This document discusses the history, diagnosis, and challenges of bipolar disorder. It traces the recognition and understanding of the disorder back to ancient Greek physicians like Hippocrates and Aretaeus. In the late 19th century, Emil Kraepelin defined manic-depressive illness and distinguished it from schizophrenia. The concept of bipolar disorder was further developed in the 20th century. It remains a highly prevalent mental illness worldwide, with genetic and biochemical contributors as well as structural brain abnormalities implicated in its pathophysiology. Managing bipolar disorder long-term poses ongoing challenges.

1. Bipolar Disorder
Old diagnosis,
Current problem,
Future challenge

2. Bipolar disorder, or manic-depressive
illness, has been recognized since at least
the time of Hippocrates, who described such
patients as "amic" and "melancholic.“
In 1899, Emil Kraepelin defined manic-depressive
illness and noted that persons
with manic-depressive illness lacked
deterioration and dementia, which he
associated with schizophrenia.

3. In 150 AD Aretaeus described mania and melancholia in the
same patient.
Same physician who described and named diabetes.

4. Kraepelin in 1913 formulated concept of “manic depressive
insanity” (which included recurrent affective disorders

5. Leonhard in 1957 elaborated concept of bipolarity

6. Goodwin in early 1970’s described Bipolar II;
Akiskal broadened concept of illness to Bipolar
Spectrum;
Gorman and McCrank pointed out importance
of anxiety disorders

7. • Common illness affecting 2% of the world population
(5% if one includes spectrum disorders)
• Consistently among 10 leading causes of medical
disability in the world
• 6th leading cause of medical disability in the
developed nations
• Prominent cognitive abnormalities
• Particularly recalcitrant mental health problem
• Symptomatic at least half the time
• Can have impaired social function even when
symptom-free
B
I
P
O
L
A
R
D
I
S
O
R
D
E
R

8. Depressive Symptoms
• Depressed mood
• Diminished interest or pleasure in all, or
almost all, activities
• Decreased or increased appetite
• Significant weight loss or gain
• Insomnia or hypersomnia
• Psychomotor agitation or retardation
• Fatigue or loss of energy
• Feelings of worthlessness or excessive or
inappropriate guilt
• Diminished ability to think or concentrate
• Recurrent thoughts of death
• Recurrent suicidal ideation or attempts

9. Manic Symptoms
• Inflated self-esteem or grandiosity.
• Decreased need for sleep
• More talkative than usual
• Flight of ideas or subjective
experience that thoughts are
racing.
• Distractibility
• Increase in goal-directed activity
or psychomotor agitation.
• Excessive involvement in
pleasurable activities that have a
high potential for painful
consequences

10. Bipolar Disorder and the Creative Genius
Thinking Outside the Box
Many famous historical figures gifted with creative talents may
have been affected by bipolar disorder. Wolfgang Amadeus
Mozart , Ludwig van Beethoven, Virginia Woolf, Isaac
Newton, and Robert Schumann, Salah Jaheen, Almotanabee,
Van Gogh are some people whose lives have been researched
to discover signs of mood disorder

11. Wolfgang Amadeus Mozart
1756-1791
Composer of over 600 musical works
Mozart’s movements and behaviour: a
case of Tourette’s syndrome?
Was Mozart Autistic? Exploring the
Relationship Between Autism and
Creativity
Wolfgang Amadeus Mozart's psychopathology
in light of the current conceptualization of
psychiatric disorders.

12. Wolfgang Amadeus Mozart's psychopathology
in light of the current conceptualization of
psychiatric disorders.
Huguelet P, Perroud N.
Department of Psychiatry of Geneva, Service de psychiatrie adulte, 36, rue du XXXI Décembre, CH-1207
Geneva, Switzerland. philippe.huguelet@hcuge.ch
Abstract
The study of Mozart's letters and biography leads us to reconsider the
psychiatric disorders from which he suffered. Indeed, it seems that
Mozart demonstrated depressive episodes, some of which were severe
and corresponded to the criteria of the DSM-IV classification. However,
the arguments put forward by other authors supporting the occurrence
of manic or hypomanic episodes (thus constituting a bipolar disorder
diagnosis) are not supported by sufficient historic proof. Indeed, the
length of time that the behaviors suggesting manic symptoms lasted is
not compatible with such a diagnosis. Rather, Mozart's mood swings
and impulsive behavior correspond to some traits of a personality
disorder, that is, for the most part, symptoms of the dependent
personality disorder. Evidence for this diagnosis appears most notably in
Mozart's reactions to his wife's absences, but also in occasional
behaviors as well as mood lability. The divergences in the classification
of Mozart's symptoms, either into the field of bipolar disorders or into
that of personality disorders, are closely linked to the nosological
uncertainties that are still a source of debate in today's psychiatric
research. We discuss a means of overcoming this limitation by
considering the concept of "soft bipolar spectrum," a
conceptualization that corresponds to Mozart's psychiatric history.

14. DSM-IV-TR
Classification of Bipolar Disorders
Bipolar Disorder
Not Otherwise
Specified
Bipolar features
that do not meet
criteria for any
specific bipolar
disorders
Bipolar I Bipolar II Cyclothymic
At least 2 years of
numerous periods
of hypomanic and
depressive
symptoms*
One or more
major depressive
episodes
accompanied
by at least one
hypomanic
episode
FEMALE>MALE
One or more
manic or mixed
episodes, usually
accompanied by
major depressive
episodes
MALE=FEMALE
* Symptoms do not meet criteria for manic and depressive episodes.
First, ed. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Text Rev.
Washington, DC: American Psychiatric Association; 2000:345-428.

15. Manic episode 1 week
Hypomnic episode 4 days
Depressive Episode 2 weeks
Mixed episode 1 week
Cyclothymia 2 years

16. Akiskal's Schema of Bipolar Subtypes
(Psychiatric Clinics of North America 22:3, September 1999; Medscape Family
Medicine, 2005;7[1])
Bipolar I: full-blown mania
Bipolar I ½: depression with protracted hypomania
Bipolar II: depression with hypomanic episodes
Bipolar II ½: cyclothymic disorder
Bipolar III: hypomania due to antidepressant drugs
Bipolar III ½: hypomania and/or depression associated with
substance use
Bipolar IV: depression associated with hyperthymic temperament
Bipolar V: recurrent depressions that are admixed with dysphoric
hypomania
Bipolar VI: late onset depression with mixed mood features,
progressing to a dementia-like syndrome

18. Epidemiology
• Mortality/Morbidity
 Bipolar disorder has significant morbidity and mortality rates.
 Approximately 25-50% of individuals with bipolar disorder attempt suicide,
and 11% actually commit suicide.
• Race
 No racial predilection exists.
• Sex
 Bipolar I disorder occurs equally in both sexes;
 rapid-cycling bipolar disorder (4 or more episodes a year) is more common
in women than in men.
 Incidence of bipolar II disorder is higher in females than in males.
• Age
 The age of onset of bipolar disorder varies greatly.
 The age range for both bipolar I and bipolar II is from childhood to 50
years, with a mean age of approximately 21 years,(15-19 years),(20-24
years).
 Onset of mania in people older than 50 years should lead to an
investigation for medical or neurologic disorders such as cerebrovascular
disease.

19. Bipolar Disorder challenges

20. Bipolar disorder has a number of contributing factors,
including genetic, biochemical, psychodynamic, and
environmental elements
Biochemical causes
Evidence is mounting of the contribution of glutamate to both bipolar and major
depressions. A postmortem study of the frontal lobes with both these disorders
revealed that the glutamate levels were increased
catecholamine hypothesis, which holds that an increase in epinephrine
and norepinephrine causes mania and a decrease in epinephrine and norepinephrine
causes depression.
Hormonal imbalances and disruptions of the hypothalamic-pituitary-adrenal
axis involved in homeostasis and the stress response may also contribute to
the clinical picture of bipolar disorder.
Psychodynamic mania serves as a defense against the feelings of
depression
Environmental
external stresses or the external pressures may serve to
exacerbate some underlying genetic or biochemical
predisposition.
Pregnancy is a particular stress for women with a manic-depressive
illness history and increases the possibility of
postpartum psychosis

21. Bipolar Disorder
• Highly heritable (80% genetic contribution)
– Multiple genes
– 16 different chromosomal regions
• Structural and Functional Brain Abnormalities
– amygdala, anterior cingulate and prefrontal cortex,
putamen, thalamus/hypothalamus

22. Pathophysiology
• 80% genetic contribution
– Complex genetic disorder, multiple different
common disease alleles.
– 16 different chromosomal regions
• Two particular genes, ANK3 (ankyrin
G) and CACNA1C (alpha 1C subunit
of the L-type voltage-gated calcium
channel).
• ANK3 is an adaptor protein found at axon initial segments
that regulates the assembly of voltage-gated sodium
channels and both ANK3 and subunits of the calcium
channel are down-regulated in mouse brain in response
to lithium, indicating a possible therapeutic mechanism of
action of one of the most effective treatments for bipolar
disorder.

23. Pathophysiology
• Diacylglycerol kinase eta (DGKH) gene. DGKH is a key protein in the
lithium-sensitive phosphatidyl inositol pathway.
• Glycogen Synthase Kinase 3-beta (GSK3β). Lithium-mediated inhibition of
GSK3β is thought to result in down-regulation of molecules
involved in cell death and upregulation of neuroprotective
factors .
• GSK3β is a central regulator of the circadian clock and lithium-mediated
modulation of circadian periodicity is thought to be a
critical component of its therapeutic effect.
• COMT gene (Catechol-O-methyltransferase ) has important role in
Intelligence, BP, schizophrenia
• CLOCK gene(Circadian Locomotor Output Cycles Kaput ): a dominant-negative
mutation in the CLOCK gene normally contributing to
circadian periodicity in humans results in manic-like behavior in
mice.

24. Pathophysiology
• Manic behavior in CLOCK mutant mice includes
hyperactivity, decreased sleep, reduced anxiety,
and an increased response to cocaine→→
provides a shared biological basis for the high rate
of substance abuse observed in clinical
populations of subjects with bipolar disorder.
• Experimenters were able to abolish the manic
behaviors by rescuing expression of normal
CLOCK specifically in the ventral tegmental area
of the mouse brain. This area is rich in D2
receptors.

25. Pathophysiology • Oligodendrocyte-myelin-related genes
appear to be decreased in brain tissue from
persons with bipolar disorder.
• loss of myelin is thought to disrupt
communication between neurons, leading to
some of the thought disturbances observed
in bipolar disorder and related illnesses.
• Brain imaging studies of persons with bipolar
disorder also show abnormal myelination in
several brain regions associated with this
illness.
Gene expression and neuroimaging: mood disorders and
schizophrenia, may share some biological underpinnings, possibly
related to psychosis.

26. • Lithium and Valproate effect: up-regulation of Cytoprotective
protein Bcl-2 in the frontal cortex and the hippocampus!!.
• Neuro-imaging studies suggest evidence of cell loss or
atrophy in these same brain regions in bipolar and mood
disorders patients. Thus, another suggested cause of
bipolar disorder is damage to cells in the critical brain
circuitry that regulates emotion.
• According to this hypothesis, mood stabilizers and
antidepressants are thought to alter mood by
stimulating cell survival pathways and increasing levels
of neurotrophic factors to improve cellular resiliency.

27. Bipolar disorder and Schizophrenia
• Bipolar disorder and schizophrenia share common
susceptibility genes on chromosome 6.
• These genes are located in a section of the
chromosome containing genes involved in immunity
and controlling how and when genes turn on and off.
This connection can help explain the
link between environmental stress and
schizophrenia and possibly bipolar
disorder.

28. Bipolar disorder and Schizophrenia
Bipolar Disorder Shared Genes Schizophrenia

29. Alzheimer’s Disease
Mental Illness
Schizophrenia Bipolar Disorder
&
Genetics
Depression

30. Mental Illness & Genetics

31. Evidence-based markers of Bipolar Disorder
• The patient has had repeated episodes of major depression (four or more; seasonal shifts
in mood are also common).
• The first episode of major depression occurred before age 25 (some experts say before
age 20, a few before age 18; most likely, the younger you were at the first episode, the
more it is that bipolar disorder, not "unipolar", was the basis for that episode).
• A first-degree relative (mother/father, brother/sister, daughter/son) has a diagnosis of
bipolar disorder.
• When not depressed, mood and energy are a bit higher than average, all the time
("hyperthymic personality").
• When depressed, symptoms are "atypical": extremely low energy and activity; excessive
sleep (e.g. more than 10 hours a day); mood is highly reactive to the actions and actions
of others; and (the weakest such sign) appetite is more likely to be increased than
decreased. Some experts think that carbohydrate craving and night eating are variants of
this appetite effect.
• Episodes of major depression are brief, e.g. less than 3 months.
• The patient has had psychosis (loss of contact with reality) during an episode of
depression.
• The patient has had severe depression after giving birth to a child ("postpartum
depression").
• The patient has had hypomania or mania while taking an antidepressant (remember,
severe irritability, difficulty sleeping, and agitation may -- but do not always -- qualify for
"hypomania").
• The patient has had loss of response to an antidepressant (sometimes called "Prozac
Poop-out"): it worked well for a while then the depression symptoms came back, usually
within a few months.
• Three or more antidepressants have been tried, and none worked.

32. ANXIOUS DEPRESSION
COULD BE "BIPOLAR"?!

33. Differential Diagnoses
Anxiety Disorders Posttraumatic Stress Disorder
Cushing Syndrome Schizoaffective Disorder
Head Trauma Schizophrenia
Hyperthyroidism Systemic Lupus Erythematosus
Hypothyroidism
Other Problems to Be Considered
•Cancer
•Neurosyphilis
•Epilepsy (See the Medscape Epilepsy Resource Center.)
•Fahr disease
•AIDS
•Multiple sclerosis
•Medications (eg, antidepressants can propel a patient into mania; other medications may include
baclofen, bromide, bromocriptine, captopril, cimetidine, corticosteroids, cyclosporine, disulfiram,
hydralazine, isoniazid, levodopa, methylphenidate, metrizamide, procarbazine, procyclidine)
•Circadian rhythm desynchronization
•Attention deficit hyperactivity disorder (ADHD), especially in children and adolescents
•Cyclothymic disorder
•Multiple personality disorder
•Oppositional defiant disorder (in children)
•Substance abuse disorders (eg, with alcohol, amphetamines, cocaine, hallucinogens, opiates)

34. Medical Care
Inpatient hospital treatment
The indications for hospitalization in a person with bipolar disorder include the
following:
•Danger to self:
•Danger to others:
•Total inability to function:
•Medical conditions that warrant medication monitoring
Partial hospitalization or a day-treatment program
In general, these patients have severe symptoms but have a level of control and a
stable living environment.
Outpatient treatment: has 4 major goals.
1. First, look at areas of stress and find ways to handle them. This is a form of
psychotherapy.
2. Second, monitor and support the medication.
3. Third, develop and maintain the therapeutic alliance.
4. The fourth aspect involves education.

35. Evidence-based guidelines
for treating
bipolar disorder

38. Medication Why you might choose it
lamotrigine/Lamictal
•Depression is the dominant symptom , Rapid cycling , Need all the antidepressant you can get ,
Afraid of weight gain
lithium
•Classic bipolar I symptom pattern: euphoric mania and severe depressions ,,Significant manic
symptoms, Need all the antidepressant you can get , Suicide risk is a concern, Very inexpensive
quetiapine/Seroquel
•Depression and agitation are both severe , Severe sleep problems, Anxiety is a significant symptom,
No family history of diabetes
divalproex/Depakote
•Need something strong and fast, Male, and not afraid of weight gain, Rapid cycling , Significant manic
symptoms
carbamazepine/Tegretol
•Rapid cycling ,Severe sleep problems, Can't take Depakote (e.g. afraid of weight gain risk) ,Can't
afford Trileptal, or need the stronger option
olanzapine/Zyprexa
•Emergency-level symptoms, Need help really fast ,Can use on "as-needed" basis ,(If you continue to
use it regularly) Not afraid of weight gain
oxcarbazepine/Trileptal
•Milder symptoms, can risk a possibly weaker agent , Significant manic symptoms , Alternative to
Depakote as a starting place, Low long-term risk is appealing
omega-3 fatty acids/
fish oil
•"Natural"; biggest known risk is "seal burps" , Milder symptoms, can risk a weaker agent , You want to
add a possible mood stabilizer without adding more "medication“, Depression is a major symptom
•Willing to take a lot of pills, or swallow (flavored) fish oil
verapamil
•Possible alternative for pregnancy, Low side effect risk
•Tried many other medications but not ready for clozapine
clozapine
•Tried everything else , Severe symptoms , Ready for major weight gain, weekly blood tests , Ready
for one of the most effective medications we have
atypical (2nd
generation)
antipsychotics
•Low-dose boosters for specific problems (as add-ons to "real" mood stabilizers?) Seroquel: for sleep
and agitation; has weight gain risk
•risperidone: for elderly, at very low doses; or BPI perhaps -- tricky antidepressant effects in some
•Geodon: no clear role; but hey, it causes less weight gain than Zyprexa, and really helps an
occasional patient
•Abilify: strong antimanic, not so clear regarding depression -- but still learning about this one (as of
1/2009)

39. 12/15/2014