Download - Bipolar Disorder

BIPOLAR DISORDER

Dr. D. Phani Bhushan, Prof & H. O. D Department of PsychiatryNRI Medical College & GH

overview

• History

• Genetics

• Neuroimaging

• Neurobiology

• What is– Mania– Hypomania– Depressive episode

• Bipolar I disorder

• Bipolar ll disorder

• Cyclothymic disorder

• Rapid cycling

• Substance induced

• CANMAT guideline for BPAD

• Mood Stabilizers

• ECT in BPAD

BIPOLAR DIORDER

• Chronic, reclusive & recurrent major mood disorder

• Often misdiagnosed

• Has high rates of psychiatric & medical morbidity

• Has high risk of suicide

• Management can be a constant challenge

Historical perspective

• Known since Hippocrates times described mania and depression as “ amic and melancholic”

• Clear connections between mania and melancholia established only in 19th century by jules Baillarger

• Emil krapelin – Manic- depressive insanity

• 1st introduced in DSM-3(1980), ICD10 (1992)

Abraham Lincoln

Past US President

Winston Churchill

Past UK prime Minister

Colonel Gaaddafi

ExpresidentLibia

Bipolar people in history

Genetics

• Genome- wide association studies which are more powerful than linkage studies, have been used to assess for multiple causative disease genes

• Family, twin and adoption studies all support a significant genetic burden in bipolar disorder

• Genetic variants near the ADRENOMEDULLIN (ADM) gene on chromosome11 p15 may be specific to Bipolar II Disorder

…Contd

• Bipolar Disorder is phenotypically heterogeneous

• Lithium responders may have a unique genetic make-up that is distinct from that of individuals with other bipolar disorder

• Epigentetics( Gene expression) investigates gene and Environment (GXE) interplay.

Neuroimaging

• BPD associated with– lateral ventricle enlargement– White matter changes– ↓ in total cortical volume

• More evidence is emerging to support the use of imaging markers for the Diagnosis of BPD and for differentiation of BPD from UPD

Neuroimaging Contd

• Higher rates of Deep white matter hyperintensities

• Smaller Cerebral Cortex• Bigger Hippocampus and Basal Ganglia• Interplay between immune system and

BPD is very complex at multiple levels

Neurobiology

• Mechanism of mood stabilisers may involve the Inhibition of Cyclooxygenase-2( COX2)and or reduction in proinflammatory cytokines.

• BDNF crosses Blood –Brain barrier, its levels in serum are highly correlated with its levels in CSF.

• Peripheral BDNF may serve as a Biomarker of mood states and disease progression for Bipolar Disorder.

Neurobiology.

• Neurobiological correlates of BPD– Limbic hyperactivity– Frontal Hypoactivity

• Brain glutamate levels are elevated in BD patients- supports the idea that glutamate play an important role in the pathophysiology of BD

• Negative Effects of illness burden on Prefrontal NAA( n-acetyl aspartate). Li treated patients improve NAA levels to that of Healthy controls.

Manic Episode

• Period of –Abnormally & persistently elevated,

expansive, or irritable mood –abnormally and persistently increased

goal-directed activity or energy,• lasting at least 1 week and present

most of the day, nearly every day (or any duration if hospitalization is necessary).

Three or more of

1.Inflated self-esteem or grandiosity.2.Decreased need for sleep 3.More talkative than usual or pressure to keep

talking.4.Flight of ideas or subjective experience that

thoughts are racing.5.Distractibility 6.Increase in goal-directed activity, psychomotor

agitation 7.Excessive involvement in activities that have a high

potential for painful consequences (buying sprees, sexual indiscretions, or foolish business investments)

• Causing marked impairment in social or occupational functioning

• not due to the physiological effects of a substance or to another medical condition.

Hypomanic Episode• A distinct period of abnormally and persistently

elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and present most of the day, nearly every day.

• The episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization. If there are psychotic features, the episode is, by definition, manic.

• The episode is not attributable to the physiological effects of a substance, Other medical Condition.

Major Depressive EpisodeFive or more of in two week period1.Depressed mood most of the day( feels sad, empty, or hopeless tearful). 2. Markedly diminished interest or pleasure in almost all activities3. Significant weight loss or weight gain ( a change > 5% of body weight in a month4. Insomnia or hypersomnia.5. Psychomotor agitation or retardation 6. Fatigue or loss of energy 7. Feelings of worthlessness or excessive or inappropriate guilt 8.Diminished ability to think or concentrate, or indecisiveness, nearly every day 9. Recurrent thoughts of death (recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide)

• The symptoms cause impairment in social, occupational, or other important areas of functioning.

• Not attributable to substance or another medical condition.

Unipolar vs Bipolar

Bipolar depression was associated with

•Bipolar family history.

•Earlier age of onset.

•Greater number of previous depressive episodes.

•Co morbities were more common in bipolar depression.

•Atypical features.

•Loss of response during antidepressant treatment.

Bipolar I Disorder

• at least one manic episode

• not better explained by schizoaffective disorder, schizophrenia, schizophreniform disorder, delusional disorder or other specified or unspecified schizophrenia spectrum and other psychotic disorder

• Severity– Mild, Moderate and Severe

Modifiers

• Anxious distress• Mixed features• Rapid cycling • Melancholic features • Atypical features • Mood-congruent psychotic features • Mood-incongruent psychotic features • Catatonia • Peripartum onset• Seasonal pattern

Bipolar I disorder

• Prevalence rate- 0.6%

• Male to female ratio – 1.1:1

• Mean age of onset 18 years

• Late onset manic Sx -suspect medical condition

• More common in high income countries than low income countries

• Females more likely to express rapid cycling and mixed episodes and depressive episodes

• 15 times more suicide risk than genral population

Differential Diagnosis

• Major Depressive Disorder

• Other Bipolar disorders (1)

• Anxiety disorders– GAD, Panic Disorder, PTSD,

• Substance/ medication Induced

• Attention- Deficit/ Hyperactivity Disorder

• Personality Disorder

• Disorders with prominent irritability

Bipolar II Disorder

• Hypomania + Depressive Episode• Never been a Manic Episode• 12 month prevalence 0.3 %• Average age of onset mid 20s• Most often begins with depressive episode• Risk is high among relatives of Bioplar II

disorder• Suicide risk in bipolar II > Bipolar I• Most of patients become functional in between

episodes

Differential Diagnosis

• Major Depressive disorder

• Cyclothymic Disorder

• Schizophrenia spectrum & other related psychotic disorder.

• Panic or other anxiety disorder

• Substance use disorder

• ADHD

• Personality Disorder

Cyclothymic Disorder

• Numerous periods of hypomanic Sx that do not meet criteria for hypomanic episode

• Numerous periods with depressive Sx that do not meet criteria for a major depressive episode

• Duration- 2 years ( 1 year in children and adolescents)

• Sx not due to drugs/ other medical condition

• Significant impairment in social and occupational functioning

Rapid Cycling

• Four or more distinct episodes of mania, hypomania, or depression within a 12-month period.

• Risk factors: – Female– Antidepressant use– Younger age of onset– Thyroid disease (overt

or subclinical)

• Good response with valproate rather than Li

• Avoid antidepressants

• First line– Valproate in Bipolar 1– Lamotrigine in Bipolar

II

Reccurent Depressive Disorder

• Repeated Episodes of Depression

• With out any history of Independent episodes of mood elevation or over activity that fulfill the criteria Mania.

Substance induced

• Alcohol

• Phencyclidine and other hallucinogens

• Sedative,hypnotic & anxiolytic

• Amphetamine or Other stimuli

• Cacaine

Bipolar Disorder types

Bipolar 0 disorder Schizophrenia

Bipolar 1/2

disorder Schizobipolar disorder

Bipolar I disorder "Classic" bipolar disorder

Bipolar I 1 /2 Depression with protracted hypomania

Bipolar II disorder Hypomania plus major depressionBipolar II1/2 disorder

Depression superimposed on cyclothymic temperement

Bipolar III disorder Recurrent depression plus hypomania occurring solely in association with antidepressant or other somatotherapy

Bipolar III 1/2 Mood swings that persist beyond stimulant and/or alcohol abuse

Bipolar IV disorderDepression superimposed on a hyperthymic temperament

Bipolar V disorderRecurrent depressions without discrete hypomania, but mixed hypomanic episodes (irritability/agitation/racing thoughts) during depression

Bipolar VI Disorder

Bipolarity in the frame of dementia

Management

• Management involves treatment of acute episodes & maintenance therapy

• After the resolution of acute episodes, maintenance treatment is aimed at prevention of future episodes

• When a 1st line treatments are unsuccessful try alternate first line treatments before proceeding to 2nd line Rx

• Judicious use of psychosocial interventions, alternate somatic treatments such as ECT, and the numerous experimental agents offer additional promise for management of Bipolar Disorder

CANMAT GUIDELINES FOR BPD

• Introduction• Foundations of management• Acute management of bipolar mania• Acute management of bipolar depression• Maintenance therapy for bipolar disorder• Special populations• Acute and maintenance management of bipolar II

disorder• Safety and monitoring•

Criteria for Rating strength of Evidence

1 Meta analysis or replicated double blind( DB), Randomized controlled trial ( RCT) that include placebo as control

2 At least one DB- RCT with placebo or active comparison condition

3 Prospective uncontrolled trial with at least 10 or more subjects

4 Anecdotal reports or expert opinion

Treatment Recommendations

1st line Level 1 or level 2 evidence plus clinical support for efficacy and safety

2nd line Level 3 evidence or higher plus clinical support for efficacy and safety

3rd line Level 4 evidence or higher plus clinical support for efficacy and safety

Not Recommended

Level 1 or 2 evidence of lack of efficacy

Acute mania Phrmacotherapy

1st line 2nd line 3rd line

Mono therapy:LithiumDivalproexOlanzapineRisperidoneQuetiapineAriparazoleZiprasidoneAsenapinePaliperidoneAdjunctive therapy with Li or DivalproxRisperidoneQuetiapineAripaprazole

MonotherapyCarbamazepineCarbamazepine ERECTHaloperidolCombination TherapyLi + Divalproex

MonotherapyChlorpromazineClozapineOxcarbamazepineTamoxifenCariprazineCombination therapyLi/ Divalproex + haloperidolLi+ Carbamazepine, adjunctive tamoxifen

Not Recommended MonotherapyGabapentin,Topiramate,lamotrigine,verapamil, TiagabineNot Recommended Combination TherapyRisperidone+ Carbamazepine, Olanzapine + Carbazepine

Acute bipolar I Depression


Mono therapy:LithiumLamotrigineQuitiapineQuitiapine XRCombination TherapyLi or Divalprox + SSRIOlanzapine + SSRILi + DivalproexLi or Divalproex + Bupropion

MonotherapyDivalproexLurasidoneCombination TherapyQuitiapine+SSRI, adjunctive modafinilLi / Divalproex + LamotrigineLi / Divalproex + Lurasidone

MonotherapyCarbamazepineOlanazapineECTCombination therapyLi+ Carbamazepine, Li + PramipexoleLi / Divalproex +venlafaxineLi + MAOI, Li/ DV +AAP +TCA,Li / Divalproex / Carbazepine + SSRIQuitiapine +Lamotigine

Not Recommended MonotherapyGabapentin,Aripaprazole, ZiprasidoneNot Recommended Combination TherapyAdjunctive ziprasidone, adjunctive levitricetam

Acute bipolar II Depression


QuitiapineQuitiapine XR

LiLamotrigineDivalproexCombination TherapyLi / Divalproex + antidepressantsLi / Divalproex + atypical antipsychotics + antidepressants

MonotherapyAntidepressants

Combination therapyQuitiapine +LamotigineAdjunctive ECT, N- acetyl cysteine, T3,

Maintainance of Bipolar Disorder


Mono therapy:LithiumlamotrigineDivalproexOlanzapineRisperidoneQuetiapineAriparazoleAdjunctive therapy with Li or DivalproxRisperidoneQuetiapineAripaprazoleziprasidone

MonotherapyCarbamazepinePaliperodoneCombination TherapyLi + DivalproexLi + CarbamazepineLi/ Divalproex + OlanzapineLi + ResperidoneLi + lamotrigineOlanzapine +Fluoxetine

MonotherapyAsenapineAdjunctive therapyPhenytoinClozapineECTTopiramateOmega 3 fattyacidsOxcarbazepineGabapentinasenapine

Not Recommended MonotherapyGabapentin,Topiramate, antidepressantsAdjunctive TherapyFlupenthixol

Maintainance Rx of Bipolar II Disorder


LithiumLamotrigineQuitiapine

LiDivalproexCombination TherapyLi / Divalproex /atypical antipsychotic+antidepressantsAdjunctiveQuitiapineLamotrigine

CarbamazepineOxcarbazepineAtypical antipsychotic agentECTFluoxetine

Not RecommendedGabapentin

Mood stabilizers

• Lithium

• Anticonvulsants– Valproic acid– Carbamazepine– Oxcarbamazepine– Lamotrigine– Topiramate– Zonisamide– Gabapentin– Pregabalin

• Atypical antipsychotics– Risperidone– Olanzepine– Quetiapine– Ziprasidone– Aripiprazole

• Other agents– Benzodiazepines– Omega 3 fatty acids– Thyroid hormone

Lithium

• used for short-term, long-term, and prophylactic management

• as an adjunctive medication in the treatment of major depressive disorder.

• Lithium is rapidly and completely absorbed after oral administration and is excreted through kidneys.

Usual Dosage Range• 1800 mg/day in divided doses (acute)• 900–1200 mg/day in divided doses (maintenance)

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• Mechanism of action through Neurotropic properties.

• Supposed to act through modulating G- proteins or inhibiting 2nd messenger such as Inositol mono phosphate which effect signal transduction for neurotransmitters.• Lithuim efficacy is best established for treating and

preventing mania than depression• It is also effective in preventing Suicide• Less effective for Rapid Cycling or mixed episodes

Adverse Effects

• GI side effects like Nausea and Vomitting

• Weight gain • Tremor

– usually 8 to 12 Hz • Renal-

– Diabetes insipidus– Interstitial fibrosis.

• Thyroid– Hypothyroidism

• Cardiac – Resembles like

Hypokalemia on EKG– T wave flattening /

inversion

• Dermotologic – Acneiform, follicular

and Maculopapular eruptions, pretibial ulcerations

– Worsening of Psoriasis48

Li in special population

• Elderly persons should initially be given low dosages, their dosages should be switched less frequently than are those of younger persons.

• Li administered in 1st trimester of pregnancy child is prone to Cardiovascular anomalies (most common- Ebstein’s anomaly)

• Lithium is excreted into breast milk and should be taken by a nursing mother only after careful evaluation of potential risks and benefits.

• Li is Contraindicated in Cardiac and Renal Patients 49

SODIUM VALPROATE

• Used for – Acute mania– Mixed episodes– Seizure Disorder– Migraine prophylaxis

• Metabolised by Liver– Hepatic

glucoronidation– Mitochondrial Beta

oxidation

• Therapeutic action due to Enhancemnet of GABA ,Glutamate and modulation of Na+ and Ca+2 chanells

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SODIUM VALPROATE

• Better tolerated than li or carbamazepine • Adverse effects-teratogenicity and hepatotoxicity,

pancreatitis, thrombocytopenia and somnolence in elderly.

• PCOD, weight gain , hirsutism, alopecia.• Contraindicated in Patients with Hepatic failure and frequent

monitoring of Liver function tests in 1st few months of treatment.

CARBAMAZEPINE

•Mood stabilizer•Antiepileptic•Trigeminal neurolgia •Auto inducer- increares its own metabolism by inducing cytochromal enzymes•On Chronic administration T1/2 devreases from 26 to 12 hours

• Acts on GABA, Na+, Ca+,k+.with particular site of action on ἀ unit of Na Chanell.

Adverse Events

• Dosage-Related :– Double/ blurred vision, – Vertigo,– GI distrubances – Hematologic effects

• Idiosyncratic:– Agranulocytosis– Aplastic aneamia– Maculo popular Rash– Steven-jonhsons

syndrome– Hepatic failure– Pancreatitis

• Watch for fever, sore throat, rash,petechiae, bruising, and easy bleeding

• Steven jhonson syndrome discontinue the drug start Prednisolone.

• Secreted renally lower dose in Renal impairment

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Drug Interactions

Cytochrome enzyme inducer

•decreases the blood concentrations of oral contraceptives, resulting in breakthrough bleeding and uncertain prophylaxis against pregnancy.

• should not be administered with monoamine oxidase inhibitors (MAOIs), which should be discontinued at least 2 weeks before initiating treatment with carbamazepine. .

•When carbamazepine and valproate are used in combination, the dosage of carbamazepine should be decreased, because valproate displaces carbamazepine binding on proteins, and the dosage of valproate may need to be increased.

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OXCARBAMAZEPINE-

• May be effective in acute mania.

• Dosages are 50% higher than carbamazepine.

• Starting 300-600mg/d, increasing 300mg/d and max. 900-2400mg/d.

• Better tolerated than carbamazepine, less neurotoxicity and rash, less induction of enzymes.

• Adverse Effects-– ataxia,– rash,– hyponatremia.

LAMOTRIGINE

• uses– maintenance treatment

particularly preventing depressive episodes

– Acute bipolar depression– Rapid cycling disorders– Treatment resistant mood

disorders.

• Adverse Effects– Rash.

• Drug interactions– Significant and well

charecterised interactions with other anti convusants

– Valproate ↑ lamotrigine levels in serum

– Lamotigine ↓ valproate levels by 25%

– Carbamazepine, phenytoin phenobarbital ↓ lamotrigine concentrations

Topiramate

• Bipolar Disorder

• Alcohol / smoking Deaddiction

• Seizures

• Migraine Prophylaxis

• Possible actions on GABA, Glutamate,Ca+ and NA+ Channels

• Also a weak Carbonic anhydrase inhibitor

Topiramate

• Adverse effects– Metabolic acidosis– Secondary narrow angle glaucoma

• Use with caution in Cardiac and hepatic impairment

• Excreted by kidney lower the dose in renal impairment

Atypical antipsychotics

• Risperidone(2-6mg)• Paliperidone(3-12mg)• Olanzapine(10-20 mg)• Quetiapine(400-800mg)• Ziprasidone(80-160mg)• Aripiprazole(15-30mg).

• Atypicals are highly preferred over typicals because of low risk of EPS.

• Risk of weight gain ,metabolic side effects with atypicals.

• Clozapine & olanzapine high risk for weight gain followed by risperidone & quitiapine.

• Ziprasidone & aripiprazole are weight neutral.• Children & adolescence are more susceptable to EPS

and other side effects of atypicals than are adults.

Electroconvulsive therapy-

• Patients with treatment refractory bipolar depression or in those who are suicidal, ECT remains the best option.

• Also useful in pregnant women with severe bipolar depression.

• Risk of memory impairment, acute confusion.• Anticonvulsants are withdrawn prior to ECT

Prophylaxis in BPAD

• Lithium

• Valproate

• Carbamazepine

• Lamotrigine

• Atypical antipsychotics.

• Gabapentin/topiramate.

• Calcium channel blockers.

Bipolar disorders in child and adolescence-

• Extreme irritablity that is severe & persistent and may include aggressive outbursts and violent behavior.

• In between outbursts children may continue to be angry or dysphoric.

• High rates of comorbid ADHD, conduct disorder, anxiety disorder.

• Treatment-mood stabilizers, antipsychotics.

• Stabilize mania before treating comorbid ADHD.

BIPOLAR DISORDER IN WOMEN

• Bipolar II and rapid cycling more in women.• More depressive and mixed episodes.• Higher risk of antidepressant induced mania.• Risperidone and typical antipsychotics –

significantly elevated prolactin levels.• Valproate- risk of PCOD.• Carbamazepine- decrease efficacy of OCP’s.

PREGNANCY

• Pregnancy itself does not have a therapeutic or preventive effect on episode recurrence.

• Discontinuation of medications during pregnancy decreases the duration of recurrence latency.

• Teratogenic effects- valproate>carbamazepine>lithium>lamotrigine.

• Pharmacotherapy should be avoided particularly first trimester.

• Folate supplementation 3 months before conception reduces risk of neural tube defects.

• ECT may be useful.

LACTATION

• Breast feeding while taking lithium is not recommended

• Breast feeding while taking valproate, carbamazepine, lamotrigine or atypical antipsychotics can be cautiously considered with careful monitoring of the infant and if necessary obtain infant blood drug levels.