Psychotropics in Psychiatric Patient

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Psychotropics in Psychiatric Patient Bipolar
disorderPharmacology and Clinical Applications
of Mood Stabilizers

• Pongsatorn Meesawatsom
• B.Pharm., M.Sc. (Pharmacology)
• Faculty of Pharmacy
• Srinakarinwirote 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
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 200810(2)165-179.
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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 200810(2)165-179.
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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 200833110133.
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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 200612256264.
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Lithium is inhibitor of GSK-3?
DDT 200813295-302.
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Protein kinase C inhibitors inhibitmanic
behaviours
Biol Psychiatry 200659(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 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

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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

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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 200661Suppl976-81.
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Advances in Psychiatric Treatment 200612256264.
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Symptoms and Signs of Toxic Effects of Lithium
NEJM 1994331(9)591-598.
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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.

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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 valproateare 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 gt 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 gt 50 year of
  age
• Pregnancy

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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

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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 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

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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 200713 S38S46.
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Lithium and valproate (VPA), at therapeutically
relevant concentrations, robustly activate the
extracellular receptor coupled kinase (ERK) MAPK
cascade.
Neuropsychopharmacology Reviews 200833110133.
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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 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
  treatment-resistant 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 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.

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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
2006100422.
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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
• ClozapineCBZ

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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) syndromeAnticonvulsant
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
Epoxide hydrolase
CBZ
OXC
Drug Safety 199921489-501
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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 200727(10)14251439.
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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 199921489-501.
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Assessment of whether a patients dermatologic
reaction to an anticonvulsant drug is a case of
AHS
Pharmacotherapy 200727(10)14251439.
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Questions To Clarify a Patient's Previously
Reported "Allergy" to an Anticonvulsant Drug
Pharmacotherapy 200727(10)14251439.
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Management of patients with AHS
Drug Safety 199921489-501.
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Comparison between DRESS syndrome and serum
sickness-like reaction (SSLR)
Clin Dermatol 200523171-181.
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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