ByDr. Maged Al Adrousy Lecturer of psychiatry- Cairo university

introduction

Bipolar disorder is an episodic, potentially life-long, disabling disorder that can be difficult to diagnose.

known as Manic Depression, Results in pathological mood swings from mania to depression, These mood swings occur spontaneously.

Euthymia

Mania

Depression

Euthymia

Mania

Depression

History Bipolar Disorder

200 CE First reports 1654 Jean Pierre Falret

“folie circulaire" (circular insanity) Familial illness

1913 Emil Kraepelin Manic - Depressive

1930’s ECT first used 1949 Lithium first used 1950 Chlorpromazine first used 1952 Genetic link recognized 1980 Bipolar Disorder term adopted 1995 Depakote approved for BP 2003 First atypical approved for BP

Types of Mood Disorders

DSM IV Major Depressive

Disorder Dysthymic Disorder Bipolar Disorder Type I Bipolar Disorder Type II Cyclothymic Disorder NOS

Mixed Phase Rapid Cyclers Bipolar Spectrum (BPS)

86%

2%

2%

10%

MDD

BP I

BP II

NOS

50%

2%15%

33% MDD

BP I

BP II

BPS

Bipolar disorder is a cyclical mood disorder Abnormally elevated mood or irritability

alternates with depressed moodbipolar I – at least one manic or mixed episodebipolar II – at least one major depressive episode

and at least one hypomanic episodeCyclothymia = hypomania with “minor” depression“Bipolar spectrum” = Depression + other

complexities Bipolar NOS or Mood DO NOS

Structure of a Recurrent Illness

Underlying illness

Precipitant

Episode

Spectrum of Illness Course

Purely episodic course:-interepisode stability-no mixed states-infrequent episodes-good recovery-low incidence of complications

Radical mood instability:-’interepisode’ instability -mixed states-frequent episodes-incomplete recovery-high incidence of complications-early onset-stronger genetic loading?

Episodic Unstable

Course of illness dictates response strategies for the acute episode

DIAGNOSTIC CRITERIA FOR MANIC EPISODES

THREE TO FOUR OF THE FOLLOWING CRITERIA ARE REQUIRED DURING THE ELEVATED MOOD PERIOD

Highly inflated or grandiose self-esteem

Decreased need for sleep, or rested after only a few hours of sleep

Pressured speech

Racing thoughts and flight of ideas

Easy distractibility, failure to keep attention

Increased goal-directed activity

High excess involvement in pleasurable activities (sex, travel, spending money)General criteria for a manic episode require a period of

elevated, expansive, or irritable mood that lasts 1 week or requires hospitalization. A general medical condition and substance abuse must be ruled out before these symptoms are considered mania.

Manic Episode: Differential Diagnoses

Differential diagnosis Consider if . . . Mood disorder due Mood disorder due to a general medical to a general medical conditioncondition

Substance-inducedSubstance-inducedmood disordermood disorder

Hypomanic episodeHypomanic episode

Mixed episodeMixed episode

Major medical condition Major medical condition present present

First episode at >50 years of First episode at >50 years of ageage

Symptoms in context of Symptoms in context of intoxicationintoxicationor withdrawalor withdrawal

History of treatment for History of treatment for depressiondepression

Mood disturbance not severeMood disturbance not severeenough to require enough to require hospitalizationhospitalizationor impair functioningor impair functioning

Manic episode and MDE in 1 Manic episode and MDE in 1 weekweek

Manic Episode: Differential Diagnoses (cont.)

AD/HDAD/HD Early childhood mood disturbance Early childhood mood disturbance onset onset

Chronic rather than episodic courseChronic rather than episodic course

No clear onsets and offsets No clear onsets and offsets

No abnormally elevated moodNo abnormally elevated mood

No psychotic features No psychotic features

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). 4th ed. 1994.

Differential diagnosis Consider if . . .

Depressed mood and/or loss of interest

or pleasure 2 weeks duration Associated symptoms

Physical: insomnia/hypersomnia, appetite/weight change, decreased energy, psychomotor change

Psychological: feelings of guilt or worthlessness, poor concentration/indecisiveness, thoughts of death/suicidal intentions (SI)

Major Depressive Episode: DSM-IV Criteria

…and 4 of the following symptoms

Physical Sleep disorder Appetite change Fatigue Psychomotor

retardation

Psychological Low self

esteem/guilt Poor

concentration/indecisiveness

Thoughts of death/SI

Mixed Episode: Diagnostic Criteria Criteria met for both manic episode

+ MDE for 1 week Symptoms

Are sufficient to impair functioning or

Necessitate hospitalization or

Are accompanied by psychotic features

Epidemiology

Peak age of onset: adolescence through early 20s Onset of first manic episode after age 40 years is

“red flag” to consider substance use or general

medical condition

Lifetime suicide rates range from 10% to 15%

Seasonal variation Depression more common in spring and autumn Mania more common in summer

Characteristics BPD I BPD II

Prevalence 1.6% 0.5%

Ethnic/racial differential None None

Gender differential M = F F›M (?)

Bipolar Disorders: Epidemiology

Characteristics BPD I BPD II

Bipolar Disorders: Epidemiology

Hypomanic episodes in BPD II immediately precede or follow MDEs in 60% to 70% of cases

First-degree relatives may have increased rates of BPD I, BPD II, and MDD

Recurrent in >90% of cases

First-degree relatives have increased rates of BPD I, BPD II, and MDD

Course

Familial pattern

Diagnostic Dilemmas: Unipolar Versus Bipolar

No evidence of hypomania, cyclothymia, hyperthymic personality, or family history of BPD1 manic episodeRecurrent major depression with hypomania and/or cyclothymic temperament

Recurrent major depression without spontaneous hypomania but often with hyperthymic temperament and/or family history of BPD

Unipolar

BPD IBPD II

BPD NOS

Bipolar vs unipolar

BD II

CYCLOTHYMIC DISORDER

Cyclothymic disorder is a recurrent, chronic, mild form of bipolar disorder in which mood typically oscillates between hypomania and dysthymia.

If a manic episode or depressive episode is experienced, cyclothymic disorder is not diagnosed. http://www.allaboutdepression.com/cyclothymia/

images/graphic2.gif

CYCLOTHYMIC DISORDER

EPIDEMIOLOGY ETIOLOGY

The lifetime prevalence of cyclothymic disorder is 0.4%

to 1%.

Genetic and familial studies reveal an association with

other mood disorders

The rate appears equal in men and women, although women are usually more likely to seek treatment

CLINICAL MANIFESTATIONS OF CYCLOTHYMIC DISORDER Cyclothymic disorder is a milder form of

bipolar disorder consisting of recurrent mood disturbances between hypomania and dysthymic mood.

A single episode of hypomania is sufficient enough to diagnose cyclothymic disorder, although most individuals also have dysthymic periods.

Cyclothymic disorder is never diagnosed when there is a history of mania, major depressive episode, or mixed episode.

Etiology

Heritability

Evidence for heritability is much stronger for bipolar than for unipolar disorders

Specific genetic association has not been consistently replicated

EVIDENCE FOR HERITABILITY OF BIPOLAR DISORDER

Family Studies- First degree relatives are 8 to 18 times more likely to have Bipolar I

2 to 10 times to have MDD.

Risk is 25% if one parent has illness, and 50% to 75% with both parents affected

FAMILY STUDIES

The majority of individuals with bipolar disorder have a positive family history of some type of mood disorder

About 50% of all bipolar I patients have at least one parent with a mood disorder

ADOPTION STUDIES

Prevalence of bipolar disorder in adopted away offspring corresponds to rates in biological, but not adoptive relatives

Twin Studies- Concordance rate in MZ twins is 33 to 90%, in DZ is 5 to 25%

Genetic Polymorphism A functional polymorphism is a genetic

variant that appears in at least 1% of a population and alters the biological functioning of the individual

Some types of polymorphisms in Mood Disorders Serotonin transporter Serotonin 2A receptor MTHF reductase Catachol -o- methyl tranferase (COMT) Tyrosine hydroxylase Cytochrome P450 metabolism of medications

Biological factors

Dysregulation in levels catecholamines (++ levels of dopamine and norepinephrine).

-- levels of serotonoine ?? Neuroendocrinal factors:• HPA axis (cortisol hypersecreation) may

affect BDNF.• Throid dysfucntion. EEG changes (kindling model) Degenerative structural brain changes.

Psychosocial factors

Life time events. Behavioral models . Psychological theories.

Impact of BD

Higher rates of mortality from other medical conditions

Increased substance abuse risk Lifetime suicide attempt risk (.02% in general

populatio Bipolar Disorder Type I – 17% Bipolar Disorder Type II – 24% 90% of completed suicides can be traced

back to a Mood Disorder High rates of cognitve defeicets affecting

Working memory Sustained attention, Abstract reasoning, Visuomotor skills, Verbal memory, Verbal fluency, Cognitive flexibility

Management

A- psychopharmacology

Mood stabilizers Atypical antipsychotics. Benzodiazepines. Channel blockers. Others Combination therapy is more

effective than monotherapy

Mood stabilizers

Lithium Conventional anti-epileptics as

carbamazepine and Na valproate. New anti-epileptics lamotrigene

gababentine, and topiramate

What Exactly Is a Mood Stabilizer?

• Some authorities suggest 2 out of 3 of the following properties:

– Antimanic, antidepressive, prophylactic

• Other experts are more stringent—requiring:

– Treatment of acute mania,

– Treatment of acute depression, AND

– Prevention of recurrent mania and depression

– Dosen’t ppt mania or depression.

• Lithium remains the gold standard

Lithium

Widely recommended treatment for Bipolar Disorder

60-80% success in reducing acute manic and hypomanic states

However… issues in non-compliance to take medication, side effects, and relapse rate with its use are being examined in terms of being the best option

Pharmacokinetics:

Peak blood levels reached in 3 hrs, fully absorbed in 8 hrs

Absorbed rapidly and completely orally Efficacy correlates with blood levels Crosses blood-brain barrier slowly and

incompletely Usually taken as a single daily dose

Kinetics Cont.

Approx. 2 wks to reach a steady state within the body

½ of oral dose excreted in 18-24 hrs,rest within 1-2 wks

Recommended 0.8-1.2 mEq/L, optimum would be 0.6-0.8 mEq/L, with 2 mEq/L displaying toxicity .

Monovalent ion not metabolized in liver, excreted by the kidney.

Pharmacodynamics

No psychotropic effect on non-Bipolars Affects nerve membranes, multiple

receptor systems and intracellular 2nd messenger impulse transduction systems.

Interacts with serotonin Potential to regulate CNS gene

expression, stabilizing neurons w/ associated multiple gene expression change.

How does a simple ion do all of this?

Even as a simple ion, it has complex effects on multiple transmitter systems and mood stabilizing attributes

This is due to a latter effect reducing a neuron’s response to synaptic input, and therefore stabilizing the membrane

Side Effects and Toxicity

Relate to plasma concentration levels, so constant monitoring is key

Higher concentrations ( 1.0 mEq/L and up produce bothersome effects, higher than 2 mEq/L can be serious or fatal

Symptoms can be neurological, gastrointestinal, enlarged thyroid, rash, weight gain, memory difficulty, kidney disfunction, cardiovascular

Not advised to take during pregnancy, affects fetal heart development

Side effects of Li

1. GIT symptoms (diarrhea intially)2. Hypokalaemia…….cardiotoxic.3. Polyuria and D.insipius (ADH).4. Tremors.5. Epileptogenic.6. Teratogenic.7. hypothyroidism8. Li toxicity may occure (ttt?)

Na valproate

Tab 200mg and 500 mg Dose 50-150 mg% Best for rapid-cycling and acute-mania Actions: through GABA potentiation,

Ca channel blockade, Na channel blockade, glutamat antagonist.

Side effects1.Hepatotoxic.2.Wt gain3.Hair loss.4.GIT symptoms.5.Tremors and sedation6.Neural tube defects

carbamazepine Tab 200mg 400 mg Dose 5-15 µg/L Action similar to valproate. Superior to lithium for rapid-cycling,

regarded as a second-line treatment for mania

Correlation between therapeutic and plasma levels (estimated between 5-10 Mg/L)

Side effects:1. Agranulocytosis2. Skin reaction3. Teratogenic4. Liver enzyme induction

Gabapentin

Primarily an anti-convulsant, yet also “off label,” or without FDA approval for treatment of Bipolar and many other anxiety, behavioral and substance abuse problems, possibly pain disorders

GABA analogue not bound to plasma proteins, not

metabolized, few drug interactions Half-Life is 5-7 hours Side Effects include

sleepiness,dizziness,ataxia and double vision

Lamotrigine

Reported effective with Bipolar, Borderline Personality, Schizoaffective, Post-Traumatic Stress Disorders

98% of administered drug reaches plasma

Half-Life is 26 hrs. Inhibits neuronal excitability and

modifies synaptic plasticity Side Effects may include dizziness,

tremor, headache, nausea, and rash

Topiramate and Tiagabine

Two newer anti-convulsants that have potential for use in the treatment of Bipolar disorder

Anticonvulsants: Efficacy in BD

Probably effective:

Lamotrigine, CBZ, oxycarbazepine, valproate

Possibly effective:

Gabapentin, zonisamide, phenytoin, levetiracetam

Ineffective/problematic:

Topiramate, tiagabine, vigabatrin

Calcium Channel Blockers Modulate transmitter release &

plasticity

Most not consistently effective, possibly due to inconsistent uptake into brain

Nimodipine reported effective in rapid-cycling, including refractory & ultra-rapid

Atypical Anti-psychotics

Risperidone seems more anti-depressant than anti-psychotic

Clozapine is effective, yet not readily used due to potential serious side effects

Olanzapine is approved for short-term use in acute mania

Quatiapine is now approved as a broad spectrum medication in BD esp (Bipolar depression).

Acetylcholinesterase Inhibitors

Potentiating the action of acetylcholine may exert relief from mania

This potentiation is the result of inhibiting the enzyme acetylcholine esterase

Omega-3 Fatty Acids

Obtained from plant or marine sources

Known to dampen neuronal signaling transduction systems in a variety of cell systems

Being investigated as a treatment for Bipolar Disorder

Three Phases of Treatment

0-2 months 2-12 months IndefiniteSymptomatic Functional Stability/adaptive

Episode Continuation Maintenance

Each phase has specific goalsEach phase has specific pharmacological and nonpharmacological rxTreatment must be harmonized across phases

Nonpharmacologic Treatments ECT

Reports of effectiveness in mania, depression, & refractory mixed states

Bilateral generally more effective Continuation ECT may prolong recovery;

maintenance? Transcranial magnetic stimulation Psychotherapy : May include cognitive

behavioral, psychodynamically oriented, family, couples, interpersonal, and self-help group therapies

Thank you