bipolar abbassia

Bipolar Disorder:Challenges & Horizons

Prof. Hisham RamyProfessor of Psychiatry (ASU)Consultant Psychiatrist (UK)

Secretary GeneralNational Mental Health Commission

Salah Jaheen

أقوم ساعاتقلبى الصبح

حزين الباب بره أطل الحنين ياخدنى

ضاع لقيته اللىاشتريته واللى

انباع قابلته واللى

وفات راح األنين

بمبى بمبىبقى الحياة

بمبى لونها

جنبك انا وجنبى وانت

ونغمض بوسةنلقى.. ويلال

حتى الضلمة

بمبى

Historical AspectsHippocrates

Historical AspectsAretaeus of Cappadocia

Historical AspectsAvicenna

Historical AspectsRobert Burton

Historical AspectsThe French

Historical AspectsKraepelin

Historical AspectsLeonard & Angst

Historical AspectsAkiskal

ChallengesWhat is Bipolar Disorder ?

• It is a spectrum of affective episodes including:

• Major depressive episode

• Manic episode

• Mixed episode

• Hypomanic episode

• 5. Unspecified

The DSM-IV categorizes it into:

Bipolar I Disorder

Bipolar II Disorder

Cyclothymia

Bipolar N.O.S.

ChallengesDSM-IV-TR: Complex

Disorder Five types of episodes:

Four subtypes

Four severity levels

Three course specifiers With or without inter-episode recovery

Seasonal pattern

Rapid cycling

American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision. Washington, DC: Author.

Challenges Complex Disorder

Bipolar spectrum:

Bipolar I: Depression &mania

Bipolar II: Depression & hypomania

Bipolar II-½: Depression & cyclothymic temp.

Bipolar III: Depression & manic switch.

Bipolar III-½: Depression & mood swings &SUD.

Bipolar IV: Depression & FH &/ or hyperthymia.

Sigmund Freud

Mania is nothing but a reaction formation to Depression

Challenges

• Prevalence: NCSR 2005

• Bipolar I: 2%

• Bipolar II: 1.5%

• Cyclothymia: 0.5%

• Bipolar Spectrum: 6%

Age <15 years33%

Age of Onset

Age 15–19 years27%

Age 20 years

39%

Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174

Time spent in episodes

Patients with bipolar disorder regularly switch between mania and depression, and the amount of time in each state can vary

Percentage time spent in each state of bipolar disorder

1Judd et al. Arch Gen Psychiatry 2002;59:530-72Judd et al. Arch Gen Psychiatry 2003;60:261-93Kupka et al. Bipolar Disord 2007;9:531-5

6%

9%

53%32%

50%

2%

47%

1%

36%

13%

48%

3%

37%

10%

51%

2%

BP II, n=86, m=13.4 years2

BP I, n=146, m=12.8 years1

BP II, n=102, m=1 year3

BP I, n=405, m=1 year3

m, mood diaries

No symptoms

Depressive

Manic / hypomanic

Mixed / rapid cycling

No symptoms

Depressive

Manic / hypomanic

Mixed / rapid cycling

21

Psychiatric comorbidity

Kessler RC, et al. Psychol Med 1997;27:1079-1089

0

20

40

60

80

100

Any anxiety

Anysubstance

Alcoholdependence

Drugdependence

Conduct Adult antisocialbehaviour

Pat

ien

ts (

%)

29%

59%

41%

61%

71%

93%

Kessler RC, et al. Arch Gen Psychiatry 2005;62:590-592National Comorbidity Survey Replication (NCS-R)

The annual lost human capital due to bipolar disorder is larger

than that due to major depression

Bipolar I or II Major depression

Prevalence in the workplace Annual lost days per ill worker

Bipolar I or II

3.1%

49.5

6.4%

31.9

Major depression

p<0.05

Prevalence and impact of bipolar disorder in the workplace (NCS-R)

Mortality in bipolar disorder

220 bipolar inpatients followed up for 22 years or more

*p<0.001 vs treated patients

Angst F, et al. J Affect Disord 2002;68:167-181

Sta

nd

ard

ised

mo

rtal

ity

rati

o

* * * *

*

Cancer Vascular diseases

Accidentor

intoxication

Suicide Othercauses

Total0

5

10

15

20

25

30

35

Untreated Treated

Personal tragedies: Van Gogh

• Born in 1853

• July 1890, at the age of 37, he walked into the fields and shot himself in the chest with a revolver

• His last words "La tristesse durera toujours"

http://en.wikipedia.org/wiki/1853

http://en.wikipedia.org/wiki/Revolver

Personal Tragedies: Hemingway

born on July 21, 1899

Several suicide attempts

1961 shot himself.

Personal Tragedies: Vivian Leih

Born in 1913

Throughout her possession by that uncannily evil monster, manic depression, with its deadly ever-tightening spirals.

Died in 1967

80% of patients that screened positive for bipolar disorder* using the MDQ had not previously been diagnosed as bipolar


MDQ, mood disorder questionnaire

*type I or II

Bipolar disorder:an under-recognised mood disorder

The magnitude of the problem

High Rate of Misdiagnosis 600 bipolar patients:

35% were symptomatic for more than10 years before correct diagnosis 10+ years

Most frequent misdiagnosis:Most frequent misdiagnosis:

Unipolar depression60%

National Depressive and Manic-Depressive Association (NDMDA), Constituent Survey. 2001; Chicago, IL.

Hirschfeld RMA, et al. J Clin Psychiatry. 2003;64:161-174.

Prior diagnoses in bipolar patients

Depression 60%

Anxiety disorder 26%

Schizophrenia 18%

Personality disorders 17%

Substance abuse 14%

Schizo-affective disorder 11%


The international BRIDGE study (Young et al, 2009),

• sample of 5,600 patients with a major depressive episode

• evaluated:

• using clinical judgment at entry

• then using broader systematic assessment to elicit reports of hypomania/mania.

• The frequency of bipolar disorder

• which was 29% at entry based on clinical judgment,

• 47% by systematic evaluation of hypomania/mania according to the bipolarity specifier (broader definition of bipolar disorder than DSM IV).

What is the Solution???What is the Solution???

Improving Recognition

Utilize family or other collateral informants Assess longitudinal factors

Determine age of first-episode onset Evaluate course to establish quality of inter-episode recovery

Evaluate family history Review response prior to treatment Assess common conditions in differential diagnosis

History Laboratories

Assess common comorbidities Aim to estimate diagnostic confidence

Sachs G. FOCUS. 2007;5(1):3-13.

Nassir Ghaemi S et al. Can J Psychiatry 2002;47:125–34.Kaye NS. J Am Board Fam Pract 2005;18:271–281.

Identifying features of bipolar depression

Family history of BD in a first-degree relative

Antidepressant-induced mania or hypomania

Hyperthymic or cyclothymic temperament

Recurrent major depressive episodes (>3)

Brief major depressive episodes (on average, <3 months)

Atypical depressive symptoms

Psychotic major depressive episodes

Nassir Ghaemi S et al. Can J Psychiatry 2002;47:125–134.Kaye NS. J Am Board Fam Pract 2005;18:271–281.

Identifying features of bipolar depression

Early age of onset of major depressive episode (<25 years)

Post-partum depression Seasonality Rapid on/off pattern, mood lability Wearing off of antidepressant efficacy (acute but not

prophylactic response) Lack of response to ≥3 antidepressant treatment trials Mixed depression, (psychomotor agitation, irritability,

racing/crowded thoughts) Substance abuse

Goldberg JF et al. Am J Psychiatry 2009;166:173–181.

Pro

port

ion

of p

atie

nts

(%)

Pressured sp

eech0

10

20

30

40

50

60

≥4 symptoms1–3 symptoms

Increase

d

self e

steem

Decrease

d

need for s

leep

Flight o

f ideas/

racing th

oughts

Distracti

biity

Increase

d activit

y

High risk b

ehavior

9.9%8.7%

15.8%

29.9%

53.9%

10.7% 9.3%

Symptoms of mania during a bipolar depressive episode

In the NIMH* Systematic Treatment Enhancement Program for BD (NIMH STEP BD), 69% had at least one manic symptom. Most prevalent symptoms: distractibility, racing thoughts, rapid speech, increased activity

*NIMH = National Institute of Mental Health

Hirschfeld RM et al. Am J Psychiatry 2000;157:1873–1875.

Mood Disorder Questionnaire (MDQ)

Brief, self-report screening instrument

Contains 13 questions on manic symptomatology

Can detect bipolar I but less sensitive for bipolar II

Positive screen if at least 7 symptom items, co-occurrence of at least 2 symptoms and moderate to severe impairment

Available at http://www.dbsalliance.org/pdfs/MDQ.pdf

http://www.dbsalliance.org/pdfs/MDQ.pdf

Angst J et al. J Affect Disord 2005;88:217–233.

Hypomania Checklist (HCL-32)

Self-rating questionnaire

Core of the instrument consists of a checklist of 32 hypomanic symptoms

Screening tool for hypomania but no difference between bipolar I and II

Individuals with a total score of 14 or more are potentially bipolar

Available at http://www.psycheducation.org/depression/HCL–32.htm

Nassir Ghaemi S et al. J Affect Disord 2005;84:273–277.

Bipolar Spectrum Diagnostic Scale (BSDS)

Self-reporting questionnaire

Consists of a descriptive story that captures subtle features of bipolar symptoms and course

Equal sensitivity for bipolar I and II/not otherwise specified

Optimum threshold for likelihood of bipolar disorder: Score ≥13

Available at http://www.psycheducation.org/depression/BSDS.htm

Post RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of Bipolar Disorders. 2009.

Graphing the longitudinal course of bipolar disease

Collect retrospective patient’s course of illness

Urge patients to continue this on a prospective basis

Provides a clear picture of the earlier course of illness, the best predictor of the future episode pattern

Clarifies pattern of prior medication responsiveness

Facilitates the recognition of low-level manic symptoms

Encourages the patient’s collaboration

Post RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of Bipolar Disorders. 2009.

Graphing the prospective course of mood disorders

PROSPECTIVE (DAILY) RATINGS

Incapacitated

Much

Some}Difficulty functioning

Not

impaired

Not impaired

Some

Much}Difficulty functioning

IncapacitatedDep

ress

ion

Man

ia

Severe

High Moderate

Low Moderate

Mild

Mild

Low Moderate

High Moderate

Severe

Co

mo

rbid

Sym

pto

ms

Imp

act

(–4

to +

4)

Lif

e

Eve

nts

Alcohol

Substance use

panic attacksPA PA

Si = suicideattempt

Hosp

Lithium

Antidepressant

MAOI

Dysphoric Mania

Approximate Dates

Lamotrigine

Carbamazepine / Oxcarbazepine

Atypical Antipsychotics

Benzodiazepines / Gabapentin

SWITCHESPER MONTH

(i.e. = 4 = ultra rapid)

SWITCHESPER DAY(i.e. ultra – ultra rapid cycling, or ultradian cycling)

(2/1

0/9

0) P

rom

oti

on

(2/1

2)

All

nig

hte

r

(3/1

) A

rres

ted

fo

r sp

eed

ing

(8/2

3/9

1) D

og

die

d

(1/1

5/9

2) G

ot

ma

rrie

d

(6/2

0/0

2) L

ost

jo

bMAOI = monoamine oxidase inhibitor; PA = panic attack; Si = suicide attempt

Treatment aims in bipolar disorder

Managementof comorbid conditions

Ultimate treatment goal – mood stabilisation

Vieta 2005

Short term

- control of acute symptoms

- prevention of relapse

- treatment acceptance / adherence

Long term

Treatment challenges in bipolar disorder

Evans 2000; Hirschfeld 2003a, 2003b Judd et al 2002, 2003; Citrome 2005; Kupka et al 2007

Initial diagnosis Bipolar disorder is often unrecognised and undiagnosed

Comorbidities Common, can hinder diagnosis

Phenotypes Bipolar I vs bipolar II, rapid cycling, mixed states

DepressionPredominant symptomatic phase,

can lead to misdiagnosis

Chronic disorderNeed for long-term symptom stability across

both poles

IntroductionPlan.

Goals.

Place.

Tools.

Input.

Input

Patient.

Informant.

Records.

Research.

GoalsShort term:

Remission.

Decrease risks.

Long term:

Maintain Remission.

Good quality of life.

GoalsBipolar disorder is characterised by recurrent episodes of major disturbance

at the two ‘poles’ of mood disturbance: mania and depression

Place

Home (outpatient).

Day hospital.

Hospital.

Tools

Pharmacotherapy.

Psychosocial treatment.

ECT.

Others.

Evidence based Tools

Pharmacotherapy & ECT

Prodrome Detection: Perry and colleagues

Psycho education: Colom and colleagues

Cognitive Therapy: Lam and colleagues,

Interpersonal and Social Rhythm Therapy (IPSRT) : Frank and colleagues

Family-Focused Therapy (FFT) and Integrated FFT/IPSRT: Miklowitz and colleagues

DrugsChoice.

Dose.

Duration.

Psychosocial Treatment

Choice.

Duration.

Setting.

Frequency.

TypesAncient Treatments

exorcism, caged like animals, beaten, burned, castrated,

mutilated, blood replaced with animal’s blood

Cognitive Behaviour Therapy (CBT)

The main assumption behind CBT is that psychological difficulties depend on how people think or interpret events (cognitions), how people respond to these events (behaviour), and how it makes them feel (emotions).

CBT aims to break the vicious cycle between thoughts, feelings and behaviours by helping people to learn more useful ways of thinking and coping.

Psycho education

Information (counselling).

EE management.

Medication management.

Support.

Compliance Enhancement

Information.

Schedule.

Life chart.

Models.

Therapeutic alliance.

OthersProdrome Detection: Perry and colleagues


ECT

Indications.

Frequency.

Number.

Procedures.

Electroconvulsive Therapy (ECT)

ECT – Efficacy

Gold standard for treatment of MDD

Response rate 70-90% compared to 40-60% with pharmacotherapy

Highly efficacious in Tx of catatonia and schizophrenia with positive Sx

ECT - Procedure

Pre-procedure – NPO, flumazenil

Performed in ECT suite, bedside or ICU

Induction with rapidly acting anesthetic (methohexital, ketamine)

Paralysis with rapidly acting NM blocker (succinylcholine)

Application of electric current to skull

Generalized tonic-clonic SZ (0.5 - 2min)

Recovery in 1-2 hours

ECT – Safety

Mortality rate depends on medical comorbidity Healthy individual: 1:10,000 mortalityRisk / benefit assessment is crucial

Common Side Effects, Temporary:Headache, myalgias Cognitive: anterograde, retrograde amnesia – worse with bilateral electrode placement

Uncommon / Rare Adverse Events Arrhythmias, MI, CVA, delirium, status epilepticus, prolonged apnea, Tx emergent mania

Mood Stabilizers

Lithium

Valproate

Carbamazepine

Lamotrigine

Topiramate (not effective)

Gabapentin (not effective)


Ideally

The ideal treatment for bipolar disorder would achieve mood stabilisation by effectively treating mania and depression and preventing relapse among patients with bipolar I and II disorder and rapid cyclers

Mood Stabilizer

“Must show efficacy in the treatment of acute mania and/or depression and the prophylaxis of subsequent manic or depressive episodes, not worsen mood symptoms or acute episodes, and not increase the likelihood of an affective switch or cycling.”

Expert Consensus Guidelines

The Evolution of Therapies for Bipolar Disorder

1950 1960 1970 1980 1990 2000

Chlorpromazine*TrifluoperazineFluphenazineThioridazineHaloperidolMesoridazine

Anticonvulsants

1940

ECT Lithium

First-generation antipsychotics and antidepressants

Risperidone+

Clozapine

Anticonvulsants

GabapentinLamotrigineTopiramateOxcarbazepine

Second-generation antipsychotics and antidepressants

Olanzapine*Quetiapine+

Ziprasidone+

CarbamazepineValproate

2002

Aripiprazole+Asenipine

ECT = electroconvulsive therapy

2. Drug Concentration

AbsorptionDistributionMetabolismElimination

Drug ResponseDependent on 3 Variables:

1. Affinity

ReceptorsEnzymes

Uptake Pumps

3. Patient

GeneticsAge

DiseaseEnvironment

Clinical Response

The Perfect Mood StabilizerThe Perfect Mood Stabilizer

Efficacy inEfficacy inManiaMania

SafetySafetyTolerabilityTolerability

Efficacy inEfficacy inDepressionDepression

A Lousy Mood StabilizerA Lousy Mood Stabilizer




LithiumLithium




DivalproexDivalproex




The Perfect Mood StabilizerThe Perfect Mood Stabilizer




A Lousy Mood StabilizerA Lousy Mood Stabilizer




LamotrigineLamotrigine




OlanzapineOlanzapine




FDA-approved treatments

Physicians’ Desk Reference 2007

Mania Mixed Maintenance Depression

Mania Depression Bipolar I Bipolar II

Mood stabiliser

Lithium – – – –

Divalproex DR – – – – –

Divalproex ER – – – –

Carbamazepine ER – – – –

Atypical antipsychotics

Risperidone – – –

Olanzapine – – –

Quetiapine

Ziprasidone – – – –

Aripiprazole – – –

Other

Lamotrigine – – – –

Olanzapine/fluoxetine – – – – –

Lithium

First medication to be found effective in Tx of mania

Narrow therapeutic index

Indications:

Acute mania

Maintenance / prophylaxis of bipolar d/o

Bipolar depression

Schizoaffective d/o, bipolar type

Lithium – Mechanism of Action

Mechanism unknown Inhibits alpha unit of G-proteins coupled to cAMP, especially in beta adrenergic receptors

This may interfere with neuronal activity occurring in mania

PIP inhibition may improve depressive Sx

Lithium - Pharmacology

Dosed to a serum therapeutic range of

0.6 – 1.2 mEq/L

Usual dosage: 900 – 1200 mg / day

Excreted unchanged by kidneys

Lithium - Adverse Effects

Neurological – dysphoria, lack of creativity, slowed reaction times, memory difficulty, tremorEndocrine – hypothyroid, hypoparathyroidCardiovascular – sick sinus syndrome Renal – polydypsia, polyuria, nephrogenic diabetes insipidus; long-term decreased GFR, nephrotic syndrome, renal insufficiencyDermatological – acne, hair loss, psoriasis, rashGastrointestinal - anorexia, nausea, vomiting, diarrheaMisc – altered carbohydrate metabolism, weight gain, fluid retention

Lithium Toxicity

Characterized by1.2 – 1.5 mEq/L: tremor, ataxia, diarrhea, nausea

1.5 – 2 mEq/L : increased risk of seizure

> 2.5 mEq/L: coma, death

In elderly or in pts. w/ renal failure, toxicity can occur within the therapeutic range

Lithium - Teratogenicity

Ebstein’s AnomalyMalformation of tricuspid valveCan be mild to severe Associated with first trimester useRisk: 1 / 1,000 in Li exposed pregnancies

(20x risk general population)

Valproate (Depakine)

IndicationsAcute mania

Maintenance / prophylaxis of bipolar d/o

More effective than Li in rapid cycling and mixed bipolar states

Adjuvant treatment in schizophrenia, schizoaffective disorder

GTC / partial Sz, prophylaxis of migraine

Valproate – Mechanism of Action

Increases the inhibitory neurotransmitter GABA by:

Inhibiting catabolism of GABA

Increasing release of GABA

Increasing GABA b receptor density

May improve neuronal responsiveness to GABA

All which points to increased seizure control but is unclear how this affects mood disorders

Valproate - Pharmacology

Metabolized by liver

90% plasma protein bound

Anticonvulsant serum level:

50 -100 mcg/mL

Blood levels for Tx of mania not established but usually the same

Valproate – Adverse Events

Gastrointestinal (nausea, dyspepsia, vomiting, diarrhea)

Neurological (sedation, ataxia, dysarthria, tremor)

Weight gain (up to 44% of patients)

Alopecia (3-12% of patients)

Transient thrombocytopenia

Persistently elevated transaminases

PCO

Valproate – Severe Adverse Events

Fatal hepatotoxicity (~2.6 in 100,000), hemorrhagic pancreatitis, agranulocytosis

Monitor LFT’s and CBC on initiation and periodically

Teratogenicity – 1st trimester use associated with increased risk of neural tube defects, craniofacial defects, fingernail hypoplasia, developmental delay

Incidence of malformations with carbamazepine is ~7.3%

Carbamazepine (Tegretol)

Indications:

Drug of choice for Tx of psychiatric Sx associated with complex – partial Sz

Mood stabilization in bipolar disorder

Unclear therapeutic range for mood disorders, usually use 8-12 mcg/mL

Carbamazepine - Pharmacology

Inhibits voltage-dependent sodium channels

70-80% protein bound

Induces its own metabolism (autoinduction), requiring increase in dose after 2-3 weeks

Metabolized by the liver, excreted by kidney

Carbamazepine – Adverse Events

Dose related –

Double/blurred vision

Vertigo

GI disturbance

Cognitive impairment

Mild leukopenia

Non-dose related –

Agranulocytosis (1 in 125,000)

Aplastic anemia

Hepatic failure (rare)

Rash

Pancreatitis

Carbamazepine – Adverse Events

Teratogenicity - in 1st trimester, increased incidence of neural tube defects (1-4%), reduced risk with folate supplementation

Lamotrigine (Lamictal)

Indications: Bipolar depression

Maintenance Tx of bipolar d/o

Refractory partial Sz

Pain d/o

Mechanism: Inhibition of glutamate release

Inhibition of voltage-gated sodium channels

Lamotrigine - Pharmacology

Moderate protein binding

Initial daily dose: 25mg /day

Increase weekly to maintenance dose of 75-250mg / day

Valproate inhibits metabolism of lamotrigine

Requires slower dose titration

Lamotrigine – Adverse Events

Rash in 10% of patients

Requires discontinuation because of risk of progression to Stevens-Johnson syndrome

Usually occurs in first 8 weeks of Tx

Aseptic meningitis


Olanzapine 5-20mg daily

Risperidone 1-6mg range daily

Quetiapine dose range 300-600mg daily

Risk of tardive dyskinesia less than typical antipsychotics but still present

Have antidepressant effect

*

Medication approved for bipolar depression Monotherapy

Lithium

Olanzapine/fluxetine

Quetiapine

Lamotrigine

Drug Specificity:Comparative Receptor Binding Profiles

Adapted from Gareri P, et al. Clin Drug Invest. 2003;23(5):287-322.* BMS Data on file.

D1 D2

5HT2A

5HT1A

A1

A2

H1

M

Clozapine Olanzapine

Risperidone

D1 D2

5HT2A

5HT1A

A1

A2

H1

Quetiapine

Ziprasidone

D2D1

5HT2A

5HT1A

A1

5HT2A

5HT1A

D2

D3

5H12C

A1A2

H1

Aripiprazole* Haloperidol

Rationale-based PharmacotherapyImportant Principles

DrugReceptor Binding Affinities

H1 D2 5-HT2C 5-HT2A α1 M1

Haloperidol 440 0.7 > 10,000 45 6 > 1,500

Aripiprazole 61 0.34 15 3.4 57 > 10,000

Olanzapine 7 11 23 4 19 1.9

Quetiapine 11 160 1,500 295 7 120

Risperidone 20 4 25 0.5 0.7 > 10,000

Ziprasidone 50 5 1 0.4 11 > 1,000

ReceptorsEffects of Receptor

Blockade

H1Sedation, weight gain,

postural dizziness

D2EPS, prolactin elevation,

antipsychotic

5-HT2C Satiety Blockade

5-HT2A Anti-EPS?

α1-adrenergic

Hypotension

M1

Deficits in memory and cognition, dry mouth,

constipation, tachycardia, blurred vision

Values represent Ki (nM); values in blue reflect the highest binding affinity for a given drug; values in green reflect the lowest affinity

Adapted from Weiden P, et al. J Clin Psychiatry. 2007;68(7):5-46.

Binding Affinities for Atypical Antipsychotics and Tricyclic Antidepressants for Norepinephrine

Transporter (NET)

Compound / drug

> 10000

35

3168

> 10000

> 10000

> 10000

2093

44*

2

13.3-35

52

0.55

Quetiapine

Norquetiapine

Clozapine

Olanzapine

Risperidone

Paliperidone

Aripiprazole

Ziprasidone

Nortriptyline

Amitriptyline

Imipramine

Desipramine

NET Ki (nM)

Data from NIMH Psychoactive Drug Screening ProgramGoldstein J, et al. Eur Psychopharmacol. 2007;17(S4):S401.*Using ex vivo methodology there was no inhibition of norepinephrine reuptake with ziprasidone at serum concentrations typically observed during treatment (Owens and Nemeroff, personal communication).

Drugs are not enough

Prodrome Detection: Perry and colleagues

Psycho education: Colom and colleagues

3. Cognitive Therapy: Lam and colleagues,


Family-Focused Therapy (FFT) and Integrated FFT/IPSRT: Miklowitz and colleagues

Antidepressants

Appropriate use and effectiveness is controversial

Antidepressant-induced mania in 20-40% with all antidepressant classes (TCAs > others)¹‚²

Increased risk of switching³:

Previous antidepressant-induced mania

Bipolar family history

Exposure to multiple antidepressant trials

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

Antidepressants

No benefit?:

Frankle WG, et al¹ (retrospective, 50 pts, 30 weeks):

No difference in length of depressive episode regardless of antidepressant status

Ghaemi S, et al² (open, randomized 33 pts, 1 year):

Relapse rate 50% within 20 weeks regardless of antidepressant status

Initiation of sustained ultradian cycling during unopposed antidepressant treatment in a bipolar II female. 30–year delay in onset of appropriate treatment

Post RM, Altshuler LL. In: Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of Bipolar Disorders. 2009.

* *

Severe

Moderate

Moderate

Mid

Mid

Aprozalam

Dep

ress

ion

Ma

nia

1942 1956 1958 1960 1962 1964 1966 1968 1970 1972

1974 1976 1980 1982 1984 1986 1988 1990 1992

continued

Severe

depressions

age 13

Hypomanias and major depressive recurrences

FluoxetineTrazodone Lithium

Carbamazepine

NimodipineAntidepressant

treatment in absence of a

mood stabiliser

Conversion to continuous ultradian

cycling following fluoxetine

Two brief bursts of ultradian cycling

FUTURE DIRECTIONS

Brain Affection

Brain affection

Structural Changes With BPD Progression:Episodes Are Associated With Brain Tissue Loss

Prefrontal Cortex ↓ Left inferior prefrontal gray volumes with ↑ illness

duration↓ Gray matter volume with ↑ ageStriatumNo difference in putamen between first- and multi-episode

patientsCerebellum↓ Cerebellar vermis volume in multi- vs first-episode patientsAmygdala↑ Amygdala volume with ↑ age in young patientsVentricles↑ Ventricular volume in multi- vs first-episode patients↑ Ventricular volume with ↑ number of manic episodes↑ Ventricular volume with ↑ number of affective episodes

HPA Axis Dysregulation in Bipolar Disorder

HPA axis hyperactivity prominent in BPD

Significant hypersecretion of cortisol; state dependent abnormalities

Dexamethasone non-suppression

Abnormal response to physical and psychological stressors

Chronic elevation of glucocorticoids

Goodwin F, Jamison K. Manic Depressive Illness. Oxford University Press; New York, NY: 2007.

Anterior Limbic Networks

Thalamus (MD)

Ventral pallidum

Ventral striatum

Amygdala

Cerebellar vermis

Hypothalamus

OFC/VLPFC DLPFC

Expression of emotions

Anterior cingulatesubgenual dorsal

Future treatment

Bifeprunox

Pramipexole

licarbazepine

GLYT1 (glycine transporter) inhibitor

Glycine site specific NMDA modulator

NK-3 antagonist

Glucocorticoid receptor type II (GRII) antagonist, progesterone receptor antagonist

THANK YOU

bipolar abbassia

Health & Medicine