New Developments in the Treatment of Mood Disorders

Roger F Haskett MDUniversity of Pittsburgh School of

MedicineWestern Psychiatric Institute and Clinic

Outline

• Pharmacotherapy• Psychotherapy• Genetics of

resilience• Brain stimulation

Recovery from Depression

Weeks From IntakeFrom Keller et al, 1992

1950s 1960s 1970s 1980s 1990s

phenelzine

isocarboxazid

tranylcypromine

imipramine

amitriptyline

desipramine

nortriptyline

clomipramine

bupropion

fluoxetine

sertraline

paroxetine

fluvoxamine

citalopram

escitalopram

venlafaxine

mirtazapine

duloxetine

desvenlafaxine

maprotiline

amoxapine

trazodone

The Evolution of Antidepressants

2000s

Classes of Antidepressants

Tricyclic Antidepressants (TCAs)Monoamine Oxidase Inhibitors (MAOI)Selective Serotonin Antidepressants (SSRIs)Serotonin and Norepinephrine Reuptake

InhibitorsOther Novel Antidepressants

– bupropion, trazodone, mirtazapine

1Trivedi MH, et al. Am J Psychiatry 2006;163:28. 2Trivedi MH, et al. N Engl J Med 2006;354:1243. 3Rush AJ, et al N Engl J Med 2006;354:1231. 4Nierenberg AA, et al. Am J Psychiatry 2006;163:1519. 5Fava M, et al. Am J Psychiatry 2006;163:1161. 6McGrath PJ, et al. Am J Psychiatry 2006;163:1531.

STAR*D Results Demonstrate Diminishing Effectiveness of Treatments in TRD

27.5%(n=790)

30.1%(n=86)

29.7%(n=83)

24.8%(n=62)

21.3%(n=51)

17.6%(n=42)

19.8%(n=24)

12.3%(n=14)

0

5

10

15

20

25

30

35

% o

f P

atie

nts

Rem

ittin

g

Citalopram(n=2,876)

Bupropion(n=279)

Buspirone(n=286)

Venlafaxine(n=250)

Bupropion(n=239)

Sertraline(n=238)

Mirtazapine(n=114)

Nortriptyline(n=121)

15.9%(n=11)

Lithium(n=69)

24.7%(n=18)

T3

(n=73)

6.9%(n=4)

Tranylcy-promine(n=58)

13.7%(n=7)

Venlafaxine + Mirtazapine

(n=51)

Level 1(n=2,876)1

Level 2 (Augment)(n=565)2

Level 3 (Switch)(n=235)5

Level 2 (Switch)(n=727)3

Level 3 (Augment)(n=142)4

Level 4 (Switch)(n=109)6

*Remission rates are after 12 weeks of treatment and are based on the HRSD-17

Treatment Resistant Depression

– First treatment:

28% remit– Second treatment:

17% - 30% remit– Third treatment:

12% - 25% remit– Fourth treatment:

7% - 14% remit

After 4 well-delivered treatments, 30% of patients will not have remitted

Strategies to Address Incomplete Response

Maximize initial treatmentsChange to other treatments

– Non-MAOI antidepressant in same or different class

– Adding or changing to a depression-focused psychotherapy

Augmenting and combining treatments

APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition

Stepped Approach toTreatment Resistant Depression

– SSRI - increase dose, extend duration, switch– bupropion, venlafaxine, duloxetine, mirtazapine– lithium augmentation– TCA trial with plasma levels– thyroid augmentation (T3, T4)– combination antidepressants– augmentation with second generation

antipsychotics– electroconvulsive therapy

Psychotherapies

• Cognitive-behavioral therapy

• Interpersonal psychotherapy

• Psychodynamic psychotherapy

• Marital and Family therapy• Combination

pharmacotherapy and psychotherapy

Personalized Medicine

DNA

Gene-Environment Interaction Studies

Functional polymorphism in the promoter region of the gene encoding MAO moderates effect of child maltreatment.– Low levels of MAO expression increased frequency of

conduct disorder, antisocial personality and adult violent crime.

Functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene moderates influence of stressful life events on depression.– 1 or 2 copies of the 5-HTT “short” allele associated with more

depression following stressful life events than2 copies of the 5-HTT “long” allele. Caspi et al, 2002,2003

Exposure to Adverse Rearing, Genotype and ACTH levels

Caspi et al. Nature Reviews Neuroscience 7, 583–590 (July 2006)

Exposure to Adverse Rearing, Genotype and ACTH levels

• Influence of exposure to early stress (peer rearing) on subsequent exaggerated responses of the limbic-hypothalamic-pituitary-adrenal axis (LHPA) responses to stress is conditioned by serotonin transporter gene promoter variation (rh-5HTTLPR) in rhesus macaques.

• When exposed to stress later in life, peer-reared animals with the short/long genotype had higher ACTH levels than animals with the long/long genotype.

• There were no differences between genotypes among animals reared with their mothers.

Barr et al, Biol Psychiatry 2004

Behavioral Epigenetics

• Epigenetic mechanisms of gene regulation alter the activity of genes without changing their DNA sequence

• Could explain how early life experiences can leave an indelible mark on the brain and influence both behavior and physical health later in life

G Miller Science 2010

Adverse Environment during Development

• Bdnf gene is down-regulated in the hippocampus of adult mice exposed to social stress in the form of chronic bullying by a bigger mouse.

• This reduction in Bdnf activity linked to epigenetic modifications

involving histones, tiny protein spools that keep DNA wrapped

up.• Chronic stress triggered increase in histone methylation that

suppresses gene activity by keeping the DNA containing the Bdnf gene tightly wound.

• Conversely anti-depressant drugs boosted histone acetylation, which helps unwind DNA from histones and promote Bdnf activity.

• Epigenetic modifications could be an important link between adverse life experiences and the risk of psychiatric disorders such as depression and anxiety.

E Nestler 2006

Neurotrophic Hypothesis of Depression

1. Loss of Brain-Derived Neurotrophic Factor (BDNF) contributes to hippocampal atrophy that underlie aspects of depression.

2. Antidepressants mediate therapeutic effects by increasing expression of neurotrophic factors (BDNF) in this region.

Neurotrophic Response to Antidepressants

– Increased BDNF in the DG– Increased survival and maturation of newborn

granule cells– Enhanced synaptic plasticity

Adachi et al, Biol Psychiatry 2008

Stress and Depression

Long term antidepressant treatment, including ECS, increases BDNF protein and mRNA levels and reverses the stress-induced downregulation of BDNF.

Exercise followed by similar changes in BDNF levels, neurogenesis, and behavioral swim tests

HPA axis and Depression

Hyperactivity present in majority of depressed patients– increased expression of CRF in hypothalamus– increased CRF levels in CSF– reduced feedback inhibition by CRF and

glucocorticoids

CRF serves as a neurotransmitter in amygdala and BNST– amygdala involved in negative emotional memory

and anxiety-like behavior

“I still don’t have the answers,but I’m beginning to ask the right questions.”

Therapeutic Brain Stimulation

• Electroconvulsive Therapy• Magnetic Seizure Therapy• Transcranial Magnetic Stimulation

(rTMS)• Vagus Nerve Stimulation (VNS)• Cortical Brain Stimulation• Deep Brain Stimulation (DBS)

Transcranial Magnetic Stimulation

Barker et al 1985

Differences between ECT and MST

• Seizure originates in superficial cortex• No electrical current passes deep through the brain• Electromagnetic pulse passes into brain without

resistance• MST stimulus more focused• No direct electrical stimulation of medial temporal

lobe structures

Administration of rTMS

Stimulation site - left dorsolateral prefrontal cortexDetermine resting motor thresholdSet stimulation intensity (120%), frequency (10

pulses/sec) and train duration (On 4 sec) & intertrain interval (Off 26 sec)

Typical treatment session > 30 min for total 3,000 stimulations

Treat 5 times / week for max 6 weeks (30 sessions)

O’Reardon et al, 2007

Advantages of rTMS

No anesthetic requiredNo cognitive disruption or

impairment

Current status of rTMSIn pivotal study, efficacy did not separate from

placebo on primary outcome measureRecent NIH supported Study George et al 2010

– Mutisite, randomized, active sham-controlled– 3 weeks left prefrontal rTMS; 3 more weeks in

improvers– OR for remission 4.2 for active rTMS (95% CI 1.32 -

13.24)– Significant interaction between AD resistance and

clinical benefit• Remitters had lower degree of treatment resistance

– No seizures, high retention rate

Possible roleIntermediate strategyAugmentationPregnancy, PPD

The Vagus Nerve Stimulator

Rationale for VNS in Depression

Mood improvement with anticonvulsant therapies– anticonvulsant drugs– ECT

Mood improvement in VNS-treated epilepsy patients– not correlated with reduced seizure frequency

Vagal nerve: Afferent Pathway to the Brain

George MS, et al. Biol Psychiatry. 2000

parabrachial nucleusnucleus (PB) locus coeruleus

orbitofrontal hypothalamuscortex

amygdala

cingulate gyrus

nucleustrack solitaire

Vagus Nerve Stimulation (VNS)

Pacemaker generator– Model 101: 8-10 years

battery life

Bipolar helical stimulation electrode

Intermittent stimulation with typical on : off time ratio of 30s : 5 min

Magnet allows on-demand patient control

VNS Programming

VNS Implant Procedure

1- to 2- hour case lengthGeneral or regional/local anesthesiaDoes NOT involve the brainChest/armpit incision for generatorNeck incision for electrodeOutpatient or inpatient Minimal complications

% R

emis

sio

n

0

5

10

15

20

25

IDS-SR HRSD24

68 10

1513

7 711

17 17

1012

17

23

MADRS

Remission; IDS-SR30 raw score 14; HRSD24 raw score 9; MADRS raw score 10

Evaluable Observed

Remission Rates Increase Over Time During Adjunctive VNS Therapy

3 Months(n=203-205)

6 Months(n=192-197)

9 Months(n=184-186)

12 Months(n=180-181)

24 Months(n=157)

Rush AJ, et al. Biol Psychiatry. 2005;58:355-363. 24-month Data, Cyberonics, Inc. Depression Physician’s Manual. Houston, Tex.

Deep Brain Stimulation

DBS of the subcallosal cingulate gyrus (SCG), including Brodmann area 25,

subcallosal cingulate gyrus (SCG), including Brodmann area 25,

Hamani, Mayberg et al 2009

DBS for TRD: 3 – 6 year follow-up

Yogi Berra

You can observe a lot just by watching

It's tough to make predictions, especially about the future

If you don't know where you are going, you might wind up someplace else

Yogi Berra

Conclusions