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Bipolar Disorder Steven L Dubovsky, M.D.
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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
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Psychosis Manic Depressive Insanity Dementia Praecox Deterioration
Remission /recurrence Manic Depressive Insanity Dementia Praecox
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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
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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
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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
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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
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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
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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
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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
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Bipolar I and II Bipolar I Bipolar II Mania Intermittent hypomania
Hypomania only Breeds true Family members have hypomania but not mania
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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Kindling
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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
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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
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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
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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
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One-Year Prospective Outcome in 258 Bipolar Patients
2/3 are continuously or intermittently ill Stanley Foundation Bipolar Network
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Types of Continuous Illness
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Number of Episodes in 1-Year Prospective Follow-up
Post RM et al: J Clin Psychiatry 2003;64:
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Treatment
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Mood Stabilizers Antimanic action
Prevent recurrences of mania and depression Better acutely for mania than depression Combinations may be necessary
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Established Mood Stabilizers
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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
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Advantages of Lithium Well established treatment
Once a day dosing in chronic treatment May have antidepressant properties May be neuroprotective
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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
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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
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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)
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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
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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
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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
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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
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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
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Evolution of Bipolar Mood Disorders
Kindling/ Sensitization Altered gene transcription Neuronal loss Antidepressant
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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
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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
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Treatment of Bipolar Depression
Mood Stabilizers Antipsychotic Drug Add Antidepressant Stop Antidepressant
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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
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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
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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
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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
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