Psychotropics in Psychiatric Patient – Bipolar disorders
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Transcript Psychotropics in Psychiatric Patient – Bipolar disorders
Psychotropics in Psychiatric
Patient – Bipolar disorder:
Pharmacology and Clinical
Applications of Mood Stabilizers
Pongsatorn Meesawatsom
B.Pharm., M.Sc. (Pharmacology)
Faculty of Pharmacy
Srinakarinwirote University
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
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.
Dialogues Clin Neurosci 2008;10(2):165-179.
Evidence base for combinations of antipsychotics with
lithium or anticonvulsants for treating mania
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
Dialogues Clin Neurosci 2008;10(2):165-179.
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 inhibit
manic 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 episode
Approved for manic episodes and maintenance
therapy
Full effect takes 1-2 weeks
Depressive episode
As adjunct to antidepressant for refractory patients
Onset 4-6 weeks
Long term use reduces suicide risk and mortality
Narrow therapeutic index
Acute mania 0.8-1.2 mEq/L
Maintenance 0.8-1 mEq/L
ADRs of lithium
GI; Nausea/ vomiting (2-3 first week)
CNS
Fine tremor (15-53%)
Obesity
Renal
Unable to concentrate urine polyuria,
polydypsia
Diabetes insipidus
Structural kidney damage
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
Incidence of lithium side effects and
effect on noncompliance
J Clin Psychiatry 2006;61[Suppl]9:76-81.
Advances in Psychiatric Treatment 2006;12:256–264.
Symptoms and Signs of Toxic
Effects of Lithium
NEJM 1994;331(9):591-598.
Treatment of lithium toxicity
Discontinue lithium and initiate gastric
lavage
Correct electrolyte and fluid imbalance
Monitor neurologic change
Give supportive care
Give dialysis if
Renal failure or severe neurologic dysfunction
Acute 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
NSAIDs
Decrease renal blood flow by inhibiting renal
prostaglandin synthesis
Ibuprofen, 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
reabsorption
Decreasing lithium dose by 40% may be helpful
ACEIs, ARBs decrease GFR
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
Lithium drug interactions:
increase lithium effect
Methyldopa, carbamazepine, calcium
channel blockers, SSRI CNS toxicity of
lithium
Antipsychotics EPS
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
‘Rebound’ affective episodes
on lithium discontinuation
The decision to stop lithium treatment will usually be
made by the specialist.
Lithium should never be stopped abruptly unless there
are signs of toxicity.
Abrupt discontinuation of lithium prophylaxis may
precipitate early recurrence of mania and depressive
episodes and patients should be advised.
Gradual discontinuation over 4 weeks may lead to a
lower recurrence rate
Antiepileptic drugs
Commonly used AEDs as mood stabilizers
Sodium valproate
Carbamazepine
Oxcarbazepine
Lamotrigine
Topiramate
Mechanism of antiepileptics
Neurologist 2007;13: S38–S46.
Lithium and valproate (VPA), at therapeutically relevant
concentrations, robustly activate the extracellular receptor
coupled kinase (ERK) MAPK cascade.
Neuropsychopharmacology Reviews 2008;33:110–133.
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
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
Effects of AEDs on Body Weight
Carbamazepine
Carbamazepine is not a first-line agent for bipolar
disorder
Generally reserved for lithium-refractory patients, rapid
cyclers, or for mixed states
Acute antimanic effects comparable to lithium and
chlorpromazine.
The combination of carbamazepine with lithium,
valproate, and antipsychotics is often used for treatmentresistant patients experiencing a manic episode
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
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
Lamotrigine
Lamotrigine effective for the prevention of bipolar
depression.
The most troublesome side effect is rash (10%), which
was 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 weightreduction 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 certain tissues.
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.
Basic & Clinical Pharmacology & Toxicology 2006;100:4–22.
AED Inhibitors
Valproate
UDP glucuronosyltransferase (UGT)
plasma concentrations of lamotrigine, lorazepam
CYP2C19
plasma concentrations of phenytoin, phenobarbital
Topiramate & Oxcarbazepine
CYP2C19
plasma concentrations of phenytoin
Hepatic Drug Metabolizing Enzymes
and Specific AED Interactions
Carbamazepine
CYP3A4 CYP2C8 CYP1A2
Inhibitors: ketoconazole, fluconazole,
erythromycin, verapamil, diltiazem
Lamotrigine
Inhibitor: valproate
UGT1A4
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.
Pharmacodyniamics DDI of AEDs
Sedation and/or weight gain
Clozapine/olanzapine + valproate
Clozapine/olanzapine + AEDs
Neutropenia, agranulocytosis
Clozapine+CBZ
Rash
Carbamazepine and lamotrigine high
Lithium worsens existing dermatologically
problems
Oxcarbazepine appears less than
carbamazepine and less than 1/3 crosssensitivity with carbamazepine
Drug eruption with eosinophilia and
systemic symptoms (DRESS)
syndrome
Anticonvulsant hypersensitivity
syndrome (AHS)
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)
Possible metabolic pathway for production of
toxic metabolites of aromatic anticonvulsants
Epoxide
hydrolase
CBZ
OXC
Drug Safety 1999;21:489-501
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% crosssensitivity with oxcarbazepine)
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
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
Objective Signs Associated with
AHS in the Reviewed Cases
Pharmacotherapy 2007;27(10):1425–1439.
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.
DRESS: Severity
Drug Safety 1999;21:489-501.
Assessment of whether a patient’s dermatologic reaction to
an anticonvulsant drug is a case of AHS
Pharmacotherapy 2007;27(10):1425–1439.
Questions To Clarify a Patient's Previously
Reported "Allergy" to an Anticonvulsant Drug
Pharmacotherapy 2007;27(10):1425–1439.
Management of patients with AHS
Drug Safety 1999;21:489-501.
Comparison between DRESS syndrome
and serum sickness-like reaction (SSLR)
Clin Dermatol 2005;23:171-181.
Initiating treatment of bipolar disorder
Advantages and Disadvantages of
Specific Maintenance Treatments
Advantages
Disadvantages
Advantages and Disadvantages of
Specific Maintenance Treatments
Advantages
Disadvantages