From the Editor

Psychopharmacology 3.0

There is little doubt that the psycho- included dozens of FGAs belonging to pharmacology revolution has been 6 classes: phenothiazines, thioxanthenes, butyrophenones, dibenzazepines, dihy- transformational for psychiatry and droindolones, and dibenzodiazepines. is also credited for sparking the Psychopharmacology 1.0 also included momentous neuroscience advances monoamine oxidase inhibitors and tricy- of the past half century. clic for depression, and for bipolar mania. Ironically, clo- Henry A. Nasrallah, MD The field of psychiatry, dominated by zapine, the incognito seed template of the Editor-in-Chief Freudian psychology for decades, radi- second-generation antipsychotic (SGA) cally evolved from psychoanalysis to class, was synthesized in 1959 with the pharmacotherapy with the discovery early wave of FGAs, and launched in that serious mental disorders are treat- Europe in 1972, only to be withdrawn able with , thus dispensing in 1974 due to agranulocytosis-induced with the couch. deaths not recognized during the clinical I remain excited Prior to 1952, the prevailing dogma trials. about the prospects was that “madness is irreversible.” The late 1980s ushered in That’s why millions of patients with var- Psychopharmacology 2.0, which was of astounding ious psychiatric disorders were locked also transformative. It began in 1987 psychopharmacologic up in institutions, which added to the with the introduction of , the stigma of mental illness. Then came the first selective serotonin receptor inhibi- advances to treat the first antipsychotic drug, chlorproma- tor. Then clozapine was resurrected in disorders of the mind zine, which “magically” eliminated the 1988 as the first FDA-approved drug delusions and hallucinations of patients for refractory schizophrenia. Being the who had been hospitalized for years. first SGA (no acute extrapyramidal side That serendipitous and historic discov- effects at all, in contrast to all FGAs), it ery was as transformational for psy- became the “mechanistic model” for all chiatry as penicillin was for infections other SGA agents, which were intro- (yet inexplicably, only the discovery of duced starting in 1993. All SGAs were penicillin received a Nobel Prize). Most designed by pharmaceutical companies’ people today do not know that before medicinal chemists to mimic clozapine’s chlorpromazine, 50% of all hospital beds receptor profile: far stronger affinity in the U.S. were occupied by psychiat- to serotonin 5HT-2A receptors than to ric patients. The massive shuttering of dopamine D2 receptors. Three partial state hospitals in the 1970s and ’80s was and several heterocyclic anti- a direct consequence of the widespread depressants were also introduced dur- To comment on this editorial or other topics use of chlorpromazine and its cohort of ing this 2.0 era, which continued until of interest: first-generation antipsychotics (FGAs). approximately 2017. Of the 11 SGAs that henry.nasrallah That was Psychopharmacology 1.0, were initially approved for schizophre- @currentpsychiatry.com spanning the period 1952 to 1987. It nia, 7 also were approved for bipolar

Current Psychiatry Vol. 17, No. 11 5 From the Editor

Editorial Staff mania, and 2 received an FDA indication opioid system is being recognized as EDITOR Jeff Bauer for bipolar depression, thus addressing a another key player in depression, with SENIOR EDITOR Sathya Achia Abraham ASSISTANT EDITOR Jason Orszt glaring unmet need. many studies showing buprenorphine WEB ASSISTANTS Psychopharmacology 3.0 has already has and anti-suicidal Tyler Mundhenk, Kathryn Wighton begun. Its seeds started sprouting over properties2 and the recent finding that Art & Production Staff CREATIVE DIRECTOR Mary Ellen Niatas the past few years with the landmark pre-treatment with naloxone blocks ART DIRECTOR Pat Fopma studies of intravenous , which the rapid antidepressive effects of ket- DIRECTOR, JOURNAL MANUFACTURING 3 Michael Wendt was demonstrated to reverse severe amine. This finding casts doubt on the PRODUCTION MANAGER Donna Pituras and refractory depression and suicidal notion that the antidepressant mecha- Publishing Staff urges within hours of injection. The nism of action of ketamine is solely PUBLISHER Sharon J. Spector DIRECTOR eBUSINESS DEVELOPMENT first ketamine product, , an mediated via its antagonism of the glu- Alison Paton intranasal formulation, is expected to be tamate N-methyl-D-aspartate (NMDA) SENIOR DIRECTOR OF SALES Tim LaPella approved by the FDA soon. In the same receptor. Another imminent innovative CONFERENCE MARKETING MANAGER Kathleen Wenzler vein, other rapid-acting antidepressants, antidepressant is a welcome paradigm shift, are being represented by brexanolone, an allo- Editor-in-Chief Emeritus James Randolph Hillard, MD developed, including IV scopolamine, steric modulator of GABA-A receptors Frontline Medical Communications IV rapastinel, and inhalable nitrous (which are known to become dormant PRESIDENT/CEO Alan J. Imhoff oxide. during pregnancy and are not reac- CFO Douglas E. Grose Three novel and important phar- tivated after delivery in women who SVP, FINANCE Steven Resnick VP, OPERATIONS Jim Chicca macologic agents have arrived in this develop postpartum depression). VP, SALES Mike Guire 3.0 era: These early developments in VP, SOCIETY PARTNERS Mark Branca VP, EDITOR IN CHIEF Mary Jo Dales • Pimavanserin, a serotonin 5HT- Psychopharmacology 3.0 augur well VP, EDITORIAL DIRECTOR, CLINICAL CONTENT 2A inverse , the first and only for the future. Companies in the phar- Karen Clemments CHIEF DIGITAL OFFICER Lee Schweizer non-dopamine–blocking antipsychotic maceutical industry (which are hated VP, DIGITAL CONTENT & STRATEGY Amy Pfeiffer approved by the FDA for the delu- by many, and even demonized and PRESIDENT, CUSTOM SOLUTIONS JoAnn Wahl sions and hallucinations of Parkinson’s kept at arm’s length by major medical VP, CUSTOM SOLUTIONS Wendy Raupers disease psychosis. It is currently in schools) are, in fact, the only entities in VP, MARKETING & CUSTOMER ADVOCACY Jim McDonough clinical trials for schizophrenia and the world that develop new medications VP, HUMAN RESOURCES & FACILITY OPERATIONS Carolyn Caccavelli Alzheimer’s disease psychosis (for for psychiatric disorders, 82% of which DATA MANAGEMENT DIRECTOR Mike Fritz which nothing is yet approved). still have no FDA-approved drug.4 Jared Sonners CIRCULATION DIRECTOR • Valbenazine, the first drug Psychiatric researchers and clinicians CORPORATE DIRECTOR, RESEARCH & COMMUNICATIONS Lori Raskin approved for tardive dyskinesia (TD), should collaborate and advise the phar- DIRECTOR, CUSTOM PROGRAMS Patrick Finnegan the treatment of which had been elu- maceutical companies about the urgent AllMedx sive and remained a huge unmet need or unmet needs of psychiatric patients PRESIDENT Douglas E. Grose for 60 years. Its novel mechanism of so they can target those unmet needs EXECUTIVE VICE PRESIDENT, SALES John Maillard action is inhibition of vesicular mono- with their massive R&D resources. EDITORIAL DIRECTOR/COO Carol Nathan amine transporter 2 (VMAT2), which In that spirit, here is my wish list In affiliation with Global Academy for reduces the putative dopamine super- of therapeutic targets that I hope will Medical Education, LLC sensitivity of TD. emerge during the Psychopharmacology PRESIDENT David J. Small, MBA • Deutetrabenazine, which was also 3.0 era and beyond: approved for TD a few months after 1. New mechanisms of action for anti- valbenazine, and has the same mecha- psychotics, based on emerging neuro- 7 Century Drive, Suite 302 nism of action. It also was approved for biological research in schizophrenia and Parsippany, NJ 07054 Tel: (973) 206-3434 Huntington’s chorea. related psychoses, such as: Fax: (973) 206-9378 www.frontlinemedcom.com Another important feature of • Inhibit microglia activation Subscription Inquiries: Psychopharmacology 3.0 is the repur- • Repair mitochondrial dysfunction [email protected] posing of hallucinogens into novel • Modulate the hypofunctional Published through an educational partnership therapies for posttraumatic stress dis- NMDA receptors with Saint Louis University order, anxiety, and depression.1 The • Inhibit apoptosis

Current Psychiatry 6 November 2018 • Enhance neurogenesis The future of psychopharmacol- • Repair myelin pathology ogy is bright, if adequate resources • Inhibit neuroinflammation and oxi- are invested. The current direct and dative stress indirect costs of mental disorders • Increase neurotropic growth factors and addictions are in the hundreds • Neurosteroid therapies (including of billions of dollars annually. Only estrogen) intensive research and disruptive dis- • Exploit the microbiome influence coveries will have the salutary dual on both the enteric and cephalic effect of healing disease and reducing brains the economic burden of neuropsychi- 2. Long-acting injectable antidepres- atric disorders. Psychopharmacology sants and mood stabilizers, because 3.0 advances, along with nonpharma- there is a malignant transformation cologic therapies such as neuromod- The psychiatrists of 1952 into treatment-resistance in mood dis- ulation (electroconvulsive therapy, orders after recurrent episodes due to transcranial magnetic stimulation, could only fantasize nonadherence.5 vagus nerve stimulation, and a about what has since 3. Treatments for personality disor- dozen other techniques in develop- ders, especially borderline and antisocial ment). Together with the indispens- become a reality personality disorders. able evidence-based psychotherapies 4. An effective treatment for such as cognitive-behavioral therapy, alcoholism. dialectical behavior therapy, and 5. Pharmacotherapy for aggression. interpersonal psychotherapy, psy- 6. Vaccines for substance use. chopharmacology represents the 7. Stage-specific pharmacotherapies leading edge of progress in psychi- (because the neurobiology of prodro- atric treatment. The psychiatrists of mal, first-episode, and multiple-episode 1952 could only fantasize about what patients have been shown to be quite has since become a reality in healing different). ailing minds. 8. Drugs for epigenetic modulation to inhibit risk genes and to over-express protective genes. It may take decades and hundreds of Henry A. Nasrallah, MD billions (even trillions) of R&D invest- Editor-in-Chief ment to accomplish the above, but I remain excited about the prospects References 1. Nasrallah, HA. Maddening therapies: How of astounding psychopharmacologic hallucinogens morphed into novel treatments. advances to treat the disorders of the Current Psychiatry. 2017;16(1):19-21. 2. Serafini G, Adavastro G, Canepa G, et al. The mind. Precision psychiatry advances efficacy of buprenorphine in major depression, will also expedite the selection of treatment-resistant depression and suicidal behavior: a systematic review. Int J Mol Sci. 2018;19(8). doi: the right for each patient 10.3390/ijms19082410. by employing predictive biomarkers. 3. Williams NR, Heifets BD, Blasey C, et al. Attenuation of antidepressant effects of ketamine Breakthrough methodologies, such as by opioid receptor antagonism. Am J Psychiatry. pluripotent stem cells, opto-genetics, 2018. doi: 10.1176/appi.ajp.2018.18020138. [Epub ahead of print]. and clustered regularly interspaced 4. Devulapalli KK, Nasrallah HA. An analysis of short palindromic repeats (CRISPR), the high psychotropic off-label use in psychiatric disorders. The majority of psychiatric diagnoses promise to revolutionize the biology, have no approved drug. Asian J Psychiatr. 2009;2(1): 29-36. diagnosis, treatment, and prevention 5. Post RM. Preventing the malignant transformation of of various neuropsychiatric disorders. bipolar disorder. JAMA. 2018;319(12):1197-1198.

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