Dr.Rachana Menon

PHARMACOTHERAPY OF MANIAPHARMACOTHERAPY OF MANIA

As we go along….

History Introduction to mood disordersDSM 4 criteria & subtypesPathogenesisPharmacology of antimanic drugsNewer approachesNon pharmacological treatmentsTreatment in special populationsTreatment of resistant mania

400 B.C- Hippocrates

30 A.D- Roman physician described melancholia-

Aretaeus of Cappadocia

1899-Emil Kraepelin

1949, John Cade

Works of Sigmund Freud

Mania & Hypomania– Distinct period of an abnormally and persistently elevated

expansive, or irritable mood lasting for at least 1 week, or less if a

patient must be hospitalized

Hypomanic episode

– At least 4 days

– Not sufficiently severe to cause impairment in social or

occupational functioning, and

– No psychotic features are present

Cyclothymia - one or more Hypomanic episodes Dysthymic (chronic depression) episodes

Euthymia

Mania

Depression

Euthymia

Mania

Depression

DSM-IV DIAGNOSIS OF MANIA

DSM-IV

Dopamine Hypothesis

Striatum, the nucleus accumbens,

olfactorytubercle.

Substantia nigra,

VTA , hypothalamus,

cortical areas

Hippocampus

Mesolimbic- mesocortical:

Control behavior, cognitive

funtion - D₂

Receptor.

Nigrostriatal: Control

Voluntary Movement

D₁ and D₂

receptor.

Tuberoinfundibular:

Control prolactin secretion

D₂ receptor.

Vesicular monoamine transporter protein (VMAT2)

CHOLINERGIC SYSTEM

Cholinergic monoaminergic interaction hypothesis

Complex interrelations of cholinergic and monoaminergic neurotransmitter

Play a role in the pathophysiology and treatment of affective disorders.

Hypocholinergic or hyperadrenergic drive would cause mania.

• By stimulation of muscarinic M4 receptors

• M4 receptors are found in high density in limbic and cortical, decrease

cAMP

Acetylcholineprecursors, such as lecithin (phosphotidylcholine) or choline in combination with lithium, have

been used to successfully treat manic patients.

Noradrenergic system

MHPGNE

GLUTAMATE HYPOTHESIS

• Major excitatory neurotransmitters in the CNS.

• Intergral for synaptic transmission in brain circuitry.

• Key regulator of synaptic strength and plasticity

• Bind to (NMDA) receptor, and an excess of

glutamatergic stimulation

• High concentration of NMDA receptors exists in the

hippocampus

Deleterious glutamate signaling

Second Messengers and Intracellular Cascades

Increase in Gs levels in frontal, temporal and occipital cortices of BD subjects.

Mononuclear leucocytes of manic patients Platelets

G PROTIENS Mood states

A significantincrease in the activity of basal and activated AC among maniacsubjects

Significant increase in PIP2 levels

The PKC signaling pathway

• Regulation of neuronal excitability

• neurotransmitter release

• long-term synaptic events

attenuation of PKC activity may play arole in the antimanic effects of mood stabilisers

Alter the conformation of the cytoskeleton throughactin filaments.

`Modulation of proteins associatedwith cytoskeleton microtubules- tau, MAP-1BMAP-2, Apoptosis

destabilization of microtubules conformation

NEURONAL SURVIVAL

CALCIUM-SIGNALING ABNORMALITIES

Abnormal Ca2+ homeostasis in bipolar disorder

• Elevated intracellular Ca2+ levels in platelets, lymphocytes and

neutrophils of patients with BD

Marked blunting of Gprotein-

activated PI hydrolysis

Altered mRNA expression of

proteins important roles in Ca2+

homeostasis

IMPase type2a,

TRPM2

ALTERATIONS OF HORMONAL REGULATIONS

Genetics…

• MZ concordance – 40 -45%• Heritability – 80 – 85%• Leading linked regions – 6q, 8q, 13q, 22q• Leading candidate genes

– BDNF– DAOA– DISC– TPH2– SLC6A$

• Genes implicated by GWAS – DGKH– CACNA1C– ANK3

Concordance in MZ

twins of 50-70%

Early-onset bipolar

disorder may be

even more genetic

Strongly

genetic

DRUG INDUCED MANIA• Levodopa• Corticosteroids • Tricyclic and monoamine oxidase inhibitor• Thyroxine • Isoniazid • Sympathomimetic drugs• Chloroquine, baclofen• Alprazolam• Captopril • Amphetamine • Phencyclidine.

CLASSIFICATION

Mood Stabiliser Anti epileptics Anti PsychoticsAnti Adrenergic

Drugs

Lithium Sodium valporate Olanzapine Clonidine

  Carbamezapine Quatepine Propranalol

  Lamotrigine Apriprazole  

  Gabapentin Zisaperidone  

  Toperamate Risperidone   

Benzodiazepines Cholinomimetics Calcium Channel Blockers

Clonazepam Physostigmine Verapramil

Lorazepam   Nifedipine

    Nimodipine

LITHIUM

Introduction of Li+ in 1949

(Li+) is the lightest of the alkali metals

Monoamines implicated in the pathophysiology of

mood disorders

Second-messenger and other intracellular

molecular mechanisms involved in signal

transduction

Gene regulation and cell survival.

Lithium increase the SE inhibitory input to VTA and SNc nuclei

Lithium at conc of 1-10 mEq/L inhibits the Ca++-dependent release of NE and DA

BEFORE

AFTER

Influence G-protein function is by modulating the posttranslationalmodification of ADP-ribosylation of Gproteins

INOSITOL MONOPHOSPHATE

Interference with PIP2 PATHWAY

Activated PLC

phosphorylation

HIPPOCAMPUSAXONAL GROWTH

Enhances the bindingof tau to microtubules which promotes microtubuleassembly

DEPHOSPHORYLATION

Decrease gene expression of PLA2

AP-1, AMI-1, PEBP-2

Bcl-2

PHARMACOKINETICS

Completely absorbed in GIT within 6–8 hours; peak plasma levels in

30 minutes to 2 hours

• Distribution: Initial volume of distribution is 0.5 L/kg, rising to 0.7–

0.9 L/kg; some sequestration in bone. No protein binding.

• Excretion: virtually entirely in urine. Lithium clearance about 20% of

creatinine. Plasma half-life about 20 hours

• Target plasma concentration: 0.6–1.4 mEq/L

• Dosage: 0.5 mEq/kg/d in divided doses

Carbonate capsules slow release tablets citrate syrup (8 mmol/

5 mL)

ThaizidesSpironolactone Amiloride FurosemideIndomethacinIbuprofen NaproxenCOX-2 inhibitorsFosinopril Lisinopril

SERUM LEVEL MONITORING

• Acceptably safe are between 0.6 and 1.5 mEq/L.

• 1.0-1.5 mEq/L- acutely manic or hypomanic patients.

• 0.6-1.0 mEq/L long-term prophylaxis.

• 0.8-1.0 mEq/L experience decreased relapse risk

• Trough from samples obtained 10-12 hours after the last

oral dose of the day.

• Trough concentration:0.8-1mEq/l Individualization of serum levels is often necessary to obtain a favorable risk-benefit relationship

•Acute poisoning - Voluntary or accidental ingestion in a previously untreated patient

•Acute-on-chronic - Voluntary or accidental ingestion in a patient currently using lithium

•Chronic or therapeutic poisoning - Progressive lithium toxicity, generally in a patient on lithium therapy

Acute Toxicity and Overdose

• Nausea, vomiting, abdominal pain, profuse diarrhea

• Polyuria,Coarse tremor

• Ataxia, coma, and convulsions

• Mental confusion, hyperreflexia, gross tremor, dysarthria, seizures,

and cranial nerve and focal neurological signs

• Coma and death.

• Cognitive and motor neurological damage irreversible, with

persistent cerebellar tremor being the most common

SERUM PLASMA LEVELS

Mmol/L Effects

0.5 None

1 Mild tremor

1.5 Coarse tremor

2 Hyperreflexia, dysarthria

2.5 Myoclonia, ataxia, confusion

> 3.0 Delirium, coma, seizures

LITHIUM TOXICITY

Role of sodium polystyrene sulfonate (Kayexalate)

•Admit patients with serum lithium levels higher than 2 mEq/L.•Admit to an ICU patients with chronically elevated lithium levels higher than 4 mEq/L

NO ANTIDOTE

HEMODIALYSIS

Adverse effects Polyuria and compensatory polydipsia

Benign, diffuse, non tender thyroditis

Benign and reversible T-wave flattening in ~20% of

patients , U wave enlargement

Sinus bradycardia, AV blocks

Dermatitis, folliculitis, and vasculitis can occur with Li+

administration

Ebstein's malformation

Floppy baby syndrome

Polymorphonuclear leukocytes

Therapeutic uses

Acute mania- 600-mg loading dose (150,300,600mg)

Prophylactic treatment of bipolar disease

Treatment-resistant major depression

Monotherapy for unipolar depression

Suicide reduction extends to unipolar mood disorder

Alzheimer type, stroke, Parkinson's disease,

Huntington's disease, amyotrophic lateral

sclerosis, progressive supranuclear palsy,

spinocerebellar ataxia

ANTIEPILEPTICS

CARBAMEZAPINE SODIUM VALPROATE LAMOTRIGINE TOPIRAMATE GABAPENTIN

CARBAMAZEPINE• Iminostilbene derivative with a tricyclic structure

• Mechanism of action

Inositol depletion as a mechanism underlying carbamazepine's mood

stabilizing properties (Williams et al., 2002).

Pharmacokinetics

• Absorbed slowly and erratically after oral administration

• 75% to 90% is protein bound

• Undergoes extensive hepatic metabolism predominantly by conversion to a

10,11-epoxide

• Substrate and inducer of CYP3A4

• Induces CYP2C, CYP3A, and UGT, thus enhancing the metabolism of drugs

degraded by these enzymes

• Half life – 20 to 40hrs

• Therapeutic plasma concentrations 6 to 12 µg/mL

Anticonvulsants ,Hormonal contraceptives NeurolepticsErythromycin,Cimetidine,Isoniazid,Fluoxetine

Therapeutic uses

• Acute bipolar mania- 400-1400mg/day

• Maintenance therapy-  4-12 ug/ml drawn at 12 hrs

after last dose, minimum of 5 days after last dose

change

• Partial seizures

• Generalized tonic-clonic seizures

• Absence seizures

• Trigeminal neuralgia.

Acute mania

400 mg/day- larger dose given at bedtime due to the

sedating properties

Titration proceeds by 200-mg increments every 24-48

hours based on clinical response and serum trough

levels

Extended-release form – FDA 2005

Better tolerated compared to older preparations

Effective as monotherapy with once-daily dosing

Immediate release forms of carbamazepine cannot be loaded

Adverse effects Nausea, vomiting, diarrhoea and visual

disturbances Hypersensitivity – rash, photosensitivity,

hepatitis, granulocyte suppression and aplastic anemia

Lyell’s syndrome,Stevens-Johnson

ADH action enhancement – hyponatremia and water retention

Teratogenicity Transient elevation of hepatic

transaminases Aplastic anemia,Agranulocytosis

 CBZ level, CBC + differential,reticulocyte countSGPT every 3 months till stable.

Oxcarbazepine 10-keto analogue of carbamazepine.

Metabolite: MHD- 10-monohydroxy derivative Half-life 8-10 h

Therapeutic use: 600 -1200 mg/day.Augmented to 1400 to 2400 mg/day in order to obtain the desired effect

DRUG INTERACTION: reduces the plasmatic levels of felodipine, verapamil,OCPS

Substitution of oxcarbazepine for carbamazepine is associated with increased levels of phenytoin and

valproic acid

Sodium valproate

• Simple branched-chain carboxylic acid

Mechanism of action

Inhibit the activity of glycogen synthase kinase-3 –ALTER

MARCK protiens

INHIBIT MYO-INOSITOL PHOSPHATASE

Reduction in arachidonic acid turnover in brain membrane

phospholipids

Interact with nuclear regulatory factors that affect gene

expression AP-1, AMI-1, PEBP-2

Increase expression of Bcl-2, which is associated with

protection against neuronal degeneration/apoptosis

Reduce isofoms of PKC

6 MECHANISMS IN COMMON!

PHARMACOKINETICS

Completely absorbed after oral administration t ½ : 14 hoursplasma proteins bound ~90%

Metabolism: beta-oxidation and UGT enzymes

Metabolites: VA Glucuronide (40% of VA) Urinary excretion3 oxo VA (33% of VA) Urinary excretion2 ene VA

Delayed but significant accumulation in brain

< 5% excreted unchanged in urine

CYP2C9 CYP2C19

Increases the serum levels of SVP

Phenytoin Phenobarbitone : 70%Lamotrigine : > 2.5 times of T ½ CBZ Metabolite increasedDPH Others:

Rufinamide, Lorazepam, Felbamate, TCAs, Zidovudine, Nimodipine

DRUGS ↓ Serum SVP

CBZ + DPH (Combined) ↓ SVP by 50% (Reduction is more in children)

Lamotrigine ↓ SVP by 25%

Estrogen (OCP) ↓ SVPOthers ↓ SVP

Meropenem, Imepenam, Rifampicin, Ritonavir

Therapeutic uses

• Acute mania

• Oral loading of VPA can achieve rapid control of symptoms- 3 days

• Day 1: single dose of 20 mg/kg

• Days 2-4 :same dose but split bid

• Day 4 : labs (VPA level, platelets, LFTs) then titrate dose to get level > 80

ug/ml or best clinical response.

• Some patients need > 100ug/ml.

Cyclothymia:DOC

Effective at surprisingly low doses,125-500 mg/day.

Maintenanace: Superior to lithium in preventing recurrence of episode.

Immediate Release-12-hour troughs are used to guide treatment

Extended Release- 24-hour trough levels

Divalproex sodium

90-120 g/mL

• Weight gain,GI distress

• Tremor, Ataxia

• Dizziness, sedation, headache, nausea, dyspepsia

• Hair loss- curly scalp hair .

• Severe hepatic damage can occur within the first six months of

treatment

• LFT TO BE MONITERED- fulminanat hepatits!!!!

• Acute pancreatitis,PCOD –RARE

SIDE EFFECTS

LAMOTROGINE

• A phenyltriazine derivative

PHARMACOKINETICS Half-life -25-35 hrs

Metabolized primarily by glucuro nidation to an inactive

2-N-glucuronide conjugate.

Renal excretion

Protein binding ~55%

The kinetics linear at steady-state within a dose range of

100 to 700 mg/day

chewable dispersable formulations

Phenytoin, CBZ, phenobarbital reduces

the t1/2 and plasma concentrations of

lamotrigine

THERPEUTIC USES• Maintenance therapeutic range: not established

75-250 mg/day (with CBZ 300-500mg/day; with VPA 50-150 mg/day

LTG monotherapy: 25 mg/day week 1

50 mg/day week 2

up to target dose of 150-200 mg/day

12.5 mg/day week 1

25 mg/day week 2

target dose of 75-100mg/day

50 mg/day wks 1-2

100 mg/day weeks 3-4wks

target dose of 300 mg/day

In combination with VPA

In combination with CBZ

50-100 mg/day

Treatment-resistant depression- 100 mg/day to 20 mg/day of

fluoxetine

• Bipolar I depression- 200mg/day (Maintenanace)

• Rapid cycling- 100 to 500 mg per day.

Fixed lithium dose (800 mg/day)

Adverse effectsDizziness, ataxia, blurred or double vision, nausea, vomiting

Stevens-Johnson syndrome and DIC

GABAPENTINE

• Consist of a GABA molecule covalently bound to a lipophilic

cyclohexane ring or isobutane.

• Centrally active GABA agonist,

• High lipid solubility

• Transfer across the blood-brain barrier.• Blocking of voltage-dependent calcium channels

Its use in bipolar disorder is based on clinical impressions of efficacy, usually as an adjunctive agent; it has not at this point been adequately

established as a primary mood stabilizer!!!!

Pharmacokinetics• Orally absorbed.Half-life: 5-7 hrs.

• Metabolism: none

• Excreted unchanged in urine

• Maintenance therapeutic range: N/A

• Dosage: 300-3600 mg/day. Dosage range is variable; when

given as an adjunct mood stabilizer

• “You must split the dose when getting into higher dosage

ranges.”

• Drug interactions: none

split dosing may be necessary for good response

Adverse Effects• Sedation • Fatigue, ataxia• Ejaculatory problems

• Caution!!!!: sudden discontinuation in patients with OCD

TopiramateSulfamate-substituted monosaccharide

Rapidly absorbed after oral administration

(10-20%) binding to plasma proteins

Mainly excreted unchanged in the urine.

Metabolism by hydroxylation, hydrolysis, and

glucuronidation with no single metabolite

t1/2 is ~24 hrs

Further double-blind studies to elucidate the antimanic and

mood stabilizing effects of topiramate are warranted.

Adverse Effects• Sedation, dizziness, anxiety, tremor, confusion• tingling in fingers, toes• GI distress,• Cognitive impairment, • Weight loss!!!• Teratogenicity,• Renal calculi!!!!

• Therapeutic use• Acute mania 100-200 mg/day, perhaps higher (for

seizure disorder 400mg/day is recommended)

400mg/day

Decrease serum levels of CBZ, VPA, digoxin, OCPs

ANTIPSYCHOTICS

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

D2

Dopaminereceptorantagonist

HIT AND RUN!!!!

Fills D2 receptors,preventing blockade by the antipsychoticagent.

10-15mg

25mg bd

5mg

20mg bd

Prophylaxis

Prophylaxis

2009

5-HT1A,5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, and 5-HT5–7 ,

Adverse effects

Benzodiazepines Lorazepam and Clonazepam

Useful adjuncts with mood stabilizers in the treatment of acute mania

• Lorazepam- 2 to 4 mg per day, three to four divided doses. Titrated up to a target dose ranging from 3 to 8 mg per day

• Clonazepam  1 - 3 mg per day, two divided doses.

• 2 to 6 mg per day, depending upon efficacy and tolerabity

• high as 24 mg per day

• Promote sleep improvement

Sedation, and respiratory depression

Hypomanic Mild to moderate manic or mixed episodes Cannot tolerate lithium

Calcium channel blockers

Nimodipine may be more effective than Verapramil

• Special promise for rapid and ultrarapid cycling patients

Verapamil and nimodipine • Controlled symptoms of mania in PREGNANCY • VERAPRAMIL- 160-320mg/day• Low teratogenecity

Treatment resistant mania• Clozapine + ECT

• Donepezil

• Gabapentin, topiramate, mexiletine,

• IV magnesium sulphate

Pediatric Use• ONLY Li+ has FDA approval for child/adolescent bipolar

disorder for ages 12 years.

Aripiprazole and risperidone 10-17yrs

Geriatric Use

• Targeting lower maintenance serum levels (0.6-0.8 mEq/L) may

reduce the risk of toxicity.

• As GFR> 60 mL/min - alternative agents, despite lithium's

therapeutic advantages

• Use of loop diuretics and angiotensin-converting enzyme inhibitors

.

30 mg/kg/day given in three divided doses will produce a Li+

concentration of 0.6-1.2 mEq/L in 5 days

PREGNANCY

Lithium- Category D

• First trimester - Ebstein’s Anomaly

• 1: 10-20,000 to 1: 1000. foetal echo is warranted, Floppy baby

syndrome

• Maternal polyuria

Valproate: Category D

Neural tube defects, limb defects, cardiac defects and facial

dysmorphism

.

Lamotrigine & Carbamazepine: Category D

Absolute risk of birth defects (~ 5-6%). n oral cleft

defect

Atypical Antipsychotic Medications

Weight gain throughout the pregnancy

• Risk of gestational diabetes. RISK-BENEFIT RATIO!!!

Novel stratergies and novel therapies

• Prophylaxis• Decreasing the episode severity• Increasing the inter-episode interva

Non-competitive, high-affinity NMDA receptor antagonist Memantine

• Demonstrated potential to relieve “manic-like” symptoms in animal models; appeared beneficial in two open-label studies

• Allopurinol • Hypothesized to be involved in the pathophysiology of mania. • An adjunct to mood stabilizer or antipsychotic

GOAL

Glutamatergic modulators

TAMOXIFEN

• Protein kinase C (PKC) inhibitor

• Antiestrogenic drug

• Crosses the blood-brain barrier and is relatively well

tolerated (up to 200 mg/d)

• starting dosage 20 mg twice daily (40 mg/d).

• Subsequently increased by 10 mg to achieve 80 mg/d in

twice-daily divided doses.

• long-term safety data are limited

• increased risk of endometrial carcinoma and uterine

sarcoma

. The Canada Network for Mood and Anxiety Treatment (CANMAT) lists it as

a third-line option

Young Mania Rating Scale (YMRS).

The GlyT1 inhibitor SSR504734

Effective as haloperidol in blocking PCP-induced CNS metabolic changes in rats.

Lurasidone - 5-HT/DA antagonist- FDA approval 2009

Possesses potent activity at 5-HT7 receptor sites, actions that, based on preclinical and early clinical studies, may be associated with cognitive benefits

Xanomeline, M1/M4 agonist, has shown antipsychotic and procognitive affects .schezo trial

Brain StimulationNon-invasive method• transcranial magnetic stimulation • transcranial direct current stimulation

Invasive method• Deep brain stimulation (DBS) that targets brain areas via

implanted electrodes• Stimulation could elicit circuit-level modifications that can

improve symptoms

ECT

• A prolonged or severe episode of mania • Severe depressive illness or refractory depression.• Catatonia.

• Should stop once a response is achieved or if the patient

develops side-effects.

THANK YOU