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Psychotropics in Psychiatric Psychotropics in Psychiatric Patient – Bipolar disorder:Patient – Bipolar disorder:
Pharmacology and Clinical Applications of Mood Stabilizers
The principle indications in the treatment of bipolar disorder
Acute mania and mixed mania
Acute depression
Maintenance therapy
Rapid cycling
Atypical antipychotics may also be superior to
lithium
Characteristics of ideal mood stabilizer
Antimanic and anti depressant efficacy
Prevents relapse/recurrence of both mania
and depression
Well-tolerated and safe for extended dose
Efficacy in mixed state and rapid cycling
Drugs used as mood stabilizer
Lithium
Atypical antipsychotics
Antiepileptics
Valproate, carbamazepine, lamotrigine
Topiramate
Evidence base for the efficacy of drugs used to treat bipolar disorder
Dialogues Clin Neurosci 2008;10(2):165-179.
Strength of evidence base (regardless of antimanic potency): +++, strong evidence (positive large placebo-controlled trials); ++, some evidence (from secondary outcomes of placebo-controlled trials or other randomized clinical trials); +, limited evidence (some evidence from small controlled studies or indirect evidence from clinical trials): ?, no evidence available other than open studies; -, evidence of lack of efficacy from controlled trials.
Evidence base for combinations of antipsychotics with lithium or anticonvulsants for treating mania
Dialogues Clin Neurosci 2008;10(2):165-179.
Evidence base for combinations of antipsychotics with lithium or anticonvulsants. Evidence base: +, positive in at least one placebo-controlled trial; ?, no evidence available from clinical trials; -, negative results in clinical trials so far
Evidence base for the efficacy of drugs used to treat acute depression and
bipolar depression
Monotherapy
lithium, lamotrigine, olanzapine, quetiapine
Combination
Lithium + lamotrigine
Mood stabilizers + antidepressants
Mood stabilizers + olanzapine/quetiapine
Olanzapine + fluoxetine
Lithium
Lithium
Mechanism of action Not fully understood
Mood-stabilizing effect has been postulated to
alteration of catecholamine neurotransmitter
concentration
Alternative postulate that Li may decrease
cyclic AMP concentrations, which would
decrease sensitivity of hormonal-sensitive
adenylcyclase receptors
Therapeutic levels of lithium directly inhibit several key enzymes that regulate recycling of inositol-l,4,5- trisphosphate (IP3)
Neuropsychopharmacology Reviews 2008;33:110–133.
Summary of the main neurobiological effects of lithium
System Effect of lithium
5-HT (serotonin) function Greatly increased
Acetylcholinesterase function Greatly increased
Sodium function Increased
Dopamine function Reduced
GABA function Increased
Inositol Reduced
cAMP Reduced
Protein kinase C Reduced
Glycogensynthase kinase-3 (GSK-3) Greatly reduced
BDNF Increased
Bcl-2 Increased
Pro-aptotic proteins (p53, BAX) Reduced Advances in Psychiatric Treatment 2006;12:256–264.
Lithium is inhibitor of GSK-3
DDT 2008;13:295-302.
Protein kinase C inhibitors inhibitmanic behaviours
Biol Psychiatry 2006;59(11):1006-20.
Pharmacokinetics
Rapid and complete absorption after oral
administration.
Low protein binding and absence of liver
metabolism.
Peak plasma levels achieved within 1.5 to 2 hours
for standard preparations
Plasma half-life of 17 to 36 hours.
95% drug excretion by the kidneys, with excretion
proportionate to plasma concentrations.
Efficacy
Manic episodeApproved for manic episodes and maintenance
therapyFull effect takes 1-2 weeks
Depressive episodeAs adjunct to antidepressant for refractory patientsOnset 4-6 weeks
Long term use reduces suicide risk and mortalityNarrow therapeutic index
Correct electrolyte and fluid imbalanceMonitor neurologic changeGive supportive careGive dialysis if
Renal failure or severe neurologic dysfunctionAcute poisoning lithium level ≥ 4mEq/L +
sign of lithium intox.
Lithium in pregnancy
Various congenital abnormalities, particularly of the heart and great vessels (Epstein's anomaly) may occur in babies exposed to lithium in utero during the first trimester.
The risk of major congenital malformations with first trimester lithium use is 4– 12%;
The alternatives to lithium— carbamazepine or sodium valproate—are associated with a marked increase in spina bifida.
Prelithium workup
Serum creatinine and electrolyte
CBC (1/3 have lithium-induced leucocytosis)
Thyroid function test (T4 and TSH)
UA
EKG in patient with heart disease or > 50 year of age
HCG (pregnancy)
Weight
Monitoring of Patients Receiving Lithium
Plasma lithium
Every 5-7 day after initiation of treatment and after any change in the dose
Every 1-6 mo during maintenance treatment
Serum creatinine every 6-12 mo
Thyroid function test 6-12 mo
UA and electrolyte 6-12 mo
EKG in patient with heart disease or > 50 year of age
Pregnancy
Lithium Drug interactions: increase lithium level
NSAIDsDecrease renal blood flow by inhibiting renal
prostaglandin synthesisIbuprofen, diclofenac and etc. lithium level 50-60%No change in lithium level: ASA, sulindac
Lamotrigine effective for the prevention of bipolar depres
sion.
The most troublesome side effect is rash (10%), which w
as occasionally serious and necessitated hospitalization.
Rapid titration may increase the risk of rash, particularly
when valproic acid is administered concomitantly.
Lamotrigine dosing titration
Topiramate
Topiramate has been used as an add-on weight-reduction medication, but there are no randomized controlled trials supporting its use in bipolar disorder
Adverse effect
Slow thinking, memory/speech problems
Kidney stone
Paresthesia
Glaucoma
AED Inducers: General Considerations
Induce synthesis of new enzymes
slower in onset/offset than inhibition
interactions
Broad Spectrum Inducers:
Carbamazepine, phenytoin,
phenobarbital/primidone
Selective CYP3A Inducers:
Felbamate, topiramate, oxcarbazepine These inducers are weaker or may induce CYP3A4 isoenzymes only in