*Remission rates are after 12 weeks of treatment and are based on the HRSD-17<br />35<br />30.1%(n=86)<br />29.7%(n=83)<br />27.5%(n=790)<br />30<br />24.8%(n=62)<br />24.7%(n=18)<br />25<br />21.3%(n=51)<br />19.8%(n=24)<br />17.6%(n=42)<br />20<br />15.9%(n=11)<br />% of Patients Remitting<br />13.7%(n=7)<br />12.3%(n=14)<br />15<br />10<br />6.9%(n=4)<br />5<br />0<br />Citalopram<br />(n=2,876)<br />Bupropion(n=279)<br />Buspirone(n=286)<br />Venlafaxine(n=250)<br />Bupropion(n=239)<br />Sertraline(n=238)<br />Mirtazapine(n=114)<br />Nortriptyline(n=121)<br />Lithium(n=69)<br />T3(n=73)<br />Tranylcy-promine(n=58)<br />Venlafaxine + Mirtazapine (n=51)<br />Level 1(n=2,876)1<br />Level 2 (Augment)(n=565)2<br />Level 3 (Switch)(n=235)5<br />Level 2 (Switch)(n=727)3<br />Level 3 (Augment)(n=142)4<br />Level 4 (Switch)(n=109)6<br />STAR*D Results Demonstrate Diminishing Effectiveness of Treatments in TRD<br />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.<br />
Treatment Resistant Depression<br />First treatment: 28% remit<br />Second treatment: 17% - 30% remit<br />Third treatment: 12% - 25% remit<br />Fourth treatment: 7% - 14% remit<br /><ul><li>After 4 well-delivered treatments, 30% of patients will not have remitted </li></li></ul><li>Strategies to Address Incomplete Response<br />Maximize initial treatments<br />Change to other treatments<br />Non-MAOI antidepressant in same or different class<br />Adding or changing to a depression-focused psychotherapy<br />Augmenting and combining treatments<br />APA Practice Guideline for the Treatment of Patients With Major Depressive Disorder, Third Edition<br />
Gene-Environment Interaction Studies<br />Functional polymorphism in the promoter region of the gene encoding MAO moderates effect of child maltreatment.<br />Low levels of MAO expression increased frequency of conduct disorder, antisocial personality and adult violent crime.<br />Functional polymorphism in the promoter region of the serotonin transporter (5-HTT) gene moderates influence of stressful life events on depression.<br />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. <br />Caspi et al, 2002,2003<br />
Exposure to Adverse Rearing, Genotype and ACTH levels<br />Caspi et al.Nature Reviews Neuroscience 7, 583–590 (July 2006)<br />
Exposure to Adverse Rearing, Genotype and ACTH levels<br /><ul><li>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.</li></ul>Barr et al, Biol Psychiatry 2004<br />
Behavioral Epigenetics<br /><ul><li>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</li></ul>G Miller Science 2010<br />
Adverse Environment during Development<br /><ul><li>Bdnf gene is down-regulated in the hippocampus of adultmice exposed to social stress in the form of chronic bullyingby a bigger mouse.
This reduction in Bdnf activity linked to epigenetic modificationsinvolving histones, tiny protein spools that keep DNA wrappedup.
Chronic stress triggered increase in histonemethylation that suppresses gene activity by keeping the DNAcontaining the Bdnf gene tightly wound.
Conversely anti-depressant drugs boosted histone acetylation, which helpsunwind DNA from histones and promote Bdnf activity.
Epigenetic modifications could be an important linkbetween adverse life experiences and the risk of psychiatricdisorders such as depression and anxiety.</li></ul>E Nestler 2006<br />
Neurotrophic Hypothesis of Depression<br />Loss of Brain-Derived Neurotrophic Factor (BDNF) contributes to hippocampal atrophy that underlie aspects of depression.<br />Antidepressants mediate therapeutic effects by increasing expression of neurotrophic factors (BDNF) in this region.<br />
Neurotrophic Response to Antidepressants<br />Increased BDNF in the DG<br />Increased survival and maturation of newborn granule cells<br />Enhanced synaptic plasticity<br />Adachi et al, Biol Psychiatry 2008<br />
Stress and Depression<br />Long term antidepressant treatment, including ECS, increases BDNF protein and mRNA levels and reverses the stress-induced downregulation of BDNF.<br />Exercise followed by similar changes in BDNF levels, neurogenesis, and behavioral swim tests<br />
HPA axis and Depression<br />Hyperactivity present in majority of depressed patients<br />increased expression of CRF in hypothalamus<br />increased CRF levels in CSF<br />reduced feedback inhibition by CRF and glucocorticoids<br />CRF serves as a neurotransmitter in amygdala and BNST<br />amygdala involved in negative emotional memory and anxiety-like behavior<br />
No direct electrical stimulation of medial temporal lobe structures</li></li></ul><li>Administration of rTMS<br />Stimulation site - left dorsolateral prefrontal cortex<br />Determine resting motor threshold<br />Set stimulation intensity (120%), frequency (10 pulses/sec) and train duration (On 4 sec) & intertrain interval (Off 26 sec)<br />Typical treatment session > 30 min for total 3,000 stimulations <br />Treat 5 times / week for max 6 weeks (30 sessions)<br />O’Reardon et al, 2007<br />
Advantages of rTMS<br />No anesthetic required<br />No cognitive disruption or impairment<br />
Current status of rTMS<br />In pivotal study, efficacy did not separate from placebo on primary outcome measure<br />Recent NIH supported Study George et al 2010<br />Mutisite, randomized, active sham-controlled<br />3 weeks left prefrontal rTMS; 3 more weeks in improvers<br />OR for remission 4.2 for active rTMS (95% CI 1.32 - 13.24)<br />Significant interaction between AD resistance and clinical benefit<br />Remitters had lower degree of treatment resistance<br />No seizures, high retention rate<br />Possible role<br />Intermediate strategy<br />Augmentation<br />Pregnancy, PPD<br />
VNS Implant Procedure<br />1- to 2- hour case length<br />General or regional/local anesthesia<br />Does NOT involve the brain<br />Chest/armpit incision for generator<br />Neck incision for electrode<br />Outpatient or inpatient <br />Minimal complications<br />
It's tough to make predictions, especially about the future<br />If you don't know where you are going, you might wind up someplace else<br />You can observe a lot just by watching<br />Yogi Berra<br />Conclusions<br />