BIPOLAR DISORDER

Indra Singh MD

Burden of the disease

Bipolar Disorder (BD)is an episodic, potentially life-long, disabling disorder

Characterized by Mood elevation Associated with significant Morbidity

and Mortality if untreated Often underdiagnosed.

Epidemiology

Lifetime prevalence BD I : 1.0% BD II : 1.1 %

Gender: BPD I : Affects men and women equally BPD II : is more common in women

Age of Onset : 15-30 years

Genetics

Lifetime risk in relatives of BD probands is 40-70% for MZ twins 5-10% for a first degree relative 0.5-1.5 % for an unrelated person

Linkage studies implicate TPH2 gene

No candidate gene identified

Diagnostic criteria

BD I Episodes of Mania Often have depression

BD II One or more depressive episodes At least one episode of hypomania

Manic episode

Persistently elevated or irritable mood, lasting at least 1 week

3 additional sx in the same period affecting• self-esteem • sleep • Speech• Thoughts• Attention• PMA • Functioning

Hypomania

Unlike Mania shorter duration of manic symptoms (at

least four days), less severe level of symptoms. Absence of Psychoses mild functional impairment Often does not often lead to

hospitalization;

Depression

Dx requires 5/9 sx during the same period

with one must be either depressed mood or loss of interest.

Symptoms should be present daily or for most of the day for at least two weeks.

The symptoms must cause clinically significant distress or impairment in functioning,

Unipolar v Bipolar depression

Patients with Bipolar depression more likely to have Family hx of BD Early age of Onset

Pts. Presenting with depression should be asked about past Mania or Hypomania

Mixed Presence of both depressive and mood elevated

sx simultaneously. May thus occur with bipolar I or bipolar II

disorder. The frequency is estimated between 20 and 70 % The most common symptoms were

irritability, racing or crowded thoughts, psychomotor agitation, or increased talkativeness concurrent with symptoms of depression.

BD

3 SUBTYPES BD I

At least 1 manic episode Major depression frequent, but not required

for dx BD II

One hypomanic + at least 1 episode of major dep

BD NOS Features do not meet criteria of BD I or II

Course of BD

90% of pt.'s with BD have at least one psych hospitalization

Course influenced by high rates of comorbid alcohol or substance abuse.

Comorbid anxiety disorder is also common

Suicide rates are high Rapid Cycling if four or more mood

episodes occurred during the previous 12 months

Course of BD

BD I marked by relapses and remissions, often alternating manic with depressive

episodes. Ninety percent of individuals have a second

manic episode within five years Depressive sx frequent over the course of

bipolar disorder than manic sx 3 x more frequently than mania in BD I 37 x more frequently than hypomania in BD

II

BD

Assessment and Rx for Mania Hypomania MIxed

Clinical Assessment

Medical comorbidity Psychiatric comorbidity Psychosocial Stressors Medications current and past Suicide risk Substance Use

Assessment Stop Anti Depressants

Beware of discontinuation syndromes symptoms

Dizziness Headache Paresthesias Nausea Diarrhea Insomnia Irritability

Reasons for Hospitalization

Delirium Marked psychotic symptoms Severe mania Suicidality or homicidality Potential for violence

ideas / intent to harm others; hx of violent behavior; severe agitation or hostility; active psychosis

Substance withdrawal or intoxication

GOALS FOR Rx

Acute Phase Focus on managing Sx and pt. safety Hospitalization often necessary

Continuation phase remission of symptoms is preserved The goal is to prevent relapse of the mood

episode. maintenance phase

and aims to prevent recurrence of a new mood episode.

Long-term or lifetime maintenance is recommended for patients who have suffered one manic episode

Rx Principles for Mood Elevated Syndromes

Assess for risk of suicide, aggressiveness, and violence to others.

Discontinue ADs Reduce their use of alcohol, caffeine,

and nicotine. In breakthrough episode assess for

adherence to Rx Treatment of mood elevated syndromes

is based upon studies in BD I

Acute Phase

Drugs used to induce remission Lithium  Anticonvulsants Antipsychotics

allow up to two weeks before determining the drug’s clinical effectiveness.

Acute Phase

• Efficacy mostly similar across first line medications

With or without Psychoses Mania or mixed With or without rapid cycling

•Response independent ofLifetime number of episodesHx of lifetime comorbid SUD

Acute Phase

If no remission within 2 weeks Switch

If no response

Add If partial response

Goal of Rx is full remission

Choice of Drug Overall First line drugs have better response than

placebo Efficacy similar across first line medications Lithium associated with reduced risk of suicide

attempts Monotherapy maybe sufficient for less severely ill

patients Combination therapy frequently for pts with

manic or mixed episodes Combination therapy is

Li + Antipsychotic Valproate + Antipsychotic

Choice of Drug

Past response to medications Side-effect profiles Comorbid medical illness Pregnancy Concurrent medications Cost

Lithium More controlled trials demonstrating the efficacy

of lithium monotherapy than any other medication

The starting dose of lithium is usually 300 mg BID

increased by 300 to 600 mg every 3-5 days Serum level

target 0.8 and 1.2 meq/L measured five to seven days after each dose increase. levels should be drawn 12 hours after the last dose

Check s Cr, Cr Cl, TFTs, CBC D annually

Lithium Acute side effects include

nausea, tremor, polyuria and thirst, weight gain, loose stools, and cognitive impairment Severe or a sudden worsening of side effects may be a sign

of lithium toxicity. long term adverse effects of lithium involve

the kidneys and thyroid gland. cardiac rhythm disturbances almost always occur in patients

with preexisting cardiac disease.

LITHIUM TOXICITYLithium conc. s/s of toxicity Management

1.2 -1.5 mEq/L Worsening tremor, n/v, diarrhea, drowsiness

Hold lithium till serum conc. Returns to normal

1.6 .2.5 meq/L Coarse tremors, apathy, drowsiness, slurred speech, ataxia, increase in s.creatinine

Hold lithium, repeat levels, assess electrolytes and renal fx, may require admission

> 2.5 mEq/L Medical emergencyn/v, diarrhea, involuntary movements, dysarthria, coarse tremors, delirium, sz, coma

Admit inpt.

Lithium drug interactions

Increase Li conc Decrease Li conc Neurotoxicity

ThiazidesLasixCaffeineDesmopressinACEIsARBsNSAIDReduced Na intake

TheophyllineVerapamilOsmotic diureticsNa bicarb antacidsIncreased Na intake

AntipsychoticsCarbamazepineMethyldopaSSRIsMAOIsVerapamil

VALPROATE starting dose of 250 mg 2-3 times per day. Increased by 250 mg - 500 mg every 1-3 days to

reach a therapeutic serum level, Oral loading and rapid titration to a full dose within

one to two days by prescribing 20 mg/kg/day Target serum level between 50 and 125 mcg/mL.

Levels should be drawn 12 hours after the last dose

efficacy increased as serum levels increased Levels should be checked at 6 to 12 month

intervals. Annual CBC D, LFTs, BMP

Valproate

Common side effects include weight gain, nausea, vomiting, hair loss, easy bruising, and tremor. Divalproex is generally used rather than

valproate to minimize gastrointestinal distress. Hepatic failure and thrombocytopenia have rarely

been associated with valproate use; liver function tests and platelets should be

monitored at 6 to 12 month intervals in all patients taking the drug

Carbamazepine

Starting Dose 100 mg to 200 mg 1-2 times per day,

Increase dose by 200 mg every 1-4 days, to a final dose of about 800 to 1000 mg per day,

effective dose range 200 and 1800 mg per day.

Therapeutic serum levels have not been established for BD.

However, many clinicians use levels established for treatment of epilepsy: 4 to 12 mcg/mL.

Atypical APs

Olanzapine Start 10-15mg /day Max 20 mg daily Side effects include

Somnolence dry mouth Dizziness Weight gain

Monotherapy or combination with Li/Depakote

Risperidone

Start 1mg BID Increase to 6mg/day Onset of action between 1-6 days Mono or combination therapy Side effects

Somnolence EPSE

Ziprasidone

Start 40mg BID Max 80mg BID Onset of action at day 2 Monotherapy Side effects:

Nausea Akathisia tremors

Aripiprazole

Start 15mg/day Max 30mg /day Mono or combination therapy Separates form placebo by day 4 Side effects

N/V insomnia akathisia

Quetiapine

100mg day 1 Up to 800mg daily Superior to placebo at day 21 Side effects

Dry mouth Dizziness Weight gain somnolence

Metabolic effects of Atypicals

Weight gain Clozapine and olanzapine : most wt.

gain Risperidone and Quetiapine : moderate Aripiprazole and Ziprasidone : minimal

Hyperlipidemia DM

Monitoring parameters

Weight and BMI Baseline, 2, 8 and 12 weeks then @ 3 months, annually

Waist circumference Baseline, annually

BP Baseline,12 weeks,anually

Fasting Plasma Glucose Baseline,12 weeks then annually

Fasting Lipid Profile Baseline,12 weeks, every 5 years

Pregnancy test Baseline

Effective Meds in Bipolar Mania/Hypomania or Mixed Episodes

Likely Beneficial Unlikely to be Beneficial or Maybe Harmful

Mania Lithium, valproate,carbamazepine,Atypical APsCombining (lithium orvalproate) with Atypical APs

GabapentinLamotrigineTopiramateAD Monotherapy

Mixed Episode Valproate, carbamazepine,aripiprazole, olanzapine,risperidone, or ziprasidone

Gabapentin Lamotrigine Topiramate

Acute Phase

Reassess every 1-2 weeks for 6 weeks Monitor treatment response at 4 to 8

weeks after initiation of treatment, after each change in treatment, and periodically until full remission is achieved.

Remission In Mania : if free from significant symptoms

for two months In Mixed episode : if free from significant

symptoms of mania or depression for 2 months

Continuation Phase

Check for Compliance. Assessment of ADR. Monitoring of serum concentration Monitor for metabolic syndrome for

those on Atypical APs Assess for improvement or change of

the core symptoms of mania and mixed Careful risk assessment for those with

s/i.

BD

Rx for Bipolar depression

Acute Phase Rx for BD Depression

Monotherapy Lithium Lamotrigine Quetiapine Olanzapine +/- fluoxetine

Combination Strategies Li+ Lamictal Augmentation with ADs for short term

Effective meds in BD depression

Likely Beneficial Unlikely to be beneficial

LithiumQuetiapineLithium with lamotrigine

AbilifyNeurontinAD Monotherapy

Goal of Maintenance Therapy

reduce residual symptoms, delay and prevent recurrence of new

mood episodes, reduce the risk of suicide, and enhance psychosocial functioning.

Indications of Maintenance

BD I BD II BD NOS

Medications for Maintenance

Lithium Lamotrigine Risperidal Consta 2nd line

Depakote Aripiprazole Olanzapine