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Dr. Ashutosh Tiwari
III yr. PG Resident
• Bipolar disorder – also known as manic-depressive illness
• In bipolar affective disorder, patients suffer episodes of mania,
hypomania and depression, classically with periods of normal
mood in between.
Symptoms of bipolar
disorder in the manic phase:
diminished need for sleep
psychotic symptoms in
• The cause of the mood swings:
preponderance of catecholamine-related activity
Drugs that increase this activity
Drugs that reduce activity of dopamine or norepinephrine
Acetylcholine or glutamate may also be involved
• 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
MOOD STABILISING AGENTS
• Lithium carbonate:
• used for acute-phase illness
• for prevention of recurrent manic and depressive episodes
• Li+ is the only mood stabilizer with data on suicide reduction in
• Carbamazepine and Valproic acid:
• for the treatment of acute mania and for prevention of its
• for prevention of recurrence (maintenance)
• Aripiprazole, chlorpromazine, olanzapine, quetiapine,
risperidone, and ziprasidone:
• for treatment of the manic phase of bipolar disorder.
• Olanzapine plus fluoxetine in combination and quetiapine:
• for treatment of bipolar depression.
LITHIUM - MOA
• acts by suppressing the formation of second messengers
involved in neurotransmitter signal transduction.
• Lithium reduces the formation of inositol triphosphate (IP3)
by inhibiting myoinositol-1-phosphatase, an enzyme in the
inositol phosphate pathway.
• This enzyme participates in the regeneration of inositol and
the inositol phosphate precursors to IP3.
• Lithium inhibits inositol monophosphatase (IMPase) and other important
enzymes in the normal recycling of membrane phosphoinositides,
including conversion of IP2 (inositol diphosphate) to IP1 (inositol
monophosphate) and the conversion of IP1 to inositol
• valproate & carbamazepine also decrease intracellular inositol
Li inhibits inositol monophosphatase (IMPase)
↓ free inositol
[the membrane precursor of IP3 & DAG]
depletion of the second-messenger source PIP2
causes reduced release of IP3 and DAG
decreased activity of PIP2 dependent pathways
(which are markedly increased during manic episode)
Mood Stabilising action
MECHANISM OF ACTION
• Bipolar Disorder : Treatment of acute mania and the prevention
of recurrences of bipolar illness
Lithium has slow onset of action (5-7 days are required for clinical
antipsychotic drugs (chlorpromazine or haloperidol) with or without
potent benzodiazepines (lorazepam or clonazepam) is preferred.
After mania is controlled, the antipsychotic drug may be stopped
and lithium continued as maintenance therapy
Sodium valproate can provide rapid antimanic effects. Once
patients are stabilized and cooperative, Lithium can be
introduced for longer-term mood stabilization, or valproate may
be continued alone
Now a days valproate, aripiprazole,
olanzapine, quetiapine, risperidone, and
ziprasidone are preferred over lithium
Advantages of Sodium Valproate over
Wider therapeutic index
• now a first line in treatment of acute mania (as valproate acts
faster than lithium)
• an alternative to antipsychotic ± benzodiazepine.
• effective in patients not responding to lithium or not
• mixed states and rapid cycling forms of bipolar disorder may
be more responsive to valproate than to lithium
• Valproic acid is widely used to treat BP; however, its
teratogenicity limits its use in women of childbearing
• Valnoctamide is an analogue of valproic acid, but it does not
undergo biotransformation to the corresponding free acid.
• It also lacks key structural groups (eg, free carboxylic groups)
implicated in valproic acid’s teratogenicity.
• In preclinical studies, valnoctamide was markedly less
teratogenic than valproic acid.
• may be used to treat acute mania and also for prophylactic
• may be used alone or, in refractory patients, in combination
• used in the maintenance therapy of bipolar disorder
• effective in reducing the frequency of recurrent depressive
cycles and in the treatment of bipolar depression
• not effective in treating acute mania
• Lamotrigine can be combined with lithium to improve its
• Olanzapine, risperidone, aripiprazole, quetiapine, with or
without a BZD, are now the first line drugs for control of acute
• for urgent parenteral therapy, but older neuroleptics are still
the most effective.
• Aripiprazole has emerged as the favoured drug for treatment
of mania in bipolar disorder
• used both as monotherapy as well as adjuvant to lithium or
• prevents mania, but not depressive episodes
• Lack of metabolic effects, favours its long-term use
• Olanzapine is also approved for maintenance therapy of
• both manic and depressive phases are suppressed
• not considered suitable for long-term therapy due to higher
risk of weight gain, hyperglycaemia, etc.
• Quetiapine is effective in bipolar depression.
• Combination of an atypical antipsychotic with valproate or
lithium has demonstrated high efficacy in acute phases as well
as for maintenance therapy of bipolar disorder.
• Depression that persists after lithium therapy is started may
respond to antidepressant drugs.
• The use of antidepressants especially TCAs in patients who
have bipolar disorder and are not taking lithium or another
mood-stabilizing drug can precipitate a manic response in
• (switch phenomenon)
Novel targets for
treatment of Bipolar
GLYCOGEN SYNTHASE KINASE 3
• GSK-3 is a kinase involved in the regulation of cell apoptosis
and synaptic plasticity.
• Its inhibition influences gene transcription, with consequent
• GSK-3 inhibition increases hippocampal levels of β-catenin, a
function implicated in mood stabilization
• Both Li+ and valproate treatment inhibit the activity of
glycogen synthase kinase-3β (GSK-3β)
• Excessive intracellular calcium influx results in increased apoptosis,
destruction of the cytoskeleton and intensification of the oxidative
• These disturbances in calcium mobilization are related in part to
hyperactivity of PKC, which has been demonstrated among
subjects with BD
• Therefore, drugs whose putative effects implicate PKC inhibition
may play a role in the treatment of BD
• Lithium and valproic acid inhibit PKC
• Tamoxifen, an estrogen antagonist (used in the treatment of
breast cancer) can cross BBB & has strong inhibitory effects on
• Omega-3 fatty acids might represent a protective factor against
the development of BD
• Omega-3 Fatty acids act as antagonists of the PI-PKC signal
transduction pathway, ultimately inhibiting PKC activity
FACTOR (BDNF) MODULATION
• BDNF and other neurotrophic factors increase cell survival by
direct neurotrophic effect and apoptosis inhibition.
• There is evidence suggesting that chronic administration of
lithium and valproate may result in increased transcription of
ENHANCED BCL2 EXPRESSION
• Bcl2 is a protein with marked anti-apoptotic activity
• involved in neuronal protection and regeneration
• In rats, chronic administration of lithium and valproate is
associated with increased levels of Bcl2 in the prefrontal areas
• atypical antipsychotic olanzapine is associated with increased
expression of Bcl2 in the prefrontal cortex and hippocampus of
• Pramipexole is a dopamine agonist currently approved for
treatment of Parkinson’s disease and is associated with
increased expression of Bcl2 in the frontal cortex
EFFECTS ON OXIDATIVE STRESS
• increased oxidative stress contributes to cellular death in BD
• Lithium and olanzapine have demonstrated antioxidant
properties, which may be partially responsible for their
MODULATION OF GLUTAMATERGIC
• the effects of lithium on the glutamatergic system are
possibly related to its neuroprotective properties.
• Glutamate is the main excitatory neurotransmitter in the CNS
• involved in the regulation of several processes, including
neuronal and synaptic plasticity, memory consolidation and
• increases in the glutamatergic transmission in the CNS bring
about prolonged synaptic excitatory transmission, with
excitotoxicity and, ultimately, neuronal death.
• Lithium is believed to inhibit the calcium influx that results
from the stimulation of the NMDA glutamate receptors and
lamotrigine, a well-established mood stabilizer, blocks the
neuronal sodium channels, thus inhibiting the release of
MODULATION OF GLUTAMATERGIC
• drugs with demonstrated effect on the glutamatergic system
may be of particular interest in the management of the
depressive phase of BD.
• Memantine: low-affinity antagonist of the NMDA glutamate
receptor, currently FDA- approved for treatment of Alzheimer’s
• Amantadine: non- competitive antagonist of the NMDA
receptor currently approved for treatment of Parkinson’s
• Ketamine: an anesthetic, ketamine is a high-affinity NMDA
antagonist seems effective in the treatment of resistant
• Riluzole: a potent glumatergic modulator, currently FDA-
approved for treatment of amiotrophic lateral sclerosis
• Ramelteon acts as a selective agonist of melatonin receptors
(MT1 & MT2) within the suprachiasmatic nucleus (SCN).
• Although approved to treat insomnia, Ramelteon is under
investigation as a treatment for bipolar disorder.
• It’s efficacy for bipolar maintenance and mania attenuation
may be because of its ability to regulate circadian rhythms.
• Regulation of circadian rhythms minimizes likelihood of
mood stability and prevents cycling to a manic and/or
NOVEL TARGETS FOR BD
• Inositol monophosphatase inhibition
• Glycogen synthase kinase 3 (GSK-3) inhibition
• Protein kinase C (PKC) inhibition
• Brain-derived neurotrophic factor (BDNF) modulation
• Enhanced Bcl2 expression
• Effects on oxidative stress
• Modulation of glutamatergic transmission
• During the last decade, significant progress in the knowledge
of BD has been achieved, mainly derived from the better
understanding of the molecular targets of mood stabilizing
• These advances have led to identify a various novel targets
which will potentially result in improved therapeutics for BD
in the near future.