The document provides an overview of bipolar disorders, including types such as Bipolar I, Bipolar II, and cyclothymic disorder, characterizing them by their mood fluctuations. It discusses treatment options including lithium carbonate, mood stabilizers, and alternative drugs, detailing their mechanisms, dosages, side effects, and interactions. The document also highlights the importance of monitoring lithium levels due to its narrow margin of safety and outlines the efficacy of various medications in the management of bipolar episodes.

1. DR. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2.  Also called mood stabilizers or drugs for Bipolar
disorders
 A mental condition marked by alternating periods of
elation and depression (high and low)
 Bipolar disorder: also known as manic-depressive
illness, is a brain disorder that causes unusual shifts
in mood, energy, activity levels, and the ability to
carry out day-to-day tasks
◦ Range from periods of extremely “up,” elated, and
energized behavior (known as manic episodes)
◦ to very sad, “down,” or hopeless periods (known as
depressive episodes)
◦ Less severe manic periods are known as hypomanic
episodes

3.  Bipolar I Disorder: defined by manic episodes that last at least 7
days, or by manic symptoms that are so severe that the person
needs immediate hospital care
◦ Usually, followed by depressive episodes, typically lasting at least 2 weeks
Episodes of depression with mixed features
◦ May also have mixed type - having depression and manic symptoms at the
same time
 Bipolar II Disorder: pattern of depressive episodes and
hypomanic episodes, but not the full-blown manic episodes
described above
 Cyclothymic Disorder or cyclothymia: defined by numerous
periods of hypomanic symptoms as well numerous periods of
depressive symptoms lasting for at least 2 years (1 year in
children and adolescents) - the symptoms do not meet the
diagnostic requirements for a hypomanic episode and a
depressive episode
 Other Specified and Unspecified Bipolar and Related Disorders:
do not match the three categories listed above

4. Bipolar I Bipolar II
 high self-esteem
 little need for sleep
 increased rate of speech
(talking fast)
 flight of ideas
 getting easily distracted
 an increased interest in
goals or activities
 psychomotor agitation
(pacing, hand wringing,
etc.)
 increased pursuit of
activities with a high risk of
danger
 changes in appetite or
weight, sleep, or
psychomotor activity
 decreased energy
 feelings of worthlessness
or guilt
 trouble thinking,
concentrating, or making
decisions
 thoughts of death or
suicidal plans or
attempts

6.  Lithium Carbonate (Li) – sedative in animals in
1949
 Alternative Drugs:
◦ Carbamazepine
◦ Sodium Valproate
◦ Lamotrigine
◦ Topiramate
 Atypical anyipsychotics – olanzapine,
risperidone, aripiprazole, quetiapine etc

7.  No acute effects in bipolar and normal person
 Neither sedative nor euphorient
 But, on prolong administration – stabilizes mood in bipolar
disorder
 In acute mania – gradually suppresses episodes (1 – 2
weeks) – continued treatment prevents cycle of mood
changes
 Reduced sleep time normalized
 MOA:
1. Effects on Electrolyte and ion transport
2. Effects on Neurotransmitters
3. Effects on 2nd Messenger generation

8.  Li is the lightest of the alkali metal atoms
 Na+ and K+ are important in this family
 Li partly replaces Na+ and distributes evenly
in extracellular and intracellular fluids
(contrast to Na+ and K+)
 Affects ionic fluxes across brain cells or
modify property of cell membranes
 However, conc. of Li in comparison to Na+
and K+ is very low

9.  Li decreases the presynaptic NA and DA
release in the brain (animals) – no affect on
5-HT release
 Corrects the imbalance in the turn over of
brain mono-amine

10.  Li has no effects on persons without mania ???
 Li inhibits hydrolysis of inositol-1-phosphate by inositol
phosphatase
 Supply of free inositol for regeneration of Phosphatidyl inositides
(source of IP3 and DAG) reduced - IP3 and DAG are important
2nd messengers
 Hyperactive neurones involved in manic state preferentially get
affected - - supply of inositol from extracellular source is very
low
 Thus spare normally operating receptors and “search out”
selectively overactive receptors – dampen signal transduction
 Valproic acid – Li like effects in mania – inhibits conc. of inositol
in human brain by inhibiting de novo inositol synthesis

11.  Inhibits actions of ADH - DI like state
 Insulin like action on glucose metabolism
 Increase in Leukocyte count
 Inhibits release of thyroid hormone –
feedback stimulation of thyroid –
compensated euthyroid state

12.  Well absorbed orally, but slowly
 Not metabolized and not protein bound
 First extracellular – enters brain - attains uniform distribution in
total body water
 CSF conc. is half of plasma - apparent Vd – 0.8L/kg at steady
state
 Li is actively reabsorbed from proximal tubule in the kidney
similar to Na+
 When Na+ is restricted larger portion of Na+ is reabsorbed -
similar is in case of Li
 2 half-life of excretion - Initially rapid excretion, then slower in
later phase – 10-12 hours Vs 16-30 hours
 Clearance is 20% of creatinine
 Steady state is attained in 5-7 days – elderly and renal
insufficiency
 Available as 300 and 400 mg tablets

13.  Individual variation in the rate of excretion
 Narrow margin of safety - monitoring
 Done 5 days after the start of treatment
 Measurement is done 12 Hrs after the last dose
- steady state (0.5 to 0.8 mEq/L for maintenance)
- 0.8 to 1.1 mEq/L for acute attack
 Toxicity above 1.5 mEq/L
 Dosing is usually in divided doses 2 -3 times of a
tablet
 Excreted in sweat, saliva, breast milk etc.

14.  Side effects are tolerable – but toxicity ….
 Nausea, vomiting and mild diarrrhoea – low dose start
 Thirst and polyuria and mild fluid retention
 Fine tremor frequently
 CNS toxicity: in rise in plasma conc.
◦ Coarse tremor, giddiness, ataxia, motor incoordination, nystagmus,
mental confusion, slurred speech and hyper-reflexia etc. etc. – delirium,
coma
◦ Occurs mainly when plasma level is high (2 mEq/L)
◦ Acute intoxication: muscle twitching, drowsiness, delirium, coma and
convulsion, vomiting, diarrhoea, albuminuria, hypotension and cardiac
arrhythmia
◦ Symptomatic treatment – osmotic diuretics, Sodium bicarbonate and
haemodialysis – also propranolol, atenolol etc.
 Long term use – diabetes insipidus, weight gain and goiter and
hypothyroidism (supplement thyroid hormone)
 Contraindicated in pregnancy – foetal goiter and cardiac
abnormalities
 Dermatitis and acne

15.  Diuretics (thiazide, furosemide): Na+ loss and
promote proximal tubular reabsorption of Na+
and Li – plasma Li rise (K+ sparing diuretics)
 Tetracyclines, NSAIDS and ACEIs: Renal clearance
of Lithium is reduced
 Reduces pressor action of NA
 Enhance Insulin/Sulfonyurea induced
hypoglycaemia
 Succinylcholine and pancuronium – prolonged
paralysis
 All Neuroleptics (haloperidol), except clozapine –
increased EPS

16.  Acute mania: Inappropriate cheerfulness or irritability, motor
restlessness, high energy, nonstop talking, flight of ideas, little
sleep, progressive loss of contact with reality and violent
behaviour – effective in controlling – but slow response – atypical
antipsychotic and BZD (clonazepam) – followed by Li
 Prophylaxis of Bipolar disorder: efficacious in 0.5 to 0.8 mEq/L
dose – lengthens interval between cycles of mood swings:
episodes of mania and depression reduced
◦ Risk benefit ration to be judged in individual cases for prolonged therapy
– depends on type of bipolar disorder (type 1 or type II)
◦ Over a decade therapy – relapse after discontinuation
 Recurrent unipolar depression: combination with antidepressants
 Recurrent neuropsychiatric illness, cluster headache and
adjuvant to antidepressants in nonbipolar major depression
 Cancer chemotherapy induced leukopenia and inappropriate
ADH secretion syndrome

17.  1st line in acute mania
 High dose acts faster than Li
 Alternative to antipsychotic ± BZD
 Lithium resistance cases or not tolerating cases
 Lithium + Valproate – resistance to monotherapy
 Prophylactic in bipolar disorders
 Atypical antipsychotic + Valproate - high
efficacy in acute mania
 Divalproex

18.  Carbamazepine: Prolong the remission of bipolar
disorder
◦ Less popular and less effective than valproate and Li
◦ Acute mania – quickly acting drug required and also high
doses – Carbamazepine limitation
◦ Long term prophylaxis and prevention of suicide –
therapeutic value not proven
◦ However, Alternative to Li
 Lamotrigine: Prophylaxis of depression in bipolar
disorder
◦ Not effective in treatment and prevention of mania
◦ Used in type 2
◦ Can be combined with Li

19.  Acute mania: 1st line drug now - Olanzapine,
risperidone, aripiprazole, quetiapine with or without
BZD except cases requiring urgent parenteral
administration
 Aripiprazole: fovoured drug for Bipolar type 1
maintenance as monotherapy or in combination with
Li and Valproate
◦ Prevents mania but not depressive episodes
 Olanzapine: Mainenance therapy of bipolar disorder –
both depressive and manic phase
◦ Long term therapy – weight gain and hyperglycaemia
 Combination of Valproate or Li with antipsychotic -
acute phases and maintenance therapy of bipolar
disorder