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

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

Acute mania 0.8-1.2 mEq/LMaintenance 0.8-1 mEq/L

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

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 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

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

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 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

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 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

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 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

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 UGT1A4

Inhibitor: valproate

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 cross-

sensitivity 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

Drug Safety 1999;21:489-501

Epoxide hydrolase

CBZ

OXC

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)

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