Download 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