Second and Third Generation Antipsychotics: A Comprehensive Handbook

By Ryan S. O'dell and Thomas L. Schwartz

The second generation antipsychotics are a complex class of psychiatric medications, applicable to a diverse range of both FDA approved treatment indications and off-label uses. This variety stems largely from the unique pharmacodynamic profile of each agent, and often necessitates the employment of unique dosing strategies across the treatment of the varied psychiatry disorders, including schizophrenia, bipolar mania and depression, major depressive disorder, and autism. Despite the shared mechanism of dopamine D2 and serotonin-2a dual receptor blockade, which mediates the antipsychotic and antimanic properties of the second generation antipsychotics, the unique pharmacodynamic signature of each agent is subsequently responsible for the additional and varied antidepressant, anxiolytic, hypnotic, and tolerability profile observed with each drug.

Using an evidence based approach, this comprehensive handbook aims to highlight and discuss data relevant to treatment indications, off-labels uses, and dosing strategies of the 11 currently FDA approved second generation antipsychotics, with a strong emphasis on the pharmacodynamic profiles of these drugs. With the advent of three relatively new antipsychotics (lurasidone in 2011, brexpiprazole in 2015, and cariprazine in 2015), this text will serve as an excellent reference for practicing physicians, research investigators, and medical students alike. This review addresses not only these clinical applications, but provides physicians with the tools necessary to optimize treatment based upon patient diagnosis, proper antipsychotic selection, and implementation of an appropriate dosing strategy, thereby striking an essential balance between treatment efficacy and patient tolerability.

• Language: English
• Publisher: AuthorHouse
• Release date: Aug 10, 2016
• ISBN: 9781524619732

Ryan S. O'dell

Ryan Stephen O’Dell graduated from the University of Rochester in 2007 with a B.S. in Neuroscience, and a B.A. in Spanish. As an undergraduate he was involved in a four-year research project in which he investigated how the primate brain coordinates complex muscle sets to achieve delicate hand and finger movements. This research translates to advanced brain-machine interface technology for the restoration of lost neurological function. Mr. O’Dell is currently enrolled as a fourth year medical student at SUNY Upstate Medical University in Syracuse, New York, where he is finishing his final year as a candidate in the dual degree M.D./Ph.D. program. In the Department of Neuroscience and Physiology, he defended a Ph.D. thesis with honors, utilized cutting edge multiphoton live imaging techniques to elucidate the role of a specific protein (Reelin) in the dynamic properties of the emerging neurite arbor in early cortical development. He discovered that a deficiency in Reelin disrupted the stability of part of the cortical neuron that receives signals from other neurons, a part called the dendrite. Interestingly, although classically associated with lissencephaly with cerebellar hypoplasia, the neurodevelopmentally-related Reelin gene has recently been implicated as a contributor to the psychiatric disorders of autism and schizophrenia. Mr. O’Dell plans to pursue a residency in Psychiatry, with the ultimate goal of uniting his training from the lab and clinic towards both a better understanding of the precise neuropathologic mechanisms of psychiatric disorders and the development of new and more targeted therapies for said disorders. Outside of lab and classroom, Ryan enjoys ultra marathon running, having completed over 60 footraces ranging from 31 to 200 miles. Dr. Schwartz is currently professor and vice chair of psychiatry and director of all adult psychiatric clinical services at SUNY Upstate Medical University, where he also directs all medical student psychiatric training as well. Active on many committees at SUNY, he also provides direct resident supervision, lectures in several courses, and directs and organizes continuing medical education events for the psychiatry department. Dr Schwartz received his medical degree from and completed his residency in adult psychiatry at the State University of New York (SUNY) Upstate Medical University in Syracuse, New York. Dr Schwartz’s abilities as a medical educator have been recognized with the Marc H. Hollander, MD, Psychiatry Award, Teacher of the Year, and Mentor of the Year awards from SUNY Upstate Medical University; Nancy Roeske, MD, Irma Bland, Certificates of Recognition for Excellence in Medical Student and Resident Education from the American Psychiatric Association, the SUNY Upstate President’s and the SUNY Chancellor’s Award for Teaching. Dr. Schwartz is the author of Stahl’s Essential Psychopharmacology” Case Studies Volume 2, and editor of Depression: Treatment Strategies and Management, 2nd Ed., Integrating Psychotherapy and Pharmacotherapy, and Antipsychotic Drugs: Pharmacology, Side Effects and Abuse Prevention and is the Deputy Editor for the journal CNS Spectrums.

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© 2016 Ryan O’Dell and Thomas Schwartz. All rights reserved.

No part of this book may be reproduced, stored in a retrieval system, or transmitted by any means without the written permission of the author.

Published by AuthorHouse 08/09/2016

ISBN: 978-1-5246-1971-8 (sc)

ISBN: 978-1-5246-1972-5 (hc)

ISBN: 978-1-5246-1973-2 (e)

Library of Congress Control Number: 2016911953

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Because of the dynamic nature of the Internet, any web addresses or links contained in this book may have changed since publication and may no longer be valid. The views expressed in this work are solely those of the author and do not necessarily reflect the views of the publisher, and the publisher hereby disclaims any responsibility for them.

O’Dell, R.S.¹ and Schwartz, T.L.²

¹MD/PhD Program, SUNY Upstate Medical University, Syracuse, NY, 13210, USA

²The Department of Psychiatry, SUNY Upstate Medical University, 328 Psychiatry and Behavioral Sciences Building, 713 Harrison Street, Syracuse, NY 13210, USA

Author Contribution Statement

RSO and TLS conducted a comprehensive review of literature, wrote, and edited the manuscript.

Competing Interests Statement

The authors declare no competing financial interests.

TABLE OF CONTENTS

List of Tables

List Of Abbreviations

Foreword

Introduction

Chapter 1: THE ‘-DONES’

1. Risperidone

2. Paliperidone

3. Ziprasidone

4. Iloperidone

5. Lurasidone

Chapter 2: THE ‘-PINES’

6. Olanzapine

7. Quetiapine

8. Asenapine

Chapter 3: The ‘-PIPS’ AND ‘-RIPS’

9. Aripiprazole

10. Brexpiprazole

11. Cariprazine

Discussion

References

Tables

LIST OF TABLES

Table 1. Treatment indications and recommended dosing strategies of the ‘-done’ second generation antipsychotics

Table 2. Treatment indications and recommended dosing strategies of the ‘-pine’ second generation antipsychotics

Table 3. Treatment indications and recommended dosing strategies of the ‘-pip’ and ‘-rip’ second generation antipsychotics

Table 4. Pharmacokinetics of the second generation antipsychotics

Table 5. Binding affinity profiles of the second generation antipsychotics

LIST OF ABBREVIATIONS

FOREWORD

The second and third generation antipsychotics (SGA/TGA) have a wide range of approved treatment indications, including schizophrenia, bipolar mania and depression, major depressive disorder, and autism. Each medication in this class varies not only in their approved treatment indications, but demonstrate a diverse spectrum of off-label uses, applicability to special populations (adults vs. adolescents), and treatment regiment (monotherapy vs. adjunct therapy). This is largely a consequence of the unique pharmacodynamic profile of each agent, which often necessitates the employment of unique dosing strategies across the treatment of these varied psychiatric disorders.

With the advent of three new SGAs in recent years (lurasidone 2011, brexpiprazole 2015, and cariprazine 2015), two of which are partial dopamine receptor agonists (now coined TGA by the authors), we aim to review data relevant to the treatment indications, off-label use, and dosing strategies of all current agents using an evidence-based approach. Where definitive data are lacking, theoretical commentary based upon pharmacodynamic profiles and less stringent clinical trials will be employed. These agents are characterized by a diverse range of clinical applications, both FDA approved and off-label. This definitive text is current and up to date regarding all available agents and should provide mental health prescribers with the tools necessary to optimize treatment based upon patient diagnosis, proper antipsychotic selection, and implementation of an appropriate dosing strategy (low, middle, or high ranges), thereby striking an essential balance between treatment efficacy and patient tolerability.

Ryan Stephen O’Dell

Thomas L. Schwartz

INTRODUCTION

The typical antipsychotics, also known as first generation antipsychotics (FGA), were developed in the 1950s and were solely approved to treat acute psychosis and manage chronic psychotic disorders, primarily schizophrenia. All FGAs are known to exert their pharmacologic effects via postsynaptic antagonism of the dopamine D2 receptor, with a requirement of at least 65.0% receptor occupancy for antipsychotic efficacy ¹ . As D2 receptor occupancy increases, antipsychotic efficacy tends to increase, but so does the risk for side effects, including hyperprolactinemia (70%) and extrapyramidal symtpoms (EPS; dystonia, akathisia, parkinsonism, neuroleptic malignant syndrome, and tardive dyskinesia at 80%). High potency FGAs (fluphenazine, thiothixene, and haldoperidol), dosed in 1.0 to 10.0s of milligrams, have a much greater risk for these side effects due to their relatively high affinity for D2 receptors as their main pharamacodynamic profile. Low potency FGAs however (chlorpromazine and thioridazine), dosed in 100.0s of milligrams, have lower EPS risk profiles (due to their higher affinities for histaminic and muscarinic receptors) and demonstrate a greater risk of sedation, orthostatic hypotension, and weight gain. As dosage increases, so does antipsychotic efficacy, again through D2 receptor blockade and subsequent attenuation of dopaminergic hyperactivity in the mesolimbic DA pathway ² , ³ . In the past, the clinical goal was to increase FGA dosages until psychotic symptoms abated, oftentimes within rapid timeframes (neuroleptization). With the advent of the second generation antipsychotics (SGA) in the mid-1990s however, came a more complex pharmacodynamic profile, thereby necessitating a more intricate dosing strategy for some agents. This manuscript will review and discuss the clinical dosing strategies based upon clinical data, the pharmacodynamic, and pharmacokinetic profiles of the eleven currently FDA approved SGAs.

Due to the unique pharmacodynamic nature of each SGA, dosing and cross-titration strategies have become significantly more complex. Unlike FGAs, with which physicians could use an equivalency table of relative affinity values for immediate 24-hour cross-titration ⁴ , ⁵ , SGAs often require a more gradual cross-titration approach, as setting up equivalencies is fraught with complications as more than sole D2 affinity must be accounted for. There are also often discrepancies between FDA recommended dosing approaches and clinical practice. This is primarily a consequence of risperidone’s initial approval in the early 1990s for the treatment of schizophrenia and the recommended rapid escalation dosing strategy of reaching 6.0 mg in 3 days. Despite FDA assurance and data supporting low EPS rates, clinicians quickly noticed much higher rates of EPS with this dosing strategy, leading to problems with patient compliance. Although a slower titration strategy attenuates side effect risks, clinicians became cautious, often under-dosing and possibly curbing antipsychotic effectiveness ⁶ . This conservative approach unfortunately carried over into the subsequently

Reviews for Second and Third Generation Antipsychotics

[Andrea A. Richmond · Rating: 5 out of 5 stars]

An overview of the Second and Third Generation Antipsychotics gave me the information I needed to understand my options as a person with Bipolar Disorder NOS. I could understand that coupled with an SNRI (SSRI or SNRI) my Seroquel dose may be able to be lowered by 100 mg. This might give me more quality hours a day! Sedation is a side effect I loathe. I'll see what my Doctor has to say.
The detailed information on the progress made in psychiatric medications for Schizophrenia, Bipolar Disorder, GAD and Autistic aggression was informative. A detailed examination of each medication including side effects was refreshing. The book was 129 pages long including references making it a well written, quick read for me. I imagine it would be a useful reference for a Psychiatrist. Hope this quick review helps someone.