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From the Editor

10 Recent paradigm shifts in the neurobiology and treatment of depression

The serendipity of half a century ago yield to more complex and evidence- that hatched hoary theories of the based models. etiology of psychopathology is fad- Usually, it would be remarkable Henry A. Nasrallah, MD ing rapidly. Transformative models to witness a single paradigm shift in Editor-in-Chief are now emerging to change the the understanding of a disor- landscape of psychiatry. der. Imagine the disruptive impact of multiple scientific shifts within Nowhere is that change in landscape the past decade! Consider the follow- more apparent than in major depression, ing departures from the old dogma The notion that the No. 1 disabling condition in all of about the simplistic old explanation of depression is simply medicine, according to the World Health depression. Organization. The past decade has gen- a ‘chemical imbalance’ erated at least 10 paradigm shifts in the 1. From in the brain is giving neurobiology and pharmacotherapeutics to neuroplasticity of depression. For half a century, our field tenaciously way to evidence that held to the monoamine theory, which the disorder is associated Clinging to simplistic tradition posits that depression is caused by with neuroinflammation Most contemporary clinicians con- a deficiency of 5-HT or NE, or both. tinue to practice the traditional model All in use today were and disrupted of depression, which is based on the developed to increase brain mono- neuroplasticity assumption that depression is caused amines by inhibiting their reuptake at by a deficiency of monoamines: sero- the synaptic cleft. Now, research points tonin (5-HT) and (NE). to other causes: The entire armamentar- • impaired neuroplasticity ium approved for use by the FDA was • a decrement of neurogenesis designed according to the amine defi- • synaptic deficits ciency hypothesis. Depressed patients • decreased neurotrophins (such as uniformly receive reuptake inhibitors brain-derived neurotrophic factor) of 5-HT and NE, but few achieve full • dendritic pathology.2,3 remission, as the Sequenced Treatment To comment on this editorial or other topics of interest, Alternatives to Relieve Depression 2. From ‘chemical imbalance’ visit www.facebook.com/ (STAR*D) study showed.1 to neuroinflammation CurrentPsychiatry, or go to As scientific paradigm shifts infil- The simplistic notion that depression is CurrentPsychiatry.com and click on the “Send Letters” link. trate clinical practice, however, the tired a chemical imbalance, so to speak, in the notion of “chemical imbalance” will brain is giving way to rapidly emerging

Current Psychiatry 10 February 2015 evidence that depression is associated Intranasal also has been Editorial Staff 4 10 with neuroinflammation. shown to be clinically efficacious. EDITOR John Baranowski Pro-inflammatory cytokines are Inhalable (laughing gas, MANAGING EDITOR Erica Vonderheid Patrice Kubik elevated in the plasma of depressed an NMDA antagonist) recently was ASSOCIATE EDITOR WEB ASSISTANTS 11 patients, and subside when the acute reported to improve depression as well. Connor Kennedy, Jacob Remaly episode is treated. Current antidepres- It is possible that parenteral admin- Art & Production Staff sants actually have anti-inflammatory istration of antidepressant agents may CREATIVE DIRECTOR Mary Ellen Niatas 5 effects that have gone unrecognized. exert a different neurobiological effect ART DIRECTOR Pat Fopma A meta-analysis of the use of anti- and provide a more rapid response than DIRECTOR, JOURNAL MANUFACTURING Michael Wendt inflammatory agents (such as nonste- oral medication. PRODUCTION MANAGER Donna Pituras roidal anti-inflammatory drugs and Publishing Staff aspirin) in depression shows promising 5. From delayed PUBLISHER Sharon J. Spector 6 efficacy. Some inflammatory markers, (weeks) to immediate onset ASSOCIATE DIRECTOR, eBUSINESS such as C-reactive protein, already have (1 or 2 hours) DEVELOPMENT Joshua Norton been reported to predict response to The widely entrenched notion that MARKETPLACE ACCOUNT MANAGER Linda Wilson 7 some antidepressants, but not to others. depression takes several weeks to CONFERENCE MARKETING MANAGER improve with an antidepressant has Kathy Wenzler 3. From 5-HT and NE pathways collapsed with emerging evidence that Editor-in-Chief Emeritus to glutamate NMDA receptors symptoms of the disorder (even sui- James Randolph Hillard, MD 8 Recent landmark studies have, taken cidal ideation) can be reversed within 1 Frontline Medical Communications 12 together, demonstrated that a single or 2 hours. IV ketamine isn’t the only CHAIRMAN Stephen Stoneburn IV dose of the N-methyl-d-aspartate example; IV scopolamine,9 inhalable EVP DIGITAL BUSINESS DEVELOPMENT/CFO Douglas E. Grose (NMDA) receptor antagonist ketamine nitrous oxide,11 and overnight sleep PRESIDENT/CEO (a psychotogenic drug of abuse FDA- deprivation13 also exert a rapid thera- Alan J. Imhoff approved only as an anesthetic) can peutic effect. This is a major rethinking PRESIDENT, CUSTOM SOLUTIONS JoAnn Wahl produce clinical improvement of severe of how quickly the curtain of severe VICE PRESIDENT, FINANCE depression and even full remission for depression can be lifted, and is great Dennis Quirk several days. Such studies demonstrate news for patients and their family. EXECUTIVE DIRECTOR, OPERATIONS Jim Chicca that the old dogma of 5-HT and NE VICE PRESIDENT, MARKETING & CUSTOMER deficiency might not be a valid over- 6. From psychological ADVOCACY Jim McDonough arching hypothesis of the depression symptoms to cortical or VICE PRESIDENT, CUSTOM PROGRAMS Carol J. Nathan syndrome. subcortical changes CORPORATE DIRECTOR, RESEARCH Long-term maintenance studies of Depression traditionally has been recog- & COMMUNICATIONS Lori Raskin ketamine to document its safety and nized as a clinical syndrome of sadness, VICE PRESIDENT, AUDIENCE DEVELOPMENT Donna Sickles continued efficacy need to be con- self-deprecation, cognitive dulling, and Subscription Services: (800) 480-4851 ducted. The mechanism of action of ket- vegetative symptoms. In recent stud- In affiliation with Global Academy amine is believed to be a rapid trigger ies, however, researchers report that for Medical Education, LLC. for enhancing neuroplasticity. low hippocampus volume14 in healthy VICE PRESIDENT, MEDICAL EDUCATION young girls predicts future depression. & CONFERENCES Sylvia H. Reitman, MBA VICE PRESIDENT, EVENTS David J. Small, MBA 4. From oral to parenteral Patients with unremitting depression administration have been reported to have an abnor- Several studies have been published mally shaped hippocampus.15 showing the efficacy of IV or intranasal In addition, gray-matter volume 7 Century Drive, Suite 302 Parsippany, NJ 07054 administration of new agents for depres- in the subgenual anterior cingulate Tel: (973) 206-3434 sion. Ketamine studies, for example, (Brodmann area 24) is hypoplastic in Fax: (973) 206-9378 www.frontlinemedcom.com were conducted using an IV infusion depressed persons,16 making that area a of a 150-mg dose over 1 hour. Other target for deep-brain stimulation (DBS). Published through an IV studies used the anticholinergic Brain morphological changes such educational partnership scopolamine.9 as a hypoplastic hippocampus might with Saint Louis University

Current Psychiatry Vol. 14, No. 2 11 From the Editor

become useful biomarkers for identify- 9. From monotherapy ing persons at risk of severe depression, to combination therapy and might become a useful adjunc- The use of combination therapy for tive biomarker for making a clinical depression has escalated with FDA diagnosis. approval of adjunctive use of atypical in unipolar and bipolar 7. From healing the mind depression. In addition, the landmark to repairing the brain STAR*D study1 demonstrated the value It is well-established that depression of augmentation therapy with a second is associated with loss of dendritic antidepressant when 1 agent fails. Other spines and arborizations, loss of syn- controlled studies have shown that apses, and diminishment of glial combining 2 antidepressants is superior Treating depression cells, especially in the hippocampus17 to administering 1.22 and anterior cingulate.18 Treating Just as other serious medical dis- involves increasing depression, whether pharmaceutical orders—such as cancer and hyper- neurotrophic factors, or somatic, involves reversing these tension—are treated with 2 or 3 changes by increasing neurotrophic medications, severe depression might enhancing neurogenesis factors, enhancing neurogenesis and require a similar strategy. The field and gliogenesis, and gliogenesis, and restoring synaptic gradually is adopting that approach. restoring synaptic and dendritic health and cell survival in the hippocampus and frontal cor- 10. From cortical folds and dendritic health tex.19,20 Treating depression involves to wrinkles on the face and cell survival in the brain repair, which is reflected, ulti- Last, a new (and unexpected) paradigm hippocampus and mately, in healing the mind. shift recently emerged, which is genu- inely intriguing—even baffling. Using frontal cortex 8. From pharmacotherapy -controlled designs, several to researchers have reported significant, Although drugs remain the predomi- persistent improvement of depressive nant treatment modality for depression, symptoms after injection of onabotu- there is palpable escalation in the use of linumtoxinA in the corrugator muscles neuromodulation methods. of the glabellar region of the face, where The oldest of these neuromodulatory the omega sign often appears in a techniques is electroconvulsive ther- depressed person.23,24 apy, an excellent treatment for severe The longest of the studies25 was depression (and one that enhances hip- 6 months; investigators reported that pocampal neurogenesis). In addition, improvement continued even after the several novel neuromodulation meth- effect of the botulinum toxin on the ods have been approved (transcranial omega sign wore off. The proposed magnetic stimulation and vagus nerve mechanism of action is the facial feed- stimulation) or are in development back hypothesis, which suggests that, (transcranial direct-current stimula- biologically, facial expression has an tion, cranial electrotherapy stimulation, impact on one’s emotional state. and DBS).21 These somatic approaches to treating the brain directly to allevi- Big payoffs coming from ate depression target regions involved research in neuroscience in depression and reduce the needless These 10 paradigm shifts in a single risks associated with exposing other psychiatric syndrome are emblematic of organ systems to a drug. exciting clinical and research advances

Current Psychiatry 12 February 2015 in our field. Like all syndromes, 8. Abdallah CG, Sanacora G, Duman RS, et al. Ketamine and rapid-acting antidepressants: a window into a depression is associated with multiple new neurobiology for therapeutics [published online October 17, 2014]. Annual Rev genetic and environmental causes; it Med. doi: 10.1146/annurev-med-053013-062946. isn’t surprising that myriad treatment 9. Furey ML, Khanna A, Hoffman EM, et al. Scopolamine produces larger antidepressant and antianxiety effects approaches are emerging. in women than in men. Neuropsychopharmacology. The days of clinging to monolithic, 2010;35(12):2479-2488. 10. Lapidus KA, Levitch CF, Perez AM, et al. A serendipity-generated models surely randomized controlled trial of intranasal ketamine are over. Evidence-based psychiatric in major depressive disorder. Biol Psychiatry. 2014; 76(12):970-976. brain research is shattering aging dog- 11. Nagele P, Duma A, Kopec M, et al. Nitrous oxide mas that have, for decades, stifled inno- for treatment-resistant major depression: a proof- of-concept trial [published December 14, 2014]. vation in psychiatric therapeutics that is Biol Psychiatry. doi: http://dx.doi.org/10.1016/j. now moving in novel directions. biopsych.2014.11.016. 12. Köhler O, Benros ME, Nordentoft M, et al. Effect Take note, however, that the only par- of anti-inflammatory treatment on depression, Depression is associated adigm shift that matters to depressed depressive symptoms, and adverse effects: a and meta-analysis of randomized patients is the one that transcends mere clinical trials. JAMA Psychiatry. 2014;71(12): with multiple genetic control of their symptoms and restores 1381-1391. 13. Bunney BG, Bunney WE. Mechanisms of rapid and environmental their wellness, functional capacity, antidepressant effects of sleep deprivation therapy: clock genes and circadian rhythms. Biol Psychiatry. causes; it isn’t surprising and quality of life. With the explosive 2013;73(12):1164-1171. momentum of neuroscience discovery, 14. Chen MC, Hamilton JP, Gotlib IH. Decreased that myriad treatment psychiatry is, at last, poised to deliver— hippocampal volume in healthy girls at risk for depression. Arch Gen Psychiatry. 2010;67(3):270-276. approaches are emerging in splendid, even seismic, fashion. 15. Tae WS, Kim SS, Lee KU, et al. Hippocampal shape deformation in female patients with unremitting major depressive disorder. AJNR Am J Neuroradiol. 2011;32(4):671-676. 16. Hamani C, Mayberg H, Synder B, et al. Deep brain stimulation of the subcallosal cingulate gyrus for Henry A. Nasrallah, MD depression: anatomical location of active contacts in clinical responders and a suggested guideline for Editor-in-Chief targeting. J Neurosurg. 2009;111(6):1209-1215. 17. Sheline YI, Gado MH, Kraemer HC. Untreated References depression and hippocampal volume loss. Am J Psychiatry. 2003;160(8):1516-1518. 1. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. 18. Redlich R, Almeoda JJ, Grotegerd D, et al. Brain N Eng J Med. 2006;354(12):1243-1252. morphometric biomarkers distinguishing unipolar and bipolar depression. A voxel-based morphometry- 2. Serafini G, Hayley S, Pompili M, et al. Hippocampal pattern classification approach. JAMA Psychiatry. neurogenesis, neurotrophic factors and depression: 2014;71(11):1222-1230. possible therapeutic targets [published online November 30, 2014]? CNS Neurol Disord Drug 19. Mendez-David I, Hen R, Gardier AM, et al. Targets. doi: 10.2174/1871527313666141130223723. Adult hippocampal neurogenesis: an actor in the antidepressant-like action. Ann Pharm Fr. 2013; 3. Duman RS, Aghajanian GK. Synaptic dysfunction 71(3):143-149. in depression: potential therapeutic targets. Science. 2012;338(6103):68-72. 20. Serafini G. Neuroplasticity and major depression, the role of modern antidepressant drugs. World J 4. Iwata M, Ota KT, Duman RS. The inflammasome: Psychiatry. 2012;2(3):49-57. pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun. 21. Rosa MA, Lisanby SH. Somatic treatments for mood 2013;31:105-114. disorders. Neuropsychopharmacology. 2012;37(1): 102-116. 5. Sacre S, Medghalichi M, Gregory B, et al. Fluoxetine and exhibit potent anti-inflammatory 22. Blier P, Ward HE, Tremblay P, et al. Combination of activity in human and murine models of rheumatoid antidepressant medications from treatment initiation arthritis and inhibit toll-like receptors. Arthritis for major depressive disorder: a double-blind Rheum. 2010;62(3):683-693. randomized study. Am J Psychiatry. 2010;167(3): 281-288. 6. Köhler O, Benros ME, Nordentoft M, et al. Effect of anti-inflammatory treatment on depression, 23. Wollmer MA, de Boer C, Kalak N, et al. Facing depressive symptoms, and adverse effects: a depression with botulinum toxin: a randomized systematic review and meta-analysis of randomized controlled trial. J Psychiatr Res. 2012;46(5):574-581. clinical trials. JAMA Psychiatry. 2014;71(12): 24. Finzi E, Rosenthal NE. Treatment of depression with 1381-1391. onabotulinumtoxinA: a randomized, double-blind, 7. Uher R, Tansey KE, Dew T, et al. An inflammatory placebo controlled trial. J Psychiatr Res. 2014;52:1-6. biomarker as a differential predictor of outcome 25. Magid M, Reichenberg JS, Poth PE, et al. Treatment of depression treatment with and of major depressive disorder using botulinum toxin nortiptyline. Am J Psychiatry. 2014;171(14): A: a 24-week randomized, double-blind, placebo- 1278-1286. controlled study. J Clin Psychiatry. 2014;75(8):837-844.

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