Chapter 1

General Introduction

BEHAVIORAL CLASSIFICATION OF DRUGS

If the purpose of administering drugs is to change behavior, then it is useful to have a behavioral classification of drug effects to make it easier to remember the applications of different drugs and to understand the relationships between them. The following behavioral classification system, based on the one presented by Julien (1992), is suggested as a way of organizing the different drugs relevant to clinical psychopharmacology. Remember, however, that: (a) drugs have been included in a particular category because of their primary use and, if side effects are considered, many drugs could be included in several categories; (b) drug effects on behavior usually change as a function of dose and therefore some drugs could be included in other categories at some doses; and (c) drugs that have similar behavioral effects may differ in chemical structure and in the effects that they have on the nervous system (Julien, 1992). Antidepressant drugs have been excluded from "CNS stimulants" because, for the most part, they do not act as stimulants in nondepressed individuals and because they have a "mood-elevating" effect in depressed individuals rather than a general stimulant effect (Julien, 1992; see Table 1.1).

Classification of Psychological Disorders

Throughout this book, the psychological disorders discussed are classified accord­ ing to the 1994 edition of the Diagnostic and Statistical Manual of Mental Disorders ( DSM-IV; American Psychiatric Association, 1994 ). TABLE 1.1 Behavioral Classification of Drugs

CNS Depressants or Sedative-Hypnotic Compounds (Clinical applications: anxiety disorders, insomnia. epilepsy, anesthesia) • barbiturates (e.g., pentobarbital) • benzodiazepine anxiolytics and hypnotics (e.g., diazepam. triazolam) • atypical anxiolytics (e.g., buspirone) • anesthetics (e.g., chloroform) • alcohol CNS Stimulants (Clinical applications: attention deficit hyperactivity disorder [ADHD], narcolepsy, weight loss) • amphetamines (e.g., dextroamphetamine) • cocaine • caffeine • nicotine Antidepressants (Clinical applications: some anxiety disorders. unipolar depression, and other affective disorders, chronic pain) • tricyclic antidepressants (e.g., desipramine) • monoamine oxidase inhibitors (e.g., moclobemide) • atypical antidepressants (e.g., fluoxetine) Antipsychotics (Clinical applications: schizophrenia, mania, and other psychoses) • phenothiazines (e.g., chlorpromazine) • butyrophenones (e.g., haloperidol) • thioxanthines (e.g., flupentixol) • atypical antipsychotics (e.g., clozapine) • lithium Analgesics (Clinical applications: relief of pain) • opioids (e.g., morphine, heroin) • aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) • acetaminophen • adjuvant analgesics Psychedelics and Hallucinogens (Clinical applications: analgesic potential of cannabinoids) • lysergic acid diethylamide (LSD) • phencyclidine (PCP) • cannabinoids, etc. Neurological Drugs

(Clinical applications: epilepsy, Parkinson's disease, spasticity; local anesthesia) • antiepileptic drugs (e.g., carbamazepine, phenytoin, sodium valproate) • anti-Parkinsonian drugs (e.g., levodopa, bromocriptine) • antispasticity drugs (e.g., baclofen) • local anesthetics (e.g., procaine)

Note. Modified from Julien ( 1992).

2 GENERAL INTRODUCTION 3

INTRODUCTION TO GENERAL PHARMACOLOGY

Definition of Terms Pharmacology is the study of the effects of drugs on the body. Given the broad nature of its subject area, pharmacology includes a number of subdisciplines. Neuropharmacology is the subdiscipline devoted to the study ofthe effects of drugs on cells of the nervous system. Psychopharmacology is the subdiscipline devoted to the study of the effects of drugs on psychological processes and behavior. Clinical psychopharmacology is a subdiscipline of psychopharmacology con­ cerned mainly with the use of drugs to treat abnormal behavior. In this book we define the term drug as "any chemical agent that affects living processes" (Benet, Mitchell, & Sheiner, 1991a, p. 1). This broad definition includes not only exogenous chemicals that are ingested deliberately or inadvertently but also endogenous chemicals such as neurotransmitters and hormones. What all drugs have in common is that they elicit their response by acting on cellular receptors. These receptors can take many forms. Pharmacokinetics is the study of the absorption, distribution, and elimination of drugs, that is, "what the body does to the drug" (Benet et al., 1991a, p. 1). Pharmacodynamics is the study of the action of drugs at cellular receptors, that is, "what the drug does to the body" (Benet et al., 1991 a, p. 1).

PHARMACOKINETICS

Drug absorption is the process by which a drug gets from the site of administration to the blood plasma (the fluid of the blood minus the red and white blood cells; blood serum is the plasma minus the blood protein, fibrinogen, see Fig. 1.1 ). There are many different routes by which drugs may be administered. In human clinical psychopharmacology, oral administration is the most common route. The following is a brief summary of the characteristics of different routes of administration:

I. oral/swallowed: absorption from the gastrointestinal tract. This route of administration is convenient but unreliable. Most of the absorption is from the large surface area in the small intestine and if the stomach is full, absorption is delayed (hence the reduced effects of alcohol on a full stomach). Many drugs that are administered orally are subject to extensive first-pass metabolism by the liver (i.e., once absorbed from the small intestine, the drug will enter the liver via the portal circulation before entering the general systemic circulation and being distributed throughout the body). Consequently, the drug may be extensively metabolized before it reaches the target receptors. 2. oral/sublingual: under the tongue. This route results in fast absorption into the systemic circulation, bypassing the gastrointestinal tract and therefore avoiding 4 CHAPTER 1

Drug is absorbed into blood plasma and distributed throughout body.

BLCXJD 0 0~ PLASMA 0 ~~0

To act on the CNS, the drug must cross the blood brain jbarrier.

PLASMA

BLOOD BRAIN BARRIER

CNS

The amount of drug available in the CNS depends on: 1) How much drug is bound to plasma protein 2) How well the drug crosses the blood brain barrier

FIG. 1.1. Schematic diagram of the processes involved in drug absorption and distri­ bution. absorption problems and first-pass metabolism in the liver. This route is useful for patients who are likely to vomit and lose medication that was swallowed. 3. rectal: absorbed directly from the rectum. This route partially avoids first-pass metabolism by the liver and is also used for patients likely to vomit and lose swallowed medication. 4. epithelial: for example, absorption through the skin. Most drugs are poorly absorbed from unbroken skin because of its low lipid 1 solubility. However, in some cases, this route may be useful for patients likely to vomit.

1Lipids are a group of organic substances that are insoluble in water but soluble in alcohol, ether, chloroform, and so on. The complex lipids found in cell membranes consist of fatty acids (Lehninger, 1982). GENERAL INTRODUCTION 5

5. inhalation: enters the bloodstream very rapidly from the lungs. There are no absorption or first-pass metabolism problems with this route of administration; however, it is potentially dangerous because it is so fast and direct. 6. injection: several possible routes: under the skin (subcutaneous [SC ]); into muscle (intramuscular [IM]); into a vein (intravenous [IV]). Drugs administered SC or IM exert their effects more quickly than those administered orally (i.e., swallowed) but the rate of absorption depends on the rate of blood flow through the injection site. The IV route is the fastest systemic injection route and the most certain in terms of obtaining the desired concentration of the drug in the blood plasma. Because the drug is injected directly into the systemic circulation, there are no problems with absorption or first-pass metabolism. However, as with inhalation, the IV route is also potentially dangerous because it is so direct.

Bioavailability is a term used to refer to the degree to which a drug reaches its target receptors or a biological fluid (e.g., blood plasma) from which the target receptors can be reached (Benet et al., 1991a; see Fig. 1.2). e Ligand binds to receptor binding l site

r------, Binding r-----, ~ RECEPTOR

CHARACTERISTICS OF RECEPTOR BINDING

i) Saturability 0 0 0 0 0 0 Saturation occurs when all the receptors are occupied 88888

ii) Selectivity Receptors are selective for specific drugs

iii) Reversibility Binding is usually reversible

FIG. 1.2. Schematic diagram illustrating the properties of receptors. 6 CHAPTER 1

Once the drug has entered the blood plasma, it is distributed throughout the body via the systemic circulation. How much drug will be available to bind to receptors on neurons in the central nervous system (CNS) depends on how well the drug crosses the blood brain barrier-a term used to describe the low permeability of capillaries that supply the CNS with blood-and the amount of drug that binds to blood proteins2 (and therefore cannot bind to CNS receptors; see Fig. 1.1). Some drugs that are used experimentally cannot be used clinically because they cross the blood brain barrier so poorly that they can only be administered directly into the brain. Other drugs bind extensively to blood proteins and therefore much of the drug does not cross the blood brain barrier. After the drug molecules3 have acted on receptors in the CNS, they are eliminated from the body. The term elimination refers to the two processes by which drugs are eliminated from the body: (a) metabolism, performed mainly (but not exclusively) by the liver; and (b) excretion, performed mainly (but not exclusively) by the kidneys. Clearance is the term used to describe the ability of the body to eliminate a drug. Elimination half-life is the time required for the concentration of the drug in the body to decay to 50% of the initial peak concentration. Drugs usually stay in the body for approximately four to five half-lives.

PHARMACODYNAMICS

Once the drug has been absorbed into the systemic circulation and distributed throughout the body, the effect that the drug elicits depends on the extent to which it acts on the target receptors (in the case of psychoactive drugs, in the CNS). It is important to remember that drugs are not distributed only to the target receptors. Drugs are usually distributed to many parts of the body and therefore have the potential to act on receptors other than the target receptors. Adverse side effects are often the result of a drug acting on receptors other than those for which it was intended. As advances in molecular biology lead to a better understanding of the structure of receptors, it is becoming possible to design drugs that activate or block a particular receptor type more selectively. A receptor is a protein component, usually on the cell membrane, which interacts with the drug in a specific way and activates intracellular biochemical events that result in the drug effect. For example, codeine works as a pain killer (analgesic) by activating opioid receptors on neurons. A drug is said to bind to a receptor, and the specific site on the receptor to which the drug molecules bind is referred to as a

2A protein consists of 100 or more amino acids linked together by peptide bonds. Two or more amino acids linked together may be referred to as a peptide (Rose, 1985). 3An atom is the smallest particle of an element (e.g., sodium), which consists of protons, neutrons, and electrons. A molecule is a combination of atoms that is particularly stable because the maximum number of electrons has been achieved in the outer shell. For example, water (H20) is a molecule consisting of two atoms of hydrogen and one atom of oxygen (Rose, 1985). GENERAL INTRODUCTION 7 binding site. Any drug that binds to a receptor binding site can be referred to as a ligand. Receptors have a number of properties (see Fig. I.2) that distinguish them from other cellular sites that may bind a drug:

I. saturability: there are a finite number of receptors. Therefore, as the drug concentration increases, the occupation of the receptors by drug molecules increases until saturation is reached and there are no more receptors avail­ able to interact with the drug. 2. selectivity: the receptor has a high degree of selectivity for the drug (determined by the size, shape, and electrical charge of the drug molecule), rather than binding anything that is molecularly similar to it. 3. reversibility: the interaction between the receptor and the drug molecules is usually reversible.

There are four main ways in which a drug may affect cell function by acting on receptors (see Fig. 1.3):

I. a drug may bind to an extracellular receptor that directly regulates the opening of an ion4 channel (e.g., benzodiazepine anxiolytic drugs). 2. a drug may bind to an extracellular receptor linked to an intracellular enzyme via an intermediary protein (e.g., cannabis). 3. a drug may bind to an extracellular receptor on a transmembrane protein and thereby activate an intracellular enzyme.5 4. a drug may cross the lipid cell membrane and act directly on receptors in the cell nucleus (e.g., steroids).

The effects of a drug on a particular type of receptor are determined by the number and nature of the receptors, the concentration of the drug at the receptors, whether the drug acts as an agonist or antagonist at the receptors. Two important properties of receptors are their affinity and efficacy. Affinity is the avidity with which a receptor will bind a particular drug. If a receptor has a high affinity for a specific drug, then a lower concentration of that drug will be necessary to achieve full occupation of the receptors. The rate at which drug molecules bind to the receptor (given by the association constant, KA) is used as an index of the affinity of a receptor for a specific drug. In drug binding studies, KA is the drug concentration at which half the maximal number of receptors are occupied; the maximal number of binding sites is referred to as Bmax· Since the formation of a drug-receptor complex is an interaction determined by the nature of the receptor and the drug molecules, the term affinity is equally applicable to the avidity with

4An ion is an electrically charged atom or molecule (Rose, 1985). 5 An enzyme is a type of protein molecule that facilitates a particular class of chemical reactions (Rose, 1985). 8 CHAPTER 1

Drug binds to receptor which regulates opening of ion channel

Drug binds to receptor coupled to G protein which activates intracellular enzymes

Enzymes activated

Drug binds to receptor on membrane protein and activates intracellular enzymes

Enzymes activated

Drug crosses cell membrane and binds to receptors in cytoplasm

FIG. I .3. Four main categories of drug action on cells. which the receptor binds the drug or the avidity with which the drug binds to the receptor (hence, some drugs are described as having a high affinity for a particular receptor). Efficacy refers to the capacity of the receptor to elicit an intracellular effect once it has interacted with a particular drug and formed a drug-receptor complex. Given equal drug concentrations and affinities for a particular receptor, some drug-receptor interactions have a larger effect on a cell than others and therefore have greater efficacy. Although efficacy strictly refers to the effects of a specific drug-receptor complex, it is often used in reference to specific drugs; for example, a high efficacy drug is one that has a large cellular effect when it interacts with a particular receptor (see Fig. 1.4 ). A drug is referred to as an agonist if it activates a receptor in forming a drug-receptor complex or as an antagonist if it forms a drug-receptor complex but does not activate the receptor and prevents the activation of the receptor by an GENERAL INTRODUCTION 9

Agonist: drug which activates a receptor Antagonist: drug which prevents activation of a receptor

0 A full agonist has high efficacy 8 c::::J 88... ••• 0 ••• A partial agonist has low efficacy 8 c::::J 88

• ~ • • An antagonist has zero efficacy c:::!:J c::::J c:!:J c:!::J

Association constant: a measure of the affinity of a drug for the receptor

0 0 0 0 c::::Jc::::Jc::::J6 high affinity low affinity

Efficacy and affinity interact to produce the observed drug effect

high efficacy /low affinity high affinity /low efficacy

FIG. 1.4. Examples of the relationship between affinity and efficacy. agonist (antagonists are essentially zero efficacy drugs). Agonists for a particular receptor will differ not only in their affinity for the receptor but in their efficacy. A high efficacy agonist is referred to as a full agonist because it is capable of eliciting the maximal effect from receptors given sufficient concentration. By contrast, a low efficacy agonist is referred to as a partial agonist because it cannot elicit the maximal effect from receptors even at high concentrations (see Fig. 1.4). Some receptors are directly linked to ion channels in the cell membrane that allow the passage of particular ions into or out of the cell when the receptor is activated (Fig. 1.3). A flow of ions (i.e., electric current) in or out of such channels is known as a channel conductance (e.g., acetylcholine increases the inward sodium conductance through ion channels associated with the acetylcholine receptor on skeletal muscle cells). Some receptors have other binding sites in addition to the 10 CHAPTER 1

binding site for the endogenous agonist, which regulate the operation of the ion channel. These additional binding sites, known as allosteric binding sites, have a regulatory effect on the function of the receptor complex. For example, a drug binding to an allosteric binding site may alter the affinity of the primary binding site for an endogenous agonist. This is the way that benzodiazepine anxiolytic drugs act to relieve anxiety. There are also different kinds of antagonist drugs. A competitive antagonist is one that binds to the same binding site as the agonist and therefore competes with the agonist for that binding site. A noncompetitive antagonist is one that has a different binding site to the agonist and therefore does not compete with the agonist. Some noncompetitive antagonists have a binding site within the ion channel associated with the receptor complex. The effect that a drug has on a biological function, whether it is muscle contraction in vitro or some aspect of behavior, can be properly described only using a dose-response or concentration-effect curve. The reason for this is that the effect of a drug can change markedly with increasing concentration at the receptors. Also, many drugs become Jess selective for specific receptor types with increasing concentration. In order to obtain a dose-response curve, the effect of a drug on a specific variable (e.g., severity of anxiety in humans) is plotted against a range of drug doses. Although occupation of a specific type of receptor increases in a sigmoid fashion with increasing drug concentration, the effects of a drug on behavior often change in a highly complex manner with increasing drug dose (e.g., an inverted U-shaped dose-response relationship; see Fig. 1.5). The greater com­ plexity of response at the behavioral level is due to the fact that behavior is shaped by the complex interaction of large numbers of cells in the CNS, only some of which may have receptors for the drug.

INDIVIDUAL VARIATION IN DRUG EFFECT AND CHANGE IN DRUG EFFECT OVER TIME

Drugs do not affect everyone in the same way, even given exactly the same dose by the same route of administration. Differences in the way individuals respond to a drug may be due to pharmacokinetic or pharmacodynamic factors, or both (see Fig. 1.6). Pharmacokinetic explanations for variation in drug effect between indi­ viduals include differences in the absorption, distribution, and metabolism of a drug. Differences in drug metabolism are particularly important because the capac­ ity to metabolize a specific drug can vary with genetic history, age, disease, pregnancy, and environmental factors that alter liver enzyme induction. Differences in drug metabolism are important in geriatric populations in whom liver function may be reduced, resulting in substantially longer half-lives for some drugs (see chapter 9). The distribution of a drug can be affected if other drugs are being taken concurrently: If different drugs compete with one another in binding to blood GENERAL INTRODUCTION 11

Response (Drug Effect) relatiOnShip

inverted U-shape relationship

Dose (Drug Concentration)

FIG. I .5. Schematic diagram illustrating possible dose-response relationships.

( INDIVIDUAL DIFFERENCES IN DRUG ACTIONS ) I I I l PHARMACOKINETIC FACTORS ) l PHARMACODYNAMIC FACTORS j I I Absorption Dru_g_ interactions Distribution I Metabolism Receptor stare genetic factors drug history age environment disease pregnancy environment

FIG. 1.6. Factors involved in variation in drug effect between individuals.

plasma proteins, the proportion of one drug that is bound to protein may decrease, resulting in higher concentrations of the other drug in the CNS. Differences in the effect of a drug may also be due to pharmacodynamic factors such as variation in the state of neurotransmitter receptors due to different drug histories and environmental experiences. The CNS effects of a drug may be radically altered if other drugs are being taken concurrently, due to interactions between the drugs at the receptors (e.g., alcohol potentiates the sedative effects of benzodiazepines ). Even within one individual, the effect of a drug may change with repeated administration over time. The most common example of this occurs when a drug has a reduced behavioral effect with repeated administration, so that a higher dose of the drug is needed in order to obtain an effect similar to that observed on initial 12 CHAPTER 1 administration. This phenomenon is known as drug tolerance and is an example of the way in which the body attempts to adapt to repeated exposure to the drug. Drug tolerance may be due to increased metabolism of the drug by the liver (metabolic or pharmacokinetic tolerance) or to a change in the way that CNS receptors respond to the drug (junctional or pharmacodynamic tolerance; see Fig. 1.7), or both.

DRUG DEPENDENCE AND ADDICTION

Drug dependence is defined as a condition in which abstinence from taking a drug results in a withdrawal syndrome. The symptoms that constitute the withdrawal syndrome may vary from autonomic effects (e.g., increased heart rate [HR], sweating) to cognitive-affective symptoms (e.g., severe anxiety about people or situations). Traditionally, a distinction has been made between physicaVphysi­ ological and psychological withdrawal symptoms. However, if one accepts the view that all psychological symptoms are mediated by CNS function, this distinc­ tion cannot be sustained: Autonomic and cognitive withdrawal symptoms are just different types of physiological symptoms.

increasing number of exposures

down regulation 000~000 of receptors ~

reduced affinity

reduced efficacy ~~0~ ~~0~ www ~~ ~~ ~~

increasing number of exposures

FIG. 1.7. Schematic illustration of the way in which down-regulation, or reduced receptor affinity or efficacy, may underlie pharmacodynamic drug tolerance. GENERAL INTRODUCTION 13

The term drug addiction is more difficult to define than drug dependence. Some authors suggest that drug addiction should be defined as an overwhelming reliance on a drug, such that a person's entire life is dominated by the pursuit of fulfilling the need for that drug (Jaffe, 1991).

SUGGESTED READINGS

Julien, R. M. (1992). A primer of drug action (6th ed.). New York: Freeman. Neal, M. J. (1988). Medical pharmacology at a glance. Oxford: Blackwell Scientific. Rang, H. P., Dale, M. M., & Ritter, J. M. (1995). Pharmacology (3rd ed.). Edinburgh: Churchill Livingstone. Chapter 2

Introduction to Neurophysiology and Neuropharmacology

Most drugs affect the nervous system by modulating chemical or synaptic trans­ mission between nerve cells (neurons). Drugs may mimic the effect of certain neurotransmitters (i.e., act as agonists), block their effects (i.e., act as antagonists), alter their synthesis or release, or alter the processes by which they are metabolized after they have acted on the postsynaptic neuron. Therefore, in order to understand how drugs affect the nervous system, it is necessary to understand something of the neurotransmitter systems they modulate.

INTRODUCTION TO NEUROPHYSIOLOGY

For a detailed review of neurophysiology, the reader should consult a comprehen­ sive text (e.g., Kandel & Schwartz, 1985). The following is a brief overview of the neurophysiology that is essential in order to understand the neuropharmacology discussed in this book. The peripheral nervous system consists of afferent nerve cells or neurons that communicate information from receptor cells in sensory organs (e.g., the eyes) to the brain and spinal cord (collectively known as the CNS), and efferent neurons that send commands from the CNS to muscles and glands that produce responses to environmental stimulation. The purpose of the CNS is to coordinate and integrate information coming from the sensory systems in order to formulate the appropriate motor commands to send to muscles and glands. Groups of afferent and efferent neurons in the peripheral nervous system are known as ganglia.

14 NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 15

The CNS consists of the spinal cord and brain. The brain may be divided into three major subdivisions: the cerebrum and diencephalon, the cerebellum, and the brainstem. The cerebrum consists of the cerebral cortex or neocortex, which constitutes the largest part of the human brain; it is extremely complex and is responsible for higher cognitive functions and voluntary behavior. The diencephalon includes the basal ganglia, limbic system, thalamus, and hypothalamus. The basal ganglia or striatum is an area that is important in the planning of motor activity and in motor control. The limbic system, which includes major structures such as the hippocampus, amygdala, and the mammillary bodies, is one of the most studied areas of the brain. The limbic system is important in learning and memory, in emotion, and is implicated in the mechanisms of psychiatric disorders as well as epilepsy and Alzheimer's disease. The thalamus is often described as a sensory relay center, because it transfers information from the spinal cord, the inner ear, and the retina, to the cerebral cortex. The hypothalamus contributes to the control of feeding, drinking, regulation of water balance and body temperature, and the control of sexual behavior. The cerebellum is one of the most important structures for the coordination of movement. It fine tunes the timing and pattern of muscle activation during move­ ments and is also important in the modification of eye movement reflexes. The brainstem consists of the midbrain, medulla, and pons. The midbrain consists of the superior and inferior colliculi and the reticular formation, pe­ riaqueductal gray, the red nucleus, the substantia nigra, the locus coeruleus, and the ventral tegmental area. Many of these structures are involved in the processing of sensory information and the coordination of muscle activity. The reticular forma­ tion includes the ascending reticular activating system, which is involved in the control of arousal. The substantia nigra is the area of the brain where cell death occurs in Parkinson's disease. The locus coeruleus is one of the major sources of norepinephrine for the neocortex, while the ventral tegmental area supplies the limbic system and neocortex with dopamine. The medulla and pons include many nuclei concerned with autonomic function, sensory function, and reflexive motor control. Finally, the spinal cord contains afferent neurons that transmit information from the body (via afferent nerve fibers) to the brain and motor neurons that transmit commands from the brain to muscles and glands. The fine tracts in the spinal cord are divided into the dorsal horn, which carries sensory information to the brain, and the ventral horn, which carries motor commands from the brain to the body. The two major types of cells in the CNS are neurons, and glial cells, which act as supporting cells to neurons. There are several types of glial cells, including astrocytes, microglia, and oligodendrocytes. As well as acting as a physical support to neurons, astrocytes and microglia clean up neuronal debris resulting from injury in a process known as phagocytosis. Astrocytes also provide neurons with nutrients. Oligodendrocytes are the glial cells that form the myelin sheath around the axons of some neurons. 16 CHAPTER2

The general structure of neurons is ;:;imilar to that of other cells of the body (see Fig. 2.1 ). It consists of a cell membrane that delineates the boundaries of the cell. The membrane itself consists of a double layer of lipid (i.e., a lipid bilayer) which is studded with specialized protein molecules of various sorts. Inside the membrane is the intracellular fluid (cytoplasm) of the cell, which contains a variety of chemicals and some organelles, including mitochrondria (critical to the energy production of the cell), endoplasmic reticulum (involved in the transport of chemi­ cals in the cytoplasm; rough endoplasmic reticulum contains ribosomes, which are the sites for protein synthesis in the cell) and Golgi apparatus (which arranges the proteins into various types of specialized membranes used by neurons, e.g., synaptic vesicles). The nucleus of the cell is itself surrounded by a nuclear membrane, which

distal dendrites

DENDRITES

SOMA

initial seg ment

AXON

FIG. 2.1. Basic anatomy of a neuron. NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 17 is also a lipid bilayer. Inside the nucleus, the nucleolus produces the cell's ribo­ somes, which are then transferred to the cytoplasm for distribution within the cell. The chromosomes, consisting of strands of deoxyribonucleic acid (DNA), store the genetic code for the organism. Protein synthesis occurs when parts of the chromo­ somes, called genes, produce messenger ribonucleic acid (mRNA), which exits the cell nucleus and binds to the ribosomes in rough endoplasmic reticulum. The production of mRNA, which carries the code from the DNA, is referred to as protein transcription. Neurons consist of three main parts: the dendrites, which receive input from other neurons via synaptic transmission; the soma (cell body), which may also receive synaptic input from other neurons and which integrates information from the dendrites and contains the nucleus of the cell; and the axon, which transmits information to other neurons (Fig. 2.1 ). Groups of neuronal somata in the CNS are referred to as nuclei (e.g., the nucleus of the solitary tract). The term synapse refers to the apposition of an axon terminal of one neuron (the presynaptic neuron) and a part of the dendrite or soma of another neuron (the postsynaptic neuron); tiny packets of neurotransmitter (quanta) are released from the presynaptic axon terminal and bind to receptors on the postsynaptic neuron. Synapses on cell somata are referred to as a.xo-somatic synapses. Synapses on dendrites are referred to as a.xo-dendritic synapses. Where the pre-and postsynaptic neurons are apposed, the postsynaptic neuron has postsynaptic densities that include the receptors for the neurotransmitter which is released. Where synapses are axo-dendritic, dendrites have specialized protuberances called dendritic spines, which form a synapse with the presynaptic axon terminal. In some cases, there are also synapses on presynaptic nerve terminals, where presynaptic receptors regulate the release of neurotransmitter (autoreceptors; see Fig. 2.2).

terminal

vessicles

'presynaptic receptors 0 SYNAPTIC CLEFT 0 0 0 (autoreceptors)

postsynaptic density

POSTSYNAPTIC NEURON

FIG. 2.2. The structure of a synapse. 18 CHAPTER 2

Neurons are distinguished from other cell types in the body by their degree of electrical excitability. When a neuron is at rest electrically, the interior of the cell near the cell membrane is electrically negative with respect to the extracellular fluid by virtue of the high concentration of negative ions inside the cell and the high concentration of sodium ions outside the cell. The neuron therefore has a resting potential of about -70 mV. When neurotransmitter binds to receptors on the dendrites or soma, it may cause changes in the electrical excitability of the neuron. Some transmitters may increase the intracellular negativity ofthe neuron by causing inhibitory postsynaptic potentials (IPSPs); such transmitters are said to have an inhibitory effect on the neuron. Other transmitters may increase the intracellular positivity of the neuron by causing excitatory postsynaptic potentials ( EPSPs); such transmitters are said to have an excitatory or depolarizing effect on the neuron. EPSPs and IPSPs are often induced in dendrites and these electrical changes are, in many cases, transmitted passively to the soma in a process called passive conduction. Under these circumstances, the further the signal has to travel, the more degraded it becomes. However, when a sufficient number of EPSPs summate, voltage-sensitive sodium channels in the soma are opened and a large influx of sodium occurs, leading to a large increase in intracellular positivity relative to the extracellular fluid. This event is known as an action potential (see Fig. 2.3). The action potential is regenerative, being sequentially induced at various points along the axon as it travels toward the axon terminals. In many neurons, the axon is insulated with a myelin sheath formed by oligodendrocytes, which helps to preserve the integrity of the electrical signal. The myelin sheath is interrupted at various points along the axon (known as nodes of Ranvier) and the process by which the action potential jumps from one node of Ran vier to the next is referred to as saltatory conduction. Once the action potential reaches the axon terminals, it causes an influx of calcium ions that leads to the release of the neuron's own neurotransmitter(s).

INTRODUCTION TO NEUROPHARMACOLOGY

The term neurotransmitter was originally reserved for endogenous chemicals that produce fast effects (i.e., on a time scale of milliseconds) on neurons (e.g., a change in the conductance of an ion channel that alters the excitability of the neuron). The term hormone was reserved for endogenous chemicals released into the systemic circulation, often far from the site of action, which produced slower effects (i.e., on a time scale of minutes to hours). However, increasingly it has been found that some fast chemical mediators, in addition to altering ionic conductance, have 'slow' effects on cells and that some chemical mediators that are released far from the site of action have some fast effects. Consequently, the distinction between neurotrans­ mitters and hormones has started to break down; in recognition of this changing view, many hormones are now referred to as neuromodulators. Currently, there are at least 50 chemical mediators that are suspected to function as neurotransmitters NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 19

2 3 4 5

time (seconds)

50 100 150 200

FIG. 2.3. Examples of extracellularly recorded action potentials from a single CNS neuron. Top: fast sampling speed showing action potential waveform. Bottom: slow sampling speed showing a series of action potentials from a single neuron. and for each transmitter there are usually several receptor subtypes that the endogenous ligand(s) will activate (i.e., the one key that opens many locks). Despite the large number of putative neurotransmitters, many pharmacologists prefer to reserve the term neurotransmitter for chemical mediators that have satisfied the following conditions (known as "Dale's criteria"; see Fig. 2.4):

1. the chemical must exist in the presynaptic terminals of some neurons, 2. the chemical must be released from the presynaptic terminals when the presynaptic neuron is stimulated, 3. experimental application of the chemical to the postsynaptic neuron must have the same synaptic effect as occurs when the chemical is released endogenously, 4. there must exist some mechanism for metabolizing the chemical once it has acted on the postsynaptic neuron and the time scale of this metabolic activity 20 CHAPTER2

i) the chemical must exist in presynaptic terminals

ii) the chemical must be released from presynaptic terminals

iii) the experimentally applied chemical must have the same effect as the endogenous chemical

iv) there must be a mechanism for metabolizing the chemical

v) antagonists must block both the endogenous and the applied chemical

FIG. 2.4. Dale's criteria for establishing that a particular neurochemical is a neuro­ transmitter.

must correspond to the time scale of the postsynaptic action of the chemical, and 5. antagonist drugs that block the effects of the chemicat when it is applied to the postsynaptic neuron experimentally must also have an antagonistic effect when the chemical is released endogenously (modified from Julien, 1992)

These criteria are not always easy to satisfy in the case of the CNS, where structures can be difficult to isolate. Consequently, the number of chemical media­ tors that have been accepted as true neurotransmitters is relatively small. Any review of neurotransmitter receptors rapidly becomes obsolete. The number of known receptors is increasing all the time and the journal Trends in Pharma­ cological Sciences (TiPS) publishes an annual update on receptor classification in order to keep readers informed about the latest developments. For the very latest NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 21 information on receptor and ion channel classification, refer to the current TiPS supplement on receptor and ion channel nomenclatures (Watson & Girdlestone, 1996). The following is a brief, elementary introduction to the best characterized neurotransmitter receptors.

SOME MAJOR NEUROTRANSMITTERS IN THE CNS

Inhibitory Amino Acids

Gamma-Aminobutyric Acid (GABA). GABA is synthesized from gluta­ mate by the enzyme, glutamic acid decarboxylase (GAD), and is metabolized by reuptake into presynaptic terminals. GABA is the major inhibitory transmitter in the brain; therefore GABA-containing neurons are widely distributed and are relevant to most CNS functions. There are two main subtypes of GABA receptor, the GABAA and GABAB subtypes. However, it is becoming apparent that there are also subtypes of the GABAA receptor. Activation of the GABAA receptor causes inhibition postsynap­ tically by increasing chloride conductance. GABAA receptors have an allosteric binding site for benzodiazepines, which acts to increase the affinity of the GABAA binding site for GABA and thereby increases its inhibitory effect. Binding of GABA to the GAB As receptor causes inhibition postsynaptically by increasing potassium conductance. Presynaptically, GAB As receptors can mediate inhibition by reducing calcium conductance. There is also evidence that GABA8 receptors can mediate a decrease in the concentration of the second messenger, cyclic adenosine monophosphate (cAMP; see section on biochemical effects of drugs). Many drugs that affect GABA transmission are used clinically. Probably the best known of these are the benzodiazepine anxiolytic (i.e., anxiety-reducing) and hypnotic (i.e., sleep-inducing) drugs that potentiate GABAergic transmission (via the GABAA receptor) and therefore increase CNS inhibition. Barbiturate anesthet­ ics, steroids, and alcohol also act on the GABAA receptor. Baclofen is a GABA8 receptor agonist that is used to reduce muscle spasms and spasticity.

Glycine. Glycine is synthesized from serine in the CNS and is metabolized by reuptake into presynaptic terminals. Glycine is found in many parts of the brain but is particularly abundant in the spinal cord. Some glycine receptors are sensitive to the antagonist strychnine and some are not. The strychnine-sensitive glycine receptors mediate inhibition, whereas the strychnine-insensitive glycine receptors exist as allosteric binding sites on N­ methyl-D-aspartate (NMDA) receptors, a subtype of excitatory amino acid receptor. In the latter case, glycine actually increases the affinity of the NMDA receptor for its agonist and thereby increases the excitatory effect. 22 CHAPTER2

The strychnine-sensitive glycine receptor mediates inhibition by increasing chloride conductance. Glycine is especially important in motor control and is released by interneurons in the spinal cord. Recently it has been discovered that glycine activation of the strychnine-insensitive glycine binding site on the NMDA receptor is a necessary corequisite for activation of the NMDA receptor by glutamate. Because the NMDA receptor is widely distributed throughout the CNS, glycine may also make an important contribution to some functions mediated by excitatory amino acid transmitters such as glutamate.

Excitatory Amino Acids

L-G/utamate and L-Aspartate. L-glutamate and L-aspartate are naturally occurring amino acids in the CNS and are metabolized by reuptake into presynaptic terminals. Glutamate is considered to be the major excitatory transmitter in the CNS and consequently most CNS neurons are excited by it. Glutamate-containing neurons are distributed throughout the CNS. Currently, there are four different subtypes of excitatory amino acid receptors:

1. kainate; 2. D,L-a-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA); 3. N-methyl-D-aspartate (NMDA); and 4. metabotropic.

Glutamate and aspartate have different affinities for the different excitatory amino acid receptor subtypes. The kainate and AMPA receptors mediate fast excitation by increasing sodium conductance. The NMDA receptor mediates slow excitation mainly by increasing calcium conductance. The NMDA receptor is unusual in that its activation is both chemically and voltage-gated: The agonist binding site must be occupied by an excitatory amino acid but the postsynaptic neuron must also be depolarized in order to relieve a blockade of its associated calcium channel by magnesium ions. The control of the NMDA receptor complex by neurotransmitters and voltage confers on it unique properties that are thought to be important in the induction of associative learning in the CNS. The metabotropic receptor subtype is the least understood of the excitatory amino acid receptors. Currently, there are eight identified subtypes of the metabotropic receptor subtype (mGluR 1-mGluR8); many of them mediate decreases in the concentration of cAMP or the activation of phosphoinositide metabolism. Drugs that act as noncompetitive antagonists at the NMDA receptor (e.g., ketamine hydrochloride) have been used as dissociative anesthetics in humans, although they are now used mostly as veterinary anesthetics. Some NMDA antago­ nists have also been investigated as potential treatments for stroke (e.g., MK-801). Because of their ubiquitous distribution, the excitatory amino acid transmitter NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 23

systems are relevant to most CNS functions. The NMDA receptor has become well-known for its contributions to CNS plasticity, both in relation to adaptive changes associated with learning and memory and maladaptive changes associated with disorders such as epilepsy.

Acetylcholine (ACh) Acetylcholine is synthesized from choline by the enzyme, choline acetyltrans­ ferase (ChAT), and is metabolized by acetylcholinesterase (AChe), an enzyme that is present in the postsynaptic membrane. ACh is the transmitter used at neuromus­ cular synapses; it is also used in the autonomic nervous system. Cholinergic neurons are widely distributed throughout the brain. However, the three main sources of ACh in the brain are the caudal group of neurons in the reticular formation, the magnocellular forebrain bundle and the septum (see Fig. 2.5). There are two main subtypes of ACh receptor, the muscarinic and nicotinic receptor subtypes. Within these subtypes there are still further subtypes: four muscarinic subtypes and three nicotinic subtypes. ACh usually has an excitatory effect, which can be mediated by the muscarinic or nicotinic receptor subtypes. Most CNS responses to ACh are mediated by muscarinic receptors. When ACh causes an inhibitory effect, this is also mediated by the muscarinic subtype and is probably due to increased potassium conductance (via the M2 muscarinic subtype). Some muscarinic receptors also mediate a reduction in cAMP concentrations or activation of phosphoinositide metabolism. Nicotinic receptors mediate excitation by increasing sodium conductance (e.g., the action of ACh on skeletal muscle). Muscarinic ACh antagonists such as benzotropine mesylate are used in the treatment of Parkinson's disease. Some drugs (e.g., tacrine) that inhibit AChe have

CEREBRUM AND DIENCEPHALON

CEREBELLUM

caudal group

BRAINSTEM

FIG. 2.5. Schematic diagram illustrating major cholinergic pathways in the CNS. 24 CHAPTER2 been used to improve memory in patients with Alzheimer's disease, although, at present, it is not clear how useful this form of therapy is (see chapter 9). Cholinergic synapses have many different functions in the CNS: They mediate input to Renshaw cells in the spinal cord; they are also believed to contribute to arousal and learning, and to motor control.

Catecholamines: Norepinephrine and Dopamine

Norepinephrine (NE). Norepinephrine (also known as Noradrenaline) is synthesized from its amino acid precursor, tyrosine, through a series of enzymatic steps. Dopamine is produced in this process, and further enzymatic action converts it to NE. NE is metabolized by monoamine oxidase (MAO, type A) and catechol- 0-methyltransferase (COMT), when it is taken up by presynaptic nerve terminals. The cell bodies of NE neurons are found only in cell groups in the pons (A5, A6 [the locus coeruleus], and A7) and medulla (AI and A2) of the brainstem. Their axons branch into many parts of the brain and spinal cord (Fig. 2.6). The central tegmental tract (from AI, A2, A5, and A7) and the dorsal tegmental bundle (from the locus coeruleus) together form the medial forebrain bundle that carries NE into the forebrain. There are two main subtypes of NE receptor (sometimes referred to as adreno­ ceptors): a and~ receptors. There are also many subtypes of a (seven) and ~(three) receptors. NE can have inhibitory or excitatory effects on neurons, depending on the subtype of NE receptor involved and the type of CNS neuron on which it is located. NE can cause increased cAMP concentrations by acting on ~ adrenocep­ tors. It can also cause decreased cAMP concentrations and reduced calcium

CEREBRUM AND DIENCEPHALON

CEREBELLUM

BRAINSTEM

FIG. 2.6. Schematic diagram illustrating major norepinephrine pathways in the CNS. NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 25 conductances by acting on some az adrenoceptors; a1 adrenoceptors can mediate activation of phosphoinositide metabolism. The a adrenoceptor antagonist, prazosin, is used to reduce high blood pressure (hypertension). The ~ antagonist, a-methylpropanolol, is used to reduce physi­ ological tremor (i.e., it is a~ blocker). Many drugs that inhibit the reuptake of NE into presynaptic terminals (e.g., tricyclic antidepressants such as desipramine) or the metabolism of NE in the presynaptic terminals (e.g., MAO inhibitors such as moclobemide) are used to treat clinical depression. The NE system is important in reinforcement and mood, arousal, and the regulation of blood pressure. Dopamine (DA). Dopamine is synthesized from the amino acid precursor, tyrosine, and is metabolized by MAO (types A and B) and COMT. All DA-con­ taining neurons exist in cell groups in the midbrain (the substantia nigra pars compacta and the ventral tegmental area). There are three main dopamine pathways (see Fig. 2.7):

I. the nigrostriatal pathway, running from the subtantia nigra pars compacta to the striatum (this pathway contains about 75% of the DA in the brain). 2. the mesolimbic and mesocortical pathways, running from the ventral teg­ mental area to the limbic system and neocortex (respectively). 3. the tuberinfundibular pathway, running from the hypothalamus to the pituitary gland.

At present, five subtypes of DA receptor have been identified, although little is known about three of them. The Dz subtype has been implicated in the mechanism by which antipsychotic drugs exert their therapeutic effects (although this idea has

CEREBRUM AND DIENCEPHALON

CEREBEULUM

BRAINSTEM

FIG. 2.7. Schematic diagram illustrating major dopaminergic pathways in the CNS. 26 CHAPTER 2

been challenged recently; see chapter 5). Activation of the D 1 receptor subtype causes an increase in cAMP concentrations. Activation of D2 receptors can cause a decrease in cAMP, an increased potassium conductance and a reduced calcium conductance. Much is still unknown about the DA receptor family. Most antipsychotic drugs act as antagonists for the DA receptor (many for the D2 subtype). Some DA agonists such as bromocriptine are used in the treatment of Parkinson's disease. The DA nigrostriatal system is important in motor control, as demonstrated by disorders such as Parkinson's disease, in which a loss of DA-containing neurons in the substantia nigra pars compacta causes severe rigidity, tremor, and hypokinesia (reduced movement). The mesolimbic and mesocortical DA systems are thought to be involved in cognition: Disorders in these systems are probably part of the neurochemical basis of schizophrenia. The tuberoinfundibular DA system regulates prolactin and growth hormone secretion. There is evidence that DAis also involved in the generation of nausea and vomiting.

Serotonin Serotonin (also known as 5-Hydroxtryptamine or 5-HT) is synthesized from the amino acid, tryptophan, through a series of enzymatic steps. It is metabolized by MAO (type A) via reuptake into presynaptic terminals. The location of serotonin­ containing neurons is similar toNE-containing neurons: large groups of cells in the pons and medulla of the brainstem, sometimes referred to as the raphe nuclei. The rostral raphe nuclei project serotonin into the neocortex, limbic system, hypothala­ mus, and cerebellum, via the medial forebrain bundle, in a similar way to norepinephrine (see Fig. 2.8).

CEREBRUM AND DIENCEPHALON

CEREBELLUM

caudal 5HT nuclei

BRAINSTEM

FIG. 2.8. Schematic diagram illustrating major serotonergic pathways in the CNS. NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 27

At present there are 14 subtypes of serotonin receptor. Serotonin can cause many different effects (e.g., increasing potassium conductance, increasing or decreasing cAMP, activating phosphoinositide metabolism), depending on the serotonin re­ ceptor subtype with which it interacts. The mechanisms responsible for these effects are poorly understood. Buspirone, a drug used in the treatment of anxiety and depression, is thought to act as an agonist at a serotonin receptor subtype (5-HT,A). Many antidepressants used in the treatment of clinical depression inhibit the reuptake (tricyclic antide­ pressants) or metabolism (MAO inhibitors) of serotonin. Serotonin pathways contribute to the control of sleep and mood, motoneuron function, sensory transmission (e.g., pain), autonomic and endocrine function.

Peptides A peptide consists of two or more amino acids that are linked. For example, adrenocorticotropic hormone consists of 39 amino acid residues. Some large peptides may be broken down in the CNS in order to exert their effect on neuronal receptors. Peptides containing more than 100 amino acids are referred to as proteins. During the last 20 years, a large number of peptides have been discovered. It is still unclear how many of them may function as neurotransmitters or neuromodu­ lators in the CNS. Peptides that are currently being studied as potential neurotrans­ mitters or neuromodulators in the nervous system include: adrenocorticotropic hormone (ACTH), angiotensin, antidiuretic hormone (ADH), bombesin, bradykinin, calcitonin gene-related peptide (CGRP), carnosine, cholecystokinin, corticotropin-releasing factor (CRF), dynorphin, the endorphins (e.g., beta-endor­ phin) and enkephalins (met- and leu-enkephalin), gastrin, growth hormone, insulin, kyotorphin, lipotropin, luteinizing-releasing hormone (LRH), melanocyte-stimu­ lating hormone (MSH), motilin, neuropeptide Y, neurotensin, oxytocin, pancreatic polypeptide, proctolin, secretin, substance P, somatostatin, substance K, thy­ rotropin-releasing hormone (TRH), and vasoactive intestinal polypeptide (VIP). The opioid peptides, which include the endorphins, enkephalins, dynorphin, and kyotorphin, are naturally occurring opioids that bind to opioid receptors in the CNS. It is clear that the enkephalins are involved in the response to pain, and many opioid analgesics bind to the same receptors as enkephalins. A number of peptides have been shown to be colocalized with classical neuro­ transmitters in the brain (Fig. 2.9). It is now generally accepted that one of the functions of peptides may be as cotransmitters, modulating the actions of transmit­ ters such as DA, NE, serotonin, ACh, and GABA.

INTRINSIC PROPERTIES OF CNS NEURONS

Up to now we have considered only ion channels in neuronal membranes that are directly linked to receptors for neurotransmitters. These receptor-operated chan- 28 CHAPTER 2

AMINO ACIDS

10 receptor subtypes

( QUATERNARY AMINES ) ( ACETYLCHOUNE ) 7 receptor subtypes

NOREPINEPHRINE

CA TECHOLAMINES 11 receptor subtypes

DOPAMINE

5 receptor subtypes

( INDOLAMINES ) ( SEROTONIN ) 14 receptor subtypes

FIG. 2.9. Summary of neurotransmitter receptor classification. nels (ROCs) are chemically gated and therefore can be opened only when transmit­ ter molecules bind to their binding site on the receptor complex. Another class of ion channels, known as voltage-operated channels (VOCs), are not chemically gated but voltage-gated-they open when a certain voltage exists across the neuronal membrane (Fig. 2.1 0). VOCs are sometimes described as intrinsic prop­ erties. As described previously, the NMDA receptor is unusual in that it is both chemically and voltage-gated. There are many different types of voltage-operated ion channels. The voltage­ operated sodium channel that is responsible for the regenerative action potential is one example. These sodium channels are closed when the neuron is at rest; however, given a certain level of depolarization, they open and bring about an action potential. There are other VOCs that are responsible for repolarizing the neuron following the occurrence of an action potential (potassium channels), and still others that reinforce or otherwise modulate potentials produced by ROCs (e.g., different types of calcium channels). The entire category of voltage-operated ion channels can be viewed as a form of amplification for the effects of synaptic transmission. Some VOCs, such as regenerative sodium channels, confer on certain types of neurons a NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 29

RECEPTOR OPERA TED CHANNEL (ROC)

receptor unbound receptor bound

channel closed channel opens

VOLTAGE OPERATED CHANNEL (VOC)

resting membrane membrane potential depolarized

channel closed channel open

Cl e •

FIG. 2.10. Schematic illustration of receptor-operated and voltage-operated ion channels.

property known as autorhythmicity, resulting in a steady rate of action potential generation even in the absence of synaptic input (Liinas, 1988). In this case, the effect of synaptic input is to modulate this intrinsic activity. Intrinsic properties are significant for drug action for two reasons. First, some drugs directly modulate the activity of certain VOCs. For example, dihydropyridine drugs, some of which are used in some types of cardiac therapy (e.g., nifedipine), can block L-type voltage-operated calcium channels in neurons. Another example is the tetrodotoxin secreted by the Japanese Puffer fish, which blocks all voltage­ operated sodium channels, and if ingested, rapidly leads to death. Second, by changing the voltage across a neuronal membrane via action on ROCs, drugs may indirectly affect VOCs; therefore part of their effect will be mediated by the latter. For example, if an ACh receptor agonist causes depolarization due to action on ACh receptor-mediated ion channels, then this increased level of depolarization may result in the opening of NMDA receptor-mediated calcium channels, thus reinforcing and amplifying the effect initiated by the ROCs.

BIOCHEMICAL EFFECTS OF DRUGS

In addition to the effects of drugs on neurotransmitter receptors and voltage-oper­ ated ion channels, many drugs affect the biochemical pathways operating within neurons. Traditionally, the subdiscipline of neuropharmacology has dealt primarily with the receptor effects of drugs and has therefore been distinct from the study of the biochemical events occurring within neurons. However, neuropharmacology and the biochemistry of neurons (neurochemistry) are increasingly overlapping 30 CHAPTER 2 fields of study. Some drug receptors (e.g., for steroids) are located in the cytoplasm rather than on the cell membrane. Many drugs affect complicated enzyme pathways within neurons (e.g., some ACh, NE, DA, serotonin, and peptide receptors). It is becoming clear that many of the long-term effects of neurological and psychiatric drugs are due to biochemical changes within neurons such as modification of existing protein and synthesis of new protein. As mentioned in chapter 1 in the section on pharmacodynamics, there are several ways that a drug can act on a cell. In the case of many of the drugs that we examine in the following chapters, the drug molecules bind to a binding site on a receptor complex that includes an ion channel; this process results in the opening of the ion channel and a rapid influx or efflux of ions. Although many drugs produce rapid changes in cell excitability in this way, others exert their effects via more indirect and slower routes. When a neurotransmitter or neuromodulator alters biochemical activity within the postsynaptic neuron, this usually happens via an intracellular second messenger. If the neurotransmitter is considered to be the "first messenger," then the "second messenger" can be thought of as the second component of the signaling system, operating within the neuron. The activation of a second messenger following receptor activation usually (but not always) occurs via a G protein, which can be conceptualized as a mechanical link between the binding site and the second messenger. For example, cannabis inhibits the production ofthe second messenger, cAMP, via an inhibitory G protein. In 1994, AI Gilman and Martin Rodbell were jointly awarded the Nobel Prize in medicine and physiology for their elucidation of the mechanism of action of G proteins. Three very important second messengers are cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) and calcium. The actions of these second messengers are not totally independent; interactions may take place between them. In the context of neurological and psychiatric drugs, cAMP and calcium are particularly important. In the case of cAMP, activation of the receptor (e.g., the ~-adrenergic receptor) by a neurotransmitter (NE) results in the activation of a G protein, which causes the enzyme adenylate cyclase to stimulate the conversion of adenosine triphosphate (ATP) to cAMP. ATP is an intracellular molecule that is manufactured by the mitochondria within cells and is used to transfer energy via the movement of phosphate groups from one molecule to another. Hence, A TP is converted to cAMP by the transfer of phosphates. cAMP produces its intracellular actions via an enzyme known as a protein kinase, which transfers a phosphate group from A TP to a protein. This process of phosphate transferral to a substrate protein is known as protein phosphorylation (Fig. 2.11). Protein phosphorylation is one of the most rapid and important biochemical events in the nervous system. Through phosphorylation of proteins that are part of receptors or voltage-operated ion channels, it is possible to alter neuronal function within seconds or minutes. Phosphorylation is known to be critical to the long-term effects of many neurological and psychiatric drugs. In the NEUROPHYSIOLOGY AND NEUROPHARMACOLOGY 31

protein phosphorylation

protein dephosphorylation

~ein phosphatase .J

FIG. 2.1 I. Schematic diagram illustrating the cascade of biochemical events involved in phosphorylation initiated by cAMP. case of cAMP, only one type of protein kinase is engaged in phosphorylation-so­ called cAMP-dependent protein kinase. The phosphorylation process can be re­ versed through de-phosphorylation, caused by protein phosphatases. cAMP itself is inactivated by phosphodiesterases (Fig. 2.11). The intracellular effects of calcium are rather more complicated than those of cAMP. Calcium activates protein kinases in association with calmodulin or diacyl­ glycerol. In the case of calcium/calmodulin, there are five known calcium/cal­ modulin-dependent protein kinases and probably several others that are associated with calcium/calmodulin. Some of the calcium/calmodulin-dependent protein ki­ nases are highly specific for the proteins that they phosphorylate, while others appear to phosphorylate a number of proteins. In the case of the calcium/diacyl­ glycerol pathway, only a single protein kinase is activated-protein kinase C (see Fig. 2.12). In some cases, activation of the NMDA receptor by glutamate results not only in increased depolarization of the postsynaptic neuron, as a result of calcium influx, but activation of calcium-dependent protein kinases such as protein kinase C. 32 CHAPTER2

2nd MESSENGER PROTEIN KINASE

( cAMP 1------_..,. ( cAMP-dependent protein kinase )

( cGMP 1------_..,. ( cGMP-dependent protein kinase )

multiple I calmodulm ~ calcium/calmodulin-dependent protein kinases

~.------.I diacylglycerol~ (~.__:_Pr_o_te_in_k_in_a_se_c____ ~

FIG. 2.12. The relationship between specific second messengers and their protein kinases.

Protein phosphorylation via the cAMP or calcium pathways can rapidly achieve a number of objectives, such as the alteration of synapses, the opening or closing of ion channels, or the release of neurotransmitter. However, protein phosphoryla­ tion may also lead to the synthesis of new protein. In this case, the protein kinase enters the cell nucleus and phosphorylates a nuclear regulatory protein associated with DNA, resulting in mRNA transcription and the synthesis of new protein in the ribosomes of rough endoplasmic reticulum. Through protein phosphorylation and protein synthesis, drugs can exert effects on CNS neurons long after the drug has been eliminated from the body and the initial electrical changes induced by the drug have subsided.

SUGGESTED READINGS

Aidley, D. J. (1989). The physiology of excitable cells (3rd ed.). Cambridge: Cambridge University Press. Cooper, J. R., Bloom, F., & Roth, R. (1991). The biochemical basis ofneuropharmacology (6th ed.). New York: Oxford University Press. Kandel, E. R., & Schwartz, J. H. (Eds.). (1985). Principles ofneural science (2nd ed.). New York: Elsevier. Rang, H. P., Dale, M. M., & Ritter, J. M. (1995). Pharmacology (3rd ed.). Edinburgh: Churchill Livingstone. Chapter 3

Drug Treatment for Anxiety Disorders

BACKGROUND INFORMATION

According to the DSM-IV (American Psychiatric Association, 1994 ), anxiety is a psychological condition that can result in any or all of the following behavioral symptoms: increased muscle tension, shortness of breath, rapid heart beat (i.e., tachycardia), dizziness, tingling skin (i.e., parathesias), restlessness, frequent urination and/or diarrhea, trembling, difficulty concentrating, sweating, insomnia, a sense of unreality, and nervousness. Most people experience these symptoms at one time or another, as a normal reaction to the stresses of life. However, when these symptoms persist and/or are particularly severe, an anxiety disorder may exist. Within the DSM-IV classification system there are 14 main categories of anxiety disorder:

I. Panic Attack: a discrete attack of panic characterized by feelings of severe apprehension and symptoms such as shortness of breath. 2. Agoraphobia: anxiety regarding places or situations in which escape might be difficult. 3. Panic Disorder Without Agoraphobia: recurring panic attacks. 4. Panic Disorder With Agoraphobia: recurring panic attacks and agorapho­ bia. 5. Agoraphobia Without History of Panic Disorder: agoraphobia with panic­ like symptoms but without a history of panic attacks. 6. Specific Phobia: severe anxiety induced by a specific object or situation, usually leading to avoidance of that object or situation.

33 34 CHAPTER 3

7. Social Phobia: severe anxiety induced by exposure to social situations, usually leading to avoidance of those situations. 8. Obsessive-Compulsive Disorder (OCD): obsessions that result in anxiety and/or compulsive behavior directed at alleviating the anxiety. 9. Posttraumatic Stress Disorder (PTSD): anxiety caused by the memory of a severely traumatic event (e.g., war experiences). 10. Acute Stress Disorder: acute anxiety caused by a major life crisis (e.g., a divorce or bereavement). 11. Generalized Anxiety Disorder (GAD): excessive anxiety arising from nor­ mallife stresses, continuous, long-term (at least 6 months). 12. Anxiety Disorder Due to a General Medical Condition: anxiety that is a direct consequence of a general medical condition (e.g., adrenal tumor, Alzheimer's disease, coronary insufficiency [i.e., insufficient blood supply to the heart via the coronary artery], hypoglycemia [i.e., insufficient glucose in the blood], hyperthyroidism [i.e., excessive activity of the thyroid gland], postconcussion syndrome, premenstrual syndrome). 13. Substance-Induced Anxiety Disorder: anxiety that is a direct consequence of drug abuse (e.g., amphetamines, caffeine, cocaine, steroids, withdrawal from CNS depressants), a prescribed medication, or a toxin. 14. Anxiety Disorder not Otherwise Specified: anxiety that does not meet the criteria for any of the specific anxiety disorders previously described. (Modified from the DSM-IV, pp. 393-394)

Whether a drug is used to treat an anxiety disorder and, if so, which one is used, depends on the precise diagnosis. The process of deciding on the categorization of a disorder is known as differential diagnosis. This procedure is important because what may first appear to be an anxiety disorder could in fact be a symptom of an underlying somatic pathology (e.g., an adrenal tumor). If wrongly diagnosed, the anxiety might be temporarily alleviated by drug treatment but the underlying cause of the anxiety would remain and might ultimately lead to more severe symptoms.

BASIC DESCRIPTION OF DRUG TREATMENTS FOR ANXIETY DISORDERS

Two main categories of drugs that are used to treat anxiety disorders are: anxiolytic drugs, which are intended to reduce anxiety; and hypnotic drugs, which are intended to induce sleep when anxiety causes insomnia. Anxiolytic drugs fall within a larger class of drugs known as CNS depressants or sedative-hypnotic drugs. CNS depressant drugs are sometimes also referred to as minor tranquilizers, to distinguish them from antipsychotic drugs that may be referred to (erroneously) as major tranquilizers. The common property of the CNS depressant drugs is that they depress CNS activity, causing relaxation and relief ANXIETY DISORDERS 35 from anxiety (hence the terms sedative and anxiolytic), drowsiness and sleep (known as pharmacological hypnosis, hence the term hypnotic), or anesthesia. Some of these drugs produce all of these effects as the dose is increased. Given a sufficiently high dose, some CNS depressants will induce a coma and a lethal respiratory depression. Some CNS depressants have a highly selective action on CNS neurons (e.g., benzodiazepines like diazepam); others do not (e.g., barbiturates and alcohol). Low doses of many of the drugs in the CNS depressant category have been used as anxiolytics, although currently benzodiazepines are most frequently used for this purpose. There are also many drugs outside the CNS depressant category that cause sedation as a side effect (e.g., antipsychotic drugs and opioid analgesics). Therefore, the distinction between CNS depressant drugs and other categories of drugs is not absolute; however, drugs in other categories are not used primarily for their sedative effects. Such drugs often potentiate the effects of CNS depressants and for this reason the potential interaction of depressants and other drugs must be carefully monitored. Some CNS depressants (e.g., benzodiazepines) are also used as muscle relaxants and antiepileptic drugs (see chapter 8).

Benzodiazepines Benzodiazepines are the anxiolytic drugs most frequently prescribed to treat anxiety disorders; therefore, most of this chapter is devoted to their use. In addition to their use in the treatment of anxiety disorders, some ben­ zodiazepines are also used to treat alcohol withdrawal, as antiepileptic drugs, and as preanesthetic agents. One benzodiazepine, alprazolam, is sometimes used as an antidepressant (Tiller & Schweitzer, 1992). Pharmacokinetics. Most benzodiazepines are well absorbed following oral administration; some (e.g., prazepam and flurazepam) undergo extensive first-pass metabolism and their effects are due to active metabolites. Following oral administration ofbenzodiazepines, the peak concentration in the blood plasma is achieved within 0.5 to 8 hours, depending on the specific drug used. Peak blood plasma concentrations of triazolam, which is commonly used as a hypnotic, are achieved within I hour. Benzodiazepines and their active metabolites bind extensively to blood plasma proteins. Benzodiazepines are metabolized mainly by the liver. However, because the metabolites are highly active in some cases, the duration of the behavioral effects may not correlate with the elimination half-life of the drug (e.g., the blood plasma half-life of flurazepam is 2 to 3 hours, however, the active metabolite of flurazepam has a half-life of at least 50 hours; see Rail, 1991, for a review). Benzodiazepines with slow rates of metabolism (e.g., flurazepam) are some­ times used for hypnotic purposes because there is less chance of "rebound" anxiety during the daytime with these compounds (e.g., compared to triazolam). 36 CHAPTER3

Behavioral Effects. Benzodiazepines, as a drug group, induce similar gen­ eral behavioral effects, but their specific pharmacological actions and behavioral effects vary (e.g., some benzodiazepines induce sleep at lower doses than others). Consequently, different benzodiazepines have different applications: Some are used primarily to relieve anxiety, some to induce sleep, some as antiepileptic drugs, and some as muscle relaxants. The behavioral effects of benzodiazepines arise almost entirely from their actions on CNS neurons, where they bind to a specific allosteric binding site on the GABAA receptor complex and potentiate the response to GABA (see the section on research validation). However, coronary vasodilation (i.e., dilation of the coronary artery supplying the heart) occurs with IV therapeutic doses of some benzodiazepines and neuromuscular blockade can also occur with very high doses (Rail, 1991). As a general rule, as the benzodiazepine dose increases, the behavioral effect proceeds from anxiolysis and sedation to hypnosis or sleep. At high doses, patients often have amnesia for events that occurred during the period of benzodiazepine action (anterograde amnesia). For this reason, benzodiazepines may be used in cases where anesthesia is not necessary but it is undesirable for the patient to remember the medical procedure (e.g., dental surgery).

Barbiturates For most purposes, especially relief from anxiety, benzodiazepines are used in preference to barbiturates. This is mainly because benzodiazepines are safer and have more selective actions. Although barbiturates have been largely superseded by benzodiazepines for sedative and anxiolytic purposes, a number of barbiturates are still available as sedatives. Their main use is as hypnotics or anesthetic agents (see Table 3.1). Barbiturates are still used in emergency treatment for convulsions (e.g., status epilepticus, i.e., a rapid succession of seizures without intervening periods of consciousness). Anesthetic doses of barbiturates may also be used to reduce cerebral swelling caused by head injury, surgery, or interruption of cerebral blood supply (cerebral ischemia; Rail, 1991). Pharmacokinetics. Barbiturates are usually administered orally when given as sedatives or hypnotics and at the doses used for these purposes, they are rapidly and completely absorbed. Their effects may begin within 10 to 60 minutes following administration, although food in the stomach may delay absorption. IV administration is used only for the induction of anesthesia (e.g., thiopental) and for the management of status epilepticus (e.g., phenobarbital). Barbiturates bind extensively to plasma proteins (e.g., at least 65% of thiopental is bound). The fast onset and rapid demise of the effects of some barbiturates is explained by their high lipid solubility: After IV administration they cross the blood brain barrier very quickly, but redistribution into muscle and fat causes a rapid reduction in the concentration of the barbiturate in the blood plasma and the brain; therefore, patients may awaken within 5 to 15 minutes after receiving an anesthetic dose (Rail, 1991). ANXIETY DISORDERS 37

Most barbiturates are almost completely metabolized by the liver before being excreted by the kidneys. Elimination is often more rapid in young patients compared to the elderly, in whom reduced liver function may slow metabolism.

Behavioral Effects. Barbiturates produce an inhibition of CNS neuronal activity that results in anxiolytic effects at the expense of significant sedation. In some cases, barbiturates may induce euphoria similar to morphine. Paradoxically, in small doses barbiturates may increase the response to pain (hyperalgesia). It is important to note that, although they may induce anesthesia, barbiturates are not analgesics and may fail to induce sedation when pain is present.

Buspirone Buspirone is a relatively new anxiolytic drug whose pharmacological actions are quite different from those ofbenzodiazepines and barbiturates, acting as an agonist at serotonin receptors, especially the 5-HT,A subtype (see Goa & Ward, 1986, for a review). Buspirone is rapidly absorbed, has a short half-life but takes weeks of continuous administration before exerting its therapeutic effects. This is one of its major disadvantages in the management of anxiety.

RESEARCH VALIDATION

The question of whether benzodiazepines have a specifically anxiolytic action is still debated and is plagued by problems in defining anxiety. However, several animal models of anxiety have been developed and these have been used to evaluate the selectivity of the anxiolytic effects of benzodiazepines. Animals that have first been rewarded for locomotor behavior, feeding or drinking, and then punished, stop responding in the presence of a conditioned stimulus that was associated with the onset of the aversive stimulus; presumably the conditioned stimulus induces anxiety. Likewise, animals placed in an unfamiliar environment show reduced exploratory behavior (neophobia), presumably due to anxiety. In both cases, benzodiazepines have been demonstrated to restore behavior to normal. By contrast, opioid analgesics and antipsychotic drugs do not result in a return of the suppressed behavior. Depressants like phenobarbital are effective in this respect only at high doses. Experimental evidence of this sort supports the contention that benzodiazepines have a specifically anxiolytic action. The predominant mode of action of all benzodiazepines is a potentiation of inhibition in the CNS mediated by the inhibitory amino acid neurotransmitter, GABA. Consistent with this hypothesis, GABA antagonists reduce or prevent the neuronal and behavioral effects ofbenzodiazepines and benzodiazepines potentiate the action of GABA on the GABAA receptor complex. The GABAA receptor 38 CHAPTER3 complex has a specific benzodiazepine binding site, which is molecularly linked to the GABA binding site. When benzodiazepines bind to the benzodiazepine binding site, the affinity of the GABA binding site for GABA increases, resulting in an increase in the influx of chloride ions through the channel associated with the receptor complex and the production ofiPSPs. Since the early 1980s, it has become clear that there exists more than one type of benzodiazepine binding site associated with GABAA receptors (see Doble & Martin, 1992, for a recent review). Nonanesthetic doses of barbiturates depress responses mediated via multiple synapses (polysynaptic responses) first. Neuronal inhibition occurs only at syn­ apses where GABA is used as a neurotransmitter; however, the inhibitory effects may not be entirely due to actions on GABA receptors. There is a barbiturate binding site on the GABAA receptor complex and barbiturates increase the chloride influx through the channel associated with this receptor, irrespective of whether or not GABA is present at the time. As the concentration of the barbiturate increases, the calcium-dependent release of transmitter is reduced, as are calcium-dependent action potentials. At high concentrations, barbiturates may also reduce the activity of voltage-sensitive sodium and potassium channels (Rail, 1991; see Sieghart, 1992, for a recent review).

USES AND MISUSES OF DRUGS USED TO TREAT ANXIETY DISORDERS

Panic Disorders

For a true panic disorder (i.e., with repeated episodes), as opposed to an acute Panic Attack, antidepressant medication may be required (Menkes, 1994 ). The first phase of treatment is usually the reduction of the frequency of panic attacks, using one of four categories of antidepressant medication:

1. alprazolam (a benzodiazepine antidepressant used for panic disorders; Shader & Greenblatt, 1993); this drug usually works within days but sedation is a problematic side effect). 2. a tricyclic antidepressant (can also treat associated depression but tricyclics may not relieve the symptoms for 2 to 3 weeks; see chapter 4). 3. an atypical antidepressant, for example, a selective serotonin reuptake inhibitor (SSRJ) (can also treat associated depression but may not relieve the symptoms for 2 to 3 weeks; see chapter 4 ). 4. a monoamine oxidase inhibitor (MAOI) (can also treat associated depression but MAOis do not relieve symptoms for 2 to 3 weeks and they can have serious interactions with some foods; see chapter 4; see Figs. 3.1 and 3.2). ANXIETY DISORDERS 39

The second phase of the treatment is a gradual re-exposure to the situations that are feared (i.e., the situations in which the patient experienced the panic attacks).

Phobias. Some clinicians suggest that tricyclic or atypical antidepressants may be useful in the treatment of phobias (Menkes, 1994; see chapter 4 ); however, psychological therapy is an important part of the treatment. Beta-blockers and MAOis have also been used in some cases (see Figs. 3.1 and 3.2).

OCD. In the case of obsessive thoughts without ritualistic behavior, antide­ pressant treatment is advised (e.g., tricyclic or atypical antidepressants; Jenike, 1991 ). There is some evidence to suggest that MAO Is may also be useful. Patients with ritualistic behavior usually require a combination of antidepressant drug treatment and behavior therapy (Jenike, 1991; see Figs. 3.1 and 3.2).

Acute Stress Disorder and PTSD. Benzodiazepine anxiolytic drugs can be useful for short-term (i.e., I to 2 weeks) relief from anxiety due to an acute life crisis (e.g., death of a spouse; Shader & Greenblatt, 1993). However, if the crisis persists, then benzodiazepine treatment should be discontinued, with a gradual reduction of the dose. In any case, the patient should be carefully monitored in order to avoid dependence problems. Again, tricyclic and atypical antidepres­ sants are also sometimes used to treat stress-induced anxiety (Menkes, 1994; Van Der Kolk et al., 1994; see Figs. 3.1 and 3.2).

GAD. This is a condition in which long-term, continuous anxiety is experi­ enced in response to the routine stresses of life ("the chronic worrier"). There is disagreement regarding the use ofbenzodiazepines to treat GAD. Some researchers argue that short-term (i.e., less than 4 weeks) treatment with a benzodiazepine is useful (e.g., Shader & Greenblatt, 1993). Others argue that psychological therapies are the preferred treatment because drugs do not treat the underlying causes of the anxiety and dependence problems may develop (e.g., Preston & Johnson, 1991). There are some indications that buspirone can be effective in the treatment of GAD (and it does not appear to have the dependence problems of benzodiazepines). However, buspirone often takes 2 to 6 weeks to reduce anxiety and during this time patients may become frustrated and noncompliant. Tricyclic and atypical antide­ pressants are also sometimes used for GAD (e.g., Menkes, 1994; see Figs. 3.1 and 3.2).

Anxiety Associated With a General Medical Condition or Drugs. In these cases the primary problem should be treated, if possible, without anxiolytic drugs. alprazolam

tricyclic antidepressant panic disorder atypical antidepressant

MAO inhibitor

tricyclic antidepressant (, ____P_ho_b_i_a_s _____ )~------1 atypical antidepressant

tricyclic antidepressant obsessive-compulsive ~----­ disorder atypical antidepressant

( benzodiazepines)

acute/posttraumatic tricyclic stress disorder antidepressant atypical antidepressant

( tricyclic J generalized anxiety 1 1------~l antidepressant ( disorder Jl------l ( atypical l l antidepressant

buspirone )

FIG. 3.1. Drug treatment options for anxiety disorders.

time to onset of therapeutic action effect ( benzodiazepines }----{=:::JG~A~B~A~(~A;i:) :::::;)f----{=~~~=( minutes )

(~~b~u~s~pi~ro~n~e-~}-----{=~5-lHQT~(1~A;t):::::;)r---<==~~~==( weeks )

inhibit reuptakeii ____{=~~~~:J antidepressants metabolism 5HT, r weeks 1\E

FIG. 3.2. Presumed mechanisms of action for drugs used to treat anxiety disorders.

40 ANXIETY DISORDERS 41

LIMITATIONS AND SIDE EFFECTS

Common side effects with sedative doses of benzodiazepines include blurred vision, headache, vertigo, weakness, nausea, diarrhea, and gastric disturbances. Some patients also experience pains in the chest and joints and incontinence. Occasionally, antiepileptic benzodiazepines increase seizure frequency in epileptic patients (see Rail, 1991, for a review). When hypnotic doses of benzodiazepines reach their peak concentration in the blood plasma, the side effects include confusion, increased reaction time, ataxia, lethargy, reduced cognitive and motor function, and dry mouth (Rail, 1991). Although hypnotics are taken before bedtime and are intended to induce sleep, these effects may persist the next day. The potential for severe side effects may increase with age, as a result of reduced liver function (Shorr & Robin, 1994 ). Nitrazepam may increase the incidence of nightmares. Flurazepam sometimes causes increased anxiety, irritability, sweating, and tachycardia. In a minority of cases, euphoria, restlessness, and hallucinations have been reported with some benzodiazepines, as well as bizarre and hostile behavior (Rail, 1991 ). Triazolam has been reported to cause a significant impairment of memory the next day (Bixler et al., 1991; Greenblatt et al., 1991). The respiratory and cardiovascular effects of benzodiazepines are minor; this is one of the main reasons that they are preferred to barbiturates. Large doses ofbenzodiazepines taken during labor may have adverse effects on the neonate, including hypothermia (reduced temperature), hypotonia (reduced muscle tension), and respiratory depression; ifthe mother has taken excessive doses of benzodiazepines over a long period, the neonate may suffer a withdrawal syndrome (Rail, 1991 ). Tolerance develops to the anticonvulsant, sedative, and muscle relaxant effects of benzodiazepines within weeks of continuous treatment. Whether, and to what extent, tolerance develops to their anxiolytic effects is more controversial. Over the last decade, evidence has accumulated to suggest that continuous benzodiazepine treatment for longer than 1 week may result in dependence (see Woods, Katz, & Winger, 1992, for a review). A severe withdrawal syndrome occurs if ben­ zodiazepine treatment is discontinued abruptly. When barbiturates are used as hypnotics, "hangover" effects may occur the following day. Impairment of judgment and fine motor skills may occur, as well as vertigo, nausea, and diarrhea. In some cases (e.g., geriatric populations), barbiturates can cause excitement rather than depression (paradoxical excitement; Rail, 1991). As well as depressing the CNS, barbiturates also depress transmission in the autonomic ganglia, which may account for the reduction in blood pressure (hypo­ tension) caused by barbiturate overdose. Barbiturates also cause respiratory depres­ sion. They do not produce any significant cardiovascular effects when given orally at sedative/hypnotic doses; however, at the higher doses used to induce anesthesia, the associated hypotension may be dangerous in persons who already have com- 42 CHAPTER 3 promised cardiac function. Kidney dysfunction may occur as a result of acute barbiturate poisoning, due mainly to hypotension (Rail, 1991 ). Barbiturates can cause hyperalgesia, as well as excitement and delerium if given in the presence of pain. They may also cause allergic reactions in persons prone to conditions such as asthma and urticaria (skin rashes). Tolerance occurs with regular use and dependence may develop in some patients (Rail, 1991). Buspirone produces adverse side effects such as headaches, dizziness, nausea, fatigue, and diarrhea. At present, there is no compelling evidence that cessation of buspirone treatment results in a withdrawal syndrome (Goa & Ward, 1986).

INTERACTIONS

Alcohol may cause a serious potentiation of the adverse side effects of ben­ zodiazepines, increasing their rate of absorption and the extent of CNS depression. Interactions with other drugs are, in general, not serious (one exception is the antiepileptic drug, sodium valproate, which can cause psychotic episodes if it is administered with a benzodiazepine; Rail, 1991). Flumazenil is a competitive benzodiazepine antagonist of high affinity and selectivity that was developed to reverse the sedation caused by benzodiazepines delivered before or during the administration of an anesthetic. At doses of 0.3 to 1.0 mg IV, flumazenil reverses the effects ofbenzodiazepines within 1 to 2 minutes. Flumazenil can be used in patients who have become comatose due to ben­ zodiazepine overdose. However, its effects are specific to benzodiazepines and it is ineffective in the case of barbiturate or tricyclic antidepressant overdose. Flu­ mazenil undergoes significant first-pass metabolism with less than 20% reaching the systemic circulation. It crosses the blood brain barrier easily, reaching peak blood plasma concentrations in 5 to 10 minutes following injection; its elimination half-life is approximately 1 hour (Laverty, 1992; Rail, 1991). Regular administration of barbiturates causes an increase in the liver enzymes that metabolize them; this results not only in increased metabolism of barbiturates but of some other endogenous chemicals (e.g., steroid hormones, cholesterol, and vitamins K and D; Rail, 1991). As well as adverse drug interactions, endocrine disorders can result from these effects. Increased metabolism partially accounts for the reduced behavioral effects of barbiturates when the same dose is administered regularly over a period of time (i.e., pharmacokinetic tolerance). Reduced effects from other sedative-hypnotic drugs like alcohol may occur (i.e., cross-tolerance). Potentially serious drug interactions can occur with other CNS depressants, espe­ cially alcohol, but also antihistamines and MAOis (Julien, 1992; Laverty, 1992; Rail, 1991).

DOSAGES

Dosages for common CNS depressant compounds are listed in Table 3.1. TABLE 3.1 Some Common CNS Depressant Compounds Drug Anxiolytic Insomnia Alcohol Antiepileptic Preanesth Duration Dose Range (mg. Withdrawal oral)

Benzodiazepines chlordiazepoxide * * long 15-100 (Librium) diazepam * * * * long 4-40 (Valium) triazolam short 0.125-0.25 (Halcion) temazepam * medium 15-30 (Restoril) oxazepam * * short 30-120 (Serax) lorazepam * * * * * medium 1-{i (Ativan) alprazolam * medium 0.75-4 (Xanax) Barbiturates

phenobarbital * long 60-100 (Nembutal) amobarbital long 65-200 (Amytal) Miscellaneous

meprobamate * medium 1,200-1,600 (Miltown) buspirone * short 15-{iO (Bus par)

Note. All doses indicated are dose ranges for adults. In most cases (e.g., for anxiolytic therapy) the daily ·dose would be divided into smaller doses administered throughout the day. Note that the specific dose used would depend on the application and that lower doses would be used in the elderly. Examples of brand names are indicated in parentheses. preanesth = preanesthesia

-~>-From Rail (1991), Pirodsky and Cohn (1992), Burwell (1992). VJ 44 CHAPTER 3

SUGGESTED READINGS

Busto, U., & Sellers, E. M. (1991 ). Anxio1ytics and sedative/hypnotics dependence. British Journal ofAddiction, 86, 1647-1652. Doble, A., & Martin, I. (1992). Multiple benzodiazepine receptors: No reason for anxiety. Trends in Pharmacological Sciences, 13, 76-81. Laverty, R. (1992) Hypnotics and sedatives. In M. Dukes (Ed.), Meyler's side effects of drugs (pp. 93-104). Amsterdam: Elsevier. Menkes, D. B. (1994, March). Antidepressant drugs. New Ethicals. 101-106. Rail, T. (1991). Hypnotics and sedatives; ethanol. In A. Goodman Gilman, T. W. Rail, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (8th ed., Vol. I, pp. 436-462). New York: Pergamon. Shader, R. I., & Greenblatt, D. J. (1993). Use of benzodiazepines in anxiety disorders. New England Journal of Medicine, 1398-1405. Woods, J. H., Katz, J. L., & Winger, G. (1992). Benzodiazepines: use, abuse and conse­ quences. Pharmacological Reviews, 44,151-347. Woods, J. H., & Winger, G. ( 1995). Current benzodiazepine issues. Psychopharmacology, 118, 107-115. Chapter 4

Drug Treatment for Affective Disorders

BACKGROUND INFORMATION

Affective disorders are disorders of mood in which a person experiences a predomi­ nantly depressed mood (unipolar depression), an abnormally elevated mood (ma­ nia), or an oscillation between depression and mania (bipolar depression [manic-depressive illness]). In the DSM-IV (American Psychiatric Association, 1994), unipolar depression is subdivided into the following categories:

I. Major Depressive Disorder: distinguished by the occurrence of at least one major depressive episode, defined as at least 2 weeks of depressed mood with at least four other symptoms of depression (see later). 2. Dysthymic Disorder: at least 2 years during which depressed mood is experienced for most of the time, in addition to other depressive symptoms that do not fulfill the criteria for a major depressive episode. 3. Depressive Disorder Not Otherwise Specified: includes disorders with depressive characteristics that do not fulfill the criteria for major depressive disorder, dysthymic disorder, includes adjustment disorder with depressed mood, or adjustment disorder with mixed anxiety and depressed mood (see DSM-IV, 1994, for details).

Bipolar depression is subdivided into the following categories:

1. Bipolar I Disorder: at least one manic or mixed episode, usually with major depressive episodes.

45 46 CHAPTER 4

2. Bipolar II Disorder: at least one major depressive episode, usually with at least one hypomanic episode. 3. Cyclothymic Disorder: at least 2 years of frequent periods of hypomanic symptoms that do not fulfill the criteria for a manic episode and frequent periods of depressive symptoms that do not fulfill the criteria for a major depressive episode. 4. Bipolar Disorder not Otherwise Specified: includes disorders with bipolar characteristics that do not fulfill the criteria for any of the specific bipolar disorders.

In addition to these types of unipolar and bipolar depression, there are two categories of mood disorder based on specific causes:

1. Mood Disorder Due to a General Medical Condition: a persistent mood disturbance that is a direct result of a general medical condition. 2. Substance-Induced Mood Disorder: a persistent mood disturbance that is a direct result of drug abuse, a prescribed medication, another treatment for depression, or a toxin.

Finally, there is a miscellaneous category, Mood Disorder not Otherwise Speci­ fied, which includes mood disorders that do not fit into any of the other categories (modified from DSM-IV, American Psychiatric Association, 1994, pp. 317-318).

Unipolar Depression Unipolar depressive disorders must be distinguished from other disorders in which depressive symptoms occur:

1. reactive sadness, a transient sadness stimulated by a specific life event and causing minimal interference with normal function. 2. grief, a prolonged reaction to a major loss (e.g., the death of a family member). However, the symptoms are specifically related to the loss: There is no loss of self-esteem and the grief usually decreases with time. 3. medical illnesses or drugs that cause depressive symptoms. The following are some examples of medical illnesses that m~y cause depressive symp­ toms: AIDS; Addison's disease (caused by reduced function of the adrenal gland, resulting in anemia [abnormally low number of red blood cells], skin pigmentation, hypotension, and diarrhea), chronic infection, diabetes, hy­ per- or hypothyroidism, asthma, influenza, multiple sclerosis, malnutrition, anemia, cancer, infectious hepatitis, premenstrual syndrome, Cushing's disease (i.e., caused by excessive secretion of adrenocorticotropic hormone by the pituitary gland), and rheumatoid arthritis. Drugs that can cause depressive symptoms include antihypertensive medications (i.e., reduce AFFECTIVE DISORDERS 47

blood pressure), steroids, anti-Parkinsonian drugs, anxiolytic drugs, contra­ ceptive medication, and alcohol.

Unipolar depression is characterized by behavioral symptoms such as sadness that pervades all aspects of life, loss of the ability to experience pleasure (anhe­ donia), loss of self-esteem, social withdrawal and apathy, unusual and excessive emotional sensitivity, pessimism, irritability, suicidal thoughts; and physiological symptoms such as sleep disturbances (i.e., insomnia or excessive sleeping), appetite disturbances (i.e., increased or decreased appetite), fatigue, reduced sex drive, mood variations during the day, loss of memory, and impaired concentration (DSM-IV, 1994). For a diagnosis of unipolar depression to be justified, both the behavioral and physiological symptoms must be present. In contrast to grief, the depressed patient may have no idea why he or she is depressed. Erosion of self-esteem often distinguishes depression from other conditions associated with depressive symp­ toms.

Bipolar Depression

In bipolar disorders, both mania and depression occur. Mania is defined as a consistent euphoric mood or irritability, associated with three or more of the following: elevated self-esteem, a reduced need for sleep, rapid speech, racing thoughts, increased distractability, agitation or hyperactivity, lack of emotional restraint, and poor judgment. There are two main classifications used for mania:

1. Bipolar I Disorder versus Bipolar II Disorder: In Bipolar I mania there are distinct episodes of depression and mania; in Bipolar II mania there are distinct episodes of depression but less severe episodes of mania, sometimes referred to as hypomania. 2. Typical Bipolar versus Rapid Cycling: In typical bipolar mania, the manic and depressive episodes last for weeks to months, perhaps punctuated by periods of normal mood. In rapid cycling mania, two or more episodes of both depression or mania occur in 1 year. In the most severe forms of rapid cycling, mood changes can occur from day to day.

As with the diagnosis of other psychiatric disorders, it is important to distinguish between true bipolar disorders and other conditions that include manic symptoms. Some medical illnesses result in mania (e.g., brain tumors, CNS syphillis, encephalitus [i.e., inflammation of the brain], influenza, and multiple sclerosis). Some drugs can also cause manic symptoms (e.g., amphetamines, cocaine, and steroids). 48 CHAPTER4

BASIC DESCRIPTION OF DRUG TREATMENT FOR UNIPOLAR AND BIPOLAR DEPRESSIVE DISORDER

Unipolar Depression Antidepressant drugs are used to treat unipolar depression. However, it is important to note that the same drugs are used to treat many disorders other than depression (e.g., some anxiety disorders, see chapter 3; pain syndromes such as trigeminal neuralgia, see chapter 6; eating disorders such as bulimia; and premenstrual syndrome; Menkes eta!., 1992; see Menkes, 1994, for a review). There are three main types of antidepressant drugs: tricyclic agents, MAO Is, and atypical agents including SSR/s. In general, there are major compliance problems with antidepressants because of the side effects that most people experience (Menkes, 1994). One of the main reasons for the popularity of SSRis, such as fluoxetine (trade name: Prozac), is their lack of side effects compared to tricyclic and MAOI antidepressants (Baron­ des, 1994). Tricyclic Agents Until recently, tricyclic agents have been some of the most commonly prescribed antidepressant medications.

Pharmacokinetics. Tricyclics are well absorbed after oral administration. Peak plasma concentrations are usually reached within 2 to 8 hours. They are widely distributed and bind readily to plasma proteins. Half-lives range from 20 (e.g., amitriptyline) to 160 hours (norfluoxetine). Most tricyclics are excreted within I week following the end of treatment (Baldessarini, 1991 ).

Behavioral Effects. In a nondepressed person, tricyclics result in sedation, a decrease in blood pressure, anticholinergic effects such as dry mouth and blurred vision, unsteadiness, and difficulty concentrating. These effects usually result in a depressed mood (dysphoria). However, when given to a depressed patient for 2 to 3 weeks, an elevation of mood occurs. There is always a delay of 2 to 3 weeks before symptomatic improvement occurs and the drug treatment must be maintained in order for the beneficial effect to be achieved. Nonetheless, adverse side effects (e.g., sedation) may appear within a few days. The explanation for the delay in the therapeutic effect is unknown. In some patients, manic excitement, euphoria, and insomnia can occur (Baldessarini, 1991; Menkes, 1994). Atypical Agents Atypical agents such as SSRis are becoming increasingly popular alternatives to tricyclics and MAOis. Atypical agents are also sometimes used for the medically AFFECTIVE DISORDERS 49 ill or for elderly patients who have difficulty tolerating the side effects of tricyclics. Most of the atypical agents not only have fewer side effects but are less toxic when the therapeutic dose is exceeded (see Nemeroff, 1994, for a review). Alprazolam is a benzodiazepine with rapid antidepressant action relative to tricyclics; however, it may not be as effective in relieving depression. Also, like other benzodiazepines, alprazolam may result in dependence (see Tiller & Schweitzer, 1992, for a review). Buspirone (also an anxiolytic drug; see chapter 3), a serotonin agonist, also takes approximately 2 to 4 weeks to exert its therapeutic effect on depressive symptoms (see Goa & Ward, 1986, for a review). Fluoxetine, an SSRI, has become one of the most popular antidepressants. It has little effect on either DA or NE and takes 2 to 3 weeks to produce its therapeutic effect. Like other SSRis (e.g., sertraline, paroxetine), fluoxetine results in few of the side effects associated with tricyclics and MAOis. The SSRis can, however, cause significant nausea, diarrhea, insomnia, and sexual dysfunction (see Nemeroff, 1994, for a review). Fluoxetine has also been associated with an increased suicide risk (Hamilton & Opler, 1992; Hawthorne & Lacey, 1992); however, this claim remains controversial (Beasley et al., 1991; Brewerton, 1991 ). MAO Is MAOis are as effective as tricyclics and atypical agents in the treatment of depression but became unpopular because of severe and unpredictable interactions with some foods and other drugs. New MAO Is have been developed that are specific for particular types of MAO. Moclobemide is a short-acting, reversible MAOI that is selective for the A-type of MAO (reversible inhibitor of MAO, type A or RIMA). Because it is MAO-B that is involved in tyramine metabolism, moclobemide has minimal interaction with foods containing tyramine (see the section on interac­ tions); it also has a lower overdose risk than other MAOis (Menkes, 1994).

Pharmacokinetics. There is surprisingly little information on the pharma­ cokinetic properties of MAOis (Baldessarini, 1991). However, they are well absorbed when administered orally.

Behavioral Effects. MAOis produce little or no behavioral effects in nor­ mal animals. As with tricyclics, their therapeutic effects in depressed patients do not occur for 2 or more weeks after the onset of treatment.

Bipolar Depression Lithium is the primary drug treatment for bipolar depression, although it may be only partially effective for the long-term prevention of further episodes. It is sometimes used as a supplement to antidepressant therapy (lithium supplementa­ tion) in patients with unipolar depression, when treatment with antidepressants alone is not effective (e.g., Cowen et al., 1991). 50 CHAPTER4

Lithium

Pharmacokinetics. Lithium is absorbed well from the gastrointestinal tract. Peak plasma concentrations are achieved within 2 to 4 hours following oral administration. Slow-release preparations are available to reduce the rate of absorp­ tion and thereby produce a more gradual onset of the drug effect. However, there is some evidence to suggest that absorption may be more variable with slow-release preparations and that, as a result, lower intestinal tract side effects may be more likely (Baldessarini, 1991). Lithium penetrates the blood brain barrier slowly. Plasma protein binding does not occur. The elimination half-life is approximately 20 to 24 hours and about 95% of a single dose of lithium is excreted in the urine. Determination of blood plasma levels of lithium is very important because of the risk of overdose (see later). A steady state concentration of lithium is reached after about 5 to 6 days of treatment; however, the peak plasma concentration, which may be reached shortly after administration, must be carefully monitored because of the risk of intoxication (i.e., the average plasma concentration during repeated administration may be safe but the peak of the concentration oscillations between successive doses may produce toxicity). Divided daily doses are usually used in order to reduce the peak plasma concentrations (see Baldessarini, 1991, for a detailed review). Although pharmacokinetic parameters vary between individuals, they are rea­ sonably consistent within the one patient over time. However, problems occur when there are reductions in the concentrations of other ions, especially sodium.

Behavioral Effects. At therapeutic doses, lithium has little effect on hu­ mans who are not suffering from mania: It has no sedative or stimulant properties (Baldessarini, 1991 ).

Research Validation

Antidepressants. In animals, tricyclics reduce spontaneous motor activity and impair the acquisition and performance of conditioned avoidance responses. Some of these effects are similar to diazepam. Tricyclics will potentiate the stimulant effects of amphetamines and the aggressive behavior caused by hypotha­ lamic lesions (Baldessarini, 1991). All tricyclics potentiate the action of DA, NE, and serotonin by blocking their mechanism of metabolism in the brain (i.e., reuptake at nerve terminals). Different tricyclics vary in the extent to which they affect these different transmitters. Some drugs like desipramine have large effects on the metabolism of NE but relatively little effect on serotonin; others like amitriptyline have equal action on NE and serotonin. Most tricyclics have comparatively little effect on DA metabolism and AFFECTIVE DISORDERS 51 for this reason the therapeutic actions oftricyclics are believed to be related to their potentiation of NE and/or serotonin transmission. Other stimulant drugs like amphetamines tend to potentiate DA and NE transmission equally well; this may be the reason why these drugs do not have antidepressant effects (Baldessarini, 1991; Charney, Menkes, & Heninger, 1981; Menkes, 1988). The explanation for the antidepressant action of tricyclics is complex. The biogenic amine hypothesis of depression proposed that depression is the result of a functional deficiency in NE and serotonin; consequently, administration of drugs that increase the availablity of these neurotransmitters relieves depression (see Charney et al., 1981, for a review). However, the blockade of NE and serotonin reuptake occurs very quickly, yet the therapeutic action of the drugs takes 2 to 3 weeks. This consistent result suggests that the therapeutic effects of tricyclics are related more to the chronic effects of the drugs than to the acute effects (i.e., the blockade of NE and serotonin metabolism is probably the beginning of a complex series of biochemical adjustments that develop over 2 to 3 weeks; see Menkes, 1988, for a review). In order to test this hypothesis, researchers have recorded from single neurons in animals that have undergone chronic antidepressant treatment and examined the sensitivity of these neurons to various neurotransmitters. In brain regions where a, adrenoceptors mediate excitation, chronic but not acute tricyclic treatment has been found to cause an increase in the sensitivity of postsynaptic neurons to NE (Menkes, 1988). The biochemical explanation for the enhanced sensitivity may be an increased affinity or number (i.e., up-regulation) of CNS a, adrenoceptors (see Menkes, 1988, for a review). By contrast with the increased sensitivity of a, adrenoceptors,

metabolized by both MAO-A and MAO-B, such drugs preferentially potentiate NE and serotonin transmission.

Lithium The mechanisms underlying the therapeutic effects oflithium on bipolar depression are unknown. It has been suggested that lithium may work by altering the distribu­ tion of ions in the CNS or via effects on glucose metabolism or the metabolism of NE, DA, and serotonin. At present, none of these hypotheses has been confirmed (Baldessarini, 1991 ). There is some evidence to support the idea that lithium may alter the reuptake and presynaptic storage of NE and DA in such a way that metabolism of these transmitters may be increased (i.e., the opposite effect to antidepressants). A recent hypothesis is that lithium may reduce the response of neurons to ACh and NE by reducing second messenger activity resulting from muscarinic ACh and a-adreno­ ceptor activation. However, at present this hypothesis has little substantial empirical support (see Steffens, Tupler, & Krishnan, 1993, for a review).

USES AND MISUSES OF DRUGS USED TO TREAT AFFECTIVE DISORDERS

Antidepressants The specific drug that is chosen to treat unipolar depression often depends on an assessment of the side effects with which the patient can cope (e.g., an assessment ofthe patient's motor state). An agitated and restless patient may be given a more sedating antidepressant (e.g., amitryptyline), whereas someone suffering from lethargy might be prescribed a less sedating drug (e.g., desipramine). With increas­ ing evidence that SSRis have equivalent antidepressant efficacy to tricyclics and MAOis, fluoxetine and paroxetine in particular are often being used to avoid the problematic side effects of the older antidepressants (see Nemeroff, 1994, for a review; see Figs. 4.1 and 4.2). It is important that forms of unipolar depression that result in anxiety and agitation are not mistaken for anxiety disorders. If such conditions are treated with anxiolytic drugs such as benzodiazepines, the underlying depression may worsen. It is also important to realize that depression may be associated with psychosis (i.e., disordered or delusional thinking and perceptions; see Schatzberg & Roth­ schild, 1993, for a recent review). There is evidence to suggest that in such cases patients respond better to treatment with a tricyclic antidepressant and an antipsy­ chotic drug than to an antidepressant alone (Schatzberg & Rothschild, 1993). Many psychiatrists use an atypical agent (e.g., an SSRI) or a tricyclic as the first treatment for unipolar depression and gradually increase the dose to the therapeutic AFFECTIVE DISORDERS 53

tricyclic antidepressant

atypical antidepressant

MAO inhibitor

( lithium ) bipolar depression 1------1 antipsychotics

lithium ) (~ __m_an_i_a __ ~)l------1 '-----1; antipsychotics )

FIG. 4. I. Drug treatment options for affective disorders.

time to onset action of therapeutic effect ~tr~ic~yc~l~ic~ag~e~n~ts0----f inhibit re-uptake: weeks C NE, 5-HT

~inhibit metabolism: weeks NE, 5-HT

selectively inhibit ~a~tYttP~ic~a:_l~a.l!:ge~n~ts~_r-1 5-HT re-uptake weeks

(~--"1i-"t h.:..:i.::.u:.;cm_~}------{ unknown }----{ 10 days )

FIG. 4.2. Presumed mechanisms of action for drugs used to treat affective disorders. range. Undermedication is a common error. In any case, it usually takes 2 to 3 weeks of treatment before any symptomatic improvement occurs (Menkes, 1994 ). If the depression does not respond after 3 to 4 weeks of tricyclic therapy, an alternative is to add a low dose of lithium (600-900 mg/day) to the antidepressant treatment (Cowen et al., 1991). If this is ineffective, then another tricyclic or atypical antidepressant, with a different spectrum of neurochemical action, may be used. If drug therapy is still unsuccessful, an MAOI may be used as an alternative. Finally, if the patient does not respond to any antidepressant medication, the last resort is usually electroconvulsive therapy ( ECT), which has proven to be effective in many 54 CHAPTER4 cases where drug therapy fails (although its mechanism of action is unknown; Krueger, Sackiem, & Gamzu, 1992; Sackeim et al., 1993; see Nobler & Sackeim, 1993, for a recent review; see Figs. 4.1 and 4.2). Although MAOis have traditionally been regarded as inferior to tricyclics and atypical agents because of their severe side effects, they have recently been regaining popularity. Phenelzine and tranylcypromine are two MAOis that are as effective as tricyclics and atypical agents in the treatment of depression. If dietary restrictions are observed, some of the MAO Is may actually be safer than tricyclics. Moclobemide is an MAOI that has minimal interaction with foods containing tyramine (see the section on interactions). In addition, MAO Is seem to be effective for some atypical affective disorders and in some patients who do not respond to other antidepressants. If drug therapy is discontinued as soon as symptomatic improvement occurs, then it is likely that the symptoms will return (Hirschfeld, 1994; Maj et al., 1992). Therefore, the drug treatment is usually continued for 4 to 6 months after sympto­ matic improvement has first occurred. Some patients may need antidepressants for a longer period of time.

Lithium If, on initial presentation, the patient suffering from bipolar disorder is severely manic, lithium may be prescribed with another antipsychotic drug (e.g., chlorpro­ mazine). Lithium takes about 10 days to exert its therapeutic effect; at the end of this period, other drugs can be gradually withdrawn (see Figs. 4.1 and 4.2).

Other Treatments Some researchers (e.g., Baldessarini, 1991) suggest that in the case of severe manic attacks, lithium is inferior to antischizophrenic antipsychotics for the purpose of bringing the severe mania under control. From this viewpoint, an antischizophrenic drug should be prescribed first and then lithium should be phased in as the patient becomes stable. Some psychiatrists argue that ECT is effective in the management of acute mania (see Mukherjee, Sackeim, & Schnur, 1994, for a review). Even benzodiazepines, because of their sedative actions, may be useful in controlling a severe manic episode. Lithium, however, is more effective in prevent­ ing further manic episodes than any other drug that has been tested. The typical starting dose for lithium is 600 to 900 mg/day, divided into a number of doses (maintenance dose is usually 900-1,200 mg). In the case of bipolar depression, lithium reduces the probability of further episodes of depression as well as mania. However, it may still be less effective in preventing the depressive episodes than the manic episodes. Consequently, if a patient is in the depressive phase when treatment begins, an antidepressant and lithium may be used together. The major problem with this combination therapy is the possibility that the antidepressant may cause a manic episode (Baldessarini, 1991 ). AFFECTIVE DISORDERS 55

An alternative treatment for bipolar depression, currently under investigation, are antiepileptic drugs used in the treatment of temporal lobe epilepsy (e.g., carbamazepine and sodium valproate; see Thase, 1993, for a recent review). According to Preston and Johnson ( 1991 ), carbamazepine may be especially useful for rapid cycling bipolar depression. However, Baldessarini (1991) has argued that there is no indication that drugs of this type affect depression, only mania. Preston and Johnson (1991) also suggest that MAOis may be useful in the treatment of Bipolar II disorder. Sometimes, benzodiazepines such as clonazepam and lorazepam are used as sedatives during acute mania; however they are relatively ineffective in long-term prevention. Ghadirian, Annable, and Belanger (1992) reported that treatment with lithium and a benzodiazepine has a stronger association with sexual dysfunction in bipolar patients than lithium treatment alone. Antihy­ pertensive drugs (e.g., clonidine and calcium channel antagonists) have also been used to treat bipolar depression, but with limited success (Baldessarini, 1991 ).

LIMITATIONS AND SIDE EFFECTS

Antidepressants

Tricyclics affect the autonomic nervous system by inhibiting NE reuptake at nerve terminals and by acting as antagonists at muscarinic cholinergic receptors (hence the term anticholinergic) and arrhythmias may develop (Baldessarini, 1991; Pirodsky & Cohn, 1992). Weakness and fatigue may occur due to the CNS actions of tricyclics. Some patients show an improvement in their depression and subsequently become manic. Delirium and confusion are also common. A slight tremor may occur during treatment with tricyclic antidepressants but extrapyramidal side effects are rare. Trazodone may cause permanent impotence. Overdose with tricyclics may be lethal and this is a major problem with these drugs. Some tolerance to the anticholinergic effects of tricyclics develops. Dependence on tricyclics is not common but does occur occasionally. Withdrawal should be gradual (Baldessarini, 1991; Pirodsky & Cohn, 1992). As described in the section on atypical cyclic agents, atypical antidepressants such as the SSRis produce few of the side effects common to tricyclic therapy; they may, however, cause other side effects such as nausea, headache, insomnia, and sexual dysfunction (Nemeroff, 1994). The toxic side effects of MAOis may develop in the liver, brain, and cardiovas­ cular system within just a few hours. Adverse side effects include dizziness, vertigo, 56 CHAPTER4 headache, inhibition of ejaculation, difficulty urinating, weakness, fatigue, dry mouth, blurred vision, skin rashes, and constipation. Overdose results in agitation, hallucinations, hypereflexia (i.e., exaggerated reflex activity), and convulsions (Baldessarini, 1991 ).

Lithium

Toxicity to lithium is usually caused by the rapid increase in blood concentration shortly after administration. Mild toxicity causes nausea, vomiting, abdominal pain, diarrhea, sedation, and a fine tremor; severe acute toxicity causes vomiting, severe diarrhea, coarse tremor, ataxia, mental confusion, hypereflexia, dysarthria (i.e., problems speaking due to impairment of the muscular control necessary for speech), seizures, convulsions, cranial nerve and focal neurological signs, poten­ tially leading to coma and death. Other toxic symptoms that may occur include cardiac arrhythmias, hypotension, and albuminuria (i.e., presence of albumin in the urine; Baldessarini, 1991). After lithium therapy begins, sodium, potassium, and water excretion increase for about 24 hours. Within 4 to 5 days potassium excretion returns to normal and sodium retention occurs, resulting sometimes in edema (i.e., abnormal accumula­ tion of fluid in the intercellular spaces). This effect often disappears after a few days. A minority of patients develop a benign thyroid enlargement; however, hypothyroidism is uncommon. Polydipsia (excessive thirst) and polyuria (exces­ sive secretion of urine) occur during lithium therapy and sometimes these effects can be severe. Mild polyuria commonly develops early during lithium treatment and then disappears; if it returns later in treatment then renal function should be evaluated (Baldessarini, 1991). Dermatitus and vasculitis (i.e., inflammation of blood vessels) can occur during lithium therapy. Pregnant women who use lithium while on a low sodium diet or taking drugs that promote the excretion of abnormal amounts of sodium in the urine (i.e., natriuretics) risk lithium intoxication of the neonate and themselves. There is evidence that lithium therapy in pregnant women may contribute to neonatal CNS depression, hypotonia, goiter (i.e., enlargement of the thyroid gland), and the development of cardiac murmurs. Although these abnormalities are not permanent, epidemiological data suggest that the use of lithium early in pregnancy may substantially increase the risk of serious neonatal cardiac abnormalities (Baldes­ sarini, 1991; Julien, 1992; Pirodsky & Cohn, 1992). During recovery from lithium intoxication, the patient must not be sodium- or water-depleted. Provided that renal function is normal, diuretics (i.e., drugs that increase urination) can be given to accelerate elimination of the lithium. In the case of severe intoxication, renal dialysis is used. Recovery is gradual even following AFFECTIVE DISORDERS 57 renal dialysis; thus it is believed that the intracellular concentration of lithium is the critical factor in the development of toxicity (Baldessarini, 1991 ). There is no substantial evidence for the development of tolerance to, or depend­ ence on, lithium.

INTERACTIONS

Antidepressants

Because tricyclics bind to plasma proteins, other drugs that also bind to plasma proteins may compete with them, resulting in higher concentrations of tricyclics in the CNS than expected (e.g., phenytoin, aspirin, scopolamine, phenothiazines). Some steroids, including some contraceptives, may interfere with the metabolism of tricyclics in the liver: Barbiturates (but not benzodiazepines) and cigarette smoking can increase the metabolism of tricyclics. Tricyclics enhance the effects of alcohol (Baldessarini, 1991). The interactions of SSRis with other drugs are generally less problematic than with tricyclics (Nemeroff, 1994). MAOis enhance the effects of all CNS depressants, anticholinergic drugs, and analgesics. In the case of nonselective MAO Is, serious interactions can occur with food containing tyramine (e.g., cheese, beer, wine, yeast, large amounts of coffee, citrus fruits, chocolate, and cream products). Ingestion of these foods can cause a surge in blood pressure (i.e., a hypertensive crisis), which has proven fatal in some cases (Baldessarini, 1991).

Lithium

Lithium is often used in addition to sedative, antipsychotic, or antidepressant drugs (see e.g., Cowen et al., 1991 ). Although there have been claims of an increased risk oflithium toxicity when antischizophrenic antipsychotic drugs are used at the same time, there appears to be no substantial evidence for this view. However, such drugs can prevent nausea, which may be one of the first signs of lithium toxicity. If lithium is used concurrently with antidepressants, it will cause increased secretion of urine (polyuria) while the anticholinergic effects of the antidepressant will cause urinary retention (Baldessarini, 1991).

DOSAGES

Dosages for antidepressant drugs are listed in Table 4.1. 58 CHAPTER 4

TABLE 4.1 Antidepressant Drugs

Brand Names Dose Range (mg)

Tricyclic Agents amitriptyline (Elavil) 50--300 amoxapine (Asendin) 75-450 clomipramine (Anafranil) 50--250 desipramine (Pertofran) 50--300 doxepin (Sinequan) 50--300 imipramine (Tofranil) 50--300 maprotiline (Ludiornil) 50--225 nortriptyline (Pamelor) 25-150 protriptyline (Vivactil) 10--60 trimipramine (Surmontil) 50--300 MAO Is moclobemide (Aurorix) 300--600 phenelzine (Nardi[) 30--90 tranylcypromine (Parnate) 10--50 Atypical Agents alprazolam (Xanax) 0.75-4 buspirone (Buspar) 15-60 fluoxetine (Prozac) 20--80 paroxetine (Aropax) 20--50

Note. From Menkes ( 1994), Pirodsky and Cohn ( 1992), Burwell ( 1992). The dose ranges shown are intended for adults and are often administered in divided doses over a 24-hour period.

SUGGESTED READINGS

Baldessarini, R. (1991 ). Drugs and the treatment of psychiatric disorders. In A. Goodman Gilman, T. W. Rail, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (8th ed., Vol. I, pp. 383-435). New York: Pergamon. Ball, W., & Whybrow, P. (1993). Biology of depression and mania. Current Opinion in Psychiatry, 6, 27-34. Barondes, S. H. (1994). Thinking about Prozac. Science, 263, 1102-1103. Hirschfeld, R. M. A. ( 1994). Guidelines for the long-term treatment of depression. Journal of Clinical Psychiatry, 55(Suppl. 12), 61-69. Jacobs, B. L. (1994). Serotonin, motor activity and depression-related disorders. American Scientist, 82, 456-463. Krueger, R. B., Sackhiem, H. A., & Gamzu, E. R. ( 1992). Pharmacological treatment of the cognitive side effects of ECT: A review. Psychopharmacology Bulletin, 28, 409-424. Menkes, DB. (1994). Antidepressant drugs. New Ethicals, 101-106. Nemeroff, C. B. (1994). Evolutionary trends in the pharmacotherapeutic management of depression. Journal of Clinical Psychiatry, 55(Suppl. 12), 3-15. AFFECTIVE DISORDERS 59

Nobler, M., & Sackheim, H. (1993). Pharmacotherapy and electroconvulsive therapy for mood disorders. Current Opinion in Psychiatry, 6, 10--15. Rang, H. P., Dale, M. M., & Ritter, J. M. (1995). Pharmacology (3rd ed.). Edinburgh: Churchill Livingstone. Chapter 5

Drug Treatment for Psychotic Disorders

BACKGROUND INFORMATION

Psychosis is an impaired ability to perceive reality (impaired reality testing), which may result in delusions and hallucinations, among other symptoms. According to the DSM-JV (American Psychiatric Association, I994 ), there are nine major categories of psychotic disorders:

I. Schizophrenia: a disorder lasting at least 6 months, including two or more of the following: delusions, hallucinations, disorganized speech, severely disorganized or catatonic behavior, negative symptoms. The general cate­ gory of schizophrenia includes the specific subtypes: paranoid, disorgan­ ized, catatonic, undifferentiated, and residual. 2. Schizophreniform Disorder: a disorder with symptoms similar to schizo­ phrenia lasting less than 6 months and excluding a general reduction in functioning. 3. Schizoaffective Disorder: a disorder characterized by symptoms of schizo­ phrenia (e.g., delusions, hallucinations, negative symptoms, disorganized speech, severely disorganized or catatonic behavior) and an episode of disordered mood, preceded or followed by at least 2 weeks of delusions or hallucinations without affective symptoms. 4. Delusional Disorder: a disorder in which "nonbizarre" delusions occur for at least I month, but without other schizophrenic symptoms. 5. Brief Psychotic Disorder: a psychotic disorder lasting more than I day but that subsides within I month.

60 PSYCHOTIC DISORDERS 61

6. Shared Psychotic Disorder: a disorder that develops as a result of contact with another individual who suffers from a delusion similar in nature. 7. Psychotic Disorder Due to a General Medical Condition: a disorder in which the psychotic symptoms are a result of a general medical condition. Medical illnesses which can result in psychotic symptoms include CNS tumors, brain trauma as a result of head injury, dementias such as Alzhe­ imer's disease, Huntington's disease (an hereditary disease characterized by involuntary repetitive, rapid, and jerky movements and mental deterio­ ration), multiple sclerosis, and epilepsy. 8. Substance-Induced Psychotic Disorder: a disorder in which the psychotic symptoms are a result of drug abuse, a prescribed medication, or a toxin. Drugs that can cause psychotic symptoms include cocaine, steroids, anti­ Parkinsonian drugs, psychedelics, and hallucinogens such as LSD and PCP. 9. Psychotic Disorder not Otherwise Specified: a psychotic disorder that does not fulfill the criteria for any of the previous psychotic disorders.

Schizophrenia is a particular type of psychosis in which a person suffers repeated psychotic episodes. The principal symptoms of schizophrenia include thought disorders, including delusions and hallucinations, mood disorders, such as flat or inappropriate affect, abnormal behavior, such as withdrawal from social situations. A distinction is made between two main types of schizophrenia: Type/, positive symptoms: characterized by delusions, hallucinations, and inappropriate affect; and Type II, negative symptoms: regarded as a neurodegenerative disorder, manifesting in negative symptoms such as withdrawal, loss of motivation, anhedonia, flat affect, and the absence of symptoms such as hallucinations and delusions (see Reynolds, 1992; Waddington, 1993; Wiesel, 1994, for recent reviews). There is debate as to whether these subtypes really exist, because many patients exhibit some positive and negative symptoms. Also, there is increasing evidence that schizophrenia is generally associated with enlarged ventricles and focal brain damage (Bruton et al., 1994; see Roberts, 1990a, for a review); therefore, both positive- and negative-symptom schizophrenia may be neurodegenerative disor­ ders. Nonetheless, there is consensus that the positive symptoms respond more effectively than the negative symptoms to traditional antipsychotic medication such as chlorpromazine (Reynolds, 1992).

BASIC DESCRIPTION OF DRUG TREATMENT FOR PSYCHOSIS

Antipsychotic drugs are used mainly in the treatment of patients with psychotic illnesses. However, they may also be used as antiemetics (prevent vomiting), antinauseants, and antihistamines; they can potentiate the effects of analgesics, sedatives, and general anesthetics. 62 CHAPTERS

There are four main classes of antipsychotic drugs used to treat schizophrenias. The first three are phenothiazines (e.g., chlorpromazine, thioridazine), butyrophe­ nones (e.g., haloperidol), and thioxanthines (e.g., tlupentixol). These three groups are often referred to as classical antipsychotics. Because these drugs often cause considerable extrapyramidal side-effects and sedation, they have been referred to as neuroleptics and sometimes as major tranquilizers. The fourth class is atypical antipsychotics (e.g., clozapine, sulpiride, remoxipride, risperidone).

Pharmacokinetics. Some antipsychotic drugs are absorbed in an unpre­ dictable manner when given orally. They are highly lipophilic (i.e., have a high affinity for lipids) and bind to blood proteins. Elimination half-life is usually 20 to 40 hours, however there are exceptions; the physiological effects of a single dose usually last for 24 hours. Antipsychotics are metabolized mainly by the liver (Baldessarini, 1991 ).

Behavioral Effects. In nonpsychotic humans, antipsychotic drugs reduce exploration of the environment and the expression of emotion. There may be a slowness to respond to stimuli and some drowsiness; however, cognitive functions remain largely intact. Ataxia or dysarthria do not occur within the usual therapeutic dose range. In people with schizophrenia, antipsychotics reduce agitation; those who are withdrawn exhibit an increased responsiveness. However, akathisia (i.e., the "restless legs syndrome") which is induced by the antipsychotic treatment may increase activity. Major psychotic symptoms gradually disappear over a period of days or weeks (Baldessarini, 1991; Reynolds, 1992).

RESEARCH VALIDATION

Low doses of antipsychotic drugs in animals suppress operant behavior without any loss of spinal reflexes. Exploratory behavior decreases, responses become fewer and slower without any loss of the ability to discriminate between stimuli. Conditioned avoidance responses are inhibited, as is feeding behavior. At high doses, antipsychotics induce catalepsy, a condition in which an animal becomes immobile but can be placed in any posture and will remain fixed in that position. Coma is not induced even by very high doses of antipsychotics. A variety of other effects on motor activity can be induced and these are detailed in the section on side effects (Baldessarini, 1991 ). Antipsychotic drugs affect most areas of the CNS. Most antipsychotic drugs have in common an ability to act as antagonists at the DA receptor. However, different antipsychotics act at different subtypes of DA receptor and other neuro­ transmitter receptors to differing extents (Reynolds, 1992). PSYCHOTIC DISORDERS 63

The extrapyramidal side effects of antipsychotics are produced mainly by their action as DA receptor antagonists in the nigrostriatal pathway. The antagonistic action of antipsychotics on the mesolimbic and mesocortical DA systems is considered to be at least partially responsible for their therapeutic effects in alleviating psychotic symptoms. However, it has also been suggested that the striatum may be important in the etiology of schizophrenia and that antipsychotic action in the nigrostriatal pathway may be important for the clinical therapeutic effects of these drugs (Miller, 1989). The endocrine side effects (e.g., increase in prolactin secretion) of anti psychotics are thought to be a result of their action in the tuberoinfundibular system (Baldessarini, 1991 ). The hypothesis which has dominated schizophrenia research for decades is the dopamine hypothesis, which attributes schizophrenia to a hyperactivity of the DA systems, in particular an up-regulation of Dz receptors. Originally, this hypothesis was supported by several observations:

DA agonists or DA-releasing drugs like amphetamine were observed to induce a paranoid psychosis similar to paranoid schizophrenia. Drugs that were antagonists for the Dz receptor had an antipsychotic action (e.g.,chlorpromazine ). Postmortem analyses of the brains of people with schizophrenia indicated an up-regulation of D2 receptors (see Reynolds, 1992; Wiesel, 1994, for recent reviews).

The simple dopamine hypothesis has now been discredited for several reasons as follows:

1. Drugs like PCP, which block NMDA receptors, induce schizophrenic symptoms but only facilitate dopamine transmission in subcortical regions (perhaps by blocking presynaptic NMDA receptors that inhibit dopamine release). 2. Most antipsychotic drugs have extensive actions on other transmitter recep­

tors, including a. 1-adrenoceptors, histamine, receptors, 5-HT2 receptors, and muscarinic ACh receptors. Furthermore, some atypical anti psychotics like clozapine have a relatively low affinity for D2 sites and have greater action on 5-HT2, D 1 and D4 receptors. 3. Positron emission tomography (PET) studies of untreated patients with

schizophrenia have failed to show a substantial up-regulation of D2 recep­ tors, suggesting that the earlier findings supporting D2 up-regulation were a result of drug treatment with antipsychotics (see, e.g., Seeman, Guan, & VanTol, 1993). 4. D2 blockade occurs very quickly following the initiation of treatment with anti psychotics and yet many of the therapeutic effects take weeks to develop (Reynolds, 1992). 64 CHAPTERS

5. Other neurochemical abnormalities such as a reduction in GABAergic neurons and a reduction in glutamate receptors have been documented (Reynolds, 1992). However, the relationship between these neurochemical abnormalities and pathological changes in brain structure is unclear.

Currently, the DA hypothesis is regarded as incomplete at best. Clearly, some of the initial empirical support for the hypothesis was flawed and it is now known that there are many neurochemical abnormalities in schizophrenia; whether changes in DA are the cause or the effect of other neurochemical changes remains to be elucidated (see Davis, Kahn, Ko, & Davidson, 1991, for a recent review of the DA hypothesis). Because PCP (an NMDA receptor antagonist) has been found to induce schizo­ phrenic psychosis in humans, and because changes in glutamate have been documented in people with schizophrenia (e.g., Kim, Komhuber, Schmid-Burgk, & Holzmuller, 1980), a PCP model of schizophrenia has been proposed (see Ishimaru, Kurumaji, & Toru, 1994; Javitt & Zukin, 1991; Lahti, Holcomb, Medoff, & Tamminga,1995, for recent reviews). Nonetheless, the current trend among theoreticians is to move away from "single-factor" hypotheses and to recognize that the neurochemical causes of schizophrenia are complex (Hudson, Young, Li, & W arsh, 1994 ).

USES AND MISUSES OF DRUGS USED TO TREAT PSYCHOSIS

The particular antipsychotic drug that is chosen to treat psychosis depends to a large extent on the side effects that the patient can tolerate. The different antipsychotic drugs available can be divided into low and high potency categories. Low potency drugs (e.g., chlorpromazine, thioridazine, clozapine) generally cause more seda­ tion, more anticholinergic side effects, and fewer extrapyramidal side effects; high potency drugs (e.g., haloperidol, trifluoperazine, fluphenazine, thiothixine) gener­ ally cause less sedation, fewer anticholinergic side effects, and more extrapyramidal side effects. The choice between these different medications is often based on the symptoms with which the patient presents (e.g., someone with marked agitation might receive a low potency drug with more sedative side effects; someone who is already withdrawn might be better treated with a high potency drug that has fewer sedative side effects). Schizophrenic symptoms are classified into various categories, some of which respond more to antipsychotic medication than others:

1. ego dysfunctions: delusions and hallucinations, impaired judgment, anxi­ ety, agitation, lack of emotional control. 2. characterological traits: alienation and isolation, reduced self-esteem, lack of social skills. PSYCHOTIC DISORDERS 65

3. negative symptoms: flat affect, "poverty of thought," anhedonia, lack of psychomotor activity, reduced perception (e.g., inability to sense pain; see Figs. 5.1 and 5.2).

It is mainly the ego dysfunction symptoms that antipsychotic drugs will alleviate. The negative symptoms are often resistant to antipsychotic treatment. In the first instance, low to moderate doses of an antipsychotic medication are used and the dose is "titrated" up until symptomatic relief is obtained. Although some psychiatrists believe in starting with very high doses-a procedure known as rapid neuroleptization-this approach is very controversial. Initially, the antipsychotic will cause a decrease in arousal, agitation, and an increase in emotional control. Major psychotic symptoms such as delusions and hallucinations generally take longer to respond to antipsychotic treatment. In general, !he major symptoms take 2 to 3 weeks to show a substantial improvement.

( phenothiazines )

ego dysfunction butyrophenones

thioxanthenes characterological traits ( )

atypical antipsychotics

atypical negative symptoms antipsychotics

FIG. 5.1. Drug treatment options for psychotic disorders.

time to onset of therapeutic action effect

( phenothiazines ) DA antagonist days/weeks

butyrophenones DA antagonist days/weeks

thioxanthenes DA antagonist days/weeks

atypical DA/SHT days/weeks ant1psychotics antagonist

FIG. 5.2. Presumed mechanisms of action for drugs used to treat psychotic disorders. 66 CHAPTERS

For a first episode of schizophrenia, a maintenance dose of an antipsychotic might be prescribed for a l-year period; for a patient who is suffering from repeated schizophrenic episodes, the medication might be continued for 2 to 3 years. However, the risk of tardive dyskinesia (see side effects section) means that for however long antipsychotic medication is continued, it should be administered at the lowest dose that achieves relief from the psychotic symptoms. There is con­ vincing evidence that the efficacy of antipsychotic drug therapy can be increased if it is used in conjunction with family therapy and other psychological interventions (Falloon et al., 1985; Wiesel, 1994); in particular, antipsychotic drugs may be effective at lower doses, thus reducing side effects (Falloon et al., 1985). There are several reasons why a patient may not benefit from antipsychotic medication. The first reason is noncompliance. The patient may not be taking the medication as prescribed. Sometimes this is due to adverse side effects, sometimes due to the psychotic condition interfering with the cognitive processes necessary to keep track of medication. Noncompliant patients are sometimes given time-re­ lease IM antipsychotic medication ("depot injections") in order to overcome these problems. The second reason is that the dose may not be high enough to achieve sympto­ matic relief. Because the absorption, distribution, and metabolism (i.e., pharma­ cokinetics) of drugs vary between different individuals, it may be necessary to monitor blood plasma levels of the drug in order to ensure that the dose is adequate. The final reason may be that the patient is suffering from Type II, negative symptom schizophrenia. Patients suffering from this form of schizophrenia often do not respond to the classical antipsychotics such as chlorpromazine. For these patients, atypical antipsychotics such as clozapine may be used (see section on side effects). Some clinicians suggest that benzodiazepines can be useful in these cases (see Wolkowtiz & Pickar, 1991, for a review). Because of the adverse side effects produced by classical antipsychotic drugs, and the fact that about 30% of people with schizophrenia do not obtain symptomatic relief from them, the search for better antipsychotic drugs continues (Edwards, 1994; Kane, 1993; Reynolds, 1992). Three atypical antipsychotic drugs that (in some cases) alleviate schizophrenic symptoms with fewer side effects, are clozapine, risperidone, and remoxipride. Clozapine is not new, but was developed in the 1960s and withdrawn due to the risk of agranulocytosis (see the next section). It was reintroduced in the United States in 1990 for treatment of refractory schizophrenia (e.g., Type II, negative symptom schizophrenia), conditional on strict hematological monitoring. Clozap­ ine is a low affinity, low efficacy D2 receptor antagonist, but has significant actions at the Dt and D4receptors, as well as at serotonergic, adrenergic, histaminergic, and muscarinic receptors (see Kane, 1993; Reynolds, 1992, for reviews). Some studies suggest that clozapine may be particularly useful in the treatment of adolescent schizophrenia (Birmaher, Baker, Kapur, Quintana, & Ganguili, 1992); others sug­ gest that it may have long-term benefits for cognitive function in people with PSYCHOTIC DISORDERS 67 schizophrenia (Buchanan, Holstein, & Breier, 1994). Clozapine has been reported to be effective in the treatment of schizoaffective and bipolar disorders, and in the treament ofL-Dopa-induced psychosis in Parkinson's disease (see Kane, 1993, for a review; see chapter 7). Risperidone is a high affinity S-HT2 receptor antagonist that also affects adren­ ergic and D2 receptors. It (and the S-HT2 antagonist, ritanserin) have proven especially useful in the treatment of negative symptom schizophrenia (Edwards, 1994). Remoxipride is a selective low efficacy D2 receptor antagonist with a preference for extrastriatal D2 receptors. It has similar efficacy to haloperidol in treating both the positive and negative symptoms of schizophrenia (Kane, 1993).

LIMITATIONS AND SIDE EFFECTS

Antipsychotic drugs are relatively safe (i.e., they have a high therapeutic index) and can be used over a wide range of doses. The three main categories of side effects experienced with antipsychotic medication are sedation, anticholinergic, and extrapyramidal side effects . The anticholinergic side effects include: dry mouth, blurred vision, constipation, urinary retention, sometimes confusion and loss of memory, especially in the elderly. These side effects are due to the blockade of muscarinic acetylcholine receptors in the peripheral nervous system. The extrapyramidal side effects include the following:

l. Parkinson-like effects: muscular rigidity, tremor, bradykinesia (i.e., slow­ ness of movement), masklike facial expression. Sometimes anti-Parkin­ sonian drugs may be given to reduce these side effects. 2. Akathisia: a restlessness that is distinct from anxiety. Sometimes this is treated with an anxiolytic drug such as a benzodiazepine (e.g., lorazepam; also see Wolkowitz & Pickar, 1991) or an anti-Parkinsonian drug. 3. Acute dystonias: muscle spasms, especially of the head/neck. Anti-Parkin­ sonian drugs are often used to treat this side effect (e.g., benzotropine mesylate). 4. Tardive dyskinesia: a very serious, irreversible condition that can develop late in antipsychotic therapy. Symptoms include: involuntary sucking and smacking lip and mouth movements, chorea of the limbs. Drugs such as baclofen (a GABAs agonist) and benzodiazepines are used to treat tardive dyskinesia, but not very successfully. If tardive dyskinesia develops, antip­ sychotic treatment must stop (see Reynolds, 1992, for a review).

The atypical antipsychotic, clozapine, was initially regarded as a breakthrough because of the low incidence of extrapyramidal side effects. Unfortunately, it caused several deaths due to agranulocytosis (a reduced production of leukocytes in the bone marrow) and was withdrawn from the market. Although it is now used 68 CHAPTERS only with hematological monitoring, there are still occasional fatalities (see Kane, 1993, for a review). Other side effects of clozapine include seizures (3% of patients), sedation, tachycardia, and dizziness. Risperidone has a very low risk of ex­ trapyramidal side effects; however, it may result in concentration difficulties and sedation. Remoxipride also has a low risk of extrapyramidal side effects; however, it may cause tiredness, insomnia, tremor, concentration difficulties, and akathisia (see Kane, 1993, for a review). Tolerance develops to many of the sedative effects of antipsychotic drugs. Although they are not regarded as having a high dependence liability, some physical dependence has been reported.

INTERACTIONS

Antipsychotic drugs can potentiate the actions of sedatives (including alcohol), analgesics, antihistamines and cold medications. Chlorpromazine increases drug­ induced respiratory depression.

DOSAGES

The dose ranges for antipsychotic drugs are listed in Table 5.1.

TABLE 5.1 Antipsychotic Drugs

Drug Brand Name Dose Range (mg)

Phenothiazines chlorpromazine (Thorazine) 100--1,200 thioridazine (Mellaril) 100--800 fluphenazine (Prolixin) 2-40 perphenazine (Trilafon) 8-64 trifluoperazine (Stelazine) 5-60 Thioxanthines thiothixine (Navane) 6-60 chlorprothixine (Taractan) 75-600 Butyrophenones haloperidol (Haldol) 2-100 Other Compounds loxapine (Loxitane) 20--250 pimozide (Orap) 1-20 clozapine (Ciozaril) 100--900

Note. From Pirodsky and Cohn ( 1992), Burwell ( 1992). Note that these are daily doses for adults, usually intended to be divided over each day. PSYCHOTIC DISORDERS 69

SUGGESTED READINGS

Baldessarini, R. (1991 ). Drugs and the treatment of psychiatric disorders. In A. Goodman Gilman, T. W. Rail, A. S. Nies, & P. Taylor (Eds.), The pharmacological basis of therapeutics (8th ed., Vol. I, pp. 383-435). New York: Pergamon. Davis, K. L., Kahn, R. S., Ko, G., & Davidson, M. (1991). Dopamine in schizophrenia: A review and reconceptualization. American Journal of Psychiatry, 148, 1474-1486. Dolan, R. J., Fletcher, P., Frith, C. D., Friston, K. J., Frackowiak, R. S. J., & Grasby, P.M. (1995). Dopaminergic modulation of impaired cognitive activation in theanteriorcingulate cortex in schizophrenia. Nature, 378, 180--182. Edwards, J. G. (1994). Risperidone for schizophrenia. British Medical Journal, 308, 1311-1312. Kane, J. M. (1993). New antipsychotic drugs. A review of their pharmacology and thera­ peutic potential. Drugs, 46, 585-593. Olney, J. W., & Farber, N. B. (1995). Glutamate receptor dysfunction and schizophrenia. Archives of General Psychiatry, 52, 998-1007. Reynolds, G. P. (1992). Developments in the drug treatment of schizophrenia. Trends in Pharmacological Sciences, 13, 116-121. Seeman, P., Guan, H. C., & VanTol, H. H. M. (1993). Dopamine D4 receptors elevated in schizophrenia. Nature, 365, 441-445. Silbersweig, D. A., Stern, E., Frith, C. D., Cahill, C., Holmes, A., Grootoonk, S., Seaward, J., McKenna, P., Chua, S. E., Schnorr, L., Jones, T., & Frackowirk, R. S. J. (1995). A functional neuroanatomy of hallucinations in schizophrenia. Nature, 378, 176-179. Waddington, J. L. (1993). Schizophrenia: developmental neuroscience and pathobiology. The Lancet, 341, 531-536. Chapter 6

Drug Management for Chronic Pain

BACKGROUND INFORMATION

Chronic pain is ongoing pain arising from a general medical, neurological, or psychiatric disorder. According to the DSM-IV (American Psychiatric Association, 1994 ), pain disorder is characterized by pain of sufficient severity to cause distress and disrupt normal life. DSM-IV recognizes three subcategories of pain disorder:

1. pain disorder associated with psychological factors, 2. pain disorder associated with both psychological factors and a general medical condition, and 3. pain disorder associated with a general medical condition.

Pain disorder is classified as "acute" if the duration is of less than 6 months, as "chronic" if the duration is greater than 6 months. Psychological factors are seen to play an important role in the perception of pain, and social, family, and employment-related problems are common. Substance abuse may develop as a result of chronic pain disorder (American Psychiatric Association, 1994). Self-medication is common among chronic pain sufferers and before seeking professional help, individuals may have tried a number of over-the-counter (OTC) analgesics as well as prescription analgesics prescribed for other purposes or to other individuals. It is not uncommon for chronic pain sufferers to conceal drug use from caregivers. Toxicological urine screening is often recommended, not only to assess the current level of medication but also to avoid interactions between prescribed and nonprescribed drugs and the possibility of unnecessary invasive 70 DRUG MANAGEMENT FOR CHRONIC PAIN 71 procedures (Berndt, Maier, & Schutz, 1993; see chapter 10, this volume). For the purposes of this discussion, chronic pain is divided into two general categories: chronic pain associated with shortened life expectancy and long-term chronic pain that may require management for months or even years. Although the treatment of the different types of pain within the two categories may be similar, their overall management strategies will differ significantly.

Chronic Pain Associated With Shortened Life Expectancy Chronic pain is commonly experienced by individuals with terminal cancer or AIDS. As the disease progresses, the prevalence and severity of the pain usually increases. The aim of drug therapy is to provide maximum control of pain and, as far as possible, to maintain quality of life. Long-term drug treatment effects, such as the development of dependence, are of less relevance. The optimal treatment regimen will be dependent on the immediate needs of the patient and may vary widely even between patients with almost identical disease states. In some cases, patients may choose a less than complete level of pain control in order to remain alert in the company of friends and family. In other cases, the sedative and euphoric side effects of some analgesic drugs will be desirable in order to reduce fear and distress. The management of pain associated with HIV differs from the management of advanced cancer pain in that the underlying cause of the pain (e.g., opportunistic infection) may be treatable (see O'Neill & Sherrard, 1993, for a review). However, the treatability of underlying causes has led, in some cases, to insufficient pain control; therefore analgesia needs to be considered independently of concomittent treatments. A complicating factor in AIDS may be the presence of several pain producing disorders (e.g., gastrointestinal infection and arthritis), that respond to different analgesics. A further consideration will be the immunosuppressant action of some of the more powerful analgesics (e.g., morphine) on an immune system that is already compromised.

Long-Term Chronic Pain Long-term chronic pain represents a major social and economic problem. It is estimated that at any given time in the United States, 2 million workers are incapacitated by chronic pain (Kelly, 1985). This category of pain management is especially problematic because in addition to providing adequate pain control for a period of months or years, it is also necessary to avoid the long-term effects of analgesic use such as dependence and/or toxicity. The treatment of long-term chronic pain is best managed through a pain clinic where patients will have access to a multidisciplinary approach to pain management. In almost all cases, patients suffering from chronic pain will benefit from additional 72 CHAPTER 6 management strategies (e.g., relaxation or stress management techniques, hypno­ therapy, or physiotherapy), depending on the underlying cause of the pain.

Mechanisms of Pain Pain is a complex sensation under the control of both central and peripheral mechanisms (Price, 1988). Peripherally, painful stimuli are sensed by the free nerve endings of the afferent fibres (nociceptive afferents) of primary afferent pain neurons located in the dorsal root ganglia of the spinal cord. Nociceptive afferents are found in skin, muscle, and viscera. There are two types of nociceptive afferent fibres. The small, myelinated A fibers sense heat and mechanical stimulation and their activation is associated with short latency sharp or stabbing pain. The small, unmyelinated C fibers sense chemical stimulation as well as heat and mechanical stimulation, and are known as polymodal receptors; activation of these fibers is associated with more slowly developing aching or burning pain. It has been demonstrated that the putative peptide neurotransmitter, substance P, is released from C fiber terminals and that the release of substance P may be blocked by morphine. Within the spinal cord there are two types of second-order pain neurons that receive input from the primary afferent pain neurons, via interneurons in the substantia gelatinosa: relay neurons and interneurons. The axons of the relay neurons project to the brainstem and thalamus, the interneurons project to relay neurons or other interneurons. The axons of the relay neurons ascend in the anterolateral portion of the lateral column of the spinal cord (the anterolateral system) to the thalamus and reticular formation. The axons of relay neurons in lamina I of the dorsal horn project to the thalamus. These neurons are activated only by pain receptors and mediate the sensation of sharp or stabbing pain on the body surface. The axons of relay neurons in lamina V of the dorsal horn project to the reticular formation and thalamus. These neurons are activated by input from mechanoreceptors and thermoreceptors, as well as pain receptors, and mediate the sensation of deep and diffuse pain. From the reticular formation there are projec­ tions to the periaqueductal gray region of the midbrain. Via the thalamus, the periaqueductal gray has reciprocal connections with the limbic system and it has been suggested that cognitive and emotional modulation of pain perception may be through this pathway. It has been demonstrated that stimulation of the periaqueduc­ tal gray region in humans and experimental animals produces analgesia. This stimulation-produced analgesia can be blocked by administration of the opioid antagonist, naloxone, and by depletion of serotonin, which also blocks the action of opioids (see Fig. 6.1). Pain of central origin may occur as a result of lesions in pain-related structures such as the thalamus, or damage at any point along the nociceptive pathways, including the spinal cord and peripheral nerves. Pain of central origin is often resistant to classical analgesics and treatment may require the use of adjuvant analgesics (see discussion on adjuvant analgesic drugs). DRUG MANAGEMENT FOR CHRONIC PAIN 73

anterolateral system

relay neurons o-m spinal cord

FIG. 6.1. Schematic illustration of the major pathways involved in the sensation of pain.

BASIC DESCRIPTION OF DRUGS USED FOR MANAGEMENT OF CHRONIC PAIN

Narcotic Analgesics Analgesics in this category, known as opioids, include natural and synthetic analogs of alkaloids derived from opium and synthetic agonists of the opiate receptors. Opioids act by binding to opiate receptors, which are also receptors for the endogenously occurring opioids, endorphins, enkephalins, and dynorphins. The analgesic action is thought to be produced by inhibition of nociceptive neurons in the dorsal horn of the spinal cord, preventing or decreasing the transmission of pain signals to the brain, as well as by direct action on various populations of neurons in the brain. At present, morphine is still the most effective drug commonly used for severe pain and it is the benchmark analgesic for assessing the efficacy of other analgesics. Morphine relieves pain without loss of consciousness and without diminishing 74 CHAPTER 6 other sensory experiences. Patients may report that pain is diminished or completely relieved, or that the pain is still there but that it does not bother them anymore. Morphine is most effective on dull, aching pain, but at high enough doses, even sharp, stabbing pain will be relieved. Other synthetic opioids have a similar action to morphine. Methadone is of similar potency to morphine and offers an alternative for patients who tolerate morphine poorly.

Pharmacokinetics. Opioids are well absorbed from the gastrointestinal tract after oral administration and after IM or SC injection. With all opioids, the amount of drug available after oral administration is less (approximately 25% for morphine) than after injection, due to first-pass metabolism by the liver. Codeine, methadone, levorphanol, and oxycodon have the greatest bioavailability after oral administration (approximately 60% ). The duration of action of most orally admin­ istered opioids is 4 to 6 hours. At therapeutic plasma concentrations, approximately one third of the drug is protein-bound. Plasma half-life for morphine is 2 hours, compared to 15 to 40 hours for methadone. Opioids are metabolized by the liver and excreted mainly in the urine; only small quantities are excreted unchanged.

Behavioral Effects. All drugs in the narcotic analgesic category have the potential to produce tolerance and dependence with repeated administration; their use is, therefore, subject to certain restrictions. Codeine has the least dependence liability of the opioids. In addition to producing analgesia, activation of opioid receptors may cause respiratory depression, euphoria, sedation, drowsiness, mood changes, dysphoria, and miosis (constriction of the pupil of the eye). Occasionally, delirium develops and sensitivity to pain may increase as the dose wears off. Because of the prevalence and severity of opioid side effects, opioids are sometimes combined or coadminis­ tered with other classes of analgesics (e.g., nonsteroidal anti-inflammatory drugs) in an attempt to optimize analgesia while decreasing side effects. Codeine is particularly effective when combined with aspirin-like compounds. A recent, and promising, line of research involves coadministration of morphine with drugs that increase available serotonin, and potentiate the analgesic effects of morphine without increasing side effects (Coda, Hill, Schaffer, Luger, Jacobson, et al., 1993).

Non-Narcotic Analgesics Drugs in this category are generally effective in relieving mild to moderate pain, and reducing fever. Nonsteroidal anti-inflammatory drugs (NSAIDs) also reduce inflammation, so that part of their analgesic action is due to reduction of the source of pain. Acetaminophen (paracetamol), while having virtually no anti-inflamma­ tory action, does not have many of the side effects of aspirin-like drugs, and so offers an effective alternative to aspirin when anti-inflammatory properties are not necessary. DRUG MANAGEMENT FOR CHRONIC PAIN 75

The mechanism of action of this category of drugs is not fully understood; however, aspirin and similar drugs have been demonstrated to inhibit the production of prostaglandins, which are known to contribute to inflammatory responses and fever. Inhibition of the synthesis of gastric prostaglandins may account for the gastric side effects associated with these drugs. Less is known about the action of acetaminophen. It has been demonstrated to only weakly inhibit prostaglandin synthesis, which might explain its lack of anti-inflammatory properties and gastric side effects; however the mechanism of its analgesic action and fever-reducing properties is not understood. Most of the analgesic effects of aspirin-like drugs are due to peripheral action although some CNS effects may be involved.

Pharmacokinetics. Aspirin and similar drugs are rapidly absorbed from the stomach and small intestine following oral administration. After absorption, the drugs are distributed throughout most body tissues. Plasma half-life is approxi­ mately 2 hours for most drugs in this category, some exceptions are aspirin (15 minutes), salicylate at high therapeutic doses (15 to 30 hours), and naproxen (14 hours). Metabolism takes place in many tissues, particularly the liver, and metabo­ lites are mostly excreted in the urine.

Behavioral Effects. These drugs lack the behavioral effects associated with narcotic analgesics. There is no liability for the development of tolerance and dependence.

Adjuvant Analgesic Drugs Adjuvant analgesic drugs are drugs that are not usually considered to be analgesics, but that may produce analgesic effects in some cases. Steroids are used in cases of severe inflammatory disorders and to reduce edema; however, a discussion of the use of steroids as analgesics is outside the scope of this book. The potent and selective 5-HT1 receptor agonist, sumatriptan, is used specifically for the acute treatment of migraine and cluster headache. Ergot alkaloids, most of which are vasoconstrictors, are also used for the symptomatic treatment of migraine, the most commonly used being ergotamine. The ~-adrenergic antagonist, propranalol, is used for migraine prevention as is methysergide, an ergot derivative that acts as a 5-HT receptor antagonist. Other drugs in this category include antiepileptic drugs (chapter 8), sedatives (chapter 3), muscle relaxants (chapter 3), and antidepressants (chapter 4; see Fig. 6.2).

Pharmacokinetics. Sumatriptin is effectively absorbed after SC admini­ stration (bioavailability, 96%) with decreased bioavailability after oral administra­ tion (14%; Plosker & McTavish, 1994). It is extensively metabolized and both the metabolites and parent drug are excreted in urine and feces. 76 CHAPTER6

narcotic analgesics shortened life expectancy non-narcotic analgesics long-term

adjuvant analgesics

FIG. 6.2. Drugs used in the treatment of chronic pain.

Ergotamine, administered orally, is subject to extensive first-pass metabolism and bioavailability, even when administered with caffeine to improve absorption, is probably less than I%; bioavailability increases to 50% with IM injection. Headache relief occurs in 15 minutes to 2 hours after injection, but may not occur until up to 5 hours following oral administration and, in severe attacks, may fail. Ergot derivatives are metabolized by the liver and metabolites are excreted in the bile; only traces of unchanged drug are excreted in urine and feces.

RESEARCH VALIDATION

There are a number of animal models used to determine the effectiveness of analgesic drugs, as well as to study the mechanisms underlying pain. In behav­ ioral tests, the latency of the animal to terminate a painful stimulus (e.g., the tail-flick reflex test) is measured in the absence of a drug and following the administration of the analgesics being tested. The longer the latency of the reflex, the greater the analgesic effect of the drug is said to be. The analgesic properties of test drugs are usually compared to the analgesic properties of morphine, although in the case of mild analgesics, the comparison is sometimes made to aspirin. Analgesic drugs are also tested on human volunteers. Painful but nondamaging stimuli (e.g., pressure to the achilles tendon or electrical stimulation of a tooth) are applied before and after administration of analgesic drugs. The subjects are then asked to rate the level of analgesia under the different conditions; often other, less subjective, measures are used (e.g., the amount of pressure applied to the tendon before the subject terminates the trial). In this way, the efficacy of analgesics can be tested and compared under controlled laboratory conditions. A shortcoming of such tests is that the type of pain produced by experimental means will be acute, cutaneous, or muscular, probably the "sharp" type of pain, rather than the slowly developing, " aching" pain, often encountered in clinical settings. In addition, many of the emotional factors, such as fear and anxiety, contributing to pain perception may be missing. The experimental subject knows the pain will stop after a certain amount of time, and may have been paid for submitting to the experience. DRUG MANAGEMENT FOR CHRONIC PAIN 77

USES AND MISUSES OF DRUGS USED TO TREAT CHRONIC PAIN

Although any number of conditions can produce chronic pain, the following categories are common and are generally representative of the various types of chronic pain that may be encountered.

Headache In recurrent headache, possibly more than any other category of pain, there is a cognitive and emotional component that must be considered. Chronic stress and anxiety make a significant contribution to the frequency, intensity, and duration of headaches in many headache-prone individuals. In some cases, headache relief will ultimately come not from analgesics but from the application of cognitive and behavioral strategies and stress reduction techniques. Recurrent headache may be divided into the four categories discussed here. Simple Headache. Simple headaches are usually of short duration and may occur frequently throughout the day. They are usually precipitated by stress, tension, or emotional problems and will often decrease in frequency and severity, or disappear entirely, when the underlying emotional component is resolved. Although simple headaches do not produce the vomiting and nausea associated with migraine, mild nausea, particularly following repeated episodes, may occur. Simple headaches are usually treated with non-narcotic analgesics, aspirin, ibupro­ fen, or acetaminophen.

Tension Headache. The tension headache is the most common type of chronic headache. It is caused by muscle contractions, usually of temporal and occipital muscles, which cause pain by exerting pressure on pain-sensitive tissue. The pain is usually described as "aching" rather than "throbbing" and the skin of the head and neck may be tender to the touch. As with the simple headache, there is a stress-related component to tension headaches that must be considered. The headaches usually begin in late afternoon or early evening and may be accompanied by nausea. If non-narcotic analgesics are ineffective then adjuvant analgesics may be useful (e.g. sedatives alone, or combined with a non-narcotic analgesic, are effective in some cases). The tricyclic antidepressant, amitriptyline, has been reported to reduce the duration of tension headaches, but does not eliminate them. Codeine combined with aspirin is reported to be very effective.

Migraine and Cluster Headache. Migraine is a headache of vascular origin, thought to be caused by dilation of cerebral blood vessels. The onset of a migraine attack may be preceded by an aura of 10 to 20 minutes duration (classic migraine) or may occur without an aura (common migraine). Migraine pain is usually unilateral and described as "throbbing" or "pulsing," of moderate to severe 78 CHAPTER 6 intensity, and of 4 to 72 hours duration. The headache may be accompanied by nausea, vomiting, and increased sensitivity to light and sound. Treatment for migraine may be symptomatic and/or preventativ~. Sumatriptan is the most effec­ tive symptomatic treatment available (see Plosker & McTavish, 1994, for a review). In controlled clinical trials, 50% to 67% of migraine patients reported headache relief I hour after oral administration, 70% to 80% reported relief 1 hour after SC administration (Plosker & McTavish, 1994 ). In some patients (approximately 40%) who respond to sumatriptin treatment, the headache may recur; however, this headache is usually alleviated by a second dose of sumatriptin. Other drugs for symptomatic treatment include the ergot derivatives, particularly ergotamine, which are taken at the onset of the attack and repeated at 30-minute intervals until the maximum dose has been reached, or the headache subsides. For individuals with frequently recurring migraine, preventative, rather than symptomatic, treatment may be preferable. Propranalol is the preferred drug and is effective in approximately 70% of patients. Methysergide is less effective than propranalol but may be useful in cases where propranalol is not effective. In some people, a relatively mild analgesic (e.g., ibuprofen) taken at the onset of the aura, before the onset of pain, will abort the migraine or greatly reduce its severity. Cluster headache is a rare (0.1% of the general population) type of headache that is usually severe, unilateral, of short duration but recurs one to three times daily. Attacks continue for periods of weeks or months separated by headache-free periods of months or years, hence the term cluster. Headaches are accompanied by nasal congestion, lacrimation (discharge of tears), and ptosis (drooping of the upper eyelids). It has been suggested that cluster headaches may be initiated by sinus inflammation that leads to carotid arterial tree dilation. Cluster headaches respond well to symptomatic treatment with sumatriptin, approximately 75% of patients experience relief within 15 minutes (see Plosker & McTavish, 1994, for a review). Prednisolone, a corticosteroid, administered for a short period (months), may be effective in the prevention of cluster headaches.

Arthritis and Back Pain Arthritis, back pain, and other pain-producing disorders of musculoskeletal origin almost always require more treatment than just effective analgesia, so multiple management strategies need to be initiated at the onset of the disorder. Although it may be the case that therapeutic advantages may be obtained from pain relief alone (e.g., by allowing movement in painful arthritic joints and preventing permanent stiffening), it is also possible that analgesia alone may mask an underlying disorder, allowing it to remain or become worse. Arthritis is a common disorder with advancing age, but there are also forms of the disease that affect younger people, even children. There are more than 100 types of arthritis, some are mild and inconvenient, others are severe and debilitating. One thing that all of the types of arthritis have in common is the presence of chronic DRUG MANAGEMENT FOR CHRONIC PAIN 79

pain. In milder forms of arthritis, NSAIDs and some form of physiotherapy are usually sufficient. As long as it remains effective, the drug of choice is aspirin or another NSAID; the choice will depend on the strength of analgesia required and the ability of the individual to tolerate the drug. Acetaminophen is not the drug of choice because of its lack of anti-inflammatory properties. In severe forms of arthritis, therapy may include NSAIDs plus corticosteroids (e.g., prednisolone) or immunosuppressive drugs (e.g., methotrexate). In very painful forms ofthe disease, narcotic analgesics, particularly in combination with aspirin or another NSAID, may be required. Back pain is another common form of musculoskeletal pain and is one of the most common causes of workers' compensation claims. In most forms of back pain, severe bouts of pain are usually of fairly short duration, interspersed with low-level pain or pain-free periods. The starting place for analgesic therapy depends on the acute state of the patient. A persistent, "nagging" ache may be treated with aspirin or another NSAID, plus physiotherapy. An acute attack of sciatic nerve-associated pain may require complete bed rest and an antiinflammatory plus a narcotic analgesic (e.g. aspirin plus codeine). Adjuvant analgesics, which may be useful during acute episodes, are drugs with sedative and muscle relaxant properties (e.g., diazepam or baclofen).

Pain of Neural Origin Pain of neural origin includes trigeminal neuralgia or neuropathy, nerve damage associated with trauma, for example, amputation of a limb (phantom limb pain), spinal cord injury, broken bones and severe sprains, and peripheral neuropathies (e.g., diabetic neuropathy). Pain of neural origin is often resistant to both narcotic and non-narcotic analgesics and will probably require the use of adjuvant analgesics. There are distinct types of pain associated with these disorders and the choice of treatment will depend on which type of pain occurs or predominates. Pain described as sharp or lancing, of episodic occurrence, usually responds well to anti-epileptic drugs (e.g., carbamazepine or phenytoin). Pain described as continuous background pain ("buzzing," "burning," "humming," "like an ongoing electric shock") often responds to tricyclic antidepressants (e.g., imipramine). There is also evidence that antidepressant SSRis are effective. Baclofen is often successful in the treatment of trigeminal neuralgia. Recent reports suggest that the NMDA receptor antagonist, ketamine, may be useful for the treatment of several types of neural pain.

LIMITATIONS AND SIDE EFFECTS

Narcotic Analgesics All opioids have a potential for tolerance and dependence, which limits their use and necessitates controlled withdrawal at the end of the drug treatment. These 80 CHAPTERS effects are less for codeine than for other opioids. Morphine and similar opioids produce a range of side effects that include respiratory depression, euphoria, sedation, drowsiness, mood changes, dysphoria, miosis, suppression of the immune system, bradykinesia (slowness of movement), and urinary retention. In addition, they also produce significant gastrointestinal side effects including constipation (laxatives are essential, except in the case of AIDS-related diarrhea) and nausea and vomiting that may be reduced by antiemetics. Levorphanol is reported to produce less nausea and vomiting than morphine, and it is reported that meperidine causes less constipation and urinary retention. Methodone side effects are similar to morphine; however, the elimination half-life is long and unpredictable and there is a potential for toxic cumulative effects. Doses and dose intervals need to be established on an individual basis and careful monitoring of patients is essential (Fainsinger, Schoeller, & Breura, 1993).

Non-Narcotic Analgesics The most common side effect ofNSAIDs is a tendency to develop gastric irritation and ulceration; with long-term use, anemia may occur as a result of repeated stomach bleeding episodes. Kidney or liver damage may occur with prolonged administration, particularly at high doses. Platelet aggregation is disrupted, result­ ing in prolonged bleeding time. All drugs in this category should be avoided by individuals hypersensitive to aspirin. Indomethacin has a high incidence (30%- 50%) of reported side effects, which in addition to gastric side effects include CNS effects such as severe frontal headache (25%-50% of patients with long-term use), dizziness, vertigo, and confusion. Severe depression, psychosis, and suicide have also been reported. Similar CNS effects are reported in 10% of patients taking sulindac. The reported incidence of gastric side effects with ibuprofen is less than for aspirin, however, occasional ocular disturbances are reported. Acetaminophen lacks the gastric irritant effects ofNSAIDs and does not prolong bleeding. However, there is a potential for liver damage at therapeutic doses with prolonged use and acute overdose often results in fatal liver damage (Zimmerman, 1993). In addition, there is a potentially damaging interaction with alcohol (see discussion on interactions).

Adjuvant Analgesic Drugs Sumatriptin is reported to be well tolerated, particularly after SC administration. Side effects reported after oral administration include nausea, vomiting, fatigue, dizziness, and vertigo. These effects are transient and occur within 60 minutes of drug administration. Sumatriptan is not recommended for patients with heart disease or uncontrolled hypertension. DRUG MANAGEMENT FOR CHRONIC PAIN 81

Ergotamine may cause nausea and vomiting, and weakness in the legs. Muscle pains may occur in the arms and legs, and there may be numbness and tingling in the fingers and toes. Ergotamine should not be used in individuals with liver, kidney, or vascular disease. Ergotamine-induced gangrene has been reported, so it should not be used if infection is present. Methysergide may cause gastrointestinal side effects, including nausea and vomiting, and CNS effects, including drowsiness, light-headedness, euphoria, confusion, insomnia, and hallucinations. With pro­ longed treatment, inflammatory fibrosis may occur, so a 3-week discontinuation of treatment every 6 months is recommended. Ketamine's side effects include sedation, diplopia (i.e., double vision), and nystagmus; it may also produce cognitive dysfunction such as hallucinations. As steroids are immunosuppressants, their use in AIDS-related disease is questioned (see chapter 10 for other steroid side effects).

INTERACTIONS

There is a synergistic actiOn between opioids and aspirin-like drugs, which serves to increase effective analgesia while decreasing unwanted side effects. The depres­ sant effects of opioids may be increased by tricyclic antidepressants and phe­ nothiazines. MAGis may also increase depressant effects. Severe interactions between meperidine and MAGis may include respiratory depression, convulsions, and delirium. Chlorpromazine has also been reported to increase the respiratory depressant effects of meperidine. Phenytoin has been reported to accelerate the metabolism of methadone and cause withdrawal symptoms. Many of the NSAIDs bind to plasma proteins, displacing other drugs; therefore, adjustment of dosage may be necessary. Indomethacin antagonizes the action of several types of antihypertensive drugs and acute renal failure has been associated with concomitant administration of the potassium-sparing diuretic, triamterene. An important interaction occurs between alcohol and acetaminophen (see Zim­ merman, 1993, for a review). Alcohol increases the hepatotoxicity of acetamino­ phen by increasing acetaminophen metabolism and depleting glutathione, which binds and detoxifies the active metabolite of acetaminophen. There is greater acetaminophen toxicity in heavy alcohol users.

DOSAGES

Table 6.1 shows the dose ranges, dependence factors, and actions of some common analgesics. TABLE 6.1 Some Common Analgesics

Drug Dose Range (mglday) Dependence Action

Non-Narcotic Analgesics

Aspirin 300-4,000 No NSAID, reduces mild to moderate pain, lowers fever, anti-inflammatory Ibuprofen 1,200-1,600 No NSAID, as above but more potent Acetaminophen 500-4,000 No Reduces mild to moderate (paracetamol) pain, lowers fever, no anti- inflammatory action Narcotic Analgesics . Codeine Phosphate 15-180 Yes Reduces mild to moderate . pain Morphine 10-30. Yes Very effective analgesic Pethidine 50-100 Yes Synthetic opioid, moderate to severe pain Adjuvant Analgesics Muscle Relaxants

Baclofen 10-80 ? Reduces pain due to muscle spasm Diazepam 10-40 Yes As above but sedation limits usefulness Antidepressants

Amitriptyline 50-150 No Reduces "burning pain," trigeminal pain Desipramine 50-150 No As above Imipramine 50-150 No As above Anxiolytics

Chlordiazepoxide 15-100 Yes May be useful in tension headache Diazepam 5--40 Yes As above Anti-epileptics

Carbamazepine 400-1,200 No Reduces "lancing," trigeminal pain Phenytoin 300-500 No As above Sedatives/Hypnotics

Phenobarbital 60-250 Yes Sometimes used for tension headache Chloral Hydrate 50-750 Yes Flurazepam 15-30 Yes Nitrazepam 5-10 Yes

Note. *Dependent on individual drug history. **Dose ranges are for oral administration.

82 DRUG MANAGEMENT FOR CHRONIC PAIN 83

SUGGESTED READINGS

Andersson, S., Bond, M., Mehta, M., & Swerdlow, M. (Eds.). (1987). Chronic non-cancer pain. Lancaster: MTP Press. O'Neill, W. M., & Sherrard, J. S. (1993). Pain in human immunodeficiency virus disease: A review. Pain, 54, 3-14. Price, D. D. ( 1988). Psychological and neural mechanisms ofpain. New York: Raven Press. Wall, P. D., & Melzack, R. (Eds.). (1994). Textbook of pain (3rd ed.). London: Churchill Livingstone. Chapter 7

Drug Treatment for Parkinson's Disease

BACKGROUND INFORMATION

Parkinson's disease is a degenerative disorder resulting in a severe impairment of normal motor control. It was first described by James Parkinson in 1817 as paralysis agitans. Estimates suggest that about 500,000 people in the United States alone are afflicted with Parkinson's disease. The three major, characteristic symptoms of the disease are bradykinesia (slowness and poverty of movement), rigidity, and tremor (about 4Hz to 6Hz and therefore distinct from the physiological 8Hz tremor). Parkinsonian symptoms do not appear until relatively late in the course of the disease; about 80% of the DA in the basal ganglia must be lost before obvious symptoms develop. Ultimately, loss of normal motor control may become so severe that movement is impossible. In addition to motor control impairment, about one third of Parkinson's patients will develop dementia, although it is unclear whether this is a consequence of the disease itself or the drug therapy that is used to treat the disease. Patients often die from pneumonia caused by an accumulation of fluid in the lungs during long periods of immobility, or from severe bone breakage as a result of falls (Roberston, 1992). It is importa1:t tc distinguish between Parkinson's disease and other disorders that display Parkinson-like symptoms, for example, Parkinsonian side effects may appear with antipsychotic drug treatment (see chapter 5); some people develop a familial tremor of about 4 Hz, without other Parkinsonian symptoms; poisoning with heavy metals such as manganese may cause Parkinsonian symptoms such as tremor.

84 PARKINSON'S DISEASE 85

Psychiatric Disturbances in Parkinson's Disease Approximately 20% to 60% of patients suffering from Parkinson's disease also suffer from dementia; the probablitity of dementia is increased in elderly patients and those with advanced Parkinson's disease. Dementia in Parkinson's disease is characterized by memory impairment, a slowing of cognitive processes and motor performance, often accompanied by depression. In some cases, patients who suffer from Parkinson's disease and dementia are found to have the neuropathological signs of Alzheimer's disease at autopsy (APA, 1994; Caine, 1994).

BASIC DESCRIPTION OF DRUG TREATMENT FOR PARKINSON'S DISEASE

Parkinson's disease results in a loss of DA neurons in the substantia nigra pars compacta (SNc; see chapter 2), thus most of the drug therapies used attempt to compensate for the reduced DA. Administration ofDA itself is not possible because DA does not cross the blood brain barrier. Therefore, a DA precursor is adminis­ tered, levodopa (L-Dopa), which penetrates the blood brain barrier and is converted toDA.

Levodopa L-Dopa is considered to be the best available treatment for Parkinson's disease, despite the substantial problems associated with its use. About 75% of patients suffering from Parkinson's disease respond to L-Dopa treatment. It is sometimes administered in combination with other drugs (see next section).

Pharmacokinetics. When given alone, L-Dopa is initially used in doses of 0.5 to 1.0 g daily (divided into two or more equal doses). Over a period of weeks, the dose is gradually increased to 2 to 3 g/day. L-Dopa is rapidly absorbed after oral administration and peak blood plasma concentrations are reached within 0.5 to 2 hours. The plasma half-life is 1 to 3 hours. More than 95% ofL-Dopa is converted to DA in the peripheral nervous system and therefore a decarboxylase inhibitor (e.g., carbidopa) is necessary in order to increase the amount ofL-Dopa that is available to cross the blood brain barrier and to reduce the adverse side effects arising from excess DA in the peripheral nervous system (e.g., nausea and postural hypotension). When L-Dopa crosses the blood brain barrier it is decarboxylated to DA in nerve terminals (Bianchine, 1991; Robertson, 1992).

Behavioral Effects. L-Dopa reduces bradykinesia and rigidity more con­ sistently and rapidly than tremor, although a reduction of tremor is usually obtained with continued therapy. Symptomatic improvement may take between 1 and 6 86 CHAPTER 7 months to develop in some patients. L-Dopa has no obvious effect on muscle tone or movement in non-Parkinsonian patients (Robertson, 1992). Adverse side effects are numerous (see section on limitations and side effects).

Other Drug Treatments

DA Agonists. Some success has been achieved with selective D2 agonists, in particular bromocriptine. Approximately 50% of patients who receive bro­ mocriptine as the only therapy do not benefit from it. However, those who do benefit do not suffer the long-term side effects of L-Dopa therapy. Often bromocriptine is given as a supplementary therapy to L-Dopa, especially as the effects of L-Dopa begin to wear off later in the course of the disease. When given as a supplement to L-Dopa, the usual starting dose is 2.5 mg/day (in divided doses), the maximal dose is 100 mg/day (Bianchine, 1991).

DA-Re/easing Agents. Amantadine is a drug that is thought to release DA from DA-containing nerve terminals. Unfortunately, tolerance soon develops to its therapeutic effects. Nonetheless, some clinicians use amantadine as an occasional supplementary therapy (100 mg, twice daily).

MAO-B Inhibitors. Another strategy for increasing DA in the CNS of the Parkinsonian patient is to inhibit the enzyme that metabolizes DA. Selegiline specifically inhibits the B-type of MAO that metabolizes DA (but not no­ repinephrine or serotonin), thereby increasing DA concentrations in the brain. Using selegiline, L-Dopa therapy may be reduced by about 30%. There is some evidence to suggest that treatment with both selegiline and L-Dopa early in the course of Parkinson's disease may retard the development of the disease (Neal, 1988). However, Bianchine ( 1991) suggested that the beneficial effects of selegiline are transient; it is not available for general prescription in the United States.

Muscarinic Cholinergic Antagonists. Because DA released by SNc nerve terminals in the striatum normally inhibits striatal neurons and reduces the excitability caused by excitatory cholinergic interneurons, following the degenera­ tion of SNc neurons a cholinergic hyperactivity develops in striatal neurons with muscarinic ACh receptors. If the Parkinsonian symptoms are at least partly due to an uncontrolled striatal hyperactivity caused by ACh, ACh antagonists might be expected to help. Unfortunately, this is true mainly during the early stages of Parkinson's disease. Later, when the DA loss is severe, ACh antagonists are of little use. The side effects of anticholinergic drugs (see section on limitations and side effects) limit their clinical utility; however, they are sometimes used as a supple­ ment to L-Dopa and in patients who do not respond to L-Dopa or cannot tolerate PARKINSON'S DISEASE 87 its side effects. An example of an anticholinergic drug used in the treatment of Parkinson's disease is benzotropine mesylate (0.5-6.0 mg/day).

Research Validation Parkinson's disease is due to the death of neurons in an area of the midbrain known as the substantia nigra (SN). Neurons in the SN pars compacta (SNc) project to the striatum, an area of the CNS that is involved in motor control (Fig. 7.1). The SN neurons that project to the striatum release DA (the so-called "nigrostriatal path­ way" responsible for extrapyramidal side effects following antipsychotic treatment; see chapters 2 and 5), which has an inhibitory effect on striatal neurons and opposes the excitation mediated by cholinergic interneurons within the striatum. When DA is lost during the degeneration of the SN, striatal function is disturbed by cholinergic excitation that is now unchecked by inhibitory DA. The result is a severe impair­ ment of the extrapyramidal motor system that degrades both reflexive and voluntary movement. The precise function of the extrapyramidal system in motor control is still poorly understood (see Alexander & Crutcher, 1990, for a review). The pyramidal motor system, which is concerned with voluntary movement, includes pyramidal tract neurons in the cortex, some of which project directly to the spinal

STRIATUM

to cortex via thalamus

nigrostriatal pathway

SUBSTANTIA NIGRA

FIG. 7 .I. Schematic illustration of the anatomy of the nigrostriatal pathway. 88 CHAPTER 7 cord (the corticospinal projection). However, these pyramidal neurons also send collateral fibres to many other parts of the brain, including the striatum or basal ganglia (i.e., the caudate nucleus, putamen and globus pallidus, collectively re­ ferred to as the striatum). The striatum does not project directly to spinal mo­ toneurons, but appears to serve some kind of integrative and coordinative role that is still not understood (Robertson, 1992). The pyramidal, extrapyramidal, and cerebellar motor systems can be thought of as highly integrated, parallel systems rather than a simple hierachical one (see Alexander & Crutcher, 1990, for a review). The explanation for the degeneration of neurons in the SN is unknown. One peculiarity ofSNc neurons is that they not only release DA from their axon terminals in the striatum but from their dendrites that extend into another part of the SN, the SN pars reticulata (SNr). Recent studies suggest that the DA that is released into the SNr by SNc neurons and that acts on presynaptic D1 receptors on axons descending from the striatum and terminating in the SNr, may be as important for Parkinson's disease as the DA that SNc neurons release in the striatum (see Robertson, 1992 for a review). The functions of D1 and D2 receptors in this complicated system are far from well understood, but it appears to be an oversim­ plification to suggest that anti-Parkinsonian drugs exert their therapeutic effects simply by providing DA to DA-deprived striatal neurons. The situation is made still more complicated by the fact that once deprived of DA from the SNc, striatal neurons become supersensitive to DA and the remaining SNc neurons increase their release of DA; such "compensatory" mechanisms may be one reason why Parkin­ sonian symptoms do not appear until relatively late in the course of the disease (Robertson, 1992). Exactly how anti-Parkinsonian drugs affect the up regulation of DA receptors on striatal neurons is unclear. One of the major difficulties for research into Parkinson's disease has been the development of a realistic animal model of the disorder. Until recently, the best model has been the effects of 6-hydroxyDA (6-0HDA), a selective neurotoxin that causes the death of DA neurons in the substantia nigra. Unfortunately, although this kind of experimental lesion produces akinesia (i.e., loss of normal movement) similar to Parkinson's disease in humans, in non primate species it does not produce rigidity or tremor (Caine, 1994). Progress has been made in developing an animal model of Parkinson's disease as a result of the accidental synthesis of MPTP (methyl-4-phenyl-1,2,3,6- tetrahydropyridine) by an illicit drug user. Exposure to MPTP left the drug users with permanent Parkinsonian symptoms as a result of a degeneration of their nigrostriatal systems. Researchers are now trying to determine why MPTP causes this degeneration and if the cause is related to the etiology of Parkinson's disease. The CNS DA that results from L-Dopa administration presumably acts on DA receptors on striatal neurons, substituting to some extent for the loss of DA from the SNc. However, the DA also acts on many other parts of the CNS and, as mentioned earlier, the idea that the striatum is the most important site of action has recently been questioned (see Robertson, 1992, for a recent review). PARKINSON'S DISEASE 89

One of the most exciting prospects in new therapies for Parkinson's disease is the use of cellular transplants that release DA into the striatum. In some cases, nonneural DA-producing tissue (e.g., adrenal tissue) has been implanted into the striatum, releasing uncontrolled amounts of DA. In other cases, DA-containing neural tissue has been implanted; in the latter case, the implanted tissue sprouts neurites that make synaptic contact with target neurons in the striatum (see Markham, 1993, for a review). The major obstacle for transplantation therapy is the limited survival time of the transplanted tissue; however, neurally targeted gene therapy may ultimately overcome some of these problems (e.g., Anton et al., 1994 ).

USES AND MISUSES OF DRUGS USED TO TREAT PARKINSON'S DISEASE

As is clear from the section on other drug treatments, the main drug therapy for Parkinson's disease is L-Dopa; other drug treatments such as bromocriptine and acetylcholine antagonists, if they are used at all, are typically used as supplements to L-Dopa therapy. L-Dopa slowly loses its effectiveness over a period of years and, as well as having less effect on Parkinsonian symptoms, a single drug dose may exert a therapeutic effect for a shorter period of time (end-of-dose deterioration). After about 5 years, the treatment may begin to work inconsistently (the on-off effect). During this later phase of the disease, supplemental therapy with bromocriptine may be beneficial.

LIMITATIONS AND SIDE EFFECTS

The adverse side effects of L-Dopa are a result of it being converted to DA and acting at many sites in the nervous system other than the striatum. Stimulation of DA receptors in the chemoreceptor trigger area of the brainstem results in nausea and vomiting; action on gastric DA receptors may reduce the rate at which the stomach is emptied, sometimes requiring administration of a peripheral DA antago­ nist (e.g., domperidone). Dyskinesias (i.e., abnormal involuntary movements, e.g., grimacing, head bobbing, facial tics) may develop in about 50% of patients within 2 to 4 months of the initiation ofL-Dopa therapy. Confusion, psychosis, and affective disorders often occur with long-term treat­ ment (one of the consequences ofL-Dopa therapy is a transient increase in DA in other DA pathways such as the mesolimbic and mesocortical DA systems; this may result in some of the symptoms of schizophrenia). Postural hypotension is also common. Bromocriptine produces side effects similar to L-Dopa. The side effects of anticholinergic drugs include confusion, hallucinations, and delirium. 90 CHAPTER 7

TABLE 7.1 Drug Treatment for Parkinson's Disease . Drug Trade Name Dose L-Dopa Levodopa 2-3 g/day Sinemet (+ carbidopa) Bromocriptine Parlodel 2.5-100 mg/day Amantadine Symmetrel 200 mg/day Selegiline Not available in U.S. Benzotropine mesy­ Cogent in 0.5-6 mg/day late

·ooses would usually be divided over the day.

INTERACTIONS

The efficacy of L-Dopa against Parkinsonian symptoms can be reduced by other drugs such as DA antagonists (e.g., phenothiazines) and pyridoxine (however, carbidopa prevents the latter interaction). Other drugs such as clonidine, papverine, and phenytoin may also inhibit L-Dopa's therapeutic effect, but this is not clearly established (Hansten, 1989). MAOis will induce a hypertensive response, which can be prevented by administration of carbidopa (Hansten, 1989). Antimuscarinic ACh antagonists such as benzotropine mesylate may increase the breakdown of L-Dopa in the gastrointestinal tract, resulting in reduced blood plasma levels of L-Dopa. The use of more than one antimuscarinic drug may result in adverse anti-cholinergic effects such as blurred vision and urinary retention (Hansten, 1989).

DOSAGES

The dosages for drugs used to treat Parkinson's disease are listed in Table 7 .1.

SUGGESTED READINGS

Bianchine, J. R. (1991). Drugs for Parkinson's disease, spasticity, and acute muscle spasms. In A. Goodman Gilman, T. W. Rail, A. S. Nies, & P. Taylor (Eds.), The phannacological basis of therapeutics (8th ed., Vol. 1, pp. 463-484). New York: Pergamon. Caine, D. B. (1994). Is idiopathic parkinsonism the consequence of an event or a process? Neurology, 44, 5-10. Robertson, H. A. (1992) Dopamine receptor interactions: Some implications for the treat­ ment of Parkinson's disease. Trends in Neurosciences, 15, 201-206. Chapter 8

Drug Treatment for Epilepsy

BACKGROUND INFORMATION

Epilepsy is a collective term for a group of CNS disorders characterized by repeated and sudden seizures (i.e., episodes of abnormal sensory, motor, autonomic, cogni­ tive, or emotional phenomena). The seizure activity is usually associated with abnormal electrical activity in the brain, which can be measured using an electro­ encephalogram (EEG; Rail & Schleifer, 1991). Epilepsy, of one type or another, affects approximately 20 to 40 million people worldwide (Rail & Schleifer, 1991). In addition to the seizure activity itself, there is considerable evidence to indicate that people with epilepsy have an increased risk of depression, psychosis, and anxiety disorders (e.g., Mendez, Cummings, & Benson, 1986; Mendez, Graw, Doss, & Taylor, 1993); whether this is a side effect of prolonged drug treatment or due to the neurophysiological effects of seizure activity is unclear. Epilepsy is referred to as primary or idiopathic when the cause of the seizures is unknown. Secondary or symptomatic epilepsy refers to seizures that occur as a result of another condition (e.g., a brain tumor, an infection, or cerebrovascular disease). For the purposes of treatment, epilepsy is usually classified according to the types of seizures that occur (see Table 8.1 and Fig. 8.1)

Psychiatric Disturbances in Epilepsy Since the 1980s, evidence has accumulated to suggest that there is an over­ representation of psychiatric disorders within the population of epilepsy sufferers. 91 TABLE 8.1 Seizure Classification

A. Partial Seizures

i) Simple Partial Seizures • no impairment of consciousness • convulsions confined to a single limb or muscle group (i.e., Jacksonian muscle epilepsy) • localized sensory disturbance (i.e., Jacksonian sensory epilepsy) • specific signs dependent on the area of the cortex affected ii) Complex Partial Seizures • impairment of consciousness • seizures involving confused behavior • diverse clinical signs, but usually related to abnormal, generalized EEG activity during the seizure • between seizures, evidence of focal anterior temporal lobe abnormalities iii) Partial Seizures B. Generalized Seizures (Convulsive or Nonconvulsive) i) Absence Seizures (Petit Mal) • sudden, transient loss of consciousness • associated with high-voltage, bilaterally synchronous three per second spike and wave pattern in the EEG • usually some symmetrical clonic motor activity (e.g., jerking of body, eye blinking) ii) Atypical Absence Seizures • slower onset and cessation absence seizures • EEG more heterogeneous iii) Myoclonic Seizures • isolated clonic jerks related to brief bursts of multiple spikes in the EEG iv) Clonic Seizures • rhythmic clonic contractions of all muscles • loss of consciousness • marked autonomic signs v) Tonic Seizures • opisthotonus (a spasm in which the torso is bent forward and the head and heels are bent backward) • loss of consciousness • marked autonomic signs vi) Tonic-Clonic Seizures (Grand Mal) • major convulsions • usually tonic spasms (sustained muscle contraction) of entire body musculature followed by a synchronous clonic jerking (rapid succession of muscle contraction and relaxation) • tonic-clonic phase is followed by a large-scale CNS depression vii) Atonic Seizures • loss of postural tone (e.g., sagging of the head or falling)

Note. From Rail and Schleifer (1991).

92 EPILEPSY 93

simple

secondarily partial seizures generalized

complex

absence l (Petit mal)

(atypical absence)

myoclonic J ( generalized seizures 1------i clonic J

( tonic-clonic l (Grand Mal) J atonic J

FIG. 8.1. Classification of seizures.

The severity of these disorders ranges from minor anxiety disorders to major depressive disorder and schizophrenia (e.g., Mendez et al., 1993; Victoroff, Ben­ son, Grafton, Engel, & Mazziotte, 1994 ). Recent neuropathological studies by Bruton and colleagues ( 1994) indicate that people with epilepsy who suffer from psychosis have enlarged ventricles, periventricular gliosis, and excessive focal brain damage similar to patients with psychosis but not suffering from epilepsy. In patients with epilepsy and psychosis, the psychotic symptoms typically begin 5 to 38 years following the onset of seizures (Bruton et al., 1994). Because some antiepileptic drugs (e.g., primidone, ethosuximide) are known to produce person­ ality changes, psychoses, and depression in some cases, it is unclear whether the psychiatric symptoms are a consequence of the drug therapy for epilepsy, whether the two disorders arise from a common cause, or whether chronic seizures increase the probability of the development of psychiatric disorders, for example, through increas­ ing neuronal damage (see Smith & Darlington, in press; Trimble, 1989, for reviews). Whatever the cause of psychiatric disturbances in epilepsy, the treatment of psychosis while a patient is taking antiepileptic medication is problematic: Anti­ psychotic drugs such as DA antagonists have been shown to exacerbate epilepsy by reducing seizure thresholds (see Stevens, 1991, for a review). However, antide­ pressants can be safely prescribed for patients with epilepsy who suffer from depression (Robertson & Trimble, 1985). 94 CHAPTERS

BASIC DESCRIPTION OF DRUG TREATMENT FOR EPILEPSY

Antiepileptic drugs (or anticonvulsants) are a diverse category of drugs whose antiepileptic action is poorly understood. Most antiepileptic drugs work by reduc­ ing the spread of excitation from seizure foci to other areas of the CNS. Ideally, they would prevent seizure activity without disrupting normal neuronal func­ tion and producing adverse side effects. Unfortunately, the actions of most antiepileptic drugs are not selective for seizure activity and these drugs usually result in a range of side effects, some of which can be very dangerous (see Table 8.2).

TABLE 8.2 Drugs Effective for Different Seizure Types

A. Partial Seizures

• Simple and Complex • carbamazepine • clobazam • clonazepam • clorazepate (in combination with other drugs) • phenytoin • sodium valproate • primidone • phenobarbital B. Generalized

• Absence • ethosuximide • sodium valproate • clobazam • clonazepam • trimethadione • Myoclonic • clobazam • sodium valproate • possibly phenytoin • possibly primidone (in young children) • clonazepam • Tonic--Clonic • carbamazepine • clobazam • phenytoin • sodi urn val pro ate • primidone • phenobarbital

Note. From Rail and Schleifer (1991) and Hill and Frith (1993). EPILEPSY 95

Carbamazepine Carbamazepine is structurally related to the tricyclic antidepressant drug, imi­ pramine. It is effective for simple and complex partial seizures and generalized tonic-clonic seizures. However, it is not useful for absence seizures. The absorption of carbamazepine is slow and unpredictable and its elimination half-life is short and variable between different individuals. Carbamazepine is metabolized by the liver and its induction of liver enzymes (autoinduction) means that a significant reduction in the blood plasma levels of the drug and in seizure control can occur without any change in dose. Controlled release formulations provide more stable blood plasma levels and therefore overcome some of the problems caused by the short elimination half-life. The mode of action of car­ bamazepine is unknown; however, it may act on voltage-sensitive calcium channels and voltage-sensitive sodium channels (Hill & Frith, 1993; Rail & Schleifer, 1991 ).

Clobazam Clobazam is a benzodiazepine that is effective for the control of generalized tonic-clonic and myoclonic seizures, for absence seizures, and for partial seizures. Its absorption is fast and complete; about 85 % of the drug binds to blood proteins. Clobazam acts on the GABAA receptor and enhances the inhibitory effect ofGABA (Hill & Frith, 1993).

Phenytoin Phenytoin is effective for the control of generalized tonic-clonic seizures, partial seizures, and status epilepticus. However, it may not be effective for myoclonic seizures and it is ineffective for absence seizures. Phenytoin is rapidly absorbed and extensively bound to blood proteins. Like carbamazepine, it is metabolized by the liver and induces liver enzymes. Its mechanism of action is unknown; however, it may act on voltage-dependent sodium channels (Upton, 1994).

Sodium Valproate Sodium valproate is effective for the control of generalized seizures, including absence and myoclonic seizures; it is also effective for partial seizures. It is extensively bound to blood proteins and metabolized by the liver. The mechanism of action of sodium valproate is unknown (Hill & Frith, 1993).

Ethosuximide Ethosuximide is the drug of choice for absence seizures; it is effective in preventing seizures in about 50% of patients and in reducing seizures in another 45%. It is 96 CHAPTERS

ineffective for other types of seizures. Ethosuximide is rapidly and almost com­ pletely absorbed, with very little blood protein-binding. It is metabolized by the liver and has a long elimination half-life. The mechanism of action of ethosuximide is unknown, but it may affect DA transmission (Rail & Schleifer, 1991).

Diazepam Diazepam is a benzodiazepine compound that has been discussed in detail pre­ viously in relation to the treatment of anxiety disorders (see chapter 3). In the context of epilepsy it is used specifically for status epilepticus and prolonged seizures, and is usually given IV or rectally.

Primidone Primidone is effective for partial seizures and generalized tonic-clonic seizures. It is well absorbed with little binding to blood proteins. Primidone's half-life is 3 to 22 hours and one of its two active metabolites is phenobarbitone. As for many other antiepileptic drugs, the specific mechanism of action of primidone is unknown (Hill & Frith, 1993).

Phenobarbitone Phenobarbitone is effective for the control of generalized tonic-clonic seizures and partial seizures. It is slowly but completely absorbed; about 40% to 60% of the drug is bound to plasma protein. Peak plasma concentrations do not occur for several hours after a single administration. About 25% of a phenobarbitone dose is eliminated by the kidneys unchanged. The half-life is about 100 hours in adults (Rail & Schleifer, 1991). The specific mechanism of action of phenobarbitone is unknown, but it is likely to involve action at the GABAA receptor.

RESEARCH VALIDATION

The abnormal electrical discharges that have been demonstrated in the EEG patterns of patients with epilepsy have been documented at the level of single neurons, most recently in brain slices removed from human epileptic foci during surgery. Despite the extensive documentation of the abnormal electrical activity, its etiology is still unknown (see Engel, 1989, for a review). There is evidence that epilepsy is associated with brain trauma, glial cell proliferation, neuronal loss, and a decrease in the inhibitory amino acid transmitter, GABA. However, whether such abnormalities represent the cause or an effect of EPILEPSY 97

the seizures remains unclear. Many theories exist regarding changes in the function of excitatory amino acid and other receptors; however, despite the development of many animal models (e.g., kindling), which are useful for screening anticonvulsant drugs, the etiology of epilepsy remains obscure. However, it is likely that there are multiple causative factors (see Engel, 1989, for a review).

USES AND MISUSES OF DRUGS USED TO TREAT EPILEPSY

Effective drug treatment for epilepsy is a matter of administering a drug at a dose high enough to control seizures without significant impairment of normal function (Rail & Schleifer, 1991). Complete control of seizures can be achieved in approxi­ mately 50% of patients, with a significant reduction of seizure activity in a further 25% (Rail & Schleifer, 1991). In general, treatment with one drug (i.e., monotherapy) is preferable to treatment with multiple drugs because side effects are fewer and patient compliance more likely. Noncompliance is a major problem with antiepileptic drugs and it is the most common reason for low drug levels (Hill & Frith, 1993).

LIMITATIONS AND SIDE EFFECTS

Carbamazepine The side effects of carbamazepine include nausea, headache, dizziness, and diplopia, which often disappear after the first few weeks of treatment (i.e., tolerance develops). Skin rash develops in about 5% of patients and in this case drug administration must cease. A transient leukopenia (i.e., a reduced leukocyte count) usually occurs. Rarely, aplastic anemia or hepatitis can develop. Any increase in dose should be gradual in order to avoid severe side effects and noncompliance. Withdrawal from carbamazepine should always be gradual.

Clobazam The side effects of clobazam include significant drowsiness, dizziness, and fatigue. Unfortunately, tolerance often develops to the therapeutic effects. Withdrawal from clobazam must be gradual in order to avoid a withdrawal syndrome.

Phenytoin Phenytoin can cause gum hypertophy, hirsutism (i.e., abnormal growth of facial hair), coarsening of the facial features, and skin rashes. Because of these facial side effects, it should be avoided in children and young women. Other side effects 98 CHAPTERS include impaired coordination, nystagmus, and an impairment of cognitive func­ tion. Phenytoin administration during pregnancy has been associated with an in­ creased risk of birth defects, including cleft palate.

Sodium Valproate The side effects of sodium valproate include nausea, vomiting, gastrointestinal disturbances, weight gain, thinning of the hair, tremor, thrombocytopenia (i.e., a reduction in blood platelets), inhibition of platelet aggregation, and elevation of liver enzymes.

Ethosuximide Compared to other anticonvulsants, the side effects of ethosuximide are mild. However, it can cause nausea, abdominal discomfort, anorexia, drowsiness, head­ ache, and hiccups.

Diazepam The side effects of diazepam are those that are typical for benzodiazepines (e.g., drowsiness and fatigue; see chapter 3 for further details).

Primidone The side effects ofprimidone are usually mild (e.g., drowsiness, weakness, fatigue, dizziness). However, tolerance often develops to the therapeutic effects of the drug. Some complaints about impairment of memory and concentration have been noted.

Phenobarbitone The side effects of phenobarbitone include significant drowsiness. Tolerance can develop to phenobarbitone's therapeutic effects and dependence can be a major problem.

INTERACTIONS

Carbamazepine Carbamazepine can have unpredictable interactions with other anticonvulsant drugs. Some drugs (e.g., verapamil) interfere with the metabolism of car­ bamazepine by the liver. The efficacy of oral contraceptives may be reduced because of the enzyme-inducing properties of carbamazepine. EPILEPSY 99

Clobazam

Clobazam has no significant interactions with other antiepileptic drugs such as phenytoin, phenobarbitone, and carbamazepine.

Phenytoin

Phenytoin has interactions with cimetidine, disulfram, sulphonamides, isoniazid, and antacids (which may cause an increase in the blood levels of phenytoin). Phenytoin increases the metabolism of sodium valproate, carbamazepine, and primidone. Like carbamazepine, phenytoin increases the metabolism of contracep­ tives and therefore the usual contraceptive dose may be ineffective.

Sodium Valproate

Sodium valproate interacts with many other drugs (however, not contraceptives), especially interfering with their metabolism in the liver (which can lead to toxic levels of other drugs accumulating in the blood). Other drugs that induce liver enzymes will increase the metabolism of sodium valproate.

Ethosuximide Ethosuximide does not interact significantly with other anticonvulsant drugs. However, sodium valproate may increase the blood levels of ethosuximide by inhibiting its metabolism.

Diazepam Alcohol can seriously potentiate the adverse side effects of diazepam. Although interactions with other drugs are, in general, not serious, sodium valproate can cause psychotic reactions if taken concurrently with diazepam.

Primidone Primidone interacts with carbamazepine, clonazepam, and phenytoin and these drugs may alter its metabolism. Other drugs that induce liver enzymes may also change the metabolism of primidone.

Phenobarbitone Phenobarbitone can interact significantly with other drugs as a result of the induction of liver enzymes. 100 CHAPTER 8

NEW ANTIEPILEPTIC DRUGS

There are several new antiepileptic drugs that have recently been introduced to clinical use. These include vigabatrin, gabapentin, lamotrigine, and felbamate, which are effective in the treatment of tonic-clonic seizures and partial seizures and generally have fewer side effects than traditional antiepileptic drugs. This group of new antiepileptic drugs signifies a major effort to design specific drugs that will target seizure mechanisms while having minimal adverse side effects.

Vigabatrin Vigabatrin is a synthetic derivative of GABA. Evidence so far suggests that it may be effective for partial complex seizures and generalized tonic-clonic seizures to a lesser extent (Upton, 1994). It is well absorbed and is eliminated by the kidneys without being metabolized by the liver. Vigabatrin works by binding to the active site of the enzyme that metabolizes GABA, inhibiting it and thereby increasing GABAergic transmission. Recent evi­ dence suggests that it may also cause a decrease in brain concentrations of excitatory amino acids (see Upton, 1994, for a review). Its side effects are mild and uncommon: drowsiness, fatigue and weight gain. However, personality changes and aggression have been reported in some patients. There are no significant drug interactions known at present; however, when used in conjunction with phenytoin it may reduce phenytoin levels by 20% to 40% (Upton, 1994; Walker & Sander, 1994).

Gabapentin Gabapentin is effective against partial seizures and generalized tonic-clonic sei­ zures. Its side effects are typically mild (e.g., fatigue, ataxia, dizziness, and somnolence; Upton, 1994; The U.S. Gabapentin Study Group No. 5, 1993). Gabapentin was designed to mimic the three-dimensional structure of GABA, thereby increasing GABAergic transmission in the brain. However, substantial evidence suggests that this is not the way in which it exerts its antiepileptic effects (see Upton, 1994, for a review). At present, there are several hypotheses that have been put forward regarding the mechanism of action of gabapentin: These include the voltage- and frequency-dependent blockade of sodium channels, an increase of GABA concentrations in particular brain areas, and action at a specific gabapentin binding site that inhibits major excitatory inputs (see Upton, 1994, for a review).

Lamotrigine Lamotrigine was recently developed and used as an additional therapy for patients with generalized tonic-clonic seizures or partial seizures. It is rapidly and com­ pletely absorbed and is metabolized by the liver and excreted by the kidneys with a mean half-life of approximately 29 hours. EPILEPSY 101

The mechanism of action of lamotrigine may be the inhibition of glutamate release via a blockade of voltage-dependent sodium channels (Upton, 1994 ). Its side effects are minimal and infrequent. There have been occasional reports of ataxia, dizziness, drowsiness, headache, diplopia, or skin rash. There are no significant effects on liver enzymes or the metabolism of other drugs. However, other anticonvulsant drugs that induce liver enzymes increase the metabolism of lamotrigine. Sodium valproate inhibits the liver enzymes that metabolize lamotrigine and therefore increases its blood plasma levels (Walker & Sander, 1994).

Felbamate Felbamate appears to be effective against both partial and generalized tonic-clonic seizures. Its side effects are usually mild (e.g., insomnia, ataxia, anorexia, nausea, dizziness, and somnolence; Upton, 1994). Felbamate has been shown to block voltage-dependent sodium channels. However, more recently it has been demonstrated that felbamate can act as an agonist at the GABAA receptor and a noncompetitive antagonist at the NMDA receptor channel (Rho, Doneran, & Rogawski, 1994 ), although other evidence suggests that it can act as an antagonist at the strychine-insensitive glycine binding site on the NMDA receptor (see Upton, 1994, for a review). There is some concern that if felbamate acts as a noncompetitive NMDA antagonist, similar to drugs like ketamine and phencyclidine, then it may be capable of inducing psychotic side effects in some individuals (see Smith & Darlington, in press, for a review).

DOSAGES

Table 8.3 indicates dosages for antiepileptic drugs.

TABLE 8.3 Antiepileptic Drugs

Drug Trade Names Dose (mu)

Carbamazepine Tegretol, Teril 400-1,200 Clobazam Frisium 10-30 Clonazepam Klonopin 1.5-20 Ethosuximide Zarontin 50-1,500 Phenytoin Dilantin 300-500 Phenobarbital Luminal 60-250 Primidone Mysoline 750-1,500 Sodium Valproate Depakote I ,000-3,000 Vigabatrin Sabri! 1,500-3,000 Lamotrigine Lamictal 200-400

Note. Modified from Hill and Frith ( 1993) and Rail and Schleifer ( 1991 ). Doses may be divided. 102 CHAPTER 8

SUGGESTED READINGS

Bruton, C. 1., Crow, T. 1., Frith, C. D., Johnstone, E. C., Owens, D. G. C., & Stevens, J. R. (1994). Epilepsy, psychosis and schizophrenia. Neurology, 44, 34-42. Chadwick, D. (1994). Epilepsy. Journal of Neurology, Neurosurgery and Psychiatry, 57, 264-277. Hill, R. A., & Frith, R. W. (1993, April). Anticonvulsants. New Ethicals, 43-50. Smith, P. F., & Darlington, C. L. (in press). Neural mechanisms of psychiatric disturbances in epilepsy. In H. McConnell, P. Snyder & J. Duffy (Eds.), Behavioral epilepsy: Clinical and research aspects. Washington, DC: American Psychiatric Association. Trimble, M. R. (1991). The psychoses ofepilepsy. New York: Raven Press. Upton, N. (1994). Mechanisms of action of new antiepileptic druigs: Rational design and serendipitous findings. Trends in Pharmacological Sciences, 15, 456-463. Chapter 9

Introduction to Pediatric and Geriatric Psychopharmacology

Pediatric and geriatric psychopharmacology are branches of psychopharmacology that deal with the special problems of the administration of psychiatric and neurological drugs in pediatric and geriatric populations, including drug treatment for disorders that occur mainly within these populations (e.g., attention deficit hyperactivity disorder [ADHD] in pediatric populations; Alzheimer's disease in geriatric populations).

PEDIATRIC PSYCHOPHARMACOLOGY

Drug action in infants and children is altered significantly by the changes in physiology that occur during the first year of life and especially by those that occur during the first few weeks (Cohen, 1989). Drug Absorption. Drug absorption after IM or SC injection depends on the rate of blood flow through the muscle or the SC area into which the drug is injected. Absorption may be impaired in premature infants who have reduced muscle mass and reduced blood flow into muscle and SC areas. For example, the drug may stay in the muscle and be absorbed at an unusually slow rate; if blood flow then improves, the blood plasma levels of the drug may suddenly increase and toxicity may occur. Drugs that are especially problematic in this regard include aminogly­ coside antibiotics and antiepileptic drugs (Cohen, 1989). In premature infants, gastric acid in the gastrointestinal tract develops more slowly than in full-term infants. Therefore, drugs that are partially inactivated by gastric acid in the full-term infant may not be inactivated in the premature infant; for this reason, such drugs should not be administered orally. 103 104 CHAPTER 9

Gastric emptying time may be longer than usual during the first 2 days of life, with the consequence that drugs that are absorbed mainly from the stomach may be absorbed more completely and drugs that are a~sorbed mainly from the small intestine may be absorbed more slowly. Because peristalsis (i.e., the process by which food or liquid is moved through the gastrointestinal tract) is irregular in the neonate, the amount of drug absorbed from the small intestine is unpredictable and toxicity can occur due to increased absorption caused by slow peristalsis (Cohen, 1989).

Drug Distribution. Plasma protein binding of drugs is reduced in the neo­ nate, with the consequence that the concentration of free drug available to bind to receptors in the CNS is increased. This may result in an unusually large drug effect or even toxicity. Drugs for which this is an important consideration include diazepam, phenytoin, ampicillin, phenobarbital, and local anesthetics (Cohen, 1989).

Drug Metabolism. The capacity of liver enzymes to metabolize drugs is substantially reduced in the early stages of neonatal life. Most drugs are metabolized mainly in the liver, thus in neonates the elimination of drugs can be slow, increasing the duration of the drug effect. If a pregnant mother receives a drug such as phenobarbital, which induces an early development of liver enzymes in the neonate, then metabolism of some drugs may be greater than normal, leading to a reduced therapeutic effect (Cohen, 1989; Rang et at., 1995).

Drug Excretion. During the first few weeks oflife, drugs that are eliminated from the body by the kidneys are cleared very slowly due to the low rate of glomerular filtration. If the neonate is ill, then kidney function may not mature at the usual rate and dosage adjustments have to be made (Rang et at., 1995; see Fig. 9.1).

Dosage and Compliance in Neonates and Children. Many drugs in­ tended for children are manufactured in the form of elixirs and suspensions. An elixir is an alcohol solution in which the drug is dissolved; once it is dissolved, the drug is evenly distributed throughout the vehicle and the first dose should contain the same amount of drug as the last (Cohen, 1989). Suspensions are used when the drug will not dissolve in a solution (or will not stay dissolved). Because suspensions contain drug particles that are undissolved, care must be taken in order to distribute the drug throughout the vehicle (Cohen, 1989). If the suspension is not shaken properly, the last dose may contain more drug than the first. This is a common reason for lack of therapeutic efficacy following the first few doses of a suspension. If the last doses contain significantly more drug, toxicity may result. Compliance is more complicated in the case of drug treatment in children because it relies not only on the parent's cooperation but also the child's. On PEDIATRIC AND GERIATRIC PSYCHOPHARMACOLOGY 105

Pediatric (neonates):

Absorption: developmental changes in gastrointestinal function

Distribution: reduced plasma proteins affect binding and transport

Metabolism: slow metabolism by liver enzymes

Excretion: slow glomerular filtration rate

Geriatric (over 75):

Distribution: decreased plasma proteins

Metabolism: decreased liver function affecting metabolism of some drugs

Excretion: decline in kidney function prolongs elimination, increases half-life.

FIG. 9 .1. Important phannacokinetic factors in pediatric and geriatric psychopharmacology. occasions, the child may spit out part of the drug dose and in this case, how much drug has been administered is unknown. Sometimes parents do not use calibrated medicine spoons and instead use ordinary teaspoons, which may range in volume from 2.5 to 7.8 ml (Cohen, 1989). A common compliance problem occurs when the child feels well after 3 to 4 days of drug treatment and the parents decide to terminate the drug administration, despite instructions to the contrary. Manufacturers often give specific dosage instructions for children, in mg/kg (this sort of dosage instruction is not given for adults because it is assumed that normal adult weight is 50 to70 kg) . Because of differences in pharmacokinetics between neonates and children, estimations based on body weight are often not accurate. However, in the absence of specific instructions from the manufacturer, an approxi­ mation based on weight, age, or surface area may be used (Cohen, 1989).

GERIATRIC PSYCHOPHARMACOLOGY

Geriatric psychopharmacology applies to people mainly over the age of 75. From age 45, on average, most of the major organs show a linear decay in function. Reduced renal function is probably the most important age-related change that occurs in the area of geriatric pharmacology.

Drug Absorption. There are no major changes in absorption with advanc­ ing age; however, changes in nutrition, consumption of antacids and laxatives, and changes in gastric emptying, may have an effect on drug absorption (Cohen, 1989). 106 CHAPTER 9

Distribution. In geriatric populations there is usually a decrease in blood plasma proteins such as albumin, that bind many drugs; this may result in an increase in the concentration of free drug that is available to bind to CNS receptors. On the other hand, there may be an increase in other blood proteins (a-acid glycoprotein) that bind some drugs. Therefore, the ratio of bound/free drug may change and compensations have to be made (Cohen, 1989).

Metabolism. Liver metabolism declines for some drugs but not for others (depending on the type of metabolism required, Phase I or Phase II; see Rang et al., 1995; Neal, 1988, for descriptions of these types of metabolism). However, there is also a decline in the ability of the liver to recover from injury (e.g., by alcohol). Nutritional problems may also impair liver function.

Elimination. The kidneys are responsible for the elimination of most drugs from the body; therefore the decline in kidney function with age is very important and contributes to the prolonged half-life of many drugs. If doses are not reduced correspondingly, toxicity may result. Nutritional changes associated with age may also alter pharmacokinetics. The use of inhalation anesthesia is less common in the elderly due to reduced respiratory capacity (Cohen, 1989; see Fig. 9.1).

Specific Problems With Drugs Used in Geriatric Psycho­ pharmacology. Between age 30 and 70 (especially between 60 and 70), the elimination half-lives of many barbiturates and benzodiazepines increase 50 to 150%. Aside from pharmacokinetic factors, the elderly patient may be more sensitive to some CNS depressants due to pharmacodynamic factors. Ataxia may be a particularly problematic side effect if the drug concentration becomes toxic. The elderly are especially sensitive to the respiratory side effects of opioid analgesics. The antimuscarinic side effects of phenothiazine antipsychotic drugs may exacerbate impairment of cognitive function. Some of the phenothiazines are more likely to induce orthostatic hypotension (i.e., reduced blood pressure due to change in posture) in geriatric populations. Because of increased half-lives, the doses of these kinds of drugs must be reduced appropriately. This is also true for lithium when it is used in the treatment of mania in the elderly.

Compliance. Particular attention should be given to noncompliance in the elderly. Sometimes this is accidental. For example, arthritis, tremor, visual impair­ ment, or forgetfulness may contribute to mistakes being made in taking medication. The drug history ofthe patient should be taken carefully, in order to ensure that the drugs prescribed will not interact adversely with medication prescribed for another medical condition. When necessary, drug doses should be increased very slowly, taking into consideration the longer half-lives of many drugs in this population. Drug reactions and interactions should be monitored particularly carefully. Finally, PEDIATRIC AND GERIATRIC PSYCHOPHARMACOLOGY 107

the instructions should be made as simple as possible and drug packaging should allow clear and easy access (Cohen, 1989; Rang et al., 1995). "Child-proof' packaging is often almost impossible for elderly patients to use.

EXAMPLE OF A PROBLEM IN PEDIATRIC PSYCHOPHARMACOLOGY: CHILDHOOD ADHD

Background Information

Childhood ADHD is characterized by inattentiveness, impulsivity, increased motor activity and restlessness, resulting in impaired social behavior and poor school performance (Abikoff & Gittelman, 1985; Leung, Robson, Fagan, & Lim, 1994; Zametkin et al., 1990). According to the DSM-IV (APA, 1994 ), there are three main subtypes of ADHD:

1. ADHD, Combined Type: a classification used to distinguish the presence of six or more symptoms of inattention and six or more symptoms of hyperactivity/impulsivity, which have persisted for more than 6 months. This specific diagnosis is the most common for children and adolescents withADHD. 2. ADHD, Predominantly Inattentive Type: a classification used to describe the presence of six or more symptoms of inattention with fewer than six symptoms of hyperactivity/impulsivity, for at least 6 months. 3. ADHD, Predominantly Hyperactive I Impulsive Type: a classification used to describe the presence of six or more symptoms of hyperactivity/impul­ sivity with fewer than six symptoms of inattention, for at least 6 months. (Modified from the APA,1994, p. 80).

Basic Description of Drug Treatment for ADHD

The most common drug treatment for ADHD is a stimulant such as methylphenidate or dextroamphetamine (Gadow, 1991; Hoffman & Lefkowitz, 1991; Leung et al., 1994 ). Both of these drugs are equally effective in the treatment of ADHD, although their long-term efficacy is questionable (Hoffman & Lefkowitz, 1991). Sometimes a tricyclic antidepressant or an antipsychotic drug may be prescribed when aggressive and disruptive behavior is not completely controlled by a stimu­ lant. However, neither of these classes of drugs has the same beneficial effect on all of the symptoms of ADHD as stimulants like methylphenidate (Abikoff & Gittelman, 1985; Leung et al., 1994). In addition, the use of antipsychotics in children is potentially dangerous because of the risk of tardive dyskinesia (see chapter 5). 108 CHAPTER 9

Methylphenidate is structurally related to amphetamine and therefore is a true CNS stimulant; in high doses it may lead to convulsions (Hoffman & Lefkowitz, 1991 ). After oral administration it reaches peak plasma concentrations within approximately 2 hours and its elimination half-life is 1 to 2 hours. However, comparison of standard and sustained-release preparations suggests that they have similar efficacy (Fitzpatrick, Klorman, Brumaghim, & Borgstedt, 1992). Methyl­ phenidate is metabolized by the liver and excreted via the kidneys. Pemoline has also been used to treat ADHD but may be less effective: pemoline is structurally different from methylphenidate but has similar actions on the CNS. It has a long half-life and therefore can be given only once a day. Symptomatic improvement may take 3 to 4 weeks (Hoffman & Lefkowitz, 1991).

Research Validation In experimental studies, amphetamine-related drugs have been shown to result in increased locomotor activity, increased grooming, increased alertness and, in some cases, an increase in aggressive behavior. Although the amount of behavioral activity is increased, the behavior seems relatively aimless; for example, systematic exploration of novel environments is actually reduced by amphetamine, suggesting that attention to specific objects is impaired (Rang et al., 1995). At high doses, amphetamines cause stereotyped behavior (e.g., repeated, "auto­ matic" performance of behaviors like licking or grooming that do not appear to have any purpose; Rang et al., 1995). Amphetamines, methylphenidate, and pemoline cause the release of NE, DA, and (at higher doses) serotonin from presynaptic terminals. Because the behavioral effects of amphetamines can be blocked by lesions of DA neurons in the nucleus accumbens or administration of DA antagonists, but not by lesions of the central noradrenergic bundle, it appears that it is the increased release of DA which is mainly responsible for these behavioral effects (Rang et al., 1995). It is intriguing that drugs that would normally cause hyperactivity, restlessness, and reduced attention in normal individuals should have the opposite effects in those suffering from ADHD. Although the behavioral effects of amphetamines in humans and animals without ADHD may be mediated by an increase in DA release, it does not necessarily follow that the therapeutic effects of amphetamines in ADHD are due to actions on the DA pathways, or that a dopamine abnormality underlies ADHD. There is evidence for reduced presynaptic serotonin activity in children with mixed ADHD/hyperactive conduct disorder (Stoff, Pullock, Vitello, Behar, & Bridger, 1987), although this does not appear to be the case for nonaggressive ADHD children (Weitzman, Bernhout, Wertz, Tyrano, & Rehavi, 1988).1t has been hypothesized that children and adolescents with ADHD may suffer from a DA deficit, because reduced concentrations of homovanillic acid, the major metabolite of DA, have been found in cerebrospinal fluid (Shetty & Chase, 1976). Due to its inhibitory actions, DA may serve to inhibit activity in cortical areas. Therefore, a PEDIATRIC AND GERIATRIC PSYCHOPHARMACOLOGY 109

DA deficiency might result in excessive cortical excitation, resulting in hyperac­ tivity. However, the biological basis of ADHD is likely to be more complex than this, because studies of cerebral glucose metabolism have revealed a hy­ pometabolism, especially in the premotor cortex and superior prefrontal cortex (Zametkin et al., 1990).

Uses and Misuses Questions have been raised regarding the long-term efficacy of stimulants like methylphenidate in treating ADHD (Hoffman & Lefkowitz, 1991). Some studies suggest that although methylphenidate reduces measures of inattention and impul­ sivity, the normalization of school performance requires additional, school-based interventions (DuPaul & Rapport, 1993). It is clear from such studies that drug treatment for ADHD should always be combined with behavioral intervention of some sort. Methylphenidate has also been used successfully to treat ADHD in adolescents; however, it may have less efficacy than in children (Klorman, Brumaghim, Fitzpa­ trick, & Borgstedt, 1990). Because methylphenidate is related to amphetamine, it is a drug that is some­ times abused (Hollister, 1989). Although they were once used to reduce weight, amphetamine-related drugs are generally ineffective in treating obesity (Rang et al., 1995).

Limitations and Side Effects The potential adverse side effects of the stimulants used to treat ADHD include insomnia, anorexia, weight loss, and abdominal pain (Hoffman & Lefkowitz, 1991). There is some evidence to suggest that amphetamine-related drugs can be toxic to DA, and perhaps also to serotonin neurons, when administered to animals; it is not clear whether this can occur in humans. Although it has been suggested that the use of stimulants to treat ADHD may "constrict" cognitive function by causing "overfocusing," recent studies that have examined performance on divergent thinking tests (e.g., the Wallach-Kogan [W-K] battery) have demonstrated that stimulants enhance divergent thinking (Solanto & Wender, 1989). In mentally retarded children with ADHD, the use of methylphenidate has been reported to cause motor tics and severe social withdrawal in some cases (Handen, Feldman, Gosling, Breaux, & McAuliffe, 1991).

Interactions Because amphetamine-related drugs exert at least some of their behavioral effects via enhanced DA release, other drugs that affect DA pathways can be expected to 110 CHAPTER9 interact significantly with them. For example, DA antagonists such as antipsychotic drugs will block the effects of amphetamines, whereas other stimulants that enhance DA release will exacerbate their effects. Althougb. the effects of amphetamines on NE receptors may not be significant for their behavioral effects, other drugs that manipulate NE receptors can be expected to alter the side effects of amphetamines.

Dosages

The usual dose of methylphenidate is I 0 mg, two to three times a day (with a starting dose of 5 mg, twice a day). The maximum daily dose is 60 mg. The usual dose of dextroamphetamine is 0.1 to 0.5 mglkg. The usual daily dose of pemoline is 37 to 112 mg (Burwell, 1992).

EXAMPLE OF A PROBLEM IN GERIATRIC PSYCHOPHARMACOLOGY: ALZHEIMER'S DISEASE

Background Information Alzheimer's disease affects approximately 1% to 6% of people over 65; it is currently regarded as the fourth major cause of death following heart disease, cancer, and stroke (Hardy & Allsop, 1991). Alzheimer's disease is characterized by a progressive loss of cognitive function and a deterioration of personality; ultimately the patient becomes bedridden (Hardy & Allsop, 1991 ). The three main pathological features of Alzheimer's disease are senile plaques, neurofibrillary tangles, and extensive neuronal loss (Hardy & Allsop, 1991). Because these pathological characteristics can be identified only at autopsy, the initial diagnosis is usually based on the presence of cognitive and personality deficits that fulfill the criteria for Dementia of the Alzheimer's Type (DAT; APA, 1994). Within this general category, there are several subtypes:

1. Early Onset DAT: onset of dementia is at age 65 or under. 2. Late Onset DAT: onset of dementia is after age 65. 3. DATwith Delirium: dementia with delirium superimposed. 4. DAT with Delusions: dementia in which delusions are the predominant characteristic. 5. DAT with Depressed Mood: dementia in which depressed mood is a predominant characteristic. 6. Uncomplicated DAT: dementia in which neither delirium, delusions nor depressed mood are present. 7. DATwith Behavioral Disturbance: this classification is used where severe behavioral disturbances are present (modified from APA, 1994). PEDIATRIC AND GERIATRIC PSYCHOPHARMACOLOGY 111

Basic Description of Drug Treatment for Alzheimer's Disease Presently there is no effective drug treatment for Alzheimer's disease. Drugs that potentiate ACh transmission (e.g., AChe inhibitors such as tacrine) have been used with some success. However, these drugs only retard the loss of cognitive function (Davis et al., 1992; Eagger, Levy, & Sahakian,1991; Farlow et al., 1992); there is no evidence that they have any effect on the process underlying the dementia. Tacrine has only recently become available for prescription. In 1993, the U.S Peripheral and Central Nervous System Drugs Advisory Committee approved the use of tacrine for the treatment of DA T. However, there are many countries in the world in which it is still undergoing experimental trials. Severe side effects, such as nausea and/or vomiting, diarrhea, anorexia, ataxia, and an increase in liver transami­ nases, have been noted in some patients (Davis et al., 1992).

Research Validation Many neurotransmitter deficits have been noted in Alzheimer's disease, particu­ larly a loss of ACh, associated with the degeneration of the nucleus basalis of Meynert (Carlson, 1986). However, abnormalities in DA, NE, serotonin, glutamate and somatostatin also occur (Jansen, Faull, Dragunow, & Synek, 1990; Katzung, 1989). Although AChe inhibitors such as tacrine are used to reduce the rate at which cognitive deterioration develops, researchers are investigating the potential of many other drugs to enhance cognitive function. Many of these drugs, the efficacy and safety of which are yet to be established in humans, are part of the "Smart Drug" category discussed in detail in chapter 10 (see Dawson, Reyes, & Iversen, 1992; Mondadori, 1993; Sarter, 1991, for recent reviews). One of the major obstacles to advances in the treatment of Alzheimer's disease has been the absence of a useful animal model of the disease process and the fact that the damage to the CNS is so diffuse. Recent evidence has indicated that a mutation of the ~-amyloid precursor protein (APP) gene on chromosome 21 may be implicated in the development of Alzheimer's disease (see Hardy & Allsop, 1991 for a review). Molecular biologists have recently succeeded in producing transgenic mice with an overexpression of ~-APP; such mice exhibit the neuropathological characteristics of Alzhemer's disease (Games, Adams, Allessandrini, Barbour, Berthelette et al., 1995). This may be the first animal model of human Alzheimer's disease.

SUGGESTED READINGS

Cohen, M. S. (1989). Special aspects of perinatal and pediatric pharmacology. In B. G. Katzung (Ed.), Basic and clinical pharmacology (4th ed., pp. 763-769). London: Pren­ tice-Hall. 112 CHAPTER9

Dawson, G. R., Heyes, C. M., & Iversen, S.D. (1992) Pharmacological mechanisms and animal models of cognition. Behavioural Pharmacology, 3, 285-297. DuPaul, G. J., & Rapport, M.D. (1993). Does methylphenidate normalize the classroom performance of children with attention deficit disorder? Journal ofthe American Academy of Child and Adolescent Psychiatry, 32, 190--198. Eagger, S. A., Levy, R., & Sahakian, B. J. (1991). Tacrine in Alzheimer's disease. Lancet, 337, 989-992. Gadow, K. D. (1991 ). Clinical issues in child and adolescent psychopharmacology. Journal of Consulting and Clinical Psychology, 59, 842-852. Katzung, B. G. (1989). Special aspects of geriatric pharmacology. In B. G. Katzung (Ed.), Basic and clinical pharmacology (4th ed., pp. 770--777). London: Prentice-Hall. Leung, A. K. C., Robson, W. L. M., Fagan, J. E., & Lim, S. H. N. (1994). Attention-deficit hyperactivity disorder. Postgraduate Medicine, 95, 153-160. Rang, H. P., Dale, M. M., & Ritter, J. M. (1995) Pharmacology (3rd ed.). Edinburgh: Churchill Livingstone. Royston, M. C., Rothwell, N.J., & Roberts, G. W. (1992). Alzheimer's disease: Pathology to potential treatments. Trends in Pharmacological Sciences, 13, 131-133. Sarter, M. (1991). Taking stock of cognition enhancers. Trends in Pharmacological Sci­ ences, 12, 456--461. Summers, W. K., Majovski, L. V., Marsh, G. M., Tachiki, K., & Kling, A. (1986). Oral tetrahydro-aminoacridine in long-term treatment of senile dementia, Alzheimer type. The New England Journal of Medicine, 315, 1241-1245. Chapter 10

Introduction to Drugs of Abuse

Drugs ofabuse are a heterogeneous group that, due to their desirable psychotropic effects, are subject to unhealthful and, in some cases, illegal, use. Included in this group are drugs in the "Psychedelics and Hallucinogens" category of the behavioral classification scheme, as well as some drugs already discussed in relation to psychological and neurological disorders. There are many psychiatric disorders that are related to drug abuse; these substance-related disorders are described in detail in the DSM-IV (APA,1994). Because drugs of abuse are so diverse in chemical structure and their pharma­ cological and behavioral effects, it is difficult to generalize across the group (see Fig. 10.1).

CNS DEPRESSANTS

This drug category has been discussed in detail previously in relation to the clinical treatment of anxiety disorders (chapter 3) and epilepsy (chapter 8). High on the abuse list are drugs that are prescribed for anxiety disorders and insomnia, the anxiolytics and hypnotics, especially the benzodiazepines. However, probably the foremost drug of abuse in this category is alcohol.

Alcohol Alcohol occurs naturally as a result of yeasts acting on plant sugars. It is absorbed easily from the stomach and small intestine and approximately 95% of a single dose is metabolized by the liver. One of the pecularities of alcohol is that its elimination rate does not increase with concentration, due to the saturation of the liver enzyme, 113 114 CHAPTER 10

anxiolytics

CNS depressants alcohol, ether

hypnotics

amphetamine J

\.. cocaine ) ( stimulants nicotine )

caffeine

opium ) ( narcotic analgesics heroin J codeine )

LSD )

mescaline )

( psychedelics/hallucinogens 1 ~ phencyclidine ) cannabinoids J psilocybin

solvents and glue

others ( \ steroids "smart drugs" )

FIG. 10.1. Classification of drugs of abuse. alcohol dehydrogenase. Instead, alcohol is eliminated at a maximum rate of 7 to 10 g per hour. The practical consequence of this pharmacokinetic limitation is that the higher the blood alcohol concentration, the longer it takes to eliminate it from the body. Nothing can accelerate this process. Because alcohol is eliminated in a linear fashion, it is possible to extrapolate back to the time of an accident in order to calculate the blood plasma levels of alcohol at that point in time (Rang et al., 1995). Alcohol is said to have nonspecific actions on the CNS in the sense that it does not act at just one site. Three important mechanisms by which it produces inhibitory effects in the CNS are: DRUGS OF ABUSE 115

I. acting on an ethanol site on the GABAA receptor complex, causing an influx of chloride ions (Suzdak, Schwartz, Skolnick, & Paul, 1986); 2. reducing calcium influx via presynaptic N-type calcium channels, resulting in reduced transmitter release (Gonzales & Hoffman, 1991); 3. reducing NMDA receptor activation, thereby reducing calcium influx through its associated calcium channel (Gulya, Grant, Valverius, Hoffman, & Tabakoff, 1991 ).

Despite the acute neuronal effects of alcohol, chronic alcohol consumption is associated with an increase in calcium influx through N-type calcium channels, an increase in the number of L-type calcium channels, and an increase in the number of NMDA receptors (Grant, Val veri us, Hudspith, & Tavakoff, 1990; Gulya et al., 1991; see Little, 1991, for a review). There is also evidence for a decrease in GABA receptors ( Durand & Carlen, 1984; Ticku & Birch, 1980). These neurochemical changes are associated with the development of pharmacodynamic tolerance to alcohol and may be directly responsible for the withdrawal syndrome that occurs following abstinence (Grant et al., 1990; Gulya et al., 1991; see Little, 1991, for a review). Biochemical studies suggest that the development of alcohol tolerance and dependence is at least partially a result of protein phosphorylation by protein kinase C (Messing, Sneade, & Savidge, 1990). The behavioral effects of alcohol are well known. At low doses it may produce some disinhibitory effects. However, at high doses it causes sedation; given a sufficiently high dose (e.g., 500 mg ethanol/100 ml blood; Little, 1991), alcohol will cause coma and death. Alcohol causes a loss of heat regulation, which can be potentially fatal if a drunken individual is left exposed in a cold environment. Aside from the adverse effects of chronic alcohol consumption on the CNS, it is also associated with cardiomyopathy and cirrhosis of the liver.

CNS STIMULANTS

Stimulants are some of the most abused drugs. Amphetamine was synthesized in the early 1900s. It is structurally related toNE and it mimics and potentiates the effects of NEat peripheral and CNS synapses. DA transmission is also potentiated and it is possible that serotonin is affected. At moderate doses, amphetamines cause effects such as increased alertness, euphoria, increased energy, enhanced concen­ tration and elevated mood. At high doses involving IV administration (i.e., "speed"), amphetamines can cause psychotic behavior, hallucinations and delu­ sions, fear, and repetitive behavior. Crystalline methamphetamine is often known as "crystal" and the addition of a narcotic opioid to the IV solution is known as a "speedball." Some psychedelic amphetamines have been synthesized which com­ bine amphetamines with lysergic acid diethylamide (LSD; e.g., "Ecstasy" [MDMA]; Schifano & Magni, 1994). 116 CHAPTER 10

The side effects of amphetamines include increased blood pressure, sweating, dry mouth, nausea, and vomiting. Most of the amphetamine that is ingested is eliminated unchanged in the urine; hence, urine tests can detect amphetamines up to 48 hours after use (Julien, 1992). Amphetamines have very few clinical uses. They were once thought to be useful as diet pills; however, this has been largely disproven (Rang et al., 1995). They are, however, used in the treatment of childhood ADHD (e.g., dextroamphetamine; see chapter 9) where, paradoxically, they have a calming effect. Amphetamines are also used in the treatment of narcolepsy, a condition characterized by sudden and unexpected lapses of consciousness. Dependence on amphetamines may develop. Withdrawal causes a period of rebound fatigue (i.e., the opposite effect to withdrawal from CNS depressants); however, the pleasurable "rush" that follows amphetamine use is a major factor in the development of dependence. Death that is directly attributable to amphetamines is rare. It is more common for death to result from accidents occurring while under the influence of amphetamines or from a gradual deterioration in lifestyle associated with the chronic use of the drug. Cocaine is a chemical that occurs naturally in the leaves of the erythroxylon coca tree that grows in Peru, Columbia and Bolivia. The main pharmacological action of cocaine in the CNS is to inhibit the reuptake ofDA and NE into presynaptic terminals, thereby potentiating DA and NE transmission. Many of the behavioral effects of cocaine are similar to amphetamines: increased blood pressure, increased heart rate, bronchodilation of the lungs, increased cognitive function, euphoria, and reduced fatigue. The side effects of cocaine are also similar to those of amphetamines. Whereas the effects of amphetamines last for hours, a single dose of cocaine may last only up to I hour because it is metabolized by the liver. CNS stimulation is followed by depression; at high doses, depression of respiratory centers in the brainstem may result in death. Intravenous use of cocaine is extremely dangerous and can be lethal (Julien, 1992; Rang et al., 1995). The desire for more potent forms of cocaine has led to the extraction of the drug from its diluted form using alkaline water, to make "crack" (Julien, 1992). The side effects of these high potency forms of cocaine are severe and include panic and paranoia; in some cases, the symptoms of paranoid schizophrenia can develop. Cocaine is considered to have a very high dependence liability. Nicotine is considered by many to have the highest dependence liability of any of the drugs of abuse (Stolerman & Shoaib, 1991 ). Most cigarettes contain 0.5 to 2.0 mg of nicotine, and 0.1 to 0.4 mg of this is estimated to enter the bloodstream (Julien, 1992). Nicotine exerts its effects through a direct stimulation of nicotinic ACh receptors, resulting in increased blood pressure, increased heart rate, ad­ renaline release from the adrenal glands, and increased behavioral activity. The apparent relaxation that is associated with smoking may be due to a reduction in DRUGS OF ABUSE 117

muscle tone resulting from the effects of neural feedback from skeletal muscles (Julien, 1992). The side effects of nicotine include increased irritability and tremor. The major health risk in smoking nicotine is cancer, particularly lung cancer. Caffeine is consumed in coffee, tea, soft drinks, and chocolate. Caffeine affects the CNS, heart, kidneys, lungs, and the arterial blood supply to the heart and brain (Julien, 1992). The main effect of caffeine is the inhibition of the enzyme that metabolizes the intracellular second messenger, cAMP; the increased cAMP con­ centration results in increased cellular activity. Caffeine reduces fatigue and increases behavioral activity. Its side effects include insomnia, increased heart rate, and agitation. Some dependence may develop and abrupt withdrawal can result in headaches, fatigue, and irritability.

NARCOTIC ANALGESICS

We have already discussed narcotic analgesics in relation to drug treatment of chronic pain (see chapter 6). Here we briefly review them as drugs of abuse. The term opiate is derived from opium, which is a drug occurring naturally in the opium poppy. The term opiate is reserved for drugs with a structural similarity to morphine (e.g., heroin, codeine), which is one of the major constituents of opium. The term opioid is used to refer to drugs with morphine-like effects that do not necessarily have a structural similarity to morphine (e.g., pethidine, fentanyl). Many opioids are used in medicine as analgesics. Many of the synthetic opioids have been produced in an attempt to obtain more potent analgesics. Opioids act at specific opioid receptor sites in the nervous system. There are several opioid receptor subtypes; however, morphine and heroin act mainly on the ~ and K subtypes. Aside from analgesia, opioids depress respiration, coughing, produce pupillary constriction, cause nausea, vomiting, sedation, and euphoria. The opioids have a very high dependence liability.

PSYCHEDELICS AND HALLUCINOGENS

There are many drugs in this diverse category. Therefore, we examine only three of the most popular ones. Lysergic acid diethylamide (LSD) was synthesized in 1938 and became one of the most famous of the psychedelic drugs, especially during the 1960s and 1970s. In the peripheral nervous system, LSD acts as a serotonin antagonist, but in the CNS it may work mainly as a serotonin agonist (Rang eta!., 1995). LSD causes an increase in body temperature, dilation of the pupils, increased heart rate and blood pressure, increased blood glucose, sweating and chills, headache, nausea, and vomiting (Julien, 1992). LSD is unusual in that it produces psychological effects at very small doses (e.g., 1 Jlglkg). The psychological effects are dramatic and may 118 CHAPTER 10 include hallucinations, delusions, euphoria, and dysphoria; the specific effects may depend on the personality of the individual and the context in which the drug is ingested (Julien 1992). LSD has a very low risk of toxicity; death is more likely to result from what is done under the influence of the drug. Dependence of any sort is uncommon. It is still unclear whether LSD use is associated with a greater incidence of psychotic illness or with significant risk to the fetus (Julien, 1992). Phencyclidine (PCP) was originally synthesized as a potential anesthetic agent; however, it was abandoned because it was found to produce hallucinations when patients recovered from anesthesia (Rang et a!., 1995). The mechanism of action of PCP is still poorly understood; however, it may act on a PCP site, thought to exist within the ion channel associated with the NMDA receptor. Other drugs that block the NMDA receptor channel (e.g., MK-80 1) have also been found to possess dissociative anesthetic properties and this is one of the major limitations to their clinical use in humans. Other than hallucinations and delusions, PCP is particularly dangerous because it induces analgesia and therefore an individual under its influence cannot feel pain. PCP is currently of interest in relation to schizophrenia and the possibility that an endogenous PCP-like substance may be involved in the development of schizo­ phrenic disorders (see chapter 5). Cannabis-like drugs (cannabinoids) are among the most commonly used in the category of psychedelics and hallucinogens. It is estimated that in 1988 approxi­ mately 12 million people in the United States alone used cannabinoids (Heishman, Huestis, Henningfield, & Cone, 1990). The most recent research suggests that cannabis use among adolescents has doubled since 1992 (Cimons, 1995). The behavioral effects of cannabinoids are complex and include sedation, weakness and fatigue, analgesia, appetite stimulation, impairment of perception and memory, euphoria, feelings of tranquility, rapid flow of thoughts, dizziness, dry mouth, tachycardia, reduced nausea and vomiting, reduced bronchial constriction, and anticonvulsant effects (Heishman et a!., 1990). t/-Tetrahydrocannabinol (t:/-THC) is the major psychoactive component of marijuana (see Howlett eta!., 1990, for a review). Attempts have been made to develop synthetic cannabinoid compounds that have analgesic properties without the other psychoactive effects of cannabinoids. These compounds are structurally similar to .19-THC but are more potent (Howlett eta!., 1990). Compared to opioid analgesics such as morphine, there is a low risk of overdose with cannabinoids; therefore, the development of cannabinoid analogues with potent analgesic prop­ erties might offer safer pain relief. It was originally thought that cannabis had nonspecific effects on cell mem­ branes. Cannabinoids are highly lipid-soluble and because cell membranes contain a large amount of lipid, it seemed likely that they dissolved into cell membranes and disrupted cell function. However, it has recently been demonstrated that there are specific CNS receptors for cannabinoids (Devane, Dysarz, Johnson, Melvin, & DRUGS OF ABUSE 119

Howlett, 1988; Herkenham eta!., 1990; Matsuda, Lolait, Brownstein, Young, & Bonner, 1990). Cannabis causes a reversible inhibition of the production of the second messenger, cAMP, by inhibiting adenylate cyclase activity via an inhibitory G protein. This process is probably mediated by an extracellular cannabinoid receptor. The cannabinoid receptor has recently been cloned (Matsuda eta!., 1990). The highest densities of cannabinoid binding sites are in the neocortex, hippocam­ pus, basal ganglia and cerebellum; lower densities are found in the brainstem and spinal cord (Herkenham eta!., 1990). The discovery of the cannabinoid receptor has led to speculation that an endogenous cannabinoid may exist within the CNS. In 1992, the isolation of a potential endogenous ligand for the cannabinoid receptor was reported. The authors called the substance "anandamide," following the Sanskrit word "ananda" (mean­ ing "bliss") and the chemical structure of the compound (Devane et a!., 1992; Di Marzo et a!., 1994 ).

SOLVENT VAPORS AND GLUE

Solvent vapors, such as those from gasoline and paint thinner, as well as vapor from glue, are now well established as drugs of abuse. Although it is believed that such vapors cause excitation at low doses and CNS depression at high doses, the exact mechanisms by which they produce their psychological effects are poorly under­ stood. This form of drug abuse causes many deaths, frequently due to cardiac arrhythmias (Jaffe, 1991).

STEROIDS

Anabolic steroids are steroid compounds that promote tissue growth, especially muscle growth. Androgenic steroids are steroids that have masculinizing effects. Because all androgenic steroids have anabolic effects, the term anabolic-andro­ genic steroid is used (Lukas, 1993). Anabolic-androgenic steroids are a group of natural and synthetic compounds that are chemically similar to cholesterol. The most common anabolic-androgenic steroid is testosterone; however, there are numerous analogues and derivatives. Such steroids have been abused by athletes for many decades in the hope of improving performance. In 1990, the U.S. Congress enacted the Steroids Control Act, which required anabolic-androgenic steroids to be added to Schedule III of the Controlled Substances Act, along with opioids, amphetamines, and barbiturates. Steroids like testosterone penetrate the plasma membrane of cells and bind to receptors within the cytoplasm. The bound receptor complex then moves into the cell nucleus where it causes transcription of mRNA and protein synthesis (Lukas, 1993). 120 CHAPTER 10

Although anabolic-androgenic steroids are used clinically for some disorders such as androgen deficiency or aplastic anemia, the doses used are relatively low (i.e., 75 to 100 mg per week) compared to those used illegally by some weight lifters and body builders (e.g., 1,000 to 2,100 mg per week; Lukas, 1993). The effects of steroids on athletic performance depend very much on the stage of training of the athlete: The effects on inexperienced weight lifters are negligible; however, when training has progressed to the stage where a plateau in size and strength has been reached, steroids can cause significant increases in lean body mass and strength and a decrease in body fat (Lukas, 1993). The side effects of anabolic-androgenic steroids can be severe. A reduction in serum high-density lipoprotein cholesterol occurs, together with an increase in low-density lipoprotein cholesterol. which increases the risk of coronary heart disease. Platelet clumping increases the risk of the formation of blood clots. In addition, there is an increased risk of liver disorders, particularly jaundice and tumors. Acne and oily skin are very common side effects. In males, a reduced sperm count will occur. In females, masculinizing side effects include a permanent increase in facial and body hair growth, a lowered voice, and baldness. The psychiatric side effects include increased aggression ("roid rage"), hypo­ mania, and psychosis during use, with depression developing following discontinu­ ation (Lukas, 1993; Pope & Katz, 1988). Dependence develops in approximately 57% of users: withdrawal symptoms include steroid craving, fatigue, depression, restlessness, anorexia, insomnia, reduced libido, and headaches (Lukas, 1993; Pope & Katz, 1988).

SMART DRUGS

Smart drugs, or Nootropic drugs, are a heterogeneous group of drugs that are purported to enhance cognitive function (see Sarter, 1991, for a review). In general, although some of these drugs have been shown to facilitate learning and memory in animals, few have been demonstrated to have any significant effect in humans under adequately controlled experimental conditions. Some drugs such as acetyl­ cholinesterase inhibitors (e.g., tacrine) are currently used to retard the development of cognitive dysfunction in Alzheimer's patients (see chapter 9); however, the same drugs have not been conclusively demonstrated to have any significant beneficial effects in nondemented humans. Aside from drugs that enhance cholinergic transmission, alleged nootropic drugs include serotonin receptor antagonists (e.g., zacopride, ondansetron), a-adrenocep­ tor agonists (e.g., clonidine), agonists for the glycine binding site of the NMDA receptor (e.g., cycloserine), extracts from the leaf of the Ginkgo Biloba tree (e.g., EGb 761), opioid receptor antagonists (e.g., naloxone), and calcium channel antagonists (e.g., nimodipine ), among many others (Sarter, 1991 ). The mechanisms DRUGS OF ABUSE 121 of action of these drugs vary widely and in most cases, it is not at all clear how the drugs are supposed to produce their enhancement of cognition. The search for drugs that can enhance cognition in humans suffering from diseases such as Alzheimer's disease, is an important area of psychopharmacology and neuroscience. Many new discoveries are being made in this area of research (see Dawson, Heyes, & Iversen, 1992; Mondadori, 1993, for reviews). However, the use of so-called smart drugs, often obtained iiiegally, to enhance cognition in nondemented individuals is an extremely dangerous form of drug abuse. Some of these drugs are used for medical purposes but only under strict supervision because of their potentially lethal side effects (e.g., calcium antagonists like nimodipine). Others are highly experimental. If drug side effects and interactions are problematic for the drugs that we have discussed in previous chapters, which we know quite a lot about, how much more problematic might they be for drugs that we know almost nothing about, taken without medical advice?

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A Berthelette, P., Ill, 125 Bianchine, J. R., 85, 86, 90, 123 Abikoff, H., 107, 122 Bidaut-Russell, M., 118, 121, 126 Adams, D., Ill, 125 Birch, T., 115, 131 Aghajanian, G. K., 51, 124 Birmaher, B., 66, 123 Aidley, D. 1., 32, 122 Bixler, E., 41, 123 Alexander, G. E., 87, 88, 122 Blackwell, C., Ill, 125 Allesandrini, R., Ill, 125 Bloom, F. E., 32, 123, 124 Allsop, D., 110, lll, 126 Bond, M., 83, 122 Andersson, S., 83, 122 Bonner, T. 1., 119, 128 Annable, L., 55, 125 Borgstedt, A. D., 108, 109, 125, 127 Anton, R., 89, 122 Bosomworth, J. C., 49, 122 Arndt, G., 122 Bourne, H., 123 Arntz, A., 122 Boyd, J. L., 66, 125 Aumentado, D., 125 Bredesen, D. E., 89, 122 Breaux, A. M., 109, 126 B Breier, A., 67, 123 Brever, A., 119, 124 Backonja, M., 122 Brewerton, T. D., 49, 123 Baker, R., 66, 123 Bridger, W. H., 108, 130 Baldessarini, R., 48, 49, SO, 5 I, 52, 54, 55, 56, Browstein, M. J., 119, 128 57,58,62,63,69, 122 Bruera, E., 80, 125 Ball, W., 58, 122 Brumaghim, J. T., 108, 109, 125, 127 Barbour, R., Ill, 125 Bruton, C. J., 61, 93, 102, 123 Barondes, S. H., 48, 58, 122 Buchanan, R. W., 67, 123 Beasley, C. M., 49, 122 Busto, U., 44, 123 Behar, D., 108, 130 Burwell, L., 43, 58, 68, 110, 123 Belanger, M. C., 55, 125 Benet, L. Z., 3, 5, 123 c Benson, D. F., 91, 93, 128, 131 Berkowitz, R., 39, 131 Cadas, H., 119, 124 Berndt, S., 71, 123 Cahill, C., 69, 130 Bernhout, E.,I08, 131 Caine, D. B., 85, 88, 90, 123

133 134 AUTHOR INDEX

Carlen, P. L., 115, 124 Dysarz, F. A., 118, 124 Carlson, N. R.,lll, 123 Carr, T., Ill, 125 E Chadwick, D., 102, 123 Chalmers, J. S., 49, 53, 57, 124 Eagger, S. A., Ill, 112, 125 Chapman, C. R., 74, 124 Edwards, J. G., 66, 67, 69, 125 Charney, D., 51,123 Edwards, R. H., 89, 122 Chase, T. N., 108, 130 Engel, J. Jr., 93, 96, 97, 125, 131 Check, B., 122 Engelhardt, N., 41, 125 Chua, S. E., 69, 130 Etinger, A., 119, 124 Cimino, G., 119, 124 Cimons, M., 118,121,124 F Clemens, J., Ill, 125 Coda, B. A., 74, 124 Cohen, M.S., 103, 104, 105, 106, 107, JJJ, 124 Fagan, J. E., 107, 112, 127 Cohen, P.R., 49, 53, 57, 124 Fainsinger, R., 80, 125 Cohen, R. M., 107, 109, 132 Falloon, I. R. H., 66, 125 Cohn, J. S., 43, 55, 56, 58, 68, 129 Farber, N. B., 69, 128 Coleman, E. A., 54,129 Farlow, M., 111,/25 Cone, E. J., 118, /26 Faull, R. L. M., Ill, 127 Cooper, J. R., 32, 124 Feldman, H., 109, 126 Coryell, W.,/31 Fisler, R., 39, 131 Cowen, P, 49, 53, 57, 124 Fitzpatrick, P .A., 108, 109, 125, 127 Crow, T. J., 61, 93, 102, 123 Fitzsimons, L., 54, 129 Crutcher, M.D., 87, 88, 122 Fletcher, P., 69, 124 Cummings, J. L., 91, 128 Fontana, A., 119,124 Frackowiak, R. S. J., 69, 124,130 Friston, K. J ., 69, 124 D Frith, C. D.,61, 69, 93, 102, 123, 124, 130 Frith, R. W., 94, 95, 96, 97, 101, 102, 126 Dale, M. M., 13, 32, 59, 104, 106, 107, 108, Fromm, G. H., 125 109,112,114,116,117,118,129 Darlington, C. L., 93, 101, 102, 130 Davan, D.P., 54, 129 G Davidson, M., 64, 69, 124 Davis, C. S., Ill, 124 Gadow, K. D., 107, 112, 125 Davis, K. L., 64, 69, 111,124 Games, D., Ill, 125 Dawson, G. R., Ill, 112, 121, 124 Gamsa, A., 125 de Costa, B. R., 119, 126 Gamzu, E. R., 54, 58, 59, Ill, 124, 127 De John, P., 122 Gandy, S., 125 Delgado, P .L., 51, 124 Ganguli, R., 66, 123 DeVane, C. L, 124 Ghadirian, A.M., 55, 125 Devane, W. A., 118, 119,121,124,126 Gibson, D., 119, 124 DiMarzo, V., 119,124 Gilderman, A. M., 66, 125 Doble, A., 38, 44, 124 Gillespie, F., Ill, 125 Dolan, R. J., 69, 124 Girdlestone, D., 21, 131 Dolan-Ureno, J., Ill, 125 Gittelman, R., 107, 122 Donaldson, T., Ill, 125 Goa, K. L., 37, 42, 49, 125 Donevan, S.D., 101, 129 Gobel, H., 125 Dornseif, B. E., 49, 122 Gombar, K. A., 122 Doss, R. C., 91, 93, 128 Gonzales, R. A., 115,121,125 Drachman, D. A., III, 124 Gosling, A., 109, 126 Dragunow, M., Ill, 127 Gouthro, T. A., 41,125 Dreessen, L., 122 Gracon, S. 1., lll, 124, 125 Dreyfuss, D., 39, 131 Grafton, S. T., 93, 131 DuPaul, G. J., 109, 112, 124 Grant, K. A., ll5,125, 126 Durand, D., 115,124 Grasby, P.M., 69, 124 AUTHOR INDEX 135

Grau, R., 91, 93, 128 J Greenblatt, D., 38, 39, 41, 44, 125, 130 Greengard, P., 125, 126, 128, 131 Jacobs, B. L., 58, 126 Griffin, G., 119, 124 Jacobson, R. C., 74, 124 Grootoonk, S., 69, 130 Jaffe, J. H., 13, 119, 121, 127 Gross, M., 107, 109, 132 Jansen, K., 111, 127 Guan, H. C., 63, 69, 130 Javitl, D. C., 64, 127 Gulya, K., 115, 126 Jenike M.A., 39, 127 Jerram, T., 127 H Johnson, J., 39, 55, 129 Haddox, J.D., 130 Johnson, M. R., 118, 119, 121, 124, 126 Haefely, W., 126 Johnstone, E. C., 61, 93, 102, 123, 127 Hamburger, S., 107, 109, 132 Jones, T., 69, 130 Hamilton, M.S., 49, 126 Julien, R. M., I ,2, 13, 20, 42, 56, 116, 117, 118, Hamouz, V., 125 127 Handen, B. L., 109, 126 Julier, D. L., 49, 53, 57, 124 Hansen, C., 125 Hansten, P. D., 90, 126 K Hanus., L., 119, 124 Hardy, J., 110, 111, 126 Kahn, R. S., 64, 69, 124 Harmatz, J., 41, 125 Kales, A., 41, 123 Harris, R. A., 121, 129 Kales, J.D., 41, 123 Hawthorne, M. E., 49, 126 Kane, D. J., 89, 122 Heiligenstein, J. H., 49, 123 Kane, J. M., 66, 67, 68, 69, 127 Heininger, K., 125 Kandel, E. R., 14, 32, 127 Heninger, G., 51, 123 Kapur, S., 66, 123 Henningfield, J. E., 118, 126 Katz, D. L., 120, 121, 129 Heishman, S. J., 118, 126 Katz, J. L., 41, 44, 132 Herkenham, M., 118, 119, 121, 126 Katzung, B. G., 111, 112, 127 Hershey, L.A., 111, 125 Kauer, J., 128 Heuss, D., 125 Kelly, D. D., 71, 127 Heyes, C. M., 111,112, 121,124 Kiersky, J. E., 54, 129 Higgins, G. A., 130 Kim, J. S., 64, 127 Hill, H. F., 74, 124 King, A. C., 107, 109, 132 Hill, R. A., 94, 95, 96, 97, 101, 102, 126 Kling, A., 112, 130 Hirsch, S., 125 Klorman, R., 108, 109, 125, 127 Hirschfeld, R. M. A., 54, 58, 126 Ko, G., 64, 69, 124 Hoffman, B. B., 107, 108, 109, 126 Kordower, J. H., 89, 122 Hoffman, P .L., 115, 121, 125, 126 Kornhuber, H. H., 64, 127 Holcomb, H. H, 64, 127 Krishnan, K., 52, 130 Hollister, L. E., 109, 126 Krueger, R. B., 54, 58, 127 Holmes, A., 69, 130 Kurumaji, A., 64, 126 Holstein, C., 67, 123 Holzmueller, B., 64, 127 L Hoover, T. M., 111, 124 Howard, R., 48, 128 Lacey, J. H., 49, 126 Howlett, A. C., 118, 121, 124, 126 Lahti, A. C., 64, 127 Hudson, C. J., 64, 126 Laverty, R., 42, 44, 127 Hudspith, M., 115, 125 Lefkowitz, R. J., 107, 108, 109, 126 Huestis, M. A., 118, 126 Lehninger, A. L., 4, 127 Leung, A. K. C., 107, 112, 127 Levy, R., Ill, 112, 125 lshimaru, M., 64, 126 Lewis, K. W., Ill, 125 Iversen, S.D., Ill, 112, 121, 124 Li, P. P., 64, 126 Lim, S. H. N., 107, 112, 127 136 AUTHOR INDEX

Lindblom, L. B., 130 N Linder, V., 125 Little, M.D., 119, 126 Neal, M. J., 13, 86, 106, 128 Little, H. J., 115, 121, 127 NemerofF, C. B., 49, 52, 55, 57, 58, 128 Llinas, R. R., 29, 127 Nestler, E. J., 128 Lobrace, S., 54, 128 Nicoll, R., 128 Lolait, S. J., 119,128 Nobler, M., 54, 58, 128 Luger, T. J., 74, 124 Nordahl, T. E., 107, 109, 132 Lukas, S. E., 119, 120, 121, 128 Lynn, A. B., 119,126 0

M Olney, J. W., 69, 128 O'Neill, W. M., 71, 83, 129 Magliano, L., 54, 128 Opler, L. A., 49, 126 Magni, G., 115, 130 Owens, D. G. C., 61, 93, 102, 123 Maidment, N. T., 89, 122 Maier, C., 71, 123 p Maj, M., 54, 128 Majovski, L.V., 112, 130 Malenka, R., 128 Paul, S. M., 115, 131 Pertwee, R. G., 119,124 Mana~ter, J. S., 89, 122 Mandelboum, A., 119, 124 Pickar, D., 66, 67, 131 Manfredi, R. L., 41, 123 Piomelli, D., 119, 124 Markham, C. H., 89, 122, 128 Pirodsky, D. M., 43, 55, 56, 58, 68, 129 Marsh, G. M., 112, 130 Pirozzi, R., 54, 128 Martin, 1., 38, 44, 124 Plosker, G. L., 75, 78, 129 Martin, J., 126 Pope, H. G., 120, 121, 129 Masica, D. N., 49, 123 Porter, G. E., 130 Mason, P. A., 48, 128 Preston, J., 39, 55, 129 Matsuda, L.A., 119,128 Price, D. D., 72, 83, 129 Mazziotta, J. C., 93, 131 Price, L. H., 51, 124 McAuliffe, S., 109, 126 Prudie, J ., 54, 129 McCance, S. L., 49, 53, 57, 124 Pullock, L., 108, 130 McElhiney, M. C., 54, 129 McGill, C. W., 66, 125 Q,R McKenna, P., 69, 130 McTavish, D., 75, 78, 129 Quintana, H., 66, 123 Mechoulam, R., 119,124 Rabizadeh, S., 89, 122 Medoff, D. R., 64, 127 Rail, T., 35, 36, 38, 41, 42, 43, 44, 91, 92, 94, Mehta, M., 83, 122 95, 96, 97, 101, 129 Melvin, L. S., 118, 119, 121, 124, 126 Rampey Jr., A. H., 49, 122 Melzack, R., 83, 131 Rang,H.~,/3,32,59, 104,106,107,108,109, Mendez, M. F., 91, 93, 128 112, 114, 116, 117, 118, 129 Menkes, D., 38, 39, 44, 48, 49, 51, 53, 58, 123, Rapport, M. D., 109, 112, 124 128 Razani, J., 66, 125 Messing, R. 0., 115, 128 Rehavi, M.,I08, 131 Michaels, M., 39, 131 Reynolds, G. P., 61, 62, 63, 64, 66, 67, 69, 129 Miller, H. L., 51, 124 Rho, J. M., 101, 129 Miller, R., 63, 128 Rice, K. C., 119,126 Mitchell, J. R., 3, 5, 123 Ritter, J. M., 13, 32, 59, 104, 106, 107, 108, Mitchell, P., 128 109,112,114,116,117,118,129 Mondadori, C., Ill, 121, 128 Roberts, G. W., 61, 112, 129 Moody, B. J., 54, 129 Roberts, J., 123 Moss, H. B., 66, 125 Robertson, H. A., 84, 85, 86, 88, 90, 129 Mukherjee, S., 54, 128 Robertson, M. M., 93, 129 Murphy, D. J., 49, 123 Robin, D. W., 41,130 AUTHOR INDEX 137

Robson, W. L. M., 107, 112, 127 Skolnick, P., 115, 131 Rogawski, M.A., 101, 129 Smith, P. F., 93, 101, 102, 130 Rose, S., 6, 7, 129 Sneade, A. B., 115, 128 Ross, E. M., 129 Sobell, M. B., 130 Roth, R., 32, 124 Solanto, M. V, 109, 130 Rothschild, A., 52, 130 Soyka, D., 125 Rothwell, N.J., 112, 129 Spears, G. F. S., 48, 128 Royston, M. C., 112, 129 Stannard, C. F., 130 Rumsey, J., 107, 109, 132 Steffens, D., 52, 130 Stern, E., 69, 130 s Stevens, J. R., 61, 93, 102, 123 130 Stevenson, L.A., 119, 124 Sackhiem, H. A., 54, 58, 127, 128, 129 Stoffe, D. M., 108, 130 Sadowsky, C. H., Ill, 125 Stolerman, I. P., 116, 121, 130 Summers, W. K, 112, 130 Sahakian, B.J., Ill, 112, 125 Suzdak, 115,131 Salomon, R. M., 51, 124 P. D., Swerdlow, 83, 122 Samson, H. H., 121, 129 M., Synek, B. L., Ill, 127 Sander, J. W., 100, 101, 131 Sandford, P. R., 130 Sarter, M., Ill, 112, 120,121,130 T Savidge, B., 115, 128 Saxe, G., 39, 131 Tabakoff, B., 115, /25, 126 Sayler, M. E., 49, 122 Tachiki, K., 112, /30 Schaffer, R. L., 74, 124 Taghaui, E., 48, 128 Schatzberg, A., 52, 130 Tamminga, C. A., 64, 127 Schifano, F., 115, 130 Taylor, J. L., 91, 93, 128 Schinelli, S., 119, 124 Terrence, C. F., 125 Schleifer, L. S., 91, 92, 94, 95, 96, 97, 101, 129 Thai, L. J., Ill, 124 Schmid-Burgk, W., 64, 127 Thase, M., 55, 131 Schneider, L. S., Ill, 124 Thompson, V. L., 49, 123 Schnorr, L., 69, 130 Ticku, M. K., 115,131 Schnur, D. B., 54, 128 Tiller, J., 35, 49, 131 Schoch, P., 126 Toru, M., 64, 126 Schoeller, T., 80, 125 Trimble, M. R., 93, 102, 129, 131 Schueller, S. B., 89, 122 Tupler, L., 52, 130 Schutz, H-W., 71, 123 Tyrano, 5.,108, 131 Schwartz, J-C., 119, 124 Tyson, K. L., 41, 123 Schwartz, J. H., 14, 32, 127 Schwartz, R. D., 115, 131 U,V Schweitzer, 1., 35, 49, 131 Seaward, J., 69, 130 Upton, N., 95, 100, 101, 102, 131 Seeman, 63, 69, 130 P., Val veri us, P., 115, 125, 126 Sellers, E. M., 44, 123, 130 VanDerKolk, B. A., 39, 131 Semple, W. E., 107, 109, 132 VanTol, H. H. M., 63, 69, 130 Settembrino, 1. M., 54, 129 Veltro, F., 54, 128 Shader, R.I., 38, 39, 41, 44, 125, 130 Vgontzas, A. N., 41, 123 Shapiro, L., 41, 125 Victoroff, J.l., 93, 131 Sheiner, L. B., 3, 5, 123 Vitello, B., 108, 130 Shera, D., 39, 131 Sherrard, J. S., 71, 83, 129 Shetty, T., I 08, /30 w Shoaib, M., 116,121,130 Shorr, R. 1., 41, 130 Waddington, J. L., 61, 69, 131 Sieghart, W., 38, 130 Walaas, S. 1., 128, 131 Silbersweig, D. A., 69, 130 Walker, M. C., 100, 101, 131 Simpson, G. M., 66, 125 Wall, P. D., 83, 131 138 AUTHOR INDEX

Ward, A., 37, 42, 49, 125 Woolson, R. F., Ill, 124 Ware, C. 1., 49, 53, 57, 124 Warsh, 1. 1., 64, 126 y Watson, S., 21, 131 Wender, E. H., 109, 130 Yang,J.,89, 122 Wertz, R.,I08, 131 Young, A. C., 119, 128 Whitehouse, P. 1., Ill, 124 Young, L. T., 64, 126 Whybrow, P., 58, 122 Wiesel, F-A., 61, 63, 66, 131 z Wietzman, A., I OS, 131 Williamson, M., 66, 125 Zametkin, A. 1., 107, 109, 132 Winger, G., 41, 44, 131, 132 Zimmerman, H. J., 80, 132 Winokur, G., 131 Zimmermann, M., 122 Wolkowitz, 0. M., 66, 67, 131 Zukin, S. R., 64, 127 Woods, 1. H., 41, 44, 131, 132 Subject Index

A acetaminophen, 74, 75, 77 behavioral effects, 75 Acetylcholine (ACh), 23, 24, 52, 87, Ill nonsteroidal anti-inflammatory drugs receptors, 23 (NSAIDs), 74, 75, 77, 79 Action potential, see Synaptic transmission pharmacokinetics, 75 Acute stress disorder, see Anxiety disorders research validation, 76@Subtopic 1 = Affective disorders, 45-59 side effects, 79-81 biogenic amine hypothesis, 51 Anesthetics, see Hypnotics bipolar depression, 49, 53 Anticholinergic effects, 48, 55, 67 classification of, 45-47 Anticonvulsants, see Antiepileptic drugs drug treatment options, 48, 49, 52-55 Antidepressant drugs, I, 2, 27,38-40,42,48-58 see Antidepressant drugs anxiety disorders, use in, 38, 39, 40 electroconvulsive therapy (ECT), 53, 54 atypical antidepressants, 38, 39, 40, 48, 53, mania, 47 54 symptoms, 45 buspirone, 49 unipolar depression, 48, 49, 53 see also Anxiolytic drugs, benzodiazepi­ AIDS, 46, 71, 81, 82 nes, 49, 51 Alcohol, see Drugs of abuse selective serotonin reuptake inhibitors Alzheimer's disease, see Geriatric psychophar­ (SSRJs), 38, 48, 49, 51-53 macology dosages, 58 Amnesia, 36 lithium, 49, 50, 52-54, 56, 57 Amphetamine, see Drugs of abuse, CNS stimu­ behavioral effects, 50 lants pharmacokinetics, 50 Analgesic drugs, 2, 73-82 interactions, 57 adjuvant analgesics, 75-79, monoamine oxidase inhibitors, 38, 49, pharmacokinetics, 74-76, 51-57,86 see also Pain, of neural origin, 79 behavioral effects, 49 dosages, 81, 82 dosages, 57, 58 interactions, 81 Parkinson's disease, use in, 86 narcotic analgesics, 73, 74, 77, 79, 117 pharmacokinetics, 49 behavioral effects, 74 side effects, 55, 56 pharmacokinetics, 74 tricyclic antidepressants, 38-40, 48, 50-57, non-narcotic analgesics, 74 77 139 140 SUBJECT INDEX

behavioral effects, 48 research validation, 37, 38 pharmacokinetics, 48 side effects, 41, 42 Antiepileptic drugs, 55,94-101 Aspartate, 22 dosages, 10 I Attention deficit hyperactivity disorder, see Pe­ interactions, 98, 99 diatric psychopharmacology research validation, 96, 97 Autoreceptors, 17 side effects, 97, 98@Subtopic I = Antiparkinsonian drugs, 67, 85, 86, 89, 90 B DA agonists, 86 DA-releasing agents, 86 Barbiturates, see Hypnotic drugs dosages, 90 Benzodiazepines, see Anxiolytic drugs interactions, 90 Biochemical effects, see Second messengers L-dopa, 85, 89 Bipolar disorder, see Affective disorders behavioral effects, 85 Blood-brain barrier, 4, 6 pharmacokinetics, 85 Blood plasma, 3 monoamine oxidase-inhibitors, 86, Blood serum, 3 see also Antidepressant drugs, Brain, IS monoamine oxidase inhibi­ Brainstem, I 5 tors, 49, 51-57 muscarinic cholinergic antagonists, 86 research validation, 87 c side effects, 89 Antipsychotic drugs, 2, 26, 53, 54, 61-68 Calcium, see Second messengers behavioral effects, 62 Cancer, 71 dosages, 68 Cannabis, see Cannabinoids interactions, 68 Cannabinoids, 118-119 pharmacokinetics, 62 receptor, 30, 118-119 side effects 67, 68 Cerebellum, IS Anxiety, see Anxiety disorders Cerebrum, I 5 Anxiety disorders, 33--44 Characterological traits, 64 acute stress disorder and posttraumatic Classical anti psychotics, 62 stress disorder (PTSD), 39 CNS depressants, 2, 34, 35 antidepressant drugs, use in anxiety disor­ see also, Drugs of abuse, 113-11 5 ders, 38, 39 CNS stimulants, 2, 107-109 classification of, 33, 34 see also, Drugs of abuse, II 5-117 drug treatment options, 38--40, 43 Compliance, 66, 104, 106, 107 see Anxiolytic drugs Convulsions, see Status epilepticus see also Antidepressant drugs, 38--40, Cross tolerance, 42 Hypnotic drugs, 36 Cyclic adenosine monophosphate (cAMP). see generalized anxiety disorder (GAD), 39 Second messengers obsessive compulsive disorder (OCD), 39 Cyclic guanine monophosphate (cGMP), see panic disorders, 38 Second messengers phobias, 39 symptoms, 33 0 Anxiolytic drugs, 21, 27, 34-37, 39,40--43,49, 54,55,82,96 Dale's criteria, see Neurotransmitters, criteria for benzodiazepines, 35-37,39,40,42, 49, 51, Delusions, see Psychotic disorders 54,55,96 Dementia, see Geriatric psychopharmacology, behavioral effects, 36 Alzheimer's disease, Psychotic dis­ depression, use in, 49, 5 I orders epilepsy, use in, 96 Depression, see Affective disorders pharmacokinetics, 35 Diagnostic and Statistical Manual f!lMental reversal of effects, 42 Disorders (DSM-IV), 1, 33, 34, 45, buspirone, 37, 39, 40, 49 46,60,61, 70,107,110,113 dosages, 42, 43 Diencephalon, I 5 interactions, 42, 81 Differential diagnosis, 34 SUBJECT INDEX 141

Dopamine (DA), 25, 26, 50, 52, 84-90, 108-110 Geriatric psychopharmacology, 10, 103, 105, receptors, 25, 26, 62-67 106, 110, Ill Dosages, see specific drug categories Alzheimer's disease, II 0, II I Dose-response curve, 10, II classification, II 0, I I I Drug(s), 1-5, 11-13 drug treatment options, I I I absorption, see Pharmacokinetics research validation, I I I administration, routes of, 3-5 symptoms, I I 0 behavioral classifications of, I, 2 pharmacokinetics, 105, 106 definition of, 3 Glutamate, 22, 64 effects, long-term, 30 receptors, 22-23, 31, 79 Drug addiction, 12, 13 AMPA,22 Drug dependence, see Drug tolerance kainate, 22 Drug tolerance, 11-13,41,42,55, 68, 74, 79, metabotropic, 22 86, 97, 98, I 15 NMDA, 21-23,31,79, 101 Drug withdrawal syndrome, 12, 41, 55, 68, 74, Glycine, 21 79, 97, 98, II 5-1 I 8, 120 receptor, 21, 22, Drugs of abuse, I I 3-121 cannabis, see Cannabinoids H, I classification, I 14 CNS depressants, I I 3-I I 5 Hallucinations, see Drugs of abuse, psychedel- alcohol, I 13-115 ics and hallucinogens CNS stimulants, I I 4-I I 7 Hormones, I 8 amphetamine, I 15, I 16 Hypokinesia, 26@Subtopic I = cocaine, I I 6 Hypnotic drugs, 2, 34-38, 41-43, 96 nicotine, II 6, II 7 anxiety disorders, use in, 36 caffeine, II 7 barbiturates, 36-38 narcotic analgesics, I I 7 behavioral effects, 37 psychedelics and hallucinogens, 2, 117-119 dosages,42,43 cannabis, see Cannabinoids interactions, 42 lysergic acid diethylamide (LSD), I I 7, pharmacokinetics, 36 118 see also Antiepileptic drugs, 96 phencyclidine (PCP), II 8 side effects, 41, 42 see also Hypnotic drugs, 41, 42 Interactions, see specific drug categories smart drugs, 120-121 solvents and glue, I 19 steroids, I 19, 120 M

E Major tranquilizers, 34, 62 Mania, see Affective disorders Minor tranquilizers, 34 Ego dysfunction, 64 Monoamine oxidase inhibitors, see Antidepres­ Epilepsy, 9 I -I 02 sant drugs classification of seizures, 9 I -93 Mood disorders, see Affective disorders drug treatment options, 94-96, I 00, I 0 I see Antiepileptic drugs psychiatric disturbances in, 91, 93 N symptoms, 91-93 Extrapyramidal effects, 67 Narcotics, see Analgesics, Drugs of abuse Negative symptoms, 65 F,G Nervous system, I 4, I 5 Neuroleptics, 62 Neurological disorders, 2 First pass metabolism, see Pharmacokinetics Neuron, structure of, I 4-18 Gamma-aminobutyric acid (GABA), 21, 37, 87 Neuromodulators, see Neurotransmitters receptors, 2 I, 37, 38, 40, 95, I 00, I 0 I Neuropeptides, see Neurotransmitters Generalized anxiety disorder, see Anxiety disor­ Neuropharmacology, 3, 18-32 ders Neurophysiology, I 4-18 142 SUBJECT INDEX

Neurotransmitters, 14, 17-28, 30 individual differences, I 0, II criteria for, 19, 20 metabolism, first pass, 3, 4 neuromodulators, 18, 27 Phenothiazenes, see Antipsychotic drugs receptors, see Receptors Phobias, ~ee Anxiety disorders Nootropic drugs, see Drugs of abuse, smart Posttraumatic stress disorder, see Anxiety disor- drugs ders Norepinephrine (NE) 24, 50, 52, 53, 108 Psychodelic drugs, see Drugs of abuse receptors, 24, 25, 40, II 0 Protein phosphorylation, 30--32 Psychedelics, see Drugs of abuse O,P Psychological disorders, classification of, I Psychopharmacology, 3 Obsessive-compulsive disorder, see Anxiety dis­ Psychosis, see Psychotic disorders Psychotic disorders, 60--69 orders Opioids, see Analgesic drugs, narcotic classification of, 60--61, 64, 65 "dopamine hypothesis," 63, 64 Pain arthritis, 78, 79 drug treatment options, 64-67 backpain, 78, 79 see Antipsychotic drugs central origin, of, 72 schizophrenia, 26, 61,64-67 symptoms, 60 classification, 70--72 drug treatment options, 73-79, 82 see Analgesic drugs R headache, 77-78 mechanisms of, 72, 73 Receptor(s), 3, 6-10, 17,20--32 neural origin, of, 79 activation of, 8, 27-30 pathways, 73 biochemical pathways, see Second mes- Pain killers, see Analgesic drugs sengers Panic attack, see Anxiety disorders agonist, 7-10 Paranoia, see Psychotic disorders antagonist, 7-10 Parkinson's disease, 84-90 classification of, 21, 28 drug treatment options, 85-87,90 G-proteins, 8, 30 see Antiparkinsonian drugs ligand,7 nigrostriatal pathway, 87-89 ion channels, 8, 28 psychitaric disturbances in, 85 receptor-operated channels (ROCs), 27-29 substantia nigra, 87, 88 voltage operated channels (VOCs), 28, 29 symptoms, 84, 85 Receptor binding, characteristics of, 5, 7, 9 Pediatric psychopharmacology, 103-105, affinity, 7, 9, 12 107-110 association constant, 7, 9, 12 attention deficit hyperactivity disorder down regulation, 12 (ADHD), 107-110 efficacy, 7-9, 12 dosages, II 0 reversibility, 7 drug options, 107, 108 saturability, 7 research validation, 108, I 09 selectivity, 7 side effects, I 09 up regulation, 12 symptoms, I 07 Receptor binding sites, allosteric, I 0 dosage, 104, I OS, II 0 pharmacokinetics, 103, 104 Peptides, 27 s Pharmacodynamics, 3, 6--10 individual differences, 10, II Schizophrenia, see Psychotic disorders Pharmacology, 3 Second messengers, 29-32 Pharmacokinetics, 3-6, I 03-1 06 calcium, 30--32 absorption, 3, 4, I 03, I 04, 105 cyclic adenosine monophosphate (cAMP), blood-brain barrier, 6 30--32 bioavailability, 5 cyclic guanine monophosphate (cGMP), 30 distribution, 4-6, I 04-106 Sedatives, see Hypnotics elimination, 6, 104-106 Seizures, see Epilepsy SUBJECT INDEX 143

Selective serotonin re-uptake inhibitors, Synaptic transmission, 14, 17-20,27 see Antidepressant drugs, atypical antide­ action potential, 18, 19 pressants excitatory postsynaptic potentials (EPSPs), Senility, see Geriatric psychopharmacology 18 Serotonin (5-HT), 26, 50-53 inhibitory postsynaptic potentials (IPSPs), 18 receptor, 27, 40, 50, 51, 65, 66, 117 intrinsic membrane properties, 27-29 Side effects, see specific drug categories membrane potential, 18 Sleeping drugs, see Hypnotics Smart drugs, see Drugs of abuse T Spinal cord, 15 Status epilepticus, 36, 96 Therapeutic index, 67 Steroids, see Drugs of abuse Tranquilizers, see Anxiolytic drugs Substance related disorders, 113 Tremor, 26, 84 Stimulants, 115-117 Tricyclic antidepressants, see Antidepressant Stress, see Anxiety disorders drugs Synapse, 17