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Psychotropics in Psychiatric Psychotropics in Psychiatric Patient – Bipolar disorder:Patient – Bipolar disorder:
Pharmacology and Clinical Applications of Mood Stabilizers
Pongsatorn MeesawatsomB.Pharm., M.Sc. (Pharmacology)
Faculty of PharmacySrinakarinwirote University
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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
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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
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Drugs used as mood stabilizer
Lithium
Atypical antipsychotics
Antiepileptics
Valproate, carbamazepine, lamotrigine
Topiramate
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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.
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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
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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
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Lithium
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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
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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.
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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.
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Lithium is inhibitor of GSK-3
DDT 2008;13:295-302.
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Protein kinase C inhibitors inhibitmanic behaviours
Biol Psychiatry 2006;59(11):1006-20.
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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.
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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
Acute mania 0.8-1.2 mEq/LMaintenance 0.8-1 mEq/L
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ADRs of lithium
GI; Nausea/ vomiting (2-3 first week)CNS
Fine tremor (15-53%)Obesity
RenalUnable to concentrate urine polyuria,
polydypsiaDiabetes insipidusStructural kidney damage
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ADRs of lithium
Endocrine
Hypothyroidism
CVS
Cardiac T-wave inversion
Cutaneous
Pruritic, maculopapular rash
May appear during first month of treatment
Weight gain 20% gain more than 10 kg
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Incidence of lithium side effects and effect on noncompliance
J Clin Psychiatry 2006;61[Suppl]9:76-81.
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Advances in Psychiatric Treatment 2006;12:256–264.
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Symptoms and Signs of Toxic Effects of Lithium
NEJM 1994;331(9):591-598.
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Treatment of lithium toxicity
Discontinue lithium and initiate gastric lavage
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.
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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.
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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
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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
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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
Thiazide diuretics (onset 1-2 weeks or more)Increase sodium excretion increase lithium
reabsorptionDecreasing lithium dose by 40% may be helpful
ACEIs, ARBs decrease GFR
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Condition that increase lithium level
Causes of sodium depletion
Excessive exercise/sweating
Vomiting/diarrhea
Low sodium diet/salt deficiency
Restricted dietary control
Decrease GFR
Age-related renal insufficiency
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Lithium drug interactions: increase lithium effect
Methyldopa, carbamazepine, calcium
channel blockers, SSRI CNS toxicity of
lithium
Antipsychotics EPS
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Lithium drug interactions: decrease lithium level
Methylxanthines; theophylline, caffeine (also
caffeine-containing beverages)
Cause renal vasodilation GFR
Urine alkalinizer; sodium bicarbonate
High Na+ diet excretion
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‘Rebound’ affective episodeson lithium discontinuation
The decision to stop lithium treatment will usually be m
ade by the specialist.
Lithium should never be stopped abruptly unless there
are signs of toxicity.
Abrupt discontinuation of lithium prophylaxis may preci
pitate early recurrence of mania and depressive episod
es and patients should be advised.
Gradual discontinuation over 4 weeks may lead to a low
er recurrence rate
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Antiepileptic drugs
Commonly used AEDs as mood stabilizers
Sodium valproate
Carbamazepine
Oxcarbazepine
Lamotrigine
Topiramate
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Mechanism of antiepileptics
Neurologist 2007;13: S38–S46.
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Lithium and valproate (VPA), at therapeutically relevant concentrations, robustly activate the extracellular receptor
coupled kinase (ERK) MAPK cascade.
Neuropsychopharmacology Reviews 2008;33:110–133.
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Valproate
Dosage forms
Available in 200 mg enteric-coated tablet, 500
mg slow-release tab, 200 mg/ml oral solution
Available in a slow release preparations
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Valproate
Toxicity
GI side effects in about 16% anorexia; nausea; vomiting
Dose-related CNS side effects sedation; ataxia; tremor
Alopecia; weight gain
Transient elevation of liver enzyme, hepatotoxicity
Inhibits platelet aggregation, thrombocytopenia
Teratogenicity - neural tube defects
Pancreatitis
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Effects of AEDs on Body Weight
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Carbamazepine
Carbamazepine is not a first-line agent for bipolar disord
er
Generally reserved for lithium-refractory patients, rapid c
yclers, or for mixed states
Acute antimanic effects comparable to lithium and chlorp
romazine.
The combination of carbamazepine with lithium, valproat
e, and antipsychotics is often used for treatment-resistan
t patients experiencing a manic episode
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Carbamazepine
Carbamazepine is metabolized mainly by
CYP3A4 and also act as auto-inducucer
Half life is time dependent
First 2-6 weeks: 30-35 hrs
Later: 12-20 hrs
Therapy initiated gradually eg 100 mg hs
Drug given with meals to minimize GI side
effects
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Carbamazepine
GI side effects, sedation are common
All common allergic and idiosyncratic toxic effects also occur
Augments effects of ADH; hyponatremia
Blood dyscrasias; aplastic anemia, neutropenia, thrombocytopenia
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Lamotrigine
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.
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Lamotrigine dosing titration
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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
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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
certain tissues.
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Carbamazepine PK-DDI
CBZ induced CYP3A4, 2C9 and 1A2
CYP3A4 substrates: quetiapine, aripiprazole
CYP1A2 substrates: clozapine, olanzapine, aripiprazole
Risperidone primarily metabolize by CYP2D6 and lesser extent CYP3A4.
Oral contraceptives
Onset and offset of induction effect are not immediate.
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Basic & Clinical Pharmacology & Toxicology 2006;100:4–22.
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AED Inhibitors
Valproate
UDP glucuronosyltransferase (UGT)
plasma concentrations of lamotrigine, lorazepam
CYP2C19
plasma concentrations of phenytoin, phenobarbital
Topiramate & Oxcarbazepine
CYP2C19
plasma concentrations of phenytoin
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Hepatic Drug Metabolizing Enzymes and Specific AED Interactions
Carbamazepine CYP3A4 CYP2C8 CYP1A2
Inhibitors: ketoconazole, fluconazole,
erythromycin, verapamil, diltiazem
Lamotrigine UGT1A4
Inhibitor: valproate
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Hepatic Enzyme Effects of the Antiepileptic Drugs
Inducers Inhibitors No or Minimal Effect
Carbamazepine Valproate Gabapentin
Phenytoin Felbamate Lamotrigine
Phenobarbital Topiramate*
Primidone Tiagabine
Oxcarbazepine*
Levetiracetam
Zonisamide*Inducing effect is mild but significantly increases the metabolism of oral contraceptives.
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Pharmacodyniamics DDI of AEDs
Sedation and/or weight gain
Clozapine/olanzapine + valproate
Clozapine/olanzapine + AEDs
Neutropenia, agranulocytosis
Clozapine+CBZ
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Rash
Carbamazepine and lamotrigine high
Lithium worsens existing dermatologically
problems
Oxcarbazepine appears less than
carbamazepine and less than 1/3 cross-
sensitivity with carbamazepine
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Drug eruption with eosinophilia and systemic symptoms (DRESS)
syndrome
Anticonvulsant hypersensitivity syndrome (AHS)
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Drug eruption with eosinophilia and systemic symptoms (DRESS) syndrome
DRESS is usually defined by the triad of
fever
skin eruption
internal organ involvement
A serious idiosyncratic, non- dose related
adverse reaction caused by aromatic
anticonvulsants (phenytoin, phenobarbital,
primidone, carbamazepine and lamotrigine)
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Possible metabolic pathway for production of toxic metabolites of aromatic anticonvulsants
Drug Safety 1999;21:489-501
Epoxide hydrolase
CBZ
OXC
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Oxcarbazepine
Oxcarbazepine is an analog of carbamazepine
It has similar efficacy but lack of the toxic metabolite (carbamazepine-10,11-epoxide), does not undergo autoinduction and does not have polymorphisms
Caution should be exercised in patients who sensitive to carbamazepine (30% cross-sensitivity with oxcarbazepine)
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DRESS: Symptoms
Fever and malaise + pharyngitis and cervical
lymphadenopathy (may develop to
pseudolymphoma later) are usually the
presenting symptoms
Rash start as symmetrical MP + pustules at
upper trunk & face then spread to lower EXT
Mucosal involvement is not infrequent, but
can present as conjunctivitis and ulceration
of the vaginal and buccal mucosa
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DRESS: Symptoms
Liver, kidney and hematologic system are the
most frequently involved internal organ
Mortality approximately 21% and is directly
correlated with the degree of hepatic
involvement
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Objective Signs Associated with AHS in the Reviewed Cases
Pharmacotherapy 2007;27(10):1425–1439.
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DRESS: Onset
Symptoms occurred within 3 months of
beginning therapy (at least 7 days)
It may not develop for 1-2 weeks into the
reaction and may even develop in a delayed
fashion 3 to 8 weeks after starting treatment
with the inciting drug for the first time.
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DRESS: Severity
Drug Safety 1999;21:489-501.
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Assessment of whether a patient’s dermatologic reaction to an anticonvulsant drug is a case of AHS
Pharmacotherapy 2007;27(10):1425–1439.
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Questions To Clarify a Patient's Previously Reported "Allergy" to an Anticonvulsant Drug
Pharmacotherapy 2007;27(10):1425–1439.
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Management of patients with AHS
Drug Safety 1999;21:489-501.
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Comparison between DRESS syndrome and serum sickness-like reaction (SSLR)
Clin Dermatol 2005;23:171-181.
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Initiating treatment of bipolar disorder
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Advantages and Disadvantages of Specific Maintenance Treatments
Advantages Disadvantages
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Advantages and Disadvantages of Specific Maintenance Treatments
Advantages Disadvantages