Its literature review of depression & bipolar mood disorder.

1. Bipolar Disorder
Depression&
Presentor – Kapil S. Kulkarni
Moderator – Dr. J.P. Rawat

2. What is Bipolar Disorder?
It is a mood disorder characterized by one or
more episodes of mania or hypomania
often with a history of one or more major depressive episodes.
Mood episodes: Manic, Depressed, or Mixed

3. Correct diagnosis and treatment are essential as early as
possible in the course of the illness to prevent complications
.and maximize response to treatment

4. EPIDEMIOLOGY AND
ETIOLOGY

5. Bipolar I disorder is characterized by one or more
manic or mixed mood episodes
Bipolar II disorder is characterized by one or more major
.depressive episodes and at least one hypomanic episode
Hypomania is an abnormally and persistently elevated,
expansive, or irritable mood, but not of sufficient severity to
cause significant impairment in social or occupational function
.and does not require hospitalization

6.  The lifetime prevalence of bipolar I disorder is estimated to
be between 0.3% and 2.4%.
 The lifetime prevalence of bipolar II disorder ranges from
0.2% to 5%.
 Bipolar I disorder affects men and women equally.
 Bipolar II seems to be more common in women.
 Rapid cycling and mixed mania occur more often in women.

7.  The mean age of onset of bipolar disorder is 20 yrs.
 Although onset may occur in early childhood to the mid-40s.
 If the onset of symptoms occurs after 60 years of age, then its
probably secondary to medical causes.
 The most common comorbid conditions include anxiety,
substance abuse, and eating disorder.
.

8.  The precise etiology of bipolar disorder is unknown.
-Genetically based
-Environmental factors
-Neurotransmitters

9. Genetic
The lifetime risk of bipolar disorder in relatives
of a bipolar patient is 40% to 70% for a monozygotic twin and
5% to 10% for another first-degree relative.
Dizygotic twins have 20% to 25% chances and children of
parent with bipolar disorder have 50% risk.
Environmental
HPA axis dysfunction due to environmental stress.
Neurotransmitters
NA, DA, 5HT and Glutamate are implicated.

10. PATHOPHYSIOLOGY

11. Neurochemical
 The pathophysiology of bipolar disorder has been poorly
understood.
 Imbalance of cholinergic and catecholaminergic neuronal
activity
 Bipolar disorder is also related to inositol disterbance.

12. Theories
Abnormal “programmed cell death”
Studies in animal have shown that antidepressent, lithium and
valproate indirectly regulate factors involved in cell survival.
(BDNF, Bcl2 etc)
“Kindling”
Older hypothesis, same as in epilepsy, states that genetically
predisposed persons experience minor neurological insult
( Due to excess of glucocorticoids, other acute or chronic
stressors, drug abuse)

13. Theories
These eventually result in mania.
After first episode, sufficient neuronal damage persists which
allow recurrence with or without minor environmental or
behavioral stressors.
This view also provides explanation to why anticonvulsants are
useful in BMD.

14. CLINICAL PRESENTATION
AND DIAGNOSIS

15. Symptoms
1-Mood
• Expansive/ eleted mood
• Irritable mood Mania
 Excess happiness
• Sad/ low mood
• Hopelessness Depression
• Suicidality

16. 2-Physical/Behavioral:
• Agitation
• Impulsivity
• Aggression
• Rapid, pressured speech
• Decreased need for sleep (Insomnia) Mania
• Hyper sexuality
• Increased physical energy
• Inflated self-esteem
• Grandiosity

17. Clinical Presentation
1. Lack of energy
2. Excessive lethargy
3. Lack of initiative
4. Hopelessness Depression
5. Helplessness
6. Worthlessness
7. Suicidal tendancy

18. 3-Thought Processes
Flight of ideas (FOI)
Easy distractibility
Delusions of grandeosity Mania
Ideas of reference

19. Clinical Presentation
 Suicidal ideations
 Negative thoughts
 Lack of initiative Depression
 Ideas of hopelessness
 Nihilistic delusion

20.  Lab test to rule out other medical disorder.
 A mood disorder questionnaire. (YMRS, HDRS)

21.  Bipolar I disorder (periods of major depressive, manic, and/or
mixed episodes)
 Bipolar II disorder (periods of major depression and
hypomania)
 Cyclothymic disorder (periods of hypomanic episodes and
depressive episodes)
 Bipolar disorder, NOS

22.  Bipolar I disorder diagnosis require one episode of
mania, for at least 1 week or longer with elevated,
expansive, or irritable mood , decreased
need for sleep, excessive energy.
 If Bipolar disorder 1 diagnosed as MDD and the patient is
treated by antidepressant this can precipitate mania or
induce rapid cycling of mania.

23.  The distinguishing feature of bipolar II disorder is
depression with past hypomanic episodes.

24.  Cyclothymic disorder is a chronic mood disturbance generally
lasting at least 2 year.(1 year in children and adolescents)
 Characterized by mood swings including periods of
hypomania and depressive symptoms.
 Hypomanic symptoms (grandiosity, decreased need for sleep,
pressure of speech, flight of ideas, distractibility)

25.  Patients with bipolar disorder have a high risk of suicide.

30. >= 2-week period of either depressed mood or loss of
interest, associated with at least 5 of the following
symptoms:
•Depressed/sad mood
• Decreased interest and pleasure in normal activities
• Decreased appetite, weight loss
• Insomnia or hypersomnia
• Psychomotor retardation or agitation
• Decreased energy or fatigue
• Feeling of guilt or worthlessness
• Impaired concentration and decision making
• Suicidal thoughts or attempts

31. >= 1-week period of abnormal and persistent elevated mood
(expansive or irritable), associated with at least 3 of the
following symptoms (four if the mood is only irritable):
• Inflated self-esteem (grandiosity)
• Decreased need for sleep(insomnia)
• Increased talking (pressure of speech)
• Racing thoughts (flight of ideas)
• Distractible (poor attention)
• Increased activity (either socially, at work, or sexually) or increased motor
activity or agitation
• Excessive involvement in activities that are pleasurable but have a high
risk for serious consequences (buying sprees, sexual indiscretions, poor
judgment in business ventures)

32. At least 4 days of abnormal and persistent elevated mood
(expansive or irritable); associated with at least 3 of the
following symptoms (four if the mood is only irritable):
• Inflated self-esteem (grandiosity)
• Decreased need for sleep
• Increased talking (pressure of speech)
• Racing thoughts (flight of ideas)
• Increased activity (either socially, at work, or sexually) or increased motor
activity or agitation.
• Excessive involvement in activities that are pleasurable but have a high risk
for serious consequences (buying sprees, sexual indiscretions, poor
judgment in business ventures)

33.  Criteria for both a major depressive episode and manic
episode (except for duration) occur nearly every day for
at least a 1-week period.

34.  Greater than 3 major depressive or manic episodes
(manic, mixed, or hypomanic) in 12 months.

35. • Personality disorders
• Alcohol and substance abuse or dependence
• Anxiety disorders, including panic disorder,
• Obsessive compulsive
• Eating disorders
Medical comorbidities include:
• Migraine
• Multiple sclerosis
• Cushing’s syndrome
• Brain tumor
• Head trauma

37. • Reduce the symptoms of mania
• Reduce the symptoms of bipolar depression
• Prevent the recurrence of a manic or depressive episode
• Avoid or minimize adverse treatment effects
• Promote treatment adherence
• Improve quality of life

38.  Mood stabilizing agents are the cornerstone of
treatment.
 Complete assessment and careful diagnosis to rule out
non-psychiatric causes.
 Treatment is lifelong.

39.  Interpersonal, family and group therapy.
 Cognitive-behavioral therapy (CBT).
 Electroconvulsive therapy (ECT).
 Psychoeducation.

41. Mood-stabilizing drugs are the usual first-choice treatments and
include lithium, divalproate, carbamazepine, and lamotrigine.
 Atypical antipsychotics other than clozapine are also approved for
treatment of acute mania
 Lithium, lamotrigine, olanzapine, and aripiprazole are approved for
maintenance therapy.
 Benzodiazepines are used adjunctively for mania.
 Antidepressants may be used for bipolar depression, but usually
along with a mood-stabilizing agent to prevent a mood switch to
mania
 Mood-stabilizing drugs are considered the primary
pharmacotherapy for relapse prevention.

45. Maintenance Therapy

46. First, 2 or 3 drug combination
Lithium or valproate +benzodiazepine for short term t
treatment of agitation or insomnia
If psychosis is present consider atypical antipsychotic w
with above
Alternative, carbamazepine…….no response or tolerate c
consider oxcarbazepine
Second if inadequate response ……then use 3 drugs c
combination
Lithium +Anticonvulsant +Atypical antipsychotic
Anticonvulsant +Anticonvulsant +atypical antipsychotic
Third if still inadequate response ……ECT

47. Hypomania
 First initiate and/or optimize-
Mood stabilizing medication (lithium ,DVP, or a
carbamazepine) c
Consider adding BZD for short term of g g
agitation or insomnia .
Alternative Carbamazepine……if no response consider a
antipsychotic
 Second if response is inadequate to above medication …. T
Then consider2 drug combination
Lithium +Anticonvulsant or atypical antipsychotic
Anticonvulsant + Anticonvulsant or atypical a n
antipsychotic

48. First - Mood stabilizing medication( lithium or lamotrigine)
Alternative - Anticonvulsant (valproate ,carbamazepine or o
oxcarbazepine )

49. First 2 or 3 drug combination
- Lithium or Lamotrigine +antidepressant
- Lithium + Lamotrigine
If psychosis is present …..add on antipsychotic
Alternative anticonvulsant : valproate ,Carbamazepine or o
oxcarbazepine
Second if inadequate response …consider adding on atypical a
antipsychotic (Quetiapine )
Third if inadequate response …….3 drug combination
Lamotrigine + Anticonvulsant +Antidepressant
Llamotrigine + Lithium +Antidepressant
Forth if response is inadequate …….ECT

51.  A first-line agent (Still Gold standard for BMD despite of
side effect profile)
 Mechanism of action :
Not well understood
-Altered ion transport (Na, K, Ca, Mg)
-Increased brain-derived neurotrophic factor(BDNF),
-Inhibition of second messenger systems (adenyl y
cyclase, ITP, Protein kinase C, Ca, Protein G)

52. Dosing and monitoring:
900- 1800 mg /day in acute phases
600- 900 mg /day in maintenance phase
 Has a narrow therapeutic index , periodic monitoring is
recommended.
 Serum lithium concentration of 0.6 to 1.4 mMol/L.

53. Pharmacokinetics
Half life is 18-24 hrs.
Not protein bound.
Bioavailability not affected by food.
98% drug is excreted unchanged in urine.

54. Adverse Effects
 Common : GIT upset, Tremor, and Polyuria, Polydipsia
 Nephrogenic : Lithium-induced Diabetes Insipidus (when urine
volume exceed 3 L / day)
 Hypothyroidism
 Poor concentration, Acneiform rash, Alopecia, Worsening of Psoriasis,
Weight gain ,Metallic taste, and Glucose dysfunction.
 Benign Leukocytosis
 Acute lithium toxicity …… serum concentration over 2 mEq/L

55. Acute Lithium Toxicity
Early signs- (1.5-2.0 mMol/L)- Tremulousness, anorexia,
nausea, vomiting, diarrhea, dehydration
Further (>2.0mMol/L)- Neurological menifestations-
Restlessness, muscle fasciculation, hypertonia, ataxia,
Dysarthria, drowsiness, delirium.
Cardiac problems- Hypotension, arrythmias, collapse.
If levels too high (>2.5mMol/L)- Coma, seizure or
permanent neurological damage

56.  Lithium dosage should be reduced by 33% to 50% when used
with thiazide
 Acute lithium toxicity …
-Discontinue lithium
-IV fluid to correct electrolyte imbalance
-Hemodialysis
Tremor ……………………Beta blockers
Lithium induced DI …….HCTZ, Amiloride
Hypothyroidism ………...Levothyroxine
GI upset ………………….Take medication in divided doses
with food.

57. Drug Interactions
Lithium levels are increased by- ACE inhibitors, NSAIDS, SSRIs,
Antiepileptics, Thiazide
diuretics, CCB, methyldopa,
Tetracyclines.
Lithium levels are decreased by- Theophylline, CPZ, Antacids,
Bicarbonates.

58.  Mechanism of action :
Uncertain
- Modulates voltage sensetive Na ion transport
- Enhance activity of GABA
-Enhance BDNF
 Dosing and monitoring :
500 – 1000 mg /day
The dosage is then titrated according to response,
o tolerability, and serum concentration.
Valproate is preferred over lithium for mixed I
episodes and rapid cycling.

59. Adverse Effects
Loss of appetite, Nausea, Dyspepsia, Diarrhea, Tremor, and
Drowsiness ,Weight gain, Alopecia.
Hair loss can be minimized by supplementation with a vitamin containing
selenium and zinc.
Polycystic ovarian syndrome
Thrombocytopenia
Drug is usually stopped if the platelet count<100,000/mm3.
Rare
Hepatic toxicity and pancreatitis.

60. Drug interaction :
 It is a weak inhibitor of some of the drug by metabolizing liver
enzymes.
 The risk of a dangerous rash due to lamotrigine is increased when
given concurrently with divalproex.
 When divalproex is added to lamotrigine, the lamotrigine dosage
should be reduced by 50%.
 Levels of valproate are decreased by- CBZ, Phenytoin,
Rifampicin, Topiramate
 Levels increased by- CPZ, Clarithromycin, TCA and fluoxetine.

61.  Use as mood stabilizing
 Mechanism of action
-Block Na, Ca ion channels
-Inhibit repetitive neuronal excitation
Dosing and monitoring :
400-600 mg /day
Adverse effect :
Drowsiness, Dizziness, Ataxia, Lethargy, and Confusion.
Aplastic anemia
Agranulocytosis ……rare but life threatening.
Hyponatremia, exfoliative dermatitis.

62. Drug interactions
 Carbamazepine induces the hepatic metabolism of many drugs
(Antiepileptic, antipsychotics, some antidepressants, oral
contraceptives,…) ….need dose adjustment
Carbamazepine is also an autoinducer.
 Carbamazepine can be slowed by enzyme-inhibiting drugs
(antidepressants,macrolide ,azole antifungal )

63.  Effective for the maintenance treatment of bipolar disorder
 More effective for depression relapse prevention than for mania
relapse.
Dosing and Monitoring
 25 mg daily for the first 1 to 2 weeks, then titrate according to
response upto 200 to 400 mg per day.

64. Adverse Effects :
 Maculopapular rash…..10% of patient
 Some rashes can progress to life-threatening Stevens-Johnson
syndrome
 Dizziness, drowsiness, headache, blurred vision and nausea .
Drug Interactions:
DVP……..downward adjustment
Carbamazepine …..upward adjustment

65.  Used as adjunctive therapy, especially during acute
mania episodes, to reduce anxiety and improve sleep.

66. Atypical antipsychotics act as mood stabilizers.
They are used either alone or with combination with mood
stabilizers in resistant cases.

67. Should be combined with a mood-stabilizing drug to reduce the risk of
mood switch to hypomania or mania.
TCA and SNRI…..switch mood to mania or hypomania
SSRI are used.
Bupropion …..the least one precipitate mania

68. The key issue is the relative risk of teratogenicity with drug use
during pregnancy versus risk of bipolar relapse without
treatment with consequent potential harm to both the pregnant
patient and the fetus.
Judgment depends on
-history of the patient
-whether the pregnancy is planned or unplanned.
Lithium can cause “ floppy baby” syndrome, Ebestein anomaly.
During first trimester
VPA and Carbamazepine …..neural tube defect (spinal bifida )
Carbamazepine can cause …..fetal vitamin K deficiency
Lamotrigine ……… with cleft palate

69. THANK YOU