3 print 08AC Deprtxres SMSrevisions AF...

Copyright © 2007 Neuroscience Education Institute. All rights reserved.

Difficult-to-treat Depression Difficult-to-treat Depression

Sponsored by Neuroscience Education InstituteAdditionally sponsored by American Society for the Advancement of Pharmacotherapy

This activity is supported by educational grants from AstraZeneca Pharmaceuticals LP; Cephalon, Inc.; and Shire Pharmaceuticals Inc.with additional support from Alkermes, Inc.; Eli Lilly and Company; Jazz Pharmaceuticals, Inc.; and Sepracor Inc.

Stephen M. Stahl, MD, PhDStephen M. Stahl, MD, PhDAdjunct Professor, Department of Psychiatry,

University of California, San Diego School of Medicine


Learning Objectives

Upon completion of this lecture, you should be able to:• Understand the rates of response, remission and

treatment-resistant depression • Evaluate evidence based selection of treatments

versus symptom based selection of treatments • Anticipate new treatments still in clinical

development


67 % responders

medication started

33 % non-responders

8 weeks

Antidepressant Response Rates

Stahl, SM. Essential Psychopharmacology, third edition. In press


monotherapies1st line

monotherapies2nd line

augmentation

ancillary

depression pharmacy

SSRI NDRI SNRI

5HT1A Li T3/4




augmentation

ancillary

depression pharmacy

SSRI NDRI SNRI

cognitive therapy ECT IPT VNS




augmentation

ancillary

depression pharmacy

2 antagonist NRI TCA SARI MAOI


Evidence-Based Algorithm for Antidepressants

SSRI#1

SSRI#2 NDRI SNRI +NDRI +5HT1A

augmentation optionsswitch options

option 2 doesn’t matter

2 antag TCA +Li +THY

augmentation optionsswitch options


MAOISNRI+2 antag




How well do antidepressants work?Antidepressant REMISSION Rates

33%

antidepressant treatment #1

67% 47%

20%



6-7%

40%

67% remissionafter 4

treatments


6-7%

33% nonremittersafter 4 treatments


67%

not in remission

not in remission 60%

0%

100%3

months6

months12

months

rela

pse

rate

What Proportion of Major Depressive Disorders Relapse?

0%

100%3

months6

months12

months

rela

pse

rate

after 1 treatment after 2 treatments

in remission

50%

in remission

33%


0%

100%3

months6

months12

months

rela

pse

rate

70%

in remission30%

not in remission

70%

What Proportion of Major Depressive Disorders Relapse?

0%

100%3

months6

months12

months

rela

pse

rate

after 3 treatments after 4 treatments

in remission

50%

not in remission

50%


Atypical Antipsychotics as Augmenting Agents for Inadequate Response to One SSRI/SNRI

• Only FDA approved treatment for inadequate response to an antidepressant

• Based on 2 randomized, double-blind, controlled studies (total N = 743)

• 2-20mg daily dosage

-12

-10

-8

-6

-4

-2

0Base 1 2 3 4 5 6

Week

Mea

n ch

ange

in M

AD

RS

Tota

l Sc

ore

Placebo Aripiprazole

Adapted from Berman et al. J Clin Psyc 2007


Atypical Antipsychotic as Antidepressant: Risperidone Augmentation

-12

-10

-8

-6

-4

-2

0Base 1 2 4 6

Week

Mea

n C

hang

e in

HR

SD-1

7 To

tal

Scor

e PlaceboRisperidone

Results: significant difference in reductionof HRSD-17, rate of

response and remission

n = 268Dose: .25-200 mg/day

Scale: HRSD-17

Adapted from Mahmoud et al. Annals of Int Med. 2007


Atypical Antipsychotic as Antidepressant: Ziprasidone Augmentation

0

20

40

60

80

100

Remission Response

Prop

ortio

n of

Sam

ple

(%)

n = 20 (intent to treat)6-wk open-label trial

Adapted from Papakostas. CNS Spect 2007;12(12)supp22:10-12


Atypical Antipsychotic Augmentation forTreatment-Resistant Depression:

Meta-Analysis of 10 Randomized Controlled Trials

0

20

40

60

80

100

Atypical Antipsychotics Placebo

Perc

ent i

n R

emis

sion

n = 1,500p < .05

Adapted from Papakostas. CNS Spect. 2007;12(12)supp22:10-12


depression with insomnia/GAD with insomnia

SSRI + Z drug42% remission

SSRI alone33% remission

treatment

Treating Insomnia in Depression



What is a trimonoamine modulator (TMM)?

• An agent that boosts the action of the trimonoamines serotonin, dopamine and/or norepinephrine

• Works indirectly and in combination with agents that directly modulate trimonoamines, such as the antidepressants that block monoamine transporters

• If monoamine neurons do not synthesize monoamines adequately, there is nothing released during neurotransmission, and thus no neurotransmitter reuptake to block


What agents are trimonoamine modulators (TMMs)?

• Lithium• Thyroid (T3/T4)• Modafinil (Provigil)/Stimulants• 5HT1A partial agonist buspirone• L-methyl folate• Atypical antipsychotics• ECT/VNS (vagal nerve stimulation)• TMS (transcranial magnetic stimulation• DBS (deep brain stimulation)• Psychotherapy

Copyright © 2008 Neuroscience Education Institute. All rights reserved.12-112B

overactivationnormalbaselinehypoactivation

depressed mood

Reversal of Trimonoamine Neurotransmitter Deficiency with Thyroid?

blood-brain barrier T3/T4

improved mood


improved mood

12-113


Reversal of Trimonoamine Neurotransmitter Deficiency with Lithium?

blood-brain barrierLi

Copyright © 2008 Neuroscience Education Institute. All rights reserved.12-114

Vagus Nerve Stimulation: A Trimonoamine Booster?

vagusnerve

neck

heart gutVNS


Transcranial Magnetic Stimulation (TMS): A Trimonoamine Booster?


DLPFC

VMPFCamygdala

12-115


Deep Brain Stimulation (DBS): A Trimonoamine Booster?


DLPFC

VMPFC

amygdala

12-116

OFC

electrode

Copyright © 2008 Neuroscience Education Institute. All rights reserved.12-109

BH4 Cofactor for Synthesis of DA and NE from Tyrosine Hydroxylase

Andfor the Synthesis of 5HT from Tryptophan

DA NE

BH

tyrosine

BHBHBHBH


L-methylfolate (MTHF) Regulates BH4 Production

MTHF

H H

H H

CH3

2qBH BH

4

methyleneTHF

CH2HH

H HMTHFR

neurotransmittersynthesis


How does Deplin increase trimonoamine synthesis?

BH4 (tetrahydrobiopterin)

qBH2 (quinonoid dihydrobiopterin)

MTHFR

methyleneTHF

5-MTHF

TH

Tyrosine

5HT DA

L-Dopa5-HTP

TrypH

Tryptophan

NE


Formation of L-methylfolate (MTHF) from Folic Acid (F)

F

folic acid (synthetic)

THF

H

H

H

H

tetrahydrofolate

methyleneTHF

CH2HH

H H

MTHF

H H

H H

CH3

MTHFR(methylene

tetrahydrofolatereductase)

DHF

H Hdihydrofolate (dietary)

DHFR (dihydrofolate reductase)

*Inhibited by lamotrigine*

*genetically regulated*


MTHFR Enzyme Genotype

Genotype % Residual Enzyme Activity

C/C 100

C/T 71

T/T 34

T/T10%

C/T43%

C/C47%

HomozygousPolymorphism

HeterozygousPolymorphismNormal

Prevalence of MTHFR C T Polymorphism by Genotype

*Individuals with C/T polymorphism have reduced MTHFR enzyme activity, resulting in an approximate 20% increase of homocysteine levels


• Patients who have the MTHFR C→T genotypes have a 1.36 times greater chance of developing depression (and reported to be as high as 4X the general population)3,4

• The frequency of the T/T mutation has been shown to be about 10 to 12 % in the general population and reported to be as high as 22% in Hispanic and Mediterranean populations.2

• The odds of having the T/T genotype is almost 3X as great in depressed patients verses the normal population.5,6

MTHFR Polymorphism and DepressionPrevalence of C→T Polymorphism

in General Population1Prevalence of T/T Polymorphism in

depressed patients5

1. Popakostas , J. Clinical Psychiatry; 2004, 1090-1095 4. Procopciuc L.M., Presented at Biological Psychiatry, Poster P862. Bottiglieri T, Prog in Neuro-Psychopharm & Bio Psych, 2005 5. Arinami T, AM J. Medical Genetics 19973. Bjelland, I., et. al; . Arch. Gen. Psychiatry 2003, 618– 626 6. Kelly B., Journal of Psychopharmacology 18(4) (2004) 567–571


Clinical Trial for L-Methylfolate in Depression

0

1

2

3

1 3 6

Time (Months)

Clin

ical

Out

com

e Sc

ore

Placebo MTHF

• 24 outpatients with depression• Scales:

– Clinical outcome score (Likert scale 1-6)

– HAM-D– Beck

• L-Methylfolate (MTHF) (n = 13) vs. placebo (n = 11), 15 mg/day for 6 mos

– Augmentation to continued drug regimen

• Results: significantly improved scores in methylfolate group

• Folate deficiency and methylation disturbances implicated in depression

Godfrey et al. Lancet. 1990;336:392-95


Folic Acid vs. L-methyl folate Dosing Facts

• L-methyl folate more readily crosses the blood-brain barrier

• 1 mg l-methyl folate may equal 7 mg folic acid• Most studies indicate lowest dose of 7.5 mg L-

methyl folate, equivalent to 52 mg folic acid• L-methyl folate is less likely to mask vitamin B12

deficiency• L-methyl folate has few side effects, is less

expensive than augmenting with second antidepressant

Stahl, SM. CNS Spect 2007;12(10:423-28Stahl, SM. Essential Psychopharmacology, third edition. In press


TMM Actions of MTHF and SAMe: Methylation and Neurotransmitter Synthesis

MTHF

H H

H H

CH3

methyleneTHF

HCH2

H

H H

MTHFR neurotransmittersynthesis

methylation

homocysteine

methionine

B12

SAMe

SAH


Reversal of Trimonoamine Synthesis Deficiency by L-methylfolate (MTHF): Possible Boost to Actions of

Antidepressants

12-110A


blood-brain barrier F

blocked

H

H H

3CH H


Who are candidates for L-methyl folate augmentation?

• Documented MTHFR enzyme reductions (CT/TT)- High risk populations for CT/TT (Hispanic, Mediterranean)

• Documented high homocysteine and/or low folate- High risk populations for low folate (alcoholism, anorexia, pregnancy, atrophic gastritis/Crohn’s)

• High risk populations on drugs that interfere with folate (lamotrigine, anticonvulsants)

• Those who fail to tolerate previous augmentation trials

• Patients/prescribers who prefer a natural product approach

Stahl, SM. CNS Spetr 2007;12(10):423-28


Lamotrigine

Stahl, SM. Essential Psychopharmcology, third edition. In press


Lamotrigine as a Mood Stabilizer





augmentation

ancillary

depression pharmacy

SSRI NDRI SNRIlamotrigine

BP




augmentation

ancillary

depression pharmacy


BP

hypnotic modafinilaripipDPA MTHF

H HCH3

H H




augmentation

ancillary

depression pharmacy


BP

hypnotic 5HT1A Li BZ modafinilSDAUP

DPAUP MTHF

H HCH3

H H

T3/4 stimulant




augmentation

ancillary

depression pharmacy


BP

2 antagonist NRI TCA SARI MAOI

hypnotic 5HT1A Li BZ modafinilSDAUP

DPAUP MTHF

H HCH3

H H

T3/4 stimulant

cognitive therapy ECT IPT VNS


Agomelatine

• Strong agonist at melatonin (MT1 and MT2) receptor sites• Affinity similar to melatonin• Antagonist properties at serotonin 5HT2C receptors• Increases NE and DA in frontal cortex of rats• Active as 5HT2C antagonist in stress tests of animal models;

melatonin did not produce antidepressant effects• Anxiolytic activity in Vogel conflict and social interaction tests

in rats• 5 mg dose effective and tolerated in approximately 6-week

study of depressed patients– Decreased MADRS score of 30.7 to 14.8 (n = 22)

• Studies indicate dosing of 5 to 100 mg for efficacy• Minimal side effects

Norman. Aust and NZ J of Psyc 2006;40:394-401



GABAinterneurons

LC VTANE DA

NE DA

5HT

5HT5HT

5HT2C

brainstem neurotransmitter centers

prefrontal cortex

Mechanism of 5HT2C Antagonist NDDIs:Serotonin Inhibits DA and NE Release at 5HT2C receptors

raphe

Stahl, SM. Essential Psychopharmacologythird edition. In press



GABAinterneurons

LC VTANE DA

NE release

5HT

agomelatineagomelatine

5HT2C

brainstem neurotransmitter centers

prefrontal cortex

raphe

DA release

Mechanism of 5HT2C Antagonist NDDIs: Serotonin Antagonism at 5HT2C Receptors Disinhibits NE and DA

Stahl, SM. Essential Psychopharmacologythird edition. In press


Drugs that Interact at 5HT2C Receptors:Future Treatments for Depression

• Fluoxetine (SSRI)• Trazodone (SARI)• Agomelatine (NDDI)• Flibanserin (NDDI)• Mirtazapine (alpha 2 antagonist, NaSSA)• Nefazodone (SARI)• Clozapine (AAP)• Olanzapine (AAP)• Ziprasidone (AAP)



Ketamine



Possible Actions of Anti-Glutamatergic Agents in Treatment of Depressed Bipolar Phase



Additional Emerging Treatment Optionsfor Depression

• Beta 3 agonists (amibegron)– Beta 3 receptors located in amygdala where they regulate

neuronal activity in VMPFC• Neuropeptides (nemifitide)

– Pentapeptide analog of tripeptide MIF-1, tripeptide tail of vasopressin

– Administered via subcutaneous injection– Efficacy with rapid onset, treatment-resistant patients

• NK2 antagonists (saredutant)– Excessive release of endogenous NKA in cases of stress or

MDD may benefit from blocking NK2 receptors



SUMMARY

• Treatment response to various antidepressants may depend more upon when in the sequence of treatments a given agent is used rather than its specific mechanism of action

• Symptom based treatments, targeting residual symptoms such as fatigue or insomnia, or considering prior medication intolerance may influence intuitive sequencing of treatment selection in the absence of evidence determining a better strategy

• Several treatments with novel mechanisms of action are in late clinical development

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