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Essential Psychopharmacology

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Essential Psychopharmacology CONTENTS Preface vii Chapter 1 Principles of Chemical Neurotransmission 1 Chapter 2 Receptors and Enzymes as the Targets of Drug Action 35 Chapter 3 Special Properties of Receptors 77 Chapter 4 Chemical Neurotransmission as the Mediator of Disease Actions 99 Chapter 5 Depression and Bipolar Disorders 135 Chapter 6 Classical Antidepressants, Serotonin Selective Reuptake Inhibitors, and. Noradrenergic Reuptake Inhibitors 199 Chapter 7 Newer Antidepressants and Mood Stabilizers 245 Chapter 8 Anxiolytics and Sedative-Hypnotics 297 Chapter 9 Drug Treatments for Obsessive-Compulsive Disorder, Panic Disorder, and Phobic Disorders 335 xi xii Contens Chapter 10 Psychosis and Schizophrenia 365 Chapter 11 Antipsychotic Agents 401 Chapter 12 Cognitive Enhancers 459 Chapter 13 Psychopharmacology of Reward and Drugs of Abuse 499 Chapter 14 Sex-Specific and Sexual Function-Related Psychopharmacology 539 Suggested Reading 569 Index 575 CME Post Tests and Evaluations CHAPTER 6 CLASSICAL ANTIDEPRESSANTS, SEROTONIN SELECTIVE REUPTAKE INHIBITORS, AND NORADRENERGIC REUPTAKE INHIBITORS I. Theories of antidepressant drug action A. Classifications based on acute pharmacologic actions B. The neurotransmitter receptor hypothesis of antidepressant action C. The monoamine hypothesis of antidepressant action on gene expression II. Pharmacokinetics of antidepressants A. CYP450 1A2 B. CYP450 2D6 C. CYP450 3A4 D. CYP450 inducers III. Classical antidepressants A. Monoamine oxidase inhibitors B. Tricyclic antidepressants IV. Selective serotonin reuptake inhibitors A. What five drugs share in common B. Pharmacologic and molecular mechanisms of action of the SSRIs C. Serotonin pathways and receptors that mediate therapeutic actions and side effects of SSRIs D. Not-so-selective serotonin reuptake inhibitors: five unique drugs or one class with five members? V. Selective noradrenergic reuptake inhibitors VI. Norepinephrine and dopamine reuptake blockers VII. Summary In this chapter, we will review pharmacological concepts underlying the use of several classes of antidepressant drugs, including the classical monoamine oxidase (MAO) inhibitors, the classical tricyclic antidepressants, the popular serotonin selective reuptake inhibitors (SSRIs), and the new selective noradrenergic reuptake 199 200 Essential Psychopharmacology inhibitors, as well as norepinephrine and dopamine reuptake inhibitors. The goal of this chapter is to acquaint the reader with current ideas about how these antide- pressants work. We will explain the mechanisms of action of these drugs by building on general pharmacological concepts. We will also introduce pharmacokinetic concepts for the antidepressants, namely, how the body acts on these drugs through the cytochrome P450 enzyme system. Our treatment of antidepressants in this chapter is at the conceptual level and not at the pragmatic level. The reader should consult standard drug handbooks for details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice. Theories of Antidepressant Drug Action Classifications Based on Acute Pharmacological Actions We do not currently have a complete and adequate explanation of how antidepressant drugs work. What we do know is that all effective antidepressants have identifiable immediate interactions with one or more monoamine neurotransmitter receptor or enzyme. These immediate actions provide the pharmacological foundation for the current classification of the different antidepressants. According to this classification scheme, there are at least eight separate pharmacological mechanisms of action and more than two dozen antidepressants. Most antidepressants block monoamine reuptake, but some block alpha 2 receptors and others the enzyme monoamine oxidase (MAO). Some antidepressants have direct actions on only one monoamine neurotransmitter system; others have direct actions on more than one monoamine neurotransmitter system. As discussed in Chapter 5, the immediate pharmacological actions of all antidepressants eventually have the effect of boosting the levels of monoamine neurotransmitters (Figs. 5 — 15 and 5 — 16; see also Fig. 6—1). This chapter and the following chapter will review those specific receptors and enzymes that are influenced by each of the various antidepressants immediately after administration to a depressed patient. Just how all these different immediate pharmacological actions result ultimately in an antidepressant response a few weeks after administration of an antidepressant agent—that is, the final common pathway of antidepressant treatment response—is the subject of intense research interest and debate (Fig. 6—1). Currently, there is intense focus on the gene expression that is triggered by antidepressants. The monoamine hypothesis of antidepressant action on gene expression suggests that gene expression is ultimately the most important action of antidepressants. The Neurotransmitter Receptor Hypothesis of Antidepressant Action One theory to explain the ultimate mechanism of delayed therapeutic action of antidepressants is the neurotransmitter receptor hypothesis of antidepressant action (Figs. 6—1 through 6—6). This is a hypothesis related to the neurotransmitter receptor hypothesis of depression discussed in Chapter 5 (Figs. 5—60 through 5— 62). As previously discussed, this latter hypothesis proposes that depression itself is linked to abnormal functioning of neurotransmitter receptors. Classical Antidepressants, Serotonin Selective and Noradrenergic Reuptake Inhibitors 201 FIGURE 6—1. This figure depicts the different time courses for three effects of antidepressant drugs, namely clinical changes, neurotransmitter (NT) changes, and receptor sensitivity changes. Specifically, the amount of NT changes relatively rapidly after an antidepressant is introduced. However, the clinical effect is delayed, as is the desensitization, or down regulation, of neurotransmitter receptors. This temporal correlation of clinical effects with changes in receptor sensitivity has given rise to the hypothesis that changes in neurotransmitter receptor sensitivity may actually mediate the clinical effects of antidepressant drugs. These clinical effects include not only antidepressant and anxiolytic actions but also the development of tolerance to the acute side effects of antidepressant drugs. Whether or not neurotransmitter receptors are abnormal in depression, the neurotransmitter receptor hypothesis of antidepressant action proposes that antidepressants, no matter what their initial actions on receptors and enzymes, eventually cause a desensitization, or down regulation, of key neurotransmitter receptors in a time course consistent with the delayed onset of antidepressant action of these drugs (Figs. 6—1 through 6 — 6). This time course coincides with other events, including the time it takes for a patient to become tolerant to the side effects of antidepressants. Thus, desensitization of some neurotransmitter receptors may lead to the delayed therapeutic actions of antidepressants, whereas desensitization of other neurotransmitter receptors may lead to the decrease of side effects over time. An overly simplistic view of the neurotransmitter receptor hypothesis of depression is that the normal state becomes one of depression as neurotransmitter is depleted and postsynaptic receptors then up-regulate (Fig. 6—2). Boosting neurotrans- mitters by MAO inhibition (Figs. 6—3 and 6—4) or by blocking reuptake pumps for monoamine neurotransmitters (Figs. 6—5 and 6—6) eventually results in the down regulation of neurotransmitter receptors in a delayed time course more closely related to the timing of recovery from depression (Figs. 6—1, 6—4, and 6—6). 202 Essential Psychopharmacology FIGURE 6—2. The neurotransmitter receptor hypothesis of antidepressant action—part 1. Shown here is the monoaminergic neuron in the depressed state, with up regulation of receptors (indicated in the red circle). FIGURE 6—3. The neurotransmitter receptor hypothesis of antidepressant action—part 2. Here, a monoamine oxidase (MAO) inhibitor is blocking the enzyme and thereby stopping the destruction of neurotransmitter. This causes more neurotransmitter to be available in the synapse (indicated in the red circle). Originally, it was hypothesized that desensitization of postsynaptic receptors may be responsible for the therapeutic actions of antidepressants. It is now clear that desensitization of some postsynaptic receptors is responsible for the development of tolerance to the acute side effects of antidepressants. Attention is currently being Classical Antidepressants, Serotonin Selective and Noradrenergic Reuptake Inhibitors 203 FIGURE 6—4. The neurotransmitter receptor hypothesis of antidepressant action—part 3. The consequence of long-lasting blockade of monoamine oxidase (MAO) by an MAO inhibitor is that the neurotransmitter receptors are desensitized or down-regulated (indicated in the red circle). FIGURE 6—5. The neurotransmitter receptor hypothesis of antidepressant action—part 4. Here, a tricyclic antidepressant blocks the reuptake pump, causing more neurotransmitter to be available in the synapse (indicated in the red circle). This is very similar to what happens after MAO is inhibited (Fig. 6-3). focused on the presynaptic receptors and their desensitization in order to explain the therapeutic actions of antidepressants. This will be discussed in more detail in the section on serotonin selective reuptake inhibitors (SSRIs). The Monoamine Hypothesis
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