse effects above their usually effective minimum antidepressant dose.8
All antipsychotics cause somnolence; however, the incidence may be higher in atypical antipsychotics. These data are extracted from US product labels for the various medications. Specifically, the graph indicates the number of cases needed to see significant rates of somnolence. The fewer the number (the higher the bar in this reverse presentation), the more sedating the compound relative to placebo. As illustrated, olanzapine appears to be associated with the greatest somnolence risk. In acute inpatient settings, antipsychotic-related somnolence may help calm patients and regulate the sleep cycle. However, somnolence in the long term is a liability, particularly in the elderly who may be prone to an increased risk of falls. Further, somnolence may be a reason for low physical activity, which may exacerbate increased weight gain, another effect associated with atypical antipsychotics. References: Sharif ZA. Overview of safety and tolerability of atypical antipsychotics used in primary care. Primary Care Companion J Clin Psychiatry . 2003;5(suppl 3):14-21.
This slide summarizes the incidence of clinically significant weight gain according to the prescribing information for aripiprazole, ziprasidone, risperidone, quetiapine, and olanzapine, based on short-term (<8 weeks) placebo-controlled trials. 1-5 Significant weight gain is defined as a 7% increase in weight from baseline. As seen in this graph, compared with placebo, clinically significant weight gain occurred in 29% of the patients taking olanzapine, 1 23% taking quetiapine, 2 18% taking risperidone, 3 10% taking ziprasidone, 4 and 8% taking aripiprazole. 5 With long-term exposure to olanzapine (median 238 days), up to 56% of patients experienced clinically significant weight gain. 1 References: 1. Zyprexa [package insert]. Indianapolis, IN; Eli Lilly and Company; 2004; Seroquel [package insert]. Wilmington, DE; AstraZeneca Pharmaceuticals LP; 2004; Risperdal [package insert]. Titusville, NJ; Janssen Pharmaceutica Products LP; 2003; Geodon [package insert]. New York, NY; Pfizer Inc; 2003; Abilify [package insert]. Princeton, NJ; Bristol-Myers Squibb Company and Otsuka America Pharmaceutical, Inc; 2004.
Newcomer et al performed modified oral glucose tolerance tests in 48 schizophrenic patients receiving clozapine, olanzapine, risperidone, or typical antipsychotics and 31 untreated healthy control subjects. Plasma was sampled at 0 (fasting), 15, 45, and 75 minutes after glucose load. Olanzapine-treated patients had significant glucose elevations at all time points compared with patients receiving typical antipsychotics and untreated healthy control subjects. Clozapine-treated patients had significant glucose elevations at fasting and 75 minutes postload also in comparison with patients receiving typical antipsychotics and untreated control subjects. Risperidone-treated patients had elevations in fasting and postload glucose levels, but only in comparison with untreated healthy control subjects. No differences in mean plasma glucose levels were detected when risperidone-treated patients were compared with patients treated with typical antipsychotis. No significant differences in plasma glucose levels were detected at anytime when comparing typical-antipsychotic – treated patients to untreated control subjects. This slide illustrates the effect of atypical versus conventional antipsychotics on insulin resistance using the Homeostasis Model Assessment (HOMA). compared with typical antipsychotics, olanzapine and clozapine demonstrated greater HOMA insulin resistance values. No significant alterations in HOMA insulin resistance values were seen for patients treated with risperidone or typical antipsychotics compared with untreated control subjects. References: Newcomer JW, Haupt DW, Fucetola R, et al. Abnormalities in glucose regulation during antipsychotic treatment of schizophrenia. Arch Gen Psychiatry . 2002;59:337-345.