1. Bipolar Disorder:
Challenges & Horizons
Prof. Hisham Ramy
Professor of Psychiatry (ASU)
Consultant Psychiatrist (UK)
Secretary General
National Mental Health Commission

2. ‫‪Salah Jaheen‬‬
‫ساعات أقوم‬ ‫بمبى بمبى‬
‫الصبح قلبى‬ ‫الحياة‬
‫حزين‬ ‫بقى‬
‫أطل بره‬ ‫لونها‬
‫الباب‬ ‫بمبى‬
‫ياخدنى‬ ‫و انا جنبك‬
‫الحنين‬ ‫وانت‬
‫اللى لقيته‬ ‫جنبى‬
‫ضاع‬
‫واللى‬ ‫بوسة‬

4. Historical Aspects
Hippocrates

5. Historical Aspects
Aretaeus of Cappadocia

6. Historical Aspects
Avicenna

7. Historical Aspects
Robert Burton

8. Historical Aspects
The French

9. Historical Aspects
Kraepelin

10. Historical Aspects
Leonard & Angst

11. Historical Aspects
Akiskal

12. Challenges
What is Bipolar Disorder ?
• It is a spectrum of The DSM-IV
affective episodes categorizes it into:
including:
Bipolar I Disorder
Major depressive
episode Bipolar II Disorder
Manic episode Cyclothymia
Mixed episode
Bipolar N.O.S.
Hypomanic episode
5. Unspecified

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

14. 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.

15. The flavours of bipolar spectrum 1
Adapted from Akiskal & Pinto 1999

16. The bipolar spectrum 2
Hyperthymic ‘Bipolar IV’
Depressive mixed state ‘IV ½’
Highly recurrent depression ‘bipolar V’
Adapted from Akiskal & Pinto 1999

17. Sigmund Freud
Mania is nothing
but a reaction
formation to
Depression

18. Challenges
• Prevalence: NCSR 2005
• Bipolar I: 2%
• Bipolar II: 1.5%
• Cyclothymia: 0.5%
• Bipolar Spectrum: 6%

19. Age of Onset
Age <15 years
33%
Age ≥20 years
39%
Age 15–19 years
27%
Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174

20. 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
6% 3%
32% 36%
48%
53%
9% No symptoms
13%
BP I, n=146, m=12.8 years1 Manic / hypomanic BP I, n=405, m=1 year3
Depressive
2% Mixed / rapid cycling 2%
37%
47%
50% 51%
1 2
1% 10%
BP II, n=86, m=13.4 years2 BP II, n=102, m=1 year3
1
Judd et al. Arch Gen Psychiatry 2002;59:530-7 m, mood diaries
2
Judd et al. Arch Gen Psychiatry 2003;60:261-9
3
Kupka et al. Bipolar Disord 2007;9:531-5

21. Psychiatric comorbidity
100 93%
80
71%
61% 59%
Patients (%)
60
41%
40
29%
20
0
Any Any Alcohol Drug Conduct Adult
anxiety substance dependence dependence antisocial
behaviour
Kessler RC, et al. Psychol Med 1997;27:1079-1089

22. Prevalence and impact of bipolar
disorder in the workplace (NCS-R)
p<0.05
The annual lost human capital
due to bipolar disorder is larger 49.5
than that due to major
depression
31.9
6.4%
3.1%
Bipolar I or II Major depression Bipolar I or II Major depression
Prevalence in the workplace Annual lost days per ill worker
Kessler RC, et al. Arch Gen Psychiatry 2005;62:590-592
National Comorbidity Survey Replication (NCS-R)

23. Impact of bipolar disorder on patients’ lives
Onset is usually during late adolescence and early adulthood, a time at which individuals are establishing their careers and
building long-term relationships
Healthy life Reduced by 12 years
Working life Reduced by 14 years
Life expectancy Reduced by 9 years
Employment problems Twice as common
Divorce / separation Twice as common
Results for patients developing
bipolar disorder in their mid-20s Coryell et al 1993; Scott 1995

24. Mortality in bipolar disorder
35
Untreated Treated
30 *
25
20
Standardised mortality ratio
15
10
5
* * * *
0
Cancer Vascular Accident Suicide Other Total
or
diseases intoxication causes
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

25. 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"

26. Personal Tragedies: Hemingway
born on July 21,
1899
Several suicide
attempts
1961 shot himself.

27. 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

28. Bipolar disorder:
an under-recognised mood disorder
80% of patients that screened
positive for bipolar disorder*
using the MDQ had not
previously been diagnosed as
bipolar
*type I or II
MDQ, mood disorder questionnaire
Hirschfeld RM, et al. J Clin Psychiatry 2003;64:53-59

29. The magnitude of the problem
High Rate of Misdiagnosis 600 bipolar patients:
Most frequent misdiagnosis:
Unipolar depression
60%
35% were symptomatic for more than
10 years before correct diagnosis
10+ years
National Depressive and Manic-Depressive Association (NDMDA), Constituent Survey. 2001; Chicago, IL.
Hirschfeld RMA, et al. J Clin Psychiatry. 2003;64:161-174.

30. Prior diagnoses in bipolar patients
Depression 60%
Anxiety disorder 26%
Schizophrenia 18%
Personality disorders 17%
Substance abuse 14%
Schizo-affective disorder 11%
Hirschfeld RM, et al. J Clin Psychiatry 2003;64:161-174

31. 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).

34. What is the Solution???

35. 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.

36. 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;47:125–34.
Kaye NS. J Am Board Fam Pract 2005;18:271–281.

37. 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
Nassir Ghaemi S et al. Can J Psychiatry 2002;47:125–134.
Kaye NS. J Am Board Fam Pract 2005;18:271–281.

38. 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
60
53.9%
Proportion of patients (%)
50
40 ≥4 symptoms
1–3 symptoms
29.9%
30
20 15.8%
8.7% 9.9% 10.7% 9.3%
10
0
d d h s/ iity ty r
se se p eec idea hts tib t ivi a vio
ea emrea ee sp of oug t r ac ac eh
cr c s l ed b
In este e t s se
d
D or s ur igh g t h Di ea r isk
lf f Fl cin cr
se ed res
ra In i gh
*NIMH = National Institute of Mental Health
ne P H
Goldberg JF et al. Am J Psychiatry 2009;166:173–181.

39. 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
Hirschfeld RM et al. Am J Psychiatry 2000;157:1873–1875.

40. 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
Angst J et al. J Affect Disord 2005;88:217–233.

41. 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
Nassir Ghaemi S et al. J Affect Disord 2005;84:273–277.

42. 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.

43. Graphing the prospective course of
mood disorders
Benzodiazepines / Gabapentin
MAOI
Lamotrigine
Antidepressant Atypical Antipsychotics
Lithium Carbamazepine / Oxcarbazepine
PROSPECTIVE (DAILY) RATINGS
Hosp
Severe Incapacitated Dysphoric Mania
Si = suicide
Mania
High Moderate Much
Low Moderate Some
} Difficulty functioning attempt Approximate Dates
Mild Not
impaired
Depression
Mild Not impaired
Low Moderate Some
High Moderate Much
} Difficulty functioning
Severe Incapacitated SWITCHES SWITCHES
PER MONTH PER DAY
PA PA (i.e. = 4 = ultra (i.e. ultra – ultra
Symptoms
Comorbid
panic attacks rapid) rapid cycling, or
ultradian cycling)
Alcohol
Substance use
(–4 to +4)
Impact
(3/1) Arrested for speeding
(1/15/92) Got married
(2/10/90) Promotion
(8/23/91) Dog died
(6/20/02) Lost job
(2/12) All nighter
Events
Life
MAOI = monoamine oxidase inhibitor; PA = panic attack; Si = suicide attempt
Post RM, Altshuler LL. In: Kaplan & Sadock ’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of
Bipolar Disorders. 2009.

44. Treatment aims in bipolar
disorder
Short term Long term
- prevention of
- control of acute relapse Management
symptoms of comorbid
- treatment
acceptance / conditions
adherence
Ultimate treatment goal – mood stabilisation
Vieta 2005

45. Treatment challenges in bipolar disorder
Bipolar disorder is often unrecognised
Initial diagnosis and undiagnosed
Comorbidities Common, can hinder diagnosis
Predominant symptomatic phase,
Depression can lead to misdiagnosis
Need for long-term symptom stability across
Chronic disorder both poles
Bipolar I vs bipolar II, rapid cycling,
Phenotypes mixed states
Evans 2000; Hirschfeld 2003a, 2003b
Judd et al 2002, 2003; Citrome 2005; Kupka et al 2007

46. Introduction
Plan.
Goals.
Place.
Tools.

47. Input
Patient.
Informant.
Records.
Research.

48. Goals
Short term:
Remission.
Decrease risks.
Long term:
Maintain Remission.
Good quality of life.

49. Goals
Bipolar disorder is characterised by recurrent episodes of major disturbance
at the two ‘poles’ of mood disturbance: mania and depression

50. Place
Home (outpatient).
Day hospital.
Hospital.

51. Tools
Pharmacotherapy.
Psychosocial treatment.
ECT.
Others.

52. 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

53. Drugs
Choice.
Dose.
Duration.

54. Psychosocial
Treatment
Choice.
Duration.
Setting.
Frequency.

55. Types
Ancient Treatments
 exorcism,
 caged like animals,
 beaten, burned, castrated,
mutilated, blood replaced
with animal’s blood

56. 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.

57. Psycho education
Information (counselling).
EE management.
Medication management.
Support.

58. Compliance Enhancement
Information.
Schedule.
Life chart.
Models.
Therapeutic alliance.

59. Others
Prodrome Detection:
Perry and colleagues
Interpersonal and Social Rhythm
Therapy (IPSRT) :
Frank and colleagues

60. ECT
Indications.
Frequency.
Number.
Procedures.

61. Electroconvulsive Therapy (ECT)

62. 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

63. 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

64. ECT – Safety
Mortality rate depends on medical comorbidity
Healthy individual: 1:10,000 mortality
Risk / 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

65. Mood Stabilizers
Lithium
Valproate
Carbamazepine
Lamotrigine
Topiramate (not effective)
Gabapentin (not effective)
Atypical Antipsychotics

66. 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

67. 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

68. The Evolution of Therapies for
Bipolar Disorder
1940 1950 1960 1970 1980 1990 2000 2002
ECT Lithium
First-generation Second-generation antipsychotics
and antidepressants
antipsychotics and
antidepressants Clozapine
Chlorpromazine* Risperidone+
Trifluoperazine
Olanzapine*
Fluphenazine Quetiapine+
Thioridazine Ziprasidone+
Haloperidol Aripiprazole+
Mesoridazine Asenipine
Anticonvulsants Anticonvulsants
Carbamazepine Gabapentin
Valproate Lamotrigine
Topiramate
ECT = electroconvulsive therapy Oxcarbazepine

69. Drug Response
Dependent on 3 Variables:
2. Drug Concentration 3. Patient
1. Affinity
Absorption Genetics
Receptors
Distribution Age
Enzymes
Metabolism Disease
Uptake Pumps
Elimination Environment
Clinical Response

70. The Perfect Mood Stabilizer A L ousy Mood Stabilizer
Efficacy in Efficacy in Efficacy in Efficacy in
Mania Depression Mania Depression
Tolerability Safety Tolerability Safety
L ithium Divalproex
Efficacy in Efficacy in Efficacy in Efficacy in
Mania Depression Mania Depression
Tolerability Safety Tolerability Safety

71. The Perfect Mood Stabilizer A L ousy Mood Stabilizer
Efficacy in Efficacy in Efficacy in Efficacy in
Mania Depression Mania Depression
Tolerability Safety Tolerability Safety
L amotrigine Olanzapine
Efficacy in Efficacy in Efficacy in Efficacy in
Mania Depression Mania Depression
Tolerability Safety Tolerability Safety

72. FDA-approved treatments
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 – – – –  –
Physicians’ Desk Reference 2007

73. 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

74. Slide 74
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

75. 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

76. Lithium - Adverse Effects
Neurological – dysphoria, lack of creativity, slowed
reaction times, memory difficulty, tremor
Endocrine – hypothyroid, hypoparathyroid
Cardiovascular – sick sinus syndrome
Renal – polydypsia, polyuria, nephrogenic diabetes
insipidus; long-term  decreased GFR, nephrotic
syndrome, renal insufficiency
Dermatological – acne, hair loss, psoriasis, rash
Gastrointestinal - anorexia, nausea, vomiting,
diarrhea
Misc – altered carbohydrate metabolism, weight
gain, fluid retention

77. Lithium Toxicity
Characterized by
1.2 – 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

78. Lithium - Teratogenicity
Ebstein’s Anomaly
Malformation of tricuspid valve
Can be mild to severe
Associated with first trimester
use
Risk: 1 / 1,000 in Li exposed
pregnancies
(20x risk general population)

79. Valproate (Depakine)
Indications
Acute 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

80. 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

81. 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

82. 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

83. 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,

84. 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

85. Carbamazepine - Pharmacology
 Inhibits voltage-dependent sodium
channels
 70-80% protein bound
 Induces its own metabolism
(autoinduction), requiring increase in dose
after 2-3 weeks

86. Carbamazepine – Adverse Events
Dose related – Non-dose related –
Double/blurred Agranulocytosis (1
vision in 125,000)
Vertigo Aplastic anemia
GI disturbance Hepatic failure (rare)
Cognitive Rash
impairment
Pancreatitis
Mild leukopenia

87. Carbamazepine – Adverse
Events
Teratogenicity - in 1st trimester,
increased incidence of neural tube
defects (1-4%), reduced risk with
folate supplementation

88. 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

89. 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

90. 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

91. Atypical Antipsychotics
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
*

92. Medication approved for bipolar
depression Monotherapy
Lithium
Olanzapine/fluxetine
Quetiapine
Lamotrigine

93. Drug Specificity:
Comparative Receptor Binding Profiles
Quetiapine Clozapine Olanzapine
D1 D2 M D1 D2
5HT2A
H1
5HT1A
5HT2A
H1 A1
A2 5HT1A
A2
A1
Aripiprazole* Ziprasidone Risperidone Haloperidol
5H12C A1 D2
D1
5HT1A
D3
H1
A1
A2 D2
5HT1A
5HT2A
5HT2A
Adapted from Gareri P, et al. Clin Drug Invest. 2003;23(5):287-322.
*
BMS Data on file.

94. Rationale-based Pharmacotherapy
Important Principles
Effects of Receptor
Receptor Binding Affinities Receptors
Blockade
Drug
H1 D2 5-HT2C 5-HT2A α1 M1 Sedation, weight gain,
H1
postural dizziness
Haloperidol 440 0.7 > 10,000 45 6 > 1,500 EPS, prolactin elevation,
D2
antipsychotic
Aripiprazole 61 0.34 15 3.4 57 > 10,000 5-HT2C Satiety Blockade
Olanzapine 7 11 23 4 19 1.9 5-HT2A Anti-EPS?
α1-
Hypotension
Quetiapine 11 160 1,500 295 7 120 adrenergic
Deficits in memory and
Risperidone 20 4 25 0.5 0.7 > 10,000 cognition, dry mouth,
M1
constipation, tachycardia,
Ziprasidone 50 5 1 0.4 11 > 1,000 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.

95. Binding Affinities for Atypical Antipsychotics
and Tricyclic Antidepressants for Norepinephrine
Transporter (NET)
Compound / drug NET Ki (nM)
Quetiapine > 10000
Norquetiapine 35
Clozapine 3168
Olanzapine > 10000
Risperidone > 10000
Paliperidone > 10000
Aripiprazole 2093
Ziprasidone 44*
Nortriptyline 2
Amitriptyline 13.3-35
Imipramine 52
Desipramine 0.55
Data from NIMH Psychoactive Drug Screening Program
Goldstein 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).

96. Drugs are not enough
Prodrome Detection: Perry and colleagues
Psycho education: Colom and colleagues
3. 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

97. 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

98. 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

99. 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

100. Initiation of sustained ultradian cycling during
unopposed antidepressant treatment in a bipolar II
female. 30–year delay in onset of appropriate treatment
Severe Two brief bursts of
ultradian cycling
Mania
Moderate
Mid * *
Depression
Mid
Moderate
1942 1956 1958 1960 1962 1964 1966 1968 1970 1972
Hypomanias and major depressive recurrences
Severe
Fluoxetine Carbamazepine
depressions Trazodone Lithium
Nimodipine
age 13 Aprozalam Antidepressant
treatment in
absence of a
mood stabiliser
continued
1974 1976 1980 1982 1984 1986 1988 1990 1992
Conversion to
continuous ultradian
cycling following fluoxetine
Post RM, Altshuler LL. In: Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. Mood disorders: Treatment of
Bipolar Disorders. 2009.

101. FUTURE DIRECTIONS

102. Brain Affection

103. Brain Affection

104. Brain affection

105. 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 ↑ age
Striatum
No difference in putamen between first- and multi-episode
patients
Cerebellum
↓ Cerebellar vermis volume in multi- vs first-episode patients
Amygdala
↑ Amygdala volume with ↑ age in young patients
Ventricles
↑ Ventricular volume in multi- vs first-episode patients
↑ Ventricular volume with ↑ number of manic episodes
↑ Ventricular volume with ↑ number of affective episodes

106. 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.

107. Anterior Limbic Networks
Thalamus (MD)
Cerebellar
vermis
Ventral pallidum Amygdala
Hypothalamus
Ventral striatum
Anterior cingulate
OFC/VLPFC DLPFC
subgenual dorsal
Expression of emotions

108. 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

109. THANK YOU