cover pathophysiology and treatment of mania and bipolar disorder.

1. ASADULLAH R.Ph, CRCP
2012-MPHIL-1795

2. Mania
 Madness, frenzy
 “A Phase of Bipolar disorders characterized by
expansiveness, elation, agitation, hyper
excitability, hyperactivity, and increased speed of
thought or speech(flight of ideas)”.
 A mood disorder, In a senses opposite to depression.
 “A period of seven or more days of unusually and
continuously effusive and open elated or irritable
mood, where the mood is not caused by
drugs/medication or a medical illness and
(a) is causing obvious difficulties at work or in
social relationships and activities, or
(b) requires admission to hospital to protect the
person or others, or
(c) the person is suffering psychosis.”

3. Bipolar disorder
 Bipolar disorder, or manic-depressive illness
(MDI), is one of the most common, severe,
and persistent mental illnesses. Bipolar
disorder is a serious lifelong struggle and
challenge.
 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.

4.  Unipolar major depressive disorder and bipolar
disorder share depressive symptoms, but bipolar
disorder is defined by episodes of mania or
hypomania.
 Bipolar disorder constitutes 1 pole of a spectrum
of mood disorders that includes including bipolar I
(BPI), bipolar II (BPII), cyclothymia (oscillating
high and low moods), and major depression.

5. Manic Episode
 characterized by at least 1 week of profound
mood disturbance, characterized by elation,
irritability, or expansiveness . At least 3 of the
following symptoms must also be present:
 Grandiosity
 Diminished need for sleep
 Excessive talking or pressured speech
 Racing thoughts or flight of ideas
 Clear evidence of distractibility
 Increased level of goal-focused activity at home, at
work, or sexually
 Excessive pleasurable activities, often with painful
consequences

6. Hypomanic Episode
 Hypomanic episodes are characterized by an
elevated, expansive, or irritable mood of at
least 4 days‟ duration. At least 3 of the following
symptoms are also present:
 Grandiosity or inflated self-esteem
 Diminished need for sleep
 Pressured speech
 Racing thoughts or flight of ideas
 Clear evidence of distractibility
 Psychomotor agitation at home, at work, or sexually
 Engaging in activities with a high potential for painful
consequences

7. Neurobiology OF MANIA AND BIPOLAR
DISORDER*
Ambiguous till date
Biogenic amine neurotransmitters:
Noradrenergic system:
NE turnover increase in the cortical and thalamic areas of BD
subjects where decrease in depression
 Serotogenic system:
Reduced 5-hydroxytryptamine (5- HT)1A receptor binding potential in
raphe and hippocampus- amygdala of brain in depressed patients
Dopaminergic system
 DA agonists are effective antidepressants and are able to
precipitate mania.
 D2 receptor found in caudate, putamen, nucleus accumbens,
cerebral cortex and hypothalmus is negativly coupled to adenylyl
cyclase. Older antipsychotics act through blockage of D2 receptors
, which eventualy result in extrpyramidal system (muscle rigidty ,
involuntry movement, pseudoparkinsonism)

8. Cholinergic system
 cholinergic tone decrease during mania , pilocarpine elicit
pupillary constriction ,
 The response of pilocarpine enhance after lithium and VPA
,adding evidence on the effects of lithium perhaps
potentiating brain cholinergic systems
 relative inferiority of noradrenergic compared to
cholinergic tone was associated with depression, while the
reverse was associated with mania
Receptor Nature Pathway
D2 Inhibitory Presynaptic: decr Ca+ conduct
Postsynaptic:Gi, incr K+ conduct ,decr cAMP
M3 Excitatory Gq ,incr IP3 & DAG
Alpha 1 Excitatory Gq ,incr IP3 & DAG
5 HT-2 Excitatory Gq ,incr IP3 & DAG

9. Signal pathways abnormalities*
cellular signaling pathways interact at various levels, allow
the cell to receive, process, and respond to information
 signaling pathways represent major targets for a
number of hormones, including glucocorticoids, thyroid
hormones, and gonadal steroids , may explain mood
disorder with alterd hormonal level.
(e.g. the frequent onset of bipolar disorder in puberty,
triggering of episodes in the postpartum period)
G Protein abnormalities:
Postmortem brain studies have reported increased levels
of the stimulatory G protein (Gαs) accompanied by
increases in post-receptor stimulated adenylyl cyclase
(AC) activity in BD.

10. The protein kinase C signaling pathway:
PKC is one of the major intracellular mediators of signals
generated upon external stimulation of cells via a variety of
neurotransmitter receptors M1, M3, M5 α1 5-HT2A . PKC induce
the hydrolysis of various membrane phospholipids.
increased PKC activity and translocation found in different
experiments of BD brains moreover attenuation of PKC activity
may play a role in the antimanic effects of lithium and VPA.
Novel selective PKC inhibitors if devolped may have very useful
action against mania. Tamoxifen is underinvestigation.
Abnormalities of calcium signaling
 Calcium ions play a critical role in regulating the synthesis and
release of neurotransmitters, neuronal excitability,
 elevations in both resting and stimulated intracellular Ca2+
levels in platelets, lymphocytes and neutrophils of patients with
BD.
*The underlying neurobiology of bipolar disorder, world psychiatry
HUSSEINI K MANJI,1 JORGE A QUIROZ,1 JENNIFER L PAYNE,1 JASKARAN SINGH,1 BARBARA P LOPES,1 JENILEE S VIEGAS,1 and

11. Genetic abnormalities*
Genes associated with mania and BP include:
Glycogen synthase kinase 3 (GSK-3):
GSK3β is a central regulator of the circadian clock.
Negative mutation in the CLOCK gene normally
contributing to circadian periodicity in humans
results in behavior mimicking mania.
ANK3(ANKYRIN G):
ANK3 is an adaptor protein found at axon initial
segments that regulates the assembly of voltage-
gated sodium channels.
CACNA1C (alpha 1C subunit of the L-type
voltage-gated calcium channel)
ANK3 and subunits of the calcium channel are
down-regulated in mouse brain in response to
lithium, which indicates a possible therapeutic
mechanism of action

12. Genetic abnormalities*
Diacylglycerol kinase eta (DGKH) gene:
 GWAS published by 2011 pointed first intron
of diacylglycerol kinase eta (DGKH) gene, a
key protein in the lithium-sensitive
phosphatidyl inositol pathway.
 Lithium-mediated inhibition of GSK3β is
thought to result in downregulation of
molecules involved in cell death and
upregulation of neuroprotective factors.

13. 1:Stephen Soreff, MD President of Education Initiatives, Nottingham, NH; Faculty,
Boston University, Boston, MA and Daniel Webster College, Nashua, NH

14. Differential Diagnosis
∂ Acute intoxication with recreational drugs, such
CLINICAL FEATURES OF MANIA
as amfetamines, amfetamine derivatives (MDMA:
Characteristicand cocaine appearance mania.
Ecstasy), Clinical can mimic
Mood Elevated or irritable
Talk Chronic use of cannabis can of ideas
∂ Fast, pressurized, flight induce manic like
features.
Energy Excessive
∂ Cushing's syndrome had a secondarywealth, power, influence or
Ideas Grandiose, self-confident, delusions of manic illness
of religious significance, sometimes persecutory
∂ corticosteroids can induce mania
∂ Dopamine agonists (e.g. bromocriptine) are also
Cognition Disturbance of registration of memories
known to sometimes induce secondary mania.
Physical Insomnia, mild to moderate weight loss, increased libido
∂ The excited phase of catatonic schizophrenia can
sometimes be mistaken for mania. excessive drinking or
Behaviour Disinhibition, increased sexual activity,
spending
Hallucinations Fleeting auditory or, more rarely, visual

15. Treatment
Pharmacotherapy
Drug Mania Mixed Maintenance Depression
Lithium X X
Valporate XR X
Carbamazepine X X
Lamotrigine X
Arippiprazole X X X
Ziprasidone X X
Resperidone X X
Asenapine X X
Quetiapine X X
Chlorpromazine X
Olanzapine X X X
Table. FDA-Approved Bipolar Treatment Regimens

16. • Lorazepam, Clonazepam
Anixloytic
Mood
• Lithium carbonate
Stabilizer
• Carbamazepine, valporate sodium, Divalporate
Anticonv sodium,Lamotrigine,
ulsant
• Risperidone,Olanzapine,Quetiapine
Atypical
antipsycho ,Airpiprazole,Asenapine
tics
Typical • Loxapine.Chlorpromazine, Fluphenazine
Antipsychoti
cs

17. Acute treatment of mania: an update on new medications.
Case School of Medicine, Mood Disorders Program, University Hospitals Case Medical Center, 11400 Euclid Avenue, Suite 200, Cleveland, OH 44106, USA.
Prashant.Gajwani@uhhs.com

18. Mood Stabilizer
LITHIUM:
 In use since the 1870s.
 Initially used to treat depression, gout, and
neutropenia, and for cluster headache
prophylaxis,
 In 1940s FDA banned the use of lithium
because of fatalities but lifted in 1970.
 Narrow therapeutic index that predisposes
poisoning with relatively minor changes in
medications or health status.
 May protect and preserve the hippocampal
volumes, also claimed neuroprotective.

19. Pharmacokinetics

20. Indications & Uses
 Acute manic or mixed episodes in patients with
BPI and BPII.
 Major Depression
 Schizoaffective and Schizophrenic Disorders
 Disorders of Impulse Control
 Psychiatric Disorders in Children
 Neutropenia and Anemia
secondary to antineoplastic drugs
 Hyperthyroidism
radioactive iodine, surgery, propylthiouracil are preferred.a
 SIADH
Demeclocycline is preferred for syndrome of inappropriate ADH
secretion.

21. Contraindication
 Renal or cardiovascular disease,
 Severe debilitation, dehydration, sodium
depletion,
 Concomitant therapy with diuretics; very high risk
of lithium toxicity under such conditions.
 History of Leukemia

22. Mechanism of Action:
Effects on Electrolytes and Ion Transport
 Lithium is closely related to sodium in properties.
 It can substitute for sodium in generating action potentials and in
Na+-Na+ exchange across the membrane. It inhibits the latter
process, but does not significantly affect the Na+/Ca2+ exchange
or Na+/K+ ATPase .
Effects on Neurotransmitters
 Lithium appears to enhance some of the actions of serotonin,
though findings have been contradictory.
 Its effects on norepinephrine are variable. The drug may
decrease norepinephrine and dopamine turnover, and these
effects.
 Lithium also appears to block the development of dopamine
receptor supersensitivity that may accompany chronic therapy
with antipsychotic agents.
 Finally, lithium may augment the synthesis of acetylcholine,
perhaps by increasing choline uptake into nerve terminals.

23. Mechanism of Action:
Effects on Second messenger:
 One of the best-defined effects of lithium is its action on inositol
phosphates.
 IP3 and DAG are important 2nd messengers for both -adrenergic
and muscarinic transmission. Lithium inhibits several important
enzymes in the normal recycling of membrane phosphoinositides,
including
 conversion of IP2 to IP1 (inositol monophosphate) and the
 conversion of IP to inositol.
This block leads to a depletion of phosphatidylinositol-4,5-
bisphosphate (PIP2), the membrane precursor of IP3 and DAG.
Over time, the effects of transmitters on the cell will diminish in
proportion to the amount of activity in the PIP2-dependent
pathways.
Iisolated brain tissue study indicate that lithium can inhibit
 norepinephrine-sensitive adenylyl cyclase. Such an effect could
relate to both its antidepressant and its antimanic effects

24.  Lithium may uncouple receptors from their G
proteins; indeed, two of lithium„s most common
side effects, polyuria and subclinical
hypothyroidism, may be due to uncoupling of the
vasopressin and TSH receptors from their G
proteins.

25. Dosage:
 May start with lower dose to minimize adverse
drug reactions
 900-2400 mg/day divided q6-8hr (immediate
release tabs) OR 900-1800 mg divided q12hr PO
if using extended release tabs
 Desirable serum lithium concentrations are 0.6-
1.2 mEq/L; although higher serum concentration
may be needed not to exceed 1.5 mEq/L
 Administration: Take preferably with food
Monitor
 Serum lithium 12 hr after dose; 2 times/week
until serum concentration and clinical condition
stabilizes; thereafter q2month

26. Interaction:
Drug Severity Possible interaction
Sibutramine Contraindicated Increase toxicity by
Pharmacodynamics synergism
Candesarttan Use Alternative Increase Li level
Linezolid Use Alternative Increase serotonin level by
inhibiting MAO
Locaserin Use Alternative Both Increase serotonin level
Furazolidone Use Alternative Increase serotonin level
Tranylcypromine Use Alternative Increase serotonin level
Vilazodone Use Alternative Serotonin syndrome
Aspirin Monitor closely Decrease renal clearence of Li
Carbamazepine Monitor closely Risk of neurotoxicity
Citalopram Monitor closely Enhance serotonergic effect
Haloperidol Monitor closely Risk of neurotoxicity

27. Side Effect:
COMMON SE:
 GI distress ,Upper LiCo3,Lower SR
 Hand tremor, poor coordination
 Sedation/lethargy
 Weight gain
 Polyuria / polydipsia
 Cognitive (memory ,concentration
Serious AE
 Renal:
Nephrogenic Diabetes insipidus ,Tubular interstitial
nephritis(treatment thiazide diuretic/amiloride)
 compensatory goiter without true hypothyroidism
 Neurological disorders ataxia, mental confusion, delusion,
hallucinations
 Teratogenic (Pregnancy Category D)

28. Over Dose/Poisoning:
The likelihood of toxicity increases with increasing serum
Lithium levels.
Threshold level:1.5mEq/l Serum
Signs of toxicity: Below 2.0mEq/l
Diarrhea, vomiting, drowsiness, muscular
weakness and lack of coordination
Higher Level 2.0/3.0mEq/l
giddiness, ataxia, blurred vision, tinnitus
and a large output of dilute urine
Treatment:
No Specific Antidote, discontinue drug, Eliminate ion
Follow protocol as for Barbiturate poisoning, Correct fluid
/Electrolyte

29. Anticonvulsants:
VALPROIC ACID
FDA Seizure/Epilepsy 78, BiPolar disorder „96
1st marketed AED, Effective ant manic, BP depression
Therapeutic effect level 50-125 mg/l
Fetal Hepatotoxic ,pancreatitis (free radical effect)
Not to used for Posttraumatic seizure
Best for rapid-cycling and acute-mania

30. Pharmacokinetics:
Bioavailability: 81-89% of delayed-release
Peak Plasma Concentration: 115-145 mcg/mL (IV)
Protein Bound: 10-19%
Volume of distribution: 92 L
Metabolism: Liver, Excretion: Liver
Metabolites: 2-propyl-3-ketopentanoic acid
Half-Life: 6-16 hr; 10-67 hr (neonates)

31. •Indication& Dosage:
 Bipolar Mania
Initial 25 mg/kg/day PO
Increase rapidly to achieve lowest therapeutically
effective dose,Maximum: 60 mg/kg/day
 Partial Seizures
PO: 10-15 mg/kg/day PO initially, THEN up to 30-
60 mg/kg/day
 Migraine, Prophylaxis
250 mg PO q12hr
 Status Epilepticus
 Schizophrenia
Maximum dose for an adult is 60mg/kg daily except 1g/kg/daily for
migraine*
Dose adjustment require in hepatic impairement.
*Abbott Laboratories. Depakene (valproic acid) solution and liquid-filled capsules prescribing information. North Chicago, IL; 2009 Nov.

32. •Mechanism Of Action:
 GABA level in the brain
 facilitate glutamic acid decarboxylase (GAD),
the enzyme responsible for GABA synthesis,
 An inhibitory effect on the GABA transporter
GAT-1b thus blocking degradation of GABA.
 hyperpolarize membrane potentials by
increasing membrane k conductance. 1(katzung pharmacology)

33. Drug interaction:
 Doripenum, eratopenum, imipenem,
meropenem,vorinostat, have serious
interaction ,increase hepatic metabolism1 .
 Protein bounded drugs increase free VPA
level e.g. Aspirin,
carbamazepine,warfarin,digoxin etc
 VPA decrease level of liver metabolized
drugs(cytochrome p450) e.g. carbamazepine,
phenytoin,TCA,lamotrigine
 P450 inducers decrease VPA level.
 Mechanism of the drug interaction between valproic acid and carbapenem antibiotics in monkeys and rats journal of health
sciences 2007

34. Teratogenic potential :
 Pregnancy Category: D; known to cause
neural tube defects in fetus
 Lactation: excreted in milk

35. Carbamazepine :
An anticonvulsant and specific analgesic for
trigeminal neuralgia,psychomotor, seizure.
 Stabilizes inactivated state of sodium channels,
thereby making neurons less excitable
 May reduce activity of necleus ventralis of the
thalamus or decrease synaptic transimisssion or
summation of temporal stimulation
 dose range: 800-1200 mg/day PO in divided
doses
 Therapeutic range: 4-12 mg/L [16.9-50.8
micromoles/L] Maximum dose of 1600 mg/day
 Pregnency category D, enter in breast milk.

36. Atypical Antipsychotics
QUETIAPINE
A 2nd genration psychotropic agent, convenience evidence for
mania treatment
 Absorption
Bioavailability: 100%,Peak Plasma Time:1.5 hr;6 hr XR
 Distribution
Protein Bound: 83%,Vd: 6-14 L/kg
 Metabolism
Hepatic CYP3A4
 Elimination
Half-life elimination: 6 hr
 Excretion: Urine 73%; feces 20%

37. Indications & Dosage:
 Bipolar I Disorder, Mania
Monotherapy or as an adjunct to lithium or
divalproex
Dose :400-800 mg/day
 Bipolar I Disorder, Maintenance
Immediate-release: 400-800 mg/day PO q12hr
 Insomnia (Off-label)
Usually start 25 mg PO qHS
 Major Depressive Disorder
Dosage range: 150-300 mg/day
 Alcohol Dependence (Off-label)
25-50 mg PO qHS; not to exceed 300 mg

38. Mechanism of Action:
 interact with serotonin (5HT2) and dopamine D1
and D2 receptors.
 higher selectivity for 5HT2 relative to D2 to low
EPS
 high affinity at histaminergic and adrenergic
alpha1 receptors, with a lower affinity at
adrenergic alpha2 receptors.

39. Drug Interaction:
 Increased risk of drowsiness and postural
hypotension when used with alcohol.
 CYP3A4 inducers Phenytoin,CBZ decrease level
 CYP3A4 inhibitors Ketoconazole ,erythromycin
increase level.
Pregnancy Category: C
 Neonates exposed in 3rd trimester are at risk for
EPS or withdrawal symptoms
 Lactation: excreted in breast milk, breast
feeding is not recommended

40. Tardive dyskinesia :
 Tardive dyskinesias are involuntary movements of the
tongue, lips, face, trunk, and extremities.
 TD can be caused by long-term treatment with
dopamine antagonists. Neuroleptics, Amisulpride,
antiemetic metoclopramide, a potent D2 dopamine
receptor antagonist, may cause TD, particularly in
elderly patients. antihistamines, fluoxetine,
 Atypical antipsychotics particularly Quetiapine and
clonazapine are used to reduced the tardive
dyskinesia.*
 * A single-blind, randomized trial comparing quetiapine and haloperidol in the treatment of tardive dyskinesia Emsley R, Turner HJ, Schronen
J, Botha K, Smit R, Oosthuizen PP.
Department of Psychiatry, University of Stellenbosch, Cape Town, South Africa

41. Ziprasidone :
 2nd generation antipsychotic
 Used for bipolar I, schizophrenia, Acute agitation
 MOA:
Antagonist at dopamine (D2), serotonin (5HT1D,
5HT2A) receptors
Agonist at serotonin 5HT1A receptor
Moderately inhibits reuptake of norepinephrine
and serotonin
Also has alpha-blocking & antihistaminic activity
 Risk of QT prolongation.
 Less chance of hyperglycemia or diabetes and
EPS.

42. Loxapine :
 1st generation antipsychotics
 Dibenzoxazepine antipsychotic; blocks mesolimbic D1 and D2
receptors in the brain; also has anti-serotonin 5HT2 activity
 extrapyramidal disease, parkinsonian, somnolence, tardive
dyskinesia
 10—20 mg PO q 24hr
 Inhaled preparation is in pipeline ,10mg Od, but FDA has
Pulmonary saftey concerns1
 Loxapine, as with all other antipsychotics has label warning
“Elderly patients with dementia-related psychosis treated with
antipsychotic drugs are at an increased risk of death”2
 European medicine agency recmnded loxapine for the rapid
control of agitation in adult with BP or schizophernia.(2012)
 1 . Inhaled loxapine for agitation revisited: focus on effect sizes from 2 Phase III randomised controlled trials in persons with schizophrenia or bipolar disorder.
Citrome L. New York Medical College, Valhalla
 2. Antipsychotic drugs: sudden cardiac death among elderly patients.
 Narang P, El-Refai M, Parlapalli R, Danilov L, Manda S, Kaur G, Lippmann S.2010

43. Prospective antimanic drugs:
 Tamoxifen
a nonsteroidal antiestrogen used to
treat breast cancer, is a potent and
selective PKC inhibitor that crosses
the blood-brain barrier.
 Asenapine
Increase level of dopamine, NE and
acetylcholine in cortical and limbic
brain areas. also prevent from
depression and protect cognitive
function.

44. GRATULATE FOR
ATTENTION