An overview of commonly used mood stabilizers.

2.  No consensus definition.
 Any medication that is able to decrease
vulnerability to subsequent episodes of
mania or depression; and not exacerbate the
current episode or maintenance phase of
treatment. (Sachs -1996)
 “There is no such thing as a mood stabilizer”
-FDA

3.  1817 – Lithium was discovered as a chemical
element.
 1871 – First recorded use as a treatment of mania.
 1876 – Li2CO3 used in the prevention of depression.
 By the beginning of 20th century - use of Lithium
largely abandoned due to its toxicity.
 1949 – Use of Lithium for mania rediscovered by
John Cade.
 1970- FDA approved use of Lithium for mania.
 1995- Sodium valproate approved for acute mania.

4.  Soft drink 7up had
contained Lithium
citrate from 1929-
1950.
 Marketed as good
for relieving
alcoholic hangouts.

5.  Lithium
 Anticonvulsants- Carbamazepine, Sodium
Valproate, Lamotrigine, Gabapentin & Pregabalin,
Topiramate etc.
 Atypical antipsychotics - Olanzapine,
Quetiapine, Risperidone, Aripiprazole .

6.  Indications for use:
 1. Acute treatment of mania
 2. Prophylaxis of bipolar affective disorder ( More
effective in preventing manic than depressive
relapse)
 3. Augmentation of antidepressants in resistant
depression
 4. Prevention of aggressive behaviour in patients
with learning difficulties

7.  Estimated suicide rate in bipolar patients :
10-15%
 Lithium reduces both attempted and completed
suicide by , 80%

8.  May work by affecting
signal transduction
1. Through inhibition of 2nd
messenger enzymes (eg:
inositole monophosphate)
2. By modulation of G proteins
3. By interaction at various
sites within downstream
signal transduction
cascades. ( eg: inhibition of
GSK3, PKC)
Exact mechanism of action is not certain.

9.  Renal functions
 Thyroid functions
 ECG for patients with risk factors / existing
cardiac disease.

10.  Narrow therapeutic index
 Essential to measure plasma concentrations
during treatment.
 1st- 4-7 days
 2 weekly until the plasma level is satisfactory
 6 weekly
 3 monthly when plasma level is very stable unless
more frequent monitoring is indicated.
 GFR,TFT – 6 monthly

11.  For prophylaxis
 Minimum effective level : 0.4 mmol/L
 Optimal range : 0.6 - 0.75 mmol/L
 Treatment of acute mania
 0.8 - 1.0 mmol/L

12.  Fine tremour/ Dry mouth/ Metallic taste/ Fatigue
 Weight gain (esp. women)
 Hair loss/ coarsening of hair texture
 Polyuria/ polydipsia ( due to blocking of ADH)
 Nephrogenic diabetes insipidus ( reversible in short to medium
term Rx)
 Reduction in GFR ( 1/3 of young patients – GFR < 60mL/min)
 Interstitial nephritis ( Rarely)
 Thyroid enlargement ( 5% - reversible )
 Hypothyroidism ( 20% of women)
 Hyperparathyroidism – hypercalcaemia
 Reversible ECG changes :T wave flattening, inversion/widening of
QRS
 Reversible leucocytosis
 Fetal abnormalities (esp. cardiac – Ebstein anomaly)

13.  Human teratogen.
 Continuation during pregnancy should be
considered carefully ( with likelihood of relapse
during pregnancy)
 If continued, plasma levels should be monitored
closely.

14.  > 1.5mmol/L - Early toxic effects
 Gastrointestinal effects (increasing anorexia, nausea,
diarrhoea)
 CNS effects (muscle weakness, drowsiness,
ataxia,coarse tremor, poor coordination, slurring of
speech, confusion, muscle twitching)
 > 2.0mmol/L – Serious toxic effects
 Disorientation
 Seizures
 Coma
 Death

15.  Mostly involve reduced plasma Na levels
 Low salt diet
 Dehydration
 Drug interactions
▪ diuretics (esp.Thiazides)
▪ NSAIDS
▪ ACE inhibitors
▪ Angio.2 receptor blockers
▪ some antibiotics like metronidazole

16.  Stop lithium immediately.
 High intake fluids.
 Extra NaCl to stimulate osmotic diuresis.
 If level > 3.0 mmol/L
 Peritoneal / haemodialysis is indicated.

17.  Risk of manic relapse ( even in patients
symptomless for 5 years)
 Recommended not to start Lithium without
an intention to continue for at least 3 years.
 Discontinuation should done slowly at least
over 1 month.

18.  Indications in mood disorders
1. Treatment of acute mania
2. Prophylaxis of bipolar disorder
 Effectiveness in prophylaxis of unipolar/
bipolar depression is not well established.
 Overall efficacy is less than that of Lithium.

19.  Blocks voltage sensitive Na+ channels (VSSC)
-At a site within the channel on alpha subunit
 Reduces glutamate release
 Decreases turnover of norepinephrine and
dopamine.
 Facilitates 5HT neurotransmission.

20.  Drowsiness, dizziness, ataxia, diplopia, nausea –
common at the beginning of treatment
 Agranulocytosis – Rare -1:10000 to 1:25000.
 Relative lecopenia – common.
 Rashes – 5% . Exfoliative dermatities- Rare.
 Elevation of LFT. Hepatitis – Rare.
 Disturbance of cardiac conduction.
 Teratogenicity ( Neural tube defects)
 Reduces plasma thyroxin level – clinical
hypothyroidism is rare.

21.  Pre-treatment tests :
 Baseline FBC, BU, SE, LFT - Recommended.
 Baseline weight.
 Monitoring:
 Repeat FBC, BU, SE, LFT and Weight
measurement in 6 months.
 Use in women of childbearing age :
 If cannot be avoided , adequate contraceptive
method should be used.
 Prophylactic folic acid 5mg/daily.

22.  Structurally related to carbamazepine.
 Prodrug.
 Active form - eslicarbazepine.
 Mechanism of action – similar to
carbamazepine.
 Less sedating , less BM toxicity and less hepatic
enzyme inducing than carbamazepine.
 Mood stabilizer effects not proven.
 Used off label due to better tolerability than
carbamazepine. (esp. for mania)

23.  Indications in mood disorders:
1.Treatment acute mania
2. Prophylaxis of bipolar disorder
 Shown to be useful for patients unresponsive
to Lithium and carbamazepine .
 Believed to be more effective than Lithium in
treating rapid cycling and mixed episodes of
mania.

24.  Exact mechanism of action is uncertain.
 Three possibilities:
1. Inhibition of voltage-sensitive Na+ channels
(VSSC) – Diminish excitatory glutamate
neurotransmission.
2. Enhancing actions of GABA – promote inhibitory
neurotransmission.
3. Regulating downstream signal transduction
cascades – promote neuroprotection and long term
plasticity.

25.  GI disturbances, tremour, sedation, tiredness –
common.
 Weight gain
 Transient hair loss
 Elevation of liver enzymes
 Thrombocytopenia
 Inhibition of platelet aggregation
 Acute pancreatitis
 Rashes
 Polycystic ovarian disease
 Teratogenicity – (Spina bifida, ASD, cleft palate,
hypospadias, polydactyly, craniosynostosis)

26.  Pre- treatment tests:
 Baseline FBC, LFTs and weight.
 Monitoring:
 Repeat FBC, LFTs after 6 months.
 Monitoring of BMI.
 Use in women of childbearing age :
 should not be routinely used to treat bipolar illness in
women of childbearing age.
 If used, lowest possible dose is advisable.
 Prophylactic folic acid 5mg/daily.

27.  Indications in mood disorders
1. Acute treatment of bipolar depression
2. Prophylaxis for bipolar depression
 Used alone, it does not have significant acute
or prophylactic anti-manic actions.

28.  Similar to carbamazepine
 1. Blocks voltage sensitive Na+ channels
(VSSC) -At a site within the channel on alpha
subunit
2. Reduces excitatory glutamate
neurotransmission.

29.  Rarely, serious side effects:
 Angioedema
 Steven Johnson syndrome
 Toxic epidermal necrolysis
 Use in women of
childbearing age :
 Risk of cleft palate – (low
risk)
Skin rashes – 3% , usually maculopapular
Nausea/headache/diplopia/blurred vision/dizziness/ataxia/tremor

30.  Structural analogues of GABA.
 Mechanism of action :
 inhibition of alpha-2 delta subunit of voltage-
gated Ca++ channels.
 Not considered to be effective mood
stabilizers.
 Anxiolytic, sedative and analgesic properties.
 May be useful as adjunctive treatments to
other mood stabilizers.

31.  Anticonvulsant and antimigraine drug.
 Not clearly effective as a mood stabilizer.
 Mechanism of action:
 Enhance GABA function and Reduce glutamate
function by interfering with Na+ and Ca++
channels.
 Useful as an adjunctive treatment in bipolar
disorder by reducing weight gain, insomnia
and anxiety.

32.  Atypical antipsychotics proved to be effective
in preventing recurrence of mania.
 New data suggest certain atypical
antipsychotics are effective in ,
 treating bipolar depression
 preventing recurrence of depression.

33.  5HT2A antagonism
Reduces glutamate hyperactivity – Action shared by
several anticonvulsants used as mood stabilizers.
 Increasing trimonoamine neurotransmitters
(5HT, NA, DA)
Important in improving mood in depression.

34.  Majority of bipolar patients need treatment
with several medications.
 Doses of each agent can be lowered to tolerable
levels .
 Synergy among agents provides greater efficacy
than a single agent in high dose.

35.  Atypical antipsy. + Lithium
 Atypical antipsy. +Valproate
 Lithium +Valproate
 Lamotrigine +Valproate
 Lamotrigine + Lithium
 Lamotrigine + Lithium +Valproate

36.  Lithium + Carbamazepine
Neurotoxicity
 Lamotrigine + Carbamazepine