1. DALL'ACUTO AL MANTENIMENTO IL TRATTAMENTO DELLA SCHIZOFRENIA , DELL'AGITAZIONE PSICOMOTORIA, DEI DISTURBI BORDERLINE E DEL DISTURBO BIPOLARE, CON L'UTILIZZO DEGLI ANTIPSICOTICI ATIPICI DI II GENERAZIONE

2. Antipsychotic Drugs: Development Timeline
At least as effective as typical neuroleptics with regard to positive symptoms
More effective than typical agents with regard to negative symptoms
Much lower incidence of parkinsonian symptoms and anticholinergic effects than typical agents
TD does occur but at much lower incidence
Elevated risk of metabolic side effects
Weaker effect on negative symptoms than positive symptoms
Significant parkinsonian symptoms and anticholinergic effects (poor compliance and potentially disabling)
Tardive dyskinesia in a minimum of 20% of patients who receive chronic neuroleptic treatment.

3. Factors affecting antipsychotic response
Receptor pharmacology
(binding capacity)
Pharmacogenetics
(CYP450)
Pharmacokinetics
Tolerability and
Patient Variables
Comorbid condition/
polypharmacy

4. Clinical trials show mean values, not individual data
YMRS
Observation day 7 14 21 28 35 42
0.0
10.0
20.0
30.0
40.0
YMRS=Young Mania Rating Scale

5. Clinical trials show mean values, not individual data
Observation day 7 14 21 28 35 42
0.0
10.0
20.0
30.0
40.0
YMRS

6. Variable Lithium Response Rate
Rapid
Cycling (30%)
Nonrapid
Cycling
(70%)
Dysphoric
Manic
Euphoric
Substance
Abuse
(Current and/
or History) No
(-) Family
History
(+) Family
>3
Episodes
Few Lifetime
DMI
Pattern
MDI D M
Poor
Response
Adequate
DMI = Depression and mania inventory; MDI = Mania and depression inventory
Frye MA, Ketter TA, Altshuler LL, et al. J Affect Disord. 1998;48:

7. Lithium and Suicidal Behavior9 8 7 6 5 4 3 2 1
Suicide Acts per 100 Patients (Years)
Before
Lithium
(N=310)
During
Lithium
(N=310)
First Year
After Lithium
(N=185)
Later Years
After Lithium
(N=133)
Tondo L, Baldesarini RJ, Hennen J, et al. J Clin Psychiatry. 1998(Aug);59(8):

8. First-generation (typical) antipsychotics
Reduce manic symptoms in bipolar disorder
Block dopamine D2 receptors in the mesolimbic pathway
However, D2 receptor antagonism is not specific to the mesolimbic dopamine pathway
Blockade of other dopamine pathways can lead to unwanted side effects such as feeling apathetic, anhedonic, lacking motivation, and physical adverse events
Clorpromazina vs placebo
Qualche studio vs litio
Stahl’s essential psychopharmacology. Antipsychotics and
mood stabilisers. 3rd edition. © Cambridge University Press, 2002
Hirschfeld et al; for the Working Group of Bipolar Disorder. Practice guideline for the treatment of patients with bipolar disorder. 2nd edition. © APA, 2002

9. Limitations of first-generation antipsychotics
Dopamine pathway
Effect of D2 receptor antagonism
Mesocortical
Worsens negative and cognitive symptoms in schizophrenia
Nigrostriatal
Motor side effects, collectively termed extrapyramidal symptoms (EPS)
Long-term treatment can lead to tardive dyskinesia
Tuberoinfundibular
Increase prolactin levels in plasma, resulting in galactorrhoea, irregular menstrual periods and bone demineralisation in women, and sexual dysfunction in both sexes
Stahl SM. Stahl’s essential psychopharmacology. Antipsychotics and mood stabilisers. 3rd ed. © Cambridge University Press, 2002; Stahl SM. Antipsychotics. Stahl’s neuroscience and mental health pocketbook series. © Neuroscience Education Institute, 2008

10. Adverse effects associated with first-generation antipsychotics
Type
Description
Anticholinergic effects1,2
Dry mouth, blurred vision, constipation, urinary retention, and exacerbation of narrow-angle glaucoma; cognitive impairment
Antiadrenergic effects1,3
Orthostatic hypotension (may result in fainting) and sedation
Antihistaminic effects3
Sedation and weight gain
Seizures1
Lowering of seizure threshold may occur
Hepatic abnormalities4
Mild and transient elevations of liver enzymes can occur
Haematological abnormalities4
Transient decrease in white blood cell production, or in production of platelets and other blood cells
Retinitis pigmentosa4
Rare inflammation of the retina accompanied by deposits of pigmentation – can cause significant vision loss
QT-interval prolongation4
Changes in the QT interval that can cause a rare but potentially life-threatening arrhythmia (torsade de pointes)
1Andreasen & Black. Introductory textbook of psychiatry. 4th ed. © APA, 2006; 2Keltner & Folks. Psychotropic drugs. 4th ed. © Elsevier Mosby, 2005; 3Schatzberg & Nemeroff (eds). Essentials of clinical psychopharmacology. 2nd ed. © APA, 2006; 4Sadock et al (eds). Kaplan & Sadock’s comprehensive textbook of psychiatry. 9th ed. Lippincott Williams & Wilkins, 2009

11. Acute EPS following treatment with first-generation antipsychotics
Type
Description
Akathisia
Subjective and objective motor restlessness, e.g., anxiety, an inability to relax, jitteriness, pacing, and rocking motions
Can appear within 2–3 days of starting treatment with a first-generation antipsychotic, but usually appear after approximately 5 days
Most common acute EPS
Dystonia
Contraction of the muscles in the head and neck, leading to involuntary movements, such as:
Eyes rolling back into the head
Tongue protrusion
Rigid arching of the back
Muscle contraction in the larynx that can lead to gagging
Often the earliest adverse effect, occurring within hours or a few days of starting treatment with a first-generation antipsychotic
Parkinsonism
Symptoms of tremor, rigidity, shuffling gait, and dyskinesia
Mild symptoms include decreased facial expression and gestures, and difficulty initiating activities
Commonly occurs within 5–30 days of starting treatment with a first-generation antipsychotic
Sadock et al (eds). Kaplan & Sadock’s comprehensive textbook of psychiatry. 9th ed. © Lippincott Williams & Wilkins, 2009

12. Second-generation antipsychotics
Developed to overcome the unfavourable safety profile of the first-generation agents
Lower risk of EPS
Two subgroups:
Serotonin/dopamine antagonists
Partial dopamine agonists
Stahl’s essential psychopharmacology. Antipsychotics and mood stabilisers. 3rd edition. © Cambridge University Press, 2002
Hirschfeld et al; for the Working Group of Bipolar Disorder. Practice guideline for the treatment of patients with bipolar disorder. 2nd edition. © APA, 2002

13. Dopamine activity blocked by antipsychotic
D2 antagonism
Postsynaptic neurone D2
Dopamine
Reduced excitatory transmission
Presynaptic neurone
First-generation antipsychotic
Serotonin
5-HT2A
Dopamine activity blocked by antipsychotic
Serotonin binding reduces dopamine released

14. Dopamine release increased
D2/5-HT2A antagonism D2
Dopamine
Increased excitatory transmission
Second-generation antipsychotic
Serotonin
5-HT2A
Dopamine release increased
Postsynaptic neurone
Presynaptic neurone

15. Serotonin/dopamine antagonists Mechanism of action
Pathway
Effect of 5-HT2A antagonism
Mesolimbic
Not sufficient to reverse blockade of D2 receptors, therefore effective at treating mania associated with bipolar disorder
Indirect regulation of dopamine activity through changes in glutamate release
Nigrostriatal
Counteracts the D2 receptor blockade and reduces the risk of EPS
Mesocortical
Possible beneficial effect on negative symptoms by opposing D2 receptor antagonism
Possible effect on improvement of cognitive symptoms – conflicting evidence
Tuberoinfundibular (hypothalamic)
Lower risk of hyperprolactinaemia by counteracting the blockade of D2 receptors
Effects on prolactin differ among second-generation antipsychotics
Stahl SM. Stahl’s essential psychopharmacology. Antipsychotics and mood stabilisers. 3rd ed. © Cambridge University Press, 2002

16. Comparative pharmacokinetic parameters of newer antipsychotics
Bioavailability (%)
Protein binding (%)
Half-life (hours)
Time to reach steady state (days)
CYP enzymes responsible for biotransformation*
Clozapine
12–81 97
6–33
4–8
CYP1A2, CYP2C19 (CYP3A4, CYP2D6)
Risperidone 68 90
3–24
4–6
CYP2D6, CYP3A4
Paliperidone 28 74 23
4–5
N/A
Olanzapine
60–80 93
20–70
5–7
CYP1A2, CYP2D6
Quetiapine
9 ± 4 83
5–8
2–3
CYP3A4
Ziprasidone 60
>99
4–10
Aripiprazole 87
48–68 14
CYP3A4, CYP2D6
Asenapine 35 95 24 3
CYP1A2
Table adapted from Spina and Leon. Basic Clin Pharmacol Toxicol 2007;100:4–22 and individual product prescribing information
CYP, cytochrome P450

17. Enzyme Substrate Inhibitor Inducer
CYP1A2
Clozapine, olanzapine
Fluvoxamine, ciprofloxacin
Carbamazepine, smoking
CYP2C19
Fluoxetine, fluvoxamine
Carbamazepine, phenytoin
CYP2D6
Aripiprazole, clozapine, olanzapine, risperidone, conventional antipsychotics
Bupropion, fluoxetine, paroxetine, duloxetine
CYP3A4
Aripiprazole, clozapine,, quetiapine, ziprasidone
Azole antifungal
Most of macrolide except azitromycin
ARVs; indinavir, nelfinavir, ritonavir
Carbamazepine,phenytoin, rifampin, phenobarbital

18. Different Potency of Treatments

19. Comparative receptor signature
5-HT2C
5-HT2A
5-HT7
5-HT2B
5-HT6
2B D3 H1 D4
1A
2A
2C D2 D1
5-HT5
5-HT1A
5-HT1B H2 M1
Clozapine
Olanzapine
Quetiapine
Asenapine
pKi
Haloperidol
Aripiprazole
Ziprasidone
Risperidone
This slide illustrates the receptor-binding profile of asenapine compared with other antipsychotics. Receptor binding is compared with the binding at dopamine D2 receptors, depicted by the dashed lines, as binding at these receptors is well known to be associated with resolution of specific symptoms of schizophrenia and bipolar disorder.1
Asenapine has a unique human receptor signature, with binding affinity and antagonistic properties that differ appreciably from those of other antipsychotic drugs.1
Shahid M, Walker GB, Zorn SH, Wong EHF. Asenapine: a novel psychopharmacologic agent with a unique human receptor signature. J Psychopharmacol 2009; 23: 65–73.
Dashed line=respective affinity of each agent for D2 receptor; pKi, a measure of binding affinity
Shahid et al. J Psychopharmacol 2009;23:65–73

20. Antipsychotics are different from each other
Retail Full Promotional Slide Deck
Antipsychotics are different from each other
D2 antagonism
Positive symptom efficacy, EPS, endocrine effects
5-HT2A antagonism
Negative symptom efficacy, reduced EPS
High 5-HT2A/D2 affinity ratio
Antipsychotic efficacy, reduced EPS (compared to D2 antagonism alone)
5-HT1A agonism
Antidepressant and anxiolytic activity, improved cognition, reduced EPS
5-HT1D antagonism
Antidepressant activity
5-HT2C antagonism
1 antagonism
Postural hypotension
H1 antagonism
Sedation, weight gain
M1 antagonism
Anticholinergic side effects (eg, cognitive impairment)
Potential clinical implications of receptor activities of antipsychotics3,4:
The diverse actions of antipsychotic agents on a range of specific receptors potentially underlie their differing therapeutic and tolerability profiles.
It is generally accepted that D2-dopaminergic receptor antagonism plays a key role in the treatment of positive symptoms of schizophrenia. However, antagonism at these receptors is also believed to underlie EPS and hyperprolactinemia-related side effects (endocrine effects), and it also may be involved in the development of tardive dyskinesia (TD).
Antagonism at serotonergic 5-HT2A receptors appears to be involved in improving negative symptoms of schizophrenia, and possibly reduced EPS. Most newer antipsychotics are antagonists at serotonergic 5-HT2A receptors.
It also appears that a higher ratio of affinity for 5-HT2A relative to D2 receptors is associated with efficacy and lower EPS liability.
Agonism at 5-HT1A receptors has been associated with both anxiolytic and antidepressant activity, whereas 5-HT1D receptor antagonism may be associated with antidepressant activity.
5-HT2C receptor agonism has been found to exacerbate positive symptoms in schizophrenics and to induce weight loss. It is, therefore, possible that antagonists at these receptors will have the opposite effect (ie, improved positive symptoms and weight gain).
Inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake is believed to be one of the possible mechanisms associated with antidepressant effects.
Antagonism of 1-adrenoceptors has been associated with sedation, postural hypotension, sexual dysfunction, and possibly weight gain.
Antagonism of H1-histaminergic receptors has been associated with both sedation and weight gain.
Antagonism of M1-muscarinic receptors is associated with anticholinergic side effects and cognitive impairment, reduced secretions (eg, dry mouth), gastrointestinal disturbances (eg, constipation), and paralysis of visual accommodation (eg, blurred vision).
Zorn SH, et al. Interactive Monoaminergic Brain Disorders 1999;377–393. Tandon R, et al. J Serotonin Res 1997;4:159–177. 20

21. Retail Full Promotional Slide Deck
RECEPTOR AFFINITY
Aripiprazole1,2
Olanzapine3,5
Risperidone4,5
Quetiapine4,5
Ziprasidone5,6
Clozapine4,5
Haloperidol4,5 D1
410* 31 75
455
9,5 85 25 D2
0,34* 11 3
160
4,8
125 1 D3
0,8* 49 14
340
7,2
280
2,7 D4
44* 27 7
1600 39 21 5
5-HT1A
1,7
>1000
490
2450
3,4
770
7930
5-HT2A 4
0,6
220
0,4 12 78
5-HT2C 15 26
615
1,3 8
3085 α1 57 19 2 10 46 H1
61*
155 47 6
3630 M1
>10.000
1,9
>5000
120
1475
* Data with cloned human receptors.
1. Abilify® (aripiprazole) prescribing information.
2. Lawler et al. Neuropsychopharmacology 1999,20:612;3
3. Zyprexa® prescribing information.
4. Bymasteret al. Neuropsychopharmacology 1996;14:87;5
5. Arnt and Skarsfeldt Neuropsychopharmacology 1998;18:66;
6. Gedeon® prescribing information Wesley KK et al. Neuropsychopharmacoly 2003;28:519

22. Receptor affinities of selected atypical antipsychotics: Potential Benefit
HAL
CLOZ
OLAN
RIS
QUET
ZIP
ARI D2
0.7
126 11 4
160 5
0.45
(partial)
5-HT1A
2600
875
>7100
210
>830 3
4.4
5-HT2A 45 16
0.5
295
0.4
3.4
5-HT2C
1500 23 25 1 15 1 6 7 19 10 57 2
360 8
230 87 – H1
440 20 47 61 M1
>1500
1.9
>10,000
120
>1,000
PD psychosis
Alleviate EPS risk
Sleep quality improvement
Sedative action
BPSD, autism
All values are reported as Ki (nM).
Modified from Clin Ther 2004;26:649-66

23. Receptor affinities of atypical antipsychotics: Potential risk
HAL
CLOZ
OLAN
RIS
QUET
ZIP
ARI D2
0.7
126 11 4
160 5
0.45
(partial)
5-HT1A
2600
875
>7100
210
>830 3
4.4
5-HT2A 45 16
0.5
295
0.4
3.4
5-HT2C
1500 23 25 1 15 1 6 7 19 10 57 2
360 8
230 87 – H1
440 20 47 61 M1
>1500
1.9
>10,000
120
>1,000
EPS risk and hyperprolactinemia
Sedation, weight gain
Orthostatic hypotension
Anticholinergics
All values are reported as Ki (nM).
Modified from Clin Ther 2004;26:649-66

24. Switching Antipsychotics
Adapted from Wieden J Clin Psych 2007 (68) suppl 6: 14-22

25. WFSBP Guidelines Review as stated on slide
Grunze et al. World Journal of Biological Psychiatry, 2009; 10(2): 85116

26. Recommendation Grades (RG)
Category A evidence and good risk-benefit ratio
Aripiprazole
Risperidone
Valproate
Ziprasidone
Grunze et al. World Journal of Biological Psychiatry, 2009; 10(2): 85116

27. Aripiprazole Injection Vs haloperidol as active comparator in schizophrenia
Time After First Intramuscular (IM) Injection (min) *
*P.05 vs placebo -8 -7 -6 -5 -4 -3 -2 -1 15 30 45 60 75 90
105
120
PANSS™-EC
Uncooperativeness
Poor impulse control
Hostility
Excitement
Tension
Improvement
Mean Change in PANSS™-EC Score
At the primary efficacy endpoint, the 5.25-, 9.75-, and 15-mg doses of ABILIFY Injection were statistically superior to placebo in the mean change from baseline PANSS™-EC score
With ABILIFY Injection, no additional benefit was demonstrated for 15 mg compared to 9.75 mg. A lower dose of 5.25 mg may be considered
The 1-mg dose of ABILIFY Injection is not displayed on this graphic since it does not fall within the recommended dose range
Haloperidol was superior to placebo at primary endpoint
The study was not designed for any comparison between ABILIFY Injection and the active comparator, haloperidol Injection
Placebo (n=62)
ABILIFY 9.75 mg (n=57)
Haloperidol 7.5 mg (n=60)
ABILIFY 5.25 mg (n=63)
ABILIFY 15 mg (n=58)
Baseline scores ranged between and LOCF=last observation carried forward. PANSS™-EC=Positive and Negative Syndrome Scale–Excited Component.
Daniel D et al. Presented at: 157th Annual Meeting of the American Psychiatric Association; May 1-6, 2004; New York, NY.

28. Aripiprazole in Acute Mania-0 * **
Aripiprazole (n=136)
Significantly greater improvement vs placebo: Day 4 to endpoint (Day 21)
YMRS consists of 11 items including:
Irritability
Disruptive/aggressive behaviour
Elevated mood
Insight
Increased motor activity/energy -2
Placebo (n=132) -4 -6
Mean Change From Baseline in YMRS Total Score† -8
-10
-12
*p≤.01 vs placebo **p≤.001 vs placebo
-14 2 4 7 10 14 21
if hadn’t stopped bzd at Day 10 would have seen even better results
dose per discussion earlier
agitation need higher doses or adjunctive agent
keep in mind that
The efficacy of aripiprazole (aripiprazole) in the treatment of acute manic and mixed episodes was established in two 3-week, randomized, double-blind, placebo-controlled trials
Hospitalized patients
Met DSM-IV criteria for Bipolar I Disorder
Included patients
With manic or mixed episodes
With or without psychotic features
With or without a rapid cycling course
Starting dose of aripiprazole was 30 mg/day with option to decrease to 15 mg/day for tolerability
These clinical trials allowed the use of lorazepam, a short-acting benzodiazepine, on Days 1 to 4 (6 mg/day), 5 to 7 (4 mg/day), and 8 to 10 (2 mg/day)1,2
The mean change in Y-MRS Total Score compared to placebo was the primary efficacy endpoint in both trials
Y-MRS items include: elevated mood, increased motor activity-energy, sexual interest, sleep, irritability, speech, language-thought disorder, content, disruptive-aggressive behavior, appearance, and insight.3
In the first trial shown here (N=272), aripiprazole was superior to placebo in the reduction of Y-MRS Total Score1
Mean change from baseline in Y-MRS total score: aripiprazole=-12.5, placebo=-7.2
In a second trial (N=262), aripiprazole also demonstrated significant symptom improvement in hospitalized patients with Bipolar I Disorder with acute manic or mixed episodes2
Days of Treatment
Study population included hospitalized patients with manic or mixed episodes, with or without psychotic features, and with or without a rapid cycling course
1. Sachs G, Sanchez R, Marcus R, et al. Aripiprazole in the treatment of acute manic or mixed episodes in patients with bipolar I disorder: a 3-week placebo-controlled study. J Psychopharmacol. 2006;20:
2. Keck PE, Marcus R, Tourkodimitris S, et al. A placebo-controlled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160:
3. Young RC, Biggs JT, Ziegler VE, Meyer DA. A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry. 1978;133:
†Last observation carried forward. Mean baseline YMRS scores: aripiprazole 28.8; placebo 28.5.
Starting dose 30 mg/day. Dose could be decreased to 15 mg/day for tolerability.
Modified from Sachs et al. J Psychopharmacol 2006;20:536–546

29. Change from baseline in Least Squares mean PANSS-EC
Oral Olanzapine versus oral Aripiprazole for the treatment of agitation
SEs olanzapine
–10 –9 –8 –7 –6 –5 –4 –3 –2 –1
Change from baseline in Least Squares mean PANSS-EC
Aripiprazole
Olanzapine
0.23
0.25
0.27
0.28
SEs aripiprazole
a,b 2
Baseline 3 4 5
Day
Fasting glucose, triglycerides and prolactin increased significantly more in the Olanzapine group than in the Aripiprazole Group
Repeated measures ANOVA model:
Change = baseline score + treatment + visit + Investigator + visit treatment-visit baseline score.
Adapted from Kinon BJ et al. J Clin Psychopharmacol 2008;28:601–7

30. aripiprazole in the Real World
The most frequent associations of aripiprazole in your practice :
Benzodiazepines
Classic mood stabilizers
Antihistamine/Acetylcholine
Sedative/hypnotics
Anti-Acetylcholine
Typical antipsychotics
Atypical antipsychotics
Other

31. Aripiprazole plus Lithium or Valproate
Bipolar Mania Core Efficacy Slide Deck
Aripiprazole plus Lithium or Valproate
Weeks
Improvement *
Mean (SE) change from baseline in YMRS Total score (LOCF) * ** *
This multicenter, double-blind, randomized, placebo-controlled study evaluated the efficacy, safety and tolerability of aripiprazole in combination with lithium/valproate in the treatment of patients with bipolar I mania who were partially non-responsive to lithium or valproate monotherapy
Aripiprazole in combination with lithium/valproate demonstrated statistically significant improvement from baseline in the YMRS Total score versus placebo (i.e. lithium or valproate) at Week 1 and all subsequent study visits (all p<0.05)
Aripiprazole in combination with lithium/valproate was superior to placebo on the primary efficacy measure (mean change from baseline to Week 6 LOCF in YMRS Total score): treatment difference of 2.62 points, p<0.01 ** **
Placebo + lithium/valproate (n=130)
Aripiprazole + lithium/valproate (n=247)
*p<0.05; **p<0.01 vs. placebo. Mean aripiprazole dose: 19.0 mg/day. Baseline mean YMRS Total score: placebo + lithium/valproate, 22.7; aripiprazole + lithium/valproate, 23.1
Vieta et al. Am J Psychiatry. published online April 1, 2008; doi: /appi.ajp 31

32. Proportion of Patients Without Relapse
Maintenance of Efficacy in Bipolar I Disorder: ABILIFY Tablets Significantly Delayed Time to Relapse
Significant reduction in risk of relapse vs placebo
1.0
ABILIFY 15 or 30 mg/day (n=77)
0.9
Placebo (n=83)
0.8
0.7
0.6
Proportion of Patients Without Relapse
0.5
0.4
0.3
Log rank P value=.02 vs placebo
0.2
0.1
Hazard ratio=0.52 (95% CI= )
During the randomization phase, ABILIFY (aripiprazole) was superior to placebo on time to relapse, the primary outcome measure for this study
The majority of these relapses were due to manic rather than depressive symptoms
There are insufficient data to know whether ABILIFY is effective in delaying the time to occurrence of depression in patients with Bipolar I Disorder
Physicians who elect to use ABILIFY for extended periods, that is, longer than 6 weeks, should periodically re-evaluate the long-term usefulness of the drug for the individual patient
Relapse defined as
Hospital admission for a mood episode (manic, depressive, or mixed)
Addition to or increase in psychotropic medication other than study drug for manic and/or depressive symptoms 14 28 42 56 70 84 98
112
126
140
154
168
182
196
Days
Relapse defined as:
Hospital admission for mood episode (manic, depressive or mixed)
Addition to or increase in psychotropic medication other than study drug
The majority of relapses were due to manic rather than depressive symptoms. There are insufficient data to know whether ABILIFY is effective in delaying the time to occurrence of depression in patients with Bipolar I Disorder.
Modified from Keck PE, et al. J Clin Psychiatry. 2006;67:
Keck PE, Calabrese JR, McQuade RD, et al. A randomized, double-blind, placebo-controlled 26-week trial of aripiprazole in recently manic patients with Bipolar I Disorder. J Clin Psychiatry. 2006;67:

33. Time from randomisation to relapse
Placebo + Li/Val
Aripiprazole + Li/Val
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Proportion without relapse
Relapse rate Week 52: 17% aripiprazole vs 29% PBO
Hazard ratio aripiprazole over placebo: (95% CI: 0.332–0.893) Stratified log-rank p-value=0.014 28 56 84
112
140
168
196
224
252
280
308
336
364
Days
Marcus et al. Bipolar Disord 2011: 13: 133–144.

34. Relapse to manic episode after 1 year
Relapse on Abilify + Lithium to manic state :16 %
Relapse on Lithium : 45 %
P = 0,002
Marcus;Bipolar Disorder 2011

35. No significant change in lipid or glucose parameters (fasting, LOCF) over 52 weeks
0.2
PLB + Li/Val (n=158)
ARI + Li/Val (n=156) 6
TG 4mg/dl = 0.04 mmol/l* 5
0.1 4 3
Median change from baseline
to Week 52 (mmol/L)
Median change from baseline
to Week 52 (mg/dL) 2 1 -1
Glucose
HDL-C
LDL-C TC
TG* -2
-0.1
Baseline values: glucose: placebo 90.0 mg/dL (n=157), aripiprazole 90.0 mg/dL (n=155); HDL-C: placebo 46.0 mg/dL (n=158), aripiprazole 45.0 mg/dL (n=156); LDL-C: placebo mg/dL (n=158), aripiprazole mg/dL (n=156); TC: placebo mg/dL (n=158), aripiprazole mg/dL (n=156); TG: placebo mg/dL (n=158), aripiprazole mg/dL (n=156).
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; TC, total cholesterol; TG, triglycerides.
Marcus et al. Bipolar Disord 2011: 13: 133–144.

36. No significant difference in mean weight gain
Aripiprazole adjunctive to Li/Val: weight change similar to adjunctive placebo over 52 weeks
No significant difference in mean weight gain
No significant difference in proportion of patients with clinically significant weight gain (≥7% increase from baseline)
p=ns
2.0 15
13.8%
11.8%
p=ns 12
1.5
1.07kg
Proportion of patients with ≥7% weight gain from baseline, LOCF (%)
Mean weight change from baseline to Week 52; LOCF (kg) 9
1.0
0.6kg 6
0.5 3
Also no difference in weight parameters when analysed on the OC data set:
Mean change in weight from baseline:1.61 kg for adjunctive aripiprazole vs for adjunctive placebo (aripiprazole vs placebo ns)
Proportion of patients with weight gain ≥7%: adjunctive Abilify group (18.9%) compared with the adjunctive placebo group (18.8%)
Li/Val+adjunctive placebo
Li/Val +adjunctive aripiprazole
Li/Val+adjunctive placebo
Li/Val +adjunctive aripiprazole
Median change in weight from baseline during stabilisation phase was +1.1kg overall (+1.5kg in Val+ARI subgroup and +0.9kg in LI+ARI subgroup)
No difference in LOCF dataset for mean change from baseline in body weight or incidence of significant weight gain
Also no significant difference for the OC dataset for either parameter
Marcus et al. Bipolar Disord 2011: 13: 133–144. 36

37. Contributors to Poor Health
Genetics
Lonelissness
Unhealthy Eating
Infections
Smoking
Lack of exercise
Medications
Access to Care
Irregular Sleep
Lack of activity
Lack of Support
Conflicts/Distress
Avoidance of Medical Professionals

38. Obesity Bipolar Disorder
More depressive and manic episodes
More severe acute episodes
Longer duration of acute episode
Shorter time to recurrence
More suicide attempts
Worse functioning
Fagiolini et al, J Clin Psych 2002; 63:
Fagiolini et al, Am J Psychiatry 2003; 160:
Fagiolini et al, J Clin Psych 2004; 65:
Fagiolini et al, Bipolar Disorders, 2005; 7:
Fagiolini et al., J Clin Psych, 2008;69 (4):678-9
Fagiolini et al. J Clin Psychopharm 2008; 28 (2):257-8
Fagiolini et al ; CNS Drugs 2008 ;22 (8):

39. Atypical Antipsychotics: Relative Adverse Effects
= high incidence/severity = moderate = low = low/very low = very low
Drug
Aripiprazole
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
Weight gain
Sedation
EPS
Anti-cholinergic
Hypo-tension
Prolactin elevation
EPS, Extrapyramidal Symptoms Taylor, Paton & Kerwin. The Maudsley Prescribing Guidelines 9th Edition

40. Switching antipsychotics
Histamine
rebound
Cholinergic
Rebound
Parkinson-
ism
akathisia
dyskinesia
dystonia
psychosis
Potential
switching
effects
Borison et al. Clin Therapeutics. 1996;18:592–607; Buckley. J Clin Psychiatry. 2007;68(Suppl 6):5–9;
Weiden et al. J Clin Psychiatry. 1997;58(Suppl 10):63–72

41. Aripiprazole: activity at cloned human D2 receptors
Aripiprazole is the only atypical antipsychotic with partial agonistic activity at dopamine receptors When dopamine levels are diminished, the partial agonistic activity of aripiprazole increases dopamine transmission due to a lower degree of occupation of dopaminergic receptors by dopamine
Full receptor activity
100
Dopamine
Theoretical threshold for causing psychosis
Max. response (%) 50
Aripiprazole
Partial receptor activity
And this is shown very beautifully in the next slide here, where you have
a dose response curve for the full agonist which is dopamine, and you can see there is the usual log dose response curve and we’ve put a little threshold in there, a little dotted line, to show an imaginary threshold of dopamine activation which could lead to psychosis.
We’ve also, with the red line, shown you the effects of haloperidol which blocks the receptors so there is no stimulation; haloperidol completely attenuates all the effects of dopamine if it is given before dopamine.
Now with aripiprazole (blue line) what you see is that there is about a 30% stimulation of the system, so less than the 100% that dopamine causes, but still a significant stimulation.
Now when those receptors are bound by aripiprazole, the effects of dopamine are reduced, so dopamine is then reduced to a level of effect which is below the threshold for causing psychosis so that is why aripiprazole is anti-psychotic, it reduces total dopaminergic activity to a level less than that which causes psychosis. But nevertheless, as a partial agonist it gives some dopamine throughput and that is enough to reduce the likelihood of getting extrapyramidal side-effects.
Additional notes
Aripiprazole is the only atypical antipsychotic with partial agonistic activity at dopamine receptors.
The partial agonist properties of aripiprazole at D2 receptors likely contribute to stabilisation, rather than blockade, of dopaminergic tone.
When dopamine levels are low, the partial agonistic activity of aripiprazole increases dopamine transmission due to a lower degree of occupation of dopaminergic receptors by dopamine.
Haloperidol
No receptor activity
Concentration (M)
Burris et al. J Pharmacol Exp Ther 2002;302:381–389. 41

42. Agonism, antagonism and partial agonism
Intrinsic activity describes the ability of a compound to stimulate receptors
D2 Receptor
Full receptor activity
Agonist (Dopamin)
No receptor activity
Antagonist (Haloperidol, etc.)
So looking at the pharmacology of aripiprazole, how does that help us understand its value in terms of the drug treatment for mania and schizophrenia?
Going back now to these constructs we developed before of agonism, antagonism and also partial agonism, this diagram explains this quite simply. If you look at the green blob, that’s a full agonist, that binds to the receptor and produces a big output, fat arrow full receptor activity. An antagonist like haloperidol or olanzapine binds to a receptor and has no impact itself, but also blocks the effect of the natural transmitter so there is no output. A partial agonist is a mixture of the two: as you can see it has a binding site which allows it to get into the active site of the receptor, that round blob, and that gives some stimulation of the receptor, so you get partial activity, you don’t get as much as a full agonist, but you get partial activity, but once it is bound to the receptor the full agonist can’t work and the full agonist is normally the endogenous neurotransmitter. So when the partial agonist is there the full agonist can’t access the receptor, so there is some attenuation of the effect of the full agonist, partial antagonism of that, and that is why these drugs are sometimes called agonist/antagonists because they have some effect, partial receptor stimulation, but by being on the receptor they block the effects of the endogenous neurotransmitter.
Partial receptor activity
Partieller Agonist (Aripiprazol)
Adapted from Tamminga CA et al. J Neural Transm 2002;109:411–420.

43. Switching strategies Abrupt switching Advantage Disadvantage
Low risk of drug interactions
Advantage
Withdrawal reactions
Disadvantage
Patients with serious adverse event(s)
Recommended for
Gradual switching
Low risk of withdrawal reactions, hardly any drug interactions
Danger of symptom exacerbation
Patients with low risk of relapse
Cross-tapering
Safest to prevent relapse
Drug interactions complicated
Recently stabilised patients
Time
Dose
Med Med 2
Med Med 2
Med Med 2
Three basic strategies may be used for switching antipsychotic medications: abrupt, gradual and overlapping switching.
Abrupt switching refers to an abrupt discontinuation of the current drug, possibly with some days of washout, and an immediate initiation of the new drug. The advantages of this technique are its rapidity and the lower potential for drug interactions. The possibility of various withdrawal reactions is the biggest drawback of this approach. This technique is appropriate for inpatient settings where clinical supervision is guaranteed.
Gradual switching is performed by slowly tapering the previous antipsychotic and subsequently introducing the new medication at slowly increasing doses, with or without some antipsychotic-free days in between. This minimises the risk of withdrawal symptoms and drug interactions. On the other hand, sub-therapeutic antipsychotic dosages overprolonged periods of time increase the risk of symptom exacerbation.
The most cautious strategy is an overlapping switch, also called cross-tapering. Using this approach, the new medication is started either abruptly or gradually, so that it overlaps with the current medication; this is followed by stepwise reduction of the dosage of the original medication. This technique is clearly the safest method to prevent relapse and is appropriate for recently stabilised patients who must be switched because of adverse effects, and for patients with only partial and unsatisfactory treatment response. Drawbacks include the potential risk for drug interactions and additional adverse effects while both drugs are being taken simultaneously. Some patients, especially those in poorly supervised treatment settings, may have difficulty following this more complicated strategy.
References
1. Edlinger M, et al. Switching between second-generation antipsychotics: why and how? CNS Drugs. 2005;19(1):27-42.
Med = medication
Edlinger M, et al. CNS Drugs. 2005;19(1):27-42

44. Switching from medication with: Switching to medication with:
Pharmacological Considerations when Switching between Antipsycotic
Switching from medication with:
Switching to medication with:
Possible effects
High H1 affinity
Low H1 affinity
Insomnia, restlessness
High D2-binding potential and D2 upregulation
Low D2-receptor binding
Or lower intrinsic activity
Rebound psychosis
High muscarinic binding
Low muscarinic binding
Cholinergic supersensitivity (nausea, vomiting, diaphoresis, insomnia)
Buckley. J Clin Psychiatry. 2007;68 (Suppl 6):5–9

45. Ziprasidone pharmacokinetic parametersIM
Oral
Mean t half-life (t1/2)
2.8 h
6.6 h
Time to maximum serum concentration
0.6 h
6.8 h
Time to steady state NA
1–3 days
Bioavailability after administration
100%
60%*
*20-mg dose under fed conditions
Ziprasidone Oral, Summary of Product Characteristics July 2010
Ziprasidone IM, Summary of Product Characteristics July 2010
Fagiolini A et al, Expert Opin Pharmacother. 2010;11(13):2199–2220

46. Plasma Level vs % D2 Occupancy at 12 Hours Postdose
Mamo p 820 A
Antipsychotic Efficacy
60% D2 occupancy = 120 mg/d
% Occupancy
Mamo p.820 A
5-HT2 Receptors
D2 Receptors
Studies have shown that optimal D2 occupancy for antipsychotic medication falls between the 60% and 80% range. Some studies suggest that below 60% most agents are not effective, while blocking more than 80% of D2 receptors is associated with significant increases in rates of EPS. The target dose of ziprasidone, at 120 mg/d to 160 mg/d, aligns well with the optimal D2 occupancy in the 60% to 80% range.1
Additional Information1:
This 2004 study used positron emission tomography (PET) imaging to determine the occupancy of D2 and 5-HT2 receptors at different steady-state doses of ziprasidone in patients with schizophrenia.
It showed that at 53 ng/mL (a trough plasma level associated with oral doses of 120 mg/d), ziprasidone occupied 60% of D2 receptors
At all doses, the percentage occupancy of 5-HT2 receptors was greater than that of D2 receptors
Ziprasidone doses producing trough plasma levels more than 53 ng/mL (ie, doses <120 mg/d) may maximize antipsychotic efficacy. At doses less than 120 mg/d, the effects of ziprasidone on other receptor systems—most likely 5-HT2 receptors—probably predominate
The higher blockade of serotonin 5-HT2 receptors vs dopamine D2 receptors in this PET study confirms the high 5-HT2/D2 ratio seen with ziprasidone in vitro and may explain the low rate of EPS and negative symptom improvement noted in clinical trials of the drug
Study Design: Results of a PET study to evaluate D2 and 5-HT2 receptor occupancy in 16 patients with schizophrenia or schizoaffective disorder. Patients were randomized to 4 groups to receive ziprasidone 40 mg/d, 80 mg/d, 120 mg/d, or 160 mg/d. Two groups were started on 40 mg/d or 80 mg/d and remained on this dose for the duration of the study. Two groups were started on 80 mg/d, with the dose titrated to 120 mg/d or 160 mg/d between Day 4 and Day 8. Scanning was done after 3 weeks of administration and at trough plasma levels (12-16 hours after last dose). (The [11C]-raclopride PET scans for D2 receptor occupancy were obtained over 75 minutes following injection of 10 mCi of high specific-activity [11C]-raclopride using a bolus plus infusion protocol. The [18F]-setoperone PET scans for 5-HT2 receptor occupancy were obtained over 90 minutes following a bolus injection of 5 mCi of high specific-activity [18F]-setoperone.)
Mamo D, Kapur S, Shammi CM et al. A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 2004;161:
Mamo p. 818A, B
Mamo p.818B
Ziprasidone Plasma Level ( ng/mL)
Clinical response to atypical antipsychotics occurs at approximately 60% to 80% D2 receptor occupancy
Estimated oral dose of ziprasidone associated with 60% D2 occupancy is 120 mg/d
Mamo p.818A, 820A
Mamo p.820A, 822A, 823A
Mamo p. 818A, B
Mamo 2004 p. 823 A
Adapted from Mamo D et al. Am J Psychiatry 2004;161:

47. Ziprasidone IM for acute agitation in schizophrenia
10 mg STUDY1
Mean change in BARS from baseline
Time after first injection (hours)
Ziprasidone IM 10 mg (n=63)
Ziprasidone IM 2 mg (n=54)
IMPROVEMENT 1 4
-0.5 -1
-1.5 -2
-2.5 -3
* * * * 2 3
20 mg STUDY2
Mean change in BARS from baseline
Time after first injection (hours)
Ziprasidone IM 2 mg (n=38)
Ziprasidone IM 20 mg (n=41)
IMPROVEMENT
-0.5 -1
-1.5 -2
-2.5 -3 1 4 3 2
* * *
* *
†BARS: Behavioural Activity Rating Scale. P<0.05; **P<0.01; ***P<0.001 vs control.
1. Adapted from Lesem MD et al. Journal Clinical Psychiatry 2001;62:12-18
2. Adapted from Daniel DG et al. Psychopharmacology (Berl) 2001;155:
3. FDA Psychopharmacological Drugs Advisory Committee. Briefing document for ziprasidone mesylate for intramuscular injection. February 15, Available at: accessed June , pg 38, figure 6

49. NO EDITORIAL REQUIRED: DIRECT PICKUP FROM GZ278854C – SLIDE 40
Ziprasidone Associated With Improvement in Metabolic Variables in CATIE
Weight Change
Hemoglobin A1C Levels
9.4
Lieberman 2005 p 1220 table 3 A, B, C, G
N=185
0.8
1.1
(lb) From Baseline (LOCF)
Mean Change in Weight
N=336
N=261
Mean Change in Glycosylated Hemoglobin (%) From Baseline (LOCF)
N=89
N=157
N=341
N=337
N=139
N=137
N=107
-1.6
-2.0
Cholesterol Levels
Triglycerides
Finally, CATIE results further support ziprasidone’s favorable metabolic profile. Weight change, cholesterol levels, triglyceride levels, and hemoglobin A1C levels were included as secondary outcome measurements. Ziprasidone was associated with improvement in metabolic variables in CATIE.1
Additional Information1:
The results for weight change are based on 185 ziprasidone patients, 341 risperidone patients, 337 quetiapine patients, 336 olanzapine patients, and 261 perphenazine patients
Secondary safety and tolerability outcomes were evaluated at months 1, 3, 6, 9, 12, 15, and 18. This included changes in weight and laboratory analysis
Patients in the olanzapine group demonstrated more weight gain than patients in any other group
An average weight gain of 2 lb (0.9 kg) per month
Since the measurement of glycosylated hemoglobin was added to the protocol as part of the protocol amendment, the numbers of patients were smaller for this test. There were 89 ziprasidone patients, 139 risperidone patients, 137 quetiapine patients, 151 olanzapine patients, and 107 perphenazine patients
All other laboratory variables included 143 patients in the ziprasidone group, 262 patients in the risperidone group, 268 patients in the quetiapine group, 286 patients in the olanzapine group, and 212 patients in the perphenazine group
Olanzapine had effects consistent with the potential development of the metabolic syndrome
This was associated with greater increases in glycosylated hemoglobin, total cholesterol, and triglycerides after randomization than the other study drugs, even after adjustment for the duration of treatment
Hyperglycemia-related adverse events, sometimes serious, have been reported in patients treated with atypical antipsychotics. There have been few reports of hyperglycemia or diabetes in patients treated with ziprasidone, and it is unknown if ziprasidone is associated with these events. Patients treated with an atypical antipsychotic should be monitored for symptoms of hyperglycemia
Study Design2: CATIE, an NIMH-sponsored study designed to determine the comparative effectiveness of antipsychotic drugs, was comprised of 3 phases:
Phase I randomly allocated patients to double-blind treatment with perphenazine or 1 of 4 atypical agents.
Phase II, for nonresponders, entailed 2 pathways: (a) an efficacy pathway, with open-label use of clozapine or double-blind randomization to an atypical not assigned in Phase I, or (b) a tolerability pathway, with double-blind randomization to ziprasidone or another atypical not previously assigned.
Phase III allowed for open-label treatment of patients who discontinued their Phase II medication and were willing to try another antipsychotic.
Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:
Stroup TS, McEvoy JP, Swartz MS, et al. The National Institute of Mental Health Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project: schizophrenia trial design and protocol development. Schizophrenia Bull 2003;29:15-31.
9.7
42.9
Lieberman 2005 p 1215B
(mg/dL) rFom Baseline (LOCF)
Mean Change in Cholesterol
N=268
N=286
Triglycerides (mg/dL) From Baseline (LOCF)
Mean Change in
N=262
N=268
N=286
Lieberman 2005 p 1214A
N=143
N=262
N=212
N=143
N=212
Lieberman 2005 p 1211C
Lieberman 2005 p 1215A
-9.2
Lieberman 2005 p 1221A
Ziprasidone
Risperidone
Quetiapine
Olanzapine
Perphenazine
Lieberman 2005 p 1221A
Lieberman JA et al. N Engl J Med 2005;353:
Lieberman 2005 p 1215B
Geodon USPI
Stroup 2003 p 15A,B, 20 ABC

50. Olanzapine-Associated Weight Gain Plateaus After First 39 Weeks of Treatment
LOCF; Median = 2.5 Years -8 -6 -4 -2 2 4 6 8 20 40 60 80
100
120
140
160
Weight gain by olanzapine is not dose dependent (5-20 mg dose range).
Mean Weight Change (kg) up to 3 years
OLZ (N=573)
HAL (N=103)
Weight gain during long-term olanzapine treatment was investigated in a large cohort of subjects from the olanzapine clinical trial database. This study was the largest controlled psychopharmacologic trial ever conducted, involving nearly 2000 patients with schizophrenia, schizophreniform disorder, or schizoaffective disorder. In these studies, olanzapine was evaluated in doses ranging from 5-20 mg/day and was compared with haloperidol (5-20 mg/day), the most commonly used conventional antipsychotic drug for the treatment of schizophrenia. The study consisted of a six-week acute phase followed by an extension phase to 52 weeks.
This analysis retrospectively examined 573 patients receiving olanzapine and 103 patients receiving haloperidol for 39 weeks or more from a study of 1996 patients randomly assigned 2:1 to either olanzapine, 5 to 20 mg/day, or haloperidol, 5 to 20 mg/day. After 6 weeks of acute therapy, patients continued for 1 year or more with either double-blind or open-label olanzapine therapy or double-blind haloperidol therapy.
Patients were studied to about three years of treatment. Results indicate that the rate of weight gain changed dramatically over time. The most rapid rate of weight increase occurred early on, within approximately the initial 12 weeks of olanzapine treatment.
Weight gain during long-term olanzapine treatment then began to plateau at approximately 39 weeks of treatment, a timepoint after which no further significant pair-wise differences in weight change data were seen. Weight change experienced during haloperidol treatment remained significantly below that of olanzapine at all timepoints.
The relatively rapid onset of weight gain suggests the importance of early intervention for weight gain mitigation. The data suggest that patients treated with olanzapine tend to be at progressively lower risk for further weight gain as they continue into maintenance pharmacotherapy.
Patients Observed for 39 Weeks or More; Double-blind and open-label olanzapine.
Week
Kinon BJ, et al. J Clin Psychiatry 2001;62:92-100

51. Management of Pharmacokinetic Interactions
Enzyme
Substrate
Inhibitor
Inducer
CYP1A2
Clozapine, olanzapine
Fluvoxamine, ciprofloxacin
Carbamazepine, smoking
CYP2C19
Fluoxetine, fluvoxamine
Carbamazepine, phenytoin
CYP2D6
Aripiprazole, clozapine, olanzapine, risperidone, conventional antipsychotics
Bupropion, fluoxetine, paroxetine, duloxetine
CYP3A4
Aripiprazole, clozapine,, quetiapine, ziprasidone
Azole antifungal
Most of macrolide except azitromycin
ARVs; indinavir, nelfinavir, ritonavir
Carbamazepine,phenytoin, rifampin, phenobarbital

52. Maintenance treatment
Long-term management of bipolar disorder is essential to
prevent relapse and recurrence of both (hypo)manic and depressive episodes
improve patient quality of life and reduce burden for care givers and patients

53. Kaplan-Meier survival estimate of time to depressive or manic episode
Bipolar I disorder: lithium, divalproex or placebo for relapse prevention
Kaplan-Meier survival estimate of time to depressive or manic episode
Proportion of patients remaining in study
p=0.33, divalproex vs placebo p=0.06, divalproex vs lithium
p=0.31, lithium vs placebo
Time in study (weeks)
*71–125 g/mL serum concentration **0.8–1.2 mmol/L serum concentration
Bowden et al 2000

54. Olanzapine monotherapy in recurrence prevention: time to symptomatic relapse Patients with recent manic or mixed episodes
Olanzapine (n=225)
Placebo (n=136)
Manic relapse
Depressive relapse
Proportion of patients without relapse
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 50
100
150
200
250
300
350
400
p<0.001 HR=3.90 (95% CI: 2.40, 6.33) 50
100
150
200
250
300
350
400
p<0.001 HR=2.10 (95% CI: 1.46, 3.02)
Time (days)
Tohen et al 2006

55. Aripiprazole monotherapy in recurrence prevention: time to symptomatic relapse Patients with recent manic or mixed episodes
Aripiprazole (n=77)
Placebo (n=83)
Manic relapse
Depressive relapse
Proportion of patients without relapse
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0 10 20 30 40 50 60 70 80 90
100
p=0.005 HR=0.35 (95% CI: 0.16, 0.75) 10 20 30 40 50 60 70 80 90
100
p=0.602 HR=0.81 (95% CI: 0.36, 1.81)
Time (weeks)
Keck et al 2007

56. QUETIAPINE
Five long-term, placebo-controlled, bipolar I disorder recurrence prevention trials
2 monotherapy continuation phases from EMBOLDEN I and II (BP I or II)
2 adjunct studies with lithium or divalproex (BP I only)
1 monotherapy study: quetiapine vs lithium vs placebo (BP I only)
Five bipolar recurrence prevention trials documenting the long-term efficacy of quetiapine (n=3,082)
Olausson et al 2008

57. Study 144: time to recurrence of a mood event
Study 144 (spArclE): Updated 18 December 2009
QTP vs PLA
QTP vs LI
LI vs PLA HR
0.29
0.66
0.46
95% CI
0.23, 0.38
0.49, 0.88
0.36, 0.59
p-value
<0.001
<0.01
Proportion of patients event free
1.0
0.0
0.6
0.8
0.2
0.4
0.5
0.7
0.1
0.3
0.9
Study 144: time to recurrence of a mood event
This Kaplan-Meier curve compares quetiapine with placebo or lithium in the time to recurrence of a mood event (mania, depression or mixed) up to the maximum 104-week period of the randomisation phase of the trial (ITT population). The Kaplan-Meier method is a nonparametric technique for estimating the time to an event, in this case the time to recurrence of a mood event. The calculated HR value comparing quetiapine, placebo and lithium was analysed for statistical significance using a Cox proportional model and adjusting for covariates.
In the ITT population the time to recurrence of a mood event was significantly increased as follows:
quetiapine versus placebo:HR: 0.29, 95% CI: 0.23, 0.38; p<0.001; corresponding to a risk reduction of 71%
quetiapine versus lithium: HR: 0.66, 95% CI: 0.49, 0.88; p<0.01; corresponding to a risk reduction of 34%
lithium versus placebo: HR: 0.46; 95% CI: 0.36, 0.59; p<0.001; corresponding to a risk reduction of 54%.
The incidence of recurrence of a mood event (mania, depression or mixed) were: quetiapine, n=91(22.5%); placebo, n=208 (51.5%); and lithium n=95 (26.1%).
In the interim ITT population, quetiapine significantly increased the time to recurrence of a mood event compared with placebo (HR: 0.26, 95% CI: 0.19, 0.35; p<0.001). The incidence of recurrence of a mood event (mania, depression or mixed) was significantly less for those patients taking quetiapine (n=60; 16.4%) than for patients taking placebo (n=156; 42.9%). The risk of having a mood event (mania, depression or mixed) was reduced by 74% for stable patients treated with quetiapine compared with stable patients treated with placebo.
In summary, Study 144 demonstrated that quetiapine was superior to both placebo and lithium in increasing the time to recurrence of a mood event (mania, depression or mixed) in patients with bipolar I disorder.
[Study 144 CSR – 1 April 2008: Figure and Table (pages 500 and 503)]
[Paulsson B et al. Poster presented at the World Psychiatric Association International Congress Florence, Italy (April 1-4, 2009)]
CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat;
Quetiapine (n=404)
Placebo (n=404)
Lithium (n=364) 24 56 80
104 8 16 32 40 48 64 72 88 96
Time (weeks)
Weisler 2011
ITT population

58. Study 144: time to recurrence of mania
Study 144 (spArclE): Updated 18 December 2009
Study 144: time to recurrence of mania
QTP vs PLA
QTP vs LI
LI vs PLA HR
0.29
0.78
0.37
95% CI
0.21, 0.40
0.53, 1.16
0.27, 0.53
p-value
<0.001 NS
Proportion event free
100 80 60 40
Quetiapine (n=404)
Study 144: time to recurrence of mania
This Kaplan-Meier curve compares quetiapine with placebo in the time to recurrence of mania up to the maximum 104-week period of the randomisation phase of the trial (ITT population). The calculated HR value comparing quetiapine, placebo and lithium was analysed for statistical significance using a Cox proportional model and adjusting for covariates.
In the ITT population the time to recurrence of mania was significantly increased as follows:
quetiapine versus placebo: HR: 0.29, 95% CI: 0.21, 0.40; p<0.001; corresponding to a risk reduction of 71%
lithium versus placebo: HR: 0.37; 95% CI: 0.27, 0.53; p<0.001; corresponding to a risk reduction o 63%.
However, significant increases for quetiapine versus lithium were not observed (HR: 0.78, 95% CI: 0.53, 1.16; p=0.2264)
In the interim ITT population, quetiapine significantly increased the time to recurrence of mania compared with placebo. The incidence of recurrence of mania was significantly less for those patients taking quetiapine (n=39) than placebo (n=98) in the maintenance treatment of bipolar I disorder (HR: 0.27; 95% CI: 0.19, 0.39; p<0.001). The risk of having a manic event was reduced by 73% for stable patients treated with quetiapine compared with stable patients treated with placebo.
In summary, in Study 144, quetiapine was superior to placebo in increasing the time to recurrence of mania in patients with bipolar I disorder.
[Study 144 CSR – 1 April 2008: Figure and Table (pages 524 and 527)]
[Paulsson B et al. Poster presented at the World Psychiatric Association International Congress Florence, Italy (April 1-4, 2009)]
CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat 20
Placebo (n=404)
Lithium (n=364) 8 16 24 32 40 48 56 64 72 80 88 96
104
Weeks
Paulsson et al 2009
ITT population

59. Study 144: time to recurrence of depression
Study 144 (spArclE): Updated 18 December 2009
Study 144: time to recurrence of depression
QTP vs PLA
QTP vs LI
LI vs PLA HR
0.30
0.54
0.59
95% CI
0.20, 0.44
0.35, 0.84
0.42, 0.84
p-value
<0.001
<0.01
Proportion event free
100 80 60 40
Study 144: time to recurrence of depression
This Kaplan-Meier curve compares quetiapine with placebo in the time to recurrence of depression up to the maximum 104-week period of the randomisation phase of the trial (ITT population). The calculated HR value comparing quetiapine, placebo and lithium was analysed for statistical significance using a Cox proportional model and adjusting for covariates.
In the ITT population the time to recurrence of depression was significantly increased as follows:
quetiapine versus placebo: HR: 0.30, 95% CI: 0.20, 0.44; p<0.001; corresponding to a risk reduction of 70%
quetiapine versus lithium: HR: 0.54, 95% CI: 0.35, 0.84; p<0.01; corresponding to a risk reduction of 46%
lithium versus placebo: HR: 0.59; 95% CI: 0.42, 0.84; p<0.01; corresponding to a risk reduction of 41%.
In the Interim ITT population, quetiapine significantly increased the time to recurrence of depression compared with placebo. The incidence of recurrence of depression was significantly less for those patients taking quetiapine (n=21) than placebo (n=58) in the maintenance treatment of bipolar I disorder (HR: 0.25; 95% CI: 0.15, 0.41; p<0.001). The risk of having a depressive event was reduced by 75% for stable patients treated with quetiapine compared with stable patients treated with placebo.
In summary, in Study 144, quetiapine was superior to placebo in increasing the time to recurrence of depression in patients with bipolar I disorder.
[Study 144 CSR – 1 April 2008: Figure and Table (pages 538 and 541)]
[Paulsson B et al. Poster presented at the World Psychiatric Association International Congress Florence, Italy (April 1-4, 2009)]
Quetiapine (n=404) 20
Placebo (n=404)
Lithium (n=364) 8 16 24 32 40 48 56 64 72 80 88 96
104
Weeks
Weisler 2011
ITT population
ITT, intent-to-treat; HR, hazard ratio; CI, confidence interval

60. EMBOLDEN I and II (continuation phase): 17 January 2008 [FINAL VERSION]
EMBOLDEN I and II: time to recurrence of a mood event (continuation phase)
Bipolar I disorder
Bipolar II disorder
Proportion of patients event free
1.0
0.8
0.6
0.4
HR, 0.58; 95% CI, 0.41 to 0.82
p<0.01
HR, 0.33; 95% CI, 0.18 to 0.60
p<0.001
0.2
Quetiapinea (n=56/181)
Quetiapinea (n=15/109)
Placebo (n=75/172)
Placebo (n=44/122)
0.0
100
200
300
400
100
200
300
400
Time (days)
aPatients receiving quetiapine 300 mg/day and 600 mg/day combined
Young et al 2010
Please note that in this slide set only those patients who received quetiapine in the acute phase of the EMBOLDEN I and EMBOLDEN II studies who were eligible to enter the continuation phase to assess maintenance of effect will be presented – for those patients who received placebo, lithium or paroxetine in the acute phase of EMBOLDEN I and EMBOLDEN II and were blindly switched to quetiapine 300 mg/day, please refer to the individual slide sets.
CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat 60

61. Quetiapine & Mood stabilizer time to recurrence
Studies : Updated 18 December 2009
Studies 126 and 127
Quetiapine & Mood stabilizer time to recurrence
1.0
0.9
0.8
0.7
0.6
HR: 0.30; 95% CI: 0.23, 0.40; p< Quetiapine 10.4%; placebo 27.4%
Proportion of patients event free
0.5
0.4
0.3
Primary endpoint: time to recurrence of a mood event
Primary objective: efficacy of quetiapine versus placebo when used in combination with lithium or divalproex in increasing time to recurrence of a mood event (mania, depression or mixed).
This Kaplan-Meier curve compares quetiapine plus lithium or divalproex with placebo plus lithium or divalproex on the time to recurrence of a mood event (mania, depression or mixed) up to the maximum 104-week period of the randomisation phase of the trial (ITT population). The Kaplan-Meier method is a nonparametric technique for estimating the time to an event, in this case the time to recurrence of a mood event. The calculated HR value comparing quetiapine with placebo was analysed for statistical significance using a Cox proportional model and adjusting for covariates.
Quetiapine significantly increased the time to recurrence of a mood event compared with placebo. The incidence of recurrence of a mood event (mania, depression or mixed) was significantly less for those patients taking quetiapine (n=646) than placebo (n=680), in combination with lithium or divalproex in the maintenance treatment of bipolar I disorder (HR: 0.30; 95% CI: 0.24, 0.37; p<0.0001). The risk of having a mood event (mania, depression or mixed) was reduced by 70% for stable patients treated with quetiapine compared with stable patients treated with placebo.
125 (19.3%) patients receiving quetiapine (n=646) experienced a mood event (mania, depression or mixed) compared with 343 (50.4%) patients receiving placebo (n=680).
In summary in the pooled data for Study 126 and Study 127, quetiapine, when used in combination with lithium or divalproex, is significantly better than placebo plus lithium or divalproex in increasing the time to recurrence of a mood event (mania, depression or mixed) in patients with bipolar I disorder.
[2.7.3 Summary of Clinical Efficacy – 19 June 2007: Figure EA-3 and Table EA-24 (pages 145 and 111)]
[Olausson B et al. Poster presented at the 8th International Forum on Mood and Anxiety Disorders, Vienna, Austria, November 12-14, 2008]
ITT, intent-to-treat; HR, Hazard Ratio
0.2
Quetiapine plus lithium or divalproex (n=646)
Placebo plus lithium or divalproex (n=680)
0.1
0.0 10 20 30 40 50 60 70 80 90
100
110
Time (weeks)
Olausson et al 2008
ITT population

62. Time to recurrence of mania
Studies : Updated 18 December 2009
Studies 126 and 127
Time to recurrence of mania
1.0
HR: 0.30; 95% CI: 0.22, 0.41; p< Quetiapine 9.0%; placebo 23.1%
0.9
0.8
0.7
0.6
Proportion of patients event free
0.5
0.4
Time to recurrence of mania
Secondary objective: efficacy of quetiapine versus placebo when used in combination with lithium or divalproex in increasing time to recurrence of mania.
This Kaplan-Meier curve compares quetiapine plus lithium or divalproex with placebo plus lithium or divalproex on the time to recurrence of mania up to the maximum 104-week period of the randomisation phase of the trial (ITT population). The calculated HR value comparing quetiapine with placebo was analysed for statistical significance using a Cox proportional model and adjusting for covariates.
Quetiapine significantly increased the time to recurrence of mania compared with placebo. The incidence of recurrence of mania was significantly less for those patients taking quetiapine (n=646) than placebo (n=680), in combination with lithium or divalproex in the maintenance treatment of bipolar I disorder (HR: 0.30; 95% CI: 0.22, 0.41; p<0.0001). The risk of having a mood event (mood event mania) was reduced by 70% for stable patients treated with quetiapine compared with stable patients treated with placebo.
In summary in the pooled data for Study 126 and Study 127, quetiapine, when used in combination with lithium or divalproex, is significantly better than placebo plus lithium or divalproex in increasing the time to recurrence of mania in patients with bipolar I disorder.
[2.7.3 Summary of Clinical Efficacy – 19 June 2007: Figure EA-5 and Table EA-30 (pages 147 and 117)]
[Olausson B et al. Poster presented at the 8th International Forum on Mood and Anxiety Disorders, Vienna, Austria, November 12-14, 2008]
ITT, intent-to-treat; HR, Hazard Ratio
0.3
0.2
Quetiapine plus lithium or divalproex (n=646)
Placebo plus lithium or divalproex (n=680)
0.1
0.0 10 20 30 40 50 60 70 80 90
100
110
Time (weeks)
Olausson et al 2008
ITT population

63. Time to recurrence of depression
Studies : Updated 18 December 2009
Studies 126 and 127
Time to recurrence of depression
1.0
HR: 0.30; 95% CI: 0.23, 0.40; p< Quetiapine 10.4%; placebo 27.4%
0.9
0.8
0.7
0.6
Proportion of patients event free
0.5
0.4
Time to recurrence of depression
Secondary objective: efficacy of quetiapine versus placebo when used in combination with lithium or divalproex in increasing time to recurrence of depression.
This Kaplan-Meier curve compares quetiapine plus lithium or divalproex with placebo plus lithium or divalproex on the time to recurrence of depression up to the maximum 104-week period of the randomisation phase of the trial (ITT population). The calculated HR value comparing quetiapine with placebo was analysed for statistical significance using a Cox proportional model and adjusting for covariates.
Quetiapine significantly increased the time to recurrence of depression compared with placebo. The incidence of recurrence of depression was significantly less for those patients taking quetiapine (n=646) than placebo (n=680), in combination with lithium or divalproex in the maintenance treatment of bipolar I disorder (HR: 0.30; 95% CI: 0.23, 0.40; p<0.0001). The risk of having a mood event (mood event depression) was reduced by 70% for stable patients treated with quetiapine compared with stable patients treated with placebo.
In summary in the pooled data for Study 126 and Study 127, quetiapine, when used in combination with lithium or divalproex, is significantly better than placebo plus lithium or divalproex in increasing the time to recurrence of depression in patients with bipolar I disorder.
[2.7.3 Summary of Clinical Efficacy – 19 June 2007: Figure EA-6 and Table EA-35 (pages 148 and 121)]
[Olausson B et al. Poster presented at the 8th International Forum on Mood and Anxiety Disorders, Vienna, Austria, November 12-14, 2008]
ITT, intent-to-treat; HR, Hazard Ratio
0.3
0.2
Quetiapine plus lithium or divalproex (n=646)
Placebo plus lithium or divalproex (n=680)
0.1
0.0 10 20 30 40 50 60 70 80 90
100
110
Time (weeks)
Olausson et al 2008
ITT population

64. Conclusions
Several medications are available for the treatment of Bipolar Disorder and Schizophrenia
Comorbility is more the rule than the exception
There is no medication that works better than another for all patients
There is no medication without side effects.
The side effect profile and tolerability is a major factors to inform treatment decision
Personalized Treatment should be the goal
Thank you