Management of

BiPolar Disorder(Phamacological)

Dr.D.Raj Kiran & Dr.M.Dattatrey Dept. of PsychiatryKIMS, Narketpally

Zonal PG CME, DCMS 23rd Aug 2015

1

Outline

• Introduction• Investigations • Emergency management• Acute management

– Manic or Mixed episode– Depressive episode– Rapid cycling

• Brief note on drugs• Special conditions• Maintenance treatment

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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

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

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

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.

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Emergency treatment

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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

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.

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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

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

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.

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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

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

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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

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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.

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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.

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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.

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Rapid cycling

Suggested algorithm (Yatham et al)• Allow every new treatment/ combination sufficient time to exhibit its

efficacy.

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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

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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

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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

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

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.

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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

Lamotrigine

Trial Study arms N Response rate in percentage

HAMD MADRS CGI

Calabrese, Bowden, Sachs et al, 99

LTG 50mgLTG 200mgPlacebo

666666

455137

485429

415126

Brown EB et al, 06

LTGOFC

205205

--

59.768.8

64.471.8

- 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

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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

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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 EPSE. 28

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 5HT2A receptors & their down regulation.

• Noticeable effect - day 3 to 7.

• Depression improved significantly - Quetiapine, Olanzapine & Risperidone.

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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.

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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.

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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.

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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

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.

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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.

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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

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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.

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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.

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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.

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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.

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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.

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Summary of medications

Agent Manic Mixed Depressive Maintenance Lithium

++ +

Divalproate + + +Carbamazepine + +Lamotrigine + +Olanz/Floux +Olanzapine + + +Risperidone + +Quetiapine + +Aripiprazole + + +Ziprasidone + +Lurasidone +ECT + + +/- 42

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.

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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

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).

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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.

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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.

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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.

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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

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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.

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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)

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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

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

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.

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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.

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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.

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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.

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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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