This ppt is on Management aspects of Bipolar disorders. It is presented in a Zonal PG CME of Psychiatry.

1. Management
of
BiPolarDisorder
(Phamacological)
Dr.D.Raj Kiran & Dr.M.Dattatrey
Dept. of Psychiatry
KIMS, Narketpally
Zonal PG CME, DCMS 23rD
auG 2015
1

2. Outline
• Introduction
• Investigations
• Emergency management
• Acute management
– Manic or Mixed episode
– Depressive episode
– Rapid cycling
• Brief note on drugs
• Special conditions
• Maintenance treatment
2

3. Introduction
• There is no cure for bipolar disorder; however, treatment can
decrease the associated morbidity and mortality.
• Psychiatrist should
– Perform a diagnostic evaluation
– Assess the patient’s safety and
– Level of functioning to arrive at a decision about the optimum
treatment setting.
3

4. Goals of treatment
• Establishing & maintaining a Therapeutic alliance.
• Monitoring the patient’s psychiatric status.
• Providing Education regarding bipolar disorder.
• Enhancing treatment Compliance.
• Promoting Regular patterns of activity and sleep.
• Anticipating Stressors.
• Early identification of a new episode.
• Minimizing functional Impairments.
4

5. Investigations
• Important in agitated patient.
• May be dehydrated - risk of rhabdomyolysis
• Alcohol or drug intoxication
• So-
– Electrolyte imbalance
– Hypo/ Hyper glycemia
– Thyroid status
– Liver function tests
– Renal function tests 5

6. Emergency treatment
• Sooner the agitated patient is
medicated, the better
• Widely used - IM Haloperidol.
• Atypicals - olanzapine &
risperidone - available in parenteral
form.
• IM lorazepam (1–2 mg) - short
term treatment of agitated manic
states.
6

7. Emergency treatment
7

8. Manic/ Mixed episode
• Less ill episode -
Mono-therapy with Lithium/ Valproate/ Antipsychotic
• Severe/ Mixed episode -
– Lithium+ antipsychotic or
– Valproate + antipsychotic
• Short term adjunctive therapy - Benzodiazepines.
• Mixed episode - Valproate > Lithium
8

9. Manic/ Mixed episode
• Antipsychotic - Atypical > Typical, most commonly preferred -
olanzapine, risperidone.
• Alternatives to Lithium/Valproate - Carbamazepine,
Oxcarbazapine
.
• If patient is on Antidepressants, should be tapered and stopped.
• Psychotherapies are always used in combination to
pharmacotherapy.
9

10. Manic/ Mixed episode
• Response to treatment becomes apparent < first 4-5 days of
inpatient care.
• With adequate dosing & serum levels - appreciable effect by 10-
14th
day.
• Can take upto 4 weeks to attain a stable affective state with
sufficient insight to permit OP care.
• With clinical improvement, many manic patients will develop partial
insight.
10

11. Manic/ Mixed episode
If 1st
line fails –
• Addition of Another 1st line agent.
• Addition of Carbamazepine/ Oxcarbazepine.
• Addition of Antipsychotic, if not added.
• Changing of antipsychotic (Clozapine may be effective).
• Electro Convulsive Therapy (ECT)
11

12. Bipolar Depression
• Referred to as “darker side of bipolarity”, often under diagnosed &
missed.
• Misdiagnosis as unipolar is common.
• Life time suicide- 25-50% as against unipolar (15%).
• Patients spend- 3 fold longer time in depression.
• Recovery period is longer then manic phase.
12

13. Bipolar Depression
• Effective treatment should have fewer, brief, milder episodes or
few side effects.
• Challenges - drugs for unipolar depression are less effective.
• Concern of switching - limit the use of antidepressants.
• Therapy with atleast two drugs is often required in acute &
maintenance.
13

14. Bipolar Depression
Predictors for bipolar depression
• Cyclothymic, extroverted
• Early age of onset
• Presence of postpartum onset
• Abrupt onset & termination of depressive episode
• Severe retardation
• Worsening or less response to depressive episodes
• Shorter duration of the episode
• f/h/o bipolar disorder
14

15. Bipolar Depression
•1st
line - Lithium or Lamotrigine.
•Antidepressant mono-therapy is not recommended.
•Life-threatening inanition, suicidality, psychosis, catatonia - ECT.
•Psychotherapy - used in addition to pharmacotherapy.
Inter Personal Therapy (IPT) & Cognitive Behavior Therapy (CBT).
•Psychotic features require adjunctive - antipsychotics
15

16. Bipolar Depression
• If not responding to 1st
line -
– Addition of Lamotrigine, Bupropion or Paroxetine.
• Next step would be -
– Newer antidepressants - SSRI’s or Venlafaxine or MAOI.
• Breakthrough episode - Optimize the dose of maintenance
medication.
• Antidepressant induced switch into hypomania is low in BPAD II
So can be started on antidepressants early.
16

17. Rapid cycling
• Occurrence of ≥ 4 mood disturbances in a year
• Episodes are demarcated either by partial/ full remission for
atleast 2 months or a switch to opposite polarity.
• Relatively resistant to most pharmacological treatment.
• Realistic goal  Significant reduction of symptoms than complete
prevention of symptoms.
• Despite growing therapeutic armamentarium - remains one of the
greatest challenge. 17

18. Rapid cycling
• 1st
look for - factors promoting cycling - hypothyroidism, drugs,
alcohol, hormonal treatment, endocrine disturbances.
• Anti depressants should be stopped & mood stabilizer added.
• Treatment - Valproate > Lithium, alternative - Lamotrigine
• Combining mood stabilizer agent which have predominantly anti
manic & anti depressive properties - promising.
18

19. Rapid cycling
Suggested algorithm (Yatham et al)
• Allow every new treatment/ combination sufficient time to exhibit its
efficacy.
19

20. FDA approved agents
Acute Mania
• Lithium
• Chlorpromazine
• Divalproate sodium
• Olanzapine
• Risperidone
• Quetiapine IR, XR
• Ziprasidone
• Aripiprazole
• Carbamazepine
• Asenapine
Acute Depression
• Olanzapine+Fluoxetine
• Quetiapine IR, XR
• Lurasidone (2013)
Maintenance
• Lithium
• Lamotrigine
• Olanzapine
• Aripiprazole
• Quetiapine IR, XR
• Risperidone
• Ziprasidone
20

21. Lithium
• Antimanic effects correlate - serum
lithium levels.
• Levels < 0.8 meq/l are not as
effective as those above this level.
• As mania subsides - down titrate
dose.
• The ratio of dose to plasma level is
higher in mania than in euthymia or
depression.
John F Cade description of first case rx with Li
21

22. Lithium
• Better response in bipolar depression > unipolar depression.
• Effective in prevention of future recurrences of mania/hypomania &
less effective in depression.
• Predictors of response -
– Good intermediate normalcy
– Mania followed by depression
– Absence of rapid cycling, personality disorder,
comorbidity, psychotic symptoms.
– f/h/o BPAD
– Diagnosis of primary BPAD
– Previous/ Family response to Lithium. 22

23. Valproate
• Therapeutic benefit- correlate with serum levels.
• Levels > 45µg/ml  antimanic efficacy, SEs become problematic
> 125 µg/ml.
• Starting at 30 mg/kg of body weight.
• Loading strategies have been devised for speeding up the onset of
the antimanic action.
• Loading strategy  found to be more rapidly effective than
standard - titration.
• IV loading has also been reported to be rapidly effective and may be
an option for some patients.
23

24. Valproate
Predictors of response to valproate -
• Multiple episodes
• Co-morbid alcohol use, anxiety
• Acute mania
• Rapid cycling
• Mixed episodes
• Secondary bipolar
• f/h/o anxiety disorders.
24

25. Lamotrigine
• Approved drug for refractory seizures as adjunctive therapy.
• MOA- Inhibition of Sodium & Calcium channels in presynaptic
neurons & subsequent stabilization of neuronal membrane
• No compelling evidence in acute mania, but positive evidence to
support efficacy in acute bipolar depression both in monotherapy
& in combination therapy.
• Effective in preventing depressive relapse, but questionable
efficacy in preventing manic relapse.
• Black box warning for serious rash (includes Steven-Johnson
Syndrome & Toxic Epidermal Necrolysis) Incidence- 0.1%.
25

26. Lamotrigine
Trial Study arms N Response rate in percentage
HAMD MADRS CGI
Calabrese,
Bowden,
Sachs et
al, 99
LTG 50mg
LTG 200mg
Placebo
66
66
66
45
51
37
48
54
29
41
51
26
Brown EB
et al, 06
LTG
OFC
205
205
-
-
59.7
68.8
64.4
71.8
- RCTs of Lamotrigine monotherapy in acute bipolar Depression
- LTG- lamotrigine, OFC- olanzapine-flouxetine combination
- HAMD- hamilton rating scale for depression, MADRS- montgomery depression rating scale,
- CGI- clinical global impression scale
26

27. Anti-Convulsants
• Oxcarbazepine
– Useful in patients with mild manic symptoms,
– Not established its efficacy as monotherapy.
• Topiramate - failed to demonstrate antimanic efficacy.
• Gabapentin - No antimanic efficacy.
• Phenytoin & Levetiracetam
– Antimanic activity as adjuncts,
– Monotherapy data are still lacking
27

28. First Generation Antipsychotics
• ↓Activity level & Behavioral disturbances, especially in early
course of the disease (Lithium - effective in ↓core symptoms).
• Combination with mood stabilizer is superior.
• In bipolar pts - ↑ liability of EPSE then in schizophrenia pts.
• Haloperidol -
– Equivalent to risperidone, olanzapine
– Superior than quetiapine
– Inferior to aripiprazole
– But associated with treatment emergent dep. & greater EPSE
• Perphenazine - shorter time to depression relapse & more of 28

29. Second Generation Antipsychotics
• Higher affinity for 5HT2A > D2 receptors  ↓ liability for Extra
pyramidal side effects.
• Anti manic  may be due to partial agonism at D2 receptors.
• Anti depression  may be due to blockade of 5HT2Areceptors &
their down regulation.
• Noticeable effect - day 3 to 7.
• Depression improved significantly - Quetiapine, Olanzapine &
Risperidone.
29

30. Second Generation Antipsychotics
• Olanzapine- Equivalent to Lithium in efficacy. Efficacy is increased
as add on with Li/ Val.
• Risperidone- Superior as add on therapy to mood stabilizer.
Equivalent to Li/ Val monotherapy.
• Aripiprazole- DBRCT, multi center, 3 week, comparison of 30mg
with placebo Response rate of 40%,
• Ziprasidone- DBRCT, 3 week, 40-80 mg superior to placebo.
30

31. Depot Antipsychotics
• Non adherence in maintenance phase - 20-66%.
• Lithium discontinuation  28 fold increased risk of relapse
• Advantages -
– Adequate supply for weeks
– Maintains frequent contact with professionals
– ↓ freq & severity of manic symptoms
• Disadvantages - May worsen depression phase of
illness especially with FGA depot.
31

32. Olanzapine-Fluoxetine(OFC)
• OFC - 3/25, 6/25, 6/50, 12/25, 12/50 (FDA approved).
• India - 5/20 & 10/20 (mg olanzapine/mg fluoxetine).
• Probable rationale - flouxetine’s potent 5HT2C antagonistic
property adds on to olanzapine action.
• Tohen et al - 8 week, DBRCT, multi center study –
– OFC - response rate - 56%, remission rate- 48%, which is higher
than olanzapine mono therapy & placebo.
– Emergent mania rates were same as with placebo.
– Adverse events - somnolence, wt gain, ↑ appetite, nausea.
32

33. Quetiapine IR
• Supported by BOLDER (BipOlar DEpRession) I & II trails &
EMBOLDEN (Efficay of Monotherapy seroquel in BipOLar
DEpressioN) trails.
• BOLDER I & II - 8 week, DBRCT, comparing 300mg & 600mg,
significant improvement in MADRS scores over placebo.
• Response rates - 58% & Remission rates - 53%.
• EMBOLDEN- Quetiapine was significantly more effective than
Lithium in improving MADRS score at 8 weeks.
• Low incidence of emergent mania.
• Adverse effects - dry mouth, sedation, somnolence, dizziness &
constipation.
33

34. Lurasidone
• Approved as mono & adjunctive therapy.
• Supported by PREVAIL (PRogram to EValuate the Antidepressant
Impact of Lurasidone) 1 & 2 trail.
• PREVAIL 1- Evaluate efficacy as adjunctive to Lithium/
Valproate.
• PREVAIL 2- Evaluate efficacy as monotherapy.
• Primary analysis in both the studies showed statistically
significant reductions in MADRS scores.
• Response in 52% patients.
• Low incidence of emergent mania, alteration of lipid/ glycemic
parameters.
• Adverse effects - akathisia, nausea.
34

35. Antidepressants
• Do not stabilize mood, may worsen the outcome of the opposite
pole of the illness.
• All major guidelines advise use of mood stabilizer & recommend
only as 2nd
line, in concurrent with mood stabilizer.
• Current guidelines stress to use in short term & early
discontinuation.
• Inadequate data to favor one over the other.
• But at the same time no strong evidence to avoid them in severe
bipolar depression.
35

36. Antidepressants
• Conflicting evidence for efficacy against depressive relapse:
• Protective?:
– Altshuler L, et al¹ (retrospective, 39 pts, 1 year):
• 35% relapse rate with antidepressant continuation
• 68% relapse rate with antidepressant discontinuation
– Altshuler L, et al² (prospective, 84 pts, 1 year):
• 36% relapse rate with antidepressant continuation
• 70% relapse rate with antidepressant discontinuation
36

37. Antidepressants
• No benefit ?
 Frankle WG, et al (retrospective, 50 pts, 30 weeks)
No difference in length of depressive episode regardless of
antidepressant status
 Ghaemi S, et al (open, randomised 33 pts, 1 year)
Relapse rate 50% within 20 weeks regardless of antidepressant
status.
37

38. Antidepressants
• Antidepressants can be safe and effective
• Gijsman HJ, et al: Review of 12 RCTs in Bipolar Depression
(1,088 patients):
– Antidepressants more effective than placebo
– Switch rate - 3.8% for antidepressants and 4.7% for placebo
– Tricyclics had 10% switch rate vs. 3.2% for all other
antidepressants.
– Authors believe that it is overcautious & potentially not in the
best interest of patients to discourage the use of antidepressants
for bipolar depression.
38

39. ECT
• Clear from clinical experience that it an effective & rapidly acting
treatment for mania (Fink, 06). Response rate- 80% (Mukherjee et
al, 94 Winokur et al, 90)
• Studies have suggested that Mania responds to Right sided ECT &
Depression to Left sided ECT.
• Combined use of ECT & anticonvulsants are safe & also effective.
• Found to be safe in all trimesters of pregnancy.
39

40. repetitive Trans-Magnetic
Stimulation (rTMS)
• Grisaru et al, 98- Evaluated the efficacy of Right vs Left-sided rTMS
in manic pts taking various medications and found Right sided
produced more improvement in manic symptoms.
• Michael and Erfurth, 04- Administered Right-sided prefrontal rTMS
treatments, all patients had “sustained reduction of manic
symptoms.”
• Current clinical data on the use of rTMS to treat mania are scant
and preliminary but encouraging.
40

41. Experimental drugs
• Calcium channel blockers- Verapamil, Diltiazem showed mixed
responses.
• Nimodipine- Improvement in ultrarapid bipolar (Pazzaglia et al, 98)
• Magnesium sulphate- Improvement noted in severe, treatment
resistant manic episode (Heiden et al, 99)
• Tamoxifen- found to be effective in a small series of patients (Manji
& Chen, 02), probably because of its Phophokinase C inhibition.
• Ώ 3 Fatty acids, Eicosapentanoic acid (EPA)- Unknown benefit.
41

42. Summary of medications
Agent Manic Mixed Depressive Maintenance
Lithium
+
+ +
Divalproate + + +
Carbamazepine + +
Lamotrigine + +
Olanz/Floux +
Olanzapine + + +
Risperidone + +
Quetiapine + +
Aripiprazole + + +
Ziprasidone + +
Lurasidone +
ECT + + +/-
42

43. Special features- Psychosis
• Commonly seen during episodes of mania (> half of cases) >
depression.
• Mood congruent - predictive of better outcome.
• Mood incongruent - predictive of shorter time in remission.
• Usually does not require antipsychotic
medication.
43

44. Special features- Catatonia
• 1/3rd
of patients during manic episode.
• Most common symptoms - motor excitement, mutism, stereotypic
movements.
• Associated with greater episode severity, mixed state, poorer short
term outcome.
• Neuroleptics - Poor efficacy.
• Treatment - Lorazapam, ECT.
44

45. Special features- Suicide
• General risk factors of suicide- h/o suicide attempts, suicidal
ideation, comorbid substance abuse, personality disorder, agitation,
f/h/o suicide & impulsiveness.
• Risk - Depressive phase > mixed state & presence of psychotic
symptoms > manic phase.
• Lithium long term treatment - reduction of
suicide risk (probably due to anti impulsivity factor).
45

46. Special features- Substance
use disorder
• Comorbid substance use disorder - common presentation.
• Higher rates of substance use.
• Substance use-
– Exacerbate the mood swings.
– May precipitate the mood episodes.
– Associated with fewer & slower remissions.
– Greater suicidal rates/ attempts, poor outcome.
46

47. Special features- Substance
use disorder
• Substance use disorder is commonly overlooked in BPAD.
• Patients use substance to improve the mood status.
• Treatment - both should be treated concurrently.
• Should be watchful about the substance
use effects with the BPAD pharmacotherapy.
47

48. Special features - Comorbid
Psychiatric conditions
• Personality disorder
– Greater risk of intrapsychic & psychosocial stress.
– May exacerbate / precipitate mood episodes.
– Greater symptom burden, lower recovery rates, greater
functional impairment.
– Difficulty in adhering to long term treatment.
• Others - anxiety disorders (esp- panic, OCD), ADHD.
48

49. Special features- Pregnancy
• Medications used in BPAD - high risk of birth defects.
• Effective contraceptive practices.
• ↑ Metabolism of OCP’s - carbamazepine, oxcarbamazepine &
topiramate.
• Pregnancy must be planned in consultation with psychiatrist
49

50. Special features- Pregnancy
• Decision of continuation or discontinuation of treatment - discussed
with patient, obstretician & patient party.
• Options include -
– Continuation throughout pregnancy
– Discontinuation at the beginning of pregnancy
– Discontinuation only for 1st
trimester
• Potential teratogenic risks must be balanced against risk of no
treatment.
50

51. Special features- Pregnancy
• 1st
trimester exposure to Lithium, Valproate, Carbmazepine - ↑risk
of birth defects.
• Lithium - Ebstein’s anomaly, 1-2/1000 (approx- 10-20 times).
• Valproate & Carbamazepine -
– Neural tube defects (↑ by 3-5% & 1%).
– Cranio-facial abnormalities
– Limb defects, cardiac defects
• Relatively nil teratogenicity - TCA’s, SSRI’s (especially fluoxetine,
citalopram) 51

52. Special features- Pregnancy
• Antipsychotics - alternative to lithium/ valproate.
• High potency antipsychotic - haloperidol, perphenazine,
thiothixene, trifluperazine - less anticholinergic, antihistaminergic,
hypotensive effects.
• Neonates - EPSE, but short lived.
• Newer antipsychotics - little is known about teratogenicity.
• ECT - potential treatment option. 52

53. Paediatric Bipolar
Manic/ Mixed episode
•Lithium- 1st
drug to be approved by FDA for treatment of mania >12yrs.
Others are- Risperidone, Aripiprazole & Quetiapine >10yrs &
Olanzapine >13yrs.
•Liu et al, 11- SGAs are more efficacious than traditional mood
stabilizers & appear to yield quicker response.
•Response rate- Risperidone- 68%, Li- 35% & Divalproate- 24%.
•Partial/ Non response- Remove mood destabilizing agent, Optimise
treatment & switch or combine.
•Benzodiazepines as adjunctive drugs. 53

54. Paediatric Bipolar
Hypomania- no studies in children to specifically address the isuue.
Acute depression
•Mild to Moderate depression- Psychosocial interventions like CBT,
Family focused psychotherapy
•DelBello et al, Patel et al & Chang et al-
– Response rates of Li- 48%, Quetiapine- 71%, Lamotrigine- 84%,
Carbamezapine- 43%.
•Nivoli et al, 11- In children Quetiapine monotherapy & Olanzapine-
Floxetine in acute treatment and Lamotrigine in maintenance treatment
of bipolar depression are efficious as in adults. 54

55. Maintenance treatment
• Why ? - high risk of relapse for 6 months.
• Best evidence is for the use of - Lithium & Valproate.
• Medication with which remission is obtained should be continued.
• Maintenance ECT- if patient responded to ECT in acute episode.
• Incase of use of antipsychotic - reassess for the need.
55

56. Maintenance treatment
• How long ?-
• 2yrs - 1st
episode.
• Up to 5yrs - if frequent relapses/ severe psychotic episodes, co
morbid substance use, stressful life events, poor social support.
• Long term treatment –
• Manic episode associated with significant risk & adverse
consequences
• BPAD I with ≥ 2 episodes
• BPAD II with significant functional impairment.
56

57. Maintenance treatment
• Concomitant psychosocial interventions to address illness
management, adherence, lifestyle changes, early detection.
• Group therapy, Support groups can be tried.
• Sub-threshold/ Breakthrough episode - addition of another
medication/ antipsychotic/ antidepressant/ maintenance ECT.
57

58. References
1. Practice guideline for the treatment of patients with bipolar disorder. 2nd
edition.
Hirschfeld RMA, Bowden CL et al. APA guidelines, April 2002.
2. Manic-Depressive illness- Bipolar disorders and recurrent depression. 2nd
edition.
Goodwin FK & Jamison KR.
3. Bipolar disorder- A clinicians guide to treatment management. Lakshmi NY & Vivek K.
4. Clinical practice guidelines. Violence- The short term management of disturbed/violent
behaviour in IP psychiatric settings & emergency departments. NICE guidelines, Feb
2005.
5. IACAPAP Textbook of child and adolscent mental health. Joseph M Rey. 2012.
6. Antidepressants for Bipolar Depression: A Systematic Review of Randomized,
Controlled Trials. Gijsman HJ et al. Am J Psychiatry 2004; 161:1537–1547.
7. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials,
Sheena D & Andrew M, BMC Psychiatry 2007, 7:40.
8. Lurasidone as a potential therapy for bipolar disorder- Review, Young SW et al,
Neuropsychiatric Disease and Treatment 2013:9 1521–1529.
9. Treatment of bipolar disorder : a systematic review of available data and clinical
perspectives. Fountoulakis KN & Vieta E. International Journal of
Neuropsychopharmacology (2008), 11, 999–1029.
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