A PowerPoint presentation on "Antimaniac drugs" suitable Medical and paramedical students (UG & PG), Research scholars, Faculty and others.

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