MOOD STABILIZING

AGENTS FOR
BIPOLAR DISORDER
 BIPOLAR AFFECTIVE DISORDER

 Bipolar disorder also known as

manic-depressive illness, is
characterized by severe mood
swings from mania to depression.
 Mania is an abnormally elevated
mood, while depression is an
abnormally low mood.

MANIA
Excessive happiness, irritability,
less need for sleep, racing
thoughts, increased energy, etc.
DEPRESSION
Sadness, loss of energy, increased
need for sleep, change in
appetite, thoughts of
death/suicide, etc.
 BIPOLAR AFFECTIVE DISORDER
 Occurs in 1–3% of the adult population in 3rd & 4th decades
of life
 Prevalence in men and women is the same.
 Symptoms in the manic phase are irritable mood,
hyperactivity, impulsivity, disinhibition, insomnia, racing
thoughts, and cognitive impairment.
 Key features in depressive phase are depressed mood,
sleep disturbance, anxiety, and sometimes psychotic
symptoms.
 Patients with bipolar disorder are at high risk for suicide.
BIOLOGICAL APPROACH
The biological
approach to
bipolar disorder
suggests that high
or low levels of
neurotransmitters
such as
norepinephrine,
dopamine, or
serotonin, is the
cause.
 DRUGS USED IN BIPOLAR DISORDER
IN MANIC PHASE
• LITHIUM
• CARBAMAZEPINE
• VALPROIC ACID
• LAMOTRIGINE
• Antipsychotic --- Aripiprazole, Chlorpromazine,
Olanzapine, Quetiapine, Risperidone, Ziprasidone
 DRUGS USED IN BIPOLAR DISORDER
IN DEPRESSIVE PHASE
 OLANZAPINE

 FLUOXETINE

 QUETIAPINE
 LITHIUM CARBONATE – MECHANISM OF
ACTION
Effect on Electrolyte and ion transport:
 Lithium is a monovalent cation
 Li+ distributes evenly in extracellular and intracellular
fluids (contrast to Na+ and K+) & develops relatively
small gradient across biological membranes.
 Lithium exchanges readily with Na+; it substitutes Na+
as well as K+ in various cellular transports. Also
replaces Na+ in generating action potential in nerve
cells, but is not substrate for Na+ pump & therefore
cannot maintain membrane potentials.
 LITHIUM CARBONATE – MECHANISM OF
ACTION
Effects on 2nd Messenger
 The activity of Phosphoinositide pathways is markedly
increased during a manic episode.
 Lithium act by inhibiting enzymes involved in the recycling
of Phosphoinositides
 It inhibit hydrolysis of IP by inhibiting inositol
monophosphatase (IMP) as a result supply of free inositol
for regeneration of membrane phosphatidylinositol
bisphosphate (PIP2), is reduced along with depletion of
IP3 and DAG.
MECHANISM OF ACTION
 LITHIUM CARBONATE – MECHANISM OF
ACTION
 Inhibit hormone NE-sensitive adenylyl cyclase.
 Lithium causes uncoupling of G-proteins from its
receptors.
 Also directly decrease release of glutamate,
dopamine
 Facilitates 5-HT release
 Prevents apoptosis by inhibiting GSK-3 enzyme
and facilitating BDNF.(GSK-3 enzyme limits
neurotropic & neuroprotective process).
 Apoptosis vs. Neurogenesis in the Adult
Hippocampus
 Stress, depression or drugs activate apoptosis in the
hippocampus by promoting GSK3(resulting in decreased
size of the hippocampus)
 Lithium, Valproate and Lamotrigine stimulate BDNF which
promotes adult neurogenesis in the dentate nucleus of
hippocampus.
 LITHIUM, PHARMACOKINETICS
 Readily & completely absorbed from GIT
 PPL- 30min-2hrs
 Attains uniform distribution in total body water
 Not protein bound
 Half of an oral dose is excreted with in 12 hours &
remainder taken up by cells is excreted over the next 1-2
weeks.
 Steady state is attained in 4-5 days
 Not metabolized
 LITHIUM – MONITORING OF TREATMENT
 Individual variation in the rate of excretion
 Narrow margin of safety
 Done 5 days after the start of treatment
 Measurement is done 12 hrs. after the last dose
 If no therapeutic improvement, change the dose
 Monitor the new dose level after 5 days again
 LITHIUM – ADVERSE EFFECTS
CNS:
 Fine postural hand tremor is frequent(treated with
propranolol, atenolol etc. & by decreasing dose)
 Incoordination, ataxia, dysarthria, aphasia,
choreoathetosis
 Significant weight gain ( due to central appetite
stimulation at hypothalamic sites)
GIT:
 Nausea, vomiting, diarrhea, abdominal pain
 LITHIUM – ADVERSE EFFECTS
RENAL:
 Polyuria and Polydipsia
 Nephrogenic Diabetes Insipidus
 This is due to uncoupling of G-proteins from ADH
receptors, decreasing the action of ADH &
increases water excretion.
 Long term treatment may cause
interstitial nephritis & glomerulonephropathy
 LITHIUM – ADVERSE EFFECTS
Cardiac Effects:
T-wave flattening, overdose may lead to sinus
bradycardia, AV block
Thyroid Function:
 Reversible decrease in thyroid function leads to
development of benign, diffuse non tender thyroid
enlargement and hypothyroidism (lithium
uncouples G proteins from TSH receptors)
Edema: due to its effect on sodium retention.
 LITHIUM – ADVERSE EFFECTS
Skin effects
 Allergic reactions such as folliculitis, dermatitis &
vasculitis
 Worsening of acne vulgaris, psoriasis & other
dermatological conditions
 Alopecia
Leukocytosis is always present due to its direct
effect on leukopoiesis
 LITHIUM – ADVERSE EFFECTS

PREGNANCY – contraindicated
 Crosses placenta, producing fetal & neonatal lithium
toxicity
 Also secreted in breast milk
 Cause neonatal goiter, CNS depression, hypotonia, lethargy,
cyanosis, poor suck and Moro reflexes (floppy baby
syndrome)
 Increase incidence of CV anomalies of newborn
 ANTICONVULSANTS
 Carbamazepine
 Valproic acid
 Lamotrigine
 These medications are more recently being used to treat
bipolar disorder.
About 40% of bipolar pts. are not helped by Li or cannot
tolerate the Li SEs…thus, need an alternative treatment.