1. Bipolar Disorder
Steven L Dubovsky, M.D.

2. Outline Describe spectrum of mania/hypomania
Explain neurobiology of bipolar mood disorders
Clarify course
Discuss mood stabilizers and their use
Acute
Bipolar depression
Maintenance
Highlight use of psychotherapy

3. Psychosis Manic Depressive Insanity Dementia Praecox Deterioration
Remission /recurrence
Manic Depressive Insanity
Dementia Praecox

4. It is becoming increasingly clear that we cannot distinguish
satisfactorily between these two illnesses [manic depressive
insanity and dementia praecox], and this brings home the suspicion
that our formulation of the problem may be incorrect.
Kraepelin, 1920

5. Bipolar Disorder Mania or hypomania >99% have depressive episodes
Activation alternates or mixed with depression
20%-50% of cases of depression
At least 15-20% of depressed primary care patients

6. Manic Episode Elevated, expansive or irritable mood
At least one week or any duration if hospitalized
At least 3 symptoms (4 if mood irritable)
Grandiosity
Decreased need for sleep
Increased speech/pressured speech
Flight of ideas/racing thoughts
Distractibility
Increased activity/agitation
Excessive involvement in behavior with potentially painful consequences

7. Hypomanic Episode Abnormal mood lasting at least 4 days
Same symptoms as manic episode
Change in functioning
Not severe enough to cause marked impairment or require hospitalization
Psychotic symptoms = mania

8. Spectrum of Mania Mania Hyperthymia Cyclothymia Hypomania
Psychosis
Gross impairment
Hyperthymia
Elevated activity
Reduced sleep
Optimistic
Cyclothymia
Mild mood
swings
Hypomania
Symptoms last days
No impaired functioning
or psychosis
No hospitalization

9. Common Presentations of Hypomania in Outpatients
Irritability, outbursts of rage
Arrogance, intrusiveness
Anxiety, panic attacks
Dysphoric (unpleasant) activation
Hypersensitivity to stimulation
Sensory
Interpersonal
Overcommitments, overspending
Slide 1 of 2

10. Common Presentations of Hypomania in Outpatients
Decreased sleep/insomnia without feeling tired or falling asleep during the day
Increased energy/mood mixed with depression
Feels depressed but does not look bad
Able to function well despite severe symptoms
Labile mood and behavior
Dissociation
“ADHD”
Impulsive suicidal or assaultive behavior
Slide 2 of 2

11. Bipolar I and II Bipolar I Bipolar II Mania Intermittent hypomania
Hypomania only
Breeds true
Family members have hypomania but not mania

12. Clues to Bipolarity Intense irritability Mood swings Thrill seeking
Psychotic symptoms
Early onset depression
Highly recurrent depression
Atypical depressive symptoms
Family history
Bipolar disorder
Any mood disorder in 3 consecutive generations

13. Bipolar Outcome of Depression
10-15% of major depressive disorder
4-41% in various studies
30% if bipolar spectrum
Increased likelihood of bipolar outcome in juvenile onset depression
20% of primary care patients taking antidepressants
Bipolar outcome in antidepressant-induced hypomania:
60% of adults
Mania increases true bipolar risk
100% of children and adolescents
Slide 1

14. Bipolar Outcome of Depression
Risk of bipolar conversion highest in 4 years after first depressive episode
Later conversion rate =1.25%/year
Reported risk factors for bipolar outcome of depression
Early onset
Psychosis
Atypical symptoms
Acute onset
Multiple episodes
Family history of mania
Affective disorder in multiple generations
Slide 2
JG Fiedorowicz et al: Am J Psychiatry 2011;168:40-48

15. Bipolar Outcome of Depression
NIMH Collaborative Depression Study
550 subjects with major depression
Mean follow-up 17.5 years
Bipolar conversion in 20%
12% bipolar II
8% bipolar I
Bipolar outcome predicted by
3 or more subclinical manic symptoms
Especially decreased need for sleep, high energy, increased goal directed activity, grandiosity
Sensitivity 16%
Specificity 95%
Positive predictive value 42%
Negative predictive value 82%
Many patients without subthreshold hypomanic symptoms eventually developed mania or hypomania
Psychotic symptoms
Early onset
Bipolar family history
Slide 3
JG Fiedorowicz et al: Am J Psychiatry 2011;168:40-48

16. Epidemiology Lifetime prevalence of bipolar I disorder around 1%
If milder (e.g., bipolar II) and subsyndromal (mild symptomatic) forms included, prevalence may be 6-7%
Recent national study: 1% bipolar I, 1.1% bipolar II, 2.4% subsyndromal
Not enough symptoms to qualify for mania
Enough symptoms but no impairment

17. Medical Causes of Mania and Mood Swings
Cushing’s disease
Adrenal steroids
Hypercalcemia
Thyroid disease
Right sided cerebrovascular disease
Antidepressants
Especially MAO inhibitors in non-bipolar patients
Stimulants
Cocaine

18. Bipolar Disorder is Highly Familial
Risk of bipolar disorder in first degree relatives of probands with
Unipolar depression: %
Bipolar disorder: %
Concordance rates for bipolar disorder:
MZ:
DZ: 0.20
Similar rates in twins reared separately or together
Risk of bipolar disorder in people adopted out of bipolar family is same as risk in people who remain in the family
Risk of bipolar disorder in people adopted into bipolar family is same as risk in general population

19. Bipolar Linkage Studies
Linkage to red-green color blindness in 1/3 of familial cases
X-linked trait (mother-son transmission)
Possible linkage to G6PD deficiency (close to gene for color blindness) in some studies
Linkage to RFLP (chromosome fragment) on chromosome 11p15 in Amish study with 60% penetrance
Refuted when bipolar developed in 2 people without the marker
Overlap with some regions linked to schizophrenia
Suggests shared liability (e.g., to psychosis)

20. Susceptibility Genes for Bipolar and Schizophrenia
DISC1 (disrupted in schizophrenia 1)
NRG1 (neuregulin 1)
BDNF
BRD1 (bromodomain containing 1
CLOCK (circadian locomotor output cycles kaput protein)
Increased frequency of bipolar recurrences

21. Anticipation in Mood Disorders
Children have earlier onset and more severe symptoms than parents
Study of unilinear unipolar depression
Accumulation of trinucleotide repeats
Bipolar disorder appeared with increased trinucleotide repeats

22. Kindling

23. Neurotransmitter Theories
Early theories: mania is associated with increased NE neurotransmission and depression with decreased NE transmission
Not supported by subsequent research
Neurotransmitter and receptor theories do not explain why 45% of manic patients are depressed at the same time

28. Abnormal Mood Glutamate CRF Hypersecretion Adrenal Steroids
Second
Messengers
NMDA Receptors
Glutamate
Free radicals,
proteolysis
activation of calcium-
dependent enzymes
Ca2+
Gene Expression
BDNF
BCL2
p53
GSK3β
Recruitment of
pathological pathways
Apoptosis susceptibility
Neuronal loss

29. Evolution of Bipolar Mood Disorders
Neuronal
loss
Kindling/
Sensitization
Altered gene
expression
Recurrent
depression
Rapid/ultradian
Cycling/chronicity/
psychosis
Pseudounipolar
Mania/
hypomania
Character
traits
Substance
Use

30. Common Associated Features
Highest rate of substance abuse of all psychiatric disorders
Alcohol, cocaine, stimulants most common
High familial rates of creativity and success in business
Suicide rate up to 15%
Suicide may occur in mania as well as depression
Bipolar patients more likely to kill someone else before killing themselves

31. One-Year Prospective Outcome in 258 Bipolar Patients
2/3 are continuously or intermittently ill
Stanley Foundation Bipolar Network

32. Types of Continuous Illness

33. Number of Episodes in 1-Year Prospective Follow-up
Post RM et al: J Clin Psychiatry 2003;64:

34. Treatment

35. Mood Stabilizers Antimanic action
Prevent recurrences of mania and depression
Better acutely for mania than depression
Combinations may be necessary

36. Established Mood Stabilizers

37. Lithium Intracellular Actions
↓Apoptosis susceptibility
↓NMDA activation
↓Oxidative stress
Ca2+
Slowing of circadian
phase advance
↑NO
↑NAA
↓GSK-3β
Lithium
↑bcl-2
↑NGF
↑ Synaptic plasticity
↓B-catenin
↓Apoptosis susceptibility
GSK=glycogen synthase kinase
bcl=B-cell lymphoma/leukemia (anti-apoptosis)
NO=nitric acid
NAA=N-acetylaspartate

38. Advantages of Lithium Well established treatment
Once a day dosing in chronic treatment
May have antidepressant properties
May be neuroprotective

39. Disadvantages of Lithium
Narrow therapeutic index
Blood levels must be measured
Long-term side effects
Cognitive dysfunction
Weight gain
Interference with insulin signaling
Acne
Hypothyroidism, hyperparathyroidism
?Renal damage

40. Advantages of Carbamazepine (Tegretol)
Better tolerated than lithium
Usually does not cause weight gain
May improve depression
May be better for rapid mood swings
May be useful for PTSD

41. Disadvantages of Carbamazepine
Wide dosage range
Induces its own metabolism
No established therapeutic dose or blood level
Divided dose necessary
Induces metabolism of other drugs
Including oral contraceptives
Adverse effects
Sedation
Neurotoxicity
SIADH
Occasional hypothyroidism
Bone marrow suppression extremely rare (next slide)

42. Carbamazepine and Agranulocytosis
Incidence 2/525,000
Routine CBCs not predictive
20% have initial decline in wbc count
Nevertheless, many clinicians follow routine CBCs and LFTs
Obtain CBC if clinical indication
Easy bruising
Infection
Do not combine with drugs than can depress bone marrow

43. Advantages of Divalproex (Depakote)
One bedtime dose sometimes works
Once a day and bedtime preferable for immediate release form
Sedative effect improves sleep
Extended release form (Depakote ER) given once a day
Anxiolytic
Antiaggressive

44. Disadvantages of Divalproex
Not an antidepressant
Depakote ER not studied in mood disorders
Adverse effects
Weight gain
Sedation
Hair loss
Cognitive impairment
Multiple ovarian cysts and PCOS
Pancreatitis

45. Atypical Antipsychotics
All antipsychotic drugs have antimanic properties
Does not imply prevention of recurrence
Antimanic effect demonstrated in 3-12 week placebo controlled trials for
Risperidone (Risperdal)
Olanzapine (Zyprexa)
Quetiapine (Seroquel)
Ziprasidone (Geodon)
Aripiprazole (Abilify)
Chronic studies of olanzapine positive but relied on sample enrichment and selection of subjects who were not very ill
Clozapine (Clozaril) most reliable mood stabilizer for refractory bipolar disorder
Potential for significant side effects
Weight gain
Sedation
Diabetes mellitus
Prolactinemia
Movement disorder

46. Initiating Mood Stabilizers in Outpatients
Start with low dose, e.g.,
300 mg Li
50 mg carbamazepine
mg valproate
Increase dose very slowly
Rapid dosage escalation often poorly tolerated
More adverse effects
Treatment-emergent depression or behavioral slowing
Combinations necessary for complex and chronic symptoms

47. Evolution of Bipolar Mood Disorders
Kindling/
Sensitization
Altered gene
transcription
Neuronal
loss
Antidepressant

48. Why Antidepressants are Risky in Bipolar Disorder
Transient improvement
Increased rate of recurrence of depression
Induction of hypomania
Often mixed with depressive recurrences
Manifested as irritability, anxiety
Increased complexity of illness
More treatment resistance
Research is contradictory on how to use antidepressants

49. Treatments Approved for Bipolar Depression That are Probably not Worth Using
Quetiapine (Seroquel)
Two 8-week studies
Partial improvement
No control for effect of sedation or improved sleep
Lack of mania in 8 weeks doesn’t mean anything
Lurasidone (Latuda)
6-week study
Lurasidone or placebo added to lithium or valproate
Lurasidone > placebo for MADRS reduction
-17.1 versus -13.5
Effect size 0.34
Lurasidone > placebo for CGI-BP severity reduction
-1.96 versus -1.51
Effect size 0.36
Effect sizes not impressive
Fluoxetine + olanzapine (Symbyax)
8-week study
Weight gain
50 mg fluoxetine + 12 mg olanzapine=20 mg fluoxetine

50. Treatment of Bipolar Depression
Mood Stabilizers
Antipsychotic
Drug
Add Antidepressant
Stop Antidepressant

51. Psychotherapy Improves medication adherence
Helps patient to deal more constructively with stress that precipitate acute episodes
Reduces recurrence rate
Does not cure primary dysfunction
Usually combined with medication
Effective therapies:
Interpersonal therapy
Social rhythms therapy
Family focused therapy

53. Take Home Points
Bipolar disorder is a different illness than unipolar depression
Depression often appears before mania
Course is frequently progressive
The majority of patients are chronically symptomatic
There are multiple subtypes
Bipolar I: mania and hypomania
Bipolar II: hypomania only
Masked and subsyndromal forms
Slide 1 of 3

54. Take Home Points
Different bipolar subtypes are probably associated with different patterns of familial transmission
Associated with color blindness in a minority of families
Consecutive generations
Genetic overlap with schizophrenia
Sporadic cases occur
Familial association with creativity and success in business
Pathophysiology probably involves alterations in second messenger signaling and gene expression
Since most cases are recurrent or chronic, ongoing treatment is usually necessary
Noncompliance is common
Rapid treatment discontinuation can cause worsening of illness and treatment refractoriness
Slide 2 of 3

55. Take Home Points Treatment of mania Treatment of bipolar depression
Mood stabilizer with or without antipsychotic drug
Benzodiazepine may be added for agitation
Lithium, carbamazepine and valproate are first-line treatments
All antipsychotic drugs are effective in mania
Treatment of bipolar depression
Mood stabilizer(s) first
Add antidepressant if necessary
Ongoing antidepressant treatment controversial
Maintenance treatment
One or more mood stabilizers
Antipsychotic drugs are second line treatments
Treat substance abuse
Involve the family
Slide 3 of 3