BIOMED 370: The Treatment of Mood Disorders March 9, 2005 Lawrence H. Price, M.D. Professor of...

BIOMED 370: The Treatment of BIOMED 370: The Treatment of Mood Disorders Mood Disorders

March 9, 2005March 9, 2005

Lawrence H. Price, M.D.Lawrence H. Price, M.D.Professor of Psychiatry and Human BehaviorProfessor of Psychiatry and Human Behavior

Brown University School of MedicineBrown University School of Medicine

Clinical Director and Director of ResearchClinical Director and Director of Research

Butler HospitalButler Hospital

345 Blackstone Blvd345 Blackstone Blvd

Providence, RI 02906Providence, RI 02906

Major Depression

Dysthymia

Depressive D/O NOS

Bipolar I D/O

Bipolar II D/O

Cyclothymia

Bipolar D/O NOS

Bipolar Disorders

Mood D/O due toGen Med Cond

Substance-InducedMood D/O

Mood D/O NOS

Other Mood Disorders

DSM-IV MOOD DISORDERS

Depressive Disorders

Mild

Moderate

-Psychosis

Mood-Congruent

Mood-Incongruent

+Psychosis

Severe

In Partial Remission

In Full Remission

Severity/Psychosis/Remission

Catatonic

Postpartum Onset

Chronic (Dep episodes only)

Melancholic (Dep episodes only)

Atypical (Dep episodes only)

Most recent episode

+Full Interepisode Recovery

-Full Interepisode Recovery

Longitudinal Course

Seasonal Pattern

Rapid Cycling

Course of recurrent episodes

SPECIFIERSFOR DSM-IV MOOD DISORDER EPISODES

BASIC PRINCIPLES OF BASIC PRINCIPLES OF ANTIDEPRESSANT USEANTIDEPRESSANT USE

A.A. Achieve adequate dosingAchieve adequate dosing• Gradual titration upward.Gradual titration upward.• Prepare patient for early side effects.Prepare patient for early side effects.

B.B. Treat for adequate durationTreat for adequate duration• 4-6 weeks for an acute trial.4-6 weeks for an acute trial.• 6 months or longer for maintenance.6 months or longer for maintenance.

C.C. Assess adequacy of responseAssess adequacy of response

D.D. Ensure adherenceEnsure adherence• Avoid complex dosing schedules.Avoid complex dosing schedules.• Make sure prescription is affordable.Make sure prescription is affordable.• Address side effects.Address side effects.

PHASES OF TREATMENT FOR DEPRESSIONPHASES OF TREATMENT FOR DEPRESSION

Kupfer, J Clin Psychiatry,52(suppl 5):28, 1991..

ANTIDEPRESSANT TREATMENTSANTIDEPRESSANT TREATMENTS

I. PRIMARY ANTIDEPRESSANTSI. PRIMARY ANTIDEPRESSANTS

II. MOOD STABILIZERS (Thymoleptics)II. MOOD STABILIZERS (Thymoleptics)

III. STIMULANTSIII. STIMULANTS

IV. ELECTROCONVULSIVE THERAPY (ECT)IV. ELECTROCONVULSIVE THERAPY (ECT)

V. SURGICAL APPROACHESV. SURGICAL APPROACHES

VI. COMBINATION BIOMEDICAL APPROACHESVI. COMBINATION BIOMEDICAL APPROACHES

VII. NOVEL BIOMEDICAL APPROACHESVII. NOVEL BIOMEDICAL APPROACHES

VIII. PSYCHOSOCIAL TREATMENTSVIII. PSYCHOSOCIAL TREATMENTS

IX. OTHER SOMATIC TREATMENTSIX. OTHER SOMATIC TREATMENTS

BIOMEDICAL ANTIDEPRESSANT BIOMEDICAL ANTIDEPRESSANT TREATMENTS: MONOTHERAPIESTREATMENTS: MONOTHERAPIES

I. PRIMARY ANTIDEPRESSANTSI. PRIMARY ANTIDEPRESSANTS

A. Selective serotonin reuptake inhibitors A. Selective serotonin reuptake inhibitors (SSRIs)(SSRIs)

B. Mixed monoamine reuptake inhibitorsB. Mixed monoamine reuptake inhibitors

C. Monoamine receptor antagonistsC. Monoamine receptor antagonists

D. Tricyclic (TCAs) and related D. Tricyclic (TCAs) and related heterocyclicsheterocyclics

E. Monoamine oxidase inhibitors (MAOIs)E. Monoamine oxidase inhibitors (MAOIs)

F. NMDA antagonistsF. NMDA antagonists


A. Selective serotonin reuptake A. Selective serotonin reuptake inhibitors (SSRIs)inhibitors (SSRIs)

1. Fluoxetine (Prozac®, 1. Fluoxetine (Prozac®, Sarafem®)Sarafem®)2. Sertraline (Zoloft®)2. Sertraline (Zoloft®)3. Paroxetine (Paxil®)3. Paroxetine (Paxil®)4. Fluvoxamine (Luvox®)4. Fluvoxamine (Luvox®)

5. a. Citalopram (Celexa®) 5. a. Citalopram (Celexa®)

b. Escitalopram (Lexapro®)b. Escitalopram (Lexapro®)

Selective Serotonin Reuptake Inhibitors (SSRIs): Mechanism of Action

5-HT = serotonin.

Blier and Abbott. J Psychiatry Neurosci. 2001;26:37.

Reuptake transporter

5-HT

5-HT

5-HT5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

Stimulationof postsynaptic 5-HT receptors

5-HT

5-HT

5-HT

5-HT5-HT

Inhibition of 5-HTreuptake transporter

Downregulation of presynaptic 5-HT1A

autoreceptors

5-HT

5-HT

5-HT Release

Synaptic 5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

5-HT

Selective Serotonin Reuptake Inhibitors (SSRIs): Pros/Cons

Effective in 60%-70%of patients

Ease of dosing

Broad comorbidity coverage(eg, anxiety disorders)

Lower side effect burden vs TCAs

Safer in overdose vs TCAs

Nausea and headaches

Orgasmic dysfunction anddecreased libido

Interactions with tryptophan,MAOIs, fenfluramine

Discontinuation syndrome

Weight gain

Richelson. Mayo Clin Proc. 2001;76:511.

Pros Cons


B. Mixed monoamine reuptake inhibitorsB. Mixed monoamine reuptake inhibitors

1. NE/(DA) reuptake inhibitor1. NE/(DA) reuptake inhibitor

a. Bupropion (Wellbutrin®, Zyban®)a. Bupropion (Wellbutrin®, Zyban®)

2. NE/5-HT reuptake inhibitors2. NE/5-HT reuptake inhibitors

a. Venlafaxine (Effexor®)a. Venlafaxine (Effexor®)

b. Duloxetine (Cymbalta®)b. Duloxetine (Cymbalta®)

Bupropion (1985)

Weak NA and DA reuptake inhibitor

Metabolized to less active hydroxybupropion,

threohydrobupropion and erythro-hydrobupropion

Efficacy similar to SSRIs Fewer sexual side effects Effective in smoking cessation Possible weight loss

Insomnia Asthenia Nausea Increased

seizures at higher doses

Potential for drug-drug interactions

Ascher et al. J Clin Psychiatry. 1995;56:395.Croft et al. Clin Ther. 1999;21:643.Coleman et al. Clin Ther. 2001;23:1040.

Cl

O

NH

Mechanism of Action Pros Cons

Bupropion

Venlafaxine (1993)

Wellington and Perry. CNS Drugs. 2001;15:643.Kent. Lancet. 2000;355:911.Thase et al. Br J Psychiatry. 2001;178:234 .

5-HT reuptake

inhibitor with NA reuptake

inhibition at higher doses Metabolized to

equally active O-desmethyl-venlafaxine

Higher remission rates? Pharmacologically “cleaner” than

TCAs

Nausea Sweating Orgasmic

dysfunction Hypertension Insomnia Discontinuation

syndrome Tremor Dose titration Tachycardia Cost

H3CO

CHOH

N(CH3)2


Venlafaxine

Duloxetine (2004)

Dual NA and 5-HT reuptake inhibitor

Higher remission

Effective in some pain syndromes (but so are similar drugs)

No increase in blood pressure?

Insomnia

Asthenia

Nausea

Urinary retention

Pitsikas. Curr Opin Investig Drugs. 2000;1:116.Goldstein et al. J Clin Psychiatry. 2002;63:225.

NH

O

S


Duloxetine


C. Monoamine receptor antagonistsC. Monoamine receptor antagonists

1. Serotonin receptor antagonists1. Serotonin receptor antagonists a. Trazodone (Desyrela. Trazodone (Desyrel®®)) b. Nefazodoneb. Nefazodone (Serzone (Serzone®®-withdrawn -withdrawn

2004) 2004)

2. NE/5-HT receptor antagonist2. NE/5-HT receptor antagonista. Mirtazapine (Remerona. Mirtazapine (Remeron®®))

Nefazodone (1994)

Mechanismof Action Pros Cons

Antagonist of postsynaptic 5-HT2 receptor

Weak and transient 5-HT and NA reuptake inhibitor (prob. not significant)

Metabolized to equally active hydroxynefazodone

Similar efficacy to TCAs + SSRIs (?)

Improved sleep structure vs SSRIs

Fewer sexual side effects

Somnolence

Nausea

Dizziness

Hypotension

Very rare liver failure

BID dosing and slow dose titration

Schatzberg et al. J Clin Psychiatry. 2002;63:18.Kent. Lancet. 2000;355:911.

N

Cl

NN

N

NO

O

Nefazodone

Mirtazapine (1996)

Anttila and Leinonen. CNS Drug Rev. 2001;7:249.Kent. Lancet. 2000;355:911.

Antagonist ofcentral presynaptic 2-adrenergicautoreceptors on NA neurons and heteroceptors on 5-HT neurons

5-HT2 and 5-HT3 antagonist

Unique pharmacology

Ease of dosing Lower

orgasmic dysfunction

Can be combinedwith SSRIs

Use in elderly

Somnolence Weight gain

CH3

N

N

N


Mirtazapine


D. Tricyclics (TCAs) and related heterocyclicsD. Tricyclics (TCAs) and related heterocyclics1. Tertiary amines1. Tertiary amines

a. Amitriptyline (AMI; Elavila. Amitriptyline (AMI; Elavil®®) ) b. Imipramine (IMI; Tofranilb. Imipramine (IMI; Tofranil®®))c. Clomipramine (CMI; Anafranilc. Clomipramine (CMI; Anafranil®®))d. Doxepin (DOX; Sinequand. Doxepin (DOX; Sinequan®®))e. Trimipramine (Surmontile. Trimipramine (Surmontil®®))

2. Secondary amines2. Secondary aminesa. Nortriptyline (NOR; Pamelora. Nortriptyline (NOR; Pamelor®®, ,

AventylAventyl®®) ) b. Desipramine (DMI; Norpraminb. Desipramine (DMI; Norpramin®®) ) c. Protriptyline (PRO; Vivactylc. Protriptyline (PRO; Vivactyl®®) ) d. Amoxapine (Asendind. Amoxapine (Asendin®®))

3. Tetracyclics3. Tetracyclicsa. Maprotiline (Ludiomila. Maprotiline (Ludiomil®®))

Tricyclic Antidepressants (TCAs): Proposed Mechanism of Action

NA

Stimulation of postsynaptic intracellular processes

NA

NA

NA

5-HT

5-HT

5-HT

NA

5-HT

NA

5-HT

Reuptake transporters

NA

5-HT

5-HT

NA

NA

NA

5-HT

NA

5-HT

5-HT

NA

Synaptic NA

NA = noradrenaline; 5-HT = serotonin.

Kandel et al. Principles of Neural Science. 1991.

5-HT

5-HT

NA

5-HT

Synaptic 5-HT

TCA-inhibition of NA + 5-HT reuptake transporters

Tricyclic Antidepressants (TCAs): Pros/Cons

Effective in 60%-70%of patients

Potent NA reuptake inhibitors

Some are also potent 5-HT reuptake inhibitors

Analgesic effects

Interact with cholinergic, histaminic, and adrenergic receptors, causing

– Dry mouth– Urinary hesitance– Blurred vision– Constipation– Sedation– Weight gain– Orthostatic hypotension

Cardiac conduction effects Discontinuation syndrome Potentially lethal in overdose

Feighner. J Clin Psychiatry. 1999;60(suppl 4):4.

Pros Cons


E. Monoamine oxidase inhibitors (MAOIs)E. Monoamine oxidase inhibitors (MAOIs)

1.1. HydrazinesHydrazines a. Phenelzine (Nardil®) a. Phenelzine (Nardil®) b. Isocarboxazid (Marplan®) b. Isocarboxazid (Marplan®)

2.2. Non-hydrazineNon-hydrazinea. Tranylcypromine (Parnate®)a. Tranylcypromine (Parnate®)[b. Selegiline {deprenyl} [b. Selegiline {deprenyl}

(Eldepryl®)](Eldepryl®)]

Monoamine Oxidase Inhibitors (MAOIs): Proposed Mechanism of Action

NA

Stimulation of postsynaptic intracellular processes

NA

NA

NA

5-HT

5-HT

5-HT

NA

5-HT

NA

5-HTMAO 5-HT

Reuptake transporters

NA

5-HT

NA

5-HT

NANA

5-HT

NA

NA

5-HT

5-HT5-HT

NA

Synaptic NA

NA = noradrenaline; 5-HT = serotonin.Kandel et al. Principles of Neural Science. 1991.

NA

5-HT

5-HT

MAO

5-HT

5-HT

NA

5-HT

NA

NA

5-HT

Synaptic 5-HTMAO-inhibition prevents breakdownof NA + 5-HT

Older Monoamine Oxidase Inhibitors (MAOIs): Pros/Cons

Older MAOIs – Irreversibly inhibit MAO-A and MAO-B

– Enhance synaptic levels of all 3 monoamines

Feighner. J Clin Psychiatry. 1999;60(suppl 4):4. Lotufo-Neto et al. Neuropsychopharmacology. 1999;20:226.

Pros– Effective in 60%-70% of

patients

– Some patients (eg, those with atypical depression) may respond betterto MAOIs

Cons– Food restrictions

– Orthostatic hypotension

– Weight gain

– Sexual dysfunction

– Potentially lethal drug interactions with opiates, SSRIs, sympathomimetics


F. NMDA AntagonistsF. NMDA Antagonists

1.1.Excitatory amino acid (EAA) Excitatory amino acid (EAA) release inhibitorrelease inhibitor

a. Lamotrigine (Lamictala. Lamotrigine (Lamictal®®))


II. MOOD STABILIZERS (THYMOLEPTICS)II. MOOD STABILIZERS (THYMOLEPTICS)

A. Lithium (Li; LiA. Lithium (Li; Li22COCO33, LiCl), LiCl)

B. AnticonvulsantsB. Anticonvulsants

1. Valproate (VPA; Depakote®)1. Valproate (VPA; Depakote®)

2. Carbamazepine (CBZ; Tegretol®)2. Carbamazepine (CBZ; Tegretol®)


III. STIMULANTSIII. STIMULANTS

OlderOlderA. Dextroamphetamine (DexedrineA. Dextroamphetamine (Dexedrine®®))B. Methylphenidate (RitalinB. Methylphenidate (Ritalin®®))C. Pemoline (CylertC. Pemoline (Cylert®®))

NovelNovelD. Modafinil (ProvigilD. Modafinil (Provigil®®))

E. Atomoxetine (StratteraE. Atomoxetine (Strattera®®))


IV. ELECTROCONVULSIVE THERAPY (ECT)IV. ELECTROCONVULSIVE THERAPY (ECT)

A.A. Unilateral UnilateralB.B. Bilateral Bilateral

V.V. SURGICAL APPROACHES SURGICAL APPROACHES

A.A. Orbitofrontal leucotomy Orbitofrontal leucotomyB.B. Stereotactic subcaudate tractotomy Stereotactic subcaudate tractotomyC.C. Stereotactic limbic leucotomy Stereotactic limbic leucotomy

VI. COMBINATION BIOMEDICAL VI. COMBINATION BIOMEDICAL APPROACHESAPPROACHES

Definition:Definition:

Simultaneous use of two or more Simultaneous use of two or more different drugs acting on the core different drugs acting on the core symptoms of affective illnesssymptoms of affective illness

COMBINATION MONOTHERAPY AGENTSCOMBINATION MONOTHERAPY AGENTS FOR DEPRESSIONFOR DEPRESSION

1.1. Multiple primary antidepressantsMultiple primary antidepressants (agents (agents

with different mechanisms of action)with different mechanisms of action)

ExamplesExamples: : • SSRI+NRI• SSRI+NRI

• • MRTZ+reuptake inhibitorMRTZ+reuptake inhibitor

EXCEPTIONS: MAOI+reuptake inhibitorEXCEPTIONS: MAOI+reuptake inhibitor

2.2. Thymoleptics Thymoleptics (esp. Li)(esp. Li)

3.3. StimulantsStimulants

4.4. ECTECT

OTHER COMBINATION AGENTSOTHER COMBINATION AGENTS FOR DEPRESSIONFOR DEPRESSION

1. Benzodiazepines1. Benzodiazepines2. Neuroleptics (antipsychotics)2. Neuroleptics (antipsychotics)3. Gabapentin3. Gabapentin4. Triiodothyronine (T4. Triiodothyronine (T33))

5. Estrogen, testosterone5. Estrogen, testosterone6. 5-HT6. 5-HT1A1A antagonists antagonists (pindolol)(pindolol)

7. 7. 22adrenoceptor antagonists adrenoceptor antagonists (e.g.,(e.g.,

yohimbine, idazoxan)yohimbine, idazoxan)

8. DA receptor agonists 8. DA receptor agonists (e.g., pergolide, (e.g., pergolide, bromocriptine, pramipexole, ropinirole)bromocriptine, pramipexole, ropinirole)

VII. NOVEL BIOMEDICAL VII. NOVEL BIOMEDICAL APPROACHES TO DEPRESSIONAPPROACHES TO DEPRESSION

1.1. PharmacologicPharmacologic

2.2. Neurophysiologic stimulationNeurophysiologic stimulation

NOVEL PHARMACOLOGIC NOVEL PHARMACOLOGIC APPROACHES TO DEPRESSIONAPPROACHES TO DEPRESSION

1. Novel anticonvulsants1. Novel anticonvulsantsa. Topiramate (Topamax®)a. Topiramate (Topamax®)b. Levetiracetam (Keppra®)b. Levetiracetam (Keppra®)c. Oxcarbazepine (Trileptal®)c. Oxcarbazepine (Trileptal®)d. Tiagabine (Gabatril®)d. Tiagabine (Gabatril®)

2. Antiglucocorticoids2. Antiglucocorticoidsa. Ketoconazolea. Ketoconazoleb. Metyraponeb. Metyraponec. Aminoglutethimidec. Aminoglutethimide

3. Thyroxine 3. Thyroxine (high-dose T(high-dose T44))

4. Inositol4. Inositol5. DHEA5. DHEA6. Fatty acids 6. Fatty acids (Omega-3, EPA)(Omega-3, EPA)

7. Tramadol7. Tramadol8. Hypericum perforatum 8. Hypericum perforatum (St. (St.

John’s wort)John’s wort)

9. S-adenosyl methionine 9. S-adenosyl methionine (SAM-e)(SAM-e)

10. Mifepristone 10. Mifepristone (RU-486)(RU-486)

11. Riluzole11. Riluzole12. Substance P antagonists12. Substance P antagonists13. CRF antagonists13. CRF antagonists14. Reboxetine 14. Reboxetine (Vestra)(Vestra)

15. Gepirone 15. Gepirone (5-HT1A agonist)(5-HT1A agonist)

16. Selegiline Transdermal16. Selegiline Transdermal

NOVEL NEUROPHYSIOLOGIC STIMULATION NOVEL NEUROPHYSIOLOGIC STIMULATION APPROACHES TO DEPRESSIONAPPROACHES TO DEPRESSION

1. Continuation ECT1. Continuation ECT

2. Repetitive transcranial magnetic2. Repetitive transcranial magnetic stimulation (rTMS)stimulation (rTMS)3. Magnetic seizure therapy (MST) 3. Magnetic seizure therapy (MST)

4.4. Vagus nerve stimulation (VNS)Vagus nerve stimulation (VNS)5.5. Deep brain stimulation (DBS)Deep brain stimulation (DBS)

VNS Pulse Generator & Lead

• Pacemaker-like pulse generator

• Bipolar lead with two stimulating electrodes

• Intermittent stimulation

– 30 sec on/5 min off– 24 hours/day

• On-demand therapy mode

• 10.3 mm thick

• Weighs 38 grams • Battery life of 8-12 years (Model 101)

Vagus Nerve Stimulation

• Pulse generator programming controlled through a telemetric wand attached to a PC

• ON/OFF cycle is programmable

• Typical cycle: – 30 sec ON– 5 min OFF

• • Cognitive therapyCognitive therapy

• • Behavior therapyBehavior therapy

• • Interpersonal psychotherapyInterpersonal psychotherapy

• • Brief psychodynamic therapyBrief psychodynamic therapy

•• Social skills trainingSocial skills training

VIII. VIII. PSYCHOSOCIAL ANTIDEPRESSANT PSYCHOSOCIAL ANTIDEPRESSANT TREATMENTSTREATMENTS

IX. IX. OTHER SOMATIC ANTIDEPRESSANT OTHER SOMATIC ANTIDEPRESSANT TREATMENTSTREATMENTS

•• Sleep deprivationSleep deprivation

•• Light therapyLight therapy

•• ExerciseExercise

•• Complementary and alternativeComplementary and alternative

therapiestherapies

Evolution of Antidepressants

1980s 1990s1950s1950s2000 and beyond

TCAs SSRIsMixed reuptake

inhibitors/Receptor antagonists

Peptide antagonists,

glutamatemodulators

and other noveltherapies

MAOIs

Unmet Needs With Current Antidepressant Therapies

Crown et al. J Clin Psychiatry. 2002;63:963.Pampallona et al. Br J Psychiatry. 2002;180:104.

20%-40% of patients do not respond to any single antidepressant

~50% of patients who respond have significant residual symptoms

Relapses are common, particularly after discontinuation of therapy

Suboptimal tolerability and side-effect profiles

Low long-term adherence

Manic

Hypomanic

Mixed

Depressed

Bipolar I

Hypomanic

Depressed

Bipolar II

Hypomanic Sx

Depressive Sx

Cyclothymia

DSM-IV BIPOLAR DISORDERS

Conceptual Problems in Classifying Conceptual Problems in Classifying Treatments for Bipolar DisorderTreatments for Bipolar Disorder

• AntimanicsAntimanics

• AntidepressantsAntidepressants

• Thymoleptics (Mood Stabilizers)Thymoleptics (Mood Stabilizers)

ANTIMANIC TREATMENTSANTIMANIC TREATMENTS

I. LithiumI. Lithium

II. Divalproex (Valproate; Depakote®)II. Divalproex (Valproate; Depakote®)

III. Atypical neurolepticsIII. Atypical neuroleptics‡‡

III. Carbamazepine (Tegretol®)*III. Carbamazepine (Tegretol®)*

IV. Other neuroleptics*IV. Other neuroleptics*‡‡

V. Electroconvulsive therapy (ECT)*V. Electroconvulsive therapy (ECT)*

* Not FDA-approved for mania* Not FDA-approved for mania‡ ‡ Mood-stabilizing properties of all such drugs not fully Mood-stabilizing properties of all such drugs not fully

establishedestablished

LithiumLithium

MechanismMechanism: : 5-HT and Ach function, 5-HT and Ach function, DA function; DA function; PI PI turnover; turnover; adenylate cyclase activity; regulation of G protein adenylate cyclase activity; regulation of G protein and PKC activityand PKC activity

DoseDose: : 600 - 2400 mg/day (0.5-1.5 mmol/L)600 - 2400 mg/day (0.5-1.5 mmol/L)

ProsPros:: Efficacy in mania established, with largest Efficacy in mania established, with largest

supporting databasesupporting database Response predictors knownResponse predictors known

ConsCons : : Poor tolerance, Poor tolerance, patient acceptance, narrow patient acceptance, narrow

therapeutic index therapeutic index Tremor / neurocognitive effects, weight gain, renal Tremor / neurocognitive effects, weight gain, renal

toxicity, nausea, acne, hair loss, hypothyroidismtoxicity, nausea, acne, hair loss, hypothyroidism

Signs and Symptoms of Lithium ToxicitySigns and Symptoms of Lithium Toxicity

Mild:Mild: Impaired concentration, lethargy, irritability, Impaired concentration, lethargy, irritability, muscle weakness, tremor, slurred speech, muscle weakness, tremor, slurred speech, nausea [plasma lithium = 1.0 - 1.5 meq/L]nausea [plasma lithium = 1.0 - 1.5 meq/L]

Moderate:Moderate: Disorientation, confusion, drowsiness, Disorientation, confusion, drowsiness, restlessness, unsteady gait, coarse tremor, restlessness, unsteady gait, coarse tremor, dysarthria, muscle fasciculations, vomiting dysarthria, muscle fasciculations, vomiting [plasma lithium = 1.5 - 2.5 meq/L][plasma lithium = 1.5 - 2.5 meq/L]

Severe:Severe: Impaired consciousness (with progression Impaired consciousness (with progression to coma), delirium, ataxia, generalized to coma), delirium, ataxia, generalized fasciculations, extrapyramidal symptoms, fasciculations, extrapyramidal symptoms, convulsions, impaired renal function convulsions, impaired renal function [plasma lithium > 2.5 meq/L[plasma lithium > 2.5 meq/L

Divalproex (Valproate)Divalproex (Valproate)MechanismMechanism: : GABA synthesis and release, GABA synthesis and release, GABA GABA catabolism, catabolism, effects of GABA at receptor; regulation of effects of GABA at receptor; regulation of PKC activityPKC activity

DoseDose: : 750 - 2500 mg/day (50-125 750 - 2500 mg/day (50-125 g /mL)g /mL)

ProsPros:: Efficacy in mania establishedEfficacy in mania established Better than Li in mixed states and rapid cyclersBetter than Li in mixed states and rapid cyclers Well-toleratedWell-tolerated

ConsCons : : ? Efficacy in prophylaxis ? Efficacy in prophylaxis Weight gain, nausea, hair loss, tremor, Weight gain, nausea, hair loss, tremor, platelets, liver & pancreas toxicity, ?polycystic platelets, liver & pancreas toxicity, ?polycystic

ovary diseaseovary disease

Atypical NeurolepticsAtypical Neuroleptics

1.1. Clozapine (Clozaril®)*Clozapine (Clozaril®)*

2.2. Olanzapine (Zyprexa®)Olanzapine (Zyprexa®)

3.3. Risperidone (Risperdal®)Risperidone (Risperdal®)

4.4. Quetiapine (Seroquel®)Quetiapine (Seroquel®)

5.5. Ziprasidone (Geodon®)Ziprasidone (Geodon®)

6.6. Aripiprazole (Abilify®)Aripiprazole (Abilify®)

*Not FDA-approved for mania*Not FDA-approved for mania

Atypical Neuroleptics in Bipolar Disorder: Atypical Neuroleptics in Bipolar Disorder: ConsiderationsConsiderations

• Effective in acute mania (as are conventional Effective in acute mania (as are conventional neuroleptics).neuroleptics).

• Superior to conventional neuroleptics with Superior to conventional neuroleptics with respect to adverse effects.respect to adverse effects.

• Possibly heterogeneous mechanisms of action Possibly heterogeneous mechanisms of action and clinical effects with respect to each other.and clinical effects with respect to each other.

• Possible thymoleptic properties.Possible thymoleptic properties.

• LimitationsLimitations– Limited long-term dataLimited long-term data– Adverse effectsAdverse effects– Aggressive marketing pushAggressive marketing push

CarbamazepineCarbamazepine

MechanismMechanism: : NE, DA, GABA function; NE, DA, GABA function; adenylate adenylate cyclase activity; blocks adenosine receptorscyclase activity; blocks adenosine receptors

DoseDose: : 400 - 1800 mg/day (4-15 400 - 1800 mg/day (4-15 g/mL)g/mL)

ProsPros:: Efficacy in mania establishedEfficacy in mania established Usually well-toleratedUsually well-tolerated

ConsCons: : ? Efficacy in prophylaxis ? Efficacy in prophylaxis Ataxia and neurocognitive effects, weight gain, Ataxia and neurocognitive effects, weight gain,

nausea, hair loss, leukopenia, hepatotoxicity, nausea, hair loss, leukopenia, hepatotoxicity,

Na, hepatic enzyme inductionNa, hepatic enzyme induction

Oxcarbazepine as alternative?Oxcarbazepine as alternative?

BIPOLAR ANTIDEPRESSANT BIPOLAR ANTIDEPRESSANT TREATMENTSTREATMENTS

I. LamotrigineI. Lamotrigine

LamotrigineLamotrigineMechanismMechanism: : Inhibits release of excitatory amino acids Inhibits release of excitatory amino acids

(EAAs) (e.g., glutamate, NMDA)(EAAs) (e.g., glutamate, NMDA)DoseDose: : 100 - 400 mg/day (usu. 200 mg/day)100 - 400 mg/day (usu. 200 mg/day)ProsPros::

– Efficacy in preventing bipolar depression Efficacy in preventing bipolar depression relapserelapse

– Usually well-toleratedUsually well-tolerated

ConsCons : : – ? efficacy in acute bipolar depression; doubtful ? efficacy in acute bipolar depression; doubtful

efficacy in acute mania or mania prophylaxisefficacy in acute mania or mania prophylaxis– Slow dose titrationSlow dose titration– VPA inhibits LMTG metabolism by 50%; VPA inhibits LMTG metabolism by 50%; – CBZ increases LMTG metabolism by 100%CBZ increases LMTG metabolism by 100%– Rash can lead to Stevens-JohnsonRash can lead to Stevens-Johnson

Other Agents Reported to have Antimanic Other Agents Reported to have Antimanic

or Thymoleptic Propertiesor Thymoleptic Properties 1.1. Calcium channel antagonists (esp. verapamil)Calcium channel antagonists (esp. verapamil)

2.2. Benzodiazepines (clonazepam, lorazepam) (high Benzodiazepines (clonazepam, lorazepam) (high doses)*doses)*

3.3. Thyroid hormone (hypermetabolic doses)*Thyroid hormone (hypermetabolic doses)*

4.4. Tryptophan*Tryptophan*

5.5. ClonidineClonidine

6.6. InositolInositol

7.7. DonepezilDonepezil

8.8. Novel anticonvulsants: Novel anticonvulsants: Oxcarbazepine (Trileptal®),Oxcarbazepine (Trileptal®), Tiagabine (Gabatril®), Zonisamide (Zonegran®), Tiagabine (Gabatril®), Zonisamide (Zonegran®), Levetiracetam(Keppra®)Levetiracetam(Keppra®)

9.9. Transcranial magnetic stimulation (rTMS)Transcranial magnetic stimulation (rTMS)

10.10. Surgery (esp. subcaudate tractotomy)Surgery (esp. subcaudate tractotomy)

**Primarily adjunctive (used in combination with lithium).Primarily adjunctive (used in combination with lithium).

Psychosocial Interventions in the Psychosocial Interventions in the

Management of Bipolar DisorderManagement of Bipolar Disorder • PsychoeducationPsychoeducation• Individual, family, and group Individual, family, and group

psychotherapiespsychotherapies• Support groupsSupport groups• Management of comorbid conditionsManagement of comorbid conditions• Maximization of adherenceMaximization of adherence• Legal planning (e.g., durable power Legal planning (e.g., durable power

of atty.)of atty.)• AdvocacyAdvocacy

Evolving Conceptualizations in the Evolving Conceptualizations in the Treatment of Bipolar Disorder: Implications Treatment of Bipolar Disorder: Implications for the use of Antimanics, Antidepressants, for the use of Antimanics, Antidepressants,

and Thymolepticsand Thymoleptics

Depression, acuteDepression, acute Depression, prophylacticDepression, prophylactic Mania, acuteMania, acute Mania, prophylacticMania, prophylactic Rapid-cyclingRapid-cycling Subsyndromal mood symptomatologySubsyndromal mood symptomatology Subsyndromal other symptomatologySubsyndromal other symptomatology

Approaches to Combination Treatment in Approaches to Combination Treatment in Bipolar DisorderBipolar Disorder

Acknowledge that combinations are the rule rather than the Acknowledge that combinations are the rule rather than the exceptionexception

Use evidenced-based approach--but be aware of strengths and Use evidenced-based approach--but be aware of strengths and limitations of RCTslimitations of RCTs

Consider agents with different mechanisms of actionConsider agents with different mechanisms of action

Be aware of possible synergistic effectsBe aware of possible synergistic effects

Therapeutic (e.g., Lithium + Thyroid hormone)Therapeutic (e.g., Lithium + Thyroid hormone)

Toxic (e.g., VPA + Lamotrigine)Toxic (e.g., VPA + Lamotrigine)

Consider cost/benefit ratioConsider cost/benefit ratio

Use "N=1 clinical trial strategy": Evaluate cost/benefit of each Use "N=1 clinical trial strategy": Evaluate cost/benefit of each added agent in a trial of adequate duration at adequate dose; added agent in a trial of adequate duration at adequate dose; discontinue agents without sufficient benefit discontinue agents without sufficient benefit

Strive for simplicityStrive for simplicity

BUTLER HOSPITAL BUTLER HOSPITAL MOOD DISORDERS RESEARCH MOOD DISORDERS RESEARCH

PROGRAMPROGRAMDepartment of Psychiatry and Human BehaviorDepartment of Psychiatry and Human Behavior

Brown Medical SchoolBrown Medical School

345 Blackstone Blvd345 Blackstone Blvd

Providence, RI 02906Providence, RI 02906

TEL 401- 455-6537TEL 401- 455-6537

FAX 401- 455-6534FAX 401- 455-6534

BIOMED 370: The Treatment of Mood Disorders March 9, 2005 Lawrence H. Price, M.D. Professor of...

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