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