This document provides information on bipolar disorder (BD), including its epidemiology, etiology, pathophysiology, clinical presentation, diagnosis, management, and treatment outcomes. Some key points: - BD is a chronic mood disorder characterized by episodes of mania and depression. It has a variable course with relapses and remissions. - The lifetime prevalence is 3-6.5% for disabling BD. Risk factors include genetic vulnerability and environmental/stress triggers. - Diagnosis is based on clinical presentation and history meeting DSM criteria for mood episodes. There are no biological tests. - Management involves pharmacotherapy with mood stabilizers like lithium and anticonvulsants, along with psychotherapy

1. Bipolar Disorders (BD)
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2. Presentation outline
• Introduction
• Epidemiology
• Etiology
• Pathophysiology
• Clinical presentation
• Diagnosis
• Management
• Evaluation of therapeutic outcome.
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3. Introduction
• Bipolar disorder is a mood disorder characterized by one or more episodes
of mania or hypomania, with a history of one or more major depressive
episodes
• It is a chronic illness with relapses and improvements or remissions
• It is disorder with a variable course of recurrent (cyclical) extreme
fluctuations in mood, energy, and behavior
• Cycles can be separated by long periods of stability or can cycle rapidly
• Bipolar disorder occurs with or without psychosis.
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4. Diverse episodes, frequencies, and patterns
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5. DEPRESSION
NORMAL
MOOD
MANIA
HYPOMANIA
MIXED EPISODE
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6. Epidemiology
• The lifetime prevalence of
• Disabling (syndromal) BD is 3 – 6.5% [Bipolar I (0.3 – 2.4%); Bipolar II (0.2 – 5%)]
• If subsyndromal disorders are included the figure rises to 17%
• ~50% do not receive treatment and most are homeless or in jail
• Mortality rate: X2-3 of the general population
• Mean age of onset of BD is 20 years [onset > 60 yrs secondary to medical causes)
• Early onset is associated with greater comorbidities (Substance abuse and anxiety), more
episodes, greater proportion of days depressed, and greater lifetime risk of suicide attempts.
• Susceptibility: Manias: M > F; Bipolar I: M = F; Bipolar II F > M
• Women have more bipolar depression, rapid cycling and mixed mood episodes.
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7. Comorbid Psychiatric and Medical Conditions
• Lifetime prevalence of psychiatric comorbidity = 78 – 85%
• Psychiatric comorbidities:
• Anxiety disorders, Eating disorders, substance abuse or dependence
• Make definitive diagnosis more difficult
• Poorer treatment outcome, high rates of suicidality, onset of
depression, and higher costs of treatment
• Medical comorbidities:
• Migraine, Multiple sclerosis, Brain tumor, Head trauma.
• Cushing’s syndrome.
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8. Etiology
• The precise etiology is unknown
a. Genetic vulnerability
• Monozygotic twin = 40% to 70%
• Another first-degree relative = 5% to 10%
b. Factors that may enhance gene expression
• Perinatal insult, head trauma, environmental factors, anatomical
abnormalities, psychosocial or physical stressors, nutritional factors,
dysregulation between excitatory and inhibitory, exposure to
chemicals or drugs.
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10. Suicide in Bipolar Disorder
• BP pts have higher rates of suicidal thinking, suicidal attempts, and
completed suicides
• One-third BP pts report previous suicide attempt
• Mood disorders contribute 50 – 70 % of all suicides
• 10 – 19 % with bipolar depression (bipolar I + bipolar II) commit suicide
• 10 – 15% with bipolar I disorder commit suicide
• 10 % among patients with unipolar depression commit suicide.
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11. Suicide in bipolar……..
• Suicidality risk is increased in the presence of :
• Early age at disease onset,
• High number of depressive episodes,
• Severe anxiety
• Command hallucinations/psychosis
• Comorbid alcohol abuse, Substance abuse
• Personal history of antidepressant-induced mania,
• Access to a means of suicide
• Prior suicide attempts and lethality of attempts, and
• Family history of suicidal behavior (attempted or completed suicide).
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12. Pathophysiology
• Not completely understood; But, changes in neuronal function within the
Prefrontal cortex, visual association cortex and limbic circuitry
• Early theories: an elevation of NE and DA caused mania and a reduction caused
depression, but these theories are now considered overly simplistic
• Hypothesis 1: imbalance of cholinergic and catecholaminergic neuronal activity
• 5 – HT modulates NT activity. Dysregulation of 5 – HT causes mood disturbance
• Hypothesis 2: Inositol disturbance: Lithium, valproate, and carbamazepine all have
similar effects on neuronal growth that are reversible by inositol
• Hypothesis 3: Serum brain derived neurotrophic factor (BDNF)
• BDNF is low in mania and improves with response to treatment.
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13. Diagnosis of Bipolar Disorder
a. Clinical Presentation
• General
• The patient may present in a hypomanic, manic, depressed, or
mixed state and may or may not be in acute distress.
b. Laboratory tests.
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14. a. Clinical Presentation [Mood and Affect]
Manic mood and behavior
• Euphoria
• Mood elevation (Expansive
mood or Irritable mood)
• Inflated self-esteem, Boasting
• Hostility, Aggression
Dysphoric mood and behavior
• Depression
• Anxiety, Agitation
• Violence or Suicidality
• Hopelessness.
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15. Clinical Presentation [Physical and behavioral]
• Increased physical energy
• Fatigue
• Sensory hyperactivity
• Heightened interest in pleasurable activities with a high risk of negative
consequences
• Spending sprees
• Recklessness, Impulsiveness
• Promiscuity, excessive libido, Hypersexuality)
• Insomnia (sometimes days or weeks) or Hypersomnia (sometimes).
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16. Clinical presentation……..
Cognitive symptoms
• Distractibility
• Poor insight
• Disorganization
• Inattentiveness
• Confusion
Psychotic symptoms
• Delusions of grandeur, ideas of
reference (IOR), persecution,
wealth, religion
• Racing thoughts
• flight of ideas (FOI)
• Rapid, pressured speech
• Hallucinations
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17. Clinical presentation……..
• Psychosocial
• Substance use
• Disrupted relationships
• Job loss.
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18. Bipolar Disorder - “DIGFAST”
1. Distractibility: poorly focused, multitasking; most common manic symptom
2. Impulsivity: in activities that do not display usual judgment
3. Grandiosity: inflated self-esteem; may be delusional; increased self-confidence
out of proportion to life’s circumstances
4. Flight of Ideas (FOI): complaints of racing thoughts
5. Activities: increase in goal-directed activities (social, sexual, work, school)
6. Sleep: decreased need for; differs from insomnia of depression (decreased
sleep)
7. Talkativeness: pressured speech or tendency to be more talkative.
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19. “DIGFAST”
1. Distractibility
2. Insomnia: decreased need for sleep
3. Grandiosity
4. Flight of ideas
5. Activities: increased goal-directed activities
6. Speech: pressured or more talkative
7. Thoughtlessness: “risk-taking” behaviors (sexual, financial, travel,
driving).
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20. b. Laboratory and Other Diagnostic Assessments
• There are no objective laboratory tests or procedures to diagnose bipolar
disorder, but such testing can be done to rule out other medical diagnoses
• Basic laboratory tests:
• CBC, blood chemistry screen: normal
• Urinalysis, urine toxicology, thyroid function, and white blood cell count in
elderly patients to rule out urinary tract infection
• Brain imaging: MRI and functional MRI (fMRI); alternative: CT: normal*
• Electroencephalogram (EEG): normal
• Lumbar puncture.
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21. DSM-IV-TR Criteria for Evaluation and Diagnosis of
Mood Episodes in Bipolar Disorder
• Diagnostic workup depends on clinical presentation and findings
• Mental status examination
• Psychiatric, medical, and medication history
• Physical and neurologic examination
• Psychological testing.
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24. Clinical Presentation…………
• Hallmark of a manic episode
a. Changes in mood (volatility of mood): irritable and easily frustrated,
especially when challenged
b. Excessive involvement in high risk but pleasurable activities
• Mixed episode [“irritable depression” or “dysphoric mania”] pts often have
• Comorbid alcohol and substance abuse
• Severe anxiety symptoms
• Higher suicide rate, non-response to anti-manic agents and poorer prognosis.
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DSM-IV-TR Categories of Mood Disorders
Disorder Subtype Episode(s)
1. Major depressive disorder (MDD)
or Unipolar depression
Major depressive episode
2. Dysthymic disorder Chronic subsyndromal depressive episodes
3. Bipolar disorder (BD)a
BD, type Ib ≥1 Manic episode ± ≥1 major depressive /mixed episode
BD, type IIc ≥1 Major depressive episode + 1 hypomanic episode
4. Cyclothymic disorderd Chronic fluctuations between subsyndromal depressive
and hypomanic episodes (2 years for adults and 1 year for
children and adolescents)
5. BD not otherwise specified (NOS) Mood states do not meet criteria for any specific bipolar
disorder
BD episodes should not be caused by a medical condition, substance abuse, or other psychiatric
disorder.

26. Remarks on letters at the table
• aThe length and severity of a mood episode and the interval between episodes vary from
patient to patient. Manic episodes are usually briefer and end more abruptly than major
depressive episodes. The average length of untreated manic episodes ranges from 4 to 13
months. Episodes can occur regularly (at the same time or season of the year) and often
cluster at 12-month intervals. Women have more depressive episodes than manic episodes,
whereas men have a more even distribution of episodes.
• bFor bipolar I disorder, 90% of individuals who experience a manic episode later have
multiple recurrent major depressive, manic, hypomanic, or mixed episodes alternating with
a normal mood state.
• c Approximately 5 – 15% of patients with bipolar II disorder will develop a manic episode
over a 5-year period. If a manic or mixed episode develops in a patient with bipolar II
disorder, the diagnosis is changed to bipolar I disorder.
• d Patients with cyclothymic disorder have a 15–50% risk of later developing a bipolar I or
II disorder.
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27. Clinical Course
• 3 – 10 years gap between onset and symptom presentation
• Episodes last from weeks to months with normal functioning between episodes
• Initial and subsequent episodes of BD are mostly depressive
• BP I pts spend 32% of weeks (1/3 of their time) with depressive symptoms
compared with 9% of weeks with manic or hypomanic symptoms
• BP II pts spend 50% of weeks (1/2 of their time) with depressive symptoms
and only 1% with hypomanic symptoms
• Most patients experience episodes of both mania and depression
• Minority of patients experience manic episodes alone.
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28. Course of illness……
• 90% of pts have >1 episode in lifetime whereas > 80% have > 4 episodes
• Cycle frequency and duration of episode increases with age
• Rapid cyclers (10 – 20%)
• Have ≥ 4 episodes per year
• are more common in female (70-90 %)
• Are associated with a poorer prognosis
• Have high non-response to anti-manic agents
• Risk factors for rapid cycling: Biologic rhythm dysregulation, Antidepressant or
stimulant use, Hypothyroidism, Pre-menstrual and postpartum states.
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29. Course of illness…….
• Substance abuse disorders in BP patients
• Alcohol and substance abuse is common
• BP pts with substance abuse disorders are more likely to have:
• An earlier onset of illness
• Mixed states
• Higher relapse rates
• Poorer response to treatment
• Higher suicide risk
• More hospitalizations.
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30. Management
• Desired Outcomes
• Eliminate/Reduce mood episode (mania or bipolar depression)
• Induce complete remission of symptoms (i.e., acute treatment)
• Prevent recurrences or relapses of mood (manic or depressive)
episodes (i.e., continuation phase treatment)
• Maintain or improve quality of life and improving function ➔ Return
to complete psychosocial functioning.
• Avoid or minimize adverse effects and maximize treatment adherence.
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31. Suicidality Risk
• Patients should be assessed for their potential for violence and harm
to others
• Friends or family can be asked to remove from home guns, caustic
chemicals, medications, and objects that patients might use to harm
themselves or others
• Risk factors for suicide include severity of depression, feelings of
hopelessness, comorbid personality disorder, and a history of a
previous suicide attempt.
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32. Nonpharmacologic Therapy
• Psychotherapy (CBT), Psychoeducation (individual, group, family),
interpersonal therapy
• Cognitive-behavioral therapy (CBT)
• It stresses recognizing patterns of cognition (thought) and how thoughts
influence subsequent feelings and behaviors
• Pts are taught self-management skills to change their negative thoughts in
order to feel and function better, even if external circumstances do not
change.
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33. Non-pharmacologic Therapy……..
• Psychoeducation for the patient, family and groups includes:
• Regarding chronicity of bipolar disorders;
• Psychosocial or physical stressors that precipitate an episode and
strategies for coping with stressful life events
• Early signs and symptoms of mania and depression and how to chart
mood changes
• Importance of compliance with therapy
• Development of a crisis intervention plan.
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34. Non-pharmacologic…….
• Psychoeducation: Self-management through;
• Stress reduction techniques, relaxation therapy, massage, yoga, etc.
• Sleep hygiene (regular bedtime and awake schedule; avoid alcohol or
caffeine intake prior to bedtime)
• Nutrition (regular intake of protein-rich foods or drinks and essential
fatty acids; Omega-3 fatty acids, supplemental vitamins and minerals)
• Exercise (regular aerobic and weight training at least three times a
week).
• Abstinence from substances (alcohol) and drugs that can trigger mood
episodes.
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35. Non-pharmacologic Therapy……..
• Electroconvulsive Therapy (ECT)
• Used in severe depression, mixed states, psychotic depression, treatment-
refractory mania, rapid cycling and in pts who are at high risk of suicide
• Used in intolerant (pregnant) women who cannot take carbamazepine,
lithium, or divalproex
• The best acute treatment for those who do not respond to first-line mood
stabilizers, such as lithium and valproate
• Efficacy:80%……….relapse rate?
• Drug interaction: Lithium (neurotoxicity); Discontinue 2 days before ECT until
2-3 days after.
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36. Pharmacologic Treatment
• The cornerstone of acute and maintenance treatment of bipolar disorder
• Approved Drugs by FDA For Bipolar Disorder
• Mood stabilizers
• Lithium
• Anticonvulsants: Divalproex Sodium, Carbamazepine, Lamotrigine
• Antipsychotics (AP):
• SGAs: Olanzapine, Risperidone, Quetiapine, Ziprasidone, Aripiprazole, Asenapine,
cariprazine
• FGAs: Chlorpromazine
• Adjunctive agents: Antidepressants and benzodiazepines
• CCBs: Nimodipine more effective than verapamil for rapid-cycling.
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37. Acute Therapy Recommendations of First Choice
• Treatment must be individualized
• Once diagnosed with bipolar disorder, patients should remain on a mood
stabilizer (e.g., lithium, valproate) for their lifetime
• During acute episodes, medications can be added and then tapered once
the patient is stabilized and euthymic (normal mood)
• Poly-pharmacy is the rule rather than the exception.
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38. Recommendations………Acute Therapy
• Acute Therapy: Manic Episodes
• Mild episodes:
• Monotherapy with lithium, valproic acid (VPA), or AP (olanzapine)
• VPA is preferred in mixed episodes (irritable depression /dysphoric mania),
mania with psychosis, and rapid-cycling BPD
• Lithium is the drug of choice for bipolar disorder with euphoric mania
• If no adequate response alone, both drugs may be used together,
• Responses to mood stabilizers develop slowly, taking 2 or more weeks to
become maximal; if needed add
• In mild mania: BZD (lorazepam)
• If Severe (manic or mixed) episodes or symptoms of psychosis: Atypicals
(Olanzapine or risperidone) preferred over typical.
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39. Recommendations………Acute Therapy
• Acute Therapy: Depressive Episodes (dominant):
• If depression is mild: Monotherapy with a mood stabilizer or AP
• Lithium or Quetiapine or lurasidone
• Alternative but not approved: lamotrigine, valproate
• If depression is severe: mood stabilizer or AP is inadequate
• Add antidepressants; Preferred: bupropion, venlafaxine, SSRIs.
• If response is inadequate Fluoxetine/olanzapine combination
• If response is inadequate consider adding carbamazepine
• Never use an antidepressant as monotherapy
• Non Responders: Add lamotrigine or paroxetine
• Life-threatening situations: ECT.
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40. Recommendations………Acute Therapy
• Acute Therapy: Combination therapies
• Better acute response and prevention of relapse and recurrence
than monotherapy in patients with mixed states or rapid cycling
• Common combinations in acute mood episodes
• Two mood-stabilizing drugs: Lithium plus valproate or
carbamazepine
• A mood-stabilizing drug and either an AP or AD: Lithium or
valproate plus an atypical AP.
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42. Long-Term Preventive Treatment
• The purpose of long-term (Maintenance treatment) therapy is to prevent
recurrence of both mania and depression
• As a rule, one or more mood stabilizers are employed
• Lithium, lamotrigine, aripiprazole, olanzapine and valproic acid
• Drug selection is based on what worked acutely
• Could be monotherapy or combination.
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43. Mood Stabilizers Therapeutic Principles
• Acute phase: all are equally effective
• Maintenance therapy: lithium (best) and lamotrigine are approved
• Life time maintenance for relapse prevention: mood-stabilizing
drugs.
• All require 1 – 2 weeks for full effect
• If no early response to single agent, may need to add adjunctive
agent (BZD or neuroleptic) or combo of lithium and anticonvulsant.
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44. Antipsychotics Therapeutic Principles
• 40 – 72% BD patients currently treated with AP
• Useful if psychotic symptoms are present and result in rapid
improvement: Days as opposed to weeks
• Acute mania: all atypical APs except clozapine are approved
• Bipolar depression: only quetiapine is approved
• Maintenance therapy: Olanzapine and aripiprazole are approved
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45. AP therapeutic principles…….
• Why antipsychotics?
• Failure rate with lithium may be as high as 50%
• Patient may fail to respond acutely to CBZ or VPA
• Patients with mixed, rapid cycling, substance abuse co-morbidity respond
poorly
• 70% of BD outpatients require adjunctive therapy and neuroleptics used in
more than 50%
• Drawbacks on antipsychotics
• Risk of neuroleptic malignant syndrome and tardive dyskinesia
• Risk of lithium-neuroleptic neurotoxicity.
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46. Antidepressants (ADs) Therapeutic Principles
• Avoid ADs or limiting their use to brief intervals to prevent a mood switch
to mania,
• ADs may be used for acute bipolar depression except TCAs
• Only after the patient has failed to respond adequately to optimal dose of
mood-stabilizing therapy
• With co-administration of therapeutic doses of mood stabilizers to reduce the
risk of AD-induced switching
• TCAs increased risk of inducing mania in BD I and possibly cause rapid cycling
• ADs should be withdrawn 2 to 6 months after remission and the patients
maintained on a mood stabilizer.
• Long-term antidepressants are required in some patients.
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50. Remarks on the Table
• ECT, electroconvulsive therapy; MAOI, manoamine oxidase inhibitor, SNRI, serotonin-norepinephrine reuptake inhibitor;
SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
• aUse standard therapeutic serum concentration ranges if clinically indicated; if partial response or breakthrough episode,
adjust dose to achieve higher serum concentrations without causing intolerable adverse effects; valproate is preferred
over lithium for mixed episodes and rapid cycling; lithium and/or lamotrigine is preferred over valproate for bipolar
depression.
• bLamotrigine is not approved for the acute treatment of depression, and the dose must be started low and slowly titrated
to decrease adverse effects if used for maintenance therapy of bipolar I disorder. A drug interaction and a severe
dermatologic rash can occur when lamotrigine is combined with valproate (i.e., lamotrigine doses must be halved from
standard dosing titration).
• cAntidepressant monotherapy is not recommended for bipolar depression. Bupropion, SSRIs (e.g., citalopram,
escitalopram, or sertraline), and SNRIs (e.g., venlafaxine) have shown good efficacy and fewer adverse effects in the
treatment of unipolar depression; MAOIs and TCAs have more adverse effects (e.g., weight gain) and can have a higher risk
of causing antidepressant-induced mania; fluoxetine, fluvoxamine, nefazodone, and paroxetine inhibit liver metabolism
and should be used with caution in patients on concomitant medications that require cytochrome P450 clearance;
paroxetine and venlafaxine have a higher risk for a discontinuation syndrome.
• dECT is used for severe mania or depression during pregnancy and for mixed episodes; prior to treatment,
anticonvulsants, lithium, benzodiazepines should be tapered off to maximize therapy and minimize adverse effects.
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51. Product Formulation, Dose, and Clinical Use of Agents
Used in the Treatment of Bipolar Disorder
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55. Special Populations
• Approximately 20 – 50% of women relapse postpartum;
• Prophylaxis with mood stabilizers (e.g., lithium or valproate) is
recommended immediately postpartum to decrease the risk of relapse.
• Lithium should be used at the lowest effective dose during pregnancy
• Epstein anomaly in infants exposed to lithium during the first trimester
• “floppy” infant syndrome, hypothyroidism, and nontoxic goiter in the infant.
• Valproate and carbamazepine can result in neural tube defect if taken
during the first trimester
• Administration of folic acid can reduce the risk of neural tube defects.
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56. Patients with Comorbid Diseases
• Renal insufficiency……….Avoid Li
• Heart disease…… Avoid Divalproex Sodium (DVPX)
• Liver impairment……Avoid DVPX
• Agranulocytosis……… Avoid carbamazepine
• Obesity…….. Avoid Carbamazepine/VPA.
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57. Thyroid Concerns
• People with bipolar disorder often have abnormal thyroid gland function
• T3 and T4 in lower range of “normal” cause cognitive impairment, relapse and
lethargy
• Rapid cyclers tend to have co-occurring thyroid problems and may need to
take thyroid pills in addition to their medications for bipolar disorder
• Lithium treatment may cause low thyroid levels in some people, resulting
in the need for thyroid supplementation
• Supplemental T4 benefits Li refractory patients.
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58. Insomnia
• High-potency benzodiazepine medication
• Clonazepam (Klonopin) and Lorazepam (Ativan)
• May be helpful to promote better sleep
• May be habit-forming
• Best prescribed on a short-term basis
• Other types of sedative medications……….
• Zolpidem (Ambien), are sometimes used instead.
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59. Evaluation of Therapeutic Outcomes
• Patients and family members should be actively involved in treatment
to monitor target symptoms, response, and side effects.
• Monitor for
• Mood episodes
• Medication adherence
• Adverse effects
• Suicidal ideation or attempts.
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60. Evaluation of Therapeutic Outcomes……
• Patients who have a partial response or non-response to therapy
should be reassessed for:
• An accurate diagnosis,
• Concomitant medical or psychiatric conditions and
• Medications or substances that exacerbate mood symptoms.
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61. Lithium Monitoring - Laboratory Tests
• ECG
• Fetal abnormalities…………….Pregnancy test
• Complete blood count with differential
• Platelet count/bleeding time………….Thrombocytopenia
• Electrolytes, blood urea nitrogen (BUN), creatinine,
• Urinalysis (specific gravity)
• Diabetes insipidus/development of renal failure
• Thyroid-stimulating hormone (TSH) and (Thyroid-Hypothyroidism/goiter)
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64. Thank you
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