This is a brief content about Bipolar disorder

1. Bipolar disorder
Definition: Bipolar disorder is characterized by periods of deep, prolonged,
and profound depression that alternate with periods of an excessively elevated
or irritable mood known as mania.
Bipolar disorder is divided into four subtypes based on the identification of
specific mood episodes: bipolar I, bipolar II, cyclothymic disorder, and bipolar
disorder not otherwise specified
Etiologic theories of bipolar disorder:
 The exact etiology of bipolar disorder is unknown. Bipolar disorder is
thought to be a complex genetic disease that is environmentally
influenced and caused by a wide range of neurobiologic abnormalities.
 Stressfullife events, alcohol or substance use, and changes in the sleep-
wake cycle can elicit the expression of genetic or biologic vulnerabilities
that causedysregulationof neurotransmitters,neuroendocrinepathways
and second messenger systems.
Genetic factors:
Linkage studies suggest that certain loci on genes and the X chromosome may
contribute to genetic susceptibility of bipolar disorder

2. Nongenetic factors:
1.Perinatal insult
2.Head trauma
3.Environmental factors
 Desynchronization of circadian or seasonal rhythms cause diurnal
variations in mood and sleep patterns and can result in seasonal
recurrences of mood episodes.
 Changes in the sleep-wake cycle or light-dark cycle can precipitate
episodes of mania or depression.
 Bright light therapy can be used for the treatment of winter depression
and can precipitate hypomania, mania, or mixed episodes.
4.Psychosocial or physical stressors
 Stressful life events often precede mood episodes and can increase
recurrence rates and prolong time to recovery from mood episodes.
5.Nutritional factors
 Deficiency of essential amino acid precursors in the diet can cause a
dysregulation of neurotransmitter activity (e.g., L-tryptophan deficiency
causes a decrease in 5-HTand melatonin synthesis and activity).
 Deficiency in essential fatty acids (e.g., omega-3 fatty acids) can cause a
dysregulation of neurotransmitter activity
6.Neurotransmitter/neuroendocrine/hormonaltheories
 Dysregulation between excitatory and inhibitory neurotransmitter
systems; excitatory: NE, DA, glutamate, and aspartate; inhibitory: 5-HT
and GABA.
7.Monoaminehypothesis
 An excess of catecholamines (primarily NE and DA) cause mania.
 Deficit of neurotransmitters (primarily NE, DA, and/or 5-HT) cause
depression.
8.Dysregulation of amino acid neurotransmitters
 Deficiency of GABA or excessiveglutamate activity causes dysregulation
of neurotransmitters (e.g., increased DA and NE activity).

3. 9.Cholinergic hypothesis
 Deficiency of acetylcholine causes an imbalance in cholinergic-
adrenergic activity and can increase the risk of manic episodes.
 Increased centralacetylcholine levels can increasethe risk of depressive
episodes.
10.Secondary messenger system dysregulation
 AbnormalG protein functioning dysregulates adenylatecyclase activity,
phosphoinositideresponses, sodium/potassium/calcium channel
exchange, and activity of phospholipases.
 Abnormalcyclic adenosine monophosphateand phosphoinositide
secondary messenger system activity.
 Abnormalprotein kinase C activity and signalling pathways.
11.Hypothalamic-pituitary-thyroid axis dysregulation
 Hyperthyroidismcan precipitate manic-like symptoms.
 Hypothyroidismcan precipitate a depression and be a risk factor for
rapid cycling
 Hormonalchanges during the female life cycle can cause dysregulation
of neurotransmitters (e.g., premenstrual, postpartum, and
perimenopause).
12.Membrane and cation theories
 Abnormalneuronal calcium and sodium activity and homeostasis cause
neurotransmitter dysregulation.
 Hypocalcemia has been associated with causing anxiety, mood
irritability, mania, psychosis, and delirium.
 Hypercalcemia has been associated with causing depression, stupor, and
coma.
 Extracellular and intracellular calcium concentrations may affect the
synthesis and release of NE, DA, and 5-HT, as well as the excitability of
neuronal firing.
13.Sensitization and kindling theories
 Recurrences of mood episodes causebehavioralsensitivity and
electrophysiologic kindling (similar to the amygdala-kindling models for
seizures in animals) and can resultin rapid or continuous mood cycling.

5. Evaluation and diagnosis of mood episodes:
The mood states are further separateinto four subcategories to differentiate
the currentor most recent mood episode: major depressive, manic,
hypomanic, or mixed.
1.Major depressive- DSM-IV-TR Criteria
>2-Week period of either depressed mood or loss of interest or pleasure in
normal activities, associated with
at least five of the following symptoms:
• Depressed, sad mood (adults); can be irritable mood in children
• Decreased interest and pleasurein normal activities

6. • Decreased appetite, weight loss
• Insomnia or hypersomnia
• Psychomotor retardation or agitation
• Decreased energy or fatigue
• Feelings of guilt or worthlessness
• Impaired concentration and decision making
• Suicidal thoughts or attempts
2.Manic
>1-Week period of abnormaland persistentelevated mood (expansiveor
irritable), associated with at least three
of the following symptoms (four if the mood is only irritable):
• Inflated self-esteem(grandiosity)
• Decreased need for sleep
• Increased talking (pressureof speech)
• Racing thoughts (flight of ideas)
• Distractible(poor attention)
• Increased activity (either socially, at work, or sexually) or increased motor
activity or agitation
• Excessiveinvolvement in activities that are pleasurablebut havea high risk
for serious consequences
(buying sprees, sexualindiscretions, poor judgmentin business ventures)
3.Hypomanic
At least 4 days of abnormaland persistentelevated mood (expansiveor
irritable); associated with at least three of the following symptoms (four if the
mood is only irritable)
4.Mixed
Criteria for both a major depressiveepisodeand manic episode (except for
duration) occur nearly every day for at least a 1-week period
5.Rapidcycling:
>4 Major depressiveor manic episodes (manic, mixed, or hypomanic) in 12
months

7. Treatment:
Desired outcomes:
 The desired outcome for bipolar disorder is to preventan acute manic,
hypomanic, or depressiveepisode,
 To maintain good functioning, and
 To prevent further episodes of mania or depression.

8. General approach to treatment:
The treatment of bipolar disorder can vary depending on what type of episode
the patient is experiencing. Once diagnosed with bipolar disorder, patients
should remain on a mood stabilizer (e.g., lithium, valproate) for their lifetime.
During acute episodes, medications can be added and then tapered once the
patient is stabilized and euthymic.
For example, when treating a patient for mania with psychotic features, the
patient should be on a mood stabilizer and an antipsychotic.
If treating a patient for a severe depressive episode, a clinician may need to
maximize the dose of the mood stabilizer or add another medication (e.g.,
quetiapine).
Non pharmacological therapy:
1.Electroconvulsive therapy [ECT]
2.High-intensity bright light therapy
3.Repetitive transcranialmagnetic stimulation (rTMS)
4.Vagus nervestimulation (VNS) may also havea role in treatment-resistant
rapid-cycling bipolar disorder
Life style modifications:
Adequate nutrition, sleep, exercise, and stress reduction.
Adjunctive psychoeducational programs, supportive counseling, insight
oriented psychotherapy (individual or group), couples or family therapy,
cognitive behavioral therapy, and communication enhancement training.
Pharmacological therapy:
Pharmacotherapy is crucial for the acute and maintenance treatment of
bipolar disorder and includes (mood stabilizers)
1.Lithium carbonate
2.Anti convulsants
3.AtypicalAntipsychotics
4.Adjunctiveagents like Antidepressants and Benzodiazepines

9. DRUG INITIAL DOSE
1.Lithiumsalts
Lithium carbonate 900-2400mg/day, TID
Lithium citrate -
2.Anticonvulsants
Divalproexsodium
(sodium valproate+
valproic acid)
750-3000mg/day, OD
Lamotrigine 50-400mg/day
Carbamazepine 200-1800mg/day, TID
3.Atypical antipsychotics
Olanzapine 5-20mg/day, OD
Quetiapine 50-800mg/day
Risperidone 0.5-6mg/day, OD
Ziprasidone 40-160mg/day
Aripiprazole 10-30mg/day, OD
1.Lithiumcarbonate:
Chronic lithium administration may modulate gene expression and have
neuroprotective effects
lithium has been found to have efficacy, but there can be a 6- to 8-week delay
for its antidepressant effects
Dosing is generally titrated up to achieve steady state serum lithium
concentrations of 0.6 to 1.2 mEq/L (mmol/L).
Lithium requiresregularassessmentofrenaland thyroid functioning and lithium
blood level monitoring to minimize adverse effects.
MOA:
1.Effecton Electrolytes and Ion Transport-
Lithium act by partially replacing the Na+
ions in the body. This leads to changes
in the ionic fluxes across the brain cells or in the properties of cell membranes.
2.Effect on Neurotransmitters-
Lithium decreases the release and action of neurotransmitters, such as
dopamine and norepinephrinein the brain, which may correct the imbalance in
the turnover of brain monoamines

10. 3.Effect on secondary messengers and intracellular enzymes-
In mania, these neuronal circuits become hyperactive which results in more IP3
and DAG production. Lithium selectively inhibits the hydrolysis of IP2 to IP1 and
IP1 to inositol. As a result, the levels of inositol decreases and this in turn
decreases IP3 and DAG levels
4.A specific isoform of protein Kinase-C may be effected by the lithium, which
leads to the altered protein Kinase-C mediated signalling. This results in altered
gene expression and production of proteins that ultimately prolong the
stabilization of mood.
5.Inhibition of adenylyl cyclase results in antidepressant and antimanic effects.
ADR:
- Nausea, Vomiting, Diarrhoea(Osmotic), Tremors, ataxia, oedema
(Osmotic), arrhythmias, blurred vision, glycosuria (Insulin like action),
polyuria (inhibits action of ADH on DCT), allergy
- Seizures, cerebralataxia, hypotension, ECG changes, hypothyroidism
(interferes with iodination of tyrosine), coma, leucocytosis.
- Ebstein’s anomaly in the foetus
Contraindications:
- Pregnancy (Foetalgoitre),
- lactating women (Lethargy, cyanosis and hepatomegaly in newborns)
- patient with low sodium or on diuretics (diuretics increases lithium
conc.)
- In sick sinus syndrome(Increased leucocytes)

11. 2.Anti convulsants:
MOA:
Effect on neurotransmitters of brain:
a. On Gamma Aminobutyric Acid (GABA)
GABA is a fast acting inhibitory neurotransmitter presentin the brain and spinal
cord. Several antiepileptic drugs act to increase the effect of GABA and thus
prevent the excitation of neurons
I. GABA facilitators:
These drugs elicit their action by binding to a specific site located on the GABAA
receptors in the brain. Once bound, these drugs facilitate the opening of
chloride channels, leading to the influx of more amount of chloride ions,
generation of high negative potential and hyperpolarization of the cell. Due to
this, the post synaptic nerve impulse transmission and thus excitation of the
neurons is inhibited
II. GABA reuptake inhibitors:
GABA is transported fromthe synaptic space into the neurons and glial cells for
its metabolism. This transportation of GABA is facilitated by specific GABA
transporter. Some of the antiepileptic drug bind to these transporters and
inhibit the transportation of GABA. This raises the levels of GABA in the synaptic
cleft, due to which inhibition of postsynaptic nerve impulse transmission and
excitation of neurons occurs
III. GABA Agonist:
GABA agonists act by increasing the concentrations of GABA by enhancing the
effect of enzymeGAD (glutamic acid decarboxylase), which converts glutamate
to GABA
IV. GABA-Transaminase inhibitors:
GABA-T is an enzyme responsiblefor the catabolism of GABA. Some drugs bind
irreversibly to GABA-T due to their structural similarity with GABA and inhibit
the action of the enzyme. Thus, the concentration of GABA increase with an
inhibition of postsynaptic nerve impulse transmission and excitation of the
neurons

12. b. On Glutamate
Glutamate is an excitatory neurotransmitter present in the brain. The different
receptors subtypes of glutamate are NMDA, AMPA, Kainate. Some drugs act by
binding to these receptors and inhibit influx of calcium and sodium ions and
efflux of potassium ions. Thus this preventexcitation of neurons and generation
of action potentials.
Effect on Ion channels:
a. Sodium channel inhibitors:
Antiepileptic drugs block the use-dependent or voltage-gated sodium channels
which are responsible for carrying the current required to generate an action
potential. Thus, repetitive firing of the neurons is inhibited
b. Calcium channel inhibitors:
Antiepileptic drugs act by blocking the calcium channels or calcium-dependent
potassium channels. Due to such blockade, influx of calcium currents and
ultimately the generation of action potential is inhibited. Thisfurther inhibits the
further excitation of neurons.
Drug ADRs Contraindications
Valproic acid Nausea, vomiting,
anorexia, heart burn,
tremors, ataxia, hairloss
and hepatotoxicity
In pregnancy and
lactation
Carbamazepine Ataxia, dizziness,
vertigo, diplopia, NVD,
rashes, hepatitis,
aplastic anemia
-In pregnancy and
lactation
-patients having bone
marrow depression,
hepatic disorders
-Patient having AV heart
block (CBZ block Na+
influx)
Lamotrigine Drowsiness,asthenia,
diplopia, ataxia,
agitation, skin rashes
-

13. 3.Atypical Antipsychotics:
MOA:
High affinity towards5-HT2,NA(α2)and Muscarinicand Histamine(H1)receptors
Very low affinity towards D2-receptors and inhibits these receptors.
DRUG ADRs
Olanzapine Sedation, priapism, postural
hypotension, dry mouth,
constipation, weight gain
Risperidone Postural hypotension, fewer
Aripiprazole Extrapyramidal symptoms
Clinical usage of drugs:
Hypomania:
Step 1:
Initiate mood stabilizing medication
-Consider adding a benzodiazepine(lorazepam or clonazepam) for shortterm
adjunctivetreatment of agitation or insomnia if needed, if responseis
inadequate
Step 2:
Consider a two-drug combination
i.Lithium+Anticonvulsant/Antipsychotic
ii.Anticonvulsant+Anticonvulsant/Antipsychotic
Mania:
Step 1:
Consider a two-drug combination
Lithium/Anticonvulsant/Antipsychotic+Benzodiazepine (lorazepam)
-Consider adding an antipsychotic for short-term adjunctivetreatment of
agitation or insomnia
-Do not combine antipsychotics, if responseis inadequate

14. Step2:
consider a three-drug combination
-Lithium+Anticonvulsant+Antipsychotic
- Anticonvulsant+Anticonvulsant+Antipsychotic, if responseis inadequate
Step3:
Consider ECT for mania with psychosis or catatonia
Mildtomoderate depressive episode:
Initiate mood stabilizing medication/Alternative fluoxetine+olanzapine
combination
Severe depressiveepisode:
Step:
Initiate mood stabilizing medication/Alternative fluoxetine+olanzapine
combination
-If psychosis is present, initiate an antipsychotic in combination with above, if
responseis inadequate
Step2:
Consider carbamazepineor adding antidepressant, if responseis inadequate
Step3:
consider a three drug combination:
-Lithium+Anticonvulsant(lamotrigine)+Antidepressant
-Lithium+Antipyschotic(quetiapine)+Antidepressant, if responseis inadequate
Step4:
Consider ECT for treatment-refractory illness and depression with psychosis or
catatonia

15. Special population:
Pregnancy/Lactation:
 Based on Risk benefit ratio must be weighed
 If using lithium during pregnancy, doseadjustments and closemonitoring of
serumlevels will beneeded due to changes in glomerularfiltration rates and
renal perfusion rates during pregnancy and immediately after delivery
 The use of anticonvulsants also poses a teratogenic risk when used during
pregnancy. Neural tube defects cause the most concern for clinicians
treating pregnant patients during their first trimester of pregnancy
 Administration of folate can reduce the risk of neural tube defects
 Caution should be used when prescribing antipsychotics during pregnancy
 Treatment of catatonia also varies from standard treatment in that mood
stabilizers and antipsychotics have minimal effect. Catatonic features such
as mutism, motor excitement, stereotypic movements, waxy flexibility,
negativism, echopraxia, and echolalia are best treated with
benzodiazepines, specifically lorazepam. The use of antipsychotics in
catatonia should be minimized because of an increased risk of neuroleptic
malignant syndrome.