Prescribing Psychotropics: From Drug Interactions to Pharmacogenetics

Prescribing Psychotropics: From Drug Interactions to Genetics

FOURTH EDITION

(Previously Drug Metabolism in Psychiatry)

Published by Carlat Publishing, LLC

PO Box 626, Newburyport, MA 01950

Publisher and Editor-in-Chief: Daniel J. Carlat, MD

Deputy Editor: Talia Puzantian, PharmD, BCPP

Executive Editor: Janice Jutras

All rights reserved. This book is protected by copyright.

This CME/CE activity is intended for psychiatrists, psychiatric nurses, psychologists, and other health care professionals with an interest in mental health. The Carlat CME Institute is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of ten (10) AMA PRA Category 1 Credits™. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity. The American Board of Psychiatry and Neurology has reviewed Prescribing Psychotropics: From Drug Interactions to Genetics and has approved this program as part of a comprehensive Self-Assessment and CME Program, which is mandated by ABMS as a necessary component of maintenance of certification. CME tests must be taken online at www.thecarlatreport.com or https://www.thecarlatreport.com/about/about-cme-center (for ABPN SA course subscribers).

To order, visit www.thecarlatreport.com or call (866) 348-9279

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ISBN: 978-1-7329522-6-3

eISBN: 978-1-7329522-7-0

PRINTED IN THE UNITED STATES OF AMERICA

Table of Contents

Acknowledgments

Preface

Section I: The Basics

Chapter 1. Introduction: An Overview of Drug Metabolism and a Road Map to the Book

Chapter 2. Pills, Capsules, and Wafers: How Drugs Are Formulated and Why It Matters

Chapter 3. GI Absorption, Distribution, and the Blood-Brain Barrier

Chapter 4. Basic Pharmacokinetics: Onset, Duration, and Half-Life

Chapter 5. Modified-Release Medications: XR, CR, ER, and Beyond

Chapter 6. Transdermal and Intranasal Delivery

Chapter 7. Injectable Medications

Chapter 8. Biotransformation and the Liver

Chapter 9. Excretion

Section II: Drug Interactions

Chapter 10. Drug Interactions

Chapter 11. Drug Interactions: Antidepressants

Chapter 12. Drug Interactions: Antipsychotics and Mood Stabilizers

Chapter 13. Food and Drink Effects on Medications

Chapter 14. Recreational Drug Interactions

Chapter 15. Pharmacodynamic Drug Interactions

Section III: Special Topics

Chapter 16. Generic Medications and Drug Metabolism

Chapter 17. Pharmacogenetic Testing

Chapter 18. Prescribing for the Elderly and the Young

Chapter 19. Women, Men, and Medications

Chapter 20. Drug Metabolism and Ethnicity

Appendix. Tables of Relevant Drug Interactions

Acknowledgments

For invaluable assistance, the authors wish to acknowledge:

Paul Carlat, MD, a wonderful father and psychiatrist, who test drove the book in his own practice.

Cal Colarusso, MD, a mentor who offers a full appreciation of the developmental lifespan.

Bernard Lee, MD, whose clinical judgement is a foundation for rational care of patients.

Charley Mitchell, of Lippincott Williams & Wilkins, for mentoring and teaching in the ways of publishing.

Richard Naimark, MD, a great psychiatrist, brother-in-law, and possessor of incredible common sense.

Xavier Preud’homme, MD, whose insatiable curiosity inspires the same in others.

Talia Puzantian, PharmD, BCPP, whose wealth of knowledge and wise guidance are a pillar of all of our publications at Carlat.

Sarah Rivelli, MD, for bringing judgement to uncertainty.

Neil Sandson, MD, for generosity of advice and encouragement.

Richard Weisler, MD, whose breadth of knowledge is matched only by his humility.

Marcia Zuckerman, MD, an editorial board member of The Carlat Psychiatry Report and quite possibly the most talented person on earth at making medical prose both relevant and comprehensible.

The members of the editorial boards of our four newsletters, who provide guidance and (most importantly) read and vet articles month after month after month.

Our outstanding Carlat staff, particularly our editorial team of Janice Jutras and Ilana Fogelson, who keep us pointed in the right direction.

And our patients and their families, whose experiences and questions give us the impetus to learn more and provide better care.

Preface

Most of our education as psychiatrists consists of learning how to diagnose patients and then learning how to choose the right treatment. This is important stuff. For example, I recently admitted a 36-year-old woman to the inpatient unit. The day before, she had been observed by neighbors trying to open the doors of several other apartments in her complex. When confronted, she screamed at them and said that all these domiciles are my own. The police were called, and she was admitted on an involuntary basis to our unit.

My training enabled me to quickly establish rapport, arrive at a diagnostic differential (I entertained bipolar disorder, schizophrenia, and schizoaffective disorder, among others), and efficiently ask the right questions to rule those diagnoses in or out. I decided that she was suffering a manic episode, and my psychopharmacology training directed me to the most efficacious cocktail for quelling acute mania—a combination of a mood stabilizer, an antipsychotic, and a benzodiazepine.

But here’s where the difficult decisions really begin, for this patient and others like her. Which mood stabilizer? I chose lithium. But which version of lithium? Should I start it in the morning or at night? How frequently should I dose it? When should I draw a blood level? Should I worry about other drugs the patient might be taking, such as ibuprofen for a sprained ankle?

The secret of excellent psychiatric treatment lies in the detailed answers to such questions. Over the course of our careers, we gradually learn about how different formulations of a given drug can make a big difference, how timing blood draws helps us titrate doses, how drugs can interact with one another, etc. But these lessons take many years to learn, and the answers change periodically as we learn more and with the development of new medications, new kinds of medications, and new technologies such as pharmacogenetics. There are few textbooks that focus explicitly on the details of drug metabolism and formulation—details that end up making the difference between superior treatment and treatment that is just good enough.

That’s why I wrote the first edition of this book, back in 2005. I fancifully titled it When Molecules Collide, not realizing that prospective readers would mistake it for a science fiction book. The second and third editions were retitled Drug Metabolism in Psychiatry—very faithful to the contents, but a title to go to sleep by. For the fourth edition, I teamed up with my colleagues Chris Aiken and Josh Feder to produce an expanded book, and decided to give it the somewhat more titillating title Prescribing Psychotropics: From Drug Interactions to Genetics.

I hope you like it.

Daniel J. Carlat, MD

Newburyport, MA

November, 2021

Section I

The Basics

Chapter 1

Introduction: An Overview of Drug Metabolism and a Road Map to the Book

Let’s begin this journey with a very basic question. Why do we need drug metabolism at all?

The best thinking among pharmacologists is that metabolism started when early organisms realized that they could improve their chances of survival by producing toxins and delivering them to potential predators. While poisoning enemies was good fun, a problem arose: how to avoid poisoning themselves. Metabolic enzyme systems therefore initially evolved in order to get rid of these endogenous toxins, but they turned out to be quite good at neutralizing exogenous toxins as well, such as food byproducts and (fast-forward a billion years) modern pharmaceuticals.

In order for drugs to work, they need to get into our system and into our cells. First, that means that the drug molecules have to be packaged in a delivery system that patients find attractive and are willing to swallow (see Chapter 2 on the secrets of pills and capsules)—or, sometimes they might be more efficiently delivered as patches, intranasally, or as injectables (see Chapters 6 and 7). Once the medications get into our system, they have to be absorbed and distributed. For GI absorption to happen, the stomach must grind down pills and capsules so that the molecules can come into contact with intestinal villi, where most of the actual absorption into the bloodstream takes place.

To effectively prescribe drugs, you need to know a bit about pharmacokinetics, which is the study of how long drugs stick around inside the body and what concentrations they typically achieve. The most clinically relevant parameters are half-life and area under the curve (AUC). The half-life is a measure of how rapidly half the amount of a drug is excreted, and the AUC represents the entire amount of drug that is present in the blood over a given period of time. Chapter 4 focuses on half-life, steady state, and the whole field of pharmacokinetics.

After drugs have worked their magic, we have to get rid of them. How do we accomplish this? The answer, which we discuss in Chapters 8 and 9, is that we transform them into water-soluble versions of themselves, so that they can be swept away in (watery) urine or stool. To do this, we use cytochrome P450 enzymes and glucuronidation, which you’ll learn about in Chapter 8 as well.

By the way, as part of our effort to explain drug excretion in Chapter 9, we offer you our take on the kidney, that intimidating organ that we all know we should know more about but have been studiously avoiding. We show you that the kidney is made up of nephrons that do the work of drug excretion, and how understanding the process of tubule absorption will help you feel comfortable prescribing lithium and knowing when to order lithium levels.

Before drugs get excreted, they spend some time in the bloodstream, hopefully getting into the brain and doing something constructive for our patients (see Chapter 3 for an explanation of the blood-brain barrier). Along the way, they may encounter other drugs, leading to drug-drug interactions. We cover such interactions in Chapters 10, 11, and 12, and also focus on drug-food interactions that aren’t as well known (Chapter 13) and interactions with recreational drugs (Chapter 14).

In Chapter 15 we cover the very important topic of pharmacodynamic interactions, in which some of our drugs combine forces with other drugs to cause potentially fatal assaults on the brain, such as serotonin syndrome and MAOI-induced hypertension. In that same chapter, we remind you of the dangers of anticholinergic interactions and how to minimize them in your patients.

Throughout the text, we try to keep a practical eye on how these concepts apply to your prescription pad. Toward that end, the new edition features more extensive coverage of three trends that have expanded since the first edition came out in 2005. More drugs have gone generic (Chapter 16), and a dizzying array of new formulations have become available, from delayed-release mechanisms to fast-acting dissolvable tablets (Chapters 5–7).

The third area of growth is pharmacogenetic testing, which we cover in Chapter 17. We explain the ever-controversial field of CYP450 genotyping and discuss whether commercial genetic panels are ever worth ordering. The final chapters (18–20) remind us of patient characteristics that can alter drug metabolism but do not require a genetic test to detect: age, gender, and ethnicity.

Don’t forget the appendix, which brings the most useful charts and tables together for easy reference.

Chapter 2

Pills, Capsules, and Wafers: How Drugs Are Formulated and Why It Matters

A psychopharmacologist prescribes thousands of pills over a career but is likely to have very little idea of how those medications are manufactured and formulated. In this chapter, we’ll help to remedy this knowledge gap.

Some Definitions

The word pill comes from the Latin pillula, meaning a little ball or pellet. The term was first used in its medical sense in the 1400s and referred to a package of medicinal herbs with inert substances rolled into a sphere.

In modern usage, pill and tablet are interchangeable and refer to solid forms of medicines. They are manufactured by combining the powderized active molecule with inactive fillers called excipients. Those ingredients are then compressed together into a shape and size that is easily swallowed. The excipients are used for various reasons, including to bulk up the medicine so it’s big enough to handle; to give the outer layer a pleasing taste, texture, or color; to help preserve the medicine; and to enhance the medicine’s ability to effectively dissolve in the GI tract.

Unlike pills and tablets, capsules are not solid. Capsules are dissolvable shells that contain a powder or liquid form of the medication.

Pills vs Capsules

Pills and tablets have a few advantages over capsules: lower cost, ease of cutting them in half, and longer shelf life. Their disadvantages include that they are typically harder to swallow and can have a bitter taste.

Liquid formulations are another common option to try when people have trouble swallowing medications. Many classes of psychotropic medications, including antipsychotics, antidepressants, stimulants, and anticonvulsants, are available in liquid form, and many more can be turned into a liquid by a compounding pharmacy. Liquids are also useful when patients have to taper off a medication very slowly to prevent withdrawal effects.

Orally Disintegrating Formulations

Orally disintegrating tablets (ODTs) have come on the scene over the last 20 years. Two of the most popular are olanzapine and mirtazapine ODT (formerly branded as Zyprexa Zydis and Remeron SolTab), but there are many others (see chart on page 11). In this section, we’ll discuss some of the potential advantages of ODTs and describe various situations in which you might consider prescribing them.

ODTs are designed to dissolve quickly on the tongue. The first ODTs were vitamins that fizzed up in order to make them more pleasant for children. To achieve this, pharmaceutical companies used loose-compression tableting, which is just as it sounds: a process where the tablets are compressed under low force. Loosely