canmat guideline on bipolar

1. CANMAT and ISBD guidelines for
Bipolar Disorders :
A Summary with focus on
QUETIAPINE
Dr. Subodh Sharma
Resident
NMCTH, Birgunj, Nepal

2. Quetiapine, trade name of Seroquel,
was developed by Astra Zenca Labs, in
early 1990’s.
Quetiapine has a chemical structure
similar to clozapine and olanzapine,
thus was supposed to be a drug with
similar efficacy but reduced side-
effects.

3. FDA Approval
❖ Quetiapine was initially marketed for the treatment of actue
psychosis, seen especially in Schizophrenia.
❖ It was approved for the treatment of SZ, in 1997 after two pivotal
trials, one by Small et al, and the other by Arvanitis et al.
In this they used flexible and fixed doses of quetiapine and compared it
with placebo and Haloperidol (12 mgs).
❖ They found quetiapine to be statistically better than placebo and
equivalent to haloperidol in reducing psychotic symptoms. The dose
range suggested by them was 150-750 mgs/day.

4. FDA…
❖ Quetiapine was approved by FDA in January 2004 as
mono therapy or adjuvant therapy with Litium or Valproate
for short term treatment for acute manic episodes for acute
manic disorder.
❖ It was approved as mono therapy for Bipolar Depression
in October 2006. This was the result to two pivotal trials,
known as BOLDER 1 & 2, followed by EMBOLDEN.
❖ These trials (RCT’s) included the use of quetiapine in
doses of 300- 600 mgs, v/s placebo, for a period of 8 weeks.
They concluded that patients treated to either dose were
faster to respond to treatment and achieve remission than
those receiving placebo.

5. Mechanism of Action
❖ Quetiapine is an atypical antipsychotic with
actions mainly on D2 and 5-HT2 antagonism.
❖ Highest Affinity: H1, A1
❖ Moderate: 5-HT2a, M1, 5-HT 7
❖ Lowest: 5-HT2c, D2, 5-HT1a.
❖ It has a 5-HT1a partial agonistic actions,
which along with it actions on 5-HT7, 5-HT2c
contribute to its anti-depressant effects

7. Quetiapine Clinical Uses- FDA Approved
• Acute Schizophrenia in adults & ages 13-17 years
• Schizophrenia maintenance
• Acute Mania in adults & ages 10-17 years
• Bipolar maintenance
• Bipolar depression
• Depression (Adjunct)

8. FDA approved indications Quetiapine IR Quetiapine ER
Schizophrenia
Adults Approved in 1997
Dose: 150-750 mg/day. BID, TID
Approved in 2007
Dose:400-800 mg/day
Adolescents (13-17 years) Dose: 400-800 mg/day. BID Not FDA approved
Bipolar Disorder
Bipolar Mania, Adults Approved in 2003
Dose: 400-800 mg/day, BID
Monotherapy/adjunct
Approved in 2008
Dose: 400-800 mg/day, once a day
Monotherapy/adjunct
Bipolar Mania, Children and
Adolescents (10-17 years)
Dose: 400-800 mg/day, BID
Monotherapy
Not FDA approved
Bipolar Depression Approved in 2006
Dose:300-600 mg/day
Monotherapy
Approved in 2008
Dose: 300 mg/day
Monotherapy
Maintenance Treatment Approved in 2008
Dose:400-800 mg/day
Adjunct to lithium or divalproex
Approved in 2008
Dose: 400-800 mg/day
Adjunct to lithium or divalproex
Major Depressive Disorder Not FDA approved Approved in 2009
Dose: 150-300 mg/day
Adjunct to antidepressants

9. Quetiapine Clinical Uses- Off Label
• Mixed mania
• Behavioral disturbance in dementias
• Behavioral disturbance in Parkinson’s disease and Lewy body dementia
• Psychosis associated with levodopa treatment in Parkinson’s disease
• Behavioral disturbances in children and adolescents
• Disorders associated with impulse control
• Severe treatment resistant anxiety

10. Recommendations for Quetiapine in….
• Short-term pharmacological management of agitation
• Management of acute mania
• Management of acute bipolar I depression
• Maintenance treatment in bipolar disorder
• Acute management of bipolar II depression
• Maintenance treatment of bipolar II disorder
Bipolar Disord. 2018 Mar;20(2):97-170

11. Short-term pharmacological management of agitation
Bipolar Disord. 2018 Mar;20(2):97-170

12. Hierarchical rankings of first and second-line treatments
recommended for management of acute mania

13. Bipolar Disord. 2018 Mar;20(2):97-170

14. Management of agitation
• The effectiveness of three second generation antipsychotics
(risperidone, olanzapine, quetiapine) was compared with
haloperidol in the treatment of psychotic agitation for up to
72 h in 101 patients.
• The three SGAs are as effective as haloperidol in the
treatment of agitated psychotics, but better tolerated.
• Among those, olanzapine, risperidone and quetiapine didn't
differ in a significant way.
Prog Neuropsychopharmacol Biol Psychiatry.2008;32:405‐13.

15. Management of acute mania
• 356 patients treated with quetiapine XR were randomized to
add-on lithium (n = 173) or placebo (n = 183).
• At day 43, least squares mean change in YMRS total score
was −22.8 for add-on lithium and −20.1 for add-on placebo, a
statistically significant treatment group difference of −2.69
(p < 0.001).
• The addition of lithium to quetiapine XR therapy was
associated with significantly greater efficacy than placebo as
add-on and was generally well tolerated in patients with
acute bipolar I mania.
Mean change in YMRS total score (with 95% CIs) from baseline
(observed case data, ITT set).
Int J Bipolar Disord. 2014;2:14.

16. Hierarchical rankings of first and second-line treatments
recommended for management of acute bipolar I depression
Bipolar Disord. 2018 Mar;20(2):97-170

17. Management of acute bipolar I depression
• A total of 1,497 participants in three RCTs were included.
• The overall response and remission rates were significantly
greater in the quetiapine-treated group with RRs of 1.44 and
1.37 respectively.
• Based on the limited evidence obtained from three RCTs,
quetiapine XR is effective for adult patients with MDD.
BMC Psychiatry. 2012;12:160.

18. • 24 trials of 10 treatments met eligibility criteria.
• By SMD, apparent efficacy ranked: olanzapine + fluoxetine ≥
valproate > quetiapine > lurasidone > olanzapine,
aripiprazole, and carbamazepine; ziprasidone was
ineffective, and lithium remains inadequately studied.
• Drugs were superior to placebo in only 11/24 trials (5/5
with quetiapine, 2/4 with valproate), and only lamotrigine,
quetiapine and valproate had > 2 trials.
Management of acute bipolar I depression
Pharmacopsychiatry. 2014;47:43‐52.

19. • Pooled analysis of 5 clinical trials of quetiapine
demonstrated that patients with bipolar II depression have a
similar burden of illness and quality of life to patients with
bipolar I.
• Bipolar II patients consistently showed a slower response to
treatments than bipolar I patients initially.
• After 8 weeks of treatment with quetiapine, symptom
improvements were similar between bipolar I and II
disorder subtypes.
Management of acute bipolar I depression
Ann Gen Psychiatry. 2016;15:9.

20. • Least squares mean change from baseline to week 8 in MADRS total score (ITT
population, LOCF), BPI and BPII groups.
• Rating scale range: MADRS: total score range 0–60.
• A reduction in score represents improvement in depressive symptoms
Ann Gen Psychiatry. 2016;15:9.

21. Hierarchical rankings of first and second-line treatments
recommended for maintenance treatment in bipolar disorder
Bipolar Disord. 2018 Mar;20(2):97-170

22. Maintenance treatment in bipolar disorder
• Quetiapine was also better than placebo in the prevention of
both manic and depressive relapse or recurrence.
• For any mood episode relapse or recurrence, of the active
drugs that were better than placebo, olanzapine and
quetiapine were significantly better than lamotrigine.
• With respect to the secondary outcomes of prophylactic
efficacy, only quetiapine and lithium prevented relapse or
recurrence of both polarities of the mood episode, compared
with placebo
Lancet Psychiatry. 2014;1:351‐9.

23. • This study investigated the efficacy and safety of quetiapine
monotherapy as maintenance treatment in bipolar I disorder
compared with switching to placebo or lithium.
• Quetiapine and lithium significantly increased time to
recurrence of both manic events (quetiapine: HR = 0.29;
lithium: HR = 0.37) and depressive events (quetiapine: HR =
0.30; lithium: HR = 0.59) compared with placebo.
• In patients stabilized during acute quetiapine treatment,
continuation of quetiapine significantly increased time to
recurrence of any mood, manic, or depressive event
compared with switching to placebo.
Maintenance treatment in bipolar disorder
J Clin Psychiatry. 2011;72:1452‐64.

24. • A total of 1,953 patients received open-label quetiapine with
either lithium or divalproex for up to 36 weeks.
• After at least 12 weeks of clinical stability, 628 patients were
randomly assigned to double-blind treatment with
quetiapine or placebo, in combination with lithium or
divalproex, for up to 104 weeks.
• In patients stabilized on quetiapine plus lithium or
divalproex, continued treatment was associated with a
significant risk reduction in the time to recurrence of any
mood event compared with placebo and lithium or
divalproex.
Maintenance treatment in bipolar disorder
Am J Psychiatry. 2009;166:476‐88.

25. Acute management of hypomania
• An 8-week, randomized, double-blind, placebo-controlled
trial of quetiapine in ambulatory BSD with hypomanic/mild
manic symptoms.
• Patients receiving quetiapine (average daily dose=232 mg)
had a marginally greater rate of reduction in mean total
YMRS score than patients receiving placebo (p=0.06).
• Quetiapine was more effective than placebo in reducing
manic symptoms and global bipolar symptoms as assessed
by the CGI-BP
J Affect Disord. 2010;124:157‐63.

26. Acute management of hypomania
• Adjunctive quetiapine demonstrated significantly greater
improvement than placebo in Clinical Global Impression for
Bipolar Disorder Overall Severity scores and MADRS scores.
• No significant differences were observed for YMRS scores
J Affect Disord. 2013;150:37‐43.

27. Recommendations for acute management of bipolar II depression
Bipolar Disord. 2018 Mar;20(2):97-170

28. Acute management of bipolar II depression
• Pooled analysis of 5 clinical trials of quetiapine
demonstrated that patients with bipolar II depression have a
similar burden of illness and quality of life to patients with
bipolar I.
• Bipolar II patients consistently showed a slower response to
treatments than bipolar I patients initially.
• After 8 weeks of treatment with quetiapine, symptom
improvements were similar between bipolar I and II
disorder subtypes.
Ann Gen Psychiatry. 2016;15:9.

29. • Least squares mean change from baseline to week 8 in MADRS total score (ITT
population, LOCF), BPI and BPII groups.
• Rating scale range: MADRS: total score range 0–60.
• A reduction in score represents improvement in depressive symptoms
Ann Gen Psychiatry. 2016;15:9.

30. • A total of 776 patients with bipolar II depression were
included in the ITT population (283, 289, and 204 patients
received quetiapine 300 mg/day, quetiapine 600 mg/day, or
placebo, respectively).
• Significantly higher proportions of patients receiving
quetiapine, at both doses, than placebo-treated patients
achieved response and remission at week 8 (p < 0.01).
• Quetiapine monotherapy demonstrated significant efficacy
compared with placebo and was generally well tolerated in
the treatment of bipolar II depression.
Mean change from baseline to week 8 in MADRS total score (ITT
population; LOCF).
Acute management of bipolar II depression
Int J Bipolar Disord. 2013;1:10.

31. Recommendations for maintenance treatment of bipolar II disorder
Bipolar Disord. 2018 Mar;20(2):97-170

32. Maintenance treatment of bipolar II disorder
• To examine the long term efficacy of quetiapine monotherapy
in bipolar depression in a preplanned pooling of data from the
EMBOLDEN I and II studies.
• There was a lower risk of recurrence of mood events in
bipolar II patients (HR 0.33 (95% CI: 0.18 – 0.60), P< 0.001).
• The efficacy of quetiapine monotherapy in bipolar depression
is maintained during continued treatment for 26 – 52 weeks.
• Quetiapine was generally well tolerated.
Time to recurrence of any mood event for patients with (B) bipolar II
disorder (KM survival analysis; ITT population; combined data).
World J Biol Psychiatry. 2014;15:96‐112.

33. Pharmacokinetics
❖ Absorption: Rapidly absorbed orally. Should ideally be
given with 300 calories for optimal effect.
❖ Vd: 6-14 L/Kg
❖ Protein Binding: 83%
❖ Metabolism: Primarily hepatic by CYP 3A4. Dosage
adjustment advised when used with CYP 3A4 inhibitor or
inducers.
❖ Bio-Availability: 100%
❖ Half-Life: IR: 6 Hrs, XR: 7 Hrs
❖ Time to Peak: IR: 1.5 Hrs, XR: 6 Hrs
❖ Excretion: Urine (Major), Feces (Minor), Unchanged
(1%)

34. Dose Adjustments in Cytochrome Mutations
❖ Concomitant use with strong CYP 3A4 inhibitor: (ketoconazole,
nefazodone): Decrease quetiapine to 1/6th of the original dose
when the above-mentioned drugs are used. When these drugs are
discontinued increase it 6 times
❖ Concomitant use with strong CYP 3A4 inducer: (phenytoin,
carbamezapine): Increase quetiapine to 5 fold to original dose
when combined with the above drug. When it is discontinued,
decrease quetiapine to original dose within 7- 14 days.

35. Formulations
❖ It is usually given in extended-release forms.
Extended-release (ER) forms are usually preferred when
it is used as an anti-depressant and anti-psychotic.
❖ However when used as a hypnotic, immediate release
(IR) formulations are preferred.
❖ IR is rapid onset and short duration of action.

36. Side Effects
❖ Sedation
❖ Somnolence
❖ Weight Gain and Metabolic
Syndrome
❖ Hypotension
❖ Lowest incidence of EPS
❖ Decreased T4 by 20%, in a dose
dependent manner (<1%)

37. High Risk Population
❖ Paediatric Population: Dosage adjustment is advised at an initial level while titrating the drug.
❖ Adult Population: In patients with pre-existing cardiac conditions, please monitor for QTc
prolongation. Stop drug when interval > 450 ms.
❖ Accelerates the onset of cataract, theoretically. But no proof has been found in human studies.
❖ Geriatric Population: No change in dosing. Monitor for cardiac side effects.
❖ Pregnancy: Class C
❖ Lactation: Enters breast milk. Not recommended.

38. • ❖ Increased mortality in elderly
patients with dementia-related
psychosis.
• ❖ Suicidal Thoughts and behavior:
AD’s increase the risk of suicidality in
young children and young adults.
• Quetiapine is not approved for use
in children < 10 years of age.
BLACK
BOXED
WARNING

39. Emerging Trends
❖ Quetiapine has been recently used in a few conditions apart from
the above mentioned use.
❖ Though these uses are unlabelled and yet unapproved by the FDA,
we would still like to browse through them
• ICU Delirium: Initial 50 mg/ twice daily. Max 400 mg/daily. (IR)
• OCD, treatment resistant: 50 mg/once daily (1), increase to 100 mg/day,
further increase as tolerated and required in every 2 weeks at 100 mg
increments.
• Usual dose range 50-300 mgs daily. (IR).

40. • It is the only drug approved for the treatment of
Bipolar Depression as mono therapy. The
clinical trials mentioned above have been
pivotal for FDA’s approval.
• It doesn't cause any Treatment Emergent
Affective Switches (TEAS).
• Has a spectrum of actions, both on depressive
and psychotic features. Thus acts like a one stop
solution.
• It is relatively safe and does not cause any life
threatening side effects.
• Easy dosing schedule.
WHY
QUETIAPINE???